ai

The Theory
id Practice of Industrial
Pharmacy
LEON LACHMAN, Ph.D.
Lachman Consultant Services, Inc.
Garden City, New York

HERBERT A. LIEBERMAN, Ph.D.

H. H. Lieberman Associates, Inc.
Consultant Services
Livingston, New Jersey

JOSEPH L. KANIG, Ph.D.

Kanig Consulting and Research Associates, Inc.
Ridgefield, Connecticut

THIRD EDITION
INDIAN EDITION

VARGHESE PUBLISHING HOUSE

Hind Rajasthan Building
Dadar Bombay 400 014
1987
Lea & Febiger
600 Washington Square
Philadelphia, PA 19106-4198
U.S.A.
(215) 922-1330

Library of Congress Cataloging in Publication Data

Main entry under title:

The Theory and practice of industrial pharmacy.

Includes bibliographies and index.

1. Pharmacy. 2. Drug trade. I. Lachman, Leon,
1929— II. Lieberman, Herbert A., 1920 —
III. Kanig. Joseph- L., 1921 - [DNLM: 1. Drug
Industry.
QV 704 T396]
RSI92.L331985 615M9 84-27806
ISBN 0-8121-0977-5

First Edition, 1970

Second Edition, 1976

Copyright © 1986 by Lea & Febiger. Copyright under the

International Copyright Union. All Rights Reserved. This book is
protected by copyright. No part of it may be reproduced in any
manner or by any means without written permission from the
publisher.

FIRST INDIAN REPRINT, 1987

SECOND INDIAN REPRINT, 1989
THIRD INDIAN REPRINT, 1990
FOURTH INDIAN REPRINT, 1991

Reprinted in India by special arrangement with LEA & FEBIGER

Philadelphia USA.
Indian Edition published by
Varghese Publishing House, Hind Rajasthan Building, Dadar,
Bombay 400 014.
Reprinted by Akshar Pratiroop Pvt Ltd, Bombay 400 031.
 Preface

Fifteen years have elapsed since the publication of pharmacokinetics and biopharmaceutics were
of the first edition of this book, and a decade has beginning to solve new problems associated with
gone by since the second edition was published the burgeoning array of increasingly sophisti¬
in 1976. The intervening years have witnessed cated new drug entities, and with the growing
many important changes in the held of indus¬ concerns about bioavailability of these com¬
trial pharmacy—probably more so than at any pounds from various dosage delivery systems. At
other period of time in its history. Therefore, the that time, graduate programs offered many op¬
editors were challenged to select the most quali¬ portunities for aspiring pharmaceutical scien¬
fied contributors to this third edition of the text¬ tists to deal with these exciting and innovative
book. technologic advances. Thus, there existed an
As before, the major objective of this edition is obvious need for a textbook that could bring to¬
to serve as a textbook for graduate and under¬ gether in one volume the emerging concepts,
graduate students in the pharmaceutical sci¬ new theories, and their ptactical applications in
ences. In addition, it is intended to provide a the development and production of what were
comprehensive reference source on modem in¬ then termed “dosage forms,” and what are now
dustrial pharmacy. As such, this book should be more appropriately referred to as “drug delivery
useful to practitioners in the pharmaceutical systems.”
and allied health -sciences, hospital pharmacists, Along with the development of new drug de¬
drug patent attorneys, government scientists livery systems and new drugs came new produc¬
and regulatory personnel, and others seeking tion processes and machines for manufacture,
information concerning the design, manufac¬ new control methods for accurate definition of
ture, and control of pharmaceutical dosage drug delivery, and new and improved quality
forms. control procedures. All of these innovations and
Despite the fact that the preface to a book ap¬ improvements contributed to superior quality
pears, as its title implies, at the beginning of a drug dosage forms, and in many cases, to en¬
volume, it is common practice for editors and hanced concomitant production economics. For
authors to delay its writing as one of their last example, the advent of microprocessors and
tasks. This is done in order to reflect on the small computers has begun to revolutionize the
changes or modifications that have been insti¬ capabilities inherent in modem drug production
tuted in the content and arrangement of the to an extent not foreseeable when the second
chapters in the new edition. In so doing, the edi¬ edition of this book was published.
tors are provided with an opportunity to high¬ Since the first edition of this textbook ap¬
light such major changes. peared in 1970, we have been most gratified to
Writing this preface has provided us with the learn from comments received from all parts of
opportunity to note the enomious changes in the world that this book has been well-received
pharmaceutical technology since the appear¬ and utilized as a basic teaching and reference
ance of the first edition. This book was created to text in colleges, research institutions, govern¬
fill a need that existed during the 1960s and ment agencies, and pharmaceutical and related
early 1970s, when many undergraduate and industries. These comments have also provided
graduate programs in colleges of pharmacy in¬ us with useful suggestions and ideas for this
cluded courses in industrial pharmacy to teach third edition.
the unique factors involved in the production of The multi-author approach, used in all three
commercially prepared drug dosage forms. It editions, has resulted in a uniquely prepared
was a period during which the young disciplines textbook in industrial pharmacy. This editorial
method so common to the writing of modem helping us to complete this edition. Without the
technical books permits the use of a wide range skillful sharing of their knowledge in the pages
of expertise that is necessary in dealing with the of this book, the enormous task of compiling this
manifold aspects of modem industrial phar¬ third edition of the textbook would have been
macy. It also, however, poses the problem impossible to consider.
unique to all editors, namely, the necessity of We and our contributing authors will be ex¬
gently coercing some very busy people to com¬ tremely pleased if our efforts have results in an
plete, revise, and polish their chapters. In spite improved book to serve as a teaching and refer¬
of these pressures, we are grateful for the pa¬ ence source in industrial pharmacy.
tience and forbearance of our contributors in

Garden City, New York Leon Lachman, Ph.D.

Livingston, New Jersey Herbert A. Lieberman, Ph.D.
Ridgefield, Connecticut Joseph L. Kanig, Ph.D.

iy 0 Preface
 Contributors

Michael J. Akers, Ph.D. James C. Boylan, Ph.D.

Head Adjunct Professor
Dry Products Development Department School of Pharmacy and Pharmaceutical Sciences
Eli Lilly & Company Purdue University
Indianapolis, IN W. Lafayette, IN
Director
Neil R. Anderson, Ph.D. Scientific Services
Hospital Products Division
Director
Abbott Laboratories
Solid Dosage Form Design
N. Chicago, IL
Merrell Dow Pharmaceutical Company
Indianapolis, IN
Suggy Chrai, Ph.D.
E.R. Squibb & Sons, Inc.
Kenneth E. Avis, D.Sc. New Brunswick, NJ
Goodman Professor and Chairman
Department of Pharmaceutics Carlo P. Croce, M.B.A.
College of Pharmacy Manager
University of Tennessee Package Development
Memphis, TN Warner-Lambert Company
Morris Plains, NJ
Joseph A. Bakan
Director Larry J. Coben, Ph.D.
Research and Development Division Director of Manufacturing
Eurand America Inc. Alcan Laboratories, Inc.
Vandalia, OH Ft. Worth, TX

Gilbert S. Banker, Ph.D. Anthony J. Cutie, Ph.D.

Dean and Professor of Pharmaceutics Associate Professor of Pharmaceutics
College of Pharmacy Arnold and Marie Schwartz College of Pharmacy
University of Minnesota and Health Sciences
Minneapolis, MN Long Island University
Brooklyn, NY
J.V. Battista
Patrick DeLuca, Ph.D.
Formerly Management Consultant
Professor and Associate Dean
Lakehurst, NJ
College of Pharmacy
University of Kentucky
Sanford Bolton, Ph.D. Lexington, KY
Professor arid Chairman
Department of Pharmacy and Administrative M.R. Dobrinska, Ph.D.
Sciences Research Fellow
St. John’s University Merck Sharp & Dohme Research Laboratories
Jamaica, NY West Point, PA
Joseph R. Feldkamp Lloyd Kennon, Ph.D.*
Research Engineering Specialist Formerly Associate Professor and Program Director
Monsanto Company Division of Industrial Pharmacy
St. Louis, MO Arnold and Marie Schwartz College of Pharmacy
and Health Sciences
Long Island University
Eugene F. Fiese, Ph.D, Brooklyn, NY
Pfizer Central Research
Groton, CT K.C. Kwan, Ph.D.
Executive Director
Drug Metabolism
Arthur Fischer Merck Sharp & Dohme Research Laboratories
DuPont Pharmaceuticals West Point, PA
Garden City, NY
Leon Lachman, Ph.D.
Lachman Consultant Services, Inc.
Timothy A. Hagen, Ph.D. Garden City, NY
Pfizer Central Research
Groton, CT JackH. Lazarus, M.S.*
Formerly Senior Scientist
Pharmacy Research and Development
SamirA. Hanna, Ph.D. Hoffman-LaRoche, Inc.
Vice President Nutley, N]
Quality Assurance
Industrial Division R. Saul Levinson
Bristol-Myers Company Manager
Syracuse, NY Exploratory Research
Abbott Laboratories
N. Chicago, IL
Samuel Harder, Ph.D.
Laboratory Manager Herbert A. Lieberman, Ph.D.
Pharmaceutical Research and Development President, Consultant Services
Riker Laboratories, Inc. H. H. Lieberman Associates, Inc.
St. Paul, MN Livingston, NJ

Karl Lin, Ph.D.

Stanley L. Hem, Ph.D.
Vice President of Science and Technology
Professor of Physical Pharmacy
United Laboratories
School of Pharmacy and Pharmaceutical Sciences
Manila, Philippines
Associate Dean
Graduate School Nicholas G. Lordi, Ph.D.
Purdue University
Professor of Pharmacy
W. Lafayette, IN
Graduate Director of Pharmaceutical Science
College of Pharmacy
Van B. Hostetler Rutgers University
Manager Piscataway, N]
Equipment Development
Keith Marshall, Ph.D.
Lilly Corporation Center
Eli Lilly & Company Adjunct Professor
Indianapolis, IN School of Pharmacy
University of Rhode Island
Kingston, Rl
Bernard Idson, Ph.D. Associate Director
American Cyanamid Company Department of Pharmaceutical Research and
Clifton, NJ Technologies
Smith Kline & French Laboratories
Philadelphia, PA
Joseph L. Kanig, Ph.D.
Kanig Consulting and Research Associates, Inc.
Ridgefield, CT ’Deceased.

vi • Contributors
Raymond D. McMurray, J.D.* Robert F. Schiffmann, M.S.
Formerly of McMurray and Pendergast R.F. Schiffmann Associates, Inc.
Washington, DC New York, NY

Shashi P. Mehta, Ph.D. JohnJ. Sciarra, Ph.D.

Section Head Professor of Industrial Pharmacy
Tablet Products, Research and Development Arnold and Marie Schwartz College of Pharmacy
Abbott Laboratories and Health Sciences
N. Chicago, IL Long Island University
President
Retail Drug Institute
Eugene L. Parrott, Ph.D. Brooklyn, NY
Professor of Industrial Pharmacy
College of Pharmacy
University of Iowa James A. Seitz, Ph.D.
Iowa City, IA Manager
Tablet Products, Research and Development
Pharmaceutical Products Division
Nagin K. Patel, Ph.D. Abbott Laboratories
Associate Professor of Industrial Pharmacy N. Chicago, IL
Arnold and Marie Schwartz College■ of Pharmacy
and Health Sciences
Long Island University J.P. Stanley, Ph.D.
Brooklyn, NY Formerly Technical Director
R.P. Scherer Corporation
Grosse Pointe Park, Ml
William R. Pendergast, J.D.
Arent, Fox, Kintner, Plotkin, & Kahn
Washington, DC
Ralph H. Thomas
Thomas Packaging Consultants, Inc.
Union, NJ
Albert S. Rankell, Ph.D.
Vicks Research Center
Health Care Products Division A.E. Till, Ph.D.
Richardson-Vicks Inc. Research Fellow
Shelton, CT Merck Sharp & Dohme Research Laboratories
West Point, PA

Martin M. Rieger, Ph.D.

M. & A. Rieger Associates Glenn Van Buskirk
Morris Plains, N] Director of Formulations
Ortho Pharmaceutical Corporation
Raritan, N]
Edward G. Rippie, Ph.D.
Professor
Department of Pharmaceutics Joe L. White, Ph.D.
College of Pharmacy Professor of Soil Mineralogy
University of Minnesota Department of Agronomy
Minneapolis, MN Purdue University
W. Lafayette, IN
J.D. Rogers, Ph.D.
Research Fellow John H. Wood, Ph.D.
Merck Sharp & Dohme Research Laboratories Professor
West Point, PA Coordinator of Research and Graduate Program
Department of Pharmacy and Pharmaceutics
School of Pharmacy
Medical College of Virginia Campus
Virginia Commonwealth University
‘Deceased. Richmond, VA

Contributors • vii
James L. Yeager, Ph.D. K.C. Yeh, Ph.D.
Project Manager Senior Research Fellow
Scientific Affairs Merck Sharp & Dokme Research Laboratories
Abbott International, Ltd. West Point, PA
N. Chicago, IL

viii • Contributors
 Contents

Section I. Principles of Pharmaceutical Processing

1. Mixing 3
EDWARD G. RIPPIE
2. Milling 21
EUGENE L. PARROT
3. Drying 47
ALBERT S. RANKELL, HERBERT A. LIEBERMAN, ROBERT F. SCHIFFMANN
4. Compression and Consolidation of Powdered Solids 66
KEITH MARSHALL
5. Basic Chemical Principles Related to Emulsion and Suspension
Dosage-Forms 100
STANLEY L. HEM, JOSEPH R. FELDKAMP, JOE L. WHITE
6. Pharmaceutical Rheology 123
JOHN H. WOOD
7. Clarification and Filtration 146
S. CHRAI

Section II. Pharmaceutical Dosage Form Design

8. Preformulation 171
EUGENE F. FIESE, TIMOTHY A. HAGEN
9. Biopharmaceutics 197
K.C-. KWAN, M.R. DOBRINSKA, J.D. ROGERS, A.E. TILL, K.C. YEH
10. Statistical Applications in the Pharmaceutical Sciences 243
SANFORD BOLTON

Section III. Pharmaceutical Dosage Forms

11. Tablets 293
GILBERT S. BANKER, NEIL R. ANDERSON
12. Tablet Coating 346
JAMES A. SEITZ, SHASHI P. MEHTA, JAMES L. YEAGER

ix
 13. Capsules 374
Part One Hard Capsules 374
VAN B. HOSTETLER
Part Two Soft Gelatin Capsules 398
J.P. STANLEY
Part Three Microencapsulation 412
J.A. BAKAN
14. Sustained Release Dosage Forms 430
NICHOLAS G. LORDI
15. Liquids 457
J.C. BOYLAN
16. Pharmaceutical Suspensions 479
NAGIN K. PATEL, LLOYD KENNON*, R. SAUL LEVINSON
17. Emulsions 502
MARTIN M. RIEGER
18. Semisolids 534
BERNARD IDSON, JACK LAZARUS*
19. Suppositories 564
LARRY J. COBEN, HERBERT A. LIEBERMAN
20. Pharmaceutical Aerosols 589
JOHN J. SCIARRA, ANTHONY J. CUTIE
21. Sterilization 619
KENNETH E. AVIS, MICHAEL J. AKERS
22. Sterile Products 639
KENNETH E. AVIS

Section IV. Product Processing, Packaging, Evaluation, and

Regulations
23. Pilot Plant Scale-Up Techniques 681
^ SAMUEL HARDER, GLENN VAN BUSKIRK
24. Packaging Materials Science 711
CARLO P. CROCE, ARTHUR FISCHER, RALPH H. THOMAS
25. Production Management 733
J.V. BATTISTA
26. Kinetic Principles and Stability Testing 760
LEON LACHMAN, PATRICK DELUCA, MICHAEL J. AKERS
27. Quality Control and Assurance 804
LEON LACHMAN, SAMIR A. HANNA, KARL LIN
28. Drug Regulatory Affairs 856
WILLIAM R. PENDERGAST, RAYMOND D. MCMURRAY*

INDEX 883

Deceased.

x • Contents
Mixing
EDWARD G. R1PPIE

The process of mixing is one of the most com¬ shear rates and the applied stress. Forces of
monly employed operations in everyday life. shear are generated by interactions between
Owing in part to the almost limitless variety of moving fluids and the surfaces over which they
materials that can be mixed, much remains to flow during mixing. The rate of shear may be
be learned regarding the mechanisms by which defined as the derivative of velocity with respect
mixing occurs. to distance measured normal to the direction of
For our purposes, mixing is defined as a proc¬ flow (dv/dx). The viscosity (dynamic) is the ratio
ess that tends to result in a, randomization of dis¬ of shear stress to the shear rate. For Newtonian
similar particles within a system. This is to be fluids, the rate of shear is proportional to the
distinguished from an ordered system in which applied stress, and such fluids have a dynamic
the particles are arranged according to some it¬ viscosity that is independent of flow rate. In con¬
erative rule and thus follow a repetitive pattern. trast, non-Newtonian fluids exhibit apparent
It is possible to consider the mixing of particles dynamic viscosities that are a function of the
differing only by some vector quantity, such as shear stress.
spatial orientation or translational velocity. In The flow characteristics and mixing behavior
this chapter, however, we will deal solely with of fluids are governed by three primary laws or
particles distinguishable by means of scalar principles: conservation of mass, conservation of
quantities, e.g., composition, size, density, energy, and the classic laws of motion^ The
shape, or a combination of these. The following equations that result from the application of
text is intended as an introduction to the funda¬ these simple laws of conservation and motion to
mental concepts that lead to an understanding systems used for mixing are often complex and
of the techniques employed in the chemical and are beyond the scope of this discussion. An un¬
pharmaceutical industries to obtain satisfactory derstanding cf the fundamental principles of
mixing. A list of general references is included fluid dynamics, however, will help the reader to
at the end of the chapter for those who desire visualize the overall process of fluids mixing.
further reading on this subject. Mixing Mechanisms. Mixing mechanisms
for fluids fall essentially into four categories:
Fluids Mixing bulk transport, turbulent flow, laminar flow, and
molecular diffusion. Usually, more than one of
these processes is operative in practical mixing
Fundamentals situations.
Flow Characteristics. Fluids may generally 1. Bulk transport. The movement of a rela¬
be classified as Newtonian or non-Newtonian, tively large portion of the material being mixed
depending on the relationship between their from one location in the system to another con-

3
stitutes bulk transport. A simple circulation of mixing. Thus, when small eddies are predomi¬
material in a mixer, however, does not necessar¬ nant, the scale of turbulence is low.
ily result in efficient mixing. For bulk transport An additional characteristic of turbulent flow
to be effective it must result in a rearrangement is its intensity, which is related to the velocities
or permutation of the various portions of the with which the eddies move. A composite pic¬
material to be mixed. This is usually accom¬ ture of eddy size versus the velocity distribution
plished by means of paddles, revolving blades, or of each size eddy may be described as a complex
other devices within the mixer arranged so as to spectrum. Such spectra are characteristic of the
move adjacent volumes of the fluid in different turbulent flow and are used in its analysis.
directions, thereby shuffling the system in three 3. Laminar mixing. Streamline or laminar
dimensions. flow is frequently encountered when highly vis¬
2. Turbulent mixing. The phenomenon of tur¬ cous fluids are being processed. It can also occur
bulent mixing is a direct result of turbulent fluid if stirring is relatively gentle and may exist adja¬
flow, which is characterized by a random fluctu¬ cent to stationary surfaces in vessels in which
ation of the fluid velocity at any given point the flow is predominantly turbulent. When two
within the system. The fluid velocity at a given dissimilar liquids are mixed through laminar
instant may be expressed as the vector sum of its flow, the shear that is generated stretches the
components in the x, y, and z directions. With interface between them. If the mixer employed
turbulence, these directional components fluc¬ folds the layers back upon themselves, the num¬
tuate randomly about their individual mean val¬ ber of layers, and hence the interfacial area be¬
ues, as does the velocity itself. tween them, increase exponentially with time.
In the case of turbulent flow in a pipe, the This relationship is observed because the rate of
mean velocity in the direction of flow through increase in interfacial area with time is propor¬
the pipe is positive, of course, and varies some¬ tional to the instantaneous interfacial area.
what depending on the distance from the pipe Example. Consider the case wherein the
wall. In contrast, the mean velocity perpendicu¬ mixer produces a folding effect and generates a
lar to the wall is zero. The churning flow charac¬ complete fold every 10 seconds. Given an initial
teristic of turbulence results in constantly fluid layer thickness of 10 cm, a thickness re¬
changing velocities in these directions. This is duction by a factor of 1 O'8 is necessary to attain
in contrast to laminar flow in which the velocity layers 1 nm thick, which approximate molecular
components at a given point in the flow field dimensions. Since a single fold results in a layer
remain constant, at their mean value. thickness reduction of one half, n folds are re¬
In general, with turbulence, the fluid has dif¬ quired where:
ferent instantaneous velocities at different loca¬
tions at the same instant in time. This observa¬ (l/2)n = 1CT8
tion is true of both the direction and the
magnitude of the velocity. If the instantaneous or in logarithmic form, log [(Vi)11] = n log Vi =
velocities at two points in a turbulent flow field log 1CT8 = -8. Therefore:’
are measured simultaneously, they show a de¬
gree of similarity provided that the points se¬ n = -8/log Vi = 26.6
lected are not too far apart. There is no velocity
correlation between the points, however, if they Thus, the time required for mixing is equal to n
are separated by a sufficient distance. times 10 seconds (266 sec), or 4.43 min.
Turbulent flow can be conveniently visualized Mixers may also operate by simply stretching
as a composite of eddies of various sizes. An the fluid layers without any significant folding
eddy is defined as a portion of fluid moving as a action. This mechanism does not have the
unit in a direction often contrary to that of the stretch compounding effect produced by folding,
general flow. Large eddies tend to break up, but may be satisfactory for some purposes in
forming eddies of smaller and smaller size until which only a moderate reduction in mixing scale
they are no longer distinguishable. The size dis¬ (to be defined in detail later) is required. It
tribution of eddies within a turbulent region is should be pointed out, however, that by this
referred to as the scale of turbulence. process alone, an exceedingly long time is re¬
It is readily apparent that such temporal and quired for the layers of the different fluids to
spatial velocity differences as result from turbu¬ reach molecular dimensions. Therefore, good
lence within a body of fluid produce a randomi¬ mixing at the molecular level requires a signifi¬
zation of the fluid particles. For this reason, tur¬ cant contribution by molecular diffusion after
bulence is a highly effective mechanism for the layers have been reduced to a reasonable

4 • The Theory and Practice of Industrial Pharmacy

thickness (several hundred molecules) by lami¬ overall process and on the time over which mix¬
nar flow. ing is carried out. Unless molecular diffusion
4. Molecular diffusion. The primary mecha¬ occurs, however, the composition of the lumps
nism responsible for mixing at the molecular varies discontinuously from one to the next. In
level is diffusion resulting from the thermal other words, each lump retains a constant and
motion of the molecules. When it occurs in con¬ uniform internal composition. This can be al¬
junction with laminar flow, molecular diffusion tered only if molecular diffusion in the case of
tends to reduce the sharp discontinuities at the liquids and gases, or interparticulate motion in
interfaces between the fluid layers, and if al¬ the case of powders, tends to eliminate concen¬
lowed to proceed for sufficient time, results in tration gradients between adjacent lumps. On
complete mixing. this basis, Danckwerts defined “two quantities
The process is described quantitatively in to describe the degree of mixing—namely the
terms of Fick’s first law of diffusion: scale of segregation and the intensity of segrega¬
tion.”
The scale of segregation is defined in a man¬
ner analogous to the scale of turbulence dis¬
cussed earlier, and may be expressed in two
where the rate of transport of mass, dm/dt, ways: as a linear scale or as a volume scale. The
across an interface of area A is proportional to linear scale may be considered to represent an
the concentration gradient, dc/dx, across the in¬ average value of the diameter of the lumps pres¬
terface. The rate of intermingling is governed ent, whereas the volume scale roughly corre¬
also by the diffusion coefficient, D, which is a sponds to the average lump volume.
function of variables including fluid viscosity The intensity of segregation is a measure of
and the size of the diffusing molecules. The the variation in composition among the various
sharp interface between dissimilar fluids, which portions of the mixture. When mixing is com¬
has been generated by laminar flow, may be plete, the intentsity of segregation is zero.
rather quickly obliterated by the ensuing diffu¬ 6. Time, dependence. In any given case, the
sion. Considerable time may be required, how¬ mechanisms that are active in bringing about
ever, for the entire system to become homogene¬ mixing are time-dependent in their relative im¬
ous. portance as the process of mixing proceeds. For
The concentration gradient at the original example, consider the mixing of two miscible
boundary is a decreasing function of time, ap¬ liquids of different densities contained in a verti¬
proaching zero as mixing approaches comple¬ cal tank of cylindric form. The denser liquid is
tion. Since the amount of material passing a placed in the bottom of the tank, and an approxi¬
boundary plane in a given time depends on the mately equal volume of the less dense fluid is
concentration gradient, the time required to at¬ layered on top. Mixing is to be done with a
tain complete uniformity may be considerable down-draft propeller mounted on a vertical shaft
unless the fluid layers are very thin. midway between the tank bottom and the inter¬
5. Scale and intensity of segregation. The face between the liquids.
quality of mixtures must ultimately be judged If the propeller is operated at a speed suffi¬
upon the basis of some measure of the random cient to produce turbulent flow in its discharge
distribution of their components. Such an evalu¬ region, mixing occurs initially, to any significant
ation depends on the selection of a quantitative degree, only by mechanisms that reduce the
method of expressing the quality of randomness scale of segregation. Until such time as both
or “goodness of mixing.” Danckwerts has sug¬ fluids are present in the region of turbulence,
gested two criteria that are statistically defined created by the impeller, only bulk transport is
and may be applied to mixtures of mutually sol¬ effective in the mixing process. The convection
uble liquids, fine powders, or gases. Perhaps the results from the flow generated by thp pumping
greatest value of these concepts lies in the in¬ action of the propeller. When the scale of segre¬
sight they give the pharmacist or chemical engi¬ gation has been reduced to the point at which
neer regarding the physical nature of the mix¬ both fluids are present in the turbulent zone,
tures produced. turbulent mixing becomes an important means
Bulk transport, turbulent flow, and laminar of further reduction in scale. Convection is still
flow all result in the intermingling of “lumps” of of importance here, however, largely because it
the liquids to be mixed. The shape and size of serves to bring the entire tank contents to the
these lumps largely depend on the relative con¬ turbulent zone in a comparatively short time.
tribution of each of these mechanisms to the As the scale of segregation is reduced, with a

MIXING • 5
resulting increase in interfacial area, molecular
diffusion becomes significant. As pointed out
earlier, diffusion is necessary for the effective
reduction of the intensity of segregation to zero,
at which time mixing is complete.
The increase in scale observed in the latter
part of the mixing process, as shown in Figure
1-1, results from molecular diffusion, which
equalizes the composition of adjacent portions of
fluid, resulting in large regions with an interme¬
diate composition. At the completion of mixing,
the composition becomes uniform throughout
the fluid, and the linear scale of segregation in¬
creases in value to a number equal in magnitude
to the dimension of the mixing tank.

Equipment
c
Batch Mixing. When the material to be
FIG. 1-2. A and B, Diagrammatic representation of
mixed is limited in volume to that which may be
cylindric tanks in which tangential and radial flow occur,
conveniently contained in a suitable mixer, respectively. C, Side view of a similar tank in which axial
batch mixing is usually most feasible. A system flow occurs. These diagrams represent systems in which
for batch mixing commonly consists of two pri¬ only one type of flow occurs, in contrast to the usual situa¬
mary components: (1) a tank or other container tion in which two or more of these flow patterns occur
suitable to hold the material being mixed, and simultaneously.
(2) a means of supplying energy to the system so
as to bring about reasonably rapid mixing. Power
may be supplied to the fluid mass by means of shape and pitch of the blades. Three basic types
an impeller, air stream, or liquid jet. Besides of flow may be produced: radial, axial, and tan¬
supplying power, these also serve to direct the gential. These may occur singly or in various
flow of material within the vessel. Baffles, vanes, combinations. Figure 1-2 illustrates these pat¬
or ducts also are used to direct the bulk move¬ terns as they occur in vertical cylindric tanks.
ment of material in such mixers, thereby in¬ Propellers characteristically produce flow paral¬
creasing their efficiency. lel to their axes of rotation, whereas turbines
1. Impellers. The distinction between impel¬ may produce either axial or tangential flow, or a
ler types is often made on the basis of type of combination of these.
flow pattern they produce, or on the basis of the Propellers of various types and form are used
but all are essentially a segment of a multi¬
threaded screw, that is, a screw with as many
threads as the propeller has blades. Also, in com¬
mon with machine screws, propellers may be
either right-or left-handed depending on the di¬
rection of slant of their blades. As with screws,
propeller pitch is defined as the distance of axial
movement per revolution if no slippage occurs.
Although any number of blades may be used,
the three-blade design is most common for use
with fluids. The blades may be set at any angle
or pitch, but for most applications, the pitch is
approximately equal to the propeller diameter.
Propellers axe most efficient when they can be
FIG. 1-1. The intensity of segregation, I, and the scale of run at high speed in liquids of relatively low vis¬
segregation, S, as a function of time. Bulk transport, tur¬ cosity.
bulent mixing, and molecular diffusion are predominant Although some tangential flow occurs, the pri¬
over the time periods A, B, and C, respectively. The linear
mary effect of a propeller is to induce axial flow.
scale of segregation may be seen to increase at the end of
the mixing operation. The final mixture will be uniform in
Also, intense turbulence usually occurs in the
composition and may be considered a single lump with a immediate vicinity of the propeller. Consider, for
linear scale equal to the linear dimensions of the mixer. example, a down-draft propeller vertically

6 • The Theory and Practice of Industrial Pharmacy

 undesirable effects. With such mixers, for ex¬
ample, ingredients should not be layered when
they are added to the mixing tank. Such vertical
stratification can persist after very long mixing
times.
2. Air jets. Subsurface jets of air, or less com¬
monly of some other gas, are effective mixing
devices for certain liquids. Of necessity and for
obvious reasons, the liquids must be of low vis¬
cosity, nonfoaming, unreactive with the gas
employed, and reasonably nonvolatile. The jets
are usually arranged so that the buoyancy of the
bubbles lifts liquid from the bottom to the top of
the mixing vessel. This is often accomplished
with the aid of draft tubes. (Fig. 1-4). These
serve to confine the expanding bubbles and en¬
FIG. 1-3. Impeller blade types (only one blade shown), top trained liquid, resulting in a more efficient lift¬
and side views. A and B, Radial flow design: C and D, ing action by the bubbles. The overall circulation
mixed radial-axial flow design. For axial pumping, the
in the mixing vessel brings fluid from all parts of
blade must be set at an incline to the axis of the shaft.
the tank to the region of the jet itself. Here, the
intense turbulence generated by the jet pro¬
mounted midway to the bottom of a tank. Mod¬ duces intimate mixing.
erate radial and tangential flow occurring above 3. Fluid jets. When liquids are to be pumped
and below the blades, acting in conjunction with into a tank for mixing, the power required for
the axial flow near the shaft, brings portions of pumping often can be used to accomplish the
fluid together from all regions of the tank and mixing operation, either partially or completely.
passes them through the intense turbulence In such a case, the fluids are pumped through
near the blades. nozzles arranged to permit good circulation of
Turbines are usually distinguished from pro¬ material throughout the tank. In operation, fluid
pellers in that the blades of the latter do not have jets behave somewhat like propellers in that
a constant pitch throughout their length. When they generate turbulent flow in the direction of
radial-tangential flow is desired, turbines with
blades set at 90-degree angle to their shaft are
employed (Fig. 1-3A,B). With this type of impel¬
ler, radial flow is induced by the centrifugal
action of the revolving blades. The drag of the
blades on the liquid also results in tangential
flow, which in many cases is undesirable.
Turbines having tilted blades produce an axial
discharge quite similar to that of propellers (Fig.
1-3C,D). Because they lend themselves to a sim¬
ple and rugged design, these turbines can be
operated satisfactorily in fluids 1000 times more
viscous than fluids in which a propeller of com¬
parable size can be used.
Paddles also are employed as impellers and
are normally operated at low speeds, 50 rpm or
less. Their blades have a large surface area in
relation to the tank in which they are employed,
a feature that permits them to pass close to the
tank walls and effectively mix viscous liquids or
semisolids, which tend to cling to these sur¬
faces. Circulation is primarily tangential, and
consequently, concentration gradients in the
FIG. 1-4. Vertical tank with centrally located air jet and
axial and radial directions may persist in this
draft tube. Bubbles confined within the draft tube rise, in¬
type of mixer even after prolonged operation. ducing an upward fluid flow in the tube. This flow tends to
Operating procedures should take these charac¬ circulate fluid in the tank, bringing it into the turbulent
teristics into account so as to minimize their region in the vicinity of the jet.

mixing • 7
their axes. They do not in themselves, however, quired with a properly baffled tank of equivalent
generate tangential flow, as do propellers. Jets size. This is due to the presence of regions
also may be operated simply by pumping liquid within such tanks in which circulation is poor.
from the tank through the jet back into the tank. Side-entering propellers are often effectively
4. Baffles. Bulk transport is important in mix¬ employed. Swirl is seldom a problem with such
ing (see under previous section, “Mixing Mech¬ an arrangement, as the tank geometry relative to
anisms”) and is particularly desirable in the ini¬ the impeller provides a baffling effect and re¬
tial stages, when segregation may be present on sults in circulation of material from top to bot¬
a large scale. For bulk fluid flow to be most effec¬ tom in the vessel. A major drawback of such a
tive, an intermingling must occur between ma¬ system is the difficulty in sealing the propeller
terial from remote regions in the mixer. To ac¬ entry port. The packing around the shaft must
complish this, it is frequently necessary to assure a positive seal but must allow reasonably
install auxiliary devices for directing the flow of free rotation. Such a seal is also a source of con¬
the fluid, usually baffle plates. Baffle placement tamination and may be difficult to clean.
depends largely on the type of agitator used. Continuous Mixing. The process of contin¬
Centrally mounted vertical shaft impellers uous mixing produces an uninterrupted supply
tend to induce tangential flow, which is often of freshly mixed material and is often desirable
manifested in the formation of a vortex about when very large volumes of material are to be
the impeller shaft. This is particularly character¬ handled. It can be accomplished essentially in
istic of turbines with blades arranged perpendic¬ two ways: in a tube or pipe through which the
ular to the impeller shaft. The tangential motion material flows and in which there is very little
does not in itself produce any mixing, except back flow or recirculation, or in a chamber in
possibly near the tank walls where shear forces which a considerable amount of holdup and re¬
exist. Instead, swirl and the resultant vortex for¬ circulation occur. (Fig. 1-5).
mation reduce the mixing intensity by reducing To ensure good mixing efficiency, such de¬
the velocity of the impeller relative to the sur¬ vices as vanes, baffles, screws, grids, or combi¬
rounding fluid. In addition, severe vibration may nations of these are placed in the mixing tube.
occur, often with damaging results, if the vortex As illustrated in Figure 1-5A, mixing takes
reaches the impeller, where bubbles in the fluid place mainly through mass transport in direc¬
can result in uneven loading of the impeller tions normal to that of the primary flow. Mixing
blades. in such systems requires the careful control of
Sidewall baffles, when vertically mounted in the feed rate of raw materials if a mixture of uni¬
cylindric tanks, are effective in eliminating ex¬ form composition is to be obtained. The require¬
cessive swirl and further aid the overall mixing ment of exact metering in such a device results
process by inducing turbulence in their proxim¬ from the lack of recirculation, which would
ity. For these reasons, the power that can be effi¬ otherwise tend to average out concentration gra¬
ciently applied by the impeller is significantly dients along the pipe. Where suitable metering
increased by the use of such baffles. devices are available, this method of mixing is
Vertical movement of the fluid along the walls very efficient. Little additional power input over
of the tank can be produced by arranging baffles that required for simple transfer through a pipe
in a steep spiral down the tank sides. It should is necessary to accomplish mixing.
be pointed out that if an elaborate baffle system When input rate is difficult to control and
seems necessary, the situation is best corrected fluctuations in the ratio of added ingredients are
by a change in impeller design so as to provide unavoidable, continuous mixing equipment of
the desired general flow pattern. For example, a the tank type is preferred. Fluctuations in com-
vertically mounted propeller in a cylindric tank,
if set slightly to one side of the tank and canted a
small amount in the direction opposite to its ro¬
tation, often can be operated efficiently without
baffles. With such an arrangement, the small
amount of tangential flow induced by the propel¬
A B
ler’s off-center discharge stream will offset the
swirl induced by its rotation. FIG. 1-5. Continuous fluids mixing devices. A, Baffled
An asymmetric or angular tank geometry rela¬ pipe mixer; B, mixing chamber with flow induced recircu¬
lation. Both types induce turbulence in the fluid; however,
tive to the impeller may be used to produce an
recirculation is desirable when overall fluctuations occur
effect similar to that of baffles. Such a technique in the material fed to the mixer, since these fluctuations
is useful in swirl prevention* but in many cases will not be eliminated by simple transverse mixing in a
necessitates a longer mixing time than that re¬ pipe.

8 • The Theory and Practice of Industrial Pharmacy

 For comparison purposes, set k equal to
0.1 min“1, and examine the ratio of C0 to C, after
5 min of operation, with the mixing tank(s) at an
initial concentration of Cc and with a constant
inlet concentration of C,. When a single tank is
used, Cq/Cj equals 0.393, whereas with two
tanks in series, each having one-half the vol¬
ume, Co/Cj is 0.264. This effect appears more
pronounced at shorter times and less so over
longer periods in relation to k, when CQ closely
approaches Q.
FIG. 1-6. Diagram of a perfectly mixed tank in a flow
stream with flmv rate dv/dt. C, and CD represent the con¬
centrations entering and leaving the tank at any given in¬
~ = 1 - e“1/2 = 0.393
'-'i
stant. Material balance requires that the total amount of
fluid leaving the tank in a given time is equal to the total
amount entering in the same period of time. -p9-= 1 -e”1 -e'1 =0.264
'-'i

position of the final mixture are greatly reduced An effect similar to that obtained with two
by the dilution effect of the material contained tanks can be observed with a turbine agitated
in the tank. tank having vertical sidewall baffles. If the tur¬
For example, consider a tank of volume V, bine impeller is located near the middle of the
which is stirred so as to be perfectly mixed at all tank, two regions of mixing occur above and
times, as illustrated in Figure 1-6. If each incre¬ below the impeller as shown in Figure 1-7. Mass
ment of added material is instantaneously dis¬ transport between these zones is relatively slow.
tributed evenly throughout the vessel, and if the This has the effect of two areas of rapid mixing,
concentrations of the equal volumes entering and the mixer behaves in a manner analogous to
and leaving the mixer are designated as C, and two independent tanks connected in series.
C0 respectively, conservation of mass requires Complex arrays of interconnected tanks, both in
that: series and in parallel, can be used for special
mixing situations. The differential equations
that arise from such systems may be solved by a
V-^2-
dt
= (C, -Cl—
CJdt
(2) variety of methods depending on their form. The
reader is referred to mathematical texts for the
where dv/dt is the rate of flow of material appropriate techniques. The great variety of agi¬
through the tank. For a given concentration dif¬ tation systems that may be used for continuous
ference (Cj - C0) and flow rate, the rate of mixing in tanks has been discussed in connec¬
change of concentration of the effluent with tion with batch mixing.
time, dCg/dt, is inversely proportional to tank
volume. Two tanks in series, each having vol¬
ume V/2 or half that of the single tank just dis¬
cussed, would be even more effective in reduc¬
ing concentration fluctuations while having the
same holdup. This is true when the random
fluctuations in concentration occur over small
volume increments compared with the tank vol¬
umes. It is essentially a serial dilution effect.
Example, When integrated, equation (2)
yields the expression:

C0 = Ci(l - e~kt)

where k = dv/Vdt. When two identical tanks,

each of volume V/2, are connected in series, the
relationship between input and output concen¬ FIG. 1-7. Diagram of a turbine agitated, continuous mix¬
ing tank with vertical side wall baffles. Two zones of mix¬
trations becomes:
ing are shown, above and below the impeller. Net effect of
such a device is similar to that obtained by the operation of
C0 = C,(l - e_2kt - 2kte_2kt) two tanks, of the type shown in Figure 1 -6, in series.

mixing • 9
 quent dispersal throughout the mass of material
Mixer Selection to be mixed. In a general sense, the processes of
Equipment Selection. One of the first and homogenization, suspension formation, and
often most important considerations in any mix¬ emulsification may be considered forms of mix¬
ing problem is equipment selection. Factors that ing. Inasmuch as these topics are covered in
must be taken into consideration include (1) the Chapters 5, 16, and 17, they are considered
physical properties of the materials to be mixed, from only a mechanistic standpoint here.
such as density, viscosity, and miscibility, (2) The mixing of two immiscible liquids requires
economic considerations regarding processing, the subdivision of one of the phases into glob¬
e.g., time required for mixing and the power ules, which are then distributed throughout the
expenditure necessary, and (3) cost of equip¬ bulk of the fluid. The process usually occurs by
ment and its maintenance. In any given case, a stages during which the large globules are suc¬
number of these factors may be taken into con¬ cessively broken down into smaller ones. Two
sideration; however, a few general guidelines primary forces come into play here: the interfa¬
can be drawn. A more extensive discussion of cial tension of the globules in the surrounding
this subject may be found in the literature.L_s liquid, and forces of shear within the fluid mass.
1. Monophase systems. The viscous character The former tends to resist the distortion of glob¬
and density of the fluid(s) to be mixed determine ule shape necessary for fragmentation into
to a large extent the type of flow that can be pro¬ smaller globules, whereas the forces of shear act
duced and also, therefore, the nature of the mix¬ to distort and ultimately disrupt the globules.
ing mechanisms involved. Fluids of relatively The relationship between these forces largely
low viscosity are best mixed by methods that determines the final size distribution in the mix¬
generate a high degree of turbulence and at the ture.
same time circulate the entire mass of material. Selection of equipment depends primarily
These requirements are satisfied by air jets, upon the viscosity of the liquids and is made
fluid jets, and the various high-speed impellers according to the mechanism by which intense
discussed earlier. A viscosity of approximately shearing forces can best be generated. In the
10 poise may be considered as a practical upper case of low-viscosity systems, high shear rates
limit for the application of these devices. are required and are commonly produced by
Thick creams, ointments, and pastes are of passing the fluid under high pressure through
such high viscosity that it is difficult if not im¬ small orifices or by bringing it into contact with
possible to generate turbulence within their bulk rapidly moving surfaces. Devices for accom¬
and laminar mixing, and molecular diffusion plishing these high rates are described in Chap¬
must be relied upon. Mixing of such fluids may ter 17, Emulsions.
be done with a turbine of flat blade design. A Highly viscous fluids, such as are encoun¬
characteristic feature of such impellers is the tered in the production of ointments, are effi¬
relative insensitivity of their power consumption ciently dispersed by the shearing action of two
to density and/or viscosity. For this reason, they surfaces in close proximity and moving at differ¬
are particularly good choices when emulsifica¬ ent velocities with respect to each other. This is
tion or added solids may change these quantities achieved in paddle mixers, in which the blades
significantly during the mixing operation. This clear the container walls by a small tolerance.
property of turbines is due to the mechanisms by Such mixers are relatively efficient since they
which they produce their characteristic radial not only generate sufficient shear to reduce
flow: (1) density- and viscosity-dependent fluid globule size but if properly constructed, also in¬
entrainment into the area of blades and (2) cen¬ duce sufficient circulation of material to ensure
trifugal displacement in the axial direction, also a uniform dispersion throughout the completed
dependent upon these variables. The effects of mixture.
density and viscosity tend to cancel out since The mixing of finely divided solids with a liq¬
they contribute in both a positive and negative uid of low viscosity in the production of a sus¬
way to the circulation. When compared with a pension depends on the separation of aggregates
propeller of similar size, flat blade turbines of the into primary particles and the distribution of
radial flow type have a significantly lower pump¬ these particles throughout the fluid. These proc¬
ing capacity, which makes them less suitable for esses are often carried out in a single mixing
mixing in large tanks. operation, provided that shear forces of suffi¬
2. Polyphase systems. The mixing of systems cient intensity to disrupt aggregates can be gen¬
composed of several liquid or solid phases pri¬ erated. High-speed turbines, frequently fitted
marily involves the subdivision or deaggregation with stators to produce increased shearing
of one or more of the phases present, with subse¬ action, are often employed. When aggregation is

! 0 • The Theory and Practice of Industrial Pharmacy

not a problem, or when deaggregation is to be
carried out following a general mixing step, the
equipment used in mixing of suspensions is es¬
sentially the same as that previously discussed
for liquids of comparable viscosity.
As the percentage of solids is increased or if
highly viscous fluids are employed, the solid-
liquid system takes on the consistency of a paste
or dough. In these cases, the forces required to
induce shear are considerable, and equipment
FIG. 1-9. Cross section of a three-roll mill showing hopper
used is of heavy design. The choice of a mixer is (A), rolls fB.C.D), and scraper (E). Directions of roller ro¬
limited to those that either knead or mull the tation are indicated. Speed of rotation of the rollers in¬
material. Kneaders operate by pushing masses creases from B to D. Material placed in the hopper passes
of the material past each other and by squeezing between rolls B and C and then C and D in succession and
and deforming them at the same time. Such is finally collected on the scraper.
mixers may take several forms, but usually have
counter-rotating blades or heavy arms that work
the plastic mass. Shear forces are generated by smooths the mixture, which adheres to roll C. A
the high viscosity of the mass and are effective scraper, E, is arranged to continuously remove
in deaggregation as well as distribution of the the mixed material from roller D. The arrange¬
solids in the fluid vehicle. A diagram of a sigma- ment is such that no material can reach the
blade mixer with overlapping blades is shown in scraper that has not passed between both sets of
Figure 1-8. rolls.
Mulling mixers are efficient in deaggregation The extreme case of solid-liquid mixing is one
of solids, but are typically inefficient in distribut¬ in which a small volume of liquid is to be mixed
ing the particles uniformly through the entire with a large quantity of solids. This process is
mass. Previously mixed material of uniform essentially one of coating the solid particles with
composition, but containing aggregates of solid liquid and of the transfer of liquid from one par¬
particles, is suitable for mixing in these devices. ticle to another. In this type of mixing, the liquid
In the event of segregation during mulling, a is added slowly to reduce the tendency of the
final remixing may be necessary. particles to lump; however, the process is not
Roller mills consisting of one or more rollers one of fluids mixing, but one of solids mixing.
are in common use. Of these, the three-roll type When the particles tend to stick together be¬
seems to be preferred (Fig. 1-9). In operation, cause of the surface tension of the coating liq¬
rollers composed of a hard abrasion-resistant uid, the equipment used is the same as that for
material and arranged to come into close prox¬ pastes. If the solids remain essentially free flow¬
imity to each other are rotated at different rates ing, the equipment is the same as that used for
of speed. Material coming between the rollers is solids mixing, which is discussed under that
crushed, depending on the gap, and is also heading later in this chapter.
sheared by the difference in rates of movement Correlation. Many of the mixing character¬
of the two surfaces. In Figure 1-9 the material istics attributed to the various impellers, jets and
passes from the hopper, A, between rolls B and other mixing equipment can be considerably al¬
C, and is reduced in size in the process. The gap tered, often unfavorably, by changes in the rela¬
between rolls C and D, which is usually less tive size, shape, or speed of-their component
than that between B and C, further crushes and parts. Although methods of scale-up are usually
considered in relation to the problem of going
from laboratory scale to pilot plant to production
scale, they are also of fundamental value in un¬
derstanding the proper operation of a given
mixer, regardless of its size.
Exact analytic descriptions of the flow pat¬
terns, turbulent or otherwise, that occur in mix¬
ers are generally so complex as to defy solution,
CROSS SECTION-A TOP VIEW if indeed they may be mathematically formu¬
lated at all. For these reasons, an empiric ap¬
FIG. 1-8. Schematic drawing of a top-loading sigma-blade
mixer with overlapping blades. The top view shows the
proach, involving comparison of the system
relationship of the counter rotating blades to the overall under study with systems of known perfor¬
geometry of the mixer. mance, is employed for the prediction of the de-

MIXINC, • 11
sired operational conditions. Significant varia¬ where v and L are the terms previously defined
bles that must be taken into account include the and g is the acceleration of gravity. In the case of
dimensions of the mixer and its mechanical high Froude numbers, the inertial forces pre¬
components as well as their location within the dominate over those due to gravity. Should such
mixer. Included also are impeller speed or jet conditions prevail in an unbaffled tank agitated
pumping rate, fluid density, fluid viscosity, and by a vertical, centrally located turbine, vortex
height of fill of the mixer. In short, any factor formation results. This group is important
that can possibly influence the behavior of the whenever there is an interaction between gravi¬
materials as they are mixed is potentially impor¬ tational and inertial forces.
tant. The power that may be dissipated in a mixer
1. Dimensionless groups. The method is based by an impeller or other device is related to the
upon dimensionless groups that characterize the power number:
mixing systems. These groups consist of combi¬
nations of the physical and geometric quantities
that affect the fluid dynamics and hence also af¬ Pn (5)
fect the mixing performance of a given piece of
equipment. The measurable quantities consti¬ where p' is the pressure increment responsible
tuting a given dimensionless group are arranged for flow. The power number is thus the ratio be¬
so that their units of measurement cancel. tween the forces producing flow and the inertial
These unitless numbers, therefore, represent forces that resist it. The power number can also
ratios between pertinent variables or parame¬ be written as:
ters.
Large numbers of useful dimensionless
Pg
groups have been developed and employed (6)
under various circumstances for the correlation ~ (<o3d5
of mixer performance data as well as for the de¬
sign of mixers. Three of the more important where P is the power input, d is the impeller
groups serve to illustrate the utility of the diameter, and oj is its rotational velocity.
method. These are the Reynolds number, Re, the 2. Correlation equations. Before the dimen¬
Froude number. Fr, and the power number, Pn. sionless groups discussed here can be employed
The Reynolds number is commonly defined in useful calculations, it is necessary to find a
by the expression: satisfactory functional relationship between
them upon which to base the desired correla¬
vL£ tions. This is accomplished by means of the
Re (3) methods of dimensional analysis.1,6
V
Although a complete correlation function
where v is the velocity of the fluid relative to the must take into account all the variables in a
surfaces of the equipment involved. The density given system, satisfactory results may be ob¬
and dynamic viscosity are denoted by £ and 17, tained if only the most significant variables are
respectively. The dimension of length, L, is cho¬ considered. Therefore, while the general dimen¬
sen in various ways depending on the system. sionless equation for correlating power input
For example, in the case of fluid flowing through contains several dimensionless groups in addi¬
a pipe, it is taken as pipe diameter. For gas bub¬ tion to the Reynolds and Froude numbers, these
bles, it is taken as bubble diameter, and for im¬ latter two quantities are usually sufficient for
pellers, as impeller diameter. The subgroup vL£ correlations with the power number if geometri¬
is indicative of inertial forces in the system, and cally similar systems are investigated. The
the Reynolds number indicates the ratio be¬ power number is thus commonly written as a
tween these and the viscous forces. At high function of Re and Fr in the exponential form:
Reynolds numbers, the former predominate and
the flow is turbulent, whereas at low values of Pn = GR|F6 (7)
Re, laminar flow occurs. A transition range is
known to exist since the transition from laminar The exponents a and b and the constant G
to turbulent flow is not abrupt. must be determined experimentally. G is not a
In systems in which gravitational effects universal constant since it may take on different
occur, the Froude number should be taken into values for different ranges in the magnitude of
account. This group is defined by the equation: the associated dimensionless groups. It is rea¬
sonably constant, however, over ranges in which
vi no gross changes in flow character occur. The
Fr = (4)
gL

12 • The Theory and Practice of Industrial Pharmacy

exponents a and b, which should be considered product of the pitch and rpm. Thus, fluid veloc¬
as empiric quantities, also remain remarkably ity is given by the following:
constant over considerable ranges of operating
conditions. v = (0.8)(15)(T 750) _ 35Q cm sec-i
Consider, for example, a propeller operating at (60)
a speed at which the flow is predominantly lami¬
nar. In such a system, the exponent, a, of the The Reynolds number, from equation (3), is
Reynolds number is found to be -1, and b is equal to:
zero, since vortex formation does not occur
under these conditions. The correlation equa¬ Re = .(35g)(lfl,05)=3675
tion can then be written: (1.5)

Pg _ Gy Since this is within the turbulent range, equa¬

£io3 d° a>d2g
(8) tion (10) applies. Therefore, the power required
under the new conditions, Pn, as compared with
Upon rearrangement, the functional relation¬ that needed previously, P0, is given by:
ship of power input to the several variables is
apparent:

P = Gg“ V2d3 (9)

Thus, power input is proportional to viscosity,

and dependent on the second and third powers = 67.8
of the propeller velocity and diameter, respec¬
tively. The density of the fluid is not a factor On the basis of these calculations, it may be de¬
under these conditions of operation. cided that the increased speed of mixing result¬
The literature indicates that the same mixer ing from this design change does not warrant
operating under completely baffled conditions the additional power required.
with turbulent flow can be expected to exhibit The foregoing conclusions are valid only if
power numbers that are independent of Re and geometric similarity is maintained in the mixing
Fr; that is, the coefficients a and b in the correla¬ systems. Also, the value of G, while reasonably
tion equation will both be zero. The power num¬ constant over the ranges of laminar flow and
ber is thus equal to the experimentally deter¬ fully developed turbulence, is not numerically
mined constant G, and the power input may be the same in these two regions.
expressed by the equation: These examples illustrate the usefulness of
dimensionless groups in predicting and calculat¬
P = Gg-1£«3d5 (10) ing the influence of systematic variables on the
mixing process. The same general technique is
Here, the power required for a given flow is in¬ also useful in correlations involving more com¬
dependent of viscosity but linearly dependent on plex systems, which require additional groups
density, in contrast to laminar flow. Also, in this for satisfactory calculations.
case, power input is more sensitive to changes
in the rotational speed and the diameter of the Solids Mixing
propeller than with laminar flow.
Example. Consider a 500 = L, baffled mixing
vat agitated by means of a centrally mounted Fundamentals
15-cm diameter propeller at 1750 rpm. To pro¬ The theory of solids mixing has not advanced
vide more rapid mixing, the propeller rpm is much beyond the most elementary of concepts
doubled, and its diameter increased to 23 cm. and, consequently, is far behind that which has
This design change requires a more powerful been developed for fluids. This lag can be attrib¬
drive motor, but in order to make an estimate of uted primarily to an incomplete understanding
the increase needed, several variables must be of the ways in which particulate variables influ¬
considered. Given that the viscosity of the fluid ence such systems and to the complexity of the
is 1.5 poise and the specific gravity is 1.05, the problem itself.
Reynolds number can be estimated. If the pro¬ When viewed superficially, such multipar¬
peller pitch is 0.8 diameters per revolution, it ticulate solids as pharmaceutical bulk powders
will pump liquid at a velocity determined by the or tablet granulations are seen to behave some-

M1XING • 13
what like fluids. That is, to the casual observer, way be considered a unique indication of shape.
they appear to exhibit fluid-like flow when they For example, one cannot differentiate between
are poured from one container to another and rods and flat discs by the use of a single shape
seem to occupy a more or less constant bulk vol¬ factor. This limitation somewhat complicates
ume. Dissimilar powders can be intimately correlations and interpretations of particulate
mixed at the particulate level much like miscible shape effects on mixing.
liquids, at least in principle. Contrary to these A large number of shape factors have been
similarities with fluids, however, the mixing of defined and used in studies of multiparticulate
solids presents problems that are quite different solids systems. A typical example is that of a sur¬
from those associated with miscible liquids. The face shape factor, as, defined by the expression:
latter, once mixed, do not readily separate arid
can be poured, pumped, and otherwise sub¬
jected to normal handling without concern for
unmixing. In addition, they can be perfectly
mixed in any standard equipment, with the pri¬ The total surface area of the powder is s, having
mary concerns being power efficiency and time n, particles of projected diameter dr Powders
required. In contrast, well-mixed powders are whose particles are highly irregular in shape
often observed to undergo substantial segrega¬ generally exhibit large values of as.
tion during routine handling following the mix¬ Example. To calculate a value of as that is use¬
ing operation. Such segregation of particulate ful for purposes of comparison with other mate¬
solids can occur during mixing as well and is rials, consider a system of monodisperse spheres
perhaps the central problem associated with the of diameter 2r. The surface shape factor as will
mixing and handling of these materials. be independent of sample size, so that for sim¬
Particulate Solids Variables. Particle size plicity, a single particle will be taken as the sam¬
and particle size distribution are important since ple. In this case, equation (11) takes the form.
they largely determine the magnitude of forces,
gravitational and inertial, that can cause inter¬ 4T7T2
particulate movement relative to surface forces,
which resist such motion. As a consequence of “s " (2r)2 ~ 77
high interparticulate forces, as compared with
gravitational forces, few powders of less than Had the idealized particles been perfect cubes,
100 microns mean particle size are free-flowing. having edges of length d, then equation (11)
Most powders, including those encountered in would become:
pharmaceutical systems, have a wide range in
particle size with the actual distribution deter¬
mined to some extent by the method of prepara¬
tion. An excellent discussion of the statistics of
small particles is given by Herdan.7 The value for as can be seen to increase substan¬
Particle density, elasticity, surface roughness, tially as the particles become more angular and
and shape also exert, their influence on the bulk deviate from a spherical shape.
properties of powders. Of these, particle shape is Forces Acting in Multiparticulate Solids
perhaps the most difficult variable to describe Systems. As pointed out previously, forces that
and is commonly expressed by scalar quantities operate at a particulate level during the mixing
known as shape factors. When applied to, solids process are essentially of two types: (1) those
mixing, shape factors provide a number index to that tend to result in movement of two adjacent
which mixing rate, flow rate, segregation rate, particles or groups of particles relative to each
angle of repose, and other static or dynamic other and (2) those that tend to hold neighboring
characteristics can be related. However, the lim¬ particles in a fixed relative position. This divi¬
itations as well as the attributes of shape factors sion is arbitrary, and often a clear distinction
should be understood. cannot be made, for reasons that will become
As scalar quantities, shape factors serve as evident.
proportionality constants between mean particle In the first category are forces of acceleration
diameters and particle surface area and volume. produced by the translational and rotational
They also serve to relate results of experimental movements of single particles or groups of parti¬
particle size measurements by different meth¬ cles. Such motion can result either from contact
ods. In spite of their utility in these ways, shape with the mixer surfaces or from contact with
factors do not describe the shape of the particles other particles. In either case, the efficiency of
they characterize. Thus, a single factor can in no momentum transfer is highly dependent on the

14 • The Theory and Practice of Industrial Pharmacy

elasticity of the collisions. In general, much
more rapid and efficient interchange of momen¬
tum would be expected if loss by inelasticity was
minimal.
The shape and surface “roughness” of the par¬
ticles involved in a collision determine, to a large
measure, the distribution of the transferred
momentum between translational and rotational
modes. That is, all other factors being equal, par¬
ticles with a high coefficient of friction are likely
to exchange rotational momentum more readily.
This momentum exchange can also be expected
to depend more on the “available surface” area FIG. 1-10. Relative numbers of neighboring particles per
than on the density or the mass of the particle. unit area as a function of distance measured in particle
Rotating aggregates experience centrifugal diameters from reference particles. Measurements are
made center-to-center of relatively spherical particles
forces (that tend to break them into smaller units
under both close and loose packing arrangements.
and aid the mixing process.
Gravitational forces also operate and, of
course, act on all particles at all times in propor¬ a wide spectrum of particulate properties, which
tion to their mass. result in an equally wide range of bulk proper¬
Included in the second category of forces, ties. The latter may be classified as being char¬
namely those that resist particulate movement, acteristic of either a static or dynamic state of
are interparticulate interactions associated with the system.
the size, shape, and surface characteristics of Attempts to correlate the gross properties of
the particles themselves. Powders that have powders with the nature of the individual parti¬
high “cohesive” forces due to interaction of their cles have been somewhat more successful in
surfaces can be expected to be more resistant to systems under static conditions than when the
intimate mixing than those whose surfaces do particles are in a state of flow. This is not unex¬
not interact strongly. Factors that influence this pected since inertial forces become important
type of interaction are surface polarity, surface when the particles are in motion, and the result¬
charge, and adsorbed substances such as mois¬ ing transfer of momentum and kinetic energy is
ture. a complex function of the particulate variables.
In moving from one location to another, rela¬ Mixing Mechanisms. It has been generally
tive to its neighbors, a particle must surmount accepted that solids mixing proceeds by a combi¬
certain potential energy barriers. These arise nation of one or more mechanisms.
from forces resisting movement insofar as 1. Convective mixing. This mechanism may
neighboring particles must be displaced. This be regarded as analogous to bulk transport as
effect is a function of both particle size and discussed in connection with fluids mixing.
shape and is most pronounced when high pack¬ Depending on the type of mixer employed, con¬
ing densities occur. Particle shape is important vective mixing can occur by an inversion of the
because as the shape of a particle deviates more powder bed, by means of blades or paddles, by
significantly from a spherical form, the free means of a revolving screw, or by any other
movement it experiences along its major axes method of moving a relatively large mass of ma¬
also diverges. terial from one part of the powder bed to an¬
Recent studies by several workers, on particu¬ other.
late beds and by means of computer simulation, 2. Shear mixing. As a result of forces within
have demonstrated the existence of these barri¬ the particulate mass, slip planes are set up. De¬
ers;' They are manifested by peaks and valleys in pending on the flow characteristics of the pow¬
the radial location frequency distribution of par¬ der, these can occur singly or in such a way as to
ticles in a bed relative to a reference particle. give rise to laminar flow. When shear occurs
Figure 1-10 illustrates distributions typical of a between regions of different composition and
bed of particles of relatively uniform size. This parallel to their interface, it reduces the scale of
diagram shows that moderate bed expansion, segregation by thinning the dissimilar layers.
short of total fluidization, facilitates interparticu¬ Shear occurring in a direction normal to the in¬
late motion, and hence mixing, by reducing the terface of such layers is also effective since it too
magnitude of the energy barriers and shortening reduces the scale of segregation.
the distance between preferred locations. 3. Diffusive mixing. Mixing by “diffusion” is
In general, powders and divided solids possess said to occur when random motion of particles

MIXING • 15
within a powder bed causes them to change po¬ ders. Powders that are not free-flowing or that
sition relative to one another. Such an exchange exhibit high forces of cohesion or adhesion be¬
of positions by single particles results in a reduc¬ tween particles of similar or dissimilar composi¬
tion of the intensity of segregation. Diffusive tion are often difficult to mix owing to agglomer¬
mixing occurs at the interfaces of dissimilar re¬ ation. The clumps of particles can be broken
gions that are undergoing shear and therefore down in such cases by the use of mixers that
results from shear mixing. It may also be pro¬ generate high shear forces or that subject the
duced by any form of agitation that results in powder to impact. When these powders have
interparticulate motion. been mixed, however, they are less susceptible
These mechanisms will be considered further to segregation because of the relatively high in¬
in connection with the various types of mixer in terparticulate forces that resist interparticulate
common use. motion leading to unmixing.
The general flow characteristics of powders It is sometimes possible to select pharmaco¬
determine to a great extent the ease with which logically inert excipients that have a selective
the primary particles can be mixed. That is, they affinity for an active mixture component. The
determine how easily masses of powder can be particle-to-particle binding between drug and
transported through the powder bed, and also inert carrier, which results in such mixtures,
how easily these masses can be broken down to can greatly improve homogeneity and stability
permit intimate mixing of individual particles. It toward separation of components. This tech¬
is only through the latter process that the inten¬ nique is most valuable when potent drugs are to
sity of segregation can be reduced. be mixed in relatively low percentages. When
The mixing of particles whose surfaces are the drug is added as a fine powder, it can be
nonconducting (electrically) often results in the made to coat carrier particles uniformly, and as a
generation of surface charges, as evidenced by a consequence, to be mixed uniformly throughout
tendency of the powder to clump following a pe¬ the batch. Usually, this is best accomplished by
riod of agitation. Surface charging of particles selecting an excipient that has a polarity similar
during mixing is undesirable, for it tends to de¬ to that of the drug. For example, a steroid would
crease the process of interparticulate “diffu¬ adhere well to lipid-like surfaces. In this case,
sion.” however, inclusion of significant amounts of
Unfortunately, surface charges in powder waxy or fatty materials in a tablet formulation
beds axe not readily measurable. If the bed were may cause disintegration or dissolution difficul¬
electrically insulated during agitation, its net ties. When stability is not a problem, it is often
charge would be zero, whereas the intensity of more practical to place the drug in relatively di¬
charge on individual particles could be quite lute solution and spray it on an inert excipient.
high. In such a system, a given particle may be After drying, this drug excipient mixture can be
singly charged positively or negatively, multiply mixed with the remainder of the formulation.
charged with like charges, or multiply charged In practice, the problem of segregation is most
with either an equal or unequal number of posi¬ severe when one is working with free-flowing,
tive and negative charges. The net charge of a cohesionless, or nearly cohesionless particulate
powder can be determined and is often taken as matter. Segregation has been attributed to vari¬
a measure of the tendency of the particles to ous types of mixers: those that generate princi¬
undergo charge separation. pally convective motion have been classified as
Charging of powder beds and the undesirable “nonsegregating,” while those that produce
effects it produces can be prevented or reduced shear or diffusive mixing are termed “segregat¬
in many cases by surface treatment, which is ing.” The circumstances that result in segrega¬
usually accomplished by adding small amounts tion, however, can be generalized from a funda¬
of surfactants to the powder, thereby increasing mental physical standpoint. Consider a bed of
the conductivity of the surface. The problem can randomly mixed particles of two or more types in
also-be solved in some cases by mixing under a state of agitation, with particles constantly
conditions of increased humidity (above 40%). moving around and past each other. Mixing oc¬
Segregation Mechanisms. As mentioned curs when particle motion is random and leads
previously, particulate solids tend to segregate to a nonselective reordering of individual parti¬
by virtue of differences in the size, density, cles. Where particle motion is selective, how¬
shape, and other properties of the particles of ever, a sorting effect occurs. The following has
which they are composed. The process of segre¬ been suggested:8
gation occurs during mixing as well as during
subsequent handling of the completed mix, and [The] necessary and sufficient conditions for segrega¬
it is most pronounced with free-flowing pow¬ tion to occur in such a system are twofold: (i) that

16 • The Theory and Practice of Industrial Pharmacy

various mixture components exhibit mobilities for in¬
terparticulate relative displacement which differ, and
(ii) that the mixture experience either a field which
exerts a directional motive force on the particles or a
gradient in a mechanism capable of inducing or modi¬
fying interparticulate movement.

The conditions outlined here are present to a FIG. 1-11. Three types of tumbling mixers shown
greater or lesser degree in all mixers, regardless mounted on a common shaft: A, twin-shell; B, cubic; C,
cylindric. In operation, the asymmetric geometry results
of their type or mode of operation. They also
in a sideways movement of material in addition to the
occur during mixer emptying, during filling of tumbling action of the mixers. Of the three types, the twin-
capsule- or tablet-making hoppers, during flow shell is the most popular.
through the hopper itself, and even in a tablet
machine feed frame. In reality, the various
mechanisms that lead to mixing provide the quite effective because the bulk transport and
conditions but not the mechanisms that can lead shear, which occur in tumbling mixers gener¬
to segregation. ally, are accentuated by this design. A bar con¬
The requirements for segregation, as previ¬ taining blades that rotate in a direction opposite
ously postulated, can arise in a variety of ways. to that of the twin shell often is used to improve
Differences in mixture component mobilities agitation of the powder bed, and may be replaced
can result from differences in particle sizes, by a hollow tube for the injection of liquids.
shapes, density, and surface characteristics. Other mixers of this same general type take
While other characteristics may also be impor¬ the form of cylinders, cubes, or hexagonal cylin¬
tant, these are recognized as significant in most ders (Fig. 1-11), and may be rotated about al¬
cases. The second requirement for segregation most any axis depending on the manufacturer.
can be met by the earth’s gravitational field, or The efficiency of tumbling mixers is highly
by a centrifugal, electrical, magnetic field gener¬ dependent on the speed of rotation. Rotation
ated in the course of processing. Even in the that is too slow does not produce the desired in¬
absence of such fields, this requirement can be tense tumbling or cascading motion, nor does it
satisfied by a gradient in shear rate within the generate rapid shear rates. On the other hand,
powder bed. rotation that is too rapid tends to produce cen¬
According to theory, it should be possible to trifugal force sufficient to hold the powder to the
prevent segregation by eliminating either one of sides of the mixer and thereby reduce efficiency.
the necessary conditions for its existence. Total The optimum rate of rotation depends on the
avoidance of undesirable environmental condi¬ size and shape of the tumbler and also on the
tions during the course of mixing and process¬ type of material being mixed, but is commonly
ing is virtually impossible. If a mixture gives in the range of 30 to 100 rpm.
persistent trouble regarding homogeneity, it is A second class of mixer employs a stationary
usually best to try to improve the characteristics container to hold the material and brings about
of the mixture rather than the mixer. With free- mixing by means of moving screws, paddles, or
flowing materials, the goal is to make all compo¬ blades. Since this mixer does not depend en¬
nents as alike as possible in size, shape, and tirely on gravity as do the tumblers, it is useful
density (in that order). in mixing solids that have been wetted and are
therefore in a sticky or plastic state. The high
shear forces that are set up are effective in
Equipment breaking up lumps or aggregates. Well-known
Batch Mixing. A common type of mixer con¬ mixers of this type include the following. (1) The,
sists of a container of one of several geometric ribbon blender (Fig. 1-12), consists of a horizon¬
forms, which is mounted so that it can be rotated tal cylindric tank usually opening at the top and
about an axis. The resulting tumbling motion is fitted with helical blades. The blades are
accentuated by means of baffles or simply by vir¬ mounted on a shaft through the long axis of the
tue of the shape of the container. The popular tank and are often of both right- and left-hand
twin-shell blender is of this type and takes the twist. (2) In the helical flight mixer, powders are
form of a cylinder that has been cut in half, at lifted by a centrally located vertical screw and
approximately a 45-degree angle with its long allowed to cascade to the bottom of the tank. Of
axis, and then rejoined to form a “V” shape. This these two, types, the ribbon blender is the more
is rotated so that the material is alternately col¬ popular.
lected in the bottom of the V and then split into When finely divided powders of a sticky con¬
two portions when the V is inverted. This is sistency are to be mixed, high shear rates and

MIXING • 17
 ally accomplished by the arbitrary choice of a
statistical function that indicates the uniformity
of composition of the powder bed.
When analytic procedures are available, the
intensity and scale of segregation, as defined by
Danckwerts, serve as useful criteria, but only
when large-scale segregation is not present.
A large number of statistical quantities have
been used by researchers in the area of solids
FIG. 1-12. Side view of a top-loading ribbon blender. The
blades are mounted on the horizontal axle by struts (not
mixing to express a “degree of mixing”; how¬
shown) and are rotated to circulate the material to be ever, they all provide essentially the same type
mixed. The spiral blades are wound (in most cases) in op¬ of information concerning the mixture. More
posite directions to provide for movement of material in important than the choice of a degree of mixing
both directions along the axis of the tank. These mixers is the method of sampling employed. Unless
may be emptied either through ports in the bottom or by
samples that accurately represent the system
inverting them.
are taken, the most elaborate statistical analysis
is worthless.
forces are necessary to permit intimate mixing The standard deviation or variance of the se¬
at the particulate level. This may be accom¬ lected samples from the mean composition of
plished if the scale of segregation is first reduced the system serves as a useful measure of the
by means of the mixers previously discussed. overall quality of a mixture. Samples may be
The roughly mixed material can then be run withdrawn periodically during discharge of the
through a hammer mill, which effectively pro¬ mixture or may be taken directly from the mixer
duces “diffusive” mixing by breaking up aggre¬ by a sampling “thief.”
gates. The process can be repeated if necessary. In the evaluation of a mixture, care must be
Continuous Mixing. A characteristic of sol¬ taken that the scale of scrutiny is appropriate.
ids mixing equipment is that all else being That is, the samples chosen must be large
equal, mixtures produced by large mixers have enough to contain sufficient particles to repre¬
greater variations in composition than those pro¬ sent accurately the region from which they were
duced by small mixers. This is an important taken, yet not so large as to obscure important
consideration when relatively small portions of small-scale variations in composition. The selec¬
the mixture are required to fall consistently tion of a scale of scrutiny also depends on the
within a narrow composition range. The produc¬ ultimate use of the mixture. For example, sam¬
tion of tablets and capsules are examples of ples of the same weight as the final tablet are
pharmaceutical processes in which composition proper for evaluating a tablet granulation. Analy¬
uniformity is critical. sis of multiple samples of this size would allow
The effective volume of a solids blender may prediction of tablet-to-tablet variations due to
be reduced considerably by the use of continu¬ imperfect mixing.
ous mixing equipment. Continuous mixing In terms of statistics, “perfect” mixtures are in
processes are somewhat analogous to those dis¬ reality random mixtures. That is, the number of
cussed under fluids mixing. Metered quantities particles of a given component, in samples of
of the powders or granules are passed through a uniform weight from a perfect mixture, is deter¬
device that reduces both the scale and intensity mined by chance, and will at best vary about a
of segregation, usually by impact or a shearing mean value. The statistical considerations be¬
action. The output may be transferred directly to come more complicated as the number of com¬
the capsule filling or tablet machines. Control of ponents increases and their size distributions
mixing efficiency in such a system must ulti¬ differ. In the simple case of a binary mixture of
mately depend on an analysis of the dosage equal-sized particles of two different compo¬
forms as they are produced. The feasibility of nents, the statistics follow the binomial distribu¬
such a process depends on the availability of tion having mean, pt, and standard deviation, tr.
rapid analytic procedures. Thus, the following equations apply:

pt = np (12)
Mixer Selection
Measures of Mixing Degree. Mixer selec¬ a = Vnp(I - p) (13)
tion and evaluation depend on a quantitative
measure of the degree of mixing. This is gener¬ where n is the number of particles in the sam-

18 • The Theory and Practice of Industrial Pharmacy

pie, and p is the number fraction of particles of not be made to produce good mixtures, when
the component of interest in the mixture. they are operated incorrectly, simply by mixing
Example. For purposes of illustration, con¬ for a long period of time. The process of solids
sider a capsule formulation consisting of a mix¬ mixing is accompanied by the process of segre¬
ture of equal-sized pellets of two different com¬ gation, as pointed out earlier, in which particles
positions, A and B. The pellets are mixed in the having different characteristics preferentially
number ratio of 3 parts of A to 7 parts of B. The concentrate in various regions of the mixer. Be¬
problem is to predict the variation in content of cause of this, the mixture reaches an equilib¬
capsules containing 500 pellets each, assuming rium state of mix that is a function of speed of
random mixing with no systematic segregation. operation of the mixer.
In such a system, collecting a sample of 500 pel¬ The statement is often made that solids mix¬
lets at a time is equivalent to picking out 500 ers result in unmixing if mixing is continued for
pellets one at a time randomly. Thus, the selec¬ an excessive length of time. Such observations
tion of pellets follows the binomial distribution, are a result of improper operation of the mixer or
in which the expected composition of the sam¬ the use of the wrong mixer or both. Such a
ple and its expected variability in composition mixer produces an equilibrium mixture having a
are given by equations (12) and (13), respec¬ significant degree of segregation. When the
tively: material is loaded into the mixer to cause an in¬
termingling of the various solids as they migrate
p = np = (500)(0.3) = 150 toward their steady state locations, the apparent
mixing-unmixing phenomenon is seen.
a = Vnp(l - p) = [(500)(0.3)(0.7)]1/2 = 10.2 A second cause of apparent unmixing after
prolonged mixer operation is the milling that
One sees that on the average, a capsule will inadvertently occurs because of abrasion of the
contain 150 type A pellets, the remaining 350 particles. This frequently occurs during scaling
being type B. The number standard deviation up to production from small laboratory mixers.
calculated from equation (13) is 10.2. In a nor¬ The often substantial fill weights of production
mal distribution, 68% of the measurements (in mixers can generate high shear forces between
this case, the number of type A pellets per cap¬ particles sliding past each other under a heavy
sule) lie within plus or minus one standard devi¬ load of material above. As a consequence, the
ation (10.2 pellets) of the mean (150 pellets per particle size distribution after mixing may bear
capsule). This means that even with perfect ran¬ only slight resemblance to the original distribu¬
dom mixing, approximately only 68% of the cap¬ tion. An expected and common effect is the gen¬
sules would contain 150 ± 10.2, or approxi¬ eration of fine particulate matter (fines), which
mately 140 to 160 pellets of type A among 500 can dilute lubricants and otherwise modify for¬
pellets each. mulation properties.
It can be inferred from this example that as
the number of particles in a sample is increased,
the percentage variation in composition from
sample to sample decreases, all else being equal.
In evaluating the cause of problems with con¬ References
tent uniformity related to tablets and capsules,
1. Johnstone, R. E., and Thring, M. W.: Pilot Plants,
the statistics of the sample should be consid¬ Models and Scale-Up Methods in Chemical Engineer¬
ered. Calculations involving multicomponent ing. McGraw-Hill, New York, 1957.
mixtures are more complicated, as has previ¬ 2. Uhl, V. W., and Gray, J. B.: Mixing—Theory and Prac¬
ously been mentioned, and are covered in refer¬ tice. Vol. I. Academic Press, New York, 1966.
ences listed at the end of this chapter. 3. Uhl, V. W., and Gray, J. B.: Mixing—Theory and Prac¬
tice. Vol. II. Academic Press, New York, 1967.
Power Requirements. Unlike fluids mix¬
4. Sterbacek, Z., and Tausk, P.: Mixing in the Chemical
ing, the requirements for power of a given solids Industry. Pergamon Press, New York, 1965.
mixing operation cannot be readily predicted. 5. Bridgeman, P. W.: Dimensional Analysis. Yale Univer¬
This is not a problem, however, since efficiency sity Press, New Haven, 1931.
of power utilization parallels operating condi¬ 6. Perry, R. H. Chilton, C. H., and Kirkpatrick, S. D.:
tions for optimum mixing. Consequently, mini¬ Chemical Engineers’ Hand-book. 4th ed. McGraw-
Hill, New York, 1963.
mum power is that required to operate the mixer
7. Herdan, G.: Small Particle Statistics. Academic Press,
for the time necessary to reach a satisfactory New York, 1960.
steady state. 8. Rippie, E. G., and Chou, D. H.: Powder Technol.,
Unlike most liquids mixers, solids mixers can¬ 21:205, 1978.

MIXING ' 19
General References Oldshue, J. Y.: Fluid Mixing Technology. Chemical Engi¬
neering Magazine. American Institute of Chemical
Nagata, S.: Mixing: Principles and Applications. John Engineering (AIChE), New York, 1983.
Wiley and Sons, New York. 1975. Randolph, J.: Mixing in the Chemical and Allied Indus¬
Nauman, E. B,: Mixing in Continuous Flow Systems. tries. Noyes Development Corp., Park Ridge, NJ, 1967.
John Wiley and Sons, New York, 1983. Weidenbaum, S. S.: Mixing of Solids. Advances in Chem¬
Nielsen, L. E.: Predicting the Properties of Mixtures: ical Engineering. Vol. 2. Academic Press, New York,
Mixture Rules in Science and Engineering. Marcel 1958, p. 209.
Dekker, New York, 1978.

20 • The Theory and Practice of Industrial Pharmacy

 2
Milling
EUGENE L. PARROTT

Few materials used in pharmaceuticals exist in influences the duration of adequate serum con¬
the optimum size, and most materials must be centration, rheology, and product syringeability
comminuted at some stage during the produc¬ of a suspension of penicillin G procaine for intra¬
tion of a dosage form. Milling is the mechanical muscular injection.2 The rectal absorption of
process of reducing the particle size of solids. aspirin from a theobroma oil suppository is re¬
Various terms (crushing, disintegration, disper¬ lated to particle size.3 Increased antiseptic
sion, grinding, and pulverization) have been action has been demonstrated for calomel oint¬
used synonymously with comminution depend¬ ment when the particle size of calomel has been
ing on the product, the equipment, and the proc¬ reduced.4 The size of particles used in inhala¬
ess. tion aerosols determines the position and reten¬
Milling equipment is usually classified as tion of the particles in the bronchopulmonary
coarse, intermediate, or fine according to the system.5 Fincher has reviewed the influence of
size of the milled product. Size is conventionally particle size of medicinal compounds and its re¬
expressed in terms of mesh (number of open¬ lationship to absorption and activity.6 Size may
ings per linear inch of a screen). As an arbitrary affect texture, taste, and rheology of oral suspen¬
classification for the consideration of pharma¬ sions in addition to absorption.7
ceuticals, coarse milling produces particles Extraction or leaching from animal glands
larger than 20-mesh, intermediate milling pro¬ (liver and pancreas), and from crude vegetable
duces particles from 200- to 20-mesh (74 to 840 drugs, is facilitated by comminution. The time
microns), and fine milling produces particles required for extraction is shortened by the in¬
smaller than 200-mesh. A given mill may oper¬ creased area of contact between the solvent and
ate successfully in more than one class: a ham¬ the solid and the reduced distance the solvent
mer mill may be used to prepare a 16-mesh has to penetrate into the material. The control of
granulation and to mill a crystalline material to a particle size in the extraction process provides
120-mesh powder. for more complete extraction and a rapid filtra¬
tion rate when the solution is filtered from the
marc. Similarly, the time required for dissolu¬
Pharmaceutical Applications tion of solid chemicals in the preparation of solu¬
The surface area per unit weight, which is tions is shortened by the use of smaller particles.
known as the specific surface, is increased by The drying of wet masses may be facilitated by
size reduction. This increased specific surface milling, which increases the surface area and
affects the therapeutic efficiency of medicinal reduces the distance the moisture must travel
compounds that possess a low solubility in body within the particle to reach the outer surface.
fluids by increasing the area of contact between Solvolytic decomposition of solids initially oc¬
the solid and the dissolving fluid. Thus, a given curs at surface irregularities and is increased by
weight of a finely powdered medicinal com¬ the presence of solvates or moisture. Microniza-
pound dissolves in a shorter time than does the tion and subsequent drying increase the stability
same weight of a coarser powder. The control of because the occluded solvent is removed.8
fineness of griseofulvin led to an oral dosage reg¬ In the manufacture of compressed tablets, the
imen half that of the originally marketed prod¬ granulation of the wet mass results in more
uct. 1 Control of particle size and specific surface rapid and uniform drying. The dried tablet gran-

21
ulation is then milled to a particle size and distri¬ diameter of an irregular particle with a volume V
bution that will flow freely and produce tablets of is:
uniform weight. The flowability of powders and
granules in high-speed filling equipment and in
tablet presses affects product uniformity. Rela¬
tionships between flow rate and particle size The effective diameter of particles based on
have been reported.9-11 The role of size reduc¬ their rate cf sedimentation is commonly used in
tion in tablet manufacturing has been dis¬ pharmacy. The time required for the particle to
cussed.12 settle between two fixed points in a suitable liq¬
The mixing or blending of several solid in¬ uid is experimentally determined and allows
gredients of a pharmaceutical is easier and more evaluation of the rate of sedimentation. By use
uniform if the ingredients are approximately the of Stokes’ equation (see under “Sedimentation”
same size.13 This provides a greater uniformity in this chapter), the effective diameter is calcu¬
of dose. Solid pharmaceuticals that are artifi¬ lated. This effective, or Stokes’, diameter is the
cially colored are often milled to distribute the diameter of a sphere that requires the same time
coloring agent to ensure that the mixture is not to settle between two fixed points in the liquid as
mottled and is unifoim from batch to batch. does the irregular particle.
Even the size of a pigment affects its color. In addition to the two effective diameters de¬
Lubricants used in compressed tablets and scribed, several other diameters are defined and
capsules function by virtue of their ability to coat their values are calculated in Table 2-1 for 261
the surface of the granulation or powder. A fine particles measured by microscopy. The arithme¬
particle size is essential if the lubricant is to tic average diameter is the sum of the diameters
function properly.14 The milling of ointments, of the separate particles divided by the number
creams, and pastes provides a smooth texture of particles. If n1( n2, and nn are the number of
and better appearance in addition to improved particles having diameters d^ d2, and dn, respec¬
physical stability. tively, the average diameter is:

, _ n]d! + n2d2 + . . . nndn _ S(nd)

dave “ n, + n2 + . . . nn “ 2n
Size Distribution and (2)
Measurement
The average diameter of a group of 261 particles
In naturally occurring particulate solids and
can be calculated from the data in Table 2-2.
milled solids, the shape of particles is irregular,
The average diameter is:
and the size of the particles varies within the
range of the largest and smallest particle. There
is no known method of defining an irregular par¬
ticle in geometric terms; however, statistical dave = ~26T~ = 2°'6 ^

methods have been developed to express the

size of an irregular particle in terms of a single The geometric mean diameter is the nth root
dimension referred to as its diameter. If this di¬ of the product of the n particles measured:
ameter is measured by a standardized procedure
for a large number of particles, the values may dgeo = ^didz ■ • • dn (4)
be expressed by several diameters. It is only re¬
quired that the surface area is proportional to Using the logarithmic form of this equation, the
the square of the diameter and the volume is geometric mean diameter of the 261 particles is
proportional to the cube of the diameter. calculated by use of the following:
For an irregular particle, an equivalent parti¬
cle with the same surface or volume may be sub¬ = S(n log d)
log dg
stituted. For convenience of mathematical treat¬ 2n
ment, an irregular particle is considered in _ 336.0874
terms of an equivalent sphere. The size of the (5)
261
particle can then be expressed by a single pa¬
rameter, d (the diameter). The volume of a parti¬ = 1.2876
cle may be determined by displacement in a liq¬
uid and equated to the volume of a hypothetic and
sphere possessing an equivalent diameter. As
the volume of a sphere is 7rd3/6, the equivalent d„eo = antilog 1.2876 = 19.4 pm (6)

22 • The Theory and Practice of Industrial Pharmacy

Table 2-1. Definitions of Various Diameters and Their Values for 261 Particles Measured by Means of
an Optical Micrometer

Number in
Mean of Each Size-
Size-group Size-group, d group, n nd log d n log d nd.2 nd3 nd4

4 to 7.9 /un 6 /u.m 5 30 0.7782 3.9910 180 1080 6480

8 to 11.9 10 15 150 1.0000 15.0000 1500 15,000 150,000
12 to 15.9 14 46 644 1.1461 52.7206 9016 126,224 1,767,136
16 to 19.9 18 68 1224 1.2553 85.3604 22,032 396,476 7,138,368

20 to 23.9 22 58 1276 1.3424 77.8592 28,072 617,584 13,586,848

24 to 27.9 26 32 832 1.4150 45.2800 21,632 562,432 14,623,232
28 to 31.9 30 22 660 1.4771 32.4962 19,800 594,000 17,820,000
32 to 35.9 34 10 340 1.5315 15.3150 11,560 393,040 1,336,336

36 to 39.9 38 2 76 1.5798 3.1596 2888 109,744 2,085,136

40 to 43.9 42 2 84 1.6232 3.2464 3528 148,176 6,222,392
44 to 47.9 46 0 0 1.6628 0 0 0 0
48 to 51.9 50 1 50 1.6990 1.6990 2500 125,000 6,250,000
261 5366 336.0874 122,708 3,088,756 70,985,928

Diameter Definition Diameter for 261 Particles

/ 2nd2 /122,708
Mean surface ds = ds = 21.7 fim
V 2n * 261

3/ Xnd3 3/ 3,088,756
Mean volume dv = d,- - = 22.8 /tun
V Sn v 261

2nd3 3,088,756
Mean volume-surface d.s = dvs 25.2/um
2nd2 122,708

2nd4 70,985,928
Weight mean dw = d„. = 22.9 ix m
2nd3 3.088,756

Table 2-2. Summation for the Determination of the Median Diameter of 261 Particles Measured by an
Optical Micrometer

Number in Number Less Than Percentage of Particles Percentage of Particles ■Less

Each Size- Maximum of Size- in Each Size- Than Maximum
Size-group group, n group group Size of Group

4 to 7.9 /tun 5 5 1.9 1.9

_ 8 to 11.9 15 20 5.8 7.7
12 to 15.9 46 66 17.7 25.4
16 to 29.9 68 134 26.0 51.4

20 to 23.9 58 192 22.2 73.6

24 to 27.9 32 224 12.4 85.8
28 to 31.9 22 246 8.4 94.2
32 to 35.9 10 256 3.8 98.0

36 to 39.9 2 258 0.8 98.8

40 to 43.9 2 260 0.8 99.6
44 to 47.9 0 260 0 99.6
48 to 51.9 1 261 0.4 100

MILLING • 23
 The median diameter is the diameter for determine the percentage frequency of distribu¬
which 50% of the particles measured are less tion of particle sizes. The most precise method of
than the stated size. An inspection of Table 2-2 data presentation is tabular form, as in Table
shows that 134 particles of the 261 are less than 2-1. The data may be presented as a bar graph or
18 microns; therefore, the median diameter is histogram of the frequency as a function of par¬
approximately 18 microns. Cumulative plots are ticle size. Size-distribution data are commonly
those in which the percentage of particles less presented graphically because a graph is more
than (or greater than) a given particle size are concise and permits easy visualization of the
plotted against size. As shown in Figure 2-1 for mean and skewness of distribution. A size-fre¬
the data in Table 2-2, the cumulative percentage quency curve is a plot of the percentage frequen¬
less than the stated size is plotted against size, cies of various particles against the mean of size-
and the median diameter is read from the 50% groups. The size-frequency curve in Figure 2-2
value of the curve. is drawn from the data in Table 2-1. The arith¬
The arithmetic or geometric mean and the metic and geometric mean diameters are indi¬
median have no physical significance. The cated. The mode is the maximum in the size-fre¬
meaningful choice of diameter depends on its quency curve.
relevance to some significant physical property. An infinite number of particle size distribu¬
The packing and flow of a powder or granulation tions may have the same average diameter or
depends on its volume; thus, if packing is a median. For this reason, parameters other than
prime consideration, the size should be ex¬ a median or average diameter are required to
pressed as a mean volume diameter. Dissolution define the size of a powder. A powder should be
and adsorption processes are a function of the characterized with a size-frequency curve.
surface area of the particles, and with these Size distributions that follow the probability
processes, the particle size should be expressed law are referred to as normal or Gaussian distri¬
as a mean surface diameter. As sedimentation is butions, as shown in Figure 2-2. This normal-
an important property of suspensions, the size of probability distribution is symmetric about a ver¬
the suspended solids should be expressed as a tical axis. The size-frequency distribution of
Stokes’ diameter. ground material is usually skewed with the
number of particles increasing with decreasing
size. It is believed that the size distributions of
Representation of Data
When a material is milled, the particles have a
variety of sizes as determined by flaw structure.
The purpose of particle size measurement is to

SIZE
FIG. 2-1. Cumulative distribution plot used to determine FIG. 2-2. Size-frequency distribution of 261 particles
the median size. measured by microscopy.

24 • The Theory and Practice of Industrial Pharmacy

 ured; therefore, the distribution is not asymp¬
totic, and the plots on the probability grids often
depart from linearity at the extremes. This does
not detract from the usefulness of such plots, as
the areas extending from the extremes to infin¬
ity are negligible compared to the area contained
under the distribution curve between the largest
and the smallest particles measured.
The calculations involved in computing the
mean diameter and the standard deviation are
reduced by the use of probability grids. The
median diameter for both grids is obtained by
reading from the curve the size corresponding to
50% value on the probability scale. In the arith¬
FIG. 2-3. Arithmetic-probability plot of data in Table 2-2. metic-probability plot, the mean is the arithme¬
tic average; in the logarithm-probability plot, the
50% size is the geometric mean. The standard
milled material follow an exponential law. If the deviations can be obtained from the arithmetic-
distribution is asymmetric or skewed, it fre¬ probability plot from the relation:
quently can be made symmetric and will follow
the normal-probability law if the sizes are re¬
placed by the logarithms of the sizes. (7 = 84.13% size - 50% size
Size-frequency data are conveniently plotted (7)
a = 50% size - 15.87% size
on an arithmetic-probability or logarithm-proba¬
bility grid. For a normal distribution, a plot of the
and from the logarithm-probability plot from the
cumulative percentage less (or greater) than the
relation:
stated size against size produces a straight line.
In Figure 2-3, using the data from Table 2-2,
_ 84.13% size
(the size is plotted against the cumulative per¬
centage less than the stated size using an arith¬ <Tgeo 50% size
metic-probability grid. For a skewed distribu¬
(8)
_ 50% size
tion, a plot of the cumulative percentage less (or 15.87% size
greater) than the stated size against the loga¬
rithm of size generally produces a straight line, Using these probability functions, Hatch de¬
as shown in Figure 2-4.
rived equations relating various types of diame¬
When the plots are made on either probability
ters by use of the standard deviation and
grid, the distributions must be asymptotic on
mean.15 These statistical parameters are a func¬
both extremes. In practice, there may be a larg¬
tion of the size and numeric frequency of the
est and smallest particle in the material meas-
particles for a given size. To calculate their val¬
ues, the size-distribution data must be ex¬
pressed in terms of a numbers frequency. In
microscopy, this requirement is met directly;
however, in sieving and sedimentation methods,
the data obtained provide a weight distribution.
Fortunately, as shown in Table 2-3, equations
have been derived relating the weight distribu¬
tion data to statistical diameters. The prime on
the dj,eo and o-geo signify a weight distribution
rather than a numbers distribution. The geomet¬
ric standard deviations for a weight and num¬
bers distribution are practically identical.
To illustrate the use of these equations, the
data from a sample of magnesium hydroxide
given in Table 2-6 are plotted in Figure 2-4 with
the cumulative percentage less than stated size
on the probability grid and the size on the loga¬
PERCENT LESS THAN STATED SIZE
rithmic grid. The geometric mean diameter cor¬
FIG. 2-4. Logarithm-probability plot of data in Table 2-6. responding to the 50% value on the cumulative

MILLING • 25
Table 2-3. Definitions of Diameters of Nonuniform Particulate Systems in Terms of the Parameter of
Size Distribution Curves by Number and by Weight

Diameter Numbers Distribution Weight Distribution

Geometric mean, log dgeo = log dgeo' - 6.9078 log2 a%J

2(n log d)
ge° 2n

Arithmetic mean, log dave = log dgeo + 1.151 log2 trgeo log dave = log dgeo' - 5.756 log2 crgeo'
2nd
ave 2n

Mean surface, log ds = log dgeo + 2.3026 log2 <rseo log dB = log dgeo' - 4.6052 log2 crgeo'

Mean volume, log dv = log dgeo + 3.4539 log2 <rgeo log dv = log dgeo' - 3.4539 log2 crgeo'

Mean volume-surface log dvs = log dgeo + 5.7565 log2 crgeo lOg dvs = lOg dgeo' -1.1513 log2 CTgeo'

2nd3
vs 2nd2

percentage axis is 29.2 microns. The geometric With special lenses and ultraviolet light, the
standard deviation is: lower limit may be extended to 0.1 micron. In
the ultramicroscope, the resolution is improved
, _ 84.13% size by use of a darkfield illumination. The size range
<Tgeo ~ 50% size of the ultramicroscope is from 0.01 to 0.2 mi¬
(9) cron.
40 _ The diameters of the particles on the slide are
29.2 137^m measured by means of a calibrated filar microm¬
eter eyepiece. The hairline of the eyepiece is
Knowing the value of the geometric mean diam¬ moved by the micrometer to one edge of a parti¬
eter and the geometric standard deviation, the cle, and the reading on the micrometer is re¬
Hatch and Choate equations may be used to cal¬ corded. The hairline is then moved to the oppo¬
culate statistical diameters given in Figure 2-4. site edge of the particle being measured, and the
For example, the mean surface diameter of the micrometer is read. The difference between the
sample of magnesium hydroxide is: two readings is the diameter of the particle. All
of the particles are measured along an arbitrary
log ds = loggeo - 4.606 logVgeo fixed line.
log d, = log 29.2 - (4.606 x 0.0187) Graticules or eyepieces with grids of circles
(10) and squares are used to compare the cross-sec¬
= 1.3793 tional area of each particle in the microscopic
ds = 23.9 /am field with one of the numbered patterns. The
number of particles that best fits one of the
numbered circles is recorded. The field is
changed, and the procedure is repeated with
Microscopy another numbered circle. This procedure is re¬
Microscopy is the most direct method for size peated until the entire size range is covered.
distribution measurement. Its lower limit of ap¬ In both techniques, the magnification is de¬
plication is determined by the resolving power of termined by the use of a calibrated stage mi¬
the lens. A particle cannot be resolved if its size crometer, as the magnification is not equal to
is close to the wave length of the light source. the product of the nominal magnification of the
For white light, an ordinary microscope is used objective and the eyepiece.
to measure particles from 0.4 to 150 microns. The particulate field to be counted should be

26 • The Theory and Practice of Industrial Pharmacy

random. The total number of fields to be Table 2-4. Designations and Dimensions ofU.S.
counted depends on the number of particles per Standard and Tyler Standard Sieves
field. In principle, the number of particles meas¬
ured should be great enough so that the results U.S. Standard Tyler Standard
do not change on measuring a larger number.
Micron Mesh Micron Mesh
The British Standard on microscopic counting
recommends at least 625 particles. If the particle 5660 3 Vi 5613 3 V2
size distribution is wide, it may be necessary to 4760 4 4699 4
count more particles. If the particle size distribu¬ 4000 5 3965 5
tion is narrow, as few as 200 particles may be 3360 6 3327 6
sufficient. 2830 7 2794 7
There is considerable variation among opera¬ 2380 8 2362 8
tors using the microscopy technique. Photomi¬ 2000 10 1651 10
crographs, projections, and automatic scanners 1680 12 1397 12
have been used to lessen operator fatigue. 1410 14 1168 14
The diameters measured by a microscope and 1190 16 991 16
1000 18 883 20
defined in Table 2-1 are number parameters,
840 20 701 24
since microscopy involves a counting procedure.
710 25 589 28
590 30 495 32
Sieving 500 35 417 35
420 40 351 42
Sieving is the most widely used method for 350 45 295 48
measuring particle size distribution because it is 297 50 246 60
inexpensive, simple, and rapid with little varia¬ 250 60 208 65
tion between operators. Although the lower limit 210 70 175 80
of application is generally considered to be 50 177 80 147 100
microns, micromesh sieves are available for ex¬ 149 100 124 115
tending the lower limit to 10 microns. 125 120 104 150
A sieve consists of a pan with a bottom of wire 105 140 88 170
cloth with square openings. In the United 88 170 74 200
States, two standards of sieves are used. In the 74 200
Tyler Standard Scale, the ratio of the width of 62 230
openings in successive sieves is V2. The Tyler 53 270
Standard Scale is based on the size of opening 44 325
(0.0029") in a wire cloth having 200 openings 37 400
per linear inch, i.e., 200-mesh. The United
States Standard Scale proposed by the National
Bureau of Standards in general uses the ratio to the sample retained is arbitrary, but by con¬
V2, but it is based on an opening of 1 mm (18- vention, the size of the particles retained is
mesh). The two standard sieves are compared in taken as the arithmetic or geometric mean of the
Table 2-4. two sieves (a powder passing a 30-mesh and re¬
The procedure involves the mechanical shak¬ tained on a 45-mesh sieve is assigned an arith¬
ing of a sample through a series of successively metic mean diameter of (590 + 350)/2 or 470
smaller sieves, and the weighing of the portion microns).
of the sample retained on each sieve. The type of If the weight distribution obtained by sieving
motion influences sieving: vibratory motion is follows a logarithm-probability distribution, the
most efficient, followed successively by side-tap Hatch-Choate equations given in Table 2-3 per¬
motion, bottom-tap motion, rotary motion with mit conversion of the weight to a number distri¬
tap, and rotary motion. Time is an important fac¬ bution.
tor in sieving. The load or thickness of powder
per unit area of sieve influences the time of siev¬
ing; for a given set of sieves, the time required to Sedimentation
sieve a given material is roughly proportional to Sedimentation methods may be used over a
the load placed on the sieve. Therefore, in size size range from 1 to 200 microns to obtain a size-
analysis by means of sieves, the type of motion, weight distribution curve and to permit calcula¬
time of sieving, and load should be standardized. tion of the particle size. The sedimentation
A typical size-weight distribution obtained by method is based on the dependence of the rate of
sieving is shown in Table 2-5. The size assigned sedimentation of the particles on their size as

MILLING • 27
 Table 2-5. Weight-Size Distribution of Granular Sodium Bromide as Measured by U.S. Standard
Sieves

Arithmetic Mean
Sieve Number Size of Weight Retained % Retained Weight
(Passed/Retained) Openings on Smaller Sieve on Smaller Sieve Size

(1) (2) (3) (4) (2) x (4)

30/45 470 pm 57.3 g 13.0 6100

45/60 300 181.0 41.2 12,380
60/80 213 110.0 25.0 5320
80/100 163 49.7 11.3 1840
100/140 127 20.0 4.5 572
140/200 90 22.0 5.0 450
400.0 100.0 26,662

26,662
dave = ioo = 267

expressed by Stokes’ equation:

SUCTION TO FILL

I 18rj x PIPET TO
d Stokes (11) I 0*M L. MARK
^ (P ~ Po)g t

where dStokes is the effective or Stokes’ diameter, TWO-WAY STOPCOCK

■q is the viscosity of the dispersion fluid, x/t is the
rate of sedimentation or distance of fall x in time
t, g is the gravitational constant, and p and p0 are
the densities of the particle and the medium,
respectively. Stokes’ equation is applicable to
free spheres that are falling at a constant rate. If
the concentration of the suspension does not
exceed 2%, there is no significant interaction
between the particles, and they settle inde¬
pendent of one another.
The pipet method (Andreasen) is the simplest
means of incremental particle size analysis. A
1% suspension of the powder in a suitable liquid
medium is placed in the pipet (Fig. 2-5). At
given intervals of time, samples are withdrawn
from a specified depth without disturbing the
suspension, and they are dried so that the resi¬
due may be weighed. By means of Stokes’ equa¬
tion, the particle diameter corresponding to each
interval of time is calculated, with x being the
height of the liquid above the lower end of the
pipet at time t when each sample is withdrawn.
As the sizes of the particles are not uniform, the
particles settle at different rates. The size-distri¬
bution and concentration of the particles vary
along the length of the suspension as sedimen¬ FIG. 2-5. At measured time intervals, a 10-ml sample is
tation occurs. The larger particles settle at a withdrawn by aspiration at a depth that can be read from
faster rate and fall below the pipet tip sooner the scale etched on the Andreasen Pipet.

28 • The Theory and Practice of Industrial Pharmacy

Table 2-6.Weight-Size Distribution of Magnesium Hydroxide as Determined by Andreasen Pipet
Using Water as Medium

Particle Diameter
Weight of Calculated by Means
Time Height Residue Percentage of of Stokes’ Equation
(sec) (cm) (9) Initial Suspension Om)

120 20.0 0.0912 92.4 44.5

240 19.6 0.0591 59.9 30.5
360 19.2 0.0321 32.5 25.1
420 18.8 0.0134 13.9 22.9
480 18.4 0.0107 10.9 20.7
600 18.0 0.0089 9.0 18.5
720 17.2 0.0069 7.0 16.8

than the smaller particles; thus, each sample sorption, electrical conductivity, light and x-ray
drawn has a lower concentration and contains scattering, permeametry, and particle trajectory.
particles of smaller diameters than the previous More extensive treatment of particle size meas¬
sample. urement is given by various authors.16-19
From the weight of the dried sample, the per¬
centage by weight of the initial suspension is
calculated for particles having sizes smaller than Theory of Comminution
the size calculated by Stokes’ equation for that At present, there is meager basic understand¬
time. The weight of each sample residue is ing of the mechanism and quantitative aspects
called the weight undersize, and the sum of the of milling.20'25 The mechanical behavior of sol¬
successive weights is known as the cumulative ids, which under stress are strained and de¬
weight undersize. Typical data obtained by use of formed, is shown in the stress-strain curve in
the Andreasen pipet are given in Table 2-6. In Figure 2-6. The initial linear portion of the curve
Figure 2-4, the plot of logarithm of size against is defined by Hooke’s law (stress is proportional
the percentage less than the stated size pro¬ to strain), and Young’s modulus (slope of linear
duces a straight line and allows the evaluation of portion) expresses the stiffness or softness in
geometric mean diameter and standard devia¬ dynes per square centimeter. The stress-strain
tion. The geometric mean diameter correspond¬ curve becomes nonlinear at the yield point,
ing to the graphic 50% size is 29.2 microns. The which is a measure of the resistance to perma¬
standard deviation, which is evaluated as the nent deformation. With still greater stress, the
ratio of the 84.13% size to the 50% size (40/ region of irreversible plastic deformation is
29.2), is 1.37. With these two values, the weight
distribution obtained by sedimentation may be
converted into number distribution by use of the
Hatch-Choate equations. For example, if one
wishes to calculate the mean surface diameter,
the appropriate equation selected from Table 2-3
is:

log ds = log dgeo - 4.6052 log2 <r'geo

= log 29.2 - (4.6052 log2 1.37) (12)
ds = antilog 1.3793 = 23.9 /am

Other Methods
The major methods for particle size distribu¬
tion measurements, i.e., microscopy, sedimenta¬
tion, and sieving, have been discussed to illus¬
trate the principles involved. Other useful Strain
methods of measuring particle size involve ad¬ FIG. 2-6. Stress-strain diagram for a solid.

milling • 29
reached. The area under the curve represents the points of application of the force are shifted.
the energy of fracture and is an approximate The energy for the new surfaces is partially sup¬
measure of the impact strength of the material. plied by the release of stress energy. Crystalline
In all milling processes, it is a random matter materials fracture along crystal cleavage planes;
if and. when a given particle will be fractured. If noncrystalline materials fracture at random. If
a single particle is subjected to a sudden impact an ideal crystal were pressed with an increasing
and is fractured, it yields a few relatively large force, the force would be distributed uniformly
particles and a number of fine particles, with rel¬ throughout its structure until the crystal disinte¬
atively few particles of intermediate size. If the grated into its individual units. A real crystal
energy of the impact is increased, the larger par¬ fractures under much less force into a few rela¬
ticles are of a smaller size and more numerous, tively large particles and several fine particles,
and although the number of fine particles is in¬ with relatively few particles of intermediate size.
creased appreciably, their size is not greatly Crystals of pure substances have internal weak¬
changed. It seems that the size of the finer parti¬ nesses due to missing atoms or ions in their lat¬
cles is related to the internal structure of the tice structures and to flaws arising from me¬
material, and the size of the larger particles is chanical or thermal stress.20
more closely related to the process by which A flaw in a particle is any structural weakness
comminution is accomplished. that may develop into a crack under strain. It
Size reduction begins with the opening of any has been proposed that any force of milling pro¬
small cracks that were initially present. Thus, duces a small flaw in the particle. The useful
larger particles with numerous cracks fracture work in milling is proportional to the length of
more readily than smaller particles with fewer new cracks produced. A particle absorbs strain
cracks. In general, fine grinding requires more energy and is deformed under shear or compres¬
energy, not only because of the increased new sion uiitil the energy exceeds the weakest flaw
surface, but also because more energy is needed and causes fracture or cracking of the particle.
to initiate cracks. The strain energy required for fracture is propor¬
For any particle, there is a minimum energy tional to the length of the crack formed, since
that will fracture it; however,- conditions are so the additional energy required to extend the
haphazard that many particles receive impacts crack to fracture is supplied by the flow of the
that are not sufficient to fracture them and are surrounding residual strain energy to the crack.
eventually fractured by some excessively force¬ The Griffith theory of cracks and flaws as¬
ful blow. As a result, the most efficient mills uti¬ sumes that all solids contain flaws and micro¬
lize less than 1% of the energy input to fracture scopic cracks, which increase the applied force
particles and create new surfaces.26 The rest of according to the crack length and focus the
the energy is dissipated in (1) elastic deforma¬ stress at the atomic bond of the crack apex.27,28
tion of unfractured particles, (2) transport of The Griffith theory may be expressed as:29,30
material within the milling chamber, (3) friction
between particles, (4) friction between particles iYe
and mill, (5) heat, (6) vibration and noise, and T = a/— (13)
v c
(7) inefficiency of transmission and motor.
If the force of impact does not exceed the elas¬
tic limit (region of Hooke’s law), the material is where T is tensile stress, Y is Young's modulus, e
reversibly deformed or stressed. When the force is the surface energy of the wall of the crack, and
is removed, the particle returns to its original c is the critical crack depth required for fracture.
condition, and the mechanical energy of stress A linear relationship between the square of ten¬
in the deformed particle appears as heat. For sile strength of minerals and the critical height
polymeric materials, hysteresis is frequent. for drop weight impact suggests that the square
When a force is released and applied to a poly¬ of tensile strength is a useful criterion of impact
meric material, an elastic loop, or hysteresis, fracture.31
occurs in the stress-strain cycle; the area of the Thermodynamic treatment of the milling
loop represents the dissipation of stress energy process has been attempted, but there is con¬
(usually heat). fusion about the meaning of surface tension,
A force that exceeds the elastic limit fractures surface stress, and surface energy of solids. In
the particle. Usually, the surfaces of particles addition, there is some question as to whether a
are irregular, so that the force is initially taken reversible path may be devised for a milling
on the high portion of the surface, with the re¬ process. Thermodynamics have shown that the
sult that high stresses and temperatures may be work to fracture a particle depends on surface
set up locally in the material. As fracture occurs, energy,32 and that the yield stress depends on

30 • The Theory and Practice of Industrial Pharmacy

the rate of strain and temperature of the fluid produce a change in size, dD, of unit mass of
filling the particle pore.33 Fracture is predicted material, and where C and n are constants.
to be more efficient at an elevated tempera¬ In 1885, Kick suggested that the energy re¬
ture.34 quirement, E, for size reduction is directly re¬
The weakest flaw in a particle determines its lated to the reduction ratio (Di/D2), where D,
fracture strength; it controls the number of par¬ and D2 are the diameters of the feed material
ticles produced by fracture. Particles with the and discharged product, respectively. Thus, if a
weakest flaws fracture most easily and produce certain horsepower is required to mill a given
the largest particles; however, they are not nec¬ weight of material from 1000 to 500 microns,
essarily easier to mill to a given size, as they may the same energy would be required to reduce the
require several more stages of fracture than par¬ size from 500 to 250 microns. Kick’s theory may
ticles of the same size whose weakest flaw is be expressed as:
stronger.
The immediate objective of milling is to form
E = C In (16)
cracks that spread through the deformed parti¬ D2
cles at the expense of strain energy and produce
fracture. The useful work is directly proportional The constant C may be regarded as a reciprocal
to the new surface area. Since the crack length efficiency coefficient. In the engineering litera¬
is proportional to the square root of the new sur¬ ture, C = Kkfc, where fc is the crushing strength
face area produced, the useful work is inversely of the material and Kk is known as Kick’s con¬
proportional to the square root of the product stant. If n = 1, the general differential equation
diameter minus the feed diameter.35 The energy reduces to Kick’s equation. Kick’s proposal was
E' expended in producing new surface is: developed on a stress-strain diagram for cubes
under compression and represents the energy
required to effect elastic deformation before
E' (14)
fracture occurs.38 Kick’s equation assumes that
the material has flaws distributed throughout its
where Dj is the diameter of the material fed to internal structure that are independent of parti¬
the mill, D2 is the diameter of the product dis¬ cle volume. Experimental and theoretic values
charged from the mill, and E is the energy input. apply best to coarse milling.39
The efficiency of the milling process is influ¬ In 1867, von Rittinger proposed that the en¬
enced by the nature of the force as well as by its ergy required for size reduction is directly pro¬
magnitude. The rate of application of force af¬ portional to the increase in surface as expressed
fects comminution, as there is a time lag be¬ by the following relationship:40
tween the attainment of maximum force and
fracture. Often, materials respond as brittle ma¬ E = k,(S2 - SO (17)
terials to fast impact and as plastic materials to a
slow force. The greater the rate at which the where k] includes the relationship between the
force is applied, the less effectively the energy is particle surface and diameter, and S2 and S2 are
utilized, and the higher is the proportion of fine the specific surface before and after milling, re¬
material produced. As the rate of milling is in¬ spectively. In terms of particle diameters:
creased, more energy is expended. To produce a
new surface in milliseconds may require three to
four times as much energy as the production of
the same new surface area in seconds.36
E-C’(£~5r) (18)
In the engineering literature, C’ = Krfc, where
Kr is known as Rittinger’s constant.
Energy for Comminution Equation (18) applies precisely only under the
The energy required to reduce the size of par¬ conditions that all energy is transferred into sur¬
ticles is inversely proportional to the size raised face energy, and that the energy of comminu¬
to some power. This may be expressed mathe¬ tion required per unit of surface is independent
matically as:37 of particle size. Rittinger’s equation is less appli¬
cable if appreciable deformation occurs. It is
dE C most applicable to brittle materials undergoing
(15)
dD Dn fine milling, in which there is minimal deforma¬
tion and a rapid production of new surfaces with
where dE is the amount of energy required to concomitant surface-energy absorption.39

MILLING • 31
 If n = 2 (because the surface is proportional to tial equation yields Bond’s equation:
the square of the diameter), the solution of the
general differential equation yields Rittinger’s
E =
equation.39 Rittinger’s theory ignores particle
deformation before fracture although work is the (24)
product of force and distance.
= 2C'
In 1952, Bond suggested that the energy re¬
quired for size reduction is inversely propor¬
tional to the square root of the diameter of the Equation (22) in the form of equation (24) is:
product.41,42 This may be expressed mathemati¬
cally. 1
Wt = 10 W) (25)
Vd;
Wt a 1/VD^ (19)
where 10 W, equals 2C\
where Wt is the total work of comminution in If fracture characteristics of a material were
kilowatt hours per short ton of milled material, constant over all size ranges, and if the efficien¬
and D2 is the size in microns through which cies of all mills were equal, then the work index
80% by weight of the milled product will pass. would be a true constant, and the energy re¬
The total work, Wt, if defined as the kilowatt quired to mill from any feed size to any product
hours per ton required to subdivide from an infi¬ size could be readily calculated from one test es¬
nitely large particle size to a certain product of tablishing the work index. In fact, the work
size Da, is proportional to 1/VD), since i/Vrhis index is not a true constant, but a parameter that
infinitely small when D is infinitely large. How¬ changes with shifts in particle size distribution.
ever, W is proportional to (l/VDa) - (1/VD^) Best use of a work index occurs when conditions
when W is the work in kilowatt hours per ton of under which the work index is determined ap¬
material to mill from microns to D2 microns. proximate those of the final application.
Thus: The work index may be determined by actual
milling tests. For example, if in 6 min, ten tons
Wt _W_ of limestone with an initial size of 1600 microns
(20) were passed through an impact mill to produce a
1/VW2 ~ (l/VD^) - (1/VEh)
size of 400 microns, the power consumption as
measured by a watt-hour meter was 30 ldlowatt-
If Wt is called a work index, W1( and is re¬ hours. The work index for limestone in this mill
quired to be the work input to subdivide from an may be calculated by use of equation (21):
infinitely large size to a product size of 100 mi¬
crons, then by substitution in equation (20): 30 VT600 \ (400
(26)
10 { V1600 - V400'^ 100
Wi = W
vpj D,
(21)
100 Wi = 12 kilowatt-hours per ton
vd;-vd;
The dry grind work index is usually 1.3 times
If the work index is known, the total input of
the wet grind value. For a certain material by
energy necessary to mill with the same effi¬
laboratory ball mill tests, it was determined that
ciency from any feed size to any product size
the work index is 12.07 kilowatt-hours per short
measured in microns may be found from the fol¬
ton. The energy expended in reducing the size
lowing:
of this material from 1190 to 149 microns by ball
mill is calculated as:

I7 <22>
100
E = 12.07 (27)
which may be rearranged to: 149 / 1190
V 149
= 6.40 kilowatt-hours per short ton

which is equivalent to 8.53 horsepower-hours

If n = 1.5, the solution of the general differen- per short ton.

32 • The Theory and Practice of Industrial Pharmacy

Distribution and Limit of where y is cumulative weight percentage
smaller than size D, k is a size modulus for a
Comminution given distribution, and a is a distribution modu¬
As discussed, the variation in size is com¬ lus. The size relationship of many fractured
monly expressed as a size-frequency distribu¬ homogeneous materials is described by the
tion curve. As milling progresses, the particle Schuhmann equation. When the cumulative
size-frequency distribution has a narrower range weight percentage less than a stated size is plot¬
and a finer mean size. As shown in Figure 2-7, a ted on logarithm-logarithm paper against size, -a
material with initially a monomodal size distri¬ straight line is obtained with a slope of a, and it
bution develops a bimodal size distribution as intersects the 100% ordinate line at the thep-
milling occurs. The primary component gradu¬ retic maximum-sized particle equal to k.4S For
ally decreases in weight, and the secondary com¬ impact milhng, a—» 1; for abrasion milling,
ponent increases in weight. This reduction of a-» 0.
weight is accompanied by a decrease in modal As an example, consider sodium chloride sub¬
size of the primary component and is caused by divided at three impact energies to produce the
preferential fracture of larger particles. The size distributions plotted in Figure 2-8 as the
modal size of the secondary component remains cumulative weight percentage finer (y) than the
essentially constant. Continued milling tends to size D, corresponding to the sieve on which it is
eliminate the primary component. The process retained. The experimental size distributions
is repeated if the material is then transferred to a are well described by the Schuhmann equation.
second mill for finer size reduction.43 As the par¬ The extrapolated straight line for the energy of
ticle-size distribution changes, milling charac¬ 18.1 kg cm/cm3 intersects the 100% ordinate
teristics (work index) change because the abun¬ line at 1.9 mm, and the slope is 1.17.
dance or shortage of flaws varies at different When plotted on logarithm-logarithm paper
sizes. for impact fracture of sodium chloride, as shown
A minimum of two specifications is necessary in Figure 2-9, equation (35) yields a straight
to characterize a specific size distribution (85% line, where a and C are constants and the slope
through a 60-mesh screen and 5% through a is (1 - n). If several milling experiments are
325-mesh screen). In the simplest case, one conducted in which the energy inputs and the
number establishes the limits of particle sizes size distributions are measured, then n, the ex¬
involved, and another number determines the ponent in the fundamental energy-size reduc-
weight relationships in the various size ranges.
Schuhmann44 experimentally verified the em¬
piric equation:

y = 100 (D-/k)a (28)

S ize Size, mm
FIG. 2-7. Diagrammatic representation of the effect of FIG. 2-8. Particle size-frequency distributions resulting
progressive milling on particle size-frequency distribution. from, various energies of impact on sodium chloride.

milling • 33
 given size differs. For these reasons, the experi¬
mental proof of the relationship between energy
E and size reduction is difficult.
Verification of an energy-size reduction rela¬
E tionship is also difficult because of the definition
o of energy actually causing fracture and other
Di forms of energy in the milling process. As frac¬
JC
ture depends on strain energy of elastic defor¬
mation, the energy seems to be related to size
cn reduction. Although strain energy absorbed by
v_
a> slow compression is easily measured, strain en¬
c ergy absorbed by impact is difficult to measure
UJ
because of the complex milling process involv¬
H—
o ing translatory motion, vibratory motion, plastic
o deformation, and sound.
Q.
Another difficulty in establishing energy-size
E
reduction relationships arises from the fact that
each equation implies that n is a constant inde¬
FIG. 2-9. Energy-size reduction relationship for impact of pendent of the mechanism and quantity of size
sodium chloride.
reduction. Probably n is a variable that depends
tion equations, may be determined. The only on the material and manner by which it is frac¬
limitation is that for both, size distributions and tured. The following derivation shows a general
shapes of the size distribution curves are the method by which n and C may be calculated
using a single distribution plot for any milling
same and are displaced only laterally with a
test.
change in energy input.
As shown in Figure 2-9, if a logarithm-loga¬ If equations (15) and (28) are combined, the
rithm plot is made of the energy inputs against energy E required to reduce an element of
the size modulus, a straight line with a slope of weight of material dy from size Dm to size D is:
(1 - n) is produced. For sodium chloride subdi¬
vided by an impact mill, the slope is 1.76.
E = f f° (-C dD]/D]n)dy (30)
Frequently, milled powders have a logarithm- JD„ JD,
probability distribution as expressed by the
equation: As size distribution is described by the Schuh-
In D-2
mann equation:
Ay =
V277 In r-V
In D, 100a Tya-l
dy = ka dD (31)
expj- in -j-/ (V2 In a) ' j d(ln D) (29)
Thus:
where Ay is the weight fraction of particles be¬
tween diameters Dj and D2, Dge0 is the geomet¬ E=£ (~C dD,/Djn) Da_1 dD
ric mean diameter, and cr is the geometric stan¬
dard deviation.46 The manipulations of these (32)
equations are tedious, and the calculations are
simplified by use of logarithm-probability paper, Ca
as previously discussed. E =
(n - l)ka L a - n + 1 aDn
It is experimentally impossible to fracture par¬
ticles of one uniform size to particles of a smaller n a-n+1 D
and still uniform size, as required by equations (33)
a-n+1 aD„
(15), (16), and (18). Accurate description of the
weight relationships of sizes in a given material
For materials following the Schuhmann distri¬
by a single number is also impossible, because
bution, D0^ 0. Thus:
for a given size modulus, there is theoretically
an infinite number of size distributions to which
the modulus may refer. Also, the energy re¬ Ca
E =■ (34)
quired to produce each size distribution from a La - n + 1 aD„

34 • The Theory and Practice of Industrial Pharmacy

If Dm is large compared to k, then: of roughly 6 x 107 cm2/cm3. Milling limit refers
to the size distribution to which a milling opera¬
Ca ki-n
tion tends as a consequence of mill characteris¬
E = (35) tics, material properties, and operating condi¬
(n - l)(a - n + 1)
tions when given sufficient time.
Equation (35) is real only if n is greater than I The milling process is affected by time. When
and less than (a + 1). From experimentally de¬ the resident time in a mill is brief, the material is
termined size distributions, a has been found to subjected to a relatively constant fracture-pro¬
be as great as 1.5, but is usually approximately ducing environment. Changes in milling condi¬
0.8. The values of n range from 1 to 2'.5. This tions that are insignificant for short milling peri¬
range was empirically chosen for equations (16), ods may be controlling factors in prolonged
(18), and (20). For hard, brittle materials, (a — milling. In prolonged milling, the milling envi¬
o°otv + 1) approaches zero, and its value cannot ronment may not be constant.
be accurately found. Consequently, the constant As the particle becomes smaller with pro¬
C cannot be determined accurately; however, for longed milling, the probability that an individual
any specific milling conditions, the following particle will be involved in a fracture dimin¬
term is constant: ishes. As size reduction proceeds, the mean
stress required to cause fracture increases
Ca through the depletion of cracks, while the mag¬
A = (36) nitude of available local stress decreases. Be¬
(n - l)(a - n + 1)
cause of diminishing local stress and increasing
aggregation, increases in energy expenditures
The general energy-size reduction equation—
are useless, and size reduction reaches some
equation (15)—may then be expressed as:
practical milling limit.47
An empiric equation was suggested by Har¬
E = Ak(1-n) (37)
ris48 to express a limiting specific surface, Sm:
where A is a mill constant that can be deter¬
S = Sm [1 — exp (-KEn)] (39)
mined easily for any size reduction test when
the exponent n has been determined as dis¬
where E is energy input, and K is a constant that
cussed. In the example of sodium chloride sub¬
depends on milling conditions.
divided by impact, n is 1.76, and the mill con¬
As shown in Figure 2-10, after 5 hours of ball
stant may be calculated by the following:
milling, the size reduction of sulfadimethoxine
18.1 = A i.9(1-176) reaches a limiting value.49 The data fits the
(38) equation:
A = 29.5
= ki exp (-k2S) (40)
In pharmacy, relatively small amounts of ma¬
terials are milled, and the extent of size reduc¬
tion is determined by the enhancement of clini¬
cal efficacy and product characteristics, and by
the facilitation of production, rather than by
energy expenditure. The proposed theories of
comminution are suitable for specific applica¬
tions and are to be used in a qualitative manner.
The only reliable means for determining the size
reduction provided by a given mill is experimen¬
tal testing with the actual material.
According to the general differential equation
of size reduction and its special cases, a material
given sufficient time may be milled to unlimited
fineness; however, in these equations, the size
and energy input are inadequately defined. If
the ultimate size reduction by mechanical
means were attributed to the unit of the crystal Milling Tim e , hr
lattice, the limit of comminution would be ap¬ FIG. 2-10. Increase of surface area of sulfadimethoxine
proximately 1CT3 microns (or a specific surface with passage of ball-milling time.

milling • 35
where kj and k2 are parameters dependent on The total mass of material in a size smaller
physical properties of the material and coher¬ than the largest size may increase, although the
ency, respectively. amount of original material of that size must
The type of mill and its operation influence always decrease. As particles formed from frac¬
the milling limit. Excessive clearance between ture of larger particles may enter the size of in¬
the impacting surfaces Emits size reduction. In terest faster than the original material is frac¬
wet milling, the fineness decreases with in¬ tured to a smaller size, the total mass of the size
creased viscosity, which depends on the disper¬ of interest is increased. A set of first-order differ¬
sion medium, the size and concentration of par¬ ential equations was proposed and verified over
ticles, and the shear rate. In tumbling mills, as. a 30-min milling period by Sedlatschek and
the particles become smaller and more numer¬ Bass.54 The weight percentage of particles, Mb
ous, friction diminishes, and the material be¬ having a size range between and D, has a
haves as a semisolid. Larger particles can arch rate change, dM,/dt, given by:
and protect smaller ones from impact. Fine par¬
ticles may coat the grinding medium and cush¬
= AjjMi - t (44)
ion larger particles from impact. at k=i+i

where the rate of change, dMj/dt, is:

Milling Rate
The mass and size of particles and the time in
AklMk (45)
the mill affect the milling rate. It has been re¬ at k=i
ported that batch milling of britde materials in i
small mills follows a first-order law.50,51 The In general, AM = 2 Aik
original particles are fractured to produce first- k=i-1
generation particles, which are then fractured to n
produce second-generation particles, which are where 2 Mk = 100 %.
also fractured, and so on. As this is analogous to k=l
the process of radioactive decay, milling rate is
expressed in terms of a decay constant, A, which For example, a material is milled into four ar¬
is a function of particle size and varies with the bitrary groups, i = 1, 2, 3, and 4, with size limits
size of the material introduced into the mill,52 0.0 to 0.1, 0.1 to 0.2, 0.2 to 0.3, and 0.3 to
and the size of the grinding medium in a ball 0.4 mm, respectively. For these limits, equa¬
mill.53 tions (35) and (36) have the following forms.
If impact milling follows a first-order rate, the For Group 4, the largest size:
number of particles, N, that survive fracture is
the product of the initial number, N0, and the dM 4 - . / Ar\\

probable fraction surviving fracture at time t: — A44M4 (46)

N — N0 exp ( At) (41) For Group 3:

When the average mass of a particle in a given dm3

— A33M3 A43M4 (47)
size range is constant, then N/N0 is equivalent dt
to M/M0, where M is the mass of particles yet
unfractured and M0 is the initial mass. The mill¬ For Group 2:
ing rate is:
dM2
dM — A22M2 A32M3 A42M4 (48)
= -AM (42) dt
dt
For Group 1:
For brief milling time, the survival probability
is approximately (1 - At), and the most probable
fraction of initial material fractured is 1 — (1 — --^jp = A41M4 - A31M3 - A21M2 (49)
At), or At. The weight of material that has been
comminuted is: For a mass balance:

M0 - M = M0 At (43) A44 — A43 A- A42 A A41 (50)

36 • The Theory and Practice of Industrial Pharmacy

 A33 ~ ^32 + ^31 (51)

4-22 — ^21 (52) TO

CTCLONE

These equations express the rate at which the

largest size, Group 4, decays; the rate at which
Group 3, the next size smaller, decays as modi¬
fied by the contributions from Group 4; the rate
at which Group 2 decays as modified by the con¬
tributions from Groups 4 and 3; and the rate at
which the smallest size of material decays as
modified by the contributions of all groups.
The milling process has also been described CUTTER FLUID-ENERGY
by use of an integrodifferential equation.55 Ma¬
trix algebra methods requiring computer solu¬
tion have been proposed.56

Types of Mills
A mill consists of three basic parts: (1) feed
chute, which delivers the material, (2) grinding
mechanism, usually consisting of a rotor and
stator, and (3) a discharge chute. The principle
of operation depends on direct pressure, impact FIG. 2-11. Diagrammatic representation of four types of
from a sharp blow, attrition, or cutting. In most mills commonly used in processing pharmaceuticals. (See
mills, the grinding effect is a combination of text under “Fluid-Energy Mill” for explanation of labels
these actions. The most commonly used mills in A-D.)
pharmaceutical manufacturing are the rotary
cutter, hammer, roller, and fluid-energy
mill. '0-57-59 Diagrammatic representations of time, as its discharge is impeded by the mass of
these mills are shown in Figure 2-11. General material. This provides a greater reduction of
characteristics of the types of mills are given in particle size, but the capacity of the mill is re¬
Table 2-7. duced, and power consumption is increased.
The manner in which an operator feeds a mill Choke feed is used when a small amount of ma¬
markedly affects the product. If the rate of feed terial is to be milled in one operation.
is relatively slow, the product is discharged read¬ The rate of discharge should be equal to the
ily, and the amount of undersize or fines is mini¬ rate of feed, which is such that the milling parts
mized. If the mill is choke fed at a fast rate, the can operate most effectively. Most mills used in
material is in the milling chamber for a longer pharmaceutical operations are designed so that

Table 2-7. General Characteristics of Various Types of Mills

Type of Mill Action Product Size Used For Not Used For

Cutter cutting 20- to 80-mesh fibrous, crude friable material

animal and
vegetable drugs

Revolving attrition and 20- to 200-mesh fine grinding of soft material

impact abrasive material
Hammer impact 4- to 325-mesh almost all drugs abrasive material
Roller pressure 20- to 200-mesh soft material abrasive material
Attrition attrition 20- to 200-mesh soft and fibrous abrasive material
material
Fluid-energy attrition and 1 to 30 pm moderately hard soft and sticky
impact and friable material
material

MILLING • 37
 the force of gravity is sufficient to give free dis¬ units; the smaller mills are especially useful for
charge generally from the bottom of the mill. For developmental and small-batch milling.
ultrafine grinding, the force of gravity is re¬ A hammer mill can be used for granulation
placed by a fluid carrier. A current of steam, air, and close control of the particle size of powders.
or inert gas removes the product from the attri¬ The size of the product is controlled by selecting
tion, fluid-energy, or high-speed hammer mill. the speed of the hammers and the size and type
The powder is removed from the fluid by cyclone of the screen. Speed is crucial. Below a critical
separators or bag filters. impact speed, the rotor turns so slowly that a
If the milling operation is carried out so that blending action rather than comminution is ob¬
the material is reduced to the desired size by tained. This results in overloading and a rise in
passing it once through the mill, the process is temperature. Microscopic examination of the
known as open-circuit milling. A closed-circuit particles formed when the mill is operating
mill is one in which the discharge from the mill¬ below the critical speed shows them to be sphe¬
ing chamber is passed through a size-separation roidal, indicating not an impact action, but an
device or classifier, and the oversize particles are attrition action, which produces irregularly
returned to the grinding chamber for further shaped particles. At very high speeds, there is
reduction of size. Closed-circuit operation is possibly insufficient time between hammers for
most valuable in reduction to fine and ultrafine the material to fall from the grinding zone. In
size. wet milling of dispersed systems with higher
Hammer Mill. The hammer mill is an im¬ speeds, the swing hammers may lay back with
pact mill using a high-speed rotor (up to an increased clearance; for such systems, fixed
10,000 rpm) to which a number of swinging hammers would be more effective.
hammers are fixed. The material is fed at the top Figure 2-12 shows the influence of speed on
or center, thrown out centrifugally, and ground the particle size-frequency curves for boric acid
by impact of the hammers or against the plates milled at 1000, 2450, and 4600 rpm in a ham¬
around the periphery of the casing. The clear¬ mer mill fitted with a screen having 6.35-mm
ance between the housing and the hammers circular holes.
contributes to size reduction. .The material is The screens that retain the material in the
retained until it is small enough to fall through milling chamber are not woven but perforated.
the screen that forms the lower portion of the The particle size of the discharged material is
casing. Particles fine enough to pass through the
screen are discharged almost as fast as they are
<D
formed. Nl
The hammer mill can be used for almost any
type of size reduction. Its versatility makes it
popular in the pharmaceutical industry, where it
is used to mill dry materials, wet filter-press
cakes, ointments, and slurries. Comminution is
effected by impact at peripheral hammer speeds
of up to 7600 meters per minute, at which speed
most materials behave as if they were britde.
Brittle material is best fractured by impact from
a blunt hammer; fibrous material is best reduced
in size by cutting edges. Some models of ham¬
mer mills have a rotor that may be turned 180
degrees to allow use of either the blunt edge for
fine grinding or the knife edge for cutting or
granulating.
In the preparation of wet granules for com¬
pressed tablets, a hammer mill is operated at
2450 rpm with knife edges, using circular or
square holes of a size determined by what will Size, pm
pass without clogging (1.9 to 2.54 cm). In mill¬
FIG. 2-12. Influence of speed on the size-frequency distri¬
ing the dried granulation, the mill is operated at
bution of boric acid flakes milled by a hammer mill operat¬
1000 or 2450 rpm with knife edges and circular ing with impact edge forward and fitted with a round hole
holes in the screen (0.23 to 0.27 cm). Hammer No. 4 screen (hole diameter: 6.35 mm). Key: •, 1000 rpm;
mills range in size from 5 to 500 horsepower □, 2450 rpm; and O, 4600 rpm.

38 • The Theory and Practice of Industrial Pharmacy

 (a)

z O L0W

7 / //OH!GH

Size, um
FIG. 2-14. Influence of screen size on the size-frequency
distribution of a terra alba granulation milled with a ham¬
mer mill operating at 2450 rpm, and a comparison with
the granulation milled by a vertical hammer mill fitted
with a no. 10 screen. Key: O, hammer mill, 0.84 mm; 9,
hammer mill, 1.65 mm; and □, vertical hammer mill.

herringbone design consists of a series of slotted

FIG. 2-13. In a hammer mill, particle size is influenced holes repeated across the surface of the screen at
by speed (a) and thickness of screen (b). an angle of 45 degrees to the length of the
screen. A herringbone design is preferred for
grinding crystalline material and for continuous
smaller than the screen hole or slot, as the parti¬ operation. A herringbone design with the width
cles exit through the perforation on a path ap¬ of the slot equal to the diameter of a round hole
proximately tangential to the rotor. For a given grinds more coarsely than the round hole. A her¬
screen, a smaller particle size is obtained at a ringbone design should not be used for fibrous
higher speed, as is shown in Figure 2-13. Efforts material, as it is possible for the fibers to align
to strengthen a screen by increasing its thick¬ themselves along the slots and pass through
ness influence particle size. For a given rotor with inadequate size reduction.
speed and screen opening, a thicker screen pro¬ A cross slot at right angles to the path traveled
duces a smaller particle, which is also illustrated by the hammer is not used in fine grinding be¬
in Figure 2-13. cause it clogs readily; a cross slot is recom¬
Figure 2-14 shows the influence of screen size mended for milling slurries. The jump-gap
on the size-frequency distribution of a tablet screen is a series of bars so arranged that the
granulation that was passed through a 4-mesh particle approaches a ramp, which deflects the
screen after wet granulation with acacia, a blend particle into the chamber away from the opening
of terra alba, and two active ingredients, to¬ of the screen. The jump-gap screen is for abra¬
gether constituting 4.2% of the formulation. The sive and clogging materials.
dried granulation was milled at 2450 rpm Hammer mills are compact with a high capac¬
through a Type A plate having 1.65-mm open¬ ity. Size reduction of 20 to 40 microns may be
ings, and a Type B screen having 0.84-mm achieved; however, a hammer mill must be op¬
openings. The granulation was also milled in a erated with internal or external classification to
hammer mill with a vertical rotor operating at produce ultrafine particles. Because inertial
medium speed and fitted with a no. 10 screen. A forces vary with mass as the inverse cube of the
comparison of the particle size-frequency distri¬ diameter, small particles with a constant veloc¬
butions is shown in Figure 2-14. ity impact with much less kinetic energy than
A circular hole design is the strongest screen larger ones, and the probability that particles
and the most difficult to keep from clogging. It is less than a certain size will fracture decreases
recommended for the grinding of fibers. The rapidly. In addition, small particles pass through

MILLING • 39
the screen almost as fast as they are formed. where r is the radius of the ball mill. For exam¬
Thus, a hammer mill tends to yield a relatively ple, a ball mill 1.2 m in diameter is run at
narrow size distribution. Hammer mills are sim¬ 48 rpm and is found to be milling unsatisfacto¬
ple to install and operate. The speed and screen rily. The critical angular velocity of the mill is:
can be rapidly changed. They are easy to clean
and may be operated as a closed system to re¬ f980“
(54)
duce dust and explosion hazards. "c V o.6
Ball Mill. The ball mill consists of a horizon¬
tally rotating hollow vessel of cylindric shape o)c = 4.04 radian per second
with the length slightly greater than its diame¬
ter. The mill is partially filled with balls of steel The actual angular velocity of the mill is
or pebbles, which act as the grinding medium. If 2 7t (48/60) or 5.02 radians per second; there¬
pebbles are used, it is known as a pebble mill; if fore, the speed of rotation is too high, and the
rods or bars are used, it is known as a rod mill. balls are being carried around in contact with
The rod mill is particularly useful with sticky the walls with little relative movement. If 0.6 <uc
material that would hold the balls together, be¬ is selected, 0.6 x 4.04 or 2.42 radians per sec¬
cause the greater weight of the rods causes them ond would be the angular velocity, which is
to pull apart. The tube mill is a modified ball mill equivalent to 60 x 2.4/2 tt or 23 rpm. This is
in which the length if about four times that of half of the speed of the unsatisfactory operation.
the diameter and in which the balls are some¬ At and above the critical speed, no significant
what smaller than in a ball mill. Because the size reduction occurs. The critical speed nc is
material remains in the longer tube mill for a given by the equation:
greater length of time, the tube mill grinds more
finely than the ball mill. The ball mill may be 76.6
nc (55)
modified to a conical shape and tapered at the Vd
discharge end. If balls of different size are used
in a conical ball mill, they segregate according to where D is the diameter of the mill in feet. A
size and provide progressively finer grinding as larger mill reaches its critical speed at a slower
the material flows axially through the mill. Re¬ revolution rate than a smaller mill (a 228.6-cm
cently, small-scale vibration ball mills, which ball mill and a 11.4-cm jar mill may have critical
produce particles of a few microns, have been speeds of 28 and 125 rpm, respectively).
introduced.60 These oscillate 1500 to 2500 cy¬ Ball mills are operated from 60 to 85% of the
cles per minute through an amplitude of approx¬ critical speed. Over this range, the output in¬
imately 4 mm. creases with the speed; however, the lower
Most ball mills utilized in pharmacy are batch- speeds are for finer grinding. An empiric rule for
operated; however, there are available continu¬ the optimum speed of a ball mill is:
ous ball mills, which are fed through a hollow
trunnion at one end, with the product dis¬ n = 57 - 40 log D (56)
charged through a similar trunnion at the oppo¬
site end. The outlet is covered with a coarse where n is the speed in revolutions per minute
screen to prevent the loss of the balls. and D is the inside diameter of the mill in feet.
In a ball mill rotating at a slow speed, the balls In actual practice, the calculated speed should
roll and cascade over one another, providing an be used initially in the process and modified as
attrition action. As the speed is increased, the experience is acquired.
balls are carried up the sides of the mill and fall For a given feed, smaller balls give a slower
freely onto the material with an impact action, but finer grinding. The smaller balls provide
which is responsible for most size reduction. smaller voids than the larger balls; conse¬
Ball milling is a combination of impact and attri¬ quently, the void through which material can
tion. If the speed is increased sufficiendy, the flow without being struck by a ball is less, and
balls are held against the mill casing by centrifu¬ the number of impacts per unit weight of mate¬
gal force and revolve with the mill. The critical rial is greater. It has been suggested that the op¬
speed of a ball mill is the speed at which the timum diameter of a ball is approximately pro¬
balls just begin to centrifuge with the mill. Thus, portional to the square root of the size of the
at the critical speed, the centrifugal force is feed:59
equal to the weight of the ball, and the critical
angular velocity, wc, may be expressed: Dbau2 = kD (57)

coc = (53) where Dbaii and D are the diameters of the ball

40 • The Theory and. Practice of Industrial Pharmacy

 and the feed particles, respectively. If the diame¬ In addition to being used for either wet or dry
ters are expressed in inches, k may be consid¬ milling, the ball mill has' the advantage of being
ered to be a grindability constant varying from used for batch or continuous operation. In a
55 for hard to 35 for soft materials. Small balls batch operation, unstable or explosive materials
facilitate the production of fine material, but may be sealed with an inert atmosphere and sat¬
they are ineffective in reducing large-sized feed. isfactorily ground. Ball mills may be sterilized
The charge of balls can be expressed in terms and sealed for sterile milling in the production of
of percentage of volume of the mill (a bulk vol¬ ophthalmic and parenteral products. The instal¬
ume of balls filling one half of a mill is a 50% ball lation, operation, and labor costs involved in ball
charge). To operate effectively, a ball charge milling are low. Finally, the ball mill is unsur¬
from 30 to 50% of the volume of the mill is re¬ passed for fine grinding of hard, abrasive mate¬
quired. rials.
The amount of material to be milled in a ball Fluid-Energy Mill. In the fluid-energy mill
mill may be expressed as a material-to-void ratio or micronizer the material is suspended and
(ratio of the volume of material to that of the conveyed at high velocity by air or steam, which
void in the ball charge). The efficiency of a ball is passed through nozzles at 100 to 150 pounds
mill is increased as the amount of material is per square inch (psi). The violent turbulence of
increased until the void space in the bulk vol¬ the air and steam reduces the particle size
ume of ball charge is filled; then, the efficiency chiefly by interparticular attrition. Air is usually
of milling is decreased by further addition of used because most pharmaceuticals have a low
material. melting point or are thermolabile. As the com¬
Increasing the total weight of balls of a given pressed air expands at the orifice, the cooling
size increases the fineness of the powder. The effect counteracts the heat generated by milling.
weight of the ball charge can be increased by As shown in Figure 2-11, the material is fed
increasing the number of balls or by using a ball near the bottom of the mill through a venturi
composed of a material with a higher density. injector (A). As the compressed air passes
Since optimum milling conditions are usually through the nozzles (B), the material is thrown
obtained when the bulk volume of the balls is outward against the wall of the grinding cham¬
equal to 50% of the volume of the mill, variation ber (C) and other particles. The air moves at
in weight of the balls is normally effected by the high speed in an elliptical path carrying with it
use of materials of different densities. Thus, the fine particles that pass out of the discharge
steel balls grind faster than porcelain balls, as outlet (D) into a cyclone separator and a bag col¬
they are three times more dense. Stainless steel lector. The large particles are carried by centrif¬
balls are also preferred in the production of oph¬ ugal force to the periphery, where they are fur¬
thalmic and parenteral products, as there is less ther exposed to the attrition action. The design
attrition and less subsequent contamination of the fluid-energy mill provides internal classi¬
with particulate matter. fication, which permits the finer and lighter par¬
In dry milling, the moisture should be less ticles to be discharged and the heavier oversized
than 2%. With batch processing, dry ball milling particles, under the effect of centrifugal force, to
produces a very fine particle size. With wet mill¬ be retained until reduced to a small size.
ing, a ball mill produces 200-mesh particles Fluid-energy mills reduce the particle to 1 to
from slurries containing 30 to 60% solids. From 20 microns. The feed should be premilled to
the viewpoint of power consumption, wet grind¬ approximately a 20- to 100-mesh size to facili¬
ing is more efficient than dry grinding. A slower tate milling. A 2-inch laboratory model using 20
speed is used in wet milling than in dry milling to 25 cubic feet per minute of air at 100 psi mills
to prevent the mass from being carried around 5 to 10 grams per minute. In selecting fluid-en¬
with the mill. A high viscosity restricts the mo¬ ergy mills for production, the cost of a fluid-en¬
tion of the grinding medium, and the impact is ergy source and dust collection equipment must
reduced. With 1.27-cm steel balls, a viscosity be considered in addition to the cost of the mill.
from 1000 to 2400 centipoises (cp) is satisfac¬ Cutting Mill. Cutting mills are used for
tory for wet milling. tough, fibrous materials and provide a succes¬
Wetting agents may increase the efficiency of sive cutting or shearing action rather than attri¬
milling and the physical stability of the product tion or impact.
by nullifying electrostatic forces produced dur¬ The rotary knife cutter has a horizontal rotor
ing comminution. For those products containing with two to 12 knives spaced uniformly on its
wetting agents, the addition of the wetting agent periphery turning from 200 to 900 rpm and a
at the milling stage may aid size reduction and cylindric casing having several stationary
reduce aggregation. knives. The bottom of the casing holds a screen

MILLING • 41
that controls the size of the material discharged tor. At a point between the rotor and stator, the
from the milling zone. The feed size should be motion imparted by the rotor ceases, and hy¬
less than 1 inch thick and should not exceed the draulic shearing force exceeds the particle-parti¬
length of the cutting knife. For sizes less than cle attractive forces holding the individual parti¬
20-mesh, a pneumatic product-collecting sys¬ cles in an aggregate. The particle size of milled
tem is required. Under the best operating condi¬ particles may be smaller than, the clearance, be¬
tions, the size limit of a rotary cutter is 80-mesh. cause the high shear is the dispersing force. In
A disc mill consists of two vertical discs; each emulsification, a clearance of 75 microns may
may rotate in opposite directions (double-runner produce a dispersion with an average particle
disc mill), or only one may rotate (single-runner size of 3 microns. The milled liquid is dis¬
disc mill), with an adjustable clearance. The charged through an outlet in the periphery of
disc may be provided with cutting faces, teeth, the housing and may be recycled.
or convolutions. The material is premilled to Rotors and stators may be smooth-surfaced or
approximately 40-mesh size and is usually sus¬ rough-surfaced. With a smooth-surfaced rotor
pended in a stream of air or liquid when fed to and stator, there is a thin, uniform film of mate¬
the mill. rial between them, and it is subjected to the
Roller Mill. Roller mills consist of two to five maximum amount of shear. Rough-surfaced
smooth rollers operating at different speeds; mills add intense eddy currents, turbulence, and
thus, size reduction is effected by a combination impaction of the particles to the shearing action.
of compression and shearing action. Rough-surfaced mills are useful with fibrous
Colloid Mill. A colloid mill consists of a materials because fibers tend to interlock and
high-speed rotor (3000 to 20,000 rpm) and sta¬ clog smooth-faced mills.
tor with conical milling surfaces between which A colloid mill tends to incorporate air into a
is an adjustable clearance ranging from 0.002 to suspension. Aeration may be minimized by use
0.03 inches, as indicated by the schematic dia¬ of a vertical rotor, which seals the point at which
gram in Figure 2-15. The rotor speed is 3000 to the rotor shaft enters the housing, and keeps the
20,000 rpm. The material to be ground should rotor and stator in contact with the liquid. The
be premilled as finely as possible to prevent wasted energy of milling, which appears as heat,
damage to the colloid mill. may raise the temperature of a liquid by as much
In pharmacy, the colloid mill is used to proc¬ as 40°. The passage of cooling water through the
ess suspensions and emulsions; it is not used to mill jacket may reduce the temperature by as
process dry materials. The premilled solids are much as 20°. Sanitary design mills, which may
mixed with the liquid vehicle before being intro¬ be sterilized, are available.
duced into the colloid mill. Interfacial tension
causes part of the material to adhere to, and to
rotate with, the rotor. Centrifugal force throws Factors Influencing Milling
part of the material across the rotor onto the sta- The properties of a solid determine its ability
to resist size reduction and influence the choice
of equipment used for milling. The specifica¬
tions of the product also influence the choice of
a mill. The grindability of coal is expressed in
terms of numbers of revolutions of a standard¬
ized ball mill required to yield a product of which
80% passes a 200-mesh screen. Although a sim¬
ilar expression could be applied to pharmaceuti¬
cal materials, no quantitative scale has been
adopted to express hardness. It is perhaps as
useful to speak of hard, intermediate, and soft
materials. Hard materials (iodine, pumice) are
those that are abrasive and cause rapid wear of
mill parts immediately involved in size reduc¬
tion. \
The physical nature of the material deter¬
mines the process of comminution. Fibrous ma¬
terials (glycyrrhiza, rauwolfia) cannot be
crushed by pressure or impact; they must be cut.
FIG. 2-15. Colloid mill with a rotor and stator with a Friable materials (dried filter cake, sucrose) tend
narrow clearance that may be adjusted. to fracture along well-defined planes and may be

42 • The Theory and Practice of Industrial Pharmacy

milled by an attrition, impact, or pressure proc¬ Specifically, crystals of phenobarbital (initial
ess. The presence of more than 5% water hin¬ size of 310 microns) milled to 22.7 microns grew
ders comminution and often produces a sticky to 38.9 microns after 4 weeks at 60°C; however,
mass upon milling. This effect is more pro¬ crystals milled to 31.5 microns showed little
nounced with fine materials than with larger growth on storage.
particles. At concentrations of water greater
than 50%, the mass becomes a slurry, or fluid
suspension. The process then is a wet milling Selection of a Mill
process, which often aids in size reduction. An In general, the materials used in pharmaceu¬
increase in moisture can decrease the rate of ticals may be reduced to a particle size less than
milling to a specified product size. Glauber’s salt 40-mesh by means of ball, roller, hammer, and
and other drugs possessing water of crystalliza¬ fluid-energy mills. The types of mill used to re¬
tion liberate the water at low temperatures, duce some typical pharmaceutical materials are
causing clogging of the mill. Hygroscopic mate¬ shown in Table 2-8. The choice of a mill is based
rials (calcium chloride) rapidly sorb moisture to on (1) product specifications (size range, particle
the extent that the wet mass sticks and clogs the size distribution, shape, moisture content, phys¬
mill. ical and chemical properties of the material);
The heat during milling softens and melts (2) capacity of the mill and production rate re¬
materials with a low melting point. Synthetic quirements; (3) versatility of operation (wet and
gums, waxes, and resins become soft and plas¬ dry milling, rapid change of speed and screen,
tic. Heat-sensitive drugs may be degraded or safety features); (4) dust control (loss of costly
even charred. Pigments (ocher and sienna) may drugs, health hazards, contamination of plant);
change their shade of color if the milling tem¬ (5) sanitation (ease of cleaning, sterilization);
perature is excessive. Unstable compounds and (6) auxiliary equipment (cooling system, dust
almost any finely powdered material may ignite collectors, forced feeding, stage reduction);
and explode if the temperature is high. (7) batch or continuous operation; and (8) eco¬
Other product specifications influence the nomical factors (cost, power consumption, space
choice of a mill. The shape of the milled parti¬ occupied, labor cost).
cles may be important. An impact mill produces After consideration of these factors (listed in
sharp, irregular particles, which may not flow Table 2-9) for a specific milling problem, it is
readily. When specifications demand a milled suggested that the equipment manufacturer be
product that will flow freely, it would be better to consulted and its pilot laboratory be utilized, as
use an attrition mill, which produces free-flow¬ there exists a wide variety of mills differing in
ing spheroidal particles. details of design and modifications. The indus¬
Milling may alter crystalline structure and trial pharmacist should evaluate the pilot study
cause chemical changes in some materials. Wet personally to observe the temperature of the in¬
milling may be useful in producing a suspension let and outlet air, the temperature of the milled
that contains a metastable form causing crystal material, and the size reduction performance at
growth and caking. For example, when cortisone different mill speeds. A size-frequency analysis
acetate crystals are allowed to equilibrate with should be made on samples from each condition
an aqueous vehicle, subsequent wet milling pro¬ of operation. Samples should be recycled to find
vides a satisfactory suspension.61 Starch, amy- if there is buildup in the milling chamber. The
lose, and amylopectin may be broken down by a pilot evaluation is important because laboratory
vibratory mill to a wide molecular weight procedures of size reduction do not duplicate
range.62 Powdered povidone breaks down into milling conditions in production mills.
lower molecular weight polymers during ball
milling.63 Pure C12- and C16-fatty acids may be
decarboxylated and converted to the hydrocar¬ Techniques of Milling
bon containing one less carbon atom by ball mill¬ In addition to the standard adjustments of the
ing with wet sand.64 Milling well-dried micro- milling process (i.e:, speed, screen size, design
crystalline cellulose from 1 to 25 hours of rotor, load), special techniques of milling may
decreases its crystallinity.65 Excessive shear of a be useful.
colloid mill may damage polymeric suspending Special Atmosphere. Hygroscopic material
agents so that there is a loss of viscosity.66 A de¬ can be milled in a closed system supplied with
crease in particle size of crystals in a hammer dehumidified air. Theimolabile, easily oxidiza-
mill was reported to increase the rate of crystal ble, and combustible materials should be milled
growth during storage, owing to alterations in in a closed system with an inert atmosphere of
crystal lattice and the formation of active sites.67 carbon dioxide or nitrogen. Almost any fine dust

MILLING *43
 Table 2-8. Index for Milling to Less Than 40-mesh Size

Materials Mill

Acetanilid ball, roller, hammer, fluid-energy

Alum ball, roller, hammer, fluid-energy
Antibiotics ball, hammer, colloid, fluid-energy
Ascorbic acid ball, roller, hammer, fluid-energy
Barium sulfate hammer, colloid, fluid-energy
Benzoic acid hammer, fluid-energy
Boric acid ball, roller, hammer, fluid-energy
Caffeine roller, hammer
Calcium stearate hammer, colloid, fluid-energy
Carboxymethylcellulose ball, hammer, colloid, fluid-energy
Citric acid hammer, fluid-energy
Color, dry ball, hammer, fluid-energy
Color, wet hammer, colloid, fluid-energy
Filter-cake fluid energy ball, roller, hammer, colloid
Gelatin hammer
Iodine hammer, fluid-energy
Methylcellulose ball, hammer
Sodium acid phosphate hammer, fluid-energy
Sodium benzoate hammer, fluid-energy
Sodium metaphosphate hammer, fluid-energy
Sodium salicylate hammer, fluid-energy
Stearates hammer, fluid-energy
Sugar hammer, fluid-energy
Urea ball, hammer, fluid-energy
Vitamins ball, hammer, fluid-energy
Wax hammer, colloid, fluid-energy

(dextrin, starch, sulfur) is a potential explosive beeswax may be reduced in a hammer mill to
mixture under certain conditions and especially 100-mesh size with the use of dry ice.
if static electrical charges result from the proc¬ Pretreatment. For a mill to operate satisfac¬
essing. All electrical switches should be explo¬ torily, the feed should be of the proper size and
sion-proof, and the mill should be grounded. enter at a fairly uniform rate. If granules or in¬
Temperature Control. As only a small per¬ termediate-sized particles are desired with a
centage of the energy of milling is used to form minimum of fines, presizing is vital. Pretreat¬
new surface, the bulk of the energy is converted ment of fibrous materials with high-pressure
to heat. This heat may raise the temperature of rolls or cutters facilitates comminution.
the material many degrees, and unless the heat Subsequent Treatment. If extreme control
is removed, the solid will melt, decompose, or of size is required, it may be necessary to recycle
explode. To prevent these changes in the-mate¬ the larger particles, either by simply screening
rial and to avoid stalling of the mill, the milling the discharge and returning the oversize parti¬
chamber should be cooled by means of a cooling cles for a second milling, or by using air-separa¬
jacket or a heat exchanger. Stainless steel equip¬ tion equipment in a closed circuit to return the
ment (Type 304 with no. 4 finish) is routinely oversized particles automatically to the milling
used in preparing pharmaceuticals because it chamber. With materials to be reduced to mi¬
minimizes contamination and reaction with the cron size, an integrated air-separation, conveyor,
drugs. With the use of refrigerants, the mill and collection element usually are required,.
must be .constructed of stainless steel since cast Dual Process. The milling process may
iron becomes brittle and may shatter at low tem¬ serve simultaneously as a mixing process if the
peratures. feed materials are heterogeneous. If hot gas is
Waxy and low-melting-point materials are circulated through a mill, the mill can be used to
chilled before milling. If this is not sufficient to comminute and dry moist solids simultaneously.
embrittle the material, it may be fed to the mill The fluid-energy mill has been suggested as a
simultaneously with dry ice. Stearic acid and means of simultaneous size reduction and dis-

44 • The Theory and Practice of Industrial Pharmacy

Table 2-9. Factors in Selection of a Mill arylalkyl sulfonic acid, calcium stearate, oleic
acid, and triethanolamine salts have been use¬
Material
ful. These dispersing agents are especially use¬
Physical property, hard, soft, fibrous, elastic, hygroscopic,
ful in the revolving mill if coating of the balls
solvated
occurs; the addition of less than 0.1% of surface-
Size
active agent may increase the production rate of
Moisture content
Melting point
a ball mill 20 to 40%.
Flammability Wet grinding is beneficial in further reducing
Thermolability the size, but flocculation restricts the lower limit
Subsequent processing to approximately 10 microns. Wet grinding elim¬
inates dust hazards and is usually done in low-
Operation
speed mills, which consume less power. Some
Size specification of milled material
useful dispersing agents in wet grinding are the
Ease of sanitization
silicates and phosphates.
Ease of sterilization
Ease of adjustments during operation
Contamination of milled material
Versatility References
Capacity 1. Kraml, M., Dubue, J., and Gaudry, R.: Antibiot.
Batch or continuous Chemother., 12:232, 1962.
Wet or dry 2. Ober, S. S., Vincent, H. C., Simon, D. E., and Freder¬
Rate of introduction of material ick, K. J.: J. Am. Pharm. Assoc., Sci. Ed., 47:667,
Space occupied 1958.
Labor cost 3. Parrott, E. L.: J. Pharm. Sci., 64:878, 1975.
4. MacDonald, L. H., and Himelick, R. E.: J. Am.
Auxiliary Equipment Pharm. Assoc., Sci. Ed., 37:368, 1948.
Dust collector 5. Kanig, J.: J. Pharm. Sci., 52:513, 1963.
Mechanical introduction of material 6. Fincher, J. H.: J. Pharm. Sci., 57:1825, 1968.
Temperature control: jacket, refrigerated air, liquid nitro¬ 7. Tingstad, J. E.: J. Pharm. Sci., 53:955, 1964.
gen, dry ice 8. Garrett, E. R., Schumann, E. L., and Grostic, M. F.:
J. Am. Pharm. Assoc., Sci. Ed., 48:684, 1959.
Inert atmosphere: carbon dioxide, nitrogen
9. Sumner, E. D., Thompson, H. O., Poole, W. K., and
Air sweep Grizzle, J. E.: J. Pharm. Sci., 55:1441, 1966.
Safety 10. Gold, G., Duvall, R. N., Palermo, B. T., and Slater,
Expiosivity J. G.: J. Pharm. Sci., 57:668, 1968.
11. Danish. F. Q., and Parrott, E. L.: J. Pharm. Sci.,
irritativity
60:548, 1971.
Toxicity 12. Cooper, J., and Rees. J. E.: J. Pharm. Sci., 61:1511,
Safety features incorporated into mill 1972.
13. Parrott, E. L.: Drug and Cosm. Ind., 115:42, 1974.
From Parrott, E. L.: J. Pharm. Sci., 63:826, 1974. Reproduced
14. Danish, F. Q., and Parrott, E. L.: J. Pharm. Sci.,
with permission of the copyright owner, the American Pharma¬
60:752, 1971,
ceutical Association.
15. Hatch, T.: J. Franklin Inst., 215:27, 1933.
16. Orr, C., Jr., and DallavaBe, J. M.: Fine Particle Meas¬
urement. Macmillan Company, New York, 1959.
persion. It has been suggested that the particles 17. Irani, R. R , and Callis, C. F.: Particle Size Measure¬
ment, Interpretation and Application. John Wiley &
in a fxuid-energy mill can be coated with almost
Sons, New York, 1963.
a monomolecular film by premixing with as little 18. Dallavalle, J. M.: Micromeritics. 2nd Ed. Pitman Pub¬
as 0.25% of the coating agent. lishing Corporation, New York. 1948.
Wet and Dry Milling. The choice of dry or 19. Edmundson, I. C.: Advances in Pharmaceutical Sci¬
wet milling depends on the use of the product ences. Vol. 2. Academic Press. New York, 1967.
and its subsequent processing. If the product 20. Piret, E. L.: Chem. Eng. Prog., 49:56, 1953.
21. Heywood. H.: J. 1. C. Chem Eng. Soc., 6:26, 1951.
undergoes physical or chemical change in water,
22. Austin. L. G., and Klimpel, R. R.: Ind. Eng. Chem..
dry milling is recommended. In dry milling, the 56:18, 1964.
limit of fineness is reached in the region of 100 23. Bond, F. C.: Min. Eng., 4:484, 1952.
microns when the material cakes on the milling 24. Riley, R. V.: Chem. Proc. Eng., 46.T89, 1965.
chamber. The addition of a small amount of 25. Parrott, E. L.: J. Pharm. Sci., 63:813, 1974.
grinding aid may facilitate size reduction. The 26. Kwong, J. N. S., Adams, J. T., Jr., Johnson, J. F., and
Piret, E. L.: Chem. Eng. Prog., 45:508, 1949.
use of grinding aids in pharmacy is limited by
27. Griffith, A. A.: Phil. Trans. Roy. Soc. London, Ser. A,
the physiologic and toxicologic restrictions on 221:163, 1921.
medicinal products. In certain cases, the addi¬ 28. Schoenert, K.: Trans. A1ME, 251:21, 1972.
tion of ammonium salts, aluminum stearate, 29. Orowan, E.: Dissolution in Metals. American Insti-

MILLING • 45
 tute of Mineral and Petroleum Engineers, New York, 48. Harris, C. C.: Trans. AIME, 238:17, 1967.
1954, Chapter 3. 49. Kaneniwa, N., Ikekawa, A., and Hashimoto, D.:
30. Orowan, E.: Z. Kristallogr., A89.-327, 1934. Chem. Pharm. Bull., 21:676, 1973.
31. Jomoto, E., and Majima, H.: Can. Inst. Min. Met. 50. Kirk-Othmer: Encyclopedia of Chemical Technology.
Bull , 65:68, 1972. Vol. 18. 2nd Ed. John Wiley and Sons, New York,
32. Zeleny, R. A., and Piret, E. L.: Ind. Eng. Chem. Proc¬ 1969, p. 336.
ess, ties. Develop., 1:337, 1962. 51. Klimpel, R. R., and Austin, L. G.: Ind. Eng. Chem.
33. Boozer, G. D., Miller, K. H., and Serdenqecti, S.: Pro¬ Fundam., 9:230, 1970.
ceedings of the 5th Symposium on Rock Mechanics. 52. Roberts, E. J.: Trans. AIME, 187:1267, 1950.
Pergamon, New York, 1963, p 579. 53. Bowdish, F. J.: AIME, SME Preprint No. 61B2, 1961.
34. Dijingheuzian, L. E.: Can. Inst. Min. Met. Bull., 54. Sedlatschek, K., and Bass, L.: Powder Met. Bull.,
45:658, 1952. 6.148, 1953.
35. Bond, F. C.: Chem. Eng., 59:242, 1952. 55. Reid, K. J.: Chem. Eng. Sci., 20:953, 1965.
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und seine Anwendung. Arthur Felix, Leipsig, Ger¬ 59. Perry, J. H.: Chemical Engineers’ Handbook. 4th Ed.
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199:313, 1954. 1971.
40. von Rittinger, R. P.: Lehrbuch der Aufber- 61. Macke, T. J., U.S. Pat. 2,671,759. 1954.
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1970.

46 • The Theory and Practice of Industrial Pharmacy

Drying
ALBERT S. RANKELL, HERBERT A. LIEBERMAN,
and ROBERT F. SCHIFFMANN

There is hardly a pharmaceutical plant engaged weight, thereby lowering the cost of transporta¬
in the manufacture of tablets or capsules that tion and storage. Other uses include aiding in
does not contain dryers. Unfortunately, the op¬ the preservation of animal and vegetable drugs
eration of drying is so taken for granted that ef¬ by minimizing mold and bacterial growth in
forts for achieving increased efficiency in the moisture-laden material and facilitating commi¬
production of tablets do not include a study of nution by making the dried substance far more
drying. This chapter introduces the industrial friable than the original, water-containing drug.
pharmacist to the theory and fundamental con¬ Dried products often are more stable than
cepts of drying. moist ones, as is the case in such diverse sub¬
Definition. For the purpose of this discus¬ stances as effervescent salts, aspirin, hygro¬
sion, drying is defined as the removal of a liquid scopic powders, ascorbic acid, and penicillin.
from a material by the application of heat, and is The drying reduces the chemical reactivity of
accomplished by the transfer of a liquid from a the remaining water, which is expressed as a
surface into an unsaturated vapor phase. This reduction in the water activity of the product.
definition applies to the removal of a small Various processes for the removal of moisture
amount of water from moisture-bearing table are used in the production of these materials.
salt as well as to the recovery of salt from the sea After the moisture is removed, the product is
by evaporation. Drying and evaporation are dis¬ maintained at low water levels by the use of
tinguishable merely by the relative quantities of desiccants and/or low moisture transmission
liquid removed from the solid. packaging materials. The proper application of
There are, however, many nonthermal meth¬ drying techniques and moisture-protective
ods of drying, for example, the expression of a packaging requires a knowledge of the theory of
solid to remove liquid (the squeezing of a wetted drying, with particular reference to the concept
sponge), the extraction of liquid from a solid by of equilibrium moisture content.
use of a solvent, the adsorption of water from a
solvent by the use of desiccants (such as anhy¬
drous calcium chloride), the absorption of mois¬ Psychrometry
ture from gases by passage through a sulfuric A critical factor in drying operations is the
acid column, and the desiccation of moisture vapor-carrying capacity of the air, nitrogen, or
from a solid by placing it in a sealed container other gas stream passing over the drying mate¬
with a moisture-removing material (silica gel in rial. This carrying capacity determines not only
a bottle). the rate of drying but also the extent of drying,
Purpose. Drying is most commonly used in i.e., the lowest moisture content to which a
pharmaceutical manufacturing as a unit process given material can be dried. The determination
in the preparation of granules, which can be dis¬ of the vapor concentration and carrying capacity
pensed in bulk or converted into tablets or cap¬ of the gas is termed psychrometry. The air-
sules. Another application is found in the proc¬ water vapor system is the system most com¬
essing of materials, e.g., the preparation of dried monly employed in pharmaceutical drying oper¬
aluminum hydroxide, the spray drying of lac¬ ations and is therefore included in this
tose, and the preparation of powdered extracts. discussion.
Drying also can be used to reduce bulk and The concentration of water vapor in a gas is

47
called the humidity of the gas. Humidity may be of the wealth of information presented in a small
expressed in various ways, depending on the area. If the different curves in the chart are sep¬
information required. A knowledge of humidity arated and analyzed individually, however, their
is necessary, therefore, to understand the basic utility and ease of use becomes apparent.
principles of drying. The basic curves of the psychrometric chart
Psychrometric Chart. The humidity char¬ are shown in a simplified version in Figure 3-1.
acteristics of air are best shown graphically in a These curves are graphic representations of the
psychrometric or humidity chart. Such charts relationship between the temperature and hu¬
can be found in various handbooks.1,2 The psy¬ midity of the air-water vapor system at constant
chrometric chart has a formidable look because pressure. The temperature is shown in the hori-

DRY BiJLB TEMPERATURE (°F)

FIG. 3-1. Diagram of psychrometric chart showing the relationship of air temperature to humidity.

48 • The Theory and Practice of Industrial Pharmacy

zontal axis; the vertical axis represents absolute point A, is used to dry a wet material, the differ¬
humidity (weight of water vapor per unit weight ence in vapor pressure between the surface
of dry air). The most important curve shown is water and the air causes some of the liquid to
the curve for saturation humidity, curve CDE. evaporate. The latent heat of vaporization of the
Saturation humidity is the absolute humidity at water cools the evaporating surface below the air
which the partial pressure of water vapor in the temperature. The resultant difference in tem¬
air is equal to the vapor pressure of free water at perature causes a transfer of heat from the air to
the same temperature. Under these conditions, the liquid at a rate that increases as the tempera¬
the air is completely saturated with moisture, ture difference becomes larger. Eventually, the
and the humidity does not change when it is in heat transferred becomes equal to the heat of
contact with liquid water at the same tempera¬ vaporization, and the temperature stabilizes.
ture. The temperature that is reached is called the
The saturation humidity curve is actually the wet-bulb temperature. It is defined as the equi¬
boundary of a phase diagram. Any point on the librium temperature reached by an evaporating
curve is uniquely determined by one measure¬ surface when the rate of heat transferred to the
ment, either the temperature or the absolute surface by convection is equal to the rate of heat
humidity. The relationship between the two var¬ lost by evaporation. It is called the wet-bulb tem¬
iables can be shown more clearly by considering perature because it can be measured by means
the dotted line, FCA, which corresponds to the of a thermometer whose bulb is covered by a
absolute humidity, 78 grains water/pound dry wick saturated with water. The actual tempera¬
air. ture of the air as measured by an ordinary ther¬
At point C, the air is saturated with water mometer is called the dry-bulb temperature.
vapor, and its temperature, 60°F, is referred to as The wet-bulb temperature is a function of the
the dew point. The dew point is defined as the temperature and humidity of the air used for the
temperature to which a given mixture of air and evaporation, and thus can be employed as a
water vapor must be cooled to become saturated means of measuring humidity. For this purpose,
(i.e., to hold the maximum amount of moisture a second type of curve is superimposed on the
without condensation taking place). When the temperature-humidity curves of the psychro-
mixture is cooled to temperatures below the dew metric chart. This is the constant wet-bulb tem¬
point, such as 50°F (point F), the water vapor perature line. The constant wet-bulb tempera¬
condenses to produce a two-phase system of sat¬ ture line is AD for air at condition A, and the
urated air (condition C) and droplets of free temperature corresponding to saturation at point
water. D is the wet-bulb temperature, 67°F.
To make the air usable for drying purposes The humidity of the air is determined by
(without changing the absolute humidity), its measuring two temperatures, the wet-bulb and
temperature must be raised. If the temperature the dry-bulb temperatures. The psychrometric
is increased to 81°F (point A), the air is not com¬ chart is entered at the wet-bulb temperature,
pletely saturated and can accept more water and the coordinate is followed vertically upward
vapor. The relative saturation is usually meas¬ until it intersects the saturation or 100% relative
ured in terms of percent relative humidity, the humidity curve. Then the constant wet-bulb
ratio of the partial pressure of water vapor in the temperature line is followed until it intersects
air to the vapor pressure of free water at the the dry-bulb temperature coordinate. Now the
same temperature. The saturation humidity absolute humidity can be read direcdy, and the
curve, CDE, is thus the curve for. 100% relative relative humidity can be found by interpolation
humidity (100% RH). Curves of temperature between the curves for constant relative humid¬
versus absolute humidity at a constant relative ity. For example, let us assume a wet-bulb tem¬
humidity are plotted on the same axes at specific perature of 54°F and a dry-bulb temperature of
intervals of relative humidity. One of these 60°F. The 54°F line is followed until it intersects
curves is shown as curve GK with 50% relative the saturation humidity curve at an absolute
humidity. The relative saturation also can be humidity of 62 grains water/pound dry air.
expressed as percent humidity or percent abso¬ Then, the 54°F wet-bulb temperature line is fol¬
lute humidity, the ratio of the absolute humidity lowed until it intersects the 60°F dry-bulb tem¬
to saturation humidity at the same temperature. perature line at an absolute humidity of 53
For air at condition A, the percent absolute hu¬ grains water/pound dry air. The relative humid¬
midity is represented by the ratio of the absolute ity is found to be 70%.
humidity to the absolute humidity of saturated The constant wet-bulb temperature lines are
air at that temperature (78/161 = 48%). also valuable for determining the temperature of
If air, under the conditions represented by drying surfaces. The wet-bulb temperature is

DRYING • 49
approximately the same as the adiabatic satura¬ thermometer bulbs is induced by a motor-driven
tion temperature, i.e., the temperature that fan, and a reservoir is provided to keep the wet-
would be attained if the air were saturated with bulb wick saturated with water. The thermome¬
water vapor in an adiabatic process (a process in ters used in such an installation may be of al¬
which there is no heat gained or lost to the sur¬ most any type—mercury bulb, bimetallic strip,
roundings). This is the case when drying is car¬ vapor pressure, or electrical.
ried out with the heat supplied by the drying air Another temperature method for determining
only. Thus, for the example given above, a wet humidity is based on the dew point instead of
material being dried with air having a wet-bulb the wet-bulb temperature measurement. The
temperature of 70°F would remain at that tem¬ dew point is determined directly by observing
perature as long as there is a film of free mois¬ the temperature at which moisture begins to
ture at the surface. The assumption that the form on a polished surface in contact with the
wet-bulb temperature is equal to the adiabatic air. The surface is cooled by refrigeration until
saturation temperature does not hold true, how¬ the first fog of moisture appears.
ever, for nonaqueous systems. An entirely different method for measuring
Humidity Measurement. The most accu¬ humidity employs the hygrometer. This instru¬
rate means of measuring humidity is by the ment utilizes certain materials whose properties
gravimetric method. In this procedure, a known change on contact with air of different relative
amount of air is passed over a previously humidities. The mechanical hygrometer uses
weighed moisture-absorbing chemical such as such materials as hair, wood fiber, or plastics,
phosphorus pentoxide, and the resultant in¬ which expand or shrink with changes in humid¬
crease in weight of the chemical is measured. ity. The moisture-sensitive element is con¬
Although accurate, the gravimetric method is nected to a pointer in such a fashion that a
cumbersome and slow. For rapid determination change in length causes the pointer to move
of humidity, temperature-measurement meth¬ across a dial calibrated in humidity units. Elec¬
ods are most often used. tric hygrometers measure the change in electri¬
As indicated in the discussion of the psychro- cal resistance of moisture-absorbing materials
metric chart, humidity can be determined by with humidity.
taking two temperature measurements. The
simplest instrument for this purpose is the sling
psychrometer (Fig. 3-2). It consists of two bulb Theory of Drying
thermometers set in a frame that is attached to a Drying involves both heat and mass transfer
swivel handle. One thermometer, the dry-bulb operations. Heat must be transferred to the ma¬
thermometer, has a bare bulb; the bulb of the terial to be dried in order to supply the latent
other thermometer, the wet-bulb thermometer, is heat required for vaporization of the moisture.
covered by a wick saturated with water. The psy¬ Mass transfer is involved in the diffusion of
chrometer is whirled through the air, and the water through the material to the evaporating
two thermometer readings are taken at succes¬ surface, in the subsequent evaporation of the
sive intervals until these temperatures no longer water from the surface, and in diffusion of the
change. In psychrometers used as permanent resultant vapor into the passing air stream.
installations, the movement of air across the The drying process can be understood more
easily if attention is focused on the film of liquid
at the surface of the material being dried. The
rate of evaporation of this film is related to the
rate of heat transfer by the equation:

dW/d# = q/A (1)

where dW/d0 is the rate of evaporation pounds

of water per hour, q is the overall rate of heat
transfer (BTU per hour), and A is the latent heat
of vaporization of water (BTU per pound).
The rate of diffusion of moisture into the air
stream is expressed by rate equations similar to
those for heat transfer. The driving force is a
humidity differential, whereas for heat transfer,
it is a temperature differential. The rate equa¬
tion is as follows.

50 • The Theory and Practice of Industrial Pharmacy

 dW/de = k'A(Hs - Hg) (2) shown in equation (3). Dehumidifying the inlet
air, thus increasing the humidity differential,
where dW/d0 is the rate of diffusion expressed (Hs - Hg), is still another means of speeding up
as pounds of water per hour; k' is the coefficient the rate of drying.
of mass transfer [pounds of water/(hour) (square Rapid drying may also be accomplished
foot) (absolute humidity difference)]; A is the through the application of a microwave or die¬
area of the evaporating surface in square feet; Hs lectric field. In this case, heat is generated inter¬
is the absolute humidity at the evaporating sur¬ nally by the interaction of the applied electro¬
face (pounds of water per pound of dry air); and magnetic field with the solvent. Mass transfer
Hg is the absolute humidity in the passing air results from an internal pressure gradient estab¬
stream (pounds of water per pound of dry air). lished by the internal heat generation, while the
The coefficient of mass transfer, k', is not a mass concentration remains relatively uniform.
constant, but varies with the velocity of the air The drying rate, then, primarily depends on the
stream passing over the evaporating surface. strength of the field applied to the material.
The relationship is in the form: The utility of equation (5) in actual practice
can be demonstrated by the following analysis:
What is the effect of heating the air in a dryer to
k' = cGn (3) 150°F if the outside air is 81°F with 50% relative
humidity? From the psychrometric chart (Fig.
where c is a proportionality constant, G is the 3-1), it can be seen that for ambient air at this
rate of flow of air [pounds of dry air/(hour) condition (point A), the absolute humidity is 78
(square foot)], and n is a fractional exponent, grains water/pound dry air. Following the wet-
usually about 0.8.2 bulb temperature line from this point to the sat¬
After an initial period of adjustment, the rate uration curve (point D) yields an absolute hu¬
of evaporation is equal to the rate of diffusion of midity of 99 grains water/pound dry air.
vapor, and the rate of heat transfer [equation For the ambient air, the humidity differential
(1)] can be equated with the rate of mass trans¬ (Hs - Hg) is (99 - 78), which is equal to 21
fer [equation (2)], or: grains (0.003 pounds) water/pound dry air.
When this air is heated to 150°F, the absolute
humidity remains the same, but the relative
dW/dB = q/A = k'A(Hs - Hg). y4)
humidity is now reduced to 7%, and following
the new wet-bulb temperature line (85°F) to the
If the overall rate of heat transfer, q, is ex¬ saturation curve yields a saturation humidity of
pressed as the sum of the rates of heat transfer 185 grains water/pound dry air. The humidity
by convection, radiation, and conduction, equa¬ gradient is now 185 - 78, which is equal to 107
tion (4) is expanded to the form: grains (0.0153 pounds) water/pound dry air, an
increase of fivefold, indicating an increase in
dW/de = (qc + qr + qO/A drying rate of 500% produced by a 69°F rise in
temperature. In actual practice, the increase in
= k'A(Hs - Hg) (5) drying rate would be even higher because in¬
creasing the inlet air temperature would in¬
where qc, qr, and qk are the rates of heat transfer crease k' as well as the humidity gradient. It
by convection, radiation, and conduction, re¬ should be noted that this increase in the drying
spectively. rate does not produce a serious increase in the
The rate of drying may be accelerated by in¬ temperature of the material being dried, because
creasing any of the individual terms in equation the wet-bulb temperature of the 150°F air is only
(5). The rate of convection heat transfer, qc, can 85°F.
be increased by increasing the air flow rate and The foregoing discussion holds true as long as
by raising the inlet air temperature. The rate of there is a film of moisture on the surface of the
radiation heat transfer, qr, can be speeded up by material being dried. When the surface becomes
introducing a high-temperature radiating heat partially or completely dry, the heat and mass
source into the drying chamber. The rate of con¬ transfer equations become more complex. In
duction heat transfer, qk, can be stepped up by this case, the rate of drying is controlled by the
reducing the thickness of the material being rate of diffusion of moisture from the interior of
dried and by allowing it to come in contact with the material. This diffusion is greatly influenced
raised-temperature surfaces. Increasing the air by the molecular and capillary structure of the
velocity also speeds up the rate of drying by in¬ solid. The process becomes further complicated
creasing the coefficient of mass transfer, k', as when the drying surface causes a shrinkage of

DRYING • 51
the solid. This phenomenon can cause blocking slightly above 0% and approach infinity. Thus, a
and distortion of the capillary structure and thus small change in LOD value, from 80% to 83%,
interfere with the transfer of internal water to represents an increase in MC of 88%, or a 22%
the surface of the material. A striking example of increase in the amount of water that must be
this is the so-called “case hardening” phenome¬ evaporated per pound of dry product. Thus, per¬
non, in which the surface of the solid becomes cent MC is a far more realistic value than LOD
harder than the interior and less permeable to in the determination of dryer load capacity.
the transmission of interior moisture. Behavior of Solids During Drying. How
would one know if 8 or 12 hours are required to
dry a batch weight of material in a certain dryer?
How can one determine the size of a particular
Drying of Solids type of dryer required for drying a substance
Loss on Drying. The moisture in a solid can from one moisture level to the desired moisture
be expressed on a wet-weight or dry-weight content?
basis. On a wet-weight basis, the water content The rate of drying of a sample can be deter¬
of a material is calculated as a percentage of the mined by suspending the wet material on a scale
weight of the wet solid, whereas on the dry- or balance in a drying cabinet and measuring
weight basis, the water is expressed as a per¬ the weight of the sample as it dries as a function
centage of the weight of the dry solid. of time. In determining an accurate drying rate
In pharmacy, the term loss on drying, com¬ curve for a material in a particular oven, it is
monly referred to as LOD, is an expression of important that the drying conditions approxi¬
moisture content on a wet-weight basis, which is mate the conditions in a full-size dryer as closely
calculated as follows: as possible.
The information obtained from the drying rate
„ , wt. of water in sample determination may be plotted as moisture con¬
% LOD = -7---x 100
total wt. of wet sample tent versus time. The resultant curve is of the
type shown in Figure 3-3. The changes taking
(6) place may be seen more easily if the rate of dry¬
ing is calculated* and plotted against the mois¬
The LOD of a wet solid is often determined by
ture content as shown in Figure 3-3B. Compari¬
the use of a moisture balance, which has a heat
son of the rate of drying curve with the drying
source for rapid heating and a scale calibrated in
time curve is clarified when the moisture con¬
percent LOD. A weighed sample is placed on the
tent is plotted in reverse order, i.e., with the high
balance and allowed to dry until it is at constant
values to the left.
weight. The water lost by evaporation is read di¬
When a wet solid is first placed in a drying
rectly from the percent LOD scale. It is assumed
oven, it begins to absorb heat and increases in
that there are no other volatile materials present.
temperature. At the same time, the moisture
Moisture Content. Another measurement
begins evaporating and thus tends to cool the
of the moisture in a wet solid is that calculated
drying solid. After a period of initial adjustment,
on a dry-weight basis. This value is referred to as
the rates of heating and cooling become equal
moisture content, or MC:
and the temperature of the drying material sta¬
bilizes. As long as the amount of heat transfer by
% MC = in_sample x ]0Q radiation is relatively small, the temperature
wt. of dry sample reached equals the wet-bulb temperature of the
(7) drying air. This period of initial adjustment is
shown as segment AB in Figures 3-3A and 3-3B.
If exactly 5 g of moist solid is brought to a con¬ If the wet solid is initially at a higher tempera¬
stant dry weight of 3 g: ture than the wet-bulb temperature, it cools
down following segment A'B.

MC = x 100 = 66.7%
‘Method of determining rate of drying: The difference
5 — 3 in moisture content between any two measurements di¬
whereas LOD = •—-— x 100 = 40% vided by the time period between measurements repre¬
o
sents the rate of drying for this time period. This value is
plotted against the midpoint of the time period for a dry¬
LOD values can vary in any solid-fluid mix¬ ing rate versus time curve, or against the midpoint of the
ture from slightly above 0% to slightly below moisture content values for a drying rate versus moisture
100%, but the MC values can change from content curve.

52 • The Theory and Practice of Industrial Pharmacy

 gins, and the solid is in equilibrium with its sur¬
roundings, i.e., its temperature and moisture
content remain constant. Continued drying after
this point is a waste of time and energy.
Classification of Solids Based on Drying
Behavior. Solids may be classified into two
major categories on the basis of their drying be¬
havior, namely (1) granular or crystalline type
solids and (2) amorphous solids. The water in
crystalline solids is held in shallow and open
surface pores as well as in interstitial spaces be¬
tween particles that are easily accessible to the
surface. Materials with fibrous, amorphous, or
gelatinous structures are in the second category.
In these solids, the moisture is an integral part
of the molecular structure as well as being phys¬
ically entrapped in fine capillaries and small in¬
terior pores. Typical pharmaceuticals of the first
category are’ calcium sulfate, zinc oxide, and
magnesium oxide. Materials that fall into the
second category are starch, casein, yeast, insu¬
lin, and gelatinous inorganic materials such as
aluminum hydroxide. All of the amorphous solid
materials are more difficult to dry than granular
or crystalline solids.
FIG. 3-3. The periods of drying. The moisture in crystalline solids is lost with
little hindrance by either gravitational or capil¬
lary forces. The constant rate period is the major
At point B, the temperature is stabilized and portion of the drying curve, and this period con¬
remains constant as long as there is a film of tinues until the material has virtually no free
moisture remaining at the surface of the drying water. The falling rate period is much shorter.
solid. Between points B and C, the moisture Materials in this category are usually inorganic
evaporating from the surface is replaced by substances and consequently are not affected by
water diffusing from the interior of the solid at a heat, unless the temperature is high enough to
rate equal to the rate of evaporation. The rate of change any hydrate forms that the chemical
drying is constant, and the time BC is the con¬ may manifest. Equilibrium moisture contents
stant rate period. for these materials axe close to zero.
At point C, the surface water is no longer re¬ Moisture movement is slow in substances in
placed at a rate fast enough to maintain a contin¬ the second category. The liquid diffuses through
uous film. Dry spots begin to appear, and the structural obstacles caused by the molecular
rate of drying begins to fall off. The moisture configuration. The drying curves of these amor¬
content at which this occurs is referred to as the phous materials have short constant-rate peri¬
critical moisture content. Between points C and ods, ending at high critical moisture contents.
D, the number and area of the dry spots con¬ The first falling rate period, the period of water
tinue to grow, and the rate of drying falls stead¬ unsaturation on the surface, is relatively short.
ily. The time CD is referred to as the first falling The second drying rate period is longer, as it
rate period or the period of unsaturated surface depends on the diffusion rate of the water
drying. through the solid. The equilibrium moisture
At point D, the film of surface water is com¬ content is high, because most of the water re¬
pletely evaporated, and the rate of drying de¬ mains intimately associated within the molecu¬
pends on the rate of diffusion of moisture to the lar interstitial spaces of the substance. The
surface of the solid. Point D is referred to as the structure and physiologic activity of many-of
second critical point. Between points D and E these substances are affected by high tempera¬
the rate of drying falls even more rapidly than tures. The drying of these materials often re¬
the first falling rate, and time "DE is called the quires the use of lower temperatures, reduced
second falling rate period. pressure, and increased air flow.
When the drying rate is equal to zero, starting The condition in which a material is in equi¬
at point E, the equilibrium moisture period be¬ librium with its surroundings, neither gaining

DRYING • 53
nor losing moisture, may be expressed in terms water. The most important effects of lowered
of its equilibrium moisture content, equilibrium water activity are increased chemical stability
relative humidity, or water activity. These val¬ and reduced potential for micro-organism
ues may differ gready for various materials, and growth. Water activity can be reduced by the
in addition to affecting drying, they affect physi¬ addition of solutes such as sucrose, glycerin,
cal and chemical stability, susceptibility to mi¬ polyols, and surfactants, as well as by reduced
crobial growth, and packaging requirements. moisture content.
Equilibrium Moisture Content. The mois¬ Measurement Methods. The equilibrium
ture content of a material that is in equilibrium moisture content of a material can be deter¬
with an atmosphere of a given relativity is called mined by exposing samples in a series of closed
the equilibrium moisture content (EMC) of the chambers, such as desiccators, which are par¬
material at this humidity. It is the moisture con¬ tially filled with solutions that can maintain
tent at which the material exerts a water vapor fixed relative humidities in the enclosed air
pressure equal to the vapor pressure of the at¬ spaces. (Lists of such solutions can be found in
mosphere surrounding it; thus, it has no driving any handbook of chemistry.) The exposure is
force for mass transfer. EMC values of various continued until the material comes to constant
materials may differ greatly under the same con¬ weight. This process, which can take more than
ditions, despite the fact that they are in equilib¬ a month for some materials, can be accelerated
rium with their environment. These differences by placing a revolving fan in the chamber or by
are due to the manner in which the water is held passing air currents with proper humidity and
by the material. The water may be held in fine temperature over the material. Curves of the
capillary pores that have no easy access to the EMC versus relative humidity have been deter¬
surface, dissolved solids may reduce the vapor mined for many pharmaceutical substances.4
pressure, or the water may. be molecularly Typical curves are illustrated in Figure 3-4.
bound. Equilibrium relative humidity and water ac¬
Equilibrium Relative Humidity. The rela¬ tivity of a material can be measured by allowing
tive humidity surrounding a material at which the material to equilibrate in a small vapor tight
the material neither gains nor loses moisture is chamber, such as a glass jar, with a hygrometer
called the equilibrium relative humidity (ERH). humidity sensor (mechanical or electric)
At a given temperature, the ERH for a material mounted on the lid. This measurement proce¬
is determined by its moisture content, just as the dure is much more rapid than the EMC tech¬
EMC is determined by the surrounding relative nique; it yields practical near equilibrium values
humidity.
Water Activity. The water activity (a*,) of a
material is the ratio of the water vapor pressure
exerted by the material to the vapor pressure of
pure water at the same temperature. Pure water
is assigned an aw of unity, equivalent to an ERH
of 100%. Thus, the water activity value for a
material is the decimal fraction corresponding to
the ERH divided by 100. For example, an ERH
of 50% corresponds to an of 0.5.
The water activity value has special signifi¬
cance because it is a measure of the relative
chemical activity of the water in the material. It
is related to the thermodynamic chemical poten¬
tial by the equation:

U = U' + RT • ln(aw) (8)

where U is the chemical potential of water in the

material; U' is the chemical potential of pure
water; R is the gas law constant; T is the abso¬
lute temperature; and In is the natural loga¬
rithm.3
The smaller the water activity is, the smaller FIG. 3-4. Equilibrium moisture content curves for tablet-
are the chemical potential of the water and the tiny materials. (Adapted from Scott, M. W., Lieberman,
driving force for chemical reactions involving H. A., and Chow, F. S.: ]. Pharm. Sci., 52: 994, 19,63-3

54 • The Theory and Practice of Industrial Pharmacy

in several hours, and true end points in a day or duced by either gravity or mechanical agitation.
two.5 The resultant separation of the particles and
Knowledge of the EMC versus relative humid¬ continuous exposure of new surfaces allow more
ity curve or ERH versus moisture content for a rapid heat and mass transfer than can occur in
product allows more intelligent selection of the static beds.
drying conditions to be used. .The relative hu¬ 3. Fluidized-bed dryers—systems in which
midity of the air in the dryer must be lower than the solid particles are partially suspended in an
the ERH, corresponding to the desired moisture upward-moving gas stream. The particles are
content of the product being dried. In general, lifted and then fall back in a random manner so
the product should be dried to a moisture con¬ that the resultant mixture of solid and gas acts
tent corresponding to the EMC at the ambient like a boiling liquid. The gas-solid contact is ex¬
conditions of processing and storage. If the cellent and results in better heat and mass trans¬
moisture content differs markedly from this fer than in static and moving beds.
EMC, the product will pick up or lose moisture 4. Pneumatic dryers—systems in which the
unless precautions are taken either to maintain drying particles are entrained and conveyed in a
the product under controlled humidity condi¬ high-velocity gas stream. Pneumatic systems
tions or to use packaging materials with low further improve on fluidized beds, because there
water vapor transmission rates. is no channeling or short-circuiting of the gas
flow path through a bed of particles. Each parti¬
cle is completely surrounded by an envelope of
Classification of Dryers drying gas. The resultant heat and mass transfer
Dryers may he classified in several different are extremely rapid; thus, drying times are
ways depending on the criteria used. Two useful short.
classifications are based on either the method of Because of the great variety of available drying
heat transfer or the method of solids handling. equipment, it is impossible to describe all types
Classification according to the type of heat of dryers. Attention is devoted to those that find
transfer is important in demonstrating gross dif¬ ready application to the production of pharma¬
ferences in dryer design, operation, and energy ceuticals. These dryers are grouped according to
requirements. Classification by the method of their method of solids handling.
solids handling is more suitable when special
attention must be giv'en to the nature of the ma¬
terial to be dried. Static-Bed Systems
When dryers are classified according to their Tray and Truck Dryers. The dryers most
method of solids handling, the major criterion is commonly used in pharmaceutical plant opera¬
the presence or absence of agitation of the mate¬ tions are tray and truck dryers. An example of a
rial to be dried. A dryer that produces excessive tray dryer is illustrated in Figure 3-6. Tray dry¬
agitation is contraindicated when the dried ma¬ ers are sometimes called shelf, cabinet, or com¬
terial is friable and subject to attrition. On the partment dryers. This dryer consists of a cabinet
other hand, if the dried product is intended to be in which the material to be dried is spread on
pulverized, then the drying time can be reduced, tiers of trays. .The number of trays varies with
and the process made more efficient, by the use the size of the dryer. Dryers of laboratory size
of a dryer that produces intense agitation during may contain as few as three trays, whereas
the drying cycle. larger dryers often hold as many as twenty trays.
Classification based on the method of solids A truck dryer is one in -which the trays are
handling is shown schematically in Figure 3-5. loaded on trucks (racks equipped with wheels),
Dryers in this classification scheme are divided which can be rolled into and out of the drying
into the following types: cabinet. In plant operations, the truck dryer is
1. Static-bed dryers—systems in which there preferred over the' tray dryer because it offers
is no relative movement among the solid parti¬ greater convenience in loading and unloading.
cles being dried, although there may be bulk The trucks usually contain one or two tiers of
motion of the entire drying mass. Only a fraction trays, with about 18 or more trays per tier. Each
of the total number of particles is directly ex¬ tray is square or rectangular and about 4 to 8
posed to heat sources. The exposed surface can square feet in area. Trays are usually loaded
be increased by decreasing the thickness of the from 0.5 to 4.0 inches deep with at ieast 1.5
bed and allowing drying air to flow through it. inches clearance between the surface and the
2. Moving-bed dryers—systems in which the bottom of the tray above.
drying particles are partially separated so that Drying in tray or truck dryers is a batch proce¬
they flow over each other. Motion may be in¬ dure, as opposed to continuous drying as per-

DRYING • 55
FIG. 3-5. Classification of dryers, based on methods of solids handling.
 drying air used on pharmaceutical products are
steam or electricity. Units fired with coal, oil,
and gas produce higher temperatures at lower
cost, but are avoided because of possible product
contamination with fuel combustion products,
and explosion hazards when flammable solvents
are being evaporated. Steam is preferred over
electricity, because steam energy is usually
cheaper. If steam is not readily available, and
drying loads are small, electric heat is used.
FIG. 3-6. Tray dryer. (Courtesy of the Proctor and
Schwartz Company.) Tunnel and Conveyor Dryers. Tunnel dry¬
ers are adaptations of the truck dryer for contin¬
uous drying. The trucks are moved progressively
formed in a moving belt dryer. Batch drying is through the drying tunnel by a moving chain.
used extensively in the manufacture of pharma¬ These trucks are loaded on one side of the dryer,
ceuticals for several reasons: (1) Each batch of allowed to reside in the heating chamber for a
material can be handled as a separate entity. (2) time sufficiently long to effect the desired dry¬
The batch sizes of the pharmaceutical industry ing, and then discharged at the exit. The op¬
are relatively small (500 or less pounds per eration may be more accurately described as
batch) compared with the chemical industry semicontinuous, because each truck requires
(2000 or more pounds per hour). (3) The same individual loading and unloading before and
equipment is readily adjusted for use in drying a after the drying cycle. Heat is usually supplied
wide variety of materials. by direct convection, but radiant energy also
Tray dryers may be classified as direct or indi¬ may be used.
rect. Most tray dryers used in the pharmaceuti¬ Conveyor dryers axe an improvement over
cal industry are of the direct type, in which heat¬ tunnel dryers because they are truly continuous.
ing is accomplished by the forced circulation of The individual trucks of the tunnel are replaced
large volumes of heated air. Indirect tray dryers with an endless belt or screen that carries the
utilize heated shelves or radiant heat sources wet material through the drying tunnel. Con¬
inside the drying chamber to evaporate the veyor dryers provide for uninterrupted loading
moisture, which is then removed by either a vac¬ and unloading and are thus more suitable fox
uum pump or a small amount of circulated gas. handling large volumes of materials.
Further discussion in this section is confined to The drying curve characteristic of the mate¬
the direct (convection-type) dryer. Vacuum dry¬ rial in batch drying is altered considerably when
ers are described separately later in the chapter. continuous type dryers are used. As the mass is
The trays used have solid, perforated, or wire moved along its drying path in a continuous op¬
mesh bottoms. The circulation of drying air in eration, this mass is subjected to drying air, the
trays with a solid base is limited to the top and temperature and humidity of which are continu¬
bottom of the pan, whereas in trays with a perfo¬ ally changing. As a consequence, the “constant
rated screen, the circulation can be controlled to rate” period is not constant, but decreases as the
pass through each tray and the solids on it. The air temperature decreases, although the surface
screen trays used in most pharmaceutical drying temperature of the wetted mass remains con¬
operations are lined with paper, and the air thus stant. Thus, drying rate curves for batch drying
circulates across rather than through the drying are not equally applicable to continuous drying
material. The paper is used as a disposable tray procedures.
liner to reduce cleaning time and prevent prod¬
uct contamination.
To achieve uniform drying, there must be a
Moving-Bed Systems
constant temperature and a uniform airflow over Turbo-Tray Dryers. The turbo-tray dryer,
the material being dried. This is accomplished illustrated in Figure 3-7, is a continuous shelf,
in modem dryers by the use of a well-insulated moving-bed dryer. It consists of a series of rotat¬
cabinet with strategically placed fans and heat¬ ing annular trays arranged in a vertical stack, all
ing coils as integral parts of the unit. The air of which rotate slowly at 0.1 to 1.0 rpm. Heated
circulates through the dryer at 200 to 2000 feet air is circulated over the trays by turbo-type fans
per minute. The use of adjustable louvers helps mounted in the center of the stack. Wet mass
to eliminate nonuniform airflow and stagnant fed through the roof of the dryer is leveled by a
pockets. stationary wiper. After about seven-eighths of a
The preferred energy sources for heating the revolution, the material being dried is pushed

DOTING • 57
 ■access DOOR
are said to be fluidized. The solid particles are
continually caught up in eddies and fall back in
a random boiling motion. The gas-solids mixture
has a zero angle or repose, seeks its own level,
and assumes the shape of the vessel that con¬
MATERIAL TEMPERATURE CAN BE CONTROLLED
tains it.
AS DICTATED BY THE DRYING SPECIFICATIONS The fluidization technique is efficient for the
drying of granular solids, because each particle
is completely surrounded by the drying gas. In
addition, the intense mixing between the solids
and gas results in uniform conditions of temper¬
ature, composition, and particle size distribution
throughout the bed.
Fluidized bed drying has been reported to
offer distinct advantages over conventional tray
drying for tablet granulations.6 In general, tablet
granulations have the proper particle sizes for
good fluidization. The only requirements are
FIG. 3-7. Turbo-tray dryer. (Courtesy of the Wyssmont
Company.) that the granules are not so wet that they stick
together on drying, and that the dried product is
not so friable as to produce excessive amounts of
through radial slots onto the tray below, where it fine particles through attrition. It was found that
is again spread and leveled. The transfer of mass the fluidized bed dryer showed a twofold to six¬
from one shelf to the next is complete after one fold advantage in thermal efficiency* over a tray
revolution. The same procedure continues dryer. The fluidized bed dryer was also shown to
throughout the height of the dryer until the be significantly faster in both drying and han¬
dried material is discharged at the bottom. Be¬ dling time than the tray dryer. To avoid electro¬
cause the turbo-tray dryer continuously exposes static charge buildup and the resultant explo¬
new surfaces to the air, drying rate's are consid¬ sion hazards, fluid beds are provided with static
erably faster than for tunnel dryers. charge grounding devices.
Pan Dryers. Pan dryers are moving-bed dry¬ Types of Fluidized-Bed Dryers. The fluid-
ers of the indirect type that may operate under ized-bed dryers available for use in the pharma¬
atmospheric pressure or vacuum, and are gener¬ ceutical industry are of two types, vertical and
ally used to dry small batches of pastes or slur¬ horizontal. The design features of a vertical flu-
ries. The dryer consists of a shallow, circular idized-bed dryer are shown in Figure 3-8. The
jacketed pan having a diameter of 3 to 6 feet and fluidizing air stream is induced by a fan
•depth of 1 to 2 feet, with a flat bottom and verti¬ mounted in the upper part of the apparatus. The
cal sides. Heat is supplied by steam or hot water. air is heated to the required temperature in an
There is a set of rotating plows in the pan that air heater and flows upward through the wet
revolve slowly, scraping the moisture-laden material, which is contained in a drying cham¬
mass from the walls and exposing new surfaces ber fitted with a wire mesh support at the bot¬
to contact with the heated sides and bottom. tom. The air flow rate is adjusted by means of a
Atmospheric pan drying allows moisture to es¬ damper, and a bag collector filter is provided at
cape, whereas in vacuum dryers, in which the the top of the drying chamber to prevent carry¬
pan is completely enclosed, solvents are recover¬ over of fine particles. The unit described is a
able if the evacuated vapors are passed through batch-type dryer, and the drying chamber is
a condenser. The dried material is discharged removed from the unit to permit charging and
through a door on the bottom of the pan. dumping. Dryer capacities range from 5 kg to
200 kg and the average drying time is about 20
to 40 min. Because of the short drying time and
Fluidized-Bed Systems excellent mixing action of the dryer, no hot spots
If a gas is allowed to flow upward through a are produced, and higher drying temperatures
bed of particulate solids at a velocity greater than can be employed than are used in conventional
the settling velocity of the particles and less than, tray and truck dryers.
the velocity for pneumatic conveying, the solids
are buoyed up and become partially suspended ’Thermal efficiency is the ratio of the minimum energy
in the gas stream. The resultant mixture of sol¬ input theoretically required to dry a material to the actual
ids and gas behaves like a liquid, and the solids energy input used by the dryer.

58 • The Theory and Practice of Industrial Pharmacy

FIG. 3-8. Fluidized-bed grantlator-dryer: 1, product container; 2, blower fan; 3, air inlet pre-filter; 4, air heater (steam or
electric); 5, spray nozzle for granulating liquid; 6, fabric filter bags; 7, air volume control flap. (Courtesy of Aeromatic AG.)

The unit shown in Figure 3-8 is designed for A continuous dryer is more suitable than a
the direct preparation of tablet granulations as batch type for the drying of larger volumes of
well as for the drying of conventionally produced materials. A fluidized-bed dryer of this type,
wet granulations.7 When the unit is used as a which is suitable for pharmaceutical use, is a
granulator, the dry ingredients are placed in the horizontal vibrating conveyor dryer, shown in
chamber and fluidized while the granulating liq¬ Figure 3-9. The heated air is introduced into a
uid is sprayed into the bed, causing the particles chamber below the vibrating conveying deck
to agglomerate into granules. At the end of the and passes up through the perforated or lou¬
granulating cycle, the granules are dried by vered conveying surface, through the fluidized
heating the fluidizing air. bed of solids, and into an exhaust hood. A fluid-

59
 FIG. 3-9. Horizontal vibrating conveyor fluidized bed dryer. (Courtesy of the Jeffrey Manufacturing Company.)

ized bed of uniform density and thickness is much slower rate than does the transfer of heat
maintained in any given drying zone by the vi¬ through the shell to the interior of the droplet.
bration. Residence time in any drying zone is The resultant buildup of heat causes the liquid
controlled by the length of the zone, the fre¬ below the shell to evaporate at a far greater rate
quency and amplitude of the vibration, and the than it can diffuse to the surface. The internal
use of dams. The dryer can be divided into sev¬ pressure causes the droplet to swell, and the
eral different zones with independent control of shell becomes thinner, allowing faster diffusion.
airflow and temperature, so that drying can take If the shell is nonelastic or impermeable, it rup¬
place at the maximum desirable rate in each tures, producing either fragments or budlike
stage without sacrificing efficiency or damaging forms on the original sphere. Thus, spray-dried
heat-sensitive materials. Dryers vary in width material consists of intact spheres, spheres with
from 12 to 57 inches and in length from 10 to 50 buds, ruptured hollow spheres, or sphere frag¬
feet, with bed depths to 3 inches. Dryer capacity ments.
is limited only by the retention time produced by There are many types of spray dryers, each
conveying speeds, which range from 5 to 25 feet designed to suit the material being dried and the
per minute. In pharmaceutical operations, ca¬ desired product characteristics. One example is
pacities range as high as 1 to 2 tons per hour. shown in Figure 3-10. All spray dryers can be
considered to be made up of the following com¬
ponents: feed delivery system, atomizer, heated
Pneumatic Systems air supply, drying chamber, solids-gas separator,
Spray Dryers. Spray dryers differ from most and product collection system.
other dryers in that they can handle only fluid The feed is delivered to the atomizer by grav¬
materials such as solutions, slurries, and thin ity flow or by the use of a suitable pump. The
pastes. The fluid is dispersed as fine droplets rate of feed is adjusted so that each droplet of
into a moving stream of hot gas, where they sprayed liquid is completely dried before it
evaporate rapidly before reaching the wall of the comes in contact with the walls of the drying
drying chamber. The product dries into a fine chamber, and yet the resultant dried powder is
powder, which is carried by the gas current and not overheated in the drying process. The proper
gravity flow into a collection system. feed rate is determined by observation of the
When the liquid droplets come into contact outlet air temperature and visual inspection of
with the hot gas, they quickly reach a tempera¬ the walls of the drying chamber. If the inlet air
ture slightly above the wet-bulb temperature of temperature is kept constant, a drop in the liq¬
the gas. The surface liquid is quickly evapo¬ uid feed rate is reflected by a rise in the outlet
rated, and a tough shell of solids may form in its temperature. Excessive feed rates produce a
place. As drying proceeds, the liquid in the inte¬ lowering of the outlet temperature, and ulti¬
rior of the droplet must diffuse through this mately, a buildup of material on the walls of the
shell. The diffusion of the liquid occurs at a chamber.

60 ' The Theory and Practice of Industrial Pharmacy

 point is referred to as cyclone product. Any dust
remaining in the air may be removed by means
of a filter bag collector or a wet scrubber to avoid
air pollution. Product that reaches the walls of
the drying chamber, referred to as chamber
product, is removed at the bottom of the cham¬
ber. This chamber product is usually coarser in
size and subjected to heat longer (because of
increased retention time) than is the cyclone
product. The final dried product is usually a
mixture of both the chamber and cyclone prod¬
ucts.
Spray Drying and Spray Congealing of
Pharmaceuticals. Spray drying finds great
utility in the pharmaceutical industry because of
FIG. 3-10. Spray dryer: 1, feed tank; 2, centrifugal atom¬ the rapidity of drying and the unique form of the
izer; 3, drying chamber; 4, inlet air filter; 5, air supply fan;
final product. There are three major uses for the
6, air heater; 7, triple inlet duct; 8, adjustable air dis¬
perser; 9, cooling air fan; 10, chamber product collection; spray drying processes: (1) drying heat-sensitive
11, cyclone product collection; 12, exhaust fan. (Courtesy materials, (2) changing the physical form of
of Nichols Engineering & Research Corp.) materials for use in tablet and capsule manufac¬
ture, and (3) encapsulating solid and liquid par¬
ticles.
Spray dryer atomizers are of three basic types: Spray drying can be used to dry materials that
pneumatic atomizers, pressure nozzles, and are sensitive to heat and/or oxidation without
spinning disc atomizers. In the pneumatic atom¬ degrading them, even when high temperature
izer (also called two-fluid or gas-atomizing noz¬ air is employed. The liquid feed is dispersed into
zle), the liquid feed is broken up into droplets by droplets, which are dried in seconds because of
a high-velocity jet of air or other gas. Pneumatic their high surface area and intimate contact
atomizers are used to produce small particles with the drying gas. The product is kept cool by
and for spraying more viscous liquids than can vaporization of the enveloping liquid, and the
be handled by pressure nozzles. The pneumatic dried product is kept from overheating by rapid
atomizer, however, requires more power than removal from the drying zone.
other type atomizers to achieve the same fine Spray drying is valuable in the modification of
spray. The liquid feed is delivered by pressure materials for use in tablet and capsule formula¬
nozzles under high pressure (up to 7000 pounds tions, because the drying process changes the
per square inch) and is broken up on coming shape, size, and bulk density of the dried prod¬
into contact with the air or by impact on another uct. The spherical particles produced usually
jet or fixed plate. In spinning disc atomizers, the flow better than the same product dried by con¬
liquid is fed to the center of a rapidly rotating ventional procedures, because the particles are
disc (3000 to 50,000 ipm), where centrifugal more uniform in size and shape, with fewer
force breaks the fluid up into droplets. Spinning sharp edges. The spherical shape has the least
disc atomizers find wide utility in the spray dry¬ possible surface area, thus minimizing air en¬
ing of pharmaceuticals because of their ability to trapment between the particles. The improve¬
handle all types of liquid feeds, including high- ment in flow and reduction of air entrapment
viscosity liquids and slurries of particles that make the spray dried material suitable for use in
would clog other atomizers. the manufacture of tablets and capsules. The
Hot drying air is supplied by the blowing of air spherical particle shape is obtained by spray dry¬
over a heat exchanger. The heat may be sup¬ ing either a solution of the material or a slurry of
plied by steam, or by direct- or indirect-fired particles in a saturated solution of the same ma¬
heaters. The usual heat source in laboratory terial. In the latter case, the configuration of the
units is electricity or gas. Steam or indirect-fired suspended particle is rounded out by deposition
heaters are preferred in the spray drying of phar¬ of the material in solution. An example of a
maceuticals because their use avoids product spray dried material that is commonly, used as a
contamination with combustion products. tablet excipient is spray dried lactose.
Separation of the solid product from the efflu¬ Spray drying has proved extremely useful in
ent gas is usually accomplished by means of a the coating and encapsulation of both solids and
cyclone separator. It is referred to as the primary liquids. Solid particles are coated by spray drying
collector. The dried product collected at this a suspension of the material in a solution of the

DRYING • 61
coating agent. As the solvent is evaporated, the
coating material envelops the suspended parti¬
cle. The coating provides such valuable charac¬
teristics as taste and odor masking, improve¬
ment in stability, enteric coating, and sustained
release. Oily liquids may be encapsulated by
emulsification in water with the aid of a gum
such as acacia, or starch, and subsequent spray
drying. As the water evaporates, the oil is en¬
trapped in a shell of the gum. This process is
used for the preparation of “dry” flavor oils.
An alternative to spray for the encapsulation
of solid particles is spray chilling or spray con¬
gealing. This process consists of suspending the
particles in a molten coating material and pump¬
ing the resultant slurry into a spray dryer in
which cold air is circulated. The slurry droplets
congeal on coming into contact with the air and
are collected in the same manner as the spray
dried product.. The coating agents normally
employed are low melting materials such as
waxes. The congealing process requires a much
higher ratio of coating agent to active material
than does spray drying, because only the molten FIG. 3-11. Two-stage flash dryer. (Courtesy of the Ray¬
coating agent constitutes the liquid phase. Spray mond Div., Combustion Eng., Inc.)
congealed coatings are used mainly for taste
masking and for sustained-release formulations.
Flash Dryers. In flash drying, the moistened some of the dried material is mixed with the wet
solid mass is suspended in a finely divided state incoming solid to make it easier to mill.
in a high-velocity (3000 to 6000 feet per min¬
ute), high-temperature (300°F to 1300°F) air
stream. The dispersed particles may be carried Specialized Drying Methods
in the air stream to an impact mill, or the pneu¬ Freeze Dryers. Many products of pharma¬
matic flow itself may reduce the particle size of ceutical interest lose their viability in the liquid
friable material. The resultant attrition exposes state and readily deteriorate if dried in air at nor¬
new surfaces for more rapid drying. The dried, mal atmospheric pressures. These pharmaceuti¬
fine particulate matter passes through a duct cal materials may be heat-sensitive or they may
with an opening small enough to maintain de¬ react readily with oxygen, so that in order to be
sired air-carrying velocities. The dried solid is stabilized, they must be dehydrated to a solid
collected by a cyclone separator, which may be state. The material to be dried is first frozen and
followed by a bag collector or wet scrubber. then subjected under a high vacuum to heat
Thus, the flash dryer is an example of a parallel (supplied by conduction or radiation, or by both)
(cocurrent) airflow drying system. so that the frozen liquid sublimes leaving only
The drying process is referred to as flash dry¬ the solid, dried components of the original liq¬
ing, because the drying time is extremely short. uid. Such materials as blood serum, plasma, an¬
The drying air temperature can drop from tibiotics, hormones, bacterial cultures, vaccines,
1300°F to 600°F in two seconds and to 350°F in and many foodstuffs are dehydrated by freeze
only four seconds. The temperature of the dry¬ drying, also referred to as iyophilization, gelsic-
ing solid can be kept at 100°F or less. cation or drying by sublimation. The dried prod¬
The drying cycle in many flash dryers occurs uct can be readily redissolved or resuspended by
in one unit (single-stage conveyor). Multistage the addition of water prior to use, a procedure
units are employed for drying solids that have referred to as reconstitution.
high moisture content and contain large Freeze drying depends on the phenomenon of
amounts of bound water. Figure 3-11 illustrates sublimation, whereby water passes directly from
a two-stage unit wherein partial drying occurs in the solid state (ice) to the vapor state without
the first unit, and drying is completed in the sec¬ passing through the liquid state. As shown in
ond pneumatic conveyor dryer. In other units, the schematic pressure-temperature diagram for

62 • The Theory and Practice of Industrial Pharmacy

 point boiling point temperature
Temperature (not to scale)
F5G. 3-12, Schematic pressure-temperature diagram for water, shcnuing the conditions for various phases. (This figure is
not drawn to scale because of the wide range of pressures involved.) (From Daniels, F., and Alberty, R. A.: Physical
Chemistry. 2nd Ed., John Wiley and Sons, Inc., New York, N.Y., 1961, p. 131.)

water (Fig. 3-12), sublimation can take place at rial being dried must be higher than the partial
pressures and temperatures below the triple pressure of the enveloping atmosphere, i.e.,
point, 4.579 mm Hg absolute (4579 microns) there must be a positive vapor pressure driving
and 0.0099°C. The water in pharmaceutical force. Second, the latent heat of vaporization
products intended for freeze drying contains dis¬ must be introduced to the drying solid at such a
solved solids, resulting in a different pressure- rate as to maintain desirable temperature levels
temperature relationship for each solute. In at both the surface and interior. Third, provision
such cases, the pressure and temperature at must be made for removal of the evaporated
which the frozen solid vaporizes without conver¬ moisture.
sion to a liquid is referred to as the eutectic Freeze dryers are composed of four basic com¬
point. Freeze drying is carried out at tempera¬ ponents: (1) a chamber for vacuum drying, (2) a
tures and pressures well below this point to pre¬ vacuum source, (3) a heat source, and (4) a
vent the frozen water from melting, which vapor-removal system. The chamber for vacuum
would result in frothing, as the liquid and frozen drying is generally designed for batch operation
solid vaporize simultaneously. In actual prac¬ and thus can be compared to the vacuum shelf
tice, freeze drying of pharmaceuticals is carried dryer. Special inlet and outlet mechanisms have
out at temperatures of -10°C to -40°C, and at been designed in some drying chambers to
pressures of 2000 to 100 microns. achieve a continuous drying operation. Vacuum
Freeze drying must meet the three basic re¬ is achieved by pumps, steam ejectors, or a com¬
quirements for all types of drying, despite this bination of the two. Heat is provided by conduc¬
unusual approach to drying. First, the vapor tion or radiation, or by both. Three different
pressure of the water on the surface of the mate¬ methods for the removal of water vapor are em-

DRYING ' 63
ployed: condensers, desiccants, and pumps. The In microwave drying, the mass transfer is pri¬
water vapor is removed from the drying chamber marily the result of a pressure gradient due to
and condensed in the form of a thin layer of ice rapid vapor generation inside the material, that
on a heat-transfer surface in the condenser. The is, most of the internal moisture is vaporized be¬
ice is removed intermittently by melting it with a fore leaving the sample. Thus, the moisture is
heated fluid that is circulated through the con¬ mobilized as a vapor rather than a liquid, and its
denser, or in the case of a continuous operation, movement to the surface can be extremely rapid
by means of scraper blades. Liquid or solid because it does not depend on mass concentra¬
desiccants are often employed in the initial tion gradients or on slow liquid diffusion rates.
vapor removal to enhance the efficiency of the Industrial microwave dryers are usually of the
pumps removing the water vapor. In general, static bed continuous type. Materials to be dried
scraper blades and desiccants are used for freeze are placed on conveyor belts and conveyed
drying large-volume biologicals (e.g., serum, through the microwave applicator. Generally, a
penicillin), and usually are not used for prepar¬ stream of hot air is used simultaneously with the
ing pharmaceutical dosage forms. microwaves to sweep away the moisture evolv¬
Microwave Drying. The application of mi¬ ing from the surface of the material being dried.
crowave energy to the drying of solids represents Often, the microwave treatment is used in the
a radical departure from conventional means of last stages of hot air drying (the second falling
drying. Instead of applying heat externally to a rate period of Fig. 3-3) to remove the last re¬
material, energy in the form of microwaves is maining portion of the solvent, reducing total
converted into internal heat by interaction with drying time by 50% or more.
the material itself. This permits extremely rapid Microwave drying can be used for the drying
heat transfer throughout the material, which in of pharmaceutical materials at low ambient tem¬
turn can lead to rapid drying. peratures, avoiding high surface temperatures,
The heating effect is produced by the interac¬ case hardening, and solute migration. Micro-
tion of a rapidly oscillating electric field (915 or wave vacuum drying at low pressure (1 to
2450 megahertz) with the polarized molecules 20 mm Hg) and moderate temperature (30 to
and ions in the material. The field imposes order 40°C) can be used for drying thermolabile mate¬
on otherwise randomly oriented molecules. As rials such as vitamins, enzymes, proteins, and
the field reverses polarity, it relaxes and allows flavors.
the molecules to return to their random orienta¬ The rising cost of energy has generated a great
tion, giving up stored potential energy as ran¬ deal of interest in microwave drying. The micro-
dom kinetic energy, or heat. The interaction of waves couple directly into the solvent, and no
the alternating field with ions causes billiard- energy is used to heat the air, the walls of the
ball-like collisions with un-ionized molecules, dryer, the conveyor, or the trays. This results in
and the impact energy is converted into heat. extremely efficient energy utilization, and en¬
A given material’s molecular and ionic ergy savings of as much as 70% have been real¬
makeup intimately affects its ability to be dried, ized in industrial installations.
as is shown in the power conversion equation for
microwave heating:9

References
P = kfEV tan 5 = kffiV 1. Zimmerman, O. T., and Lavine, I.:' Psychrometric
Charts and Tables. Industrial Research Service, Dover,
NH, 1945.
where: P = the power developed, 2. Perry, R. H., and Green, D. W.: Perry’s Chemical Engi¬
(watts/unit volume) neers’ Handbook. 6th Ed. McGraw-Hill, New York,
1984.
k = a constant
3. Bone, D. P.: Food Prod. Devel., 3:81, 1969.
f = the frequency 4. Callahan, J. C., et al.: Drug Devel. and Industrial Phar¬
E = the electric field strength, macy, 8:355, 1982.
(volts/unit distance) 5. Rockland, L. B.. and Nishi, S. K.: Food Technol:,
e' = the relative dielectric constant 34:42, 1980.'
of the material being heated 6. Scott, M. W., et al.: J. Pharm Sci., 52:284,, 1963.
7. Kuelling, W., and Simon, E. J.: Pharm. Technol. Int.,
tan 8 = the loss tangent, or dissipation
3:29,1980.
factor of the material 8. Nuernberg, E.: Acta Pharm. Technol., 26:39. 1980.
e" = the loss factor of the material, 9. Lyons, D, W„ and Hatcher, J. D.: J. Heat Mass Trans¬
equal to the product e' tan 8 fer, 15:897, 1972.

64 • The Theory and Practice of Industrial Pharmacy

General References McCabe, W. L., and Smith, J. C.: Unit Operations and
Chemical Engineering. 4th Ed. McGraw-Hill, NY.
Copson, D. A.: Microwave Heating. 2nd Ed. Avi Publish¬ 1985.
ing, Westport, CT, 1975. Mellor, J. D.-. Fundamentals of Freeze Drying. Academic
Encyclopedia of Chemical Technology. Vol 8. 3rd Ed. Press, NY, 1979.
John Wiley and Sons, NY, 1979, p. 75. Perry, R. H., and Green, D. W.: Perry’s Chemical Engi¬
Goldblith, S. A., et al. (eds.): Freeze Drying and Advanced neers’ Handbook. 6th Ed. McGraw-Hill, NY, 1984, Sec¬
Food Technology. Academic Press, NY, 1974. tion 20.
Keey, R. B.: Introduction to Industrial Drying Operations. Treybal, R. E.: Mass Transfer Operations. 3rd Ed.
Pergamon Press, Elmsfond NY, 1978. McGraw-Hill, NY, 1979.
Kunii, D., and Levenspiel, O.: Fluidization Engineering. Williams-Gardner, A.: Industrial Drying. The Chemical
John Wiley and Sons, NY, 1969. Rubber Co., Cleveland, Ohio, 1971.
Masters, K.: Spray Drying Handbook. 3rd Ed. Halsted Vanecek, V., Markvart, M., and Drbohlav, R.: Fluidized
Press, NY, 1979. Bed Drying. Leonard Hill Books, London, 1966.

drying • 65
Compression and
Consolidation
of Powdered Solids
KEITH MARSHALL
Unlike other physical states of matter, powdered quantification of important variables are de¬
solids are heterogeneous because they are com¬ scribed.
posed of individual particles of widely differing
sizes and shapes, randomly interspersed with air
spaces. For this reason, it is virtually impossible The Solid-Air Interface
to characterize these complex systems fully in Atoms or ions located at the surface of any
terms of fundamental properties. Nevertheless, solid particle are exposed to a different distribu¬
considerable advances have been made in un¬ tion of intramolecular and intermolecular bond¬
derstanding powder behavior, and many useful ing forces than those within the particle. As in¬
qualitative and semiquantitative measurements dicated in Figure 4-1, they may be envisaged as
of factors important to the industrial user are unsatisfied attractive molecular forces extend¬
now available. Properties at two levels, namely ing out some small distance beyond the solid
those associated with an individual particle and surface. This condition gives rise to what is
those typical of bulk powder, are of interest in called the free surface energy of the solid, which
the context under review. plays a major role in the interaction between
Compaction of powders is the general term particles, and between a particle and its environ¬
used to describe the situation in which these ment. Many important phenomena such as ad¬
materials are subjected to some level of mechan¬ sorption, cohesion and adhesion, rate of solu¬
ical force. In the pharmaceutical industry, the tion, and crystallization are manifestations of
effects of such forces are particularly important this fundamental property of all solids.
in the manufacture of tablets and granules, in Because of these unsatisfied bonding forces at
the filling of hard-shell gelatin capsules, and in the surface of particles, those that approach
powder handling in general. each other closely enough are inherently at¬
The physics of compaction may be simply tracted and tend to stick to one another. This
stated as “the compression and consolidation of attraction between like particles is called cohe-
a two-phase (particulate solid-gas) system due to
the applied force.” Compression means a reduc¬
tion in the bulk volume of the material as a re¬
sult of displacement of the gaseous phase. Con¬
solidation is an increase in the mechanical
strength of the material resulting from particle/
particle interactions.* Before each of these si¬
multaneous processes is discussed in more de¬
tail, brief consideration is given to certain inher¬
ent properties of all powdered solids, which
contribute to the characteristics of interest. In
addition, some derived parameters that facilitate

‘Some authors have used these terms interchangeably. FIG. 4-1. Diagram of distribution of attractive bonds be¬
The unequivocal definitions used here should avoid fur¬ tween constituent ions or atoms in a solid, compared with
ther confusion. those at its surface.

66
sion. In addition, when they approach other Angle of repose methods, which result in a so-
types of particles or solid surfaces, they are at¬ called dynamic angle, are preferred, since they
tracted to them, leading to what is termed adhe¬ most closely mimic the manufacturing situation,
sion. These attractions give rise to an intrinsic in which the powder is in motion.
property of all bulk powdered solids: they resist A typical dynamic test involves a hollow cylin¬
differential movement of their constituent parti¬ der half-filled with the test powder, with one end
cles when subjected to external forces. This phe¬ sealed by a transparent plate. The cylinder is ro¬
nomenon has an important influence on several tated about its horizontal axis (Fig. 4-2b), until
operations, such as flow from hoppers or feed¬ the powder surface cascades. The curved wall is
ers, relative motion in mixers, and compression lined with sandpaper to prevent preferential slip
to produce granules or tablets. at this surface. In a second method, a sandpa¬
The overall resistance to relative movement of per-lined rectangular box is filled with the pow¬
particles may be markedly affected by two other der and carefully tilted until the contents begin
factors. First, many powders of pharmaceutical to slide, as shown in Figure 4-2c.'Values of are
interest readily develop electrostatic forces, es¬ rarely less than 20°, and values of up to 40° indi¬
pecially when subjected to internal friction, al¬ cate reasonable flow potential. Above 50°, how¬
though particle contact and separation are the ever, the powder flows only with great difficulty,
only prerequisite. The charge developed de¬ if at all.
pends on the particular material involved and With care, dynamic angle of repose measure¬
the type of motion produced in it. Usually, elec¬ ments can be replicated with relative standard
trostatic forces are relatively small, but may be deviations of approximately 2%. They are partic¬
significant because they act over a greater dis¬ ularly sensitive to changes in particle size distri¬
tance than the molecular forces. The second fac¬ bution and to moisture content, and they pro¬
tor, namely the presence of an adsorbed layer of vide a rapid means of monitoring significant
moisture on the particles, reduces the chance of batch-to-batch differences in these respects.
any complicating electrostatic effect by provid¬
ing a conducting path for charge dissipation.
When particles approach one another closely
enough, however, these films of moisture can
form liquid bridges, which hold the particles to¬
Flow Rates
gether by surface tension effects and by a nega¬ Alternatively, resistance to movement of parti¬
tive capillary pressure. cles, especially for granular powders with little
cohesiveness, may be assessed by determining
their flow rate Q through a circular orifice (a tab¬
Angles of Repose let die, for instance) fitted in the base of a
Although the contributions of each of these cvlindric container. Flow experiments with mix¬
effects cannot always be distinguished, there are tures of different size fractions of the same ma¬
relatively simple practical techniques for meas¬ terial can be particularly valuable, because in
uring resistance to particle movement. For ex¬ many instances, there exist optimum propor¬
ample, a quantity called the angle of repose of a tions that lead to a maximum flow rate, as
powder can be determined. This is the angle shown in Figure 4-3. Note that for this system,
as defined by the equation:" when the proportion of fine particles exceeds
approximately 40%, there is a dramatic fall in
the flow rate.1
Tan $ = (1) A simple indication of the ease with which a
materia] can be induced to flow is given by appli¬
It is the maximum angle that can be obtained cation of a compressibility index (I) given by the
between the freestanding surface of a powder equation:
heap and the horizontal plane, as shown in Fig¬
ure 4-2a. Such measurements give at least a I = 1 - ■
vn J
100 (2)
qualitative assessment of the internal cohesive
and frictional effects under low levels of external
loading, as might apply in powder mixing, or in where v is the volume occupied by a sample of
tablet die or capsule shell filling operations. the powder after being subjected to a standard¬
ized tapping procedure, and v0 is the volume
before tapping. Values of I below 15% usually
"See Appendix A for explanation of symbols used in for¬ give rise to good flow characteristics, but read¬
mulas throughout this chapter. ings above 25% indicate poor flowability.

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 67

 b c
FIG. 4-2. Measurement of dynamic angles of repose, 4>, as defined from the dimensions of a conical bed of the powder
(Figure a), where tan <I> = twice the powder bed height (h)/powder bed diameter (D). Figures b and c represent the rotating
cylinder and tilted box methods of measurement, respectively.

Mass-Volume Relationships Therefore, at least three interpretations of

“powder volume” may be proposed:
Volume
Although the mass of a bulk powder sample 1. The true volume (vt)—the total volume of the
can be determined with great accuracy, meas¬ solid particles, which excludes all spaces
urement of the volume is more complicated than greater than molecular dimensions, and
it may first appear. The main problem arises in which has a characteristic value for each
actually defining volumes of bulk powders, as material.
may be seen from Figure 4-4, in which three
2. The granular volume (particle volume) (Vg)—
types of air spaces or voids can be distinguished:
the cumulative volume occupied by the parti¬
cles, including all intraparticulate (but not
1. Open intraparticulate voids—those within a
interparticulate) voids. The boundary be¬
single particle but open to the external envi¬
tween open intraparticulate and interparticu¬
ronment.
late air spaces may be interpreted differently,
2. Closed intraparticulate voids—those within a so that this interpretation of volume depends
single particle but closed to the external envi¬ on the method of measurement.
ronment.
3. The bulk volume (vb)— the total volume oc¬
3. Interparticulate voids—the air spaces be¬ cupied by the entire powder mass under the
tween individual particles. particular packing achieved during the meas-

68 • The Theory and Practice of Industrial Pharmacy

 This phenomenon occurs in compressional
processes such as tabletting.
The voids present in the powder mass may be
more significant than the solid components in
certain studies. For example, a fine capillary
network of voids or pores has been shown to
enhance the rate of liquid uptake by tablets,
which in turn increases the rate of their disinte¬
gration. For this reason, a second dimensionless
quantity, the ratio of the total volume of void
spaces (vv) to the bulk volume of the material, is
often selected to monitor the progress of com-
v
pression. This ratio ~ is referred to as the po¬

rosity (E) of the material:

Vv = Vb - vt (4)

Therefore: porosity E = ——— = 1 - —

vb vb

Porosity is frequently expressed as a percentage:

FIG. 4-3. Effect of fines on the rate of flow of mixtures of
coarse granules (0.561 mm) as a function of increasing
E = 100 •
amounts of fines: (A) 0.158 mm; (♦) 0.09 mm; (*)
0.059 mm; (•) 0.048 mm. (From Jones.1 Reproduced with
permission of the copyright owner.)
For example, a cylindric tablet of 10 mm di¬
ameter and 4 mm height weighed 480 mg and
was made from material of true density 1.6
urement. Thus, this interpretation also de¬ g cm"3. The bulk volume vb is given by:
pends on method.
/ 10 f 4 3
When studying phenomena resulting in a Vb = ,7XlTo^ xTocm
change in volume, it may be convenient to con¬
sider the volume v of the sample under specific (volume of a cylinder is m^h)
experimental conditions, relative to the true vol¬
ume vt. A useful dimensionless quantity relative = (0.5)2 • 0.4 = 0.3142 cm3
volume (vr) may be defined as:
The true volume of the solid is the true density
divided by the mass, that is:

480 . , „ 0.48 A„ 3
The relative volume decreases and tends toward Vt = ToocT"" 16 = HT = °'3 cm
unity as all the air is eliminated from the mass.
Therefore, the porosity E is:

0.3 '
E =100 ■ 1 = 100(1 - 0.9548)
0.3142.
= 4.5% (approximately)

Several practical techniques axe available for

measuring the volume of powder samples. Apart
from x-ray diffraction methods, the nearest ap¬
proach to true volume is probably provided by a
FIG. 4-4. Diagram of various intraparticulate and inter- helium pycnometer. This works on the principle
particulate air spaces in a bed of powder. that within a sealed system containing helium (a

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 69

nonadsorbing gas), the change in pressure
caused by a finite change in volume of the sys¬
tem is a function of its total volume. A schematic
diagram for a typical apparatus is shown in Fig¬
ure 4-5. During operation, the volume of the sys¬
tem is varied by means of the piston until a pre¬
set constant pressure is produced. This pressure
is indicated by the sealed bellows pressure de¬
tector, which incorporates an integral electrical
contact. The piston movement (U) necessary to
achieve this pressure is read off from the scale.
This value depends on the total volume of the
system, which in turn is a function of the sam¬
ple volume in the cell. The pycnometer is first
calibrated using a sample of known volume vc
(usually a stainless steel sphere). The operating
equation for the instrument then becomes:

Vt = '[Ul ~ Usl (6)

where Uj, U2 and Us are the variable volume
scale readings for an empty cell, with standard
volume, and with test powder, respectively.
Alternatively in some instances, a large com¬
pact of the material can be prepared at high
compressional force (therefore assuming zero
porosity). Then, by accurately measuring its
overall dimensions, true volume can be calcu¬
lated. Liquid displacement by a powder pycnom¬
eter (specific gravity bottle method) can also be
used, but unless special precautions are taken to FIG. 4-6. Diagram of apparatus for determining the bulk
ensure that no air remains in the sample, the volume of powders.
results are prone to errors. For this reason, liq¬
uid displacement is probably best regarded as a
measurement of granule volume, especially if
Helium liquids that do not readily wet the powder are
used, e.g., certain inert organic liquids, or mer¬
cury.
Bulk volumes are measured in a variety of
ways, ranging from simple pouring of a known
weight into a graduated vessel to sophisticated
techniques involving standard tamping, tap¬
ping, or vibrating procedures, as shown in Fig¬
ure 4-6. In all these techniques, reproducibility
may be poor unless precise procedures are fol¬
lowed, and of course, the results greatly depend
on the particular method chosen.

Density
The ratio of mass (weight) to volume is known
FIG. 4-5. Diagram of a helium pycnometer for determin¬
ing the true volume of powders. The variable volume pis¬ as the density of the material. Three different
ton positions (V,, t/2, and Us) are read off from the scale densities for powdered solids, based on the fol¬
and are used in equation (6) (see text). lowing ratios, may be defined.

70 • The Theory and Practice of Industrial Pharmacy

 M
pt the true density

— = pg the granular density

— = Pb the bulk density

where M is the mass of the sample. Comparing

the density p of a sample under specific test con¬
ditions with the true density (sometimes called
theoretical density) of the material leads to the
dimensionless quantity pr, the relative density,
where:

P_
Pr = (7)
Pt

During compressional processes, relative den¬

sity increases to a maximum of unity when all
air spaces have been eliminated. T

Effect of Applied Forces

Deformation
When any solid body is subjected to opposing
forces, there is a finite change in its geometry,
depending upon the nature of the applied load. A
The relative amount of deformation produced by
such forces is a dimensionless quantity called b
strain. Three of the commonest kinds of strain
are illustrated in Figure 4-7. For example, if a
solid rod is compressed by forces acting at each
end to cause a reduction in length of AH from an
unloaded length of H0 (Fig. 4-7b), then the com¬
pressive strain Z is given by the equation:

Z = AH/H0 (8)

The ratio of the force F necessary to produce this

strain to the area A over which it acts is called
the stress cr, that is:

<j = F/A (9)

Because most powder masses contain some

air spaces, true analogous behavior to a solid
body should not be " expected. Nevertheless,
under low porosity conditions (high applied FIG. 4-7. Diagram shouts change in geometry (strain)
forces), comparisons do provide a useful way of of a solid body resulting from various types of applied
interpreting experimental observations, as is force: tensile strain (a), compressive strain (b), and shear
demonstrated in the following discussion. strain (c).

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 71

Compression maximum forces normally encountered in prac¬
tice.
When external mechanical forces are applied
In other groups of powdered solids, an elastic
to a powder mass, there is normally a reduction
limit, or yield point, is reached, and loads above
in its bulk volume as a result of one or more of
this level result in deformation not immediately
the following effects. The onset of loading is
reversible on removal of the applied force. Bulk
usually accompanied by closer repacking of the
volume reduction in these cases results from
powder particles, and in most cases, this is the
plastic deformation and/or viscous flow of the
main mechanism of initial volume reduction, as
particles, which are squeezed into the remaining
shown diagrammatically in Figure 4-8. As the
void spaces, resembling the behavior of model¬
load increases, however, rearrangement be¬
ing clay. This mechanism predominates in ma¬
comes more difficult, and further compression
terials in which the shear strength is less than
involves some type of particle deformation. If on
the tensile or breaking strength (see Fig. 4-7).
removal of the load, the deformation is to a large
Conversely, when the shear strength is greater,
extent spontaneously reversible, i.e., if it be¬
particles may be preferentially fractured, and
haves like rubber, then the deformation is said
the smaller fragments then help to fill up any
to be elastic. All solids undergo some elastic de¬
adjacent air space. This is most likely to occur
formation when subjected to external forces.
with hard, brittle particles and in fact is known
With several pharmaceutical materials, such as
as brittle fracture; sucrose behaves in this man¬
acetylsalicyclic acid and microcrystalline cellu¬
ner. The predisposition of a material to deform
lose, elastic deformation becomes the dominant
in a particular manner depends on the lattice
mechanism of compression within the range of
structure, in particular whether weakly bonded
lattice planes are inherently present.
Irrespective of the behavior of large particles
of the material, small particles may deform plas¬
tically, a process known as microsquashing, and
the proportion of fine powder in a sample may
therefore be significant. Asperities that are
sheared off larger, highly irregular particles
could also behave in this way, thus, particle
shape is another important factor.
The above account describes all of the possible
re pacning- mechanisms that can contribute to a reduction
in the bulk volume of a bed of powder, when
subjected to external mechanical forces. The
chemicophysical characteristics of the material
being studied determine the contribution each
effect makes as the compressional load is in¬
creased. All of the deformation effects may be
accompanied by the breaking and formation of
new bonds between the particles, which gives
rise to consolidation as the new surfaces are
pressed together.
The packaging of bulk powders and the filling '
of hard gelatin capsules mostly involve bulk vol¬
ume reductions achievable by repacking, and
possibly a minimal amount of deformation. At
the other end of the scale, in the tabletting proc¬
ess—or in such specialized techniques as roll
compacting or extruding, which involve high
levels of compressive force—repacking, elastic
deformation, plastic deformation, and brittle
fracture may all take place.
Some deformation processes (plastic deforma¬
tion, for example) are time-dependent and occur
on decompression
at various rates during the compaction se¬
FIG. 4-8. Diagram of the effect of compressimal force on a quence, so that the tablet mass is never in a
bed of powder. state of stress/strain equilibrium during the ac-

72 • Th" Theory and Practice of Industrial Pharmacy

tual tabletting event. This means that the rate at heat transfer kinetics, that temperatures high
which load is applied and removed may be a crit¬ enough to fuse typical. organic medicinal sub¬
ical factor in materials for which dependence on stances were theoretically possible. The differ¬
time is significant. More specifically, if a plasti¬ ences between this form of bond formation and
cally deforming solid is loaded (or unloaded) too cold welding are somewhat pedantic; the end
rapidly for this process to take place, the solid results are essentially the same.
may exhibit britde fracture. This is a contribut¬ In both “cold” and “fusion” welding, the proc¬
ing factor to the well-known problem of structur¬ ess is influenced by several factors, including:
ally failed tablets of some drugs as tablet ma¬
chine speed is raised. Conversely, if the dwell 1. the chemical nature of the materials
time under the compressive load is prolonged,
then plastic deformation may continue, leading 2. the extent of the available surface
to more consolidation. This phenomenon has 3. the presence of surface contaminants
recently been studied using a compaction simu¬
lator, 2 whereby it was shown that the expansion 4. the intersurface distances
of acetaminophen tablets (a material with
known laminating tendency) during decom¬ The type and degree of crystallinity in a par¬
pression was particularly sensitive to dwell time ticular material influences its consolidative be¬
under a maximum load. For this reason, rela¬ havior tinder appreciable applied force. One of
tively slower machine speeds and compression the earliest reports of such influence was that of
rolls of large diameter sometimes help with trou¬ Jaffe and Foss,4 who demonstrated that sub¬
blesome tablet formulations. stances possessing the cubic lattice arrange¬
ment were tabletted more satisfactorily than
those with a rhombohedral lattice, for example.
Consolidation The isotropic nature of the former group might
When the surfaces of two particles approach be expected to contribute to better tabletting
each other closely enough (e.g., at a separation because no alignment of particular lattice planes
of less than 50 nm), their free surface energies is required. In addition they provide three equal
result in a strong attractive force, a process planes for stress relief at right angles to each
known as cold welding. The nature of the bonds other. Lattice planes with the greatest separa¬
so formed are similar to those of the molecular tion undergo plastic deformation more readily,
structure of the interior of the particles, but be¬ since such planes are more weakly bonded. The
cause of the roughness of the particle surface particles of most pharmaceutical powders con¬
(on a molecular scale), the actual surface area sist of small crystallites, or grains, aggregated in
involved may be small. This hypothesis is fa¬ a random manner so that their crystal planes are
vored as a major reason for the increasing me¬ not aligned with one another. Such an arrange¬
chanical strength of a bed of powder when sub¬ ment adds to the material’s resistance to plastic
jected to rising compressive forces. deformation.
On the macroscale, most particles encoun¬ Of course, there are many exceptions to gen¬
tered in practice have an irregular shape, so that eralizations of this kind. For example, of the two
there are many points of contact in a bed of pow¬ chemically similar organic materials methacetin
der (see Fig. 4-4). Any applied load to the bed and phenacetin, apparently only the former can
must be transmitted through these particle con¬ be tabletted without the tendency to laminate.
tacts; under appreciable forces, this transmis¬ More importantly, perhaps, different polymor¬
sion may result in the generation of considerable phic forms and crystal habits of the same com¬
frictional heat. If this heat is not dissipated, the pound may not behave in the same way in terms
local rise in temperature could be sufficient to of compaction properties. Detection and evalua¬
cause melting of the contact area of the parti¬ tion of these seemingly unavoidable changes in
cles, which would relieve the stress in that par¬ the materials from bulk chemical plants, which
ticular region. In that case, the melt solidifies, are responsible for many of our unanticipated
giving rise to fusion bonding, which in turn re¬ tabletting problems with established products,
sults in an increase in mechanical strength of are important. Routine testing of compaction
the mass. characteristics in some type of instrumented
Many pharmaceutical solids possess a low tabletting machine constitutes a desirable and
specific heat and poor thermal conductivity, so informative part of such procedures.
that heat transfer away from the contact points One interesting observation on the more suc¬
is-slow. This behavior was quantified by Rankell cessful direct compression excipients that are
and Higuchi, 3 who were able to estimate, from commercially available concerns this “material

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 73

structure” aspect of tabletting. Without excep¬
tion, these products may be described as
microgranulations, since they consist of masses
of small crystallites randomly embedded in a
matrix of some glue-like (often amorphous) ma¬
terial. Such a combination imparts the desired
overall qualities, which result in (1) strong tab¬
lets by providing a plastically deforming compo¬
nent (the matrix) to relieve internal stresses,
and (2) strongly bonding surfaces (the faces of
the crystallites) to enhance consolidation.0
The compressional process is affected by the
extent of the available surface, the presence of
surface contaminants, and the intersurface dis¬
tances; if large, clean surfaces are brought into FIG. 4-9. The effect of increasing compressional force on
the specific surface area of a powder mass. When a powder
intimate contact, then bonding should occur.
mass is subjected u increasing compressional force, there
Brittle fracture and plastic deformation should is initial particle fracture, which gives rise to increased
generate clean surfaces, which the compres¬ surface area (O to A on graph). At some point (A), particle
sional force ensures are kept in close proximity. rebcmding becomes the dominant factor, and from then on,
This is an important rationale when considering surface area decreases (region A to B) unless tablet lamina¬
the tabletting process, since many of the prob¬ tion begins.
lems that arise can be traced to interference in
these mechanisms. For example, such lubri¬
cants as magnesium stearate form weak bonds, least a proportion of water-soluble component
so that overlubrication, or even overmixing of are often more readily formed than those with¬
lubricant into the tabletting mass, results in a out, may indicate this mechanism. The finding
continuous coating of the latter, and hence in that some overdried mixtures, in which mois¬
some cases, weak tablets. ture residues are extremely low, have inferior
Higuchi and his co-workers were among the tabletting qualities may be further evidence.
first to report experimental data in support of The known internal lubricant property of water,
these mechanisms for a pharmaceutical mate¬ however, provides an alternative, and probably
rial.6 They interpreted the plot of specific sur¬ complementary, explanation of the important
face area versus compressional force shown in role of moisture.
Figure 4-9 in terms of an initial increase in sur¬ At low levels of external force, molecular and
face area (region O to A) due to particle break¬ electrostatic forces are a source of attractive
down. At high loads (A to B), rebonding of sur¬ tendencies between individual particles. This
faces became dominant, with a resultant attraction might be encountered in the mixing of
decrease in specific surface areas. dry powders or in the filling of capsule shells.
Years later, Armstrong and co-workers de¬ Valency type molecular forces have an extremely
scribed similar curves,7 but at high compres¬ short range and are therefore unlikely to play a
sional forces (see broken line in Fig. 4-9), they major role at this stage. Van der Waals forces,
showed that some materials were subject to an however, may exert a significant effect at dis¬
increase in surface area. This increase was due tances up to 100 nm, so that once an agglomer¬
to incipient failure or lamination of the tablet ate of particles has been formed, they may serve
structure that resulted from considerable elastic to prevent its breakdown. Electrostatic forces
recovery on decompression. generated by friction or size reduction, though
The actual solubility of solids also depends generally weaker than van der Waals forces, do
somewhat on the applied pressure, so that if a have a greater range and probably produce the
film of moisture is present on the solid surface, initial agglomerate formation in many materials.
then the high pressures at points of solid contact Ionic chemicals involve the additional possibility
could force more material into solution. This dis¬ of surface polarization, which can produce
solved solid would crystallize on relief of the marked attractive tendencies.
applied stress to form a solid bridge whose If the solid particles are soft, then deformation
strength would partly depend on the rate of this under low loads could cause more intimate con¬
recrystallization. In general, slow rates should tact between the particles and enhance the
produce a more perfect crystal structure with above bonding mechanisms. Recently, however,
consequent higher strength. it has been shown that coating of a major tablet
The observation that tablets containing at ingredient by a lower melting point component

74 • The Theory and Practice of Industrial Pharmacy

powder plugs that are produced by some capsule machines.
The force necessary to split the plug using the strain-
gauged blade is measured.

(such as a lubricant) can sometimes lead to re¬

duced tensile strength of tablets, especially if
produced at slightly elevated temperatures
(10°C).S It is thought that this effect is due to
masking of van der Waals forces between the
particles and the formation of welded bonds by
the coatings.
Some capsule filling machines operate on the
“dosator principle,” that is, formation of a soft
plug, which is transferred to the capsule shell.
In such machines, the plugs are commonly held
together by one or more of the foregoing mecha¬
nisms.
A report by Augsburger and associates de¬
scribed a simple test to measure the comparative
strength of different formulations in such pow¬
FIG. 4-11. Effect of moisture content cm the ratio of trans¬
der plugs;9 the apparatus is illustrated diagram- mitted punch force to applied punch force. (After Shotton
matically in Figure 4-10. Hiestand has reviewed and Rees.’4)
in detail all the various mechanisms and their
applicability to pharmaceutical powder sys¬
tems,10 concluding that in tabletting, plastic de¬ amount of moisture present on the powder sur¬
formation is the major mechanism leading to faces is just sufficient to fill the remaining voids
increased areas of intimate contact, and hence in the bed. Any further reduction in porosity,
bonding, by cold welding. e.g., as a result of increasing compressional
force, results in this water being squeezed out to
the surface of the tablet. This expelled moisture
Role of Moisture may act as a lubricant at the die wall, but it could
At least some moisture is present in virtually also cause material to stick to the punch faces.
all capsule and tablet formulas, and concentra¬ Recent experiments have shown the effect of
tions well below the 1% level can dramatically thermal dehydration on the crushing strength of
affect the behavior of these feed materials and tablets made from certain hydrates.11 The
that of the finished product. This is demon¬ stren'gth was found to depend on the tempera¬
strated clearly by data such as that given in Fig¬ ture at which the dehydration was carried out.
ure 4-11, which shows that as little as 0.02% Scanning electron microscopy confirmed that
moisture can affect the proportion of the applied dehydration had been accompanied by a change
force transmitted to the lower punch, and at in texture of the crystals, which led to a more
0.55% moisture, the behavior is actually the re¬ porous mass.
verse of that for the totally dry material. A more Moisture is also important in moist granula¬
critical factor concerns the situation where the tion processes, in which most of the fluids in-

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 75

volved are aqueous in nature. Therefore, before der particles are wetted during the initial stage
the bonding produced in tablets is discussed in (Fig. 4-12A), liquid films will be formed on their
more detail, the special consolidative process surface and may combine to produce discrete
that is involved in the granulation of powders by liquid bridges at points of contact. The surface
the addition of a granulating liquid is consid¬ tension and negative capillary pressure in such
ered. bridges provide the cohesive force and result in
a condition called the pendular state, which has
comparatively low mechanical strength.
Granulation As the liquid content increases, several
bridges may coalesce, giving rise to the funicular
state (Fig. 4-12B), and a further modest increase
Moist Granulation in the strength of the moist granule. Eventually,
Addition of a granulating liquid to a mass of as more liquid is added and the mass is kneaded
powder may be characterized in a series of to bring particles into closer proximity, the void
stages described by Newitt and Conway-Jones;12 spaces within the granule are entirely elimi¬
these are illustrated in Figure 4-12. If the pow¬ nated. At this point, bonding is effected by inter-

76 • The Theory and Practice of Industrial Pharmacy

facial forces at the granule surface and by a neg¬ fore be determined routinely during formulation
ative capillary pressure throughout the interior development.
liquid-filled space, a condition referred to as the
capillary state (Fig. 4-12C). Further addition of
liquid results in droplet formation (Fig. 4-12D), Properties of Granules
in which the particles are still held together by Several characteristics of finished granules
surface tension, but without intragranular are of major significance because they can exert
forces; such structures are weaker. The capillary a pronounced influence on the progress of the
state coincides with the maximum strength of subsequent tabletting process and the properties
the wet granules, and optimization of many of the tablets produced. These characteristics
granulation processes involves ensuring that include packing ability and flow properties of the
this state has been achieved. For example, gran¬ bulk material, together with individual granule
ulation equipment can be instrumented with strength and porosity. Particle shape and size
torque measuring devices, which sense the distribution are important factors in packing and
change in agitator power requirements at the flow. Although the former is not easy to describe
capillary stage, as shown in Figure 4-13.13 quantitatively, the use of shape factors, such as
In many formulations, one or more compo¬ those defined by Heywood,15 and exemplified in
nents are to some extent soluble in the granulat¬ the studies of Ridgeway and Rupp,16 have
ing liquid, which itself may contain solutes, proved useful. To be specific, particles of more
such as binders. During drying, solid bridges regular shape (nearly spherical) led to lower
form in the granule as these soluble materials angles of repose and higher bulk densities. In
crystallize or precipitate out. This process re¬ general, these effects should result in better
sults in the often dramatic increase in granule granule flow properties, hence smaller tablet
strength observed during their drying. weight variation and a more efficient compres¬
A small residual moisture content sometimes sion/consolidation tabletting sequence.
optimizes strength, however, and is desirable for Granule size distributions are best determined
other reasons, notably its lubricant potential by test sieving procedures, as described in
during compaction at higher applied loads. Mi¬ ASTM 447 A for example.17 The contribution of
gration of soluble components to the surface of particle size to possible performance is difficult
the granule during drying may lead to a surface to generalize, but there is often an optimum pro
layer that is atypical of the bulk. This in turn can portion of fine particles necessary to achieve op¬
assist or hinder the consolidative performance of timum flow properties, as shown in Figure 4-3
the granules when they are subsequently com¬ The degree of packing in bulk granulation is
pressed. The migration rate can be reduced by important in its relationship to die and dosator
increasing the viscosity of the granulating fluid filling. More specifically, the porosity of a tablet
and using fluidized bed drying, as opposed to the produced under a certain compressive load is in
slower process of tray drying. In addition, the many cases a function of the initial porosity of
reports of other workers point strongly to opti¬ the packing in the die. One of the simplest ex¬
mum moisture levels for particular formula¬ pressions of this packing tendency is the com¬
tions.14 Accurate moisture levels should there- pressibility index, I, already described in equa¬
tion (2). Compressibility index values up to 15%
usually result in good to excellent flow proper¬
ties and indicate desirable packing characteris¬
tics. Values for I above 25%, on the other hand,
are obtained from materials whose compres-
sional characteristics are often a source of poor
tabletting qualities. Between these two values,
less than optimum performance might be antici¬
pated, and modification of the particle size dis¬
tribution could be advisable.

Strength of Granules
Granules should possess sufficient strength to
withstand normal handling and mixing proc¬
FIG. 4-13. Plot of change, in torque of mixer shaft during
esses without breaking down and producing
addition of granulating fluid. Point F represents an appro¬ large amounts of fine powder. On the other
priate end point to wet massing (From'Travers et al.13) hand, some size reduction during compaction

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 77

into tablets is desirable to expose the areas of less friable and often have a more regular shape,
clean surface necessary for optimum bonding thereby enhancing die-fill uniformity.
(cold welding) to take place.
Definition of “strength” with respect to indi¬
vidual granules may be interpreted in several Compression and Consolidation
ways, depending on the method of applying the
test load. Strength may be expressed in terms of
under High Loads
compressive, tensile, shear, bending, impact, The processes of tabletting, roll compaction,
and abrasion tests. Only compressive and abra¬ and extrusion all involve the application of mas¬
sion tests have been sufficiently used to provide sive compressive forces, which induce consider¬
the required data to establish general relation¬ able deformation in the solid particles. With
ships between strength and other tabletting many pharmaceutical solids and perhaps most
material or process characteristics. tabletting mixtures, these forces are large
The compressive strength, or crushing enough to exceed the elastic limit of the solid (or
strength, of granules has been investigated by at least that of one component of the mixture).
placing individual granules between platens and Plastic deformation and/or brittle fracture then
breaking them by application of a compressive results in the generation of new, clean surfaces,
load. In many formulations, there is an optimum which being pressed against one another, un¬
range of average granule crushing strength for a dergo cold welding. When the compaction force
given granule size. Granule strengths below the reaches its maximum, a bulk solid structure of a
lower limit of this range may consolidate well, certain overall strength will have been pro¬
but tend to break down during mixing, handling, duced.
and precompression, to generate fines which Irrespective of the bonding mechanism, this
retard uniform die filling. Conversely, hard structure must be strong enough to withstand
granules retain their identity up to high com- the new stresses induced during release of the
pressional forces, but may consolidate poorly applied load and those generated by ejection
and give rise to weak tablets. Such tablets may from the die (in the case of tabletting). Ideally,
disintegrate readily but sometimes have poor relief of these stresses by elastic recovery is pre¬
dissolution characteristics. ferred, since at this stage, plastic deformation—
Abrasion tests, which involve standardized and even worse, brittle fracture—may result in
tumbling of granules, can also be valuable in small failure planes, if not complete lamination,
assessing their handling properties and in read¬ since any new surfaces tend to separate rather
ily comparing the strength of different batches. than consolidate.
This type of test involves tumbling a known During normal tabletting operations, consoli¬
weight of granules for a specified time and then dation is accentuated in those regions adjacent
determining particle size distribution changes. to the die wall, owing to the intense shear to
More specifically, the increased proportion of which material is subjected, as it is compressed
fine powder, i.e., fines (of which the average par¬ axially and is pushed along the wall surface.
ticle size is less than 75 microns, or 200 mesh), This consolidation results in a “skin” of material
is noted. that is denser over the lateral tablet surface than
The quantity of granulating fluid used, and in the rest of the tablet mass. This skin is in
the concentration of any added binder are the some cases visible to the naked eye. Although
major factors contributing to an increase in this thin layer of material may contribute to ab¬
granule strength. One report has demonstrated rasion resistance, it may retard the escape of air
that for a given material, smaller initial particle during compression and the ingress of liquid
sizes led to granules of greater strength, presum¬ during dissolution, both undesirable features.
ably because of the increased occurrence of in¬ For these reasons, smaller tablet height-to-diam-
terparticulate contacts.18 Smaller granules eter ratios are preferred. This situation is advan¬
tended to be weaker, probably because they had tageous from additional standpoints, which are
not been subjected to as much work during their now to be considered.
development. The resistance to differential movement of
Soft, pqrous granules tend to form tablets that particles caused by their inherent cohesiveriess
are better consolidated under lower compres- results in the applied force not being transmitted
sional forces than tablets prepared from hard uniformly throughout the entire mass. More
and dense granules. In addition, the latter some¬ specifically, in the case of a single-station press,
times demonstrate poor dissolution characteris¬ the force exerted by the upper punch diminishes
tics as well as inferior appearance, but they are exponentially at increasing depths below it.

78 • The Theory and Practice of Industrial Pharmacy

 Thus, the relationship between upper punch Force Distribution
force Fa and lower punch force F, " may be ex¬
pressed in the form: Most investigations of the fundamentals of
tabletting have been carried out on single-sta¬
tion presses (sometimes called eccentric
Fl = Fa • e“KH/D (10)
presses), or even on isolated punch and die sets
in conjunction with a hydraulic press. The sys¬
where K is an experimentally determined mate¬
tem represented diagrammatically in Figure
rial-dependent constant that includes a term for
4-14 is typical of such arrangements, with force
the average die-wall frictional component. The
being applied to the top of a cylindric powder
values H and D are the height and diameter of
mass. This simple compaction system provides a
the tablet, respectively.
convenient way to examine the process in
The discrepancy between the two punch
greater detail. More specifically, the following
forces should be minimized in pharmaceutical
basic relationships apply. Since there must be
tabletting operations, so that there is no signifi¬
an axial (vertical) balance of forces:
cant difference in the amount of compression
and consolidation between one region of the tab¬
let and another. Reduction of die-wall friction Fa = Fl + Fd (11)
effects by having smaller tablet height-to-diame-
where FA is the force applied to the upper
ter ratios and by adding a lubricant is therefore
punch, Fl is that proportion of it transmitted to
common practice. Because of their important
the lower punch, and FD is a reaction at the die
role in the progress of the compressional se¬
quence, frictional effects warrant ffirther discus¬
sion.

Effects of Friction
At least two major components to the fric¬
tional forces can be distinguished.
1. Interparticulate friction. This arises at par¬
ticle/particle contacts and can be expressed in
terms of a coefficient of interparticulate friction
it is more significant at low applied loads.
Materials that reduce this effect are referred to
as glidants. Colloidal silica is a common exam¬
ple.
2. Die-wall friction. This results from material
being pressed against the die wall and moved
down it; it is expressed as the coefficient of
die-wall friction. This effect becomes dominant
at high applied forces when particle rearrange¬
ment has ceased and is particularly important in
tabletting operations. Most tablets contain -a
small amount of an additive designed to reduce
die-wall friction; such additives are called lubri¬
cants. Magnesium stearate is a common choice.

‘The various loads on a powder bed are sometimes ex¬

pressed in terms of force, the preferred units being new¬
tons (bj). In other instances, the force acting over a unit
cross-sectional area is used, i.e., a pressure. The unit in
this case is the newton per square meter, which is called a
pascal (Pa). To facilitate comparison, expressions origi¬
nally derived in other units have been converted to this
(SI) system throughout this chapter. (See Appendix B for
equivalents and conversion factors.)

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 79

wall due to friction at this surface. Because of Note that FR is reduced when materials of small
this inherent difference between the force ap¬ Poisson ratios are used, and that in such cases,
plied at the upper punch and that affecting ma¬ axial force transmission is optimum.
terial close to the lower punch, a mean compac¬ The frictional effect represented by pw arises
tion force, Fm, has been proposed, where: from the shearing of adhesions that occurs as
the particles slide along the die wall. It follows
that its magnitude is related to the shear
=^ (12) strength S of the particles (or the die-wall-parti-
cle adhesions if these are weaker) and the total
A recent report confirms that FM offers a prac¬ effective area of contact Ae between the two sur¬
tical friction-independent measure of compac¬ faces. Therefore, force transmission is also real¬
tion load, which is generally more relevant than ized when Fd values are reduced to a minimum,
Fa.19 In single-station presses, where the ap¬ which is achieved by ensuring adequate lubrica¬
plied force transmission decays exponentially as tion at the die wall (lower S) and maintaining a
in equation (10), a more appropriate geometric minimum tablet height (reducing Ae).
mean force, FG, might be: A common method of comparing degrees of
lubrication has been to measure the applied and
Fg = (Fa ■ FL)o s (13) transmitted axial forces and determine the ratio
Fl/Fa. This is called the coefficient of lubricant
Use of these force parameters are probably more efficiency, or R value.'20 The ratio approaches
appropriate than use of FA when determining unity for perfect lubrication (no wall friction),
relationships between compressional force and and in practice, values as high as 0.98 may be
such tablet properties as tablet strength. realized. Values below 0.8 probably indicate a
poorly lubricated system. Values of R should be
considered as relating only to the specific system
Development of Radial Force from which they were obtained, because they
As the compressional force is increased and are affected by other variables, such as compres¬
any repacking of the tabletting mass is com¬ sional force and tablet H/D ratio.
pleted, the material may be regarded to some
extent as a single solid body. Then, as with all
other solids, compressive force applied in one Die-wall Lubrication
direction (e.g., vertical) results in a decrease AH Most pharmaceutical tablet formulations re¬
in the height, i.e., a compressive stress as in Fig¬ quire the addition of a lubricant to reduce fric¬
ure 4-7b. In the case of an unconfined solid tion at the die wall. Die-wall lubricants function
body, this would be accompanied by an expan¬ by interposing a film of low shear strength at the
sion in the horizontal direction of AD. The ratio interface between the tabletting mass and the
of these two dimensional changes is known as die wall, as illustrated in Figure 4-15. Preferably,
the Poisson ratio A of the material, defined as: there is some chemical bonding between this
“boundary” lubricant and the surface of the die
wall as well as at the edge of the tablet. The best
lubricants are those with low shear strength but
strong cohesive tendencies in directions at right
The Poisson ratio is a characteristic constant angles to the plane of shear. Table 4-1 gives the
for each solid and may influence the tabletting shear strength of some commonly used lubri-
process in the following way. Under the condi¬
tions illustrated in Figure 4-14, the material is
not free to expand in the horizontal plane be¬
cause it is confined in the die. Consequently, a
radial die-wall force FR develops perpendicular
to the die-wall surface, materials with larger
Poisson ratios giving rise to higher values of F„.
Classic friction theory can then be applied to
deduce that the axial frictional force FD is re¬
lated to FR by the expression:

FD = Mw ■ Fr (15)
FIG. 4-15. Diagram illustrates the preferred characteris¬
where pw is the coefficient of die-wall friction. tics of die wall lubricants.

80 • The Theory and Practice of Industrial Pharmacy

Table 4-1. The Shear Strength of Some Lubricants

Material Shear Strength Material Shear Strength

(M Pa) (M Pa)

Stearic acid 1.32 Sodium stearate 3.32

Calcium stearate 1.47 Talc with grain 6.20
Hard paraffin 1.86 Talc across grain 7.85
Magnesium stearate 1.96 Boric acid 7.16
Potassium stearate 3.07 Graphite 7.35

cants as measured by a punch penetration test. by interparticulate slippage and (2) the filling of
By utilizing materials with low shear strength as small voids by deformation or fragmentation at
lubricants, shear failure occurs in the lubricant higher loads.
layers and not at the compressed powder or re¬ This process can be expressed mathemati¬
sultant wall interfaces (Fig. 4-15). cally:21

-K2 -K4
Ejection Forces E0-E
= Kje f + K3e ? (16)
Radial die-wall forces and die-wall friction also E0 • 0 - E)
affect the ease with which the compressed tablet
can be removed from the die. The force neces¬ where Ec is the initial porosity, E is the porosity
sary to eject a finished tablet follows a distinctive at pressure P, and K2, K3 and K4 are con¬
pattern of three stages. The first stage involves stants. The two terms on the right side of the
the distinctive peak force required to initiate equation refer to steps (1) and (2) respectively.
ejection, by breaking of tablet/die-wall adhe¬ Although equation (16) so far has only been
sions. A smaller force usually follows, namely shown to fit data from a few materials (such as
that required to push the tablet up the die wall. alumina and magnesia), it does establish that
The final stage is marked by a declining force of the degree of compression achieved for a given
ejection as the tablet emerges from the die. Vari¬ load depends upon the initial porosity (E0).
ations on this pattern are sometimes found, es¬ Therefore, the common practice of comparing
pecially when lubrication is inadequate and/or different formulations by means of testing tab¬
“slip-stick” conditions occur between the tablet lets of the same weight is undesirable. One vari¬
and the die wall, owing to continuing formation able is eliminated if experiments are carried out
and breakage of tablet/die-wall adhesions. Worn on tablet masses of the same true volume, and
dies, which cause the bore to become barrel¬ allowance should be made for varying initial val¬
shaped, give rise to a similar abnormal ejection ues of bulk volume (Vb) when interpreting the
force trace and may lead to failure of the tablet results.
structure. A more complex sequence of events during
A direct connection is to be expected between compression involves four stages, as illustrated
die wall frictional forces and the force required by the data in Figure 4-16. Stage i represents the
to eject the tablet from the die, FE. For example, initial repacking of the particles, followed by
well-lubricated systems (as indicated by a large elastic deformation (stage ii) until the elastic
R value) have been shown to lead to smaller FE limit is reached. Plastic deformation and/or brit¬
values. tle fracture then dominates (stage iii) until all
voids are virtually eliminated. At this point, the
onset of stage iv, compression of the solid crystal
Force-Volume Relationships lattice, occurs.
The end of the compressional process may be Attempts that have been made to derive equa¬
recognized as being the point at which all air tions for the first three stages, are of limited
spaces have been eliminated, i.e., vb = vt and value, because in practice, the stages are not
therefore E = 0. A small residual porosity is de¬ totally sequential. Owing to transmitted force
sirable, however, so there is particular interest variation, they may occur simultaneously in dif¬
in the relationship between applied force F^ and ferent regions of the same tablet.
remaining porosity E. Originally, it was sug¬ In many tabletting processes, however, once
gested that decreasing porosity resulted from a appreciable force has been applied, the relation¬
two-step process: (1) the filling of large spaces ship between applied pressure (P) and some vol-

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 81

 the applied compressional force F and the move¬
ments of the punches during a compression
cycle and translating this data into values of P
(applied pressure) and E (porosity). For a
cylindric tablet, P is given by:

4F
P= (20)
v D2

where D is the tablet diameter. Similarly, values

of E can be calculated for any stage from:

4w
E = 100 • (21)
pt ■ ir • D2 • H .

where w is the weight of the tabletting mass, pt

is its true density, and H is the thickness of the
FIG. 4-16. Decreasing porosity with increasing compres- tablet at that point (obtained from the relative
sional force for single-ended pressing.
punch displacement measurements). (See pre¬
vious section, “Mass-Volume Relationships.”)
The particular value of Heckel plots arises
ume parameter such as porosity (E) does be¬ from their ability to identify the predominant
come linear over the range of pressure form of deformation in a given sample. Materials
commonly used in tabletting (region iii in Fig. that are comparatively soft and that readily un¬
4-16). For example, an equation first suggested dergo plastic deformation retain different de¬
by Shapiro has been shown to fit data obtained grees of porosity, depending upon the initial
from several pharmaceutical materials:22 packing in the die.25 This in turn is influenced
by the size distribution, shape, etc. of the origi¬
Log E = Log E0 - K.P. (17) nal particles. Heckel plots for such materials are
shown by type a in Figure 4-17; sodium chloride
where E0 is the porosity when the pressure is is a typical example.
zero, and K is a constant. Another equation for Conversely, harder materials with higher yield
which there is considerable evidence, is attrib¬ pressure values usually undergo compression by
uted to Walker:23 fragmentation first, to provide a denser packing.
Label b in Figure 4-17 shows Heckel plots for
= Kj - K2 • Log P (18) different size fractions of the same material that
are typical of this behavior. Lactose is one such
material.
Type a Heckel plots usually exhibit a higher
Heckel Plots
final slope (Ky) than type £>, which implies that
The foregoing equations have been criticized the former materials have, as expected, a lower
because some of the constants apparently lack yield stress. Hard, brittle materials are, in gen¬
physical significance. Another equation, cred¬ eral, more difficult to compress than soft, yield¬
ited to Heckel,24 is free from this empiricism, ing ones because fragmentation with subse¬
however. The Heckel equation is based upon quent percolation of fragments is less efficient
analogous behavior to a first-order reaction, than void filling by plastic deformation. In fact,
where the pores in the mass are the reactant, as the porosity approaches zero, plastic deforma¬
that is: tion may be the predominant mechanism for all
materials.
The two regions of the Heckel plot are thought
Log y = KyP + Kr (19)
to represent the initial repacking stage and the
subsequent deformation process, the point of
where Ky is a material-dependent constant in¬ intersection corresponding to the lowest force at
versely proportional to its yield strength S which a coherent tablet is formed. In addition,
(Ky = 1/3S), and Kr is related to the inital re¬ the crushing strength of tablets can be corre¬
packing stage, and hence E„. The above relation¬ lated with the value of Ky of the Heckel plot;
ships may be established by simply measuring larger values of Ky usually indicate harder tab-

82 • The Theory and Practice of Industrial Pharmacy

 stage, as the applied force is removed. This leads
to a new set of stresses within the tablet as a
result of elastic recovery, which is augmented by
the forces necessary to eject the tablet from the
die. Irrespective of the consolidation mecha¬
nism, the tablets must be mechanically strong
enough to accommodate these stresses; other¬
wise, structural failure will occur.
For this reason, studies in which data are col¬
lected during both parts of the cycle have proved
valuable. In particular, the degree and rate of
relaxation within tablets, immediately after the
point of maximum compression, have been
shown to be characteristic for a particular sys¬
tem. Recording this phase of the cycle as well
can provide valuable insight into the reasons
behind inferior tablet quality and may suggest a
remedy. For example, if the degree and rate of
relaxation are high, addition of some plastically
deforming component, such as polyvinyl pyrroli-
Compressional Force done, may be advisable to reduce the risk of pro¬
nounced recovery leading to structural failure.
FIG. 4-17. Examples of Heckel plots. Curves i, ii, and Hi If the stress relaxation process involves plastic
represent decreasing particle size fractions of the same
flow, it may continue after all compressional
material. Type a curves are typical of plastically deforming
materials, while those in which fragmentation occurs ini¬ force has been removed, and the residual radial
tially tend to show type b behavior. pressure will decay with time. The plastic flow
can be interpreted in terms of a viscous and elas¬
tic parameter in series.26 This interpretation
lets. Such information can be used as a means of leads to a relationship of the form:
binder selection when designing tablet formula¬
tions. Note that Heckel plots can be influenced Log Ft = Log Fm - Kt (22)
by the overall time of compression, the degree of
lubrication, and even the size of the die, so that where Ft is the force left in the viscoelastic re¬
the effect of these variables can also be studied. gion at a time t, and Fm is the total magnitude of
Another important factor in the use of all this force at time t = 0 (i.e., when decompress¬
force-porosity relationships is that for many for¬ ion begins). K is the viscoelastic slope and a mea¬
mulations, there is a relatively narrow optimum sure of the degree of plastic flow. Materials with
residual porosity range that provides adequate higher K values undergo more plastic flow; such
mechanical strength, rapid water uptake, and materials often form strong tablets at relatively
hence, good disintegration characteristics. It is low compaction forces.
to the formulators’ advantage to identify this op¬ Alternatively, the changing thickness of the
timum range and be able to predict compressing tabletting mass due to the compactional force,
conditions needed to reach it. In addition to the and subsequently due to elastic recovery during
predictive capability, establishing behavioral unloading, can be used to obtain a measure of
patterns for a given formulation (so-called “fin¬ plastoelasticity, y.27 Specifically:
ger-printing”) may provide valuable diagnostic
information in the event that a particular batch
H0 Hr - Hm
of the product causes problems. (23)
Note also that the initial porosity can affect Hm Hc - Hm
the course of the entire compressional se¬
quence, and that in general, slow force applica¬ where H0, Hm, and Hr are the thickness of the
tion leads to a low porosity for a given applied tablet mass at the onset of loading, at the point of
load. maximum applied force, and on ejection from
the die, respectively. A linear relationship be¬
tween y and log reciprocal of the tensile strength
Decompression of the tablets has been demonstrated.27 In gen¬
In operations such as tabletting, the compres¬ eral, values of y above 9 tend to produce tablets
sional process is followed by a decompression that are laminated or capped.

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS * 83

Compaction Profiles loop (OABC') indicates the extent of departure
from ideal elastic behavior, since for a perfectly
Monitoring of that proportion of the applied
elastic body, line BC' would coincide with AB.
pressure transmitted radially to the die wall has
In many tabletting operations, the applied
been reported by several groups of workers. For
force exceeds the elastic limit (point B), and brit¬
many pharmaceutical materials, such investiga¬
tle fracture and/or plastic deformation is then a
tions lead to characteristic hysteresis curves,
major mechanism. For example, if the material
which have been termed compaction profiles.
readily undergoes plastic deformation with a
Figure 4-18 is a typical example. Remember that
constant yield stress as the material is sheared,
the radial die-wall force arises as a result of the
then the region B to C should obey the equation:
tabletting mass attempting to expand in the hor¬
izontal plane in response to the vertical com¬
Pr = Pa ~ 2S (24)
pression. The ratio of these two dimensional
changes, the Poisson ratio, is an important mate¬
where S is the yield strength of the material.
rial-dependent property affecting the compres-
Note that the slope of this plot is unity, so that
sional process. The ratio is a property of solid
marked deviation from this value may indicate a
bodies, however, and not necessarily of a porous
more complex behavior. Deviation could also be
mass of particulate solid. The anomalous results
due to the fact that the material is still signifi¬
discussed in the literature may well reflect this
cantly porous, which would invalidate the anal¬
important distinction, but certain qualitative
ogy to a solid body. Until this difference can be
deductions may still be possible.
resolved, little is to be gained in proposing math¬
For instance, when the elastic limit of the
ematical solutions for the region BC, which is
material is high, elastic deformation may make
often nonlinear anyway. This does not mean,
the major contribution, and on removal of the
however, that compaction profiles themselves
applied load, the extent of the elastic relaxation
cannot provide further useful information.
depends upon the value of the material’s modu¬
For example, since point C represents the sit¬
lus of elasticity (Young’s modulus). If this value
uation at the maximum compressional force
is low, there is considerable recovery, and unless
level, the region CD is therefore the initial relax¬
a strong structure has been formed, there is the
ation response as the applied load is removed. In
danger of structural failure. Maximum compres-
practice, many compaction profiles exhibit a
sional force levels are particularly important in
marked change in the slope of this line during
such cases, since most of the stored energy is
decompression, and a second yield point (point
released on removal of the applied load. Con¬
D) has been reported.
versely, if the modulus of elasticity is high, there
Perhaps the residual radial pressure (inter¬
is a small dimensional change on decompression
cept EO), when all the compressional force has
and less risk of failure. The area of the hysteresis
been removed, is more significant, since this
pressure is an indication of the force being
transmitted by the die wall to the tablet. As such,
it provides a measure of possible ejection force
level and likely lubricant requirements; if pro¬
nounced, it suggests a strong tablet capable of at
least withstanding such a compressive pressure.
Conversely, a low value of residual radjal pres¬
sure, or more significantly, a sharp change in
slope (DE) is sometimes indicative of at least
incipient failure of the tablet structure. In prac¬
tical terms, this may mean introducing a plasti¬
cally deforming component (e.g., PVP [polyvinyl
pyrrolidone] as binder, starch as diluent) to facil¬
FIG. 4-18. Examples of compaction profiles. Dotted line
O to A represents a highly variable response due to repack¬ itate dissipation of these stresses, and hence a
ing, while at A, elastic deformation becomes dominant and more gradual change in slope of the decom¬
continues until the elastic limit B is reached. From B to pression plot, a preferred feature. In one recent
the point of maximum compression C, deformation is pre¬ study,28 modified compaction profiles (PA - PR)
dominantly plastic, or brittle fracture is taking place. The versus (PA + PR) were able to distinguish be¬
decompression process C to D is accompanied by elastic
tween readily consolidating and nonconsolidat¬
recovery, and if a second yield point (D) is reached, by
plastic deformation or brittle fracture D to E. The decom¬ ing materials. Specifically, two characteristic
pression line B to C' represents the behavior of a largely parameters (a normal stress value at zero shear
elastic material. and a minimum shear stress value), obtained

84 • The Theory and Practice of Industrial Pharmacy

from the unloading portion of the cycle, were the material, i.e., overcome resistance to relative
shown to correlate with tensile strength and sur¬ interparticulate movement.
face hardness of the compacted materials. These workers’ estimation of the total work
involved, WT, was obtained by monitoring
punch force and the distance D through which it
Energy Involved in Compaction acted, so that:
Tablet machines, roll compactors, extruders,
f Dmax
and similar types of equipment require a high
WT = I F • dD (25)
input of mechanical work. The ways in which
JnK-o
this work is converted into other forms of energy
during these processes is of interest in both re¬ which represents the area under the entire
search and production areas. More specifically, force-displacement plot (the area ABC in Fig.
the work requirement is a key factor in machine 4-19).
design, and any proportion of the applied energy This approach oversimplifies the true picture
stored in a product such as a tablet retains a de¬ because, as can be seen from Figure 4-19, in
structive capability. which both punch forces and punch displace¬
The work involved in various phases of a tab¬ ment data have been collected throughout an
let or granule compaction operation includes entire compression-decompression press cycle,
(1) that necessary to overcome friction between WT comprises at least three components.30 The
particles, (2) that necessary to overcome friction region WF represents the work done in overcom-
between particles and machine parts, (3) that
required to induce elastic and/or plastic defor¬
mation of the material, (4) that required to
cause brittle fracture within the material, and
(5) that associated with the mechanical opera¬
tion of various machine parts.
Normally, an appreciable amount of the en¬
ergy supplied is converted to heat, which of
course does not contribute toward the main ob¬
jective of the process. On a theoretic basis, how¬
ever, this heat does provide a means of monitor¬
ing the energy balance in the system. For
example, one of the earliest experimental re¬
ports was that of Nelson and associates,29 who
compared the energy expenditure in lubricated
and unlubricated sulfathiazole granulations as
shown in Table 4-2. Lubrication reduced energy
expenditure by 75%, chiefly because of a lessen¬ FIG. 4-19. Example of force-displacement (F-D) curve.
(A) upper punch force; (A) lower punch force. The area
ing of the major component, namely energy uti¬
WF represents the work done in overcoming friction, while
lized during ejection of the finished tablet. Note that of area WD is the elastic deformation energy stored in
that lubrication has no apparent effect on the the tablet during compression. Thus, WN is the net me¬
actual amount of energy required to compress chanical energy actually used to form the tablet.

Table 4-2 Energy Expended in Compression of

400 mg Sulfathiazole Granulation

Compression Energy Expended (Joules)

Process
Unlubricated Lubricated

Compression 6.28 6.28

Overcoming die wall friction 3.35 negligible
Upper punch withdrawal 5.02 negligible
Tablet ejection 21.35 2.09

TOTALS 36.00 8.37

After Nelson et al.29

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 85

ing friction and therefore depends upon the
properties of the tablet mass. WN is the net me¬
chanical energy actually used to form the tablet,
and WD is the elastic deformation energy stored
in the tablet initially, but released during de¬
compression. If the top punch moves too quickly
during this decompression, contact with the tab¬
let may be lost. In this eventuality, the complete
work of elastic recovery of the tablet is not trans¬
ferred to the punch face, and an error is intro¬
duced into the decompression curve.
Early investigators of the technique overcame
the problem by compressing the tablet a second
time before ejecting it from the die.23 The sec¬ FIG. 4-20. Binder selection using net energy input during
ond compression-decompression cycle provides tabletting process. Because of correlation between mechan¬
ical strength of tablets and net energy input, gelatin is the
a measure (WN2) of the net energy required to
binder of choice in this example. (After deBlaey et al.33)
recompress the material to the point B (in Fig.
4-19). WN2 is equivalent to the amount of energy
involved in the elastic recovery of the tablet.
Since good correlation is usually found between
WN and the crushing strength of the tablets, gel¬
Force-Displacement (F-D) Curves atin in this example would be chosen as the best
Distinctive F-D curves related to the stress/ binder. Note too the pronounced flattening of
strain properties of the materials involved have the curve for starch, so that compression of this
now been reported by several groups of work¬ formulation at maximum FA values above the
ers.30'33 The technique has been shown to pro¬ point of inflection would not be helpful and
vide a more sensitive method for evaluating lu¬ might even be deleterious, owing to increased
bricant efficiency than the widely quoted R elastic recovery that could lead to structural fail¬
value (which is the lower to upper punch force ure of the tablet.
ratio).31 For example, the data given in Table 4-3 Because the rate of compression is known to
show that R values are incapable of distinguish¬ affect the tabletting process, an extension of the
ing between the result of incorporating lubricant use of F-D curve data has been suggested.34
in the granulation and the result of coating it on This proposition takes into account the rate of
the die wall. The WN measurements, however, loading by monitoring the power expended,
clearly indicate the lower energy expenditure if rather than the work involved. In practice, the
the granulation is lubricated. area under the F-D curve is divided by the time
The wider utility of F-D curves is exemplified over which the force is applied.
by their application to the selection of a “best”
binder (from gelatin, starch, and methylcellu-
lose) for a sulphonamide tablet, by determining
Strength of Tablets
the contribution of the three components WF, The mechanical strength of tablets has been
WN, and WD to the total work WT.33 A plot of WN described in a variety of ways, including hard¬
versus maximum compressional force produced ness, bending strength, fracture resistance, fria¬
curves such as those shown in Figure 4-20. bility, and crushing strength.35

Table 4-3 Compression of 300 mg at 440 M Pa

Unlubricated Die Wall Granulation

Lubricated Lubricated

Coefficient of
Lubrication, R 0.84 0.98 0.98
Net Work for
Compression (Nm) 5.6 4.4 3.4
Remaining Lower
Punch Pressure (MPa) 3.2 2.5 2.5

After deBlaey and Polderman.31

86 • The Theory and Practice of Industrial Pharmacy

 Crushing Strength and inverse proportionality with porosity, over
The most popular estimate of tablet strength normal ranges of compressional force.38
has been crushing strength, Sc, which may be Failure may be propagated through the tablet
defined as “that compressional force (Fc) which, along individual granule boundaries or through
when applied diametrically to a tablet, just frac¬ the granules themselves, depending on whether
tures it.”36 Most practical tests involve placing the granular bonding is weaker or stronger than
the tablet on or against a fixed anvil and trans¬ that between their composite particles. If frac¬
mitting the force to it by means of a moving ture tends to occur across granules, then gran¬
plunger, until the tablet just fractures. Since ule size influences tablet strength, smaller sizes
tablets are anisotropic and test conditions rarely leading to greatest strength for a given compres¬
provide well-defined uniform stresses, full and sional pressure 39 Conversely, if fracture along
exact interpretation of findings is difficult. With granule boundaries predominates, granule size
flat-faced anvil and plunger, the failure may be may have little influence on strength.
compressive (i.e., the tablet is crushed). If one of Knudsen proposed a general equation of the
form:40
them is knife-edged, however, then it is more
likely to be tensile (tablet splits open across a
diameter). It may then be described by the equa¬ Sc = K • d l' (28)
tion:
where d is the mean particle diameter, and the
2FC constant a is a material-dependent property. The
Sf — (26) results of Shotton and Ganderton supported this
DH
proposal,41 as can be seen from the data given in
Figure 4-21. The presence of lubricants, how¬
where ST is the tensile strength, and D and H
ever, can nullify or even reverse the trends
are the diameter and thickness of the tablet, re¬
shown in this figure, because of the weakening
spectively.
of interparticle bonds.
It has been suggested that the work Wf re¬
The inherent cohesiveness of very fine parti¬
quired to cause tablet failure correlates better
cles may enhance the consolidation process and
with other mechanical strength tests and is a
lead to even stronger tablets for a particular
more sensitive parameter for comparison with
compressive force. On the other hand, their rela-
other tabletting parameters. Wf is obtained from
the equation:

w,-^Bh ■’Til <27>

where F is the force applied to the tablet and z,

the deformation resulting from it, is represented
by the relative displacement of the anvil and
plunger.
<1>
Many crushing-strength testers are described O
k_
in the literature, and several are available com¬ o
u.
mercially. Comparisons of these have been 05
C
made,36 and three important sources of variabil¬ Ic
ity or error have been identified. Many older <n
3
manually operated types had a rate of loading u
that was operator-controlled; this could affect
the value of Sc obtained. The zero setting was
indeterminate in some cases, and in a few, the
scale reading did not accurately indicate the ac¬
tual load being applied. For these reasons, in¬
struments should be calibrated and checked pe¬
riodically, especially if this property is being
correlated with other characteristics. mm
Many reports relate crushing strength to other Mean grain diameter
process and tablet parameters.37 Among the
FIG. 4-21. Effect of particle size on the crushing strength
most.widely quoted relationships are linear pro¬ of tablets. (Applied pressure 85 MPa.) (From Shotton and
portionality with disintegration time and log FA, Ganderton.41)

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 87

tivelv high microporosity may trap more air in One report, however, does describe the practi¬
the tablets, which can give rise to capping. For cal use of indentation hardness and tensile
materials in which fracture occurs along granule strength data to define three dimensionless indi¬
boundaries, the presence of a thin film of binder ces (strain index, bonding index, and brittle
at these surfaces may lead to failure across the fracture index) that were used to quantify the
granules, which when tabletted could result in relative tabletting performance (especially lami¬
an increase in tablet strength. nation tendency) of both single components and
Reports describing SEM photomicrography of mixtures.45
tablet surfaces have provided vivid pictorial evi¬
dence of tablet microstructure and of the role of
various excipients.42 More specifically, those
Lamination (Capping) of Tablets
adjuvants used widely in direct compression One of the more common problems encoun¬
tabletting operations have been subjected to de¬ tered in compaction is that the tablet structure
tailed scrutiny by Shangraw and colleagues.43 fails on ejection from the die or during subse¬
Using this same approach, Seager and co-au¬ quent operations such as coating. Often, the fail¬
thors have been able to correlate method of gran¬ ure has the characteristic appearance shown
ule manufacture with tablet structure and prop¬ diagrammatically in Figure 4-22—hence, the
erties.44 They found that spray-dried granules term capping. The phenomenon was first
produced the strongest tablets, which dissolved thought to be due entirely to entrapment of air
at least as fast as those prepared by wet massing. within the tablet. This air would be under a
Tablets prepared using granules from both of pressure approximating that of the applied com-
these methods possessed mechanical and re¬ pressional load, and so on ejection would pos¬
lease properties superior to those of tablets made sess considerable disruptive capability. Air en¬
from previously roll-compacted material. They trapment is more likely to occur with fine
attributed this to variation in liquid penetration particle sizes of materials, which tend to pack
rates, which are related to residual porosities, poorly. Slow compressional rates and use of mul¬
and to the tablets’ degree of hydrophilicity, tistage compression presses often reduce cap¬
which is due to binder distribution. ping tendencies and have provided support for
this postulate. This concept, however, is known
to represent only one factor in what may be an
extremely complex process. For example, a re¬
Friability cent report demonstrated that when certain
The crushing strength test may not be the granulations were compressed at high speed
best measure of potential tablet behavior during under partial vacuum, classical capping was
handling and packaging. The resistance to sur¬ minimized, but was replaced by a tendency to
face abrasion may be a more relevant parameter, laminate.46
as exemplified by those tests that measure the Massive elastic recovery to relieve the inher¬
weight loss on subjecting the tablets to a stand¬ ent variation in compressional stress distribu¬
ardized agitation procedure. The most popular tion already described, when associated with
(commercially available) version is the Roche
Friabilator, in which approximately 6 g (w„) of
dedusted tablets are subjected to 100 free falls of
6 inches in a rotating drum and are then re¬
weighed (w). The friability, f, is given by:

f=100-(l-^) (29)

Values of f from 0.8 to 1.0% are regarded as the

upper limit of acceptability.
Microindentation tests have also been pro¬
posed, but the heterogeneous nature of the tab¬
let surface on the microscale renders them less
reliable than when used on homogeneous mate¬
rials, and they are more tedious to perform. For
these reasons, they have found only limited ac¬
ceptance, and then in the research rather than
production areas. FIG. 4-22. Diagram of a “capped” tablet.

88 • The Theory and Practice of Industrial Pharmacy

weakly bonded material, must be another major ably processed and interpreted, facilitate evalua¬
contributing factor in many instances. Any tech¬ tion of many of these tabletting parameters.
nique that can reduce this effect is helpful, such The value of using a single-station press for
as inclusion of components in the formula to developmental work on formulations that are to
enhance bonding and provide a matrix of plasti¬ be manufactured on multi-station presses is
cally deforming material for stress relief. In ad¬ strictly limited. This is less the case when mate¬
dition, more gradual loading and unloading of rial rather than process factors are most impor¬
the tablet mass by utilization of large compres¬ tant, unless the rate of loading is critical. The
sion rolls, precompression, and slow press sensitivity of the formulation being tested to the
speeds also reduce the tendency, as does reduc¬ loading rate, however, should be determined by
tion in maximum compressions! force. Lubri¬ compression at different speeds and by monitor¬
cant and moisture levels, tooling geometry and ing of any changes in tablet properties.
condition, and compression mechanism (the Because of this rate factor, several workers
type of press) all contribute to the properties of have elected to instrument isolated punch and
the tablets produced and demand constant con¬ die sets and to carry out compression experi¬
sideration. For this reason, attention has been ments using these sets in conjunction with a
directed to the advantages of instrumentation compression/tension testing machine. For ex¬
that can accomplish at least some of these moni¬ ample, the assembly shown in Figure 4-23 is
toring tasks. capable of monitoring all of the various forces
acting on the system as well as the punch dis¬
placements. Recently, a sophisticated system
The Instrumentation of Tablet has been described that is capable of mimicking
(in real time) the precise compression cycle of
Machines any press; thus, it has all the advantages of
Several distinct forms of instrumentation are using a single station of tooling and still follows
discussed within this section. Increasing evi¬ rotary press action.47 The system stores a repre¬
dence shows the value of instrumenting tablet sentation of the precise compression cycle of the
presses to provide information on the inherent
compaction characteristics of the major compo¬
nents in a formulation, and on the effect of addi¬
tives upon them. The emphasis, therefore, is on
properties of the materials in a research and
development environment, which perhaps could
utilize single-station machines for some of the
work. On the other hand, increasing use of high¬
speed multi-station tablet presses, coupled with
a desire to improve quality specifications for tab¬
lets, leads to forms of instrumentation intended
primarily for production machines, but of inter¬
est to the quality assurance department as well.
The technology described in the first part of
the chapter suggests that the mechanisms in¬
volved in the tabletting process center on utiliza¬
tion of the unsatisfied bonds at the solid surface.
This process is enhanced by the generation of
large areas of clean surface, which are then
pressed together, as might occur if appreciable
brittle fracture and plastic deformation were in¬
troduced into the system. It was also noted that
the behavior on decompression can markedly
affect the characteristics of the finished tablets,
because the structure must be strong enough to
accommodate the recovery- and ejection-in¬
duced stresses. Furthermore, ability to monitor
ejection forces leads to valuable information on
lubricant efficiency. Measurement of punch and
die forces plus the relative displacement of the FIG. 4-23. Diagram of instrumented, isolated punch and
punches can provide raw data, which when suit¬ die assembly.

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 89

press in a microprocessor, which in turn con¬
trols the movements of the isolated punches, so
that it reproduces the exact loading profile of the
press. Such assemblies facilitate compressional
studies at various compressional rates and pro¬
vide a convenient means of acquiring the maxi¬
mum amount of information while using the
minimum amount of time and materials. They
are now often referred to as “compaction simula¬
tors.”

Single-Station Presses
Almost all reports in the literature describe
strain gauge networks as a transducer* for
measuring the magnitude of the forces operat¬
ing during the compression cycle. Resistive
(metal foil) gauges are usually preferred, and
ideally, they should be bonded as near to the ac¬
tive site as practicable, namely at the punch
faces, so as to eliminate lack of correlation be¬
tween signals obtained from remote regions of
the machine frame and the actual forces present
in the tooling. The bonding must be over the
entire area of the correctly aligned gauge as de¬
scribed in strain gauge manuals, 8 at a site
where the elastic change in linear dimension of
the stress-bearing member (due to the applied
forces) can be measured.
FIG. 4-24. Strain-gauged punches (A) and instrumented
An example of one of the commonest arrange¬ die (B). Favored locations for mounting small linear foil
ments is shown diagrammatically in Figure strain gauges are the upper punch, lower punch holder,
‘4-24. The die-wall instrumentation requires and modified die of a single-station tablet press.
machining of the die wall to accommodate the
gauges and reduce the thickness to a point at
which adequate sensitivity is achieved. The arrangement is mounted as shown in Figure
original geometry is subsequently restored with 4-26 (“Poisson” configuration), compensation is
silicone rubber or similar material. The fore¬ provided for both temperature change and any
going procedure may necessitate annealing and bending of the piece.
subsequent rehardening and tempering of the
die. Care is needed to ensure that such treat¬
ment does not change the precise geometry of
the bore.
Assemblies such as those shown in Figure
4-24 may be connected so as to conform to a
Wheatstone bridge network (Fig. 4-25), which is
normally energized by an AC amplifier system,
the attenuated output giving a DC voltage pro¬
portional to the force being applied. Since
changes in resistance are small, a full bridge
network (with strain gauges in all four arms) is
preferable; one should bear in mind that such a
system is then input-voltage-dependent, and
therefore a stabilized supply is essential. If this

*A transducer is any device that converts a physical quan¬

tity into a more easily monitored or convenient (propor¬
tional) signal, e.g., mechanical force into a direcdy pro¬ FIG. 4-25. Simple full-bridge Wheatstone bridge circuit,
portional DC voltage. in which Rl, R2, R3, and R4 represent strain gauges.

90 • The Theory and Practice of Industrial Pharmacy

 FIG. 4-27. Piezo-electric punch instrumentation. Pre¬
ferred locations for mounting small piezo-electric force
transducers are the punch holders of a single-station press.

The advantages of piezo-electric devices include

high sensitivity, robust construction, and no
bonding to machine fabric, which therefore al¬
lows easy changing of tooling. Furthermore,
since the signal originates as an electrical
charge, the transducer may be zeroed, simply by
grounding it, regardless of initial load.
Although calibration data are supplied by the
FIG. 4-26. Poisson arrangement. In this full-bridge strain manufacturer of the above equipment, in situ
gauge network, gauges 2 and 4 are active, while gauges 1 calibration of the particular instrumentation
and 3 are temperature-compensating. against known loads is highly desirable. With
punch assemblies, this may be achieved by use
of a calibrated load cell, which can be placed on
Alternatively, transducers based upon the the die table (Fig. 4-29); its signal can be com¬
piezo-electric effect in certain crystals, notably pared with those from the instrumented
quartz, may be used. When subjected to external punches as they are simultaneously loaded. Al¬
forces, these materials develop an electrical ternatively, entire punch assemblies can be re¬
charge proportional to the effect of the force. moved from the press and mounted in an accu¬
Such a transducer is connected by a high imped¬ rate compression/tension test press. The normal
ance cable to a charge amplifier, which converts
the charge into a directly proportional DC volt¬
age. One disadvantage of such transducers is
that the charge inevitably dissipates with time,
and since a difference is being measured, they
are unsuitable for static force measurements.
Small piezo-electric load washers can easily be
mounted on, or in, the upper and lower punch
holders of single-station presses, as shown in
Figure 4-27. Radial die wall measurement is
more difficult, but has been achieved by means
of a special holder for the transducer, as illus¬
trated in Figure 4-28. Such systems, like their
strain gauge equivalents, only monitor the radial
force over a localized region of the die wall. They
FIG. 4-28. Piezo-electric die wall instrumentation. An
may give rise to misleading data, unless they are example of the use of a piezo-electric force transducer (in a
sited at the same level on the die wall as the special holder) in conjunction with a vertically split die to
region at which the tablet is being compressed. measure radial die wall forces.

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 91

FIG. 4-29. Calibration using load cell. Diagram illus¬
trates the use of a piezo-electric transducer and special
holder to calibrate the upper and lower punch instrumen¬
tation on a single-station press.

procedure with die-wall instrumentation is less

straightforward. Ideally, the necessary measure¬
ments are made by sealing the open ends of the
die cavity, then pumping in oil at known pres¬
sures and noting the response. A close-fitting
rubber plug or rubber powder in the die cavity,
however, may be regarded as a perfecdy elastic
material (thus radial die-wall reaction will be FIG. 4-30. Typical LVDT circuit. Diagram shows the pri¬
equal to any applied force) and can therefore be mary winding and two equally but oppositely wound sec¬
substituted for oil. ondaries surrounding the movable soft iron core.
The preferred form of transducer for measur¬
ing punch displacements is based on the differ¬
ential inductor principle, and is commonly a lin¬ scribed by Ho and co-workers,50 however, these
ear variable differential transformer (LVDT) as disadvantages have been overcome, and a signif¬
shown diagrammatically in Figure 4-30. The icant proportion of the stations remain active, as
movable ferrous core of the transducer is rigidly shown in Figure 4-31.
connected to the punch by a mechanical link, so Other workers have been less reluctant to uti¬
that movement unbalances the “secondary” cir¬ lize remote stationary sites on the machine
cuit, the output of which is attenuated to pro¬
duce a DC voltage directly proportional to dis¬
placement.

Multi-Station Presses
One of the major differences in the instru¬
mentation of multi-station as opposed to single¬
station presses is the inherent difficulty in re¬
trieving electrical signals from a revolving tur¬
ret. Some early workers overcame this difficulty
by employing radiotelemetry to transmit the
force signal from strain-gauged upper and lower
punches to external recorders.49 They were un¬
FIG. 4-31. Telemetry system. Diagram shews a possible
suitable for normal production conditions, since arrangement for a force and displacement measuring sys¬
only a few stations were operative, and only low tem, using radiotelemetry to retrieve the signals from a
machine speeds were possible. In a system de- multi-station tablet press.

92 • The Theory and Practice of Industrial Pharmacy

frame, in particular the upper and lower com¬ ure of the beam caused by the lower punches
pression roll carrier systems. For a given ma¬ during ejection was monitored by strain gauges
chine, the best location probably depends upon and was found to mimic the ejection response of
its actual design, but certain general points are an instrumented lower punch.
worth noting. The response of a strain gauge is Alternatively, the normal cam can be cut into
entirely a function of the change in linear di¬ three sections, each clamped to the frame by a
mension of the machine part to which it is bolt, two of which are fitted with a piezo-electric
bonded. Therefore, such changes must be suffi¬ load washer, for instance. The division should
cient to induce an adequate change in gauge be such that there is only one punch on each
resistance while not exceeding its elastic limit. section at a time (Fig. 4-33). The first transducer
In practice, this usually means that some part of then monitors the force to initiate ejection (to
the press has to be weakened by machining, an break tablet die-wall adhesions), and the second
operation in which great care must be exercised. monitors the force necessary to push the tablet
Cast iron components are unsuitable because of clear of the die. This arrangement minimizes
variability in their modulus of elasticity and the fulcrum effect, as the punches move over
Poisson ratio; therefore, only parts constructed the cam surface toward and then away from the
of steel should be selected. Sensitivity to temper¬ actual transducer location. Certain aspects of
ature changes may also influence site choice so the state of the tooling, such as sticking of the
as to avoid susceptible regions, e.g., near electric lower punches due to frictional effects, can also
motors. be detected by sensitive instrumentation of this
One of the more popular arrangements on type.
modem high-speed presses is to attach strain Mitrevej and Augsburger have recently de¬
gauges or to incorporate a piezo-electric load cell scribed a system to measure the adhesion of tab¬
into one of the tie rods, as illustrated in Figure lets to the lower punch face by attaching strain
4-32, although strain gauges may require ma¬ gauges to a small cantilever blade mounted on
chining of the rod. Other sites have included the the feed frame in front of the sweep-off attach¬
compression columns, specially modified pres¬ ment (Fig. 4-34).52 They found that the force of
sure rolls, and a modified eyebolt of the lower adhesion did not necessarily reflect the ejection
compression roll assembly. force or the lubricant activity of the formulation;
Instrumenting the normal ejection cam on a however, the system did appear to be sensitive to
rotary tablet machine by attaching strain gauges batch variations in the antiadherent quality of
to its bolts is of limited value, because the result¬ magnesium stearate.
ing signal is a summation of the effects of the Regardless of which remote site is selected for
several lower punches on it at any instant. The instrumentation, the response should always be
solution adopted by Wray employed a two-part checked—and indeed, rechecked periodically—
cam so that the region responsible for tablet against signals obtained from directly instru¬
ejection is separate and in the form of a beam mented tooling over the whole working range of
fixed at one end.51 This method necessitated the machine, to ensure constancy in the re¬
minor modifications to other parts of the ma¬ sponse relationships.
chine but did not affect normal operation. Flex¬

FIG. 4-33. Instrumented ejection cam. Diagram skeavs

FIG. 4-32. Instrumented tie rod. Diagram shows the loca¬ the preferred method of sectioning an ejection cam and the
tion of strain gauges on the tie rod linking the upper and transducer locations for monitoring ejection forces on a
leaver pressure roll carriers of a multi-station tablet press. multistation tablet press.

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 93

 TRANSDUCERS
FIG. 4-34. Instrumentation to measure “sweep-off ” force. FIG. 4-36. I.T.M.-microprocessor linkage. Diagram skews
Diagram illustrates measurement of the force of adhesion the major components of a typical instrumented tablet
between a tablet and the lower punch of a tablet press by machine interfaced to a dedicated computer system.
means of a strain-gauged cantilever blade attached to the
feed frame.

into memory locations in the computer. This

Signal Processing digital data can then be recalled, manipulated,
The signals from the instrumentation de¬ and outputted in a wide range of graphic or tabu¬
scribed in this section are usually DC voltages lar formats. By such means, active compounds
and can therefore be retrieved, stored, and proc¬ and excipients can be “fingerprinted” for their
essed by a common means. Popular practice is to compactional characteristics.53 The general
display the signals on a cathode ray oscillograph layout of a typical configuration is shown in
(CRO) since this enables instant visualization of Figure 4-36.
the instrumentation output. In the past, such
displays were often photographed to provide a
permanent record, but ultraviolet recording os¬
Role of Instrumentation in
cillographs provide better definition of traces Production
and can facilitate a larger number of simultane¬ The modem tablet production department
ous recording channels, as illustrated in Figure seeks innovation because of the trend toward
4-35. direct compression methods, the availability of
Inexpensive microcomputers that are cur¬ machines with increased output, and the desire
rently available can remove much of the tedium to lessen tablet-to-tablet variations. In addition
in reducing raw data from the recorders previ¬ the design of instrumentation that monitors, or
ously described; they are therefore the method perhaps exercises some degree of control over,
of choice. The analog signals (DC voltages) can the tabletting process is an attractive goal be¬
be fed by an A-to-D (analog-to-digital) convertor cause of the possibility of reducing labor involve¬
ment.
To date, the most popular approach has been
the attempt to limit weight and hardness devia¬
tions, based upon the premise that compres-
sional force is directly proportional to tablet
weight, providing the following:

1. The formulation is homogeneous (i.e., has

uniform density).
2. The compressional force/tablet weight func¬
tion is constant.
3. The volume of the die cavities at the point of
maximum compression is constant.

FIG. 4-35. Typical traces from I.T.M. Reproduction of

The third supposition is valid only when the
typical traces obtained from a multichannel V/V recording
oscillograph connected to an instrumented single-station overall length of the punches and tip geometry
tablet press. are constant, the die bores are uniform, and the

94 • The Theory and Practice of Industrial Pharmacy

pressure rolls are perfectly cylindric and high-speed multi-station presses is the fre¬
mounted centrally. quency response of the various components of
The output from the electronic unit of most the system. Machine outputs are now exceeding
force (and displacement) measuring systems is a 12,000 tablets per minute, which means that the
DC voltage. Therefore, in this context, the sys¬ frequency of the force pulses is approximately
tem produces a series of voltage pulses of short 0.1 kHz. Since the detection of small differences
duration, each proportional to the weight of an in individual pulses may be necessary, all units
individual tablet. These signals can be condi¬ should have flat responses well beyond this
tioned to provide a wide range of monitoring and level, up to approximately 1.0 kHz.
control facilities of increased complexity. The Instrumented tablet machine technology is
addition of a simple event marker facilitates the advancing rapidly, and its ultimate role is not yet
identification of a particular station and of any realized. It will undoubtedly lead, however, to an
tooling faults, which produce repetitive atypical even better understanding of the tabletting proc¬
signals. The individual compression pulses can ess, which in turn will assist in formulation de¬
also be used to drive counting mechanisms and velopment and batch quality control. In addi¬
to provide a reliable figure for the number of tab¬ tion, the ever-increasing demand for more fully
lets made. automated production will be facilitated by such
The foregoing devices are uncomplicated and machines.
relatively inexpensive, but usually, there is a
desire to extend the signal conditioning system
to monitor the process to some degree. For ex¬ Instrumenting Hard-Shell
ample, one can set upper and lower limits for
acceptable tablet weight and then distinguish Capsule Filling Machines
pulses from tablets lying outside these thresh¬ One group of machines for filling hard-shell
olds. When the frequency of these out-of-specifi- gelatin capsules employs dosators, which form a
cation tablets exceeds some preset value, a relay soft plug of the powder mix and then transfer it
can be tripped to activate an alarm and/or the to-the empty shell body (see Chap. 13, Part I,
machine can be automatically stopped. “Hard Capsules”). This type of action requires
In general, for a larger investment, machines that the material be somewhat cohesive, and
can be fitted with mechanical accept/reject gates that low levels of applied mechanical force are
at the machine outlet, so that individual out-of- used to form and eject the plugs. Some similarity
specification tablets can be diverted to a separate exists between these operations and tabletting,
container. This function requires a high level of and attempts to instrument the machines in a
sophistication, because the defective tablets manner that is analogous to those just described
must be “memorized” until they reach the out¬ have been made. In the first report of such in¬
let. strumentation, Cole and May described a modi¬
A second approach is to take the amplified fied dosator piston, to which strain gauges had
output signals and feed them into an averaging been bonded as shown in Figure 4-37.54 The
network. This average DC voltage is compared machine was further altered so that the twin
with a reference voltage, and any difference is dosator head had a reciprocating rather than ro¬
converted into an AC signal, which is amplified tational movement. This facilitated using the
and used to drive a two-phase servomotor. The instrumented machine through many filling
motor can be connected to the weight or pres¬ cycles without entangling the transducer leads.
sure adjustment control of the press, so that any Later workers used a mercury contact swivel to
change in the average compressional force is achieve the same end without changing the
reflected in an adjustment of either the weight machine cycle.55
or force control. Such instrumentation permits continuous
Regardless of which transducer systems, sites, monitoring of the force necessary to form the
or forces are selected, it is essential to ascertain plug during dosator filling, plus any residual
that the response of the instrumentation is a di¬ force present during carry-over to the capsule
rect function of the property needing to be moni¬ shell position and that force necessary to eject it
tored. Therefore, the work of Wray and his col¬ into the einpty shell. Such forces were found to
leagues-is important in that it establishes that range from 5N to 350N, depending on the mate¬
stresses generated in certain parts of the ma¬ rial,, presence of lubricant, and time for which
chine frame are directly proportional to the the machine had been running. Some typical
punch forces, which in turn are related to com¬ recorder traces are shown in Figure 4-38.
pressional weights.51 Among the more important findings to emerge
One final important aspect of instrumenting from such investigations is the role of even low

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 95

FIG. 4-38. Typical traces from instrumented capsule machine dosator. Force-time traces are of three materials (A, B,
lactose; C, D, compressible starch; E, F, dibasic calcium phosphate) at different levels. (From Small and Augsburger.50
Reproduced with permission of the copyright owner.)

96 • The Theory and Practice of Industrial Pharmacy

 or capsule at an early stage in development.
Consequently, any technique that can assist in
this process is particularly attractive. Because
the measurements described here are sensitive
dosator to changes in the composition and performance
of the tabletting or capsule mass, and because
piston optimum values for the various parameters can
usually be postulated, they provide a useful for¬
mulation and developmental tool and aid in so¬
lution of problems arising from batch-to-batch
variations.
During the next decade, an increasing aware¬
ness of these possibilities is anticipated, and
consequently, more profound studies of this par¬
ticular form of powder compression and consoli¬
dation are to be expected. Paralleling these es¬
sential research and development activities are
trends toward fuller automation of the facilities
in which tablets and capsules are manufactured.
Such trends place greater emphasis on the need
for a fuller appreciation of the processes in¬
volved. Because complete elucidation of the
tabletting operation, and indeed encapsulation,
has not yet been realized, it must therefore con¬
tinue to challenge contemporary investigators.

FIG. 4-37. Diagram of instrumented dosator piston.

Appendix A
levels of lubricant (0.5%) in eliminating carry¬
over forces and reducing ejection forces, partic¬
ularly during long runs. The adherence of mate¬ Symbols Used in Formulas
rial between the wall of the filling head and the A. Area
piston can also be detected as a negative force D. Diameter or displacement
after ejection and indicates a sensitive means of d. Particle diameter
detecting this potential problem. Some materials E. Porosity
such as lactose and basic dicalcium phosphate, F. Force
if unlubricated, give rise to high ejection forces f. Friability
(300N) after only a few capsules have been filled H. Height/thickness
and show the importance of determining precise h. Heigh t/thickness
lubrication needs. K. A constant
Later studies have incorporated measure¬ L. Length
ments of force and dosator piston displacement M. Mass
not unlike those described earlier for tablet ma¬ P. Pressure
chines: signals are retrieved from the rotating R. Lubricant efficiency
head by a mercury pool-slip ring assembly.56 S. Strength
With this arrangement, the work involved in the t. Time
various stages can be estimated, and the need U. Piston movement
for formulation modification established. This v. Volume
approach will undoubtedly be extended to other W. Work
types of hard-shell capsule filling equipment, w. Weight
and perhaps to production filling operations, to Z. Strain
achieve the same goals as enumerated for tablet A Poisson ratio
manufacture. H Frictional coefficient
For several reasons, including regulatory re¬ p Density
quirements and proliferation of generic prod¬ or Stress
ucts, researchers are increasingly pressured to $ Angle of repose
define the optimum formulation for a new tablet y Plastoelasticity

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 97

Appendix B SI Units
Name
Unit of Unit Symbol Definition Approximate Equivalents

BASIC UNITS
Length meter m 1 angstrom = 10-10 m
| 1 inch - 0.0254 m

Mass kilogram kg 1 pound = 0.453592 kg

1
Temperature degree kelvin “K 32°F = 0°C s 273.15°K

Time second s

DERIVED UNITS
Area square meter m2 1 square inch = 645.16 mm2
1 square foot s 0.0929 m2
!
Volume 1 cubic meter m3 1 cubic inch s 1.6387 x 10“5m3
gallon = 3.7854 x 10-3 m3

Density kilogram per

cubic meter kg m~3 1 g per cc = 10"3kg m~3
1 | pound/cu inch s 2.768 x 10-3kgm-3
1
Energy ( joule 1 J kg m2 s'2 | 1 calorie = 4.1868 j
1 1 BTU = 1055.06 J
.
Force newton N kg m s~2 1 kilogram force = 9.80665 N
(Jm-!) 1 pound force s 4.44822 N

Pressure pascal _ Pa kg nr1 s~2 atmosphere sioi.325kPa

(N nr2) pound/sq inch = 6894.76 Pa
_l
Fractions and Multiples
io-3 mlHi m 10 1 deci d 103 kilo k
10"8 micro 10-2 centi c 106 mega M
io-9 nano n 109 giga G
io-12 pico P 1012 tera T

11. Lerk, C.F., Zuurman, K. and Kussendrayer, K.: J.

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7:327, 1981. 20. Nelson, E„ Naqvi, S.M., Busse, L.W., and Higuchi,
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Pharmacy, Basel, 1978. The Powder Advisory Centre, 21. Cooper, A.R., and Eaton, L.E.: J. Am. Ceramic Soc.,
London, 1978. 45:97, 1962.

98 ■ The Theory and Practice of Industrial Pharmacy

 22. Shapiro, I.; Ph.D. Thesis, Univ. Minnesota, 1944. 40. Knudsen, F.P.: J. Amer. Ceram. Soc., 42:376, 1959.
23. Walker, E.E.: Trans. Farad. Soc., 19:60, 1923. 41. Shotton, E., and Ganderton, D.: J. Pharm. Pharma¬
24. Heckel, R. W.: Trans. Metallurgy Soc., Am. Inst. col., J3:144T, 1961.
Mech. Eng., 221:671, 1961. 42. Hess, H.: Pharm. Tech., 2:36,1978.
25. Hersey, J.A., and Rees, J.E.: Nature, 230:96, 1971. 43. Shangraw, R.F., Wallace, J.W., and Bowers, E.M.:
26. David, S.T., and Augsburger, L.L.: J. Pharm. Sci., Pharm. Tech., 5:69, 1981.
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col., 12-.93T, 1960.

COMPRESSION AND CONSOLIDATION OF POWDERED SOLIDS • 99

 o

Basic Chemical Principles

Related to Emulsion and
Suspension Dosage Forms
STANLEY L. HEM, JOSEPH R. FELDKAMP, and JOE L. WHITE

Emulsions and suspensions are unique dosage rather a gradual transition occurs. The terms in¬
forms because many of their properties are due terfacial region and interphase are often used to
to the presence of a boundary region between describe the region labeled d in Figure 5-2B. Al¬
two phases. Figure 5-1 illustrates the types of though the physical properties of interfacial re¬
boundary regions that are discussed in this gions vary smoothly upon going from one phase
chapter. In the case of emulsions, two immisci¬ to the other, the notion of a mathematical sur¬
ble liquids, usually oil and water, meet to form face that has no thickness, as in Figure 5-2A, is
an interface. In suspensions, a solid and a liquid still useful for modeling interfacial regions and
form an interface. An interface between the liq¬ has been used successfully to describe interfa¬
uid and air is also present. Although the terms cial phenomena.
interface and surface are often used inter¬ In addition, the molecules in the interfacial
changeably, the latter term usually indicates region are not locked into position but are in
boundaries in which one phase is a gas. constant motion. The average interfacial resi¬
The boundary regions are often complex. Sur¬ dence time for a molecule of a liquid is believed
face active agents, which are molecules with to be approximately 10~6 sec. Thus, the interfa¬
special properties, may be contained within a cial region of emulsions and suspensions is a
system in various forms: they may be present as dynamic, clearly identifiable region between the
single molecules in solution (Fig. 5-1A); they phases of the system.
may also be adsorbed at the air-liquid surface When the interfacial region constitutes a large
(Fig. 5-1B); they may form a layer at the oil- portion of the system—as when the globule size
water interface (Fig. 5-1C); or they may form of the dispersed phase of an emulsion is small,
oriented dusters in the aqueous phase, which or when the particle size of the solid phase of a
are called micelles (Fig. 5-1D). Attractive and suspension is small—the overall properties of
repulsive forces exist between particles, and the the system are profoundly influenced by the
outlined region surrounding the particles in Fig¬ presence of the interfacial region.
ure 5-1 indicates a region of potential interac¬ A fundamental thermodynamic equation that
tion. Thus, the objective of this chapter is to ex¬ describes emulsions and suspensions is as fol¬
amine the phenomena that occur at the lows:
boundary regions of emulsions and suspensions.
When a beaker containing 50 ml of oil layered AG = yAA (1)
on 50 ml of water is examined visually, the in¬
terface appears as a sharp discontinuity between where AG is the change in the free energy of the
the two phases, as shown in Figure 5-2A. An in¬ system accompanying a change in interfacial
terface is actually a region of finite dimension area AA, y is the interfacial tension (liquid-liq¬
that has composition and properties different uid for an emulsion or solid-liquid for a suspen¬
from either two phases. Figure 5-2B more cor¬ sion), and temperature, pressure, and composi¬
rectly describes an interface as a region that is a tion are constant. The term AG represents the
few molecules thick in which a gradation of work required to increase the area of the inter¬
composition and properties exist. The density face by an amount equal to AA. Since this work
does not jump abruptly from 1.0 to 0.9 in mov¬ is always positive, a system always tends toward
ing from the water phase to the oil phase, but that state having the lowest possible interfacial

100
 FIG. 5-1. Schematic representation of boundary regions encountered in emulsions and suspensions. Key: A, surface active
agent molecules; B, surface active agent oriented at the air-water interface; C, surface active agent oriented at the oil-water
interface; D, micelle; E, suspended particles surrounded by a region of potential interaction.

I area. This state is thermodynamically stable. sions and suspensions are thermodynamically
! Thus, for an emulsion, the thermodynamically unstable.
j stable state is a layer of oil on water, whereas a
single large particle is the thermodynamically Molecular Basis for Surface
stable state for a suspension. Although all sys¬
tems tend toward the thermodynamically stable Tension
state of minimal interfacial area (which results The nature of the interfacial region can be fur¬
in dramatic changes in properties), systems may ther illustrated by examining the forces respon¬
vary considerably in their rates of conversion. If sible for surface or interfacial tension. In a sys¬
a system undergoes only minor changes during tem of oil and water, the water molecules that
the period of interest, e.g., shelf-life., such a sys¬ are in the center of the volume of water are sur¬
tem is viewed as kinetically stable even though rounded in all directions by other water mole¬
it may be unstable with respect to some longer cules. Attractive intermolecular forces, hydro¬
time period. As a consequence, the industrial gen bonds in the case of water, exist between
pharmacist faces the challenging task of prepar¬ adjacent water molecules and cause the water to
ing a kinetically stable dosage form, i.e., a dos¬ exist as a liquid. Similarly, van der Waals attrac¬
age form whose properties remain satisfactory tive forces exist between adjacent oil molecules.
for an acceptable shelf-life, even though emul¬ As depicted in Figure 5-3, however, the water

(density 1.0) interface. Key: A, mathematical surface; B, FIG. 5-3. Molecular basis for interfacial tension between
interfacial region, d. oil and water. Key: O, oil molecule; o, water molecule.

BASIC CHEMICAL PRINCIPLES RELATED TO EMULSION AND SUSPENSION DOSAGE FORMS • 101
 o o o o o o the movable bar is pulled toward the stationary
o o o o o bar. The surface tension of the soap film can be
measured if the weight needed to counterbal¬
o c> c> o T ance the force of contraction is determined by
° O O ° ; adding weights to the movable bar. The applied
OO 0O O 00 d force (weight x acceleration due to gravity, 980
oo ooooO 00 j cm/sec2) is equal to the interfacial tension y
0000 o 0000 o 1_ multiplied by the length of the movable barrier
L. The total force is twice this value since the
0 0 00000000000 0000
soap film forms an interface with both the top
0000 00 0000000000
and bottom of the movable bar:
FIG. 5-4. The interfacial region, d, between oil and water.
Key: O, oil molecule; o, water molecule.
F = 2yL (2)

molecules in the interfacial region are not sur¬ The interfacial tension is a force per unit length
rounded by other water molecules. Thus, they when considered in this manner.
experience unequal attractive forces because of Interfacial tension may also be expressed as
the weak attractive forces between water mole¬ energy per unit area if the work needed to dis¬
cules and oil molecules. If strong attractive place the movable bar in Fig. 5-5 by a small dis¬
forces existed between the oil molecules and the tance, dx, is considered:
water molecules, the two liquids would be misci¬
ble, and no interface would exist. The imbalance dWork = Fdx (3)
of forces results in a net attractive force into the
bulk water that is normal to the interface. This Since:
net attractive force leads to a reduced number of
water molecules in the interfacial region (Fig. dA = 2Ldx (4)
5-4), and is responsible for the gradual change
in density in the interfacial region, which was Thus:
shown in Fig 5-2B. Oil molecules at this inter¬
face are also exposed to an imbalance of forces,
and a similar analysis can be made for the oil. dx = f (5)
Surface or interfacial tension is a real force
whose effects are apparent at the macroscopic Substituting equations (2) and (5) into equation
level as well as at the molecular level. This can (3) gives:
be illustrated by placing a wire frame with a
movable slide (Fig. 5-5) in a soap solution. dWork = ydA (6)
When the frame is removed from the soap solu¬
tion, a film is formed. This film contracts, and Most interfaces encountered in pharmaceuti¬
cal systems are curved. The Young Laplace
equation relates the pressure across a curved
interface, AP. to the interfacial tension y. Rt and
r2 are the radii of curvature of the interface.

AP-?(i+i) <7)
For a sphere, the two radii of curvature are
equal, and the Young Laplace equation simpli¬
fies to:

F where r is the radius of the sphere. This equa¬

FIG. 5-5. Device for measuring the surface tension of a tion predicts that a smaller bubble or droplet has
soap film. A force of F is applied to the movable bar of a greater internal pressure. Since the pressure
length, h, until the film ruptures. within a small drop of liquid is greater than that

102 •The Theory and Practice of Industrial Pharmacy

for a liquid having a flat surface, i.e., a very large cause the attractive forces between the liquid
drop, a higher vapor pressure would be expected molecules and the air molecules are weaker than
for the droplet. the attractive forces between the liquid mole¬
The Kelvin equation, which relates the vapor cules. In addition, the molecules of a gas are
pressure over a curved interface to the radius of more widely separated than the liquid mole¬
curvature is given by: cules, so there are fewer air molecules at the in¬
terface to participate in interactions with the
molecules of the liquid phase. Thus, the surface
tension of a liquid is usually higher than the in¬
terfacial tension of the liquid with another liq¬
where P° is the normal vapor pressure of the liq¬ uid.
uid, i.e., when the surface is flat, P is the vapor The surface tension of liquids provides insight
pressure over a spherical surface of radius r, and into the attractive forces between molecules of
V is the molar volume of the liquid. For water, the liquid (Table 5-2). Thus, the surface tension
P/P° is about 1.001 for drops with a radius of 1 of water decreases as the temperature increases.
micron, 1.011 if the radius is 0.1 micron, and Liquids with strong intermolecular attractive
1.114 if r is 0.01 micron. An important conse¬ forces, such as water and glycerin, have higher
quence of the Kelvin equation is that a collection surface tensions than nonpolar liquids with rela¬
of water drops of different radii is unstable, so tively weak intermolecular forces, such as liquid
that the large drops grow at the expense of the petrolatum and heptane. Also, important differ¬
smaller drops. This effect is an agreement with ences exist in the surface tension of oils. Castor
equation (1), which states that the thermody¬ oil has a higher surface tension than liquid pet¬
namically stable state of emulsions and suspen¬ rolatum, which indicates that attractive forces
sions occurs when the interfacial area is mini¬ between castor oil molecules (triglycerides of
mal. fatty acids) are stronger than those between liq¬
The interfacial tension can serve as a measure uid petrolatum molecules (hydrocarbons).
of the degree of interaction between two liquids.
As shown in Table 5-1, the interfacial tension
between water and octane is 52 dynes/cm, but
Surface Active Agents
the interfacial tension between water and octa- Solutes can alter the surface tension of water,
nol, which contains an hydroxyl that can form a as shown in Figure 5-6. Since the effect is at the
hydrogen bond with water, is 9 dynes/cm! Also, surface, it is reasonable to assume that the com¬
the interfacial tension decreases as the number position of the interfacial region has changed
of carbons decreases in the series hexadecane because of the presence of either sodium stea¬
(C16H34), dodecane (Ci2H26), octane (C8H18) rate or sodium chloride. The Gibbs equation,
and heptane (C7H]6). one of the fundamental equations of surface
The liquid molecules at the air-liquid inter¬ chemistry, was derived to describe the effect of a
face also experience an imbalance of forces be¬ solute on surface tension.1,2 The concept of sur¬
face excess is introduced by the Gibbs equation.

Table 5-1. Interfacial Tension with Water at 25°

Table 5-2. Surface Tension at 25°
Liquid. Interfacial Tension, dynes/cm
Liquid Surface Tension, dynes/cm
Mercury 131
Hexadecane 54 Water, 5° 75
Dodecane 53 Water, 25° 72
Octane 52 Water, 50° 68
Heptane 50 Glycerin 62
Carbon tetrachloride 45 Dimethyl sulfoxide 44
Benzene 35 Castor oil 39
Nitrobenzene 25 Cottonseed oil 35
Benzaldehyde 16 Liquid petrolatum 33
Diethyl ether 11 Benzene 29
Octanol 9 Chloroform 27
Ethyl acetate 7 Carbon tetrachloride 26
Heptanoic acid 7 Methanol 23
Aminobenzene 6 Ethanol 22
Butanol 2 Heptane 20

BASIC CHEMICAL PRINCIPLES RELATED TO EMULSION AND SUSPENSION DOSAGE FORMS *103
 bulk than in the interfacial region. The surface
excess of sucrose is zero, indicating a constant
sucrose concentration relative to solvent
throughout the entire solution.
The conclusions about the surface excess of
solutes, which are based on Figure 5-6 and
equation (10) (the Gibbs equation), have been
verified experimentally. The most direct meas¬
urement of surface excess of a solute was made
by rapidly passing a microtome across the sur¬
face of a solution, which removed the top layer of
the solution for analysis. The surface concentra¬
tion of solutes that caused a decrease in surface
tension was greater than the bulk concentration
and showed good agreement with the surface
FIG. 5-6. Effect of solutes on the surface tension of water. excess calculated from the Gibbs equation.3
The use of radioactive tracers has also pro¬
vided experimental verification of the surface
The term surface excess, Ta3, is an algebraic excess predicted by the Gibbs equation. Figure
quantity which when positive indicates that a 5-7 shows that the experimentally determined
greater concentration of the solute is present in concentration of tritium-labeled sodium dodecyl
a unit cross-section of the surface region than in sulfate in this interfacial region is virtually iden¬
a bulk region containing the same number of tical to the concentration predicted by applying
moles of solvent as the section of the surface the Gibbs equation to the surface tension of the
region. Likewise, a negative surface excess indi¬ solutions.
cates that a lower concentration of the solute is Thus, experimental evidence and theoretic
present in a unit cross-section of the surface re¬ analysis indicate that such solutes as sodium
gion than in a bulk region containing the same stearate and sodium dodecyl sulfate concentrate
number of moles of solvent as the surface re¬ at the interface (adsorption) while solutes com¬
gion. The superscript indicates that the surface posed of simple ions like sodium chloride un¬
excess is measured relative to a constant dergo negative adsorption, i.e., concentrate in
amount of solvent. The Gibbs equation in its the bulk. The behavior of sodium chloride is eas¬
general form is as follows: ily understood, as both sodium and chloride ions
form strong attractive forces with water by ion-
dy dipole interactions. Because of these strong at¬
ry = -RT- (10)
din a2 tractive forces, the ions concentrate in the re-

where T is temperature, y is surface tension,

and a2 is the activity of the solute.
In many cases, the system of interest is a rela¬
tively dilute solution, so that the activity of the
solute may be considered to be equal to its con¬
centration. The Gibbs equation for dilute solu¬
tions is:

dy
T2! = -RT-
din C2
(ID

The Gibbs equation states that a solute that

concentrates in the interfacial region causes a
decrease in surface tension as the concentration
of the solute is increased. Thus, the behavior of
sodium stearate solutions shown in Figure 5-6
indicates that the concentration of sodium stea¬ FIG. 5-7. Surface excess of tritium-labeled sodium
dodecyl sulfate (SDS) determined by radiotracer method
rate is greater in the interfacial region than in
(O) and calculated by the Gibbs equation from surface
the bulk solution. A solute such as sodium chlo¬ tension data (——). (From Muramatsu, M., Tajima, K. M.,
ride, which causes an increase in surface ten¬ Iwahashi, M., and Nukina, K.: J. Colloid Interface Sci., 43:
sion, is present in greater concentration in the 499, 1973.)

104 • The Theory and Practice of Industrial Pharmacy

 dium dodecyl sulfate, or sodium stearate are
termed anionic because the hydrophilic group is
negatively charged. Cationic surface active
agents include cetyl trimethyl ammonium bro¬
mide and benzalkonium chloride. Surface active
agents whose hydrophilic region is composed of
an ester or ether groups are not charged and
thus are termed nonionic.2
Furthermore, the surface active agent is ori¬
ented in a special way at the interface. The hy¬
drophilic region is in the aqueous phase while
the lipophilic region is in the oil phase (for an
oil-water interface) or in the air (for an air-water
interface).
FIG. 5-8. Effect of a series of alcohols on the surface ten¬ A further confirmation that surface active
sion of water.
agents orient at interfaces is the gradual reduc¬
tion of surface tension with the passage of time
gion containing the greatest concentration of following the addition of a surface active agent,
water molecules. until a constant value is reached (Fig. 5-9). This
Structural Requirements. Surface active behavior suggests that the surface active mole¬
agents are molecules that are adsorbed at inter¬ cules diffuse through the water until they reach
faces. For this to occur, a molecule must fulfill the interface, where they are adsorbed to form a
specific structural requirements. Figure 5-8 il¬ stable system.
lustrates one of the requirements. The effect of Effect on Properties. The presence of a
alcohol in reducing the surface tension of water surface active agent can change many proper¬
increased as the hydrocarbon chain of the alco¬ ties of a system.1 As shown in Figure 5-10, the
hol increased in length. Thus, the surface ex¬ surface tension decreases sharply as the concen¬
cess of the alcohol is directly related to the tration of surface active agent is increased, until
length of the hydrocarbon chain of the alcohol. a constant value is reached. The osmotic pres¬
The hydrocarbon chain is the lipophilic part of sure increases as expected, but at higher con¬
the alcohol, and therefore, one requirement is centrations, a constant osmotic pressure is ob¬
that a surface active agent contains a lipophilic served. The detergency, i.e., the ability of the
region. solution to dissolve oil, increases sharply once a
A second requirement is that surface active threshold concentration of surface active agent
agents also contain a hydrophilic region. The is reached. In addition, light scattering becomes
interfacial tension between paraffin oil and significant at the same threshold concentration.
water is 41 dynes/cm. Upon the addition of All of the properties shown in Figure 5-10 un¬
0.001 M oleic acid, the interfacial tension dergo a sharp change at approximately the same
dropped to 31 dynes/cm. When 0.001 M NaOH
was then added, the interfacial tension dropped
to 7 dynes/cm.4 The addition of the sodium hy¬
droxide caused the carboxylic acid group of oleic
acid to form the more hydrophilic oleate anion.
Thus, a hydrophilic region is also essential for a
surface active agent.
A balance of the hydrophilic and lipophilic
regions of a surface active agent is usually de¬
sired. The lipophilic region is expelled from the
bulk of the water phase, but the hydrophilic re¬
gion prevents the surface active agent from
being completely expelled from the water phase.
Thus, a molecule containing both a hydrophilic
and a lipophilic region is concentrated at an in¬
terface and therefore lowers surface or interfa¬
FIG. 5-9. Change in surface tension with time following
cial tension.
the addition of sodium dodecyl sulfate to water. Key: A,
Surface active agents are frequently classified 4 x 10~4 M; B, 8 x 10~4 M; C, 1.6 x 10~3 M; D, 4 x
by the charge of the hydrophilic region. Surface 10~3 M. (From Neumann, A. W., and Tanner, W.: Tenside,
active agents such as sodium lauryl sulfate, so¬ 4:220, 1967.)

BASIC CHEMICAL PRINCIPLES RELATED TO EMULSION AND SUSPENSION DOSAGE FORMS • 105
 dal-sized aggregates termed micelles, which pre¬
dominate in the system at concentrations above
the critical micelle concentration. In aqueous
solution, the aggregates of surface active agents
form, so that the hydrophilic region is in contact
with water, and the lipophilic region is shielded
from water. Two possible orientations of micelles
are shown in Figure 5-11.
Micellization is an alternative mechanism to
interfacial adsorption by which surface active
agents can satisfy their dual solubility and
thereby form a stable system.
Micellization is favored because the lipophilic
region is removed from contact with water, but
the process is opposed by the surface active mol¬
ecule’s loss of freedom as a consequence of
being held in a fixed position in the micelle, and
in the case of ionic surface active agents, by the
electrostatic repulsion of the charged polar
groups. The concentration at which micelliza¬
tion becomes significant is determined by the
balance of these factors. A low critical micelle
concentration indicates that removal of the lipo¬
philic region of the surface active agent from
FIG. 5-10. Effect of surface active agent on properties of contact with water is the dominant factor, while
water. a high critical micelle concentration indicates
that the forces opposing aggregation are signifi¬
cant.
concentration of surface active agent. Such The shape and size of micelles remain some¬
other physical properties as the boiling point, what uncertain, and it is likely that shape varies
freezing point, solubility, partial molar volume, with the concentration of the surface active
electrical conductance, and color change of dyes agent. A consensus is gradually being reached
also undergo a sharp change at the same con¬ that spherical micelles (Fig. 5-11 A) occur at con¬
centration of surface active agent. This observa¬ centrations in the region of the critical micelle
tion led to the discovery that surface active concentration. The diameter of the spheres is
agents can form aggregates called micelles, approximately twice the length of the surface
which are discussed in the next section. active agent. When the concentration of surface
active agent substantially exceeds the critical
micelle concentration, the spherical micelles are
Micelles believed to transform into lamellar micelles (Fig.
The properties of solutions containing surface 5-1 IB).
active agents change sharply over a narrow con¬ The number of surface active agent molecules
centration range, as shown in Figure 5-10. This constituting a micelle is believed to range from
concentration is called the critical micelle con¬
centration. The surface active agent has no fur¬
ther effect on the surface or interfacial tension at
concentrations above the critical micelle con¬ T T H T T
centration, which suggests that surface active
agent in excess of the critical micelle concentra¬
°A 1/ nun
tion is no longer orienting at the interface. The
fact that the osmotic pressure is essentially con¬ f H T ft
nun
stant above the critical micelle concentration
suggests the formation of a new phase, although
the system still appears to be a solution. The for¬
mation of a new phase of small particle size is
suggested by the initiation of light scattering at A B
the critical micelle concentration. FIG. 5-11. Orientation of surface active agents to form a
Surface.active agents associate to form colloi¬ spherical micelle (A) and a lamellar micelle (B).

106 • The Theory and Practice of Industrial Pharmacy

50 to 100 molecules and is characterized by the B
aggregation number. In general, the aggregation
number in aqueous solution increases with an
increase in the hydrophobic region of the sur¬
face active agent. The addition of an electrolyte
causes the aggregation number of ionic surface
active agents to increase by diminishing the re¬
pulsive charge effect. Frequently, the aggrega¬
tion number has been observed to increase in
the presence of a hydrocarbon that is adsorbed
or solubilized in the lipophilic region of the mi¬
celle. FIG. 5-12. Diagram of essential components of a film bal¬
The critical micelle concentration is also af¬ ance. Key: A, trough; B, movable barrier; C, film-covered
surface; D, film-free surface; E, surface tension monitor.
fected by the structure of the surface active
agent. In general, the critical micelle concentra¬
tion in aqueous media decreases as the lipo¬
philic nature of the surface active agent in¬ 5-12), which is used to produce a graph of the
creases. This process may be thought of as area of the film, A, versus the film pressure, n5
enhancing the expulsion of the lipophilic region This graph is called a tt-A curve. The film pres¬
from water. Branching in the lipophilic region sure is the difference between the surface ten¬
interferes with the close packing of surface ac¬ sion of the pure liquid and the surface tension of
tive agents needed for van der Waals attraction the film-covered surface.
of the hydrocarbon chains; thus, the critical mi¬ Two typical tt-A curves are shown in Figure
celle concentration increases. Ionic surface ac¬ 5-13. Usually, three characteristics of the tt-A
tive agents have a much higher critical micelle curves are examined. The slope gives informa¬
concentration than nonionic surface active tion about the nature of the packing in the sur¬
agents, as repulsive forces between the similarly face film. The smallest area the molecules oc¬
charged polar groups resist the close packing cupy before the film collapses is termed the
necessary for micelle formation. limiting area and indicates the dimension of the
Another important fact is that micelles are in molecule in the film. This information indicates
equilibrium with monomeric surface active the orientation of the molecules in the film com¬
agents in the system. Thus, both monomers and pared with the actual dimensions of the mole¬
micelles are always present in solutions of sur¬ cule. The film pressure that causes the film to
face active agents. The monomenc form will collapse is termed the collapse pressure and indi¬
predominate, however, when the concentration cates the strength of the film.
is below the critical micelle concentration so Arachidic acid, CH3(CH2)i8COOH, shows the
that micelles predominate above the critical increase in film pressure that is characteristic
micelle concentration. of a condensed or noncompressible film (Fig.
Micelles may be desirable when detergency or
solubilization of a lipid-like material is desired in
a system. Micelles are of great interest because
of their unusual catalytic effects and because
they are a good model of biologic membranes.
On the other hand, micelles dp not contribute to
the properties of emulsions, and the concentra¬
tion of surface active agent used in emulsions is
usually chosen to minimize micellization.

Interfacial Films
The nature of the interfacial film is important
in emulsions. Experimentally, direct examina¬
tion of the film at the oil-water interface is diffi¬
cult; however, techniques for studying insoluble
FIG. 5-13. Film-pressure/area curves for insoluble films
surface films are available, providing insight
of arachidic acid (A) and ethyl elaidate (B). (Reprinted
into the interfacial films in emulsions. with permission from Rosano, H. L, and LaMer, V. K.:
The principle technique employed in the J. Phys. Chem., 60:348, 1956. Copyright 1956 American
study of insoluble films is. the film balance (Fig. Chemical Society.)

BASIC CHEMICAL PRINCIPLES RELATED TO EMULSION AND SUSPENSION DOSAGE FORMS *107
5-13A). This type of film is quite rigid and be¬
haves in a manner analogous to a solid. Thus, it
is also termed a solid film. In contrast, ethyl
elaidate, C]7H33COOC2H5, shows a gradual in¬
crease in film pressure as the area per molecule
is reduced (Fig. 5-13B). This behavior is charac¬
teristic of an expanded or compressible film,
which by analogy to the states of matter is
termed a gaseous film.
The limiting area of arachidic acid is approxi¬
mately 0.18 nm2 while the limiting area of ethyl
elaidate is 0.53 nm2. The collapse pressure of
arachidic acid is 33 dynes/cm, while the collapse
pressure of ethyl elaidate is 19 dynes/cm.
The tt-A curves in Figure 5-13 indicate that FIG. 5-15. Film-pressure/area curves ofioctadecyl-
arachidic acid forms a rigid film with the mole¬ trimethyl ammonium cation in sodium chloride solutions
cules in close contact. The limiting area is simi¬ of various concentration. Key: — —0.033 M- sodium
lar to the area of the hydrocarbon chain, chloride; •—*—, 0.1 M sodium chloride; C,-(0.5M so¬
dium chloride;-, 2 M sodium chloride. (From Da¬
0.184 nm2, which suggests a vertical orientation
vies, J. T.: Proc. R. Soc. Land., A208:224, 1951.)
of arachidic acid molecules in the film. The rela¬
tively high collapse pressure in comparison with
ethyl elaidate suggests a greater degree of inter¬ interaction within the film. In the tt-A curve of
action between the closely packed hydrocarbon octadecyltrimethyl ammonium ions, this phe¬
chains of arachidic acid. The structure of ethyl nomenon can be seen as a shift in shape toward
elaidate does not allow close packing of the mol¬ a condensed type of film as the ionic strength is
ecules, and the tt-A curve indicates a film with increased (Fig. 5-15).
weaker intermolecular association. The film balance can also be used to study
Film balance experiments provide valuable mixed films. Changes in the limiting area indi¬
information on how steric factors affect the film. cate interactions between the components of the
For example, the introduction of cis-double film.
bonds into the hydrocarbon chain produces con¬ Since the objective of emulsification is to pro¬
siderable film expansion, as shown in Figure duce a tough, resilient film at the oil-water Inter¬
5-14. face, the information obtained from film balance
The presence of a charged polar group pro¬ experiments has provided valuable insights into
duces repulsion within the film, which results in the behavior of films. The principles illustrated
an expanded film; however, an increase in ionic by the tt-A curves—such as the formation of a
strength shields the charge and allows greater monomolecular film in which the molecules as¬
sume a specific orientation, and the demonstra¬
tion that the strength of the film is related to
intermolecular attraction between components
of the film—can be directly applied to the for¬
mulation of emulsions.

Measurement of Surface and

Interfacial Tension
Numerous methods have been used to mea¬
sure surface and interfacial tension. The exis¬
tence of numerous methods often indicates that
the measure is complex, and that a simple, uni¬
versally applicable method is not available. An
excellent detailed discussion of methods for
measuring surface or interfacial tension is given
by Padday.6
FIG. 5-14. Film-pressure/area curves for insoluble films
of cis-docosenoic acid (A) and trans-docosenoic acid (B).
The capillary-rise method is based on equa¬
(From Marsden, }., and Rideal, E. K.: J. Chem. Soc., 1163, tion (7), the Young Laplace equation. If a liquid
1938.) wets the walls of a capillary, the liquid surface is

108 • The Theory and Practice of Industrial Pharmacy

concave in shape and a pressure differential
exists across the interface. The pressure differ¬
ential causes the liquid to rise in the capillary
until the pressure differential described by the
Young Laplace equation is equal to the hydro¬
static pressure of the column of liquid:

AP = (fii - Pg)gh = — (12)

where p, and pg are the densities of the liquid

and gas phases, respectively, g is the accelera¬
tion due to gravity, h is the height to which the
liquid rises in the capillary, and r is the radius of
the capillary. Thus, the height to which a liquid
rises in a capillary is directly related to the sur¬
face tension of the liquid and inversely related to
the bore of the capillary tube. This simple treat¬
ment fails to account for the weight of the me¬
niscus, and it assumes a hemispherical menis¬
cus. The major difficulty with the capillary-rise
method occurs if the liquid does not completely
wet the walls of the capillary. Under ideal exper¬
imental conditions, however, this method is ex¬ FIG. 5-16. Change in shape of a pendant drop of a sodium
cellent for determining surface tension but un¬ stearate solution as a function of time, and the surface
suitable for measuring interfacial tension. tension calculated using the Young Laplace equation.
The Young Laplace equation can also be used Key: ], age = 10 sec.; y = 71.9 dynes/'em
2, age = SO sec.; y = 58.2 dynes/cm
to determine surface or interfacial tension based
3, age = 320 sec.; y = 54.4 dyneslcm
on the radius of curvature, i.e., the shape of 4, age = 1800 sec.; y = 39.2 dyneslcm.
pendant (hanging) or sessile (sitting) drops. The (Reprinted from Andreas, ]. M., Hauser, E. A., and Tucker,
use of these methods is illustrated in Figure W. B.: J. Phys. Chem., 42:1001, 1938. Published 1938
5-16, in which the shape of a pendant drop of a American Chemical Society.)
solution of sodium stearate changed with time,
reflecting the time required for the sodium stea¬
rate to equilibrate at the surface. Similar the time required for a new surface to reach its
changes would also occur in a sessile drop of equilibrium surface tension.
sodium stearate solution. Photographs of the Another approach, known as the Wilhelmy
drops are used to determine the changes in plate method, is the direct measurement of the
shape as a function of time from which the sur¬ force exerted on a piece of platinum foil that is in
face tension is determined. The pendant or ses¬ the interface. The measured or apparent weight
sile drop methods are good for studying the of the foil while in the interface, W, is equal to
aging of surfaces and are convenient for deter¬ the weight of the foil, W0, plus the force due to
mining interfacial tension if the pendant or ses¬ the surface tension. This force is equal to the
sile drop is immersed in a second immiscible liq¬ surface tension multiplied by the perimeter of
uid. the foil, which forms the interface with the liq¬
The drop-weight method is based on the fact uid. The perimeter is frequently approximated
that the weight of a drop that falls from a tube of by twice the length of the foil, L.
radius r depends on the surface tension of the
liquid. This method requires a correction factor, W = W0 + 2L (13)
as only a portion of the drop that has reached the
size of instability falls, the balance remaining The Wilhelmy plate method is relatively simple
attached to the tip. Correction tables are avail¬ and gives accurate results. It is good for studying
able, however, and satisfactory results can be the aging of the surfaces and is usually the
obtained for surface tension when the drop method used to measure surface tension during
forms in air, or for interfacial tension when the film balance experiments. It cannot be used to
tip is immersed in a second liquid. Some accu¬ measure interfacial tension.
racy is lost in the study of solutions because of The ring-detachment method has been the

BASIC CHEMICAL PRINCIPLES RELATED TO EMULSION AND SUSPENSION DOSAGE FORMS • 109
most widely used method for determining sur¬ .0H-+ H+ OH 0H~ O'
face or interfacial tension in pharmacy, although
many experimental difficulties are associated
with this method. The method depends on the pH <PZC pH - PZC pH > PZC

measurement of the force needed to detach a FIG. 5-17. pH-Dependent ionization of surface hydroxyls
ring of wire from the surface of the liquid. Ex¬ of aluminum hydroxide gel. The point of zero charge (PZC)
perimental technique is important, for the ring is the pH at which the surface is neutral.
must be a true circle, it must be horizontal in the
interface, and it must be clean. Correction fac¬
tors have been developed for this method. Under which a particle no longer migrates in the pres-
ideal conditions, it is satisfactory for measuring er e of an electric field. The PZC and i.e.p. are
the surface tension of pure liquids, but the time not necessarily identical since a surface charge
required for equilibration of the surface causes may be present even when a colloidal system is
an error to be introduced when used for solu¬ at its i.e.p.
tions. It is used for interfacial tension, but the In addition to protons and hydroxyls, surface
experimental difficulties caused by the second charge may also be created because of the pref¬
liquid phase are serious and make this use ques¬ erential adsorption of specific ions onto the sur¬
tionable. face. This type of adsorption is termed specific
adsorption because the ion becomes an integral
part of the solid phase through a chemical bond,
Origin and Effects of Surface which is usually covalent.
Ions that are specifically adsorbed are also
Charge known as potential determining ions. In many
Most insoluble materials, either solids or liq¬ cases, an electrolyte is present in the aqueous
uids, develop a surface charge when dispersed solution, which provides the anions or cations
in an aqueous medium. The surface charge may for specific adsorption. Examples of such ions
arise by several mechanisms. The ionization of are phosphate, silicate, and carbonate. If a sur¬
surface groups may produce a surface charge. face has both a pH-dependent charge and a
Proteins usually contain carboxylic acid groups, charge due to specific adsorption, then the PZC
which may ionize to form carboxylate anions, as for such a surface is different from its value in
well as amine groups, which become cationic the absence of any specific ion adsorption. An
when pH conditions favor protonation. The sur¬ example is provided by aluminum hydroxide,
face charge of proteins depends on the summa¬ which has a PZC of 9.6 when only H+ or OH-
tion of negative and positive sites and therefore bind to its surface. In the presence of specifically
depends on the pH of the aqueous medium. At adsorbed carbonate, the PZC is displaced down¬
low pH conditions, the carboxylic acid groups ward within the range of 6.0 to 8.0, depending
are undissociated, and the amine groups are on how much carbonate is preferentially ad¬
protonated to give a net positive charge. At sorbed.7 In this case, the potential determining
higher pH conditions the carboxylic acid groups ions are hydroxyl, protons, and carbonate.
ionize and the amine groups are neutral; thus, In some cases, charge arises owing to the ad¬
the protein is negatively charged. In addition to sorption of ions that are identical with those con¬
protein, a variety of colloidal systems (e.g., poly¬ stituting the insoluble phase. For example,
mers, metal oxides, etc.) develop surface charge when silver iodide particles are in equilibrium
due to the adsorption or desorption of protons, so with a solution containing both silver cations
that surfaces can become positively or nega¬ and iodide anions, the adsorption of these ions
tively charged. An important property of such depends on their affinity for water as well as
systems is the point of zero charge (PZC), which their concentration in the bulk solution phase.
represents the pH at which the net surface Thus, the surface is positively charged when the
charge is zero. For aluminum hydroxide gel, the surface excess of silver cations exceeds the sur¬
surface hydroxyls may adsorb protons and be¬ face excess of iodide anibns, and negatively
come positively charged or may donate protons charged when the surface excess of iodide ani¬
to become negatively charged (Fig. 5-17). The ons exceeds the surface excess of silver cations.
pH at which the surface hydroxyls exist in their Because the charge on the silver iodide particle
uncharged form is the point of zero charge. is determined by the concentration of silver or
Another property of colloidal systems that iodide ions," these ions are also regarded as po¬
exhibit a pH-dependent charge, although not as tential determining ions.
fundamental as the PZC, is the isoelectric point Imperfections in the crystal structure may
(i.e.p.). This property represents the pH at cause a surface charge. Many clays exhibit a

110'T/ie Theory and Practice of Industrial Pharmacy

negative surface charge because of isomorphous gether by the charged surface so that the ions
substitution, e.g., an aluminum occupies a site move with the surface (Stem layer). The surface
that is usually occupied by silicon.8 Similarly, potential is reduced from ip0 to by the Stem
the antacid magaldrate exhibits a positive sur¬ layer. The surface charge is not completely bal¬
face charge because of the substitution of alumi¬ anced by the Stem layer, and a second region,
num in crystal lattice sites normally occupied by the diffuse layer, is necessary for complete bal¬
magnesium.9 ance of the surface charge. The diffuse layer
The oil globules of an oil in water emulsion contains both anions and cations, but ions that
exhibit a surface charge if anionic or cationic are of opposite charge to the surface predomi¬
surface active agents are used as the emulsify¬ nate, so that in the neighboring area of any
ing agent. The surface active agents are oriented charged particle, there exists an ion atmosphere
at the oil-water interface, so that the charged, having a net charge that is opposite to that of the
hydrophilic groups form the outside surface. surface. This mobile layer of ions has a definite
The presence of charge at an interface has thickness, which is approximated by the so-
profound effects on the nature of the interfacial called Debye length (1/k):
region. Thus, the concept of a diffuse double
layer was developed by Gouy and Chapman to
describe the transition from points near the
charged surface to the electrically neutral bulk
solution.10 Stem made an important refinement where D is the dielectric constant of the me¬
in the double-layer theory by pointing out that dium, n is the concentration of ions in the bulk
the ions in the double layer are not point charges solution phase, e is the electronic charge, Z is
but rather real ions with finite dimensions.10 valence, k is Boltzman’s constant, and T is tem¬
Figure 5-18 presents a model of the interfacial perature. Beyond this distance (1 Ik), the net
region of a charged surface and provides a good charge density of the ion atmosphere ap¬
basis for understanding the behavior of pharma¬ proaches zero, and the electrical potential is re¬
ceutical suspensions and emulsions. A layer of duced considerably below its value at the sur¬
ions of opposite charge is sufficiently held to- face. The major factors affecting the thickness of
the double layer are the electrolyte concentra¬
tion of the solution, n, and the valence, z, of the
counter ions. Table 5-3 shows the manner by
which the thickness of the double layer de¬
creases as the concentration or the valence of
the counter ions increase.

Interparticle Forces
An area of surface chemistry in which signifi¬
cant advances in understanding are occurring is
the nature of forces between surfaces.11,12 The
following forces have been identified.
1. Electrostatic repulsive forces arise from
overlapping of the diffuse double layers of ap¬
proaching surfaces. These forces depend greatly
on the concentration and valence of electrolyte
in solution. Their range may exceed 100 nm.
2. Van der Waals attractive forces arise from
the electromagnetic fluctuations in the mole¬
cules that make up the surface. These forces
largely independent of the electrolyte and may
have a range of the same order of magnitude as
electrostatic repulsive forces.
3. Repulsive hydration forces arise from the
structuring of water in the interfacial region.
These forces are independent of electrolyte con¬
centration. At low electrolyte concentration, the
FIG. 5-18. Diffuse double-layer model of a positively contribution of this force may not be observed,
charged surface in an aqueous medium. owing to the strong electrostatic repulsive

BASIC CHEMICAL PRINCIPLES RELATED TO EMULSION AND SUSPENSION DOSAGE FORMS '111
Table 5-3. Approximate “Thickness” of the Electric Double Layer as a Function of Electrolyte Con¬
centration at a Constant Surface Potential

Concentration of Ions
of Opposite Charge to Thickness of the Double Layer, nm
that of the Particle, mmole/L Monovalent Ions Divalent Ions

0.01 100 50
1.0 10 5
100.0 1 0.5

From van Olphen, H. An Introduction to Clay Colloid Chemistry. 2nd Ed. John Wiley and Sons, New York, 1977, p. 35

forces. At high electrolyte concentration, how¬ coagulation. Thus, the DLVO theory explains
ever, the diffuse double-layer interactions are the fact that the addition of electrolyte to a colloi¬
weak, and the repulsive hydration forces may dal system causes coagulation.
determine the interaction of the surfaces. Typi¬ The concentration of electrolyte necessary to
cally, these forces have a range of only a few di¬ collapse the repulsive field and permit coagula¬
ameters (—1 nm). tion has been found to depend primarily on the
4. Bom repulsive forces are of short range and valence of the ion of opposite charge. The con¬
operate over distances of atomic dimensions. centrations of various monovalent salts needed
They are due to the repulsive effects of atomic to coagulate negative silver iodide are approxi¬
orbital overlap. mately the same (Table 5-4). Electrolytes con¬
5. Adhesive forces arise when surfaces are in taining divalent cations all require a similar con¬
contact. The adhesive forces depend on pH, spe¬ centration to induce coagulation but the
cific cations, and the crystallographic orienta¬ concentration is substantially lower than that
tion of the surfaces. required by electrolytes containing monovalent
6. Steric repulsive forces depend on the size, cations. Likewise, electrolytes containing triva-
geometry, and conformation of molecules that lent cations require the lowest concentration to
are adsorbed on the surface. Their effective induce coagulation. The strong effect of the va-
range depends on the nature of the adsorbed
molecules.
Many observed properties of a disperse system
reflect the net force of interaction between the
particles or globules that the system comprises.
Deryaguin and Landau, working in Russia, and
Verwey and Overbeek, working independently
in Holland, were the first researchers to recog¬
nize the concept of the net force between parti¬
cles.10 Thus, the concept has become known as
the DLVO theory. The original statement of the
DLVO theory considered only the balance be¬
tween electrostatic repulsive and van der Waals
attractive forces, which were the only interparti¬
cle forces understood at that time.
Figure 5-19 illustrates the repulsive double
layer and attractive van der Waals forces at three
electrolyte concentrations. The repulsive forces
predominate at low electrolyte concentration, so
that the particles experience only a repulsive
force upon approach. The particles remain inde¬
pendent, and the system is considered disper¬
sed. At high electrolyte concentration, however,
the double layer forces are gready reduced, so
that the attractive van der Waals forces predomi¬ FIG. 5-19. Effect of electrolyte concentration on repulsive
nate. These net attractive forces that the parti¬ double-layer forces and attractive van der Waals forces.
cles encounter cause the formation of an aggre¬ Key: A, low electrolyte concentration; B. intermediate elec¬
gate of particles, a process known as trolyte concentration; C, high electrolyte concentration.

112 • The Theory and Practice of Industrial Pharmacy

Table 5-4. Electrolyte Concentration to Floccu¬
late a Negative Silver Iodide Colloid

Electrolyte Coagulation Concentration, mmole/L

LiN03 165
NaN03 140
KN03 136
Ca(N03)2 2.6
Mg(N03))2 2.4
A1(N03)3 0.07

lence of the electrolyte on the double-layer re¬

pulsive force is known as the Schulze-Hardy
rule.
As can be noticed in Table 5-4, the coagulation
values for negative silver iodide are slightly dif¬ FIG. 5-20. Net potential energy curve for a particle in an
ferent depending on the particular monovalent electrolyte vehicle.
cation. The order of effectiveness of ions of a
given valence is directly related to the hydrated equation (14) and is frequently necessary to in¬
radius of the ion. The order of effectiveness is duce flocculation.
known as the Hofmeister series and is given as: A repulsive barrier termed the primary maxi¬
mum separates the secondary minimum from
Cs > Rb > NH4 > K > Na > Li the primary minimum. The magnitude of the
Mg > Ca > Ba repulsive force at the primary maximum deter¬
F > Cl > Br > N03 > I > CNS mines whether a flocculated system will remain
flocculated. If the thermal energy in the system
The DLVO theory at first provided an excel¬ is similar to, or greater than, the repulsive bar¬
lent framework for understanding the interac¬ rier, then the particles in the system are able to
tions between surfaces. Recent experiments move closer together (0.5 to 2.0 nm) and en¬
have shown, however, that unexpectedly large counter strong attraction due to the primary
repulsive forces exist at small interparticle dis¬ minimum. The strong attraction in the primary
tances, whereas the DLVO theory predicts minimum gives rise to the particle interaction of
strong attraction at small distances.13 This ob¬ coagulation. Other sources of energy, such as
servation has stimulated the search for addi¬ centrifugation or compression of the particles
tional forces and has led to the identification of due to freezing may force particles into the pri¬
the additional forces listed at the beginning of mary minimum by overcoming the primary
this section. maximum and may lead to coagulation. At low
When the repulsive hydration and Bom repul¬ electrolyte concentration, the interaction curve
sive forces are considered along with the double¬ contains a much larger primary maximum than
layer repulsive and van der Waals attractive at higher ionic strength conditions, and particle
forces, the net force diagram shown in Figure interactions are minimized. Such a suspension
5-20 is obtained. As two particles approach each is called dispersed, or peptized. If either the con¬
other in an aqueous medium of proper electro¬ centration or the valence of the background salt
lyte concentration, a weak attractive force exists is increased, the primary maximum is reduced,
just beyond the range of-the double-layer repul¬ so that such particle interactions as flocculation
sive forces. This attractive region is called the or coagulation occur.
secondary minimum and is responsible for the Recent experimental techniques allow the di¬
particle interaction termed flocculation. Parti¬ rect measurement of forces between surfaces.
cles therefore experience attraction at signifi¬ Israelachvili and Adams measured the forces
cant interparticle distances (10 to 20 nm) and between two mica surfaces in electrolyte solu¬
form the fluffy aggregates known as floccules. tions.14 Their results indicate the presence of a
The secondary minimum is not observed if long-range repulsive force that collapses as the
the repulsive forces extend further from the sur¬ electrolyte concentration increases (Fig. 5-21),
face than attractive forces. Thus, the adjustment as predicted by the DLVO theory. They also ob¬
of valence and concentration of the background served an attractive region at distances pre¬
electrolyte can alter the Debye length given in dicted for the secondary minimum (Fig. 5-22).

BASIC CHEMICAL PRINCIPLES RELATED TO EMULSION AND SUSPENSION DOSAGE FORMS *113
 State of Aggregation
Many of the physical properties of disperse
systems depend on the state of aggregation. For
example, the apparent viscosity of aluminum
hydroxycaxbonate gel is directly related to parti¬
cle-particle association. When coiilombic repul¬
sion is sufficiendy reduced by adjustment of the
bulk pH to the point of zero charge, van der
Waals attractive forces cause the particles to
aggregate. Consequently, the apparent viscosity
increases. The magnitude of the viscosity in¬
crease depends, however, on the structure of the
FIG. 5-21. Experimental results of direct measurements aggregates. Figure 5-23 illustrates the effect of
of repulsive forces as a function of separation distance be¬ pH on the apparent viscosity of two aluminum
tween two crossed mica cylinders in aqueous potassium
hydroxy carbonate gels. The viscosity of both alu¬
nitrate solutions of various concentration, m/l. (From Is-
raelachvili, J. N., and Adams, G. E.:J. C. S. Faraday Trans. minum hydroxycarbonate gels was at a maxi¬
I, 74:975, 1978.) mum when the bulk pH was at the point of zero
charge. The fact that a different maximum vis¬
cosity occurred for each aluminum hydroxycar¬
bonate gel suggests that gel 1 formed a more

FIG. 5-22. Attractive van der Waals dispersion forces be¬

tween mica surfaces measured in the region of secondary FIG. 5-23. Effect of bulk pH on apparent viscosity of alu¬
minima in various aqueous solutions. The dotted line rep¬ minum hydroxycarbonate. The point of zero charge of gel 1
resents the attractive force predicted by van der Waals (o) is 6.95, and the point of zero charge of gel 2 (a) is 6.30.
forces. The measured forces agree well with theory except (From Feldkamp, J. R., Shah, D. N., Meyer, S. L., et ai: J.
at larger separation distances, where they decay more rap¬ Pharm. Sci., 70:638, 1981. Reproduced with permission of
idly than predicted by theory. (From Israelachvili, J. N., the copyright owner, the American Pharmaceutical Associ¬
and Adams, G. E.: J. C. S. Faraday Trans. 1, 74:975, 1978.) ation.)

114 ‘The Theory and Practice of Industrial Pharmacy

 V*05Vo
SM26S3
tj'08d0

W‘OZi\la
S -! 64 So
d-064do

FIG. 5-24. Effect of particle density on interparticle dis¬

tance. Key: A, interparticle distance; V, volume of each par¬
ticle; S, total surface area; d, diameter of each particle. The
volume of each particle is reduced by 50% in each step
while the total volume of the particles is constant. (From
Feldkamp, J. R., White, J. L., and Hem, S. L.: J. Pharm.
Sci., 71:43, 1982. Reproduced with permission of the copy¬
right owner, the American Pharmaceutical Association.)

highly extended and cross-linked network of

particles.
In addition to surface charge, the particle size
of the dispersed phase has a great effect on in¬
terparticle interactions. Reducing the particle
size while maintaining a constant solids content
causes a colloidal system to have a higher parti¬ FIG. 5-25. Schematic of tension cell apparatus. Key: C,
tension cell; VA, movable plate assembly; B, collection
cle density. The effect of particle density on par¬ buret; and G, sample suspension. (From Lipka, E. A.,
ticle interactions is illustrated in Figure 5-24, in Feldkamp, J. R., White, J. L., and Hem, S. L.: J. Pharm.
which the individual particle volume is sequen¬ Sci., 70:936, 1981. Reproduced with permission of the
tially halved in a one-dimensional arrangement copyright owner, the American Pharmaceutical Associa¬
of particles. Such a system is relevant especially tion.)
because linear chains of particles are frequently
formed under the influence of van der Waals picted in Figure 5-25. The dispersed phase is
forces. Although the surface area does not in¬ confined to a chamber that is fitted with a mem¬
crease substantially upon two divisions, the av¬ brane at the bottom. The membrane is imperme¬
erage interparticle distance decreases signifi¬ able to particles but passes both water and sol¬
cantly, as can be readily observed. Since the utes, so that applying a stress in the form of a
magnitude of interparticle forces depends in¬ tension r causes the solution phase to leave the
versely upon separation distance, the force ex¬ system. The solution phase continues to flow out
erted on a given particle by all other particles is of the system until interparticle forces have in¬
greater if the average interparticle distance is creased sufficiently to prevent further collapse
small. Conversely, at low particle density, the of the colloidal matrix. By measurement of the
average interparticle distance is comparatively extent of collapse as a function of applied incre¬
large, so that the particles are less influenced by ments of tension, a may be measured. Measured
each other. values for the coefficient of bulk compressibility
The effects of decreased particle size in a col¬ are represented in Figure 5-26 for two different
loidal system are readily examined by measure¬ colloidal aluminum hydroxycarbonate systems.
ment of the coefficient of bulk compressibil¬ Although each has the same volume fraction of
ity, a: solids initially, gel 1 has a smaller particle size
than gel 2, so that gel 1 has a greater particle
1 dV density. This implies that interparticle forces
(15)
V dr ought to be greater within gel 1, according to the
preceding arguments, and that therefore gel 1
where V is the entire volume occupied by the should exhibit a more rigid, incompressible be¬
system, including both solids and solution havior. This conclusion is confirmed in Figure
phases, r represents the stress applied to the 5-26, where a is shown to be considerably
system, and the mass of solids is constant. A smaller for gel 1.
useful apparatus for measurement of a is de¬ Likewise, the tenfold increase in the viscosity

BASIC CHEMICAL PRINCIPLES RELATED TO EMULSION AND SUSPENSION DOSAGE FORMS *115
FIG. 5-2C. Compressibility of aluminum hydroxycar-
bonate gel 1 (A), and gel 2 (B) at various applied tensions.
(From Feldkamp, J. R., White, J. L., and Hem, S. L.: J.
Pharm. Sci., 71:43, 1982. Reproduced with permission of
copyright owner, the American Pharmaceutical Associa¬
tion.)

FIG. 5-28. Effect of sodium chloride concentration on the

of aluminum hydroxycarbonate gel 1 in compar¬ viscosity of 3.22% sodium montomorillonite (A) and 12%
ison with the fourfold increase in the viscosity of sodium kaolin (B) suspensions. (From van Olphen, H.: An
aluminum hydroxycarbonate gel 2 (Fig. 5-23), Introduction to Clay Colloid Chemistry. 2nd Ed. John
when the particles are neutral, is due to the Wiley and Sons, New York, 1977, p. 101.)
smaller particle size of aluminum hydroxycar¬
bonate gel 1. ferent effect on the rheology. The addition of salt
The shape of the particle also influences the collapses the repulsive double layer and permits
particle interactions. Plate-like particles can interparticle association. The edge-to-face and
undergo three different modes of particle associ¬ edge-to-edge interactions lead to a three-dimen¬
ation: face-to-face, edge-to-face, or edge-to-edge sional network of particles throughout the clay
(Fig. 5-27). The physical effects of these three suspension, which is manifested by a sharply
types of association are quite different. Face-to- increased apparent viscosity following coagula¬
face association leads to a compact arrangement tion.
while edge-to-face or edge-to-edge associations
lead to the formation of an extensive network of
particles. Mechanisms of Crystal Growth
The importance of the different types of asso¬ The si?e distribution of dispersed systems
ciation of plate-like particles can be seen in the may increase during aging, owing to three prin¬
rheology of kaolin or montmorillonite suspen¬ cipal mechanisms: Ostwald ripening; polymor¬
sions (Fig. 5-28). Kaolin favors the formation of phic transformation; and temperature cycling.
face-to-face association. Thus, upon the collapse The basis for Ostwald ripening is found in an
of the double layer by the addition of salt, large equation analogous to equation (9) (the Kelvin
aggregates of clay particles form. The overall ef¬ equation) and it applies to the equilibrium solu¬
fect of the face-to-face association is a reduction
bility of small particles.15
of particle density, and a lower apparent viscos¬
ity is observed following coagulation. Montmo¬ S 2yV
rillonite favors the formation of edge-to-face or (16)
S° rRT
edge-to-edge associations, which produce a dif¬
where S° is the solubility of infinitely large parti¬
cles, S is the solubility of a small particle of ra¬
dius r, y is the surface tension, and V is the
molar volume of the solid.
It is important to distinguish between equilib¬
rium solubility and the rate at which a substance
Foce-to-Foce Edge-to-Foce Edge-to-Edge dissolves. Dissolution rate is affected by particle
FIG. 5-27. Possible modes of particle association for size since the surface area of the solid available
plate-like particles. to the solvent increases with decreasing particle

116* The Theory and Practice of Industrial Pharmacy

size. Equilibrium solubility at a given tempera¬ leads to an increased equilibrium solubility. A
ture, however, is affected by particle size only in drop in temperature, however slight, results in a
the pkrticle size range near the colloidal dimen¬ supersaturated solution surrounding each parti¬
sion, ive., less than 5 microns. For example, the cle. Precipitation occurs to relieve the supersat-
equilibrium solubility at 25° of calcium sulfate uration, and crystal growth occurs.
with an average particle size of 2 microns is
2.085 g/L. When the average particle size is re¬
duced to 0.3 microns, the equilibrium solubility Wetting
increases to 2.476 g/L. Wetting is the displacement of either a liquid
In a practical sense, these values mean that a or gas from a surface by a second liquid. The
solution that is saturated with respect to small wetting of a solid during the manufacture of a
particles is supersaturated with respect to large suspension, or the dissolution of a tablet in the
particles of the same substance. This condition gastrointestinal tract, involves the displacement
causes crystal growth in a suspension, as solute of air from the solid surface and is the type of
diffuses from the saturated layer surrounding wetting considered in this section.2,5
small particles to the saturated layer surround¬ When a drop of liquid is brought into contact
ing the larger particles. Precipitation on the sur¬ with a flat solid surface, the equilibrium shape
face of the larger particle occurs as the saturated of the drop depends on the balance of cohesive
layer becomes supersaturated with respect to forces between the molecules of the liquid and
the equilibrium solubility of the larger particles. the adhesive forces between the molecules of
The overall effect is an increase in particle size the liquid and the solid surface. As can be seen
and a decrease in the number of particles in sus¬ in Figure 5-29, the angle that includes the liquid
pension. The ultimate conclusion of this process at the point where the drop and solid meet can
is the formation of one large particle that repre¬ vary from .0 to 180° and is termed the contact
sents the thermodynamically stable state of a angle, 0. The contact angle is a useful indication
suspension as described by equation (1). of wetting. A low contact angle indicates that
Polymorphs exhibit different equilibrium sol¬ adhesive forces between the liquid and the solid
ubilities. For example, four polymorphs of phen¬ predominate and wetting occurs, while a high
ylbutazone were identified by x-ray diffraction, contact angle indicates that the cohesive forces
thermal analysis, and infrared spectroscopy and of the liquid predominate.
were found to have substantially different equi¬ The basic equation that applies to wetting is
librium solubilities (Table 5-5). The difference the Young equation, which is based on the
in the solubility of polymorphs therefore pro¬ change in free energy caused by an increase in
vides a driving force for crystal growth in sus¬ the area of a solid that is wetted by a liquid (Fig.
pension as the particles of the more soluble 5-30). For a small, reversible change in the posi¬
polymorph go into solution and reprecipitate as tion of the liquid on the surface, there is an in¬
the less soluble, i.e., more stable, form. This crease in the liquid-solid interfacial area, AA,
process is accelerated if the drug powder used to and a corresponding decrease in the solid-air
prepare the suspension contains a mixture of interface of A A cos 0. The corresponding free
polymorphs, or if a seed of the more stable form
is introduced.
Temperature cycling may lead to crystal
growth, as solubility depends on temperature. In
most cases, solubility is directly related to tem¬
perature, so that a slight rise in temperature

Table 5-5. Equilibrium Solubility of Poly¬

morphs of Phenylbutazone

Form Equilibrium Solubility, mg/lOOmt

1 288.7
2 279.7
3 233.6
4 213.0

Adapted from Ibrahim, H. G., Pisano, F., and Bruno, A.: J.

Pharm. Sci., 66:669, 1977. Adapted with permission of the copy¬ FIG. 5-29. The use of the contact angle, 0, to characterize
right owner. the wetting of a solid by a liquid.

BASIC CHEMICAL PRINCIPLES RELATED TO EMULSION AND SUSPENSION DOSAGE FORMS *117
 A ingly, the contact angle of chloramphenicol in¬
creases from 59 to 125°, indicating a change to a
nonwetting surface when the palmitate ester is
formed. Other materials that are known to be
S (Top view}
(Side view} difficult to wet, such as high-density polyethyl¬
ene and magnesium stearate, have contact an¬
FIG. 5-30. Schematic of derivation of Young equation
based on the change in free energy caused by an increase
gles greater than 90°
in the area of a solid, A a, which is wetted by a liquid. The wetting of a powder involves several types
(From Rosen, M. ].: Surfactants and Interfacial Phenom¬ of wetting processes. Three types of wetting
ena. John Wiley and Sons, New York, 1978, p. 178.) have been identified: adhesional wetting, im-
mersional wetting, and spreading wetting.
The first step in the wetting of a powder is
energy change is given by:
adhesional wetting, in which the surface of the
solid is brought into contact with the liquid sur¬
AG = -ys/LAA - -ys/AAA + -yLM(cos0)AA
face. This step is the equivalent of going from
(17)
stage a to stage b in Figure 5-31. The particle is
then forced below the surface of the liquid as
As A A approaches zero, the ratio AG/A A ap¬
immersional wetting occurs (b to c in Fig. 5-31).
proaches zero at equilibrium, so that equation
During this step, solid-liquid interface is formed,
(17) reduces to the Young equation:
and solid-air interface is lost. Finally, the liquid
spreads over the entire surface of the solid as
Ysia = Ys/c + 7ivaCOS0 (18)
spreading wetting occurs. The work of spreading
wetting is equal to the work to form new solid-
The Young equation states that the contact
liquid and liquid-air interfaces minus the loss of
angle will be <90° if the interaction between the
the solid-air interface. For the total wetting proc¬
solid and liquid is greater than the interaction
ess, the work required is the sum of the three
between the solid and air, i.e., ys/L > ys/A. Under
types of wetting:
these conditions, wetting occurs. A general
guideline is that solids are readily wetted if their
Wtotai = -6yUAcos0 (19)
contact angle with the liquid phase is less than
90°. Table 5-6 confirms this rule of thumb, as
Therefore, the analysis supports the generaliza¬
solids that are known to be easily wetted, such as
tion drawn from the Young equation, as wetting
potassium chloride, sodium chloride, and lac¬
occurs spontaneously, i.e., without any input of
tose, have the lowest contact angles. Interest-
work into the system, if the contact angle is
<90°.
Table 5-6. Contact Angle of Solids of Pharma¬ Measurement of the contact angle is compli¬
ceutical Interest Against a Saturated Aqueous cated because hysteresis is frequently encoun¬
Solution of the Material tered. Contact angle hysteresis means that one
value for the contact angle is obtained when the
Material Contact Angle (°) liquid is advancing on the surface, and that a
different, usually lower, value is obtained when
Potassium chloride 21
the liquid is receding. Surface roughness or sur¬
Sodium chloride 28
Lactose 30
face chemical heterogeneity are causes of con-
Caffeine 43
Acetaminophen 59
Chloramphenicol 59 IX V
Phenobarbitol 70
Sulfadiazine 71
Aspirin 75
Phenacetin 78 ,
Hexobarbitol 88
Polyethylene (high-density) 100
Salicylic acid 103
(a) (b) . (c) W
Magnesium stearate 121
Chloramphenicol palmitate 125 FIG. 5-31. The three stages involved in the wetting of a
sblid cube: a -» b, adhesional wetting; b-»c, immersional
Adapted from Lerk, C.F., Schoonen, A. J. M., and Fell, J. T.: J. wetting; c -» d, spreading wetting. (From Jaycock, M. J.,
Pharm. Sci., 65: 843, 1976. Adapted with permission of the copy¬ and Parfitt, G. D.: Chemistry of Interfaces, John Wiley and
right owner. Sons, New York, 1981, p. 237.)

118 ‘The Theory and Practice of Industrial Pharmacy

 tact angle hysteresis. Consider the situation
arising when a syringe is used to inject more liq¬
uid into a drop that is on a “rough” surface. The
advancing liquid encounters solid surface and
air-filled pores. When liquid is withdrawn from
the drop, the receding liquid encounters solid
surface and liquid-filled pores, and a lower con¬
tact angle is measured.
Adsorbed impurities may also affect measure¬
ment of the contact angle. The first contact of
the liquid with the solid surface may dissolve the
impurities. The dissolved impurities may affect
both yS/L and yL/A and thereby cause a variation
in 0 as described by the Young equation. In addi¬
tion, the dissolution of impurities causes the
surface to have a different composition when
the receding contact angle is measured. There¬
fore, great care must be taken when measuring FIG. 5-32. Illustration of Taube's rule: a, adsorption of
fatty acids on carbon from aqueous solution, and b, ad¬
the contact angle, especially in the preparation
sorption of fatty acids on silica gel from toluene. (From
and pretreatment of the solid surface. Adamson, A. W.: Physical Chemistry of Surfaces, 3rd Ed.
Contact angles of finely divided solids are John Wiley and Spns, New York, 1976, p. 390.)
even more difficult to measure than the contact
angle of a liquid on a flat surface. The Washburn
equation states that the distance that a liquid
penetrates into a bed of powder in time t is pro¬ ent, most strongly adsorbs the more polar mem¬
portional to the square root of cos 0.16 This rela¬ bers of a series of related fatty acids, and that
tionship is used experimentally to evaluate the charcoal, a nonpolar surface, most strongly ad¬
wetting ability of a powder by different vehicles; sorbs the more nonpolar members of the series
the powder is packed into a glass tube, or filled of fatty acids.
into an inclined trough, and the distance that a Another useful generalization is that an in¬
vehicle penetrates in time t gives a measure of verse relationship usually exists between the
the relative wetting ability of the system.17 extent of adsorption of a solute and its solubility
in the solvent. Thus, adsorption of a solute can
be either enhanced or minimized by the selec¬
Adsorption at Solid-Liquid tion of the solvent. It is frequently helpful, there¬
fore, to consider adsorption as a type of partition
Interfaces process,
The adsorption of a solute by a solid surface Steric considerations are important for both
can occur during the preparation of suspension the substrate and the solute. Linde molecular
dosage forms as well as in a patient’s gastroin¬ sieve 5A preferentially adsorbs hexane rather
testinal tract following the coadministration of a than benzene because of its small pore size. In
soluble drug and an insoluble solid. Most ad¬ addition, bulky substituent groups on the solute
sorption mechanisms can be classed as either often reduce the degree of adsorption, probably
physical adsorption or chemisorption. The at¬ by preventing close approach of the solute to the
tractive forces in physical adsorption are due to surface.
van der Waals forces, and possibly hydrogen The basic equations used to describe adsorp¬
bonding. The attractive forces in chemisorption tion from solutions are the Langmuir and
are much stronger and include coordination Freundlich equations. These were derived for
complexes and ion exchange. the adsorption of a gas by a solid, but have been
The extent of adsorption depends on the prop¬ extended to adsorption from solution.
erties of the solute, the surface, and the solvent.1 The Langmuir equation is based on the as¬
Taub’s rule may be used to predict adsorption sumptions that (1) the molecules are adsorbed
behavior qualitatively. The rule is that a polar onto specific points of attachment on the sur--
adsorbent preferentially adsorbs the more polar face, (2) that each point of attachment can ac¬
component of a nonpolar solution. Conversely, a commodate only one adsorbed molecule, and
nonpolar adsorbent preferentially adsorbs the (3) that the energy state of any adsorbed mole¬
more nonpolar component of a polar solution. cule is independent of the presence of other ad¬
Figure 5-32 shows that silica gel, a polar adsorb- sorbed molecules on neighboring sites.

BASIC CHEMICAL PRINCIPLES RELATED TO EMULSION AND SUSPENSION DOSAGE FORMS *119
 The Langmuir equation is expressed as: the slope, lib, by the intercept, 1/ab. Figure 5-33
indicates an adsorptive capacity of 480 mg pro¬
c poxyphene hydrochloride per gram of montmo¬
(20) rillonite from the plateau of the adsorption iso¬
x/m
therm, or 490 mg propoxyphene hydrochloride
where c is the equilibrium concentration of the per gram of montmorillonite from a plot of the
solute in solution; x/m is the mass of solute, x, Langmuir equation.
per gram of adsorbate at equilibrium, m; b is the In the Freundlieh equation, a variation of the
adsorptive capacity of the solid, gram of solute Langmuir model, the heat of adsorption dimin¬
per gram of adsorbate; and a is the adsorption ishes exponentially with the number of adsorp¬
coefficient. tion sites that are occupied. This observation
Adsorption that follows the assumptions of the implies that the surface is heterogeneous, i.e.,
Langmuir equation is characterized by an ad¬ there are several types of adsorption sites. The
sorption isotherm, i.e., a plot of c versus x/m, Freundlieh equation is as follows:
which shows a sharp initial increase in the
amount adsorbed, which subsequently de¬ — = kc1/n (21)
creases with increasing concentration until a m
saturation level is reached. The saturation value
of x/m corresponds to b, the adsorptive capacity where x is the amount of solute adsorbed by a
of the solid. The adsorption of propoxyphene by mass of adsorbent, m; c is the equilibrium con¬
montmorillonite fits the Langmuir equation, as centration of the solute in solution; and k and n
can be seen in Figure 5-33. The left ordinate of are constants for the system. When adsorption
Figure 5-33 describes the adsorption isotherm. follows the Freundlieh equation, the adsorption
<2 isotherm (graph of x/m versus c) is not linear at
When the adsorption data are plotted as —- —
low concentrations, nor does it have a saturation
versus c (right ordinate of Fig. 5-33), a straight value.
line is obtained. The adsorptive capacity of the In many cases, information can be obtained
solid, b, is the reciprocal of the slope and the about the mechanism of interaction, including
adsorption coefficient a is obtained by dividing the functional groups involved by the use of in¬
frared spectroscopy.1819 The infrared bands of a
functional group that is involved in an interac¬
tion with a surface are perturbed. Thus, a com¬
parison of the infrared spectrum of the solute
with the infrared spectrum of the solute-adsorb¬
ent mixture is useful in investigating the mech¬
anism of interaction.
The orientation of a solute adsorbed by a
swelling clay can be determined by x-ray diffrac¬
tion. Adsorption by such swelling clays as mont¬
morillonite occurs mainly in the interlayer space
of the clay. X-ray diffraction can accurately mea¬
sure the distance between the clay layers. Thus,
a comparison of the dimension of the interlayer
space before and after adsorption indicates
whether adsorption has occurred in the inter¬
layer space, as well as the amount of space occu¬
pied by the adsorbate. Comparison of the molec¬
ular dimensions of the adsorbate with the
increase in interlayer spacing provides informa¬
tion about the orientation of the solute (e.g., a
EQUILIBRIUM CONCENTRATION OF single layer in parallel orientation).20
PROPOXYPHENE HYDROCHLORIDE, g/500 ml
Once adsorption occurs, several other types of
FIG. 5-33. Adsorption isotherm for propoxyphene hydro¬ reactions are of interest. Desorption refers to the
chloride by montmorillonite. Key: *, x/m versus equilib¬ release of the adsorbate and may be important if
rium concentration; and •, c/(x/m) versus equilibrium
concentration. (From McGinity, }. W., and Lach, ]. L.: J.
an adsorbed drug is exposed to different envi¬
Pharm. Sci., 65:896, 1976. Reproduced with permission of ronments during either its manufacture or use.
the copyright owner, the American Pharmaceutical Associ¬ An understanding of the adsorption mechanism
ation.) is essential for the prediction of desorption. For

120 • The Theory and Practice of Industrial Pharmacy

example, if adsorption is due to physical adsorp¬ Oxidative degradation reactions may also be
tion, dilution may cause desorption. This phe¬ catalyzed by solids if the drug is adsorbed by a
nomenon was observed in the adsorption of di- surface composed of inorganic ions that may be
goxin by montmorillonite.21 Digoxin is a neutral reduced. Certain clays contain structural ferric
molecule that is adsorbed by physical adsorp¬ iron, as well as adsorbed iron oxides or hydrox¬
tion. Digoxin is readily desorbed, however, by ides, at the clay surface. Attapulgite is such a
washing the drug-clay complex with water. clay, and the rate of oxidative degradation of
Desorption is more difficult to achieve if ad¬ hydrocortisone was accelerated significantly in
sorption occurs by chemisorption. Drugs that an attapulgite suspension.23 Sepiolite, another
are adsorbed by cation exchange can be de¬ clay belonging to the same structural class of
sorbed, however, by washing with an electrolyte clays as attapulgite, is relatively free of surface
solution or by changes in the pH of the medium, ferric iron and did not accelerate the oxidative
which cause the adsorbate to change its ionic degradation of hydrocortisone even though ad¬
form. McGinity and Lach were able to produce a sorption occurred.24 Thus, surfaces must not
sustained systemic effect of amphetamine by simply be considered sites for adsorption; the
adsorbing protonated amphetamine (i.e., cati¬ potential of the surface to accelerate chemical
onic form of amphetamine base) by montmoril¬ reactions should be taken into account as well.
lonite through cation exchange.22 The proton¬
ated amphetamine-montmorillonite complex
was stable in the low pH of the stomach, but as References
the drug-clay complex passed through the intes¬ 1. Adamson, A. W.: Physical Chemistry of Surfaces. 3rd
tine, the protonated amphetamine was exposed Ed. John Wiley and Sons, New York, 1976.
to an increasing pH. At higher pH conditions, 2. Rosen, M. J.: Surfactants and Interfacial Phenomena.
John Wiley and Sons, New York, 1978.
the protonated amphetamine was deprotonated,
3. McBain, J. W., and Humphreys, C. W.: J. Phys.
and neutral amphetamine base was formed. The Chem., 36:300, 1932.
neutral drug was not strongly adsorbed and was 4. Becher, P.: Emulsions: Theory and Practice. Rein¬
desorbed in the intestine. The electrolyte con¬ hold, New York, 1957, p. 25.
centration of the intestinal fluid may also have 5. Jaycock, M. J.; and Parfitt, G. D.: Chemistry of Inter
contributed to desorption. Thus, amphetamine faces. John Wiley and Sons, New York, 1981.
6. Padday, J. F.: Surface and Colloid Science. Vol. 1.
was desorbed slowly as the drug-clay complex
Edited by E. Matijevic. John Wiley and Sons, New
passed through the intestine, and a prolonged York, 1969, p. 101.
amphetamine blood level was obtained. 7. Feldkamp, J. R., Shah, D. N., Meyer, S. L. et al.:
An adsorbed molecule may undergo degrada¬ J. Pharm. Sci., 70:638, 1981.
tion reactions at a faster rate, owing to the ef¬ 8. Grim, R. E.: Clay Mineralogy. 2nd Ed. McGraw-Hill,
fects of the surface. Many clays are negatively St. Louis, 1968.
9. Serna, C. J., White, J. L., and Hem, S. L.: J. Pharm.
charged and therefore strongly adsorb cations
Sci., 67:324, 1978.
from solution, including protons. Thus, a higher 10. Hiemenz, P. C.: Principles of Colloid and Surface
concentration of protons exists at the clay sur¬ Chemistry. Marcel Dekker, New York, 1977.
face in an aqueous suspension than is present in 11. Israelachvili, J. N., and Ninham, B. W.: Colloid and
the bulk solution. Digoxin, which degrades by Interface Science. Vol. 1. Edited by M. Kerker et al.
acid-catalyzed hydrolysis, degraded much more Academic'Press, New York, 1978, p.15.
12. Overbeek, J. Th. G.: Colloid and Interface Science.
rapidly in a montmorillonite suspension than in
Vol. 1. Edited by M. Kerker et al. Academic Press,
a solution at the same pH.21 The catalytic effect New York, 1978, p. 431.
was found to be due to the ability of the clay 13. Adams, G. E., and Israelachvili, J. N.: Modification of
surface to serve as a site where digoxin mole¬ Soil Structure. Edited by W. W. Emerson et al. John
cules and protons are concentrated by physical Wiley and Sons, New York, 1978, p. 27.
adsorption and cation exchange, respectively. 14. Israelachvili, J. N., and Adams, G. E.: Faraday Trans.
I, 74:975, 1978.
Therefore, the probability of acid-catalyzed hy¬
15. Kahlweit, M.: Adv. Colloid Interface Sci., 5:1, 1975.
drolysis was enhanced, and an increased hydro¬ 16. Washburn, E. D.: Physiol. Rev., 17:374, 1921.
lysis rate was observed. This effect may reduce 17. Szekely, J„ Neumann, A. W., and Chuang, Y. K.: J.
the bioavailability of digoxin, as 82% of the di¬ Colloid Interface Sci., 35:273, 1971.
goxin was intact and available for absorption 18. Little, L. H.: Infrared Spectra of Adsorbed Species.
after a digoxin solution was aged for 1 hour at Academic Press, New York, 1966.
19. Ledoux, R. L., and White, J. L.: J. Colloid Interface
pH 2, 37°C (which corresponds to the estimated
Sci., 21:127, 1966.
gastric residence time). Only 2% of the digoxin 20. Porubcan, L. S., Serna, C. J., White, J. L., and Hem,
was intact, however, when a digoxin-montmoril- S. L.: J. Pharm. Sci., 67:1081, 1978.
lonite suspension was aged for 1 hour at pH 2, 21. Porubcan, L. S., Bom, G. S., White, J. L., and Hem, S.
37°. L.: J. Pharm. Sci., 68:358, 1979.

BASIC CHEMICAL PRINCIPLES RELATED TO EMULSION AND SUSPENSION DOSAGE FORMS • 121
22. McGinlty, J. W., and Lach, J. L.; J. Pharm. Sci., Davies, J. T., and Rideal, E. K.: Interfacial Phenomena.
66:63, 1977. Academic Press, New York, 1961.
23. Cornejo, J., Hermosin, M. C., White, J. L., et al.: Jaycock, M. J., and Parfitt, G. D.: Chemistry of Interfaces.
J. Pharm. Sci., 69:945, 1980. John Wiley and Sons, New York, 1981.
24. Hermosin, M.C ., Cornejo, J., White, J. L., and Hem, Kruyt, H. R.: Colloid Science. Vol. 1. Elsevier, New York,
S. L.: J. Pharm Sci., 70:189, 1981. 1952.
van Olphen, H.: An Introduction to Clay Colloid Chemis¬
try. 2nd Ed. John Wiley and Sons, New York, 1977.
Osipow, L. I.: Surface Chemistry: Theory and Industrial
Applications. Reinhold, New York, 1962.
Rosen, M. J.: Surfactants and Interfacial Phenomena,
General References John Wiley and Sons, New York, 1978.
Adamson, A. W.: Physical Chemistry of Surfaces. 3rd Ed. Ross, S.: Chemistry and Physics of Interfaces. American
John Wiley and Sons, New York, 1976. Chemical Society, Washington, D.C., 1965.
Betcher, P.: Emulsions: Theory and Practice. Reinhold, Shaw, D. J.: Introduction to Colloid and Surface Chemis¬
New York, 1957. try. 2nd Ed. Butterworths, London, 1970.

122 • The Theory and Practice of Industrial Pharmacy

 6
Pharmaceutical Rheology
JOHN h. wood

Pharmaceutical fluid preparations are recog¬ of an infinitesimal force. In practice, gravity is

nized as materials that pour and flow, having no generally regarded as the criterion of such a
ability to retain their original shape when not minimal force.
confined. The semisolids are a more nebulous To best understand the fundamental compo¬
grouping- They essentially retain their shape nents of viscous flow, consider Figure 6-1. Two
when unconfined but' flow or deform when an parallel planes are a distance x apart; between
external force is applied. Those materials that the planes, the viscous body is confined. The
readily pour from bottles and form a puddle are top, plane A, moves horizontally with velocity v
clearly fluids. Ointments or pastes that clearly because of the action of force F. The lower
retain their shape after extrusion from a tube plane B is motionless. As a consequence, there
characteristically are associated with pharma¬ exists a velocity gradient v/x between the planes.
ceutical semisohds. Obviously a continuum of This gradient is given the definition of rate of
properties exists between these limits. shear, D. The shear stress, S, is the force per unit
Rheology (from the Greek rheos meaning flow area creating the deformation.
and logos meaning science) is the study of the Example 1. If some oil is rubbed into the skin
flow or deformation under stress. In pharmaceu¬ with a relative rate of motion between the two
tical and allied research and technology, rheo¬ surfaces of 15 cm/sec, and the film thickness is
logic measurements are utilized to characterize 0.01 cm, then the shear rate is as follows:
the ease of pouring from a bottle, squeezing from
a tube or other deformable container, maintain¬ _ 15 cm/sec
ing product shape in a jar or after extrusion, rub¬
- 0.01 cm
bing the product onto and into the skin, and
even pumping the product from mixing and = 1500 sec-1
storage to filling equipment. Of extreme impor¬
tance in both product development and quality This shear stress may be applied either mo¬
assurance is the determination that the desired mentarily or continuously. Elastic deformation
attributes of body and flow are retained for the occurs if, as the force is applied, the upper plate
required shelf-life of the product. moves in the direction of the force only momen¬
tarily and then stops but returns to its original
Definitions and Fundamental position when the deforming force is removed.
On the other hand, pure viscous flow occurs if
Concepts there is continuous movement during the ap¬
The tangential application of a force to a body plied force, and no restorative motion follows
and the resultant deformation of that body are removal of the deforming force.
the essential components for a rheologic obser¬ Between the limits of elastic deformation and
vation. If this force is applied for only a short pure viscous flow, there exists a continuum of
time and then withdrawn, the deformation is combinations of these limits. Such behavior is
defined as elastic if the shape is restored, but as called viscoelastic flow. The elastic component
flow if the deformation remains. A fluid or liquid of viscosity is considered in a later section.
then becomes a body that flows under the action Newtonian fluid is a fluid in which a direct
 Velocity = v However, the dyne is the force acting for 1 sec to
produce a velocity in a 1-g mass of 1 cm/sec.
Hence, this dimensional analysis for viscosity
reduces to:

r) = g • cm-1 sec-1
= poise

In the International System of Units, which is

not yet used routinely in viscosity references,
the pascal (Pa) is the unit of stress and has the
dimensions of newtoi^meter2, where the new¬
ton is a kilogram meter/second2. Hence, equiva¬
lence occurs for the centipoise with millipascal-
seconds.
Example 2. If in example 1, the oil had the
same viscosity as water, then the force used to
FIG. 6-1. Model to demonstrate components of classic vis¬ create the shear can be determined ,as follows:
cous flow.
S
proportionality exists, for all values of shear, be¬
tween shear stress and shear rate.
Viscosity or coefficient of viscosity is the pro¬
g
1 x 10-2 poise = ■ sec-1
portionality constant between shear rate and
shear stress. Conventionally, viscosity is repre¬
sented by 17. Then: Then S = (1500)(1 x 10-2)(sec-1Xpoise)
= 15 (secJ)(dyne sec cm-2)
77 = S/D (1) = 15 dyne cm-2

The centimeter-gram-second (C.G.S.) sys¬ Example 3. In S.I. units, the above terms
tem uses grams per centimeter per second would become:
(g cm-1 sec-1) as the dimensional units of vis¬
cosity. In these units, viscosity is expressed in tj = 1 mPas
poises, a term used in recognition of the pioneer¬ D = 1500 sec-1
ing work in the 1840s of the French scientist S = 1.5 Pa
J. L. M. Poiseuille. For dilute aqueous solutions,
the common unit becomes the centipoise (10-2 Fluidity is the reciprocal of the viscosity, usu¬
poise), cp. The viscosity of water is about 1 cp. ally designated by the symbol <j>. This is an occa¬
In the newly adopted International System of sional unit of convenience but not an essential
Units (SI), the unit corresponding to the centi¬ one.
poise is the millipascal-second (mPas). Kinematic viscosity (v) is the Newtonian vis¬
A perspective of these units may be obtained cosity divided by density (17/d). The unit is now
by considering the case of Figure 6-1 when a the stoke, in honor of the English scientist who
force of 1 dyne acts to produce a velocity of studied problems of gravitational settlement in
1 cm/sec for plate A when the distance between fluids. As discussed later in this chapter, certain
plates is 1 cm, and both plates are 1 cm2 in fluid flow viscometers give values in this kine¬
cross-sectional area. Under these terms, viscos¬ matic scale.
ity is calculated as: Example 4. If the oil from examples 1 and 2
had a density of 0.82, then the kinematic viscos¬
S
ity would be:

_force/area_
velocity difference/distance
= 1 x IQ-2
dyne/cm2 0.82
(cm/sec)/cm
= 1.22 x 10-2 stokes
= dyne sec cm-2 = 1.22 centistokes

124 • The Theory and Practice of Industrial Pharmacy

 Non-newtcmian fluids are those in which there ment. Although frequendy, reference is care¬
is no direct linear relationship between shear lessly made to a lotion having a viscosity of
stress and shear rate. Most systems of pharma¬ 300 cp or to a paste or ointment having a viscos¬
ceutical interest fall into this category. The ity of 1200 poises, these are meaningless terms
shear stress necessary to achieve a given shear unless the shear rate at which the measurement
rate may increase more rapidly or less rapidly was made becomes a clear part of the statement.
than is required by the linear direct proportion¬ The fact that one number cannot characterize
ality (Fig. 6-2). the viscous behavior, however, requires the use
A pseudoplastic material is one in which the of some equation of state. One such empiric one
stress increases at less than a linear rate with is the Power Law Equation:
increasing shear rate, while a dilatant material
is one in which the increase is more rapid. Thus, S = A Dn (2)
if viscosity is calculated at each of a series of
shear rate points by use of equation (1), then the where S and D are the shear stress and shear
resultant values decrease with increasing shear rate respectively, A is an appropriate proportion¬
rate for pseudoplastic materials and increase for ality constant, and n is the Power Index. In this
dilatant ones. Measurements at such single form, n is less than 1 for pseudoplastic materials
points are frequendy referred to as apparent vis¬ and greater than 1 for dilatant materials. The
cosity to recognize clearly that the number Power Law Equation is also used with the index
quoted refers only to the condition of measure- n associated with stress rather than shear rate.
Obviously, the magnitude of the values of n are
then interchanged. Unfortunately, there is no
clear convention for such equations.
When the logarithm of both sides of equation
(2) is taken, the result is:

log S = log A + n log D (3)

Compared with the equation of a straight line,

y = b + mx, a plot of log S against log D results
in a straight line of slope n and intercept log A.
Figure 6-3 shows such plots on logarithmic scale
for one gum system as a function of gum con¬
centration.
Example 5. Calculate the parameters of the
Power Law Equation for 0.01%, 0.02%, 0.04%,
and 0.10% gum solutions. The following data
apply to this case.

Stress Stress
at at
Composition D = 1 D = 10
.01% 0.35 dyne cm2 2.1 dyne cm
.02 6.2 20
.04 61 132
.10 205 440

The slope of each line is obtained from:

_ log S(D=io'i ~ log S/D=1,

log 10 - log 1
= log (Siq/Si)
FIG. 6-2. Examples of basic types of rheograms. A, Pseu¬ 1 - 0
doplastic or power law; B, Newtonian; C, dilatant; D, pseu¬
doplastic with yield value; E, Bingham or Newtonian with
yield value; F, dilatant with yield value.

PHARMACEUTICAL RHEOLOGY • 125

 Newtonian behavior at stresses (S) greater than
the yield value (f) we have:

S - f = UD (4)

where U is the plastic viscosity and D is the

shear rate. Similarly (see Fig. 6-2), both pseudo¬
plastic and dilatant curves may appear to exhibit
yield value. The dimensional units of the yield
value must be those of the shear stress.
Because of the variety of parameters involved,
no single measurement can characterize a non-
Newtonian system. This can be seen in Fig¬
ure 6-4. A wide variety of curves can pass
through any specific value of shear stress and
shear rate, exemplified here by the common
focus of pseudoplastic, dilatant, and Newtonian
lines. At the focal point, all have the same appar¬
ent viscosity, but at no other point do they have
related values.

Properties Contributing to
Rheologic Behavior
FIG. 6-3. Logarithmic plots of the rheograms of Carbopol
In general, Newtonian liquids are either pure
941. (From Catacalos, G., and Wood, J. H.: J. Pharm. Sci., chemicals or solutions of lower molecular weight
53:1089, 1964. Reproduced with permission of the copy¬ compounds rather than of polymeric materials.
right owner, the American Pharmaceutical Association.) All interactions are such that no structure is
contributed to the liquid. Since by definition,
shear stress and shear rate are directly propor¬
^ , , , 2.1 , 20 , 132 tional, a single viscometric point can character¬
The slopes are then log Q ^ , log , log -gj-, ize the liquid rheology. Increasing temperature
440 v . decreases viscosity as it reduces intramolecular
and log ■- for the four successive copcentra- forces of attraction. Such temperature viscosity
205 : ~ ..
relationships are quickly established, regardless
tions. These reduce to 0.78, 0.51, 0.341Tand 0.33
of whether temperature is increased or de¬
respectively.
creased.
The intercept of a line is the value of y for
x = 0, or here the value of log S for (log D) = 0,
but the logarithm is zero when the number is
unity, log 1=0. Therefore, the intercepts of the
four concentrations are log 0.35, log 6.2, log 61,
and log 205. Numerically then, these values of
log S are the values log A. Hence, the values of A
are 0.35, 6.2, 61, and 205 respectively. The
Power Law Equations are then:

0.01% S = 0.35D078
0.02 S = 6.2D° 51
0.04 S = 6 ID034
0.10 S = 205D033

When-an initial finite force is necessary before

any rheologic flow can start, this initial stress is
called yield value. A Bingham plastic is repre¬
sented by a straight line or curve on the stress-
shear rate plot being displaced from the origin by FIG. 6-4. Different rheograms all have the same apparent
a finite stress value, the yield value. Thus, for viscosity at the common foci but not at any other point.

126 • The Theory and Practice of Industrial Pharmacy

 Pseudoplastic behavior is exhibited by poly¬
mer solutions and by most semisolid systems
containing some polymer components. In such
systems, there is a buildup of interlacing molec¬
ular interactions. Long straight-chain polymers
tend to have some coiling in their condition of
minimum energy. These coils can develop a
degree of interlocking. With branched polymers,
the opportunity for frictional interlock is obvi¬
ously even greater. In addition or alternatively,
intramolecular bridging may occur by simple
hydrogen bonding. This bonding may create
innumerable bridges between individual adja¬
cent molecules to create a complete cross-link¬
ing. As an example, water added to a liquid non¬
ionic in the correct ratio can create a solid gel. In
the case of silica or alumina gel, water may serve
alone or with other agents from cross-linking to
create a three-dimensional polymer structure.
Classically, most suspending agents exhibit sim¬
ilar capability for development of structure. De¬
pending on the nature of the suspending and
cross-linking materials used, these adjuvants
may or may not be in complete homogenous so¬
lution. Instead, these agents may have a strong
FIG. 6-5. The solid lines represent ascending and de¬
affinity for the solvent and yet be partially insol¬ scending rheograms for a pseudoplastic system exhibiting
uble. In systems with dispersed solids, these col¬ thixotropy. The dashed lines represent a dilatant system
loid solutions can serve as the interweaving ma¬ with a loop of rheopexy.
terial to hold the whole system together.
When shear is slowly imparted to such a sys¬
tem, deformation may initially occur with some
difficulty, but once initiated, it becomes progres¬ easy. These planes of slippage result in what is
sively easier as successive increments of force called plug flow. In such a system, one portion
are applied. The nature of the interlocking or moves with the shear stress, while the residue
interwoven structure dictates whether initial . remains at rest. As is discussed later, this results
flow occurs with difficulty until sufficient struc¬ in confusing rheologic implications for product
ture is lost or whether a sufficient initial force is performance. In general, such measurements
required to initiate motion, that is, whether a are less reproducible.
yield value has to be exceeded. In any case, con¬ Classic rheology cannot handle time-depend¬
tinued shearing breaks further linkages, so that ent phenomena except to display changes in
the apparent viscosity drops with increasing stress under continuing shear. Thixotropy is
shear. As shear stress is then decreased, the therefore a phenomenon resulting from the time
structure may or may not recover immediately. dependency of the breakdown or the rebuilding
If recovery occurs rapidly, the ascending and of structure. It is an empiric observation of good
descending shear-stress/shear-rate rheograms reliability that structure breakdown or buildup is
will be essentially superimposable. If the struc¬ an exponential function of time. Thus, if the
ture does not immediately recover, the descend¬ observed shear stress for a given shear rate is
ing rheogram will have lower stress values at followed with time, a plot of stress against time,
each shear rate than the ascending (Figure 6-5). both on the logarithmic scale, results in a
Such a body is said to be thixotropic and the straight line. Green and Weltmann used a vari¬
loop, a hysteresis loop, is in area a measure of ant of this observation to derive a coefficient of
the thixotropy. thixotropic breakdown (B) by the equation:1
Occasionally, semisolid systems in shear, par¬
ticularly those containing an appreciable solid R _ Si - S2
content or those in which structure is developed Infe/ti)
through a three-dimensional polymer (silicate
system), develop shear planes across which vir¬ where Si and S2 are the stress values at times ti
tually no interactions exist, and hence, flow is and t2 of continuous shear at any arbitrary shear

PHARMACEUTICAL RHEOLOGY *127

rate chosen for comparison. Other pharmaceutic is a historical problem originating in the equip¬
cal applications for pastes and lotions were later ment used in early measurements. Specific
developed by Weltmann.2 equipment is discussed in a later section of this
Example 6. Consider an ointment undergoing chapter. It suffices to say that in the early work
shear in a rotational viscometer at a constant with rotational viscometers, the drive force was
rate of shear. A reading is taken 5 sec after applied by hanging weights, and shear rate was
starting. The observed shear stress is then calculated from the observed rotational
14,000 dyne cm-2. After continuous shear, the speed. In this context, stress was the controlla¬
value drops to 11,500 dyne cm-2 at 50 sec and ble independent variable. Today, the drive speed
to 900 dyne cm-2 at 500 sec. Then, the coeffi¬ is set by the use of synchronous motors whose
cient of thixotropic breakdown is: speed is controlled by the applied electric fre¬
quency, by gear ratios, or by both. Under these
14,000 - 11,500 conditions of a fixed set of rotational speeds, the
dyne cm shear rate should become the independent vari¬
In (50/5)
able. The majority of rheologic data are obtained
2500 in this manner. With data obtained by capillary
2.303 rheometers using externally applied pressure,
the stress is the independent predetermined
= 1085 dyne cm 2
parameter, and shear rate is the consequential
dependent variable. The conclusions and the
Similarly:
essential data are the same, however, regardless
of how the plots are made. Typical plots for two
11,500 - 900
B = dyne cm 2 • gum systems are given in Figure 6-6.
In (500/50)
The logarithmic plots of the shear-stress/
= 1085 dyne cm 2 shear-rate relationships of these two gums are
found in Figures 6-3 and 6-7. Figure 6-3 was
Obviously, the coefficient is a function of the used to illustrate the Power Law, and the calcu¬
time interval chosen, in this case a decade. lation of its parameters.
Dilatant systems are essentially the opposite In addition, the logarithmic plot of stress and
of pseudoplastic thixotropic ones. In dilatancy as shear rate is convenient for providing an overall
shear continued, the fluid components contrib¬ summary of data taken in various shear rate
uting to lubricity between particles are excluded ranges. In the conventional arithmetic scale, low
from between the shear planes so that the re¬ shear rate data are excessively compacted in the
sulting structure develops increasing friction. presence of high shear rate observations. There
Thus, stress increases with time in a logarithmic is no other practical way to observe both low and
manner similar to that with thixotropy. A similar high shear rate observations within one graph.
hysteresis loop of rheopexy is developed in
dilatant systems. Magnesia magma is the classic
pharmaceutical example of this behavioral type.
Yield Value Determination
Usually, some yield value is also recognized in Examining Figure 6-6 for indications of yield
rheopectic systems. value as defined earlier from Figure 6-2, one
Equation (5) may be used with dilatant sys¬
tems in the same way as with thixotropic ones to
yield a coefficient of dilatant buildup.

Graphic Presentation of
Rheologic Data

Stress-Shear Rate Curves

As was mentioned with the Power Law rela¬
tionship, there is no uniformity of presentation
of shear-stress/shear-rate data as to which SMEAR RATE ( SECONDS-1 ) '

should be the dependent variable (ordinate) and

FIG. 6-6. Rheograms for Carbopol 941 and Jaguar. (From
the independent variable (abscissa). The con¬ Catacabs, G., and Wood, J. H.: J. Pharm. Sci. 53:1089,
fusion in representing the Power Law by equa¬ 1964. Reproduced with permission of the copyright owner,
tion (2) is a consequence of this ambiguity. This the American Pharmaceutical Association.)

128 • The Theory and Practice of Industrial Pharmacy

 SMEAR RATE (UNITS)

FIG. 6-8. Logarithmic representations of rheograms.

Newtonian with slope unity A; power law with slope less
than unity B; power law with slope approaching unity at
low shear rates C; power law with slope approaching zero
at low shears indicating yield value D. (From Catacalos,
FIG. 6-7. Logarithmic plot of the rheograms of Jaguar.
G., and Wood, J. H.: J. Pharm. Sci., 53:1089, 1964. Repro¬
(From Catacalos, G., and Wood, J. H.: ]. Pharm. Sci.,
duced with permission of the copyright owner, the Ameri¬
53:1089, 1964. Reproduced with permission of the copy¬
can Pharmaceutical Association.)
right owner, the American Pharmaceutical Association.)

sees that discrepancies between the real and the unity, implying classic Newtonian behavior at
ideal case appear to exist. The data for Carbopol low shear rates.
941 all behave at higher shear rates as if they Although the logarithmic plots permit an un¬
belonged to a family of curves exhibiting yield ambiguous determination of the reality of the
value at low shears. At the lower shear rates, yield value, they permit only a qualitative as¬
however, the shear stresses drop off dramati¬ sessment of its numerical magnitude.
cally, implying that a yield value does not occur Two plots for better visualization of yield value
for Carbopol 941. With the Jaguar gum, similar have become common. These are the Casson
break-off points occur, but the high concentra¬ and the Fitch plots, (Figures 6-9 and 6-10);3'4
tions of 1.4% and 1.2% do imply a yield value. the Casson is the most widely accepted. In the
In both cases, if no measurements had been Casson plot, the square root of stress is plotted
made at shear rates below 5 sec-1, the existence against the square root of the shear rate, while in
of a yield value would be unquestioned. When a the Fitch plot, the stress is direcdy plotted
gum system is assumed to have a yield value against the square root of the shear rate. The
based on rheologic measurements, but cannot
maintain a quality suspension, it is usually be¬
cause the low shear-rate values were ignored.
Often, this error is not deliberate but is governed
by the characteristics of the measuring appara¬
tus available.
If the logarithmic plot is essentially a straight
line into the low shear rates, then obviously a
true yield value does not exist, even though by
the conventional plot there appears to be a yield
value. However, if the power equation logarith¬
mic plot tends to break upward toward a con¬
stant stress for lower shear rates (Fig. 6-8), a
true yield value exists. When the logarithmic /SHEAR RATE (SEC*1) /SHEAR RATE (SEC.-'!

plots Figure 6-3 and 6-7 are examined, it is ap¬ A B

parent that for the Carbopol 941 curves, the
FIG. 6-9. Yield value plots for Carbopol 941. A, Fitch plot.
Power Law straight line tends to break upward
B, Casson plot. (From Catacalos, G., and Wood, J. H.:
toward the horizontal at low shear rates, imply¬ J. Pharm. Sci., 53:1089, 1964. Reproduced with permis¬
ing the existence of a true yield value. The Jag¬ sion of the copyright owner, the American Pharmaceutical
uar* tends to break downward toward a slope of Association.)

PHARMACEUTICAL RHEOLOGY • 129

FIG. 6-10. Yield value plots for Jaguar. A, Fitch plot. B,
Casson plot. (From Catacalos, G., and Wood, J. H.: J.
Pharm. Sci., 53:1089, 1964. Reproduced with permission
of the copyright owner, the American Pharmaceutical As¬
sociation.)

intercept on the stress axis is then defined more

clearly than is possible from other representa¬
tions. In Figures 6-9 and 6-10, it is apparent
both from the Casson and the Fitch plots that
these implications are indeed borne out. The FIG. 6-11. Aging change in apparent viscosity at different
Carbopol 941 values generate unambiguous in¬ shear rates. (From Wood, J. H., Catacalos, G., and Lieber-
tercept plots by both methods, while the Jaguar man, S. V..- ]. Pharm. Sci. 52:354, 1963. Reproduced with
permission of the copyright owner, the American Pharma¬
values all focus on the graphic origin.5
ceutical Association.)
If only higher shear rate measurements were
available, the logarithmic plot, by the changing
slopes observed, would produce uncertainty re¬ Initial rheograms were run about 3 hours after
garding a yield value; however, the conven¬ manufacture of the suspension and again at 24
tional, the Casson, and the Fitch plots would all and 48 hours. The values at 48 hours are clearly
have clearly exhibited yield values. Unfortu¬ in line with those anticipated from the first two
nately, the logarithmic plot is used rarely as in¬ times. The data through 60 days continue to in¬
surance for the low shear rate behavior. crease linearly by the logarithmic relation. The
results during the first day can predict the first
week, while those of the first week predict the
Aging of Rheologic Properties next month, and the month implies the year by a
For non-Newtonian pharmaceutical systems, linear projection.
it is necessary to characterize the changes oc¬ In the development of a lotion formulation
curring in the rheologic properties. One conven¬
ient representation 's the plotting of the appro¬
priate function of the property against time
using a double logarithmic plot.6 The logarithm
of time permits hours, days, months, and even
years to be represented on a single graph. This
plot can indicate that a continuous change in
property can occur with time (Fig. 6-11), or that
a discontinuity can be recognized during the
aging process (Fig. 6-12). The great advantage
of this plot is that data obtained on fresh samples
can contribute significantly to the recognition of
the aging pattern. Each decade of time contrib¬
FIG.'6-12. Aging curves for various process and formula¬
utes equally to the continuum of the time pat¬
tion variants of lotion subject to age hardening. (From
tern. Diffusion-controlled phenomena usually Wood, J. H., and Catacalos, G.: J. Soc. Cosm. Chem.,
display a logarithmic time dependency. 14:147, 1963. Reproduced by permission of the copyright
Consider the data represented by Figure 6-11. owner.)

130 ♦ The Theory and Practice of Industrial Pharmacy

and a processing study, the data of Figure 6-12 = ^ (100 mm Hg)(13.595 g/cm3)j
were obtained. The formulation tended to
harden with age. The departures from the flat
initial rheologic observations clearly indicated ^ mom 2\( 0-05 cm\
x (980.7 cm sec )^-———j
when this undesirable process became signifi¬
cant. Although the onset time of this hardening
remained empiric, these logarithmic time plots l 1.333 x 105 , . 2\/.05\
= (---dynes/cm2 j j
did provide a level of confidence as aging of im¬
proved formulations proceeded.
= 33300 dyne cm-2

Example 8. What is the apparent viscosity of

Types of Rheologic Instruments the fluid in example 7?

Capillary or Tube Viscometers S

When a fluid flows through a round-bore cap¬

1,= ~D
illary or tube, there is a viscous drag restraining _ 33300 dyne cm-2
the flow. The fluid in immediate contact with 20400 sec-1
the wall is motionless while that at the center is
at maximum velocity. Between these two limits = 1.63 poise
is then a velocity gradient. It may be shown that = 163 cp
D, the shear rate at the wall, for a Newtonian
liquid is given by: Substituting equations (6) and (7) into equa¬
tion (1) gives the net result:

D= (6) _ AP,t4
17 8LQ
(8)
where Q is volume flowing through the capillary
per unit time, and r is the radius of the capillary. This equation is generally referred to as
The shear stress, S, at the wall is: Poiseuille’s equation. For this form, the results of
example 8 .would be obtained without a calcula¬
APr tion of the shear rate and stress involved. As
S =
2L
(7) with many such relationships, this is an ideal
equation. It assumes that die length is much
where L is the length of the capillary and AP is greater than the radius, and that there are no
the pressure difference across the capillary, entry and exit effects at the ends of the tubing. A
which provides the appropriate force to over¬ series of corrections to the expressions for D and
come the viscous drag. S have been derived to provide corrections for
Example 7. What shear stress and shear rate these effects and for various stress-strain rela¬
develop when 2 ml/sec of a fluid are forced tionships within the fluid; however, these basic
through a 10-cm length of capillary diameter equations are remarkably adequate in providing
1 mm by a force equivalent to a 100 mm of mer¬ useful characterization on non-Newtonian sys¬
cury? tems.
The form of capillary most .frequently used is
the glass system typified by the Ostwald viscom¬
eter (Fig. 6-13). Here the AP term is the differ¬
ence in height between the upper and lower
- (4)(2 ml/sec) meniscuses of the fluid. There is a change in
(ir)(0.05 cm)3 head resulting from the flow of the liquid from
the bulb as measured by the movement between
= 20,400 sec-1 the two markings of the upper meniscus. Simul¬
taneously, the lower meniscus rises as the flow
The unit of pressure must be multiplied by the enters the lower reservoir. Therefore, measure¬
mercury density and the acceleration of gravity ments are at a varying shear stress and shear
to convert to force units. rate. This is not a problem when relative viscos¬
ity measurements are made by comparing a
o AP r standard reference t?r and the unknown pu. In
each case, the volume V flowing is the same, but

PHARMACEUTICAL RHEOLOGY • 131

 given by:

_ t; 1.005
v d .998
= 1.007 centistokes

Then, by equation (10):

^oil __ ^oil

^water t\vater

J'oil 426
1.007 224

I'oil = 1.92 centistokes

VoU d0iivoil

= (,748)(1.92)
= 1.43 cp

FIG. 6-13. Ostwald viscometer. Liquid is drawn up from A wide range of capillary lengths and diame¬
bulb E into the bulb above the mark A, and the time of fall ters permits a full range of fluids to be studied.
of the upper meniscus from line A to line C of the fluid Such instruments should, of necessity, be re¬
contained in B is measured. The diameter and length of stricted to materials that can readily flow into
the capillary D control the flew time. and out of the apparatus without rheologic
damage. Hence, these liquids should be essen¬
tially Newtonian in behavior.
the time for flow is tR and t„ respectively. The
Commercially, Ostwald viscometers are pur¬
AP term effectively becomes a height term h di¬
chased by the choice of the centistokes per sec¬
vided by the density of the fluid. It then follows,
ond constant desired. The normal expected flow
on substitution into equation (8) that:
time is 200 to 800 sec for a given instrument.
Faster times generally utilize some form of ex¬
= ( (hdu)(7n-4) \ / (hduX-rcr4) \
ternal timing. Cannon Instrument Co. (State
,u V 8L(V/tu) / V 8L(V/tJ /
College, PA) sells a range of Ostwald Viscome¬
_ tudu ters with constants ranging from approximately
0.002 to 20 centistokes per second.
Ir^r
Example 10. Quality control personnel wish to
This equation can be rearranged as: purchase an Ostwald Viscometer for routine
monitoring of the viscosity of an oil whose den¬
sity is 0.821 and whose viscosity is about 125 cp.

(VJAVJ-t <9> They wish the observed flow time to be between

200 and 400 sec. What specification instrument
should they buy?
The term 17/d was defined as the kinematic vis¬
cosity v, and so:

yu _ tu
(10) 125 cp
lR
~ 0.821 g/cm3
It is primarily in this type of situation that kine¬ = 152 centistokes
matic viscosity has its greatest use.
Example 9. The flow time for water in an Ost¬ To have a flow time of 300 sec, the constant of
wald Viscometer was measured at 20°C as the instrument should be approximately:
224 sec for the average of 5 trials. Similar meas¬
urements for an oil of density 0.748 g/cm3 were _ 150 centistokes
426 sec. What is the viscosity of the oil? The
300 sec
density of water at 20° is 0.998, and the viscosity
is 1.005 cp. The kinematic viscosity of water is = 0.5 centistokes/sec

132 • The Theory and Practice of Industrial Pharmacy

The Cannon Instrument Co. has size number piston per unit time. Hence, the shear rate ob¬
350, which has this instrument constant value. served is that prechosen by the capillary radius
Because many research and quality control and the volume terms. In this case, the force
measurements utilize some variant of the Ost- transmitted to the piston is measured by a suita¬
wald Viscometer, there are commercial instru¬ ble device, either a strain gauge on the pressure
ments that measure the time for flow between shaft or a hydraulic gauge in the pressured sys¬
the two indices with high precision by using tem. Thus, by equation (7), the shear stress is a
photoelectric timing. Schott America (New York, direct function of this force measurement.
NY) markets a system capable of automatic load¬ Instron testers, because of their constant veloc¬
ing of up to 30 samples for sequential measure¬ ity of movement, are typical components for
ment by such a timer. such a system. The Instron Engineering Corp.
Alternate versions of the classic Ostwald Vis¬ (Canton, MA) can create suitable custom instru¬
cometer have been developed to minimize in¬ ments.
herent problems of the individual practical in¬ The alternative version of Figure 6-14 re¬
struments. Thus, some instruments depend less quires that a constant force be applied to the pis¬
on the varying pressure differential, some use ton, and the resultant displacement of piston or
either pressure or vacuum as a driving force, sample extruded is measured. Typically, the
some require minimal volume, and some permit constant force is applied from gas cylinders with
successive dilutions to take place in the instru¬ a good pressure regulation system. One com¬
ment to follow concentration behavior. mercially available example is the Cannon-Man¬
In general, use of Ostwald Viscometers is re¬ ning Pressure Viscometer (Cannon Instrument
stricted to a “one-shear-range” measurement Co., State College, PA) shown in Figure 6-15.
only, and the instrument must be selected for
the individual sample under investigation.
The alternative is a general instrument con¬
taining replaceable capillary tubes and a variable
driving force. Such an instrument provides max¬
imum flexibility of use. This system is shown
schematically in Figure 6-14. A sample storage
chamber is loaded with the sample to be investi¬
gated. The sample is extruded through a capil¬
lary tube attached to one end. The chamber con¬
tents are forced through this exit capillary by the
force of the piston. Two versions are practical. In
one, the piston is driven at a constant linear rate.
Then, by equation (6), the volume extruded per
unit time is a geometrically defined constant
depending only on the volume displaced by the

FIG. 6-14. The extrusion rheometer. Either a constant

linear velocity is imparted to the piston to give a preset
volume delivery and the piston force is measured, or a pre¬
set force (air pressure) is applied and the rate of volume FIG. 6-15. Cannon-Manning pressure viscometer. (By
delivery is determined. permission from Cannon Instrument Co.)

PHARMACEUTICAL RHEOLOGY *133

The capillary is the metallic fixture between the instruments. The rotation, usually of the inner
two Swage Nuts. Pressure is applied through the member, is provided by a synchronous electric
side arm to the sample (18 ml) contained in the motor, usually with variable ratio drives that
holding vessel. The volume displaced is meas¬ provide a series of discrete speeds, with the
ured by either or both of the two glass bulbs. The other member rigid. An alternative is a motor
pressure drop occurs completely within the cap¬ that provides a continuous variation in speed by
illary so that the glass portion of the system is an appropriate transmission control or by a vari¬
not under any pressure. This instrument is ca¬ able speed motor drive. A mechanical linkage in
pable of performing rheologic studies of most the shaft measures angular displacement of the
pharmaceutical semisolid formulations: pastes, bob from the driving armature. Figure 6-16 ex¬
ointments, and creams. hibits the Brookfield manner of achieving this
These types of systems can be developed or dual function. More advanced instruments have
modified “in house” to meet specific criteria. replaced the measurements of angular displace¬
The shop work involved in creating an excellent ment with strain gauge linkages of some form to
instrument does not impose excessive demands permit direct electronic recording or digital read¬
on an adequate facility. out.
Many of the manufactured instruments of this In the mathematical derivation of the usual
type have tended to have a limited sales life be¬ expressions for shear stress S and shear rate D
cause of minimal replacement needs once the for the cup and bob situation, the existence of a
market was saturated. One of these, the Severs Newtonian fluid is assumed. In this situation,
Extrusion Rheometer,7 is discussed later in this two alternatives may be considered for the aver¬
chapter under “Specialized Pharmaceutical age shear stress and shear rate in the gap be¬
Applications of Rheology.” tween the cup and bob. These are the arithmetic
By suitable choice of the flow tubing, the (A) and geometric (G) means of the values at the
stress measurement devices, and the timing sys¬ walls of the bob and the cup. The more custom¬
tems, the extrusion systems are capable of being ary arithmetic values are:
utilized in virtually any pharmaceutical or cos¬
metic formulation system, including those in T(Rf 4- Rq)
which low shear rates are necessary to define A 47rhR?R£,
(ID
yield value. In these, as in any other measuring
device, it is essential that no rheologic damage to (k?+m n (12)
the sample occurs in loading it for measure¬ Da =
(Ro - R?)
ment.
where T is the measured torque (dyne cm) usu¬
ally obtained as the product of a scale reading
Couette Viscometers
Couette, or rotational, viscometers comprise
two members, a central bob or cylinder and a
coaxial or concentric cup. One or both are free to
rotate in relation to each other. Between these is
the test substance, in the annulus. Three basic
configurations have been utilized. These are a
rotating cup with strain measurement on the
central bob, a rotating central bob with strain
measurement on the cup, and a fixed cup with
both rotation and strain measured on the bob.
The first of these configurations originally
provided the cup rotation by the force of weights
hanging on a pan that was suspended from a
cord wound around the cup. The central bob dis¬
placement was restrained by an appropriate
spring of known modulus so that the angular
displacement could be equated to angular torque
on the bob. Later versions provided synchronous
speed drives for the cup. The second type of
couette viscometer is merely a mechanical in¬
version of the first. The third classification rep¬ FIG. 6-16. Brookfield Synchro-Lectric viscometer. (By
resents the majority of modem mass-produced ■permission from Brookfield Engineering Lab.)

134 ♦ The Theory and Practice of Industrial Pharmacy

and the instrumental restoring torque per scale Note that the revolutions per minute were con¬
unit of deflection; Rj and Ro are radii of the verted to radians per second, there being 2tt ra¬
inner member, bob, and the outer member, cup, dians per revolution.
respectively; h is the effective height or length of
the bob; and ft is the angular velocity of rotation S
in radians per second. V = 1D
The values for the geometric mean replace the
_ 79.3 dyne cm
(R2 + Ro) term in the numerators of both equa¬
tion (11) and equation (12) by 2 RjRq, yielding: 61.3 sec-1
= 1.29 cp
(13)
2'a-R1R0h Note that the same value would have been ob¬
tained for the viscosity using equation (15).
2RiRq Example 12. A rheometer with a spring con¬
Do = ft (14)
Ro ~ Ri stant and cup and bob radii as given in the previ¬
ous example is used with a known standard vis¬
Obviously, if Ri and R0 are virtually identical in cosity oil to determine the effective height of the
magnitude, that is, the annulus between the cup bob. If an oil of viscosity 1.98 cp gave a scale
and bob is very thin, these two means are identi¬ deflection of 65.1, what is the effective height of
cal. Both sets of equations yield the same value the bob?
for viscosity:
s T Rp ~ Rf
^ - ~D V 4irh[l R2Ro
_/ T \ /RS-R?) Ro ~ R?
(15) h= T
\ 4-ffhft / ‘ R?R§ ' 4nV ft RfRo

Commercial instruments supply the values of / (65.1)(388) )

R[, Ro, h, and the instrument constant that con¬ V (4)(3.1416)( 1.98) |
f30 ] 1 (2)(3.1416) /
verts the observed angular deflection to the re¬ V 60/
storing torque value T generated by that deflec¬
( (2-40)2 - (2,28)g \
tion.
Example 11. A rheometer has a cup with a \ (2.28)2(2.40)2 I
radius of 2.40 cm and a bob with a radius of = 6.06 cm
2.28 cm. The effective height of the bob is
6.0 cm. The restoring torque on the rotating bob Often, the end effects cannot be readily calcu¬
is 388 dyne cm per instrument scale division. lated for the precision geometry. An effective
When a sample is measured at a rotational speed height can then be obtained by calibration in
of 30 rpm, the scale reading is 42.1 scale divi¬ this manner and used with all further work with
sions. What are the shear stress, the shear rate, that cup and bob.
and the viscosity? When the ratio of R0/Rj exceeds 1.1, there are
reasons to feel that the use of the geometric
o T(R? + Ro) mean with equations (13) and.(14) is better than
47rhR?RS use of the arithmetic mean of equations (11) and
(12) in representing the average condition of the
(388)(42.1)(2.282 + 2.402)
material under shear in the annulus.
(4)(3.1416)(6.0)(2.28)2(2.40)2 Occasionally in equipment literature and in
= 79.3 dyne cm'2 publications, yet another pair of equations for
calculating S and D are used. These result from
and the assumption that the gap is so wide that Ro is
much greater than R2 and that only the larger
D=
(R? ± go) term is retained in the summation. The equa¬
(Ro - Ri) tions are:
[ ](2.28)2 + (2.40)2] ] 1 30 rpm "] (16)
l [(2.40)2 - (2.28)2] 1 L 60 sec min-1 J S 27rhR?

- x [2 7r radians] 2R§
D= ft (17)
= 61.3 sec-1 (Ro - R?)

PHARMACEUTICAL RHEOLOGY* 135

These equations are presented so that they may logarithmic plot permits not only the recognition
be recognized when seen in other readings. Sur¬ of apparent changes in rheologic parameters,
prisingly, the value for the viscosity is still given which are artifactual to the simplified equations
by equation (15) when these are used. There are utilized, but also a clear recognition of the entire
some rheologic empiricists who believe that rheologic picture for all conditions of shear.
equations (16) and (17) are more suitable for If it should become essential to bring values
non-Newtonian systems than are equations (13) from different cup/bob combinations into abso¬
and (14) or (11) and (12). The fundamental lute coherence, one approach is to use a series of
practitioners of rheology use a simple equation sleeves that fit into a rheometer cup. By con¬
to establish a power law relationship and then ducting measurements with one bob at a series
use equations developed with that relationship of clearances to the sleeves (cup), one can obtain
to calculate more proper values of shear stress an estimate of a limiting zero gap by extrapola¬
and shear rate. Such equations are not consid¬ tion to the zero gap condition. This usually per¬
ered in this discussion. mits a smooth transition from one measuring
Conventional pharmaceutical use of rheologic combination to the next as the product changes
instrumentation consists of obtaining a compari¬ with age in storage trials. The Contraves Vis¬
son between samples and establishing whether cometer has such a set of sleeves available for
changes occur in samples as a result of process¬ use in its cups. This versatile instrument, avail¬
ing or aging. For such use, slight systematic able from the Tekman Company (Cincinnati,
biases or errors in calculation of exact data re¬ OH), is sometimes called the Epprecht Viscome¬
sulting from the method of measurement do not ter after its designer. Another frequently used
constitute a problem, since comparisons are instrument for pharmaceutical studies is the
made within one measurement. Examples are Rotovisko (Haake Inc., Saddle River, NJ). In
the already discussed Figures 6-11 and 6-12. addition, Brookfield Engineering Inc. (Stough¬
When it is necessary to examine the rheologic ton, MA) has sets of cup and bob combinations
behavior over a shear rate range greater than available for its basic instruments.
can be covered with one instrument, slight dis¬
continuities may occur between measurement
systems, as can be seen in Figure 6-17. All cal¬ Cone and Plate Viscometers
culations in this example use the basic equa¬ In this type, the cone is a slightly beveled plate
tions without any attempt at empiric or theoretic such that ideally the angle ip between cone and
correction for differing gap sizes, end effects, or plate is only a few degrees; even in the cruder
the nonlinear behavior. forms, it is less than 10° (Fig. 6-18). The linear
In addition, it should be recognized that Fig¬ velocity at any point on the cone r from the apex
ure 6-17 is another example of the lowest shear is rft, where ft is the angular velocity while the
measurements inflecting to exhibit a very low separation is ri/>; hence, the shear rate is given
but real yield value. Thus, the use of the double by:

rft
D =
Tip
(18)
n
4>

FIG. 6-17. Type of overlapping rheograms obtained with

different cup and bob combinations, using equations with¬
out correction. (From Wood, J. H., Catacalos, G., and Lie-
berman, S. V. (J. Pharm. Sci. 52:296, 1963. Reproduced
with permission of the copyright owner, the American FIG. 6-18. Basic configuration of the cone and plate vis¬
Pharmaceutical Association.) cometer.

136 • The Theory and Practice of Industrial Pharmacy

In this case, the dimensional analysis gives: Geometrically, either the cone or the plate can
be the rotating member. The torque may be
P _ radians/sec measured either on the other member or
ip radians through the coupling drive system exacdy as in
the couette viscometers.
= sec-1 The classic instrument of this category has
been the Ferranti-Shirley Viscometer (Ferranti
This is dimensionally correct. Of greatest signif¬ Electric, Corrmack, NY), whose use in a wide
icance in equation (18) is that the shear rate at range of pharmaceutical and cosmetic literature
any point is the same, uniform, throughout the testifies to its general versatility. In addition,
gap when the cone angle is small. cone-plate systems attachments are available for
If the cone radius is R, then the shear stress S the Brookfield, Contraves, and Rotovisko sys¬
is given by: tems.

3T
S = (19)
2ttR3
Density-Dependent Viscometers
where T is the restoring torque measured by the Physically, the falling ball viscometer requires
instrument. the determination of the time t for a ball of den¬
Example 13. What is the shear stress and sity pB to fall through a fixed distance of liquid of
shear rate for a cone-plate viscometer measure¬ density pL and of viscosity 17. The equation gov¬
ment using a 5.00-cm radius cone and plate, erning this determination may be developed
with the cone rotational speed being 50 rpm, the from first principles if the ball falls freely in an
cone angle 1.8°, and the scale reading 37.6 “ocean” of liquid, that is, there is no effect from
units? The torque conversion is 1105 dyne cm the container walls. However, a general equa¬
per scale division. tion of the following form may be used regard¬
First, both the rotation and the cone angle less of whether a free fall or a slide and/or roll
must be brought to similar units, in this case, down an inclined tube is used:
radians:
V = K(Pb - PlX (20)
_n_
D= The constant K includes wall interaction factors.
4>
A liquid of known viscosity is then used to cali¬
1 min brate the instruments for general use, in a man¬
(50 rpm 2-rr radians/revolutions)
60 sec ner analogous to that with Ostwald and similar
capillary viscometers.
(1.8) (^q) (degrees)(radians/degree) Example 14. A ball of density 3.12 takes
109 sec to fall the fixed distance of an inclined
166.7 sec-1 tube viscometer when a calibrating liquid of
density 0.94 and viscosity 8.12 poises is used.
Alternately, the conversion could be to degrees: A) What is the instrumental constant? B) What
would be the viscosity of a sample oil of density
0.88 if the fall time under similar conditions was
(50 rpm)(360°/rev)^-^- min/sec 125 sec?
D =
1.8 (degrees)
A) 77 = K(pb - pL)t
= 166.7 sec-1
(Pb - PlX
Similarly, the stress is given by:
__8.12_poises
3T (3.12 - 0.94)(109) (grams/ml)(sec)
S =
2ttR3 = 0.0342 poises gram-1 ml sec.-1
_ (3)(37.6 units)(1105 dyne cm/unit)
B) 17? — 0.034 (pg P?)t
(2)(77)(5.00)3
= (0.034)(3.12 - 0.88)(125)
= 158.7 dyne cm-2 = 9.571 poises

PHARMACEUTICAL RHEOLOGY • 137

It also is apparent that: r—i

V _ KQb - L
V? K(pB — p?)t?

(Pb P?(t?)
V? =
(Pb ~ PlX^l)
.(3.12 - 0.88X125)
(3.12 - 0.94)(109) K J
= 9.57 poise

One commercial example is the Hoeppler Vis¬

cometer, a 200-mm tube with an 8-mm radius
and a normal 10° tilt from the vertical. Utilizing FIG. 6-19. The basic configuration of the double cone and
the appropriate ball, it has a workable range of the needle penetrometers.
0.01 cp to 10,000 poises. This is a one-point
measurement involving uncertain shear rate
and shear stress, however.
Similar in principle is the Bubble Viscometer. where K is an appropriate proportionality con¬
A series of sealed standard tubes have calibrated stant, W is the load in grams on the penetrome¬
oils covering a range of viscosities. Each has a ter, P is the penetration in mm (multiples of
small air bubble of exact geometry. The un¬ 0.1 mm), and n is an index. The value of K de¬
known sample is placed in an empty tube and pends on the cone angle, 9670 for 30°, 2815 for
stoppered so that it is identical in bubble content 60°, and 1040 for 90°8,9 The index n must be
to the standards. The unknown and standard determined from a plot of the classically meas¬
tubes are inverted, and the bubble rise times are ured yield value against penetration for a variety
compared to determine the standard most re¬ of samples. The value of n = 1.6 applies to mar¬
sembling the unknown. This is still a procedure garine and fat. No equivalent numbers have
that is utilized with some heavy oils. been reported for products of pharmaceutical
Certainly, these two gravity procedures have interest. However, the highest possible value of
little to offer when compared with modem rota¬ n is 2, the theoretic value utilized automatically
tion viscometers. by some workers. For relative values, either
number, or an average would not lead to a seri¬
ous error. Pharmaceutical studies seem to be
Penetrometers confined to empiric reporting of penetration val¬
These were instruments developed to mea¬ ues for comparison purposes or for following
sure the consistency or hardness of relatively graphically the penetration with time as a func¬
rigid semisolids. The cone and the needle forms tion of penetrometer load. This is not surprising
are the most commonly used in pharmacy. since rarely is the necessary time taken to cali¬
These are shown schematically in Figure 6-19. brate full rheogram yield values against penetra¬
The usual cone is that specified by the ASTM, tion parameters. This does not detract from the
which has a 30° cone point protruding from a utility of the penetrometer as an effective tool in
90° cone; however, other solid angled cones evaluating changes in yield value for ointments
have been used. In use, the cone is mounted on and semisolid creams. Its particular value is the
an instrument that measures its movement with relative rapidity and ease with which such pene¬
time. The tip is set at the surface, and a spring trometer measurements may be made.
tension is attached to the top of the cone. At time
zero, the cone is released. Usually, the penetra¬
Miscellaneous Measuring Systems
tion occurring in a fixed time is determined. The
travel distance is usually reported in decimil- A wide variety of geometries are conceivable
Iimeters, 10-4 meters. in which a test medium either moderates motion
It has been shown that these measurements of a driven object or serves to transmit force
can provide a self-consistent measure of a yield across a gradient. Thus, rising spheres, plates,
value (YV) through the following equation: rods, etc. have found utility in various forms of
rheometers. Some have practical elements for
KW utilization but often need empiric rather than
YV = pn. (21) theoretic calibration. Typical devices are the var-

138 'The Theory and Practice of Industrial Pharmacy

ious plates, rods, and T-bars characteristic of the
normal Brookfield viscometer. These measuring
systems have provided most of the practical
quality control of emulsions and semisolids for
the cosmetic and pharmaceutical industries.
Usually, some systems meet a need of special A B
convenience. They are usually calibrated FIG. 6-20. Spring and dashpot representation of vis¬
against a Newtonian oil and hence readings ob¬ coelastic elements. The Kelvin element (A) has the compo¬
tained are apparent viscosities rather than ac¬ nents in parallel position, whereas the Maxwell element
tual values. For routine evaluation and compari¬ (B) has them in series.
son, these empiric instruments are invaluable
even though the results cannot be readily trans¬
lated to absolute rheologic parameters. displacing force is removed, there is a slow re¬
turn to the original position as the internal force
of the spring drives the dashpot back to its origi¬
nal position. In summary, the elastic element
Viscoelastic Properties and has a time component for its attainment of
steady state. With the Maxwell element, when a
Measurements displacing force is applied, there is an immedi¬
Earlier in this chapter, it was emphasized that ate elastic displacement followed by a continu¬
there are time-dependent shear changes occur¬ ous tinuous viscous flow. The spring stretches
ring in samples with the creation of thixotropic immediately, and the dashpot slowly moves in¬
or rheopectic loops. The classic rheologic treat¬ dependently. When the force is removed, there
ments cannot adequately handle such changes is an immediate rebound of the elastic displace¬
except to quantitate those that occur by fixed ment, but no viscous flow occurs after that elas¬
processes. These cannot lead to other than em¬ tic recovery. The spring has returned to its origi¬
piric relationships. nal conformation, but the dashpot remains in its
The time-dependent changes in properties of new location because there is no force for a res¬
a substance undergoing shear are properly clas¬ toration.
sified as viscoelastic changes. Viscoelastic prop¬ Schematically, many of these elements may
erties are often represented by two mechanical be combined in various permutations. The re¬
analogies: a spring, and a dashpot or closed pis¬ sulting arrays can be treated mathematically to
ton. The spring symbolizes the classic elastic develop the appropriate characterizing parame¬
property that is normally associated with it. ters. Experimental instrumentation to provide
When a force is applied, it stretches a fixed dis¬ data for these mathematical treatments is avail¬
tance proportional to the force and stops. When able. They are of many types depending on the
the displacing force is withdrawn, the spring physical nature of the substance to be examined.
immediately returns to its original condition, In some cases, the instrument is a modification
and no permanent deformation occurs. The of one already described in this chapter; how¬
dashpot or piston represents the condition con¬ ever, most are product-specific or extremely
sidered in classic rheology. As in Figure 6-1, a expensive. Unfortunately, data treatment devel¬
displacement occurs, with the application of an opment is beyond the scope of this chapter. An
applied force, and continues as long as the force excellent review is provided by Barry,10 one of
is applied. When the force is removed, the mate¬ the major contributors to pharmaceutical vis¬
rial merely remains in the position it has coelastic studies.
reached by that time. No recovery occurs. Although there have been published many
In the representation of viscoelastic proper¬ excellent studies on the viscoelastic properties
ties, there are two primary elements, usually of pharmaceutical gums, mucilages, and gelling
called Kelvin and Maxwell elements. In the Kel¬ and suspending agents, their applicability in
vin element, the spring and the dashpot are generalized characterizations of perceived de¬
placed in parallel position, while in the Maxwell, sired product attributes is still needed.11'13
they are in series (Fig. 6-20). When a displacing Unfortunately, although it is apparent that the
force is applied to a Kelvin element and held parameters of classic rheology—thixotropy,
constant, there occurs a viscous flow that de¬ pseudoplasticity, and dilatancy—can be readily
creases with time. In the analog, the viscous visualized from the fundamental Kelvin and
flow occurs because of the displacing force, and Maxwell elements, measurements from within
the net magnitude of that force decreases as the one approach cannot be utilized to project or cal¬
spring stretches to balance the force. When the culate parameters in the other.

PHARMACEUTICAL RHEOLOGY *139

Specialized Pharmaceutical 200 poises, was acceptable for extrusion in this
tube. Similarly, for topical use, a range of 0.2 to 5
Applications of Rheology poises, optimally 1 poise, was preferred. Several
products for rheologic properties were then eval¬
uated as a function of shear rate. One cream
Shear Rates in Pharmaceutical with an apparent viscosity of 280 poises at a
Applications and Resultant shear rate of 10 sec-1 and of 1.8 poises at
10,000 sec-1 had a panel preference score for
Desired Viscosities extrusion of 3.4 separately for both extrusion
Henderson et al. made the first major attempt and ease of application. (A score of 3 was defined
to establish shear rates corresponding to phar¬ as agreeable.) From the study of scores as a
maceutical use.14 They set “topical application function of the logarithm of viscosity, these val¬
up to 120 sec.-1; rubbing on ointment tile, ues of 3.4 should have corresponded to 350 and
150 sec.-1; roller mill, 1000-12000 sec.-1; col¬ 1.8 poises respectively, an excellent confirma¬
loid mill, several hundred thousand sec.-1; tion of the suitability of the screening evalua¬
nasal spray (plastic squeeze bottle), 1000 sec.-1; tion. Similar procedures can be used to evaluate
and pouring from bottle, below 100 sec.-1.” To any potential product dispenser or use condition
this can be added rubbing into skin, 100 to with any desired segments of the user popula¬
10,000 sec-1, depending on the degree of rub¬ tion.
bing; squeezing from a tube or plastic bottle, 10 In practical use, shear rate is determined en¬
to 1000 sec-1, depending on orifice size and de¬ tirely by setting the desired rate of motion
livery rate; pumping of products, 1000 to through a filler or orifice, application mode, and
100,000 sec-1; high-speed filling, from 5000 to so forth without regard to the force (stress) re¬
100,000 sec-1; and yield value parameters, quired to achieve that process. Shear stress is
below 0.1 sec-1. An example of this extrusion the force required for the process to occur. If it
range is that 1 cm3/sec delivery of a liquid cream involves a human interaction, then there is a
through an orifice 10 mm in diameter imparts a perception of whether that force is less than de¬
shear rate of 10 sec-1, while for the same vol¬ sired, optimal, or excessive. Viscosity, or appar¬
ume through a 5-mm orifice, such as might ent viscosity for a non-Newtonian oil, is then
occur for a toothpaste, it is 100 sec-1 12 Only that proportionality constant relating it, which
0.1 ml/sec through a 1-mm orifice imparts a was shown by equation (1). A perceived suitable
shear rate of 1000 sec-1. viscosity is therefore a judgment on the stress
This pharmaceutical characterization, de¬ required to achieve the needed shear rate.
pending upon the application, must bridge an Alternately, visual perception of a suitable vis¬
extremely wide range of values of shear rate. cosity for a cream to hold its shape in a jar, a
The shear rate for individual use by a process lotion to pour, or a toothpaste to maintain its rib¬
may vary. The acceptability of the force neces¬ bon shape on a brush is an identical process.
sary to extrude a product from a collapsible con¬ Here, the shear rate is determined by the subjec¬
tainer is obviously dependent on the squeezing tive evaluation of an acceptable rate of deforma¬
force that the subject can exert easily. Similarly, tion or flow under the constant stress of gravity.
the force to permit rub-in of a topical product The rheologic measurement must permit a
depends on the user. clear assessment of the characteristic desired.
An interesting example of how to proceed to Thus, the rheogram for a toothpaste needs to
determine suitable product characterizations is have a shear rate comparable to that for con¬
a study by Langenbucher and Lange.15 They tainer delivery in order to assess practicality of
wished to determine suitable product character¬ extrusion. It also must have sufficient viscosity
istics for squeezing from a tube and then for recovery from low shear rates to maintain its rib¬
ease of application of a cosmetic cream or oint¬ bon shape on the brush after suitable initial flow
ment. They used a series of Newtonian oils of into the bristles for stability in handling, and it
varying viscosity to assess acceptance with a must thin readily with shear for ease in brush¬
panel. In their study, the tubes were of standard ing. This type of history need emphasizes why
aluminum with a diameter of 18 mm, a length of statements defining a suitable viscosity for a
100 mm, and a 5.3-mm orifice. Using a percep¬ product are meaningless unless they are framed
tion scale of 1 to 5 with 1 too thin and 5 too within a specific judgment of use. The wide tex¬
thick, this perception scale was found to be pro¬ ture range of commercial products, presently
portionate to the logarithm of the test medium’s acceptable as judged by commercial sales,
Newtonian viscosity. These workers determined clearly establishes that distinct segments of the
that a viscosity of 50 to 1000 poises, optimally population perceive different virtues.

140 •The Theory and Practice of Industrial Pharmacy

 A classic example in pharmaceutical rheology sheared samples, pseudo-filled, were stored
of the need for both structural breakdown under along with the product from the commercial
flow and recovery of body (viscosity) is the study filler and with an unfilled sample until thixo¬
of depot procaine penicillin G products by Ober tropic recovery had occurred. After 7 days, low
and associates.18 These workers set the two pa¬ shear rate rheograms were obtained. In Figure
rameters for the evaluation or comparison of 6-21, the apparent viscosity for each sample is
products as the ease of extrusion from a hyper- shown plotted for four arbitrary values of the low
dermic syringe with needle attached, and the shear rate evaluation: 0.5,1.0,2.5, and 10 sec-1
degree to which the extrudate would retain itself For each of these shear rates, a smooth curve
in a compact volume. An arbitrary force from a was plotted through the observations for the
5-g weight on one pan of a two-pan balance was unfilled and eight pseudo-filled samples for the
used to press a pad against the tip of the hypo¬ logarithm of apparent viscosity as a function of
dermic needle. If this force was sufficient to pseudo-filling shear rate. The observations of
plug the needle for a fixed air pressure of 200 psi viscosity of the values from the real filler were
on the syringe barrel, the formulation was then placed on the smooth curve as shown in
judged too thick. This was found to correlate the figure. In this way, it was concluded that the
with the yield value found by rheologic measure¬ two operating conditions produced shear rates of
ments. Unfortunately, their values were re¬ approximately 10,000 and 25,000 sec-1. It
ported in torque units of dyne centimeters, should be recognized that the shear rate of a
which require the instrumental parameters to filler is set by the internal action of its operation,
develop shear stress, which was given by equa¬ including the piston size and stroke or alternate
tion (11). The suitability of the depot geometry mode of fluid propulsion, the diameter of intake
was judged by the relative shape of the product and output tubes, and not just the fill volume
when injected into a gelatin gel, used as a sub¬
stitute for muscle. The symmetry of the depot
was related to the degree of thixotropic recovery
of the mass. Using these criteria, these workers
then determined how such formulation factors
as the particle size and size distribution affected
the resulting product.
Regained structure due to recovery of cross-
linking attributes of the system cannot be pre¬
sumed. In any system in which the degree of
breakdown is time-dependent, as it is in virtu¬
ally all thixotropic systems, the recovery of
structure is also time-dependent. Recovery of
structure does appear to occur much more
slowly than the original structural buildup with
aging. Rheologic measurements can be influ¬
enced by prior shear treatment if the test mate¬
rial shows any thixotropy. Therefore, no shear
that is comparable to the range of shear rate in¬
tended to be measured can be given to the sam¬
ple in removing it from its container and loading
it into the measuring instrument; otherwise, the
observations depend on the loading procedure
used.
An extreme of the treatment breakdown of SHEAR TREATMENT (SEC-1)
structure was used to evaluate the effective
FIG. 6-21. Low shear rate apparent viscosities measured
shear rate imparted by a filling machine.7 A cos¬ 7 days after treatment of a thixotropic lotion. The lotion
metic lotion subject to thixotropic breakdown was pseudofilled at eight apparent shear rates 2 days after
was put through a filler at two different delivery manufacture (solid dots) or put through two commercial
rates. At the same time, bulk sample was fillers (solid triangles). The triangles are placed on the
sheared through an extrusion rheometer at eight smoothed pseudofilled line to determine the apparent filler
shear rate, approximately 10,000 sec-1 and 25,000 sec-1.
different shear rates. The shear rate used in
(From Wood, J. H., Catacalos, G., and Lieberman, S. V.:
each case was calculated from the delivery rate J. Pkarm. Set, 52:375, 1963. Reproduced with permission
resulting from preset extrusion pressures; this of the copyright owner, the American Pharmaceutical As¬
calculation was given by equation (6). These sociation.)

PHARMACEUTICAL RHEOLOGY • 141

delivered over an allotted time. In this manner, suspend a golf ball of radius 2.13 cm and density
it is possible to evaluate the shear rate from any 1.11 in a medium of density 1.00?
production operation after sampling the mixing
tank. yy _ 8V(Pp ~ Pm)
It is vitally important in any product develop¬ A
ment that all trial formulations be tested against
assumed stresses and shear rates of manufac¬ - (980)(cm sec~2)(jrr(2.13)3 cm3)
turing, product movement, filling, and use. 7t(2.13)2 cm2
These values must be calibrated in the manner
x (7.11 - 1.00 g cm-3)
described, preferably with products characteris¬
tically used and under the normal range of oper¬ = 310 dynes cm-2
ating parameters of that facility. Excessive shear
after some storage is more deleterious to product In a similar fashion, Meyer and Cohen found
body than the same shear before aging. Thus, a theoretic yield values of 65 and 1620 dyne cm-2
product commercially filled after holding over a to suspend sand of density 2.60 and radius
long weekend rarely resembles Theologically the 0.030 cm and marbles of density 2.55 and radius
product filled soon after manufacture. Depend¬ 0.8 cm respectively.17 It was found that sand
ing on the nature of the formulation, these dif¬ suspension for several years was possible in this
ferences may be subtle or dramatic, even to the manner when they used Carbopol 934 for the
point of liquifying a paste by excessively shear¬ suspending agent. The required concentrations
ing it after aging. for sand, golf balls, and marbles, are 0.18%,
Often, the “art” of the formulation is being 0.20%, and 0.40% of this agent.
able to build into a product the ability to be Chong extended this concept by presenting a
mixed and handled in a different way from the graphic nomogram.18 (See Fig. 6-22 for the nec-
laboratory samples. Obviously, this ability is the
consequence of compensating for the shear
treatments used by different levels of emulsifi¬
ers and thickeners, so that the conversion from
laboratory to production is smooth.

Yield Value and Suspensions

Much of the early pharmaceutical literature
bears a confusing mixture of publications relat¬
ing to acceptable viscosities for emulsion and
suspension stability. The viscosities were meas¬
ured at shear rates defined by the instrumenta¬
tion used, and only rarely were extrapolations to
any true yield value attempted.
Meyer and Cohen demonstrated how the rhe¬
ologic yield value obtainable with their com¬
pany’s Carbopol permitted theoretically the
preparation of permanent suspensions.17 The
theoretic yield value (YV) for suspension must
balance or exceed the force <?f gravitational set¬
tlement. Hence, for spherical objects:

YY _ (fip Pm)
A
(22)

where g is the acceleration due to gravity, V is Porticle Radius </* >

the particle volume, pp is the particle density, pm
is the suspending medium density, and A is the FIG. 6-22. Necessary shearing stress to be balanced by
yield value for various density differences between particle
cross-sectional area of the particle (-n-R2 for and medium as a function of particle radius. (From
round particles of radius R). Chong, C. W.: J. Soc. Cosm. Chem. 14:223, 1963. Repro¬
Example 15. What yield value is required to duced by permission of the copyright owner.)

142 • The Theory and Practice of Industrial Pharmacy

essary yield value to suspend particles of varying grooves tend to minimize the squeezing out of
density and radius.) This graph relates to the fluid by syneresis and thus do appreciably raise
difference in density between particle and me¬ the shear rate range attainable before plug flow
dium and is equally valid for particles lighter is initiated. This ribbing technique may also be
than the medium, particularly in considering applied in the cone-plate configuration.
the aeration of a product that has yield value Many workers have mistakenly interpreted
characteristics. the point at which plug flow begins as the yield
Any attempt to use this yield value approach value. Obviously, it represents a significant
obviously requires that real yield values exist at characterizing parameter, but the shear at
low shear rates as discussed earlier. If the very which plug flow begins does appear to depend
low shear rate measurements break from the on geometry rather than being an intrinsic term.
Power Law toward Newtonian behavior, no per¬ In the case of the procaine penicillin study
manent formulation can result. Unfortunately, discussed in a previous section,16 this plug pa¬
no published literature other than the sand rameter is probably critical to the syringe deliv¬
study with Carbopol 934 appears to exist relating ery. Indeed, the study evaluated this material
to stability with aging for this yield value con¬ fracture point rather than a true rheologic yield
cept. value.
This loss of cross-linked structure is clearly
evident in many low shear rate measurements
in solutions of suspending agents, whether
Artifactual Observations Due to montmorillonite clays or xanthan gums20,21
Plug Flow or Slippage Planes Sometimes, structure may be broken merely by
Breakdown of structure under shear may be pouring rapidly from a storage container into the
general, or may occur locally, creating planes of rheometer. If the structure is retained in the vis¬
slippage. Frequently, a body of material may cometer, initial torque readings can be quite
remain motionless against the motionless wall of high before cross-linking structure is lost, which
results in reduced torques as the shear rate in¬
a viscosity measuring device, while the rest of
the material moves as a unit down a tube or with creases. Similar loss in structure is possible
a rotating bob. This behavior is characteristic of when suspending agents exhibit a loss in sus¬
plug flow. Such behavior negates meaningful pending power after shaking.
rheologic measurements, except that the stress
at which structural rupture occurs may be char¬
acterized for that material. Typical rheograms
resulting in this behavior are shown in Figure Measurements of Stickiness or
6-23. The Haake Rotovisko has special star¬ Tackiness
shaped bobs and ribbed bobs available to mini¬
Two types of any tendency to self-adhesion
mize this effect. It is practical to machine
have practical pharmaceutical application. The
grooves into regular viscometer bobs.19 These
first is in dermal application, where any sticking
of fingers together to a hand or any two skin sur¬
faces can be quite objectionable. The application
of rheologic principles to this problem was made
by De Martine and Cussler.22 They found a clear
relationship between perceived stickiness and a
complex computable function dependent on de¬
finable parameters.
An alternative approach, the force to pull two
surfaces apart, has been used for measuring
stickiness as dermal preparations evaporate.23
Recently, this type of measure has been devel¬
oped in detail to evaluate tackiness of coating
solutions for tablets as a function of coating
composition.24,25 Using an Instron Tester, the
full time-course of the adhesive force was fol¬
FIG. 6-23. Rkeogram for a dentrifice obtained with a Her¬
lowed during extension between the adhesive
cules Hi-Shear rheometer with smooth and ribbed bobs.
(From Wood, ]. H., Giles, W. H., and Catacalos, G.. J. Soc. surfaces. It is of interest to note that tack ap¬
Cosm. Chem., 15:565, 1964. Reproduced by permission of peared to parallel orientation effects attributable
the copyright owner.) to elastic parameters of the coating agent.

PHARMACEUTICAL RHEOLOGY- 143

Rheologic Use of Mixing Equipment suitable for most practical phar¬
maceutical and cosmetic rheology is commer¬
Equipment cially available from a variety of sources.
A major engineering use of rheologic meas¬ Rheologic measurements can provide criteria
urements are power requirements in mixers and of product acceptability because they can be cor¬
blenders. In the past, laboratory-sized equip¬ related to relevant “in use” factors of shear.
ment has been instrumented with strain gauges Recent developments in viscoelastic rheologic
to permit torque measurements to be continu¬ methodology are now moving from the academic
ously monitored. This technology is now becom¬ to the industrial applications in pharmaceutical
ing available in manufacturing equipment. technology. These will lead to further applica¬
An interesting example of such a research tions in product monitoring and evaluation.
study was the use of a Brabender Plasti-Corder
rotational torque mixer to follow the changes
occurring during a wet granulation process.26
Application of such studies permits stopping
further mixing of a granulation at a specific de¬
References
sired point in the granule agglomeration. This 1. Green, H., and Weltmann, R. N.: Thixotropy. In Col¬
can be particularly important when further mix¬ loid Chemistry. Vol. VI. Edited by J. Alexander. Rein¬
hold, New York, 1946, p. 328.
ing may create an intractable solid mass or an
2. Weltmann, R. N.: J. Soc. Cos. Chem., 7:599, 1956.
undesirable fluidizing. Because of the proprie¬ 3. Casson, N.: A flow equation for pigment-oil suspen¬
tary nature of such studies these are not likely to sions of the printing ink type. In Rheology in Dis¬
attain high visibility in the literature. perse Systems. Edited by C. C. Mill. Pergamon Press,
London, 1959, p. 84.
4. Fitch, E. B.: Ind. Eng. Chem., 51:889, 1959.
5. Catacalos, G., and Wood, J. H.: J. Pharm. Sci.,
Tabletting and Compression 53:1089, 1964.
Granulation 6. Wood, J. H., and Catacalos, G.: J. Soc. Cos. Chem.,
14:147, 1963.
Although the nature of anisotropic forces dur¬ 7. Wood, J. H., Catacalos, G., and Lieberman, S. V.:
ing compression and the resultant difference in J. Pharm. Sci., 52:375, 1963.
force vertically and laterally have been studied 8. Haighton, A. J.: J. Am. Oil Chem. Soc., 36:345,1959.
in theoretic tabletting, the rheologic implica¬ 9. Pendleton, W. W.: J. Appl. Phys., 14:170, 1943.
tions have generally not been recognized. Thus, 10. Barry, B. W.: Adv. Pharmaceut. Sci., 4:1, 1974.
11: Thurston, G. B., and Martin, A.: J. Pharm. Sci.,
dwell time differences during compression,
67:1499, 1978.
whether slugging or roller compression, can 12. Radebaugh, G. W., and Simonelli, A. P.: J. Pharm.
create flow structure differences in granula¬ Sci., 72:415, 1983.
tions. The full viscoelastic implications of the 13. Radebaugh, G. W., and Simonelli, A. P.: J. Pharm.
compression loading and unloading have re¬ Sci., 73:590, 1984.
cently been developed by Rippie and associ¬ 14. Hendersen, N. L., Meer, P. M., and Kostenbauder,
H. B.: J. Pharm. Sci., 50:788, 1961.
ates.27,28 In particular, they have demonstrated
15. Langenbucher, F., and Lange, B.: Pharm. Acta.
how the fundamental parameters clearly depend Helv., 45:572, 1969.
on the composition of the tablet.28 16. Ober, S. S., Viscent, H. C., Simon, D. E., and Freder¬
Instrumented production tablet presses are ick, K. J.: Pharm. Assoc. Sci. Ed., 47:667, 1958.
now available and widely used in the industry 17. Meyer, R. J., and Cohen, L.: J. Soc. Cosm. Chem.,
for the study of optimum processing conditions. 20:143, 1959.
18. Chong, C. W.: J. Soc. Cosm. Chem., 14:123, 1963.
Unfortunately, few of these studies have been
19. Wood, J. H., Giles, W. H., and Catacalos, G.: J. Soc.
released for publication, so that we must rely on Cosm. Chem., 15:565,uh964.
such studies as those described in this chapter 20. Wood, J. H., Catacaloi, G., and Lieberman, S. V.:
to realize the potential of such tablet investiga¬ J. Pharm. Sci., 52:354, 1963.
tions. In particular, the development of formula¬ 21. Zatz, J. L., and Knapp, S.: J. Pharm. Sci., 73:468,
tions to minimize the delay in strain release that 1984.
22. De Martine, M. L., aftd Cussler, E. L.: J. Pharm. Sci.,
contributes to capping is an area in which trade
64:976, 1975.
secrets prevent free publication. 23. Wood, J. H., and Lapham, E. A.: J. Pharm. Sci.,
53:835, 1964.
24. Chopra, S. K., and Tawashi, R.: J. Pharm. Sci.,
Summary 71:907, 1982.
25. Chopra, S. K., and Tawashi, R.: J. Pharm. Sci.,
In stability measurements, rheologic parame¬ 73:477, 1984.
ters can provide a method of documenting the 26. Schildcrout, S. A.: J. Pharm. Pharmacol., 36:502,
time-dependent changes. 1984.

144 • The Theory and Practice of Industrial Pharmacy

27. Rippie, E. G., and Danielson, D. W.: J. Pharm. Sci., Severs, E. T.: Rheology of Polymers. Reinhold, New York,
70:476, 1981. 1962.
28. Danielson, D. W., Morehead, W. T., and Rippie, E. G.: Sherman, P.: Rheology of Emulsions. Macmillan, New
J. Pharm. Sci., 72:342, 1983. York, 1963.
Stephan, K., and Lucas, K.: Viscosity of Dense Fluids.
Plenum Press, New York, 1979.
Stokes, R. H.: Viscosity of Electrolytes and Related Prop¬
erties. Pergamon Press, Elmsford, NY, 1965.
Van Wazer, J. R., Lyons, ]. W., Kim, K. Y., and Colwell,
General References R. E.: Viscosity and Flow Measurement. Interscience,
Dinsdale, A., and Moore, F.: Viscosity and Its Measure¬ New York, 1963.
ments. Chapman and Hall, London, 1962. Vinogradov, C. V.: Rheology of Polymers: Viscoelasticity
Gabelnick, H. L., and Lett, M.: Rheology of Biological Sys¬ and Flow of Polymers. Springer-Verlag, New York,
tems. Charles C Thomas. Springfield, IL, 1973. 1980.
Honwink, R.: Elasticity, Plasticity and Structure of Mat¬ Walters, K.: Rheometry. Chapman and Hall, London,
ter. 3rd Ed. Cambridge University Press, New York, 1975.
1971. Wilkinson, W. L.: Non-Newtonian Fluids, Fluid Mechan¬
Reiner, M.: Selected Papers on Rheology. Elsevier, New ics, and Heat Transfer! Pergamon Press, Elmsford, NY,
York, 1975. 1960.

PHARMACEUTICAL RHEOLOGY • 145

_7
Clarification and Filtration
s. CHRAI

The preparation of pharmaceutical dosage forms The broad span of pharmaceutical require¬
frequently requires the separation of particles ments cannot be met by a single type of filter.
from a fluid. The usual objective is a sparkling The industrial pharmacist must achieve a bal¬
liquid that is free of amorphous or crystalline ance between filter media and equipment capa¬
precipitates, colloidal hazes, or insoluble liquid bilities, slurry characteristics, and quality speci¬
drops. Sterility specifications may expand the fications for the final product. The choice is
objective to include removal of microorganisms. usually a batch pressure filter, which uses either
Filtration is defined as the process in which surface or depth principles.
particles are separated from a liquid by passing Surface filtration is a screening action by
the liquid through a permeable material. The which pores or holes in the medium prevent the
porous filter medium is the permeable material passage of solids. The depth filter permits slurry
that separates particles from the liquid passing to penetrate to a point where the diameter of a
through it and is known as a filter. Thus, filtra¬ solid particle is greater than the diameter of a
tion is a unit operation in which a mixture of tortuous void or channel. The solids are retained
solids and liquid, the feed, suspension, disper¬ within a gradient density structure by physical
sion, influent or slurry, is forced through a po¬ restriction or by absorption properties of the
rous medium, in which the solids are deposited medium.
or entrapped. The solids retained on a filter are
known as the residue. The solids form a cake on
the surface of the medium, and the clarified liq¬
uid known as effluent or filtrate is discharged Theory
from the filter. If recovery of solids is desired,
Even today, filtration is more an art than a sci¬
the process is called cake filtration. The term
ence. The filtration theory, with all its mathe¬
clarification is applied when the solids do not
matical models, has a deficiency. The deficiency
exceed 1.0% and filtrate is the primary product.
is its preoccupation with resistance to flow, al¬
Ultrafiltration may be defined as the separation
most to the exclusion of considerations of filtrate
of intermicellar liquid from solids by the use of
quality. It is possible to estimate the resistance
pressure on a semipermeable membrane.
to flow of a clean filter medium but impossible to
Filtration is frequently the method of choice
estimate with comparable accuracy what the
for sterilization of solutions that are chemically
resistance will be as the filter begins to trap sol¬
or physically unstable under heating conditions.
ids. The mathematical models do provide a
In many applications, sterile filtration is an ideal
means of showing apparent relationships be¬
technique. Sterile filtration of liquids and gases
tween variables in a process and may be valua¬
is commonly used in the pharmaceutical indus¬
ble decision-making tools in the selection of ap¬
try. Final product solutions or vehicles for sus¬
paratus and techniques for a particular filtration
pensions are sterile-filtered prior to an aseptic
application.1
filling process. Sterile filtration of bulk drug so¬
The mathematical models for flow through a
lution prior to an aseptic crystallization process
porous medium, cake filtration, and granular
eliminates the possibility of organisms being
bed filtration may differ, but all follow this basic
occluded within crystals.
rule: The energy lost in filtration is proportional
Much of the material in this chapter is based on Chap¬ to the rate of flow per unit area.
ter 18 of the previous edition, which was written by Rich¬ The flow of liquid through a filter follows the
ard A. Hill, Ph.D. basic rules that govern flow of any liquid

146
through a medium offering resistance. The rate highly compressible, flocculent, or slimy pre¬
of flow may be expressed as: cipitates may decrease or terminate flow.
2. An increase in area increases flow and life
driving force
rate =--7- (1) proportional to the square of the area since
resistance cake thickness, and thus resistance, are also
reduced.
The rate may be expressed as volume per unit
time and the driving force as a pressure differen¬ 3. The filtrate flow rate at any instant is in¬
tial. The apparent complexity of the filtration versely proportional to viscosity.
equations arises from the expansion of the re¬ 4. Cake resistance is a function of cake thick¬
sistance term. Resistance is not constant since it ness; therefore, the average flow rate is in¬
increases as solids are deposited on the filter versely proportional to the amount of cake
medium. An expression of this changing resist¬ deposited.
ance involves a material balance as well as fac¬
tors expressing permeability or coefficient of re¬ 5. Particle size of the cake solids affects flow
sistance of the continuously expanding cake. through effect on the specific cake resist¬
The rate concept as expressed in modifica¬ ance, a. A decreased particle size results in
tions of Poiseuille’s equation is prevalent in en¬ higher values of a and proportionally lower
gineering literature: filtration rates.
6. The filter medium resistance, R, usually neg¬
ligible or about 0.1 a in cake filtration, is the
dT n (aW/A + R) primary resistance in clarification filtration.
In the latter case, flow rate is inversely pro¬
where: portional to R.

V = volume of filtrate It is convenient to summarize the theoretic

T = time relationship as:
A = filter area
P = total pressure drop through cake and
Rate of filtration
filter medium
tx = filtrate viscosity (area of filter) x (pressure difference)
a = average specific cake resistance (viscosity) x (resistance of cake and filter)
W = weight of dry cake solids (3)
R = resistance of filter medium and filter
Most clarification problems can be resolved
empirically by varying one or more of these fac¬
Any convenient units may be used in this equa¬
tors. A broader understanding of filtration theory
tion, since inconsistencies are absorbed in the
is required only if cake filtration applications are
cake and filter resistances.
under consideration.
The practical limitation of this equation is that
The membrane filters are highly porous. A
the constants must be determined on the actual
number of methods are used for establishing the
slurry being handled. There is no crossover ap¬
pore size and pore size distribution. Most meth¬
plication of data, and the majority of filters are
ods are derived from the interfacial tension phe¬
selected on the basis of empiric laboratory or
nomenon of liquids in contact with the filter
pilot plant tests. Equation (2) has been inte¬
structure. Each pore in the filter acts as a capil¬
grated under various assumptions, and these
lary. For a nonwetting fluid, the following equa¬
integrated forms may be used to predict effects
tion was established by Poiseuille:5
of process changes and to evaluate test work.
The techniques for data evaluation set forth in
the section “Filter Selection” in this chapter may
be confirmed by reference to broader theoretic
discussions.2-4
Interpretation of the basic equation, however,
where:
leads to a general set of rules:
p = applied pressure
1. Pressure increases usually cause a propor¬ y = liquid surface tension
tionate increase in flow unless the cake is 0 = contact angle between liquid and solid
highly compressible. Pressure increases on r = radius of the pore

CLARIFICATION AND FILTRATION • 147

Filter Media fected by mold, fungus, or bacteria, provides an
The surface upon which solids are deposited extremely smooth surface for good cake dis¬
in a filter is called the filter medium.6'7 For the charge, and has negligible absorption properties.
pharmacist selecting this important element, Both cotton and nylon are suitable for coarse
the wide range of available materials may be straining in aseptic filtiations, since they can be
bewildering. The selection is frequently based sterilized by autoclaving. Monofilament nylon
on past experience, and reliance on technical cloth is extremely strong and is available for
services of commercial suppliers is often advisa¬ openings as small as 10 microns. Teflon is supe¬
ble. rior for most liquid filtration, as it is almost
A medium for cake filtration must retain the chemically inert, provides sufficient strength,
solids without plugging and without excessive and can withstand elevated temperatures.
bleeding of particles at the start of the filtration. Woven wire cloth, particularly stainless steel,
In clarification applications, in which no appre¬ is durable, resistant to plugging, and easily
ciable cake is developed, the medium is the pri¬ cleaned. Metallic filter media provide good sur¬
mary factor in achieving clarity, and the choice faces for cake filtrations and usually are used
is limited to materials that will remove all parti¬ with filter aids. As support elements for disposa¬
cles above a desired size. Sterile filtration im¬ ble media, wire screens are particularly suitable,
poses a special requirement, since the pore size since they may be cleaned rapidly and returned
must not exceed the dimension of microorga¬ to service. Wire mesh filters also are installed in
nisms unless the filter is adsorptive, and since filling fines of packaging equipment. Their func¬
the medium should be sterilizable. tion at this point is not clarification, but security
Filter media are available in different materi¬ against the presence of large foreign particles.
als and forms. The filter fabrics are commonly Nonwoven filter media include felts, bonded
woven from natural fibers such as cotton and fabrics, and kraft papers. A felt is a fibrous mass
from synthetic fibers and glass. The properties that is free from bonding agents and mechani¬
of these fibers and glass applicable for media se¬ cally interlocked to yield specific pore diameters
lection are tabulated in Table 7-1. that have controlled particle retention. High
Filter cloth, a surface type medium, is woven flow rate with low pressure drop is a primary
from either natural or synthetic fiber or metal. characteristic. Felts of natural or synthetic ma¬
Cotton fabric is most common and is widely terial function as depth media and are recom¬
used as a primary medium, as backing for paper mended where gelatinous solutions or fine par¬
or felts in plate and frame filters, and as fabri¬ ticulate matter are involved. Bonded fabrics are
cated bags for coarse straining. Nylon is often made by binding textile fibers with resins, sol¬
superior for pharmaceutical use, since it is unaf¬ vents, and plasticizers. These materials have not

Table 7-1. Fiber Properties For Filter Media Selection

Temperature Wet Breaking Price

Recommended Safe Tenacity Acid Alkali Ratio to
Fiber Limit (°F) (g/denier) Resistance Resistance Cotton

Cotton 210 3.3 6.4 Poor Fair 1

Polyester (Dacron) 300 6.0 8.2 Very good Good 2.7
Dynel modacrylic ,200 3.0 Excellent Excellent 3.2
Glass (spun) 750 3.0 4.6 Excellent Fair 6.0
Glass (continuous 550 3.9 4.7 Excellent Fair 2.2
filament)
Nylon 250 2.1 8.0 Fair Excellent 2.5
Acrylic (Orion) 300 1.8 2.1 Excellent Fair 2.7
Polyethylene 165 1.0 3.0 Excellent Excellent 2
Polypropylene 175 3.5 8.0 Excellent Excellent ' 1.75
Saran 160 1.2 2.3 Excellent Excellent 2.5
Teflon 475 1.9 Excellent Excellent 25.0
Polyvinylchloride 165 1.0 3.0 Good Excellent 2.7
Wool 210 0.76 1.6 Very good Fair 3.7
Rayon and acetate 210 1.9 3.9 Poor Fair 1

Excerpted by special permission from Chemical Engineering, 70.177, 1963. Copyright © 1963 by McGraw-Hill. Inc., New York, NY
10020.

148 • The Theory and Practice of Industrial Pharmacy

found wide acceptance in dosage form produc¬ to 10“2 microns (10 to 100 A) and are formed by
tion because of interactions with the additives. etching cylindric pores into a solid matrix. Ultra¬
Kraft paper is a pharmaceutical standard. Al¬ filtration membranes are fragile and require
though limited to use in plate and frame filters supporting substrates because of the high-pres¬
and horizontal-plate filters, it offers controlled sured differences required during filtration.
porosity, limited absorption characteristic, and a Most types of filter media are also available as
low cost. The latter is important since concern cartridge units. These cartridges are economical
over cross-contamination makes a disposable and convenient when used to remove low per¬
medium attractive to pharmacy. White papers centages of solids ranging in particle size from
are preferred, and they may be crinkled to pro¬ 100 microns to less than 0.2 micron. The car¬
duce greater filtration area. A support of cloth or tridge may be a surface or depth filter and con¬
wire mesh is necessary in large filter presses to sists of a porous medium integral with plastic or
prevent rupture of the paper with pressure. metal structural hardware. Synthetic and natu¬
Porous stainless steel filters are widely used ral fibers, cellulose esters and fiberglass, fluori-
for removal of small amounts of unwanted solids nated hydrocarbon polymers, nylon, and ceram¬
from liquids (clarification) such as milk, syrup, ics are employed for the manufacture of
sulfuric acid, and hot caustic soda. Porous me¬ disposable cartridges. Porous materials for
tallic filters can be easily cleaned and repeatedly cleanable and reusable cartridges use stainless
sterilized. steel, Monel, ceramics, fluorinated hydrocarbon
Membrane filter media are the basic tools for polymers, and exotic metals.
microfiltration and ultrafiltration. They are used Surface-type cartridges of corrugated, resin-
commonly in the preparation of sterile solutions. treated paper are common in hydraulic fines of
Membrane filters classified as surface or screen processing equipment, but are rarely applied to
filters are made of various esters of cellulose or finished products. Ceramic cartridges have the
from nylon, Teflon, polyvinyl chloride, polyam¬ advantage of being cleanable for reuse by back-
ide, polysulfone, or silver. The filter is a thin flushing, and porcelain filter candles are accept¬
membrane, about 150 microns thick, with 400 to able for some sterile filtrations along with mem¬
500 million pores per square centimeter of filter brane filters in cartridge form. Sintered metal or
surface. The pores are extremely uniform in size woven-wire elements are also useful, but fine-
and occupy about 80% of filter volume. This wire mesh lacks strength. The metallic-edge fil¬
high porosity permits flow rates at least 40 times ters overcome this problem by allowing liquid to
faster than those obtained through other media pass between rugged metal strips, which are
of comparable particle retention capability. separated by spacers of predetermined thick¬
Because of surface screening characteristics, ness. Depth-type cartridges consist of fibrous
prefiltration is often required to avoid rapid clog¬ media, usually cotton, asbestos, or cellulose. The
ging of a membrane. The selection of a mem¬ cartridge may be formed by felting or by resin¬
brane filter for a prxticular application is a func¬ bonding fibers about a mandrel. Effective units
tion of the size of the particle or particles to be are also manufactured by winding yam around a
removed. An approximate pore size reference central supporting screen. The depth cartridge
guide can be set down as follows: is always a disposable item since cleaning is not
feasible.
Pore Size (micron) Particle Removed

0.2 (0.22) All bacteria Filter Aids

0.45 All coliform group bacteria Justification for use of filter aids may be found
0.8 All airborne 'particles in equation (2), which shows the rate of filtra¬
1.2 All nonliving particles consid¬
tion to be inversely proportional to the resistance
ered dangerous in i.v. fluids
of the solids cake. Therefore, the pressure drop
5 All significant cells from body
across the system is directly proportional to the
fluids
filtration rate, the thickness of the cake, and the
liquid viscosity for flow through porous media,
The fragility of membrane filters is partially when laminar flow conditions exist in the filter
overcome by the use of monofilament nylon as a media or cake. It is also inversely proportional to
supporting web within the membrane structure. the density of the liquid and square of the parti¬
The distinction between ultrafiltration and cle diameter. Poorly flocculated solids offer
microfiltration lies in the nature of the filter higher resistance than do flocculated solids or
medium. Ultrafiltration membranes contain solids providing high porosity to the cake. In the
pores of relatively narrow size distribution 10“3 case of cake filtration, the rate varies with the

CLARIFICATION AND FILTRATION • 149

square of the volume of liquid. When the vol¬ low concentrations of filter aid, the flow rate is
ume of the filter cake solids per unit volume of slow because of low permeability. As the filter
filtrate is low, the solids formed on the filter aid concentration increases, the flow rate in¬
medium may penetrate the voidspace, thus creases and peaks off. Beyond this point, the
making the filter medium more resistant to flow. flow rate decreases as the filter aid concentra¬
At a higher concentration of solids in a suspen¬ tion is increased.
sion, the bridging over of openings over the The ideal filter aid performs its functions
voidspace, rather than blinding of the openings, physically or mechanically; no absorption or
seems to predominate. Slimy or gelatinous mate¬ chemical action is involved in most cases. The
rials, or highly compressible substances, form important characteristics for filter aids are the
impermeable cakes with high resistance to liq¬ following;10
uid flow. The filter medium becomes plugged or
slimy with accumulation of solids, and the flow
of filtrate stops. A filter aid acts by reducing this 1. It should have a structure that permits for¬
resistance.8'^ mation of pervious cake.
Filter aids are a special type of filter medium. 2. It should have a particle size distribution
Ideally, the filter aid forms a fine surface deposit suitable for the retention of solids, as re¬
that screens out all solids, preventing them from quired.
contacting and plugging the supporting filter
medium. Usually, the filter aid acts by forming a 3. It should be able to remain suspended in the
liquid.
highly porous and noncompressible cake that
retains solids, as does any depth filter. The dura¬ 4. It should be free of impurities.
tion of a filtration cycle and the clarity attained
5. It should be inert to the liquid being filtered.
can be controlled as density, type, particle size,
and quantity of the filter aid are varied. The 6. It should be free from moisture in cases
quantity of the filter aid greatly influences the where the addition of moisture to the fluid
filtration rate. If too little filter aid is used, the would be undesirable.
resistance offered by the filter cake is greater
than if no filter aid is used, because of added The particles must be inert, insoluble, incom¬
thickness to the cake. On the other hand, if high pressible, and irregularly shaped. Filter aids are
amounts of filter aid are added, the filter aid classified from low flow rate (fine: mean size in
merely adds to the thickness of the cake without the range of 3 to 6 microns) to fast flow rate
providing additional cake porosity. Figure 7-1 is (coarse: mean size in the range of 20 to 40 mi¬
a typical plot of filter aid concentration versus crons). Clarity of the filtrate is inversely propor¬
permeability. In the figure, flow rate and perme¬ tional to the flow rate, and selection requires a
ability are directly proportional to each other. At balance between these factors. Filter aids are
considered to be equivalent in performance
when they produce the same flow rate and fil¬
tered solution clarity under the same operating
conditions when filtering a standard sugar solu¬
tion.1 Table 7-2 lists the advantages and disad¬
vantages of filter aid material.
Diatomite (diatomaceous earth) is the most
important filter aid. Processed from fossilized
diatoms, it has an irregularly shaped porous par¬
ticle that forms a rigid incompressible cake.
Since diatomite is primarily silica, it is relatively
inert and insoluble. Perlite, an aluminum sili¬
cate, forms filter cakes that are 20 to 30% less
dense than diatomic cakes. Perlite is not a po¬
rous incompressible particle, but it has an eco¬
nomic advantage over diatomite.
Cellulose, asbestos, and carbon filter aids are
also commercially available. Cellulose is highly
Filter Aid Quantity (Percent) compressible and costs two to four times more
FIG. 7-J. Experimental determination of flow rate as a than diatomite or perlite. It is reserved for appli¬
function of filter aid quantity discloses correct operating cations where the liquids may be incompatible
level. with silica compounds. Cellulose is used as a

150 •The Theory and Practice of Industrial Pharmacy

Table 7-2. The Advantages and Disadvantages of Filter Aid Materials

Chemical
Material Composition Advantages Disadvantages

Diatomaceous Silica Wide size range available; Slightly soluble in dilute acids and
earth fines reduced by calcination; alkalies.
can be used for very fine filtra¬
tion.
Expanded Silica and Wide size range available; . More soluble than diatomites in
perlite aluminosili¬ not capable of finest retention of acids and alkalies; may give
cates diatomites. highly compressible cakes.

Asbestos Aluminosilicate Usually used in conjunction with Chemical properties similar to

diatomites; very good retention on perlite.
coarse screens.
Cellulose Cellulose Used mainly as a coarse precoat; Expensive
high purity; excellent chemical
resistance—slightly soluble in di¬
lute and strong alkalies, none in
dilute acids.
Carbon Carbon May be used for filtering strong al¬ Available in coarser grades only;
kaline solutions expensive

Reprinted from Akers, R., and Ward, A.-, liquid filtration theory and filtration treatment. In Filtration Principles and Practices, Part I.
Edited by C. Orr. Marcel Dekker, Inc., New York, 1977, p. 237, by courtesy of Marcel Dekker, Inc.

coarse precoat. It is available in high-purity ma¬ prevent disruption of the cake. Body mix (direct
terial and has excellent chemical resistance. addition of filter aid to the filter feed) is more
Asbestos has good retention on coarse screens, common in batch pharmaceutical operations.
but has limited application because of high cost, The filter aid, 1 to 2 pounds per pound of con¬
and because of concern over its toxicity should taminant, or 0.1 to 0.5% of total batch weight, is
the fibers carry over into the filtrate. Asbestos mixed into the feed tank. This slurry is recircu¬
filters may be used in pharmaceutical industry if lated through the filter until a clear filtrate is
their application is followed by a membrane fil¬ obtained; filtration then proceeds to completion.
ter. Nonactivated carbons that are not suitable The body-mix method minimizes equipment
for decolorization or absorption are rarely used requirements and cross-contamination poten¬
in pharmaceutical applications because of clean¬ tials.
liness problems. They may be used for filtering Often, a filter aid may be used that performs
strong alkaline solutions. Commercial blends of its function not physically or mechanically, but
various filter aids are common, and these speci¬ chemically, by reacting with the solids. These
alities, particularly those intended as water scav¬ chemicals may cause the solids depositing in a
engers in oil filtrations, must be considered in filter bed to adhere more strongly to the filter
selection of a filter aid. medium. Water-soluble polymers such as floccu¬
Filter aids may be applied by precoating or lating agents are often used as filter aids. The
body-mix techniques.8,9 Precoating requires polymers may be derived from vegetable or ani¬
suspending the filter aid in a liquid and recircu¬ mal sources, or they may be produced syntheti¬
lating the slurry until the filter aid is uniformly cally. Compounds produced by modification of
deposited on the filter septum. The quantity var¬ the chemical structure, such as starch, may be
ies from 5 to 15 pounds per 100 square feet of filter aids to more costly synthetic materials.
filter area, or that sufficient to deposit a cake Vie Water-soluble polymers may be classified as
to Vs inches thick. The liquid is preferably a por¬ nonionic, anionic, or cationic, depending on
tion of the feed or retained filtrate from a prior their property to ionize in water. There are a few
cycle, since the physical properties of the commercially available water-soluble cationic
precoat liquid must approximate those of the polymers. These include acrylamide copoly¬
material to be filtered. Precoating should pro¬ mers, polyethyleneimine, and derivatives of ca¬
ceed at the same flow rates and pressures to be sein, starch, and guar gum.1
used in final filtration, and the transition from Filter aids are chosen by trial and error in ei¬
precoat liquid to regular feed must be rapid to ther laboratory or plant. Within ranges previ-

CLARIFICATION AND FILTRATION "151

ously indicated, the filter aid is usually selected a liquid increases as the pressure is increased.
to give acceptable filtrate at the highest flow Since'the number of holes is reduced, it is more
rate; however, in pharmaceutical operations in difficult for molecules to move around. Increas¬
which quality is a primary consideration, the se¬ ing the temperature of heavy pharmaceutical
lection usually favors the fine grades, which syrups lowers the viscosity and increases filtra¬
yield low flow rates. The most important phar¬ tion rates. Most liquids must be maintained at a
maceutical factor is inertness. A filter aid may high temperature during filtration to prevent the
have such extensive absorption properties that formation of crystals. The filtration of cosmetic
desired colored substances and active principles products at low temperatures, approximately
are frequently removed. The total quantity of 5°C, is also common. The consequent reduction
any ingredient absorbed may be small, but it in flow rate is tolerated, since the goal is reduced
may be a considerable portion of the original solubility of contaminants or perfume oils, re¬
concentration. sulting in their more effective removal. Filtra¬
Filtration efficiency also may be affected by tion at room temperature would yield a liquid
changes in temperature, since there is an in¬ that might cloud at the lower temperatures en¬
verse relationship of flow rate to viscosity. The countered by the product under field conditions.
viscosities of most liquids decrease with in¬
crease in temperature. According to the “hole
theory,” there are vacancies in a liquid, and Filter Selection
there is a continuous movement of the mole¬ In designing or selecting a system for filtra¬
cules into these vacancies, thus causing vacan¬ tion, the specific requirements of the filtration
cies to move around. This movement of vacan¬ problem must be defined. The following ques¬
cies permits flow, but requires energy. This tions should be answered before any assistance
energy is the activation energy with which a is requested from the manufacturers of filtration
molecule has to move into a vacancy. The acti¬ equipment.1213
vation energy is more readily available at higher
temperatures than at lower temperatures. Thus, 1. What is to be filtered—liquid or gas?
the liquid can flow more easily at higher temper¬
atures than at lower temperatures.11 Table 7-3 2. What liquid or gas is to be filtered?
lists the viscosities of some common liquids at 3. What is the pore size required to remove the
different temperatures. Equation (5) represents smallest particle?
the relationship of the coefficient of viscosity to
temperature. 4. What is the desired flow rate?
5. What will the operating pressure be?
tj = AeE/RT (5)
6. What are the inlet and outlet plumbing con¬
where: nections?
7. What is the operating temperature?
17 = coefficient of viscosity of the liquid
8. Can the liquid to be filtered withstand the
E = activation energy
R = ideal gas constant special temperature required?
T = absolute temperature 9. What is the intended process—clarification
A = pre-exponential factor or filtration?

According to the “hole theory,” the viscosity of 10. Will the process be a sterilizing filtration?
11. Will the process be a continuous or batch
filtration?
Table 7-3. Viscosity of Liquids in Centipoise
12. What is the volume to be filtered?
Liquid Temperature (°C)
13. What time constraints will be imposed, if
0 25 50 75 any?

Water 1.793 0.895 0.549 0.380 Once the purpose of the process has been de¬
Ethanol 1.79 1.09 0.698 —
termined, the selection of the filter medium can
Benzene 0.9 0.61 0.44 — be made. For example, for a sterilizing filtration,
From Daniels, F., and Alberty, R. A.: Irreversible processes in a 0.2-micron pore size is used; for clarification, a
solution. In Physical Chemistry. 3rd Ed. Edited by F. Daniels and plate and frame filter or woven-fiber filter may
R.A. Alberty. John Wiley and Sons, New York, 1966. be used. In general, a pore size smaller than the

152 • The Theory and Practice of Industrial Pharmacy

smallest particle to be removed is selected. The
filter medium should be compatible with the liq¬
uid or gas to be filtered. It is advisable to check
the chemical compatibility charts provided by
the vendors for selection of filter type. Filter
type, cellulose, polytetrafluoroethylene (PTFE),
fiber, metal, polyvinylidene difluoride, nylon, or
polysulfones may be selected based on the
chemical resistance to the most aggressive in¬
gredient in the liquid. For vent filters or gaseous
filtration, a hydrophobic filter medium should be
chosen.
Filtration surface area is calculated after the
filter media, pore size, required flow rate, and
pressure differentials are established. For a liq¬
FIG. 7-2. Ideal filtration systeg- (f™™ Cole’1 c- and
uid having a viscosity significandy different
Shumsky, R.: Pharm. Tech., 1
from that of water (1 cp), the clean water flow
rate is divided by the viscosity of the liquid in
centipoises to obtain the approximate initial flow
rate for the liquid in question. For gaseous filtra¬
tion at elevated temperature and exit pressures,
the standard flow rate (20°C, 1 atmosphere)
must be corrected by equation (6), the gaseous
filtration flow rate formula:

F = F ( 293 V P + AP/2 \
0 V273 + t A 14.7 + AP/2/
(6)

where:

F = corrected flow rate

F0 = standard flow rate from chart (20°C, 1 at¬
mosphere)
t = temperature of air or gas (°C)
P = exit pressure (psia)
AP = pressure drop through the system (psi) wuioc, \i ivlit

Tech.. 1:39, 1977.)

If the pressures are expressed in kg/cm2, the
term 14.7 in equation (6) becomes 1.03.
The optimum system often requires use of a
series of filters in a single multilayered filter
containing layers of various pore sizes or a prefil-
ter followed by a final filter. Optimum perform¬
ance is obtained when the filters in a series ex¬
haust their dirt-holding capacities at the same
time. When the flow resistance across each filter
in the series approaches the limiting pressure
drop, the dirt-holding capacity of the system is
considered expended. Figures 7-2 through 7-5
illustrate the prefilters with adequate and inade¬
quate dirt holding capacity. In Figure 7-3, the
coarse prefilter does not provide sufficient reten¬
tion efficiency, thus causing the poorly pro¬
tected final filter to clog prematurely. Too fine a
filter, on the other hand, has enough retention
mth adequate retentive prefil-
efficiency but insufficient dirt-holding capacity, FIG. 7-4. Filtration system*-- ctty, (From Cole,]. C.
and it plugs very quickly, as illustrated in Figure ter but inadequate dirt-hotawy r ^gjj \
7-4. As shown in Figure 7-5, both filters—the and Shumsky, R.: Pharm. ‘ec ’

clabificat'0NANDFILTRATION‘153
 media. Particulate matter above 30- to 40-mi-
cron particles may be noticeable. Most pharma¬
ceutical filtrations therefore aim for removal of
particles of 3 to 5 microns or less. A nephelome-
ter, an instrument that measures the degree of
light scattering (Tyndall effect) in dilute suspen¬
sions, is an excellent tool for assessing effective¬
ness in this range.
The nephelometer gives a quantitative value
to the formulator’s quality specification of “spar¬
kling clear.” This value may be used to compare
results using different filtration media. Figure
7-6 shows a typical curve obtained from filtra¬
tion of an elixir through disposable cartridges
and standard kraft paper. If an existing process
FIG. 7-5. Filtration system with adequate prefilter. (From is to be shifted from paper on a filter press to
Cole, ]. C., and Shumsky, R.: Pharm. Tech., 1:39, 1977.) cartridges, this curve permits selection of an ele¬
ment that gives comparable performance. The
final filter and the “correct” prefilter—will have technique also may be applied to assessment of
almost expended their dirt-holding capacities as filter aid effectiveness by determining transmit¬
the last of the batch is filtered. A final filter that tance as a function of filter-aid type, quantity, or
is not protected by prefilter has a short filter fife. method of use.
When a prefilter is used in combination with a In addition to improving clarity, filter aids are
final filter, the efficiency of the prefilter is maxi¬ used to increase flow rates. Figure 7-1 indicates
mum. In these cases, it is important that the a typical flow rate pattern as the amount of fi. ter
O-ring seal sits directly on the membrane itself aid is increased. Exceeding an optimum quan¬
and not on the prefilter. Therefore, the diameter tity can frequently lead to decreased flow rate
of the disc prefilter selected should be somewhat without improving clarity. The filter aid quantity
smaller than the diameter of the final filter. can be expressed as a percentage of cake solids,
Table 7-4 lists the diameter of the filter and the a percentage of filter aid in body mix, or the
diameter of the prefilter when used in combina¬ weight applied as a precoat per unit of filter area.
tion. Seating the O-ring on the prefilter often
fails to produce a seal, thus causing the filtration
system to leak. This leakage may result in the
filtrate being exposed to contamination.

Nonsterile Operations
Although filtration analysis can be sophisti¬
cated, pilot plant studies are usually basic. The
common problems are to select the media, deter¬
mine the time required, and if possible, estimate
when a semicontinuous cycle should be termi¬
nated for cleaning.
For nonsterile polish filiations, the quality
level must be established prior to choice of

Table 7-4. Diameter of Filter and Correspond¬

ing Prefilter When Used in Combination

Filter Size Prefilter Size

(mm) (mm)
Porosity Rating of Cartridge
25 22
47 35 Filter ( Microns)
90 75
142 124 FIG. 7-6. A nephelometer reading of a filtrate provides
data that may be used to compare performance of different
293 257
media.

154 •The Theory and Practice of Industrial Pharmacy

Flow rate should be determined for each case at V
constant pressure and after a uniform time in¬
terval. The maximum filter aid level used in lab¬
oratory tests must be within the cake capacity of
projected or existing plant equipment.
The question of time for a filtration cycle is
resolved by determining total volume versus
time during a test run at pressures approximat¬
ing normal operating conditions. Flow rate de¬
creases with time as the media plugs or as the
cake builds up. Plotting log total volume per unit
area versus log time usually gives a straight line
suitable for limited extrapolation (Fig. 7-7). If Non-Productive^—0—►Productive Time
the filter area of production equipment is fixed, Time (Minutes) (Minutes)
the time to filter a given batch size may be esti¬
mated. Alternately, the filter area required to FIG. 7-8. The optimal filtration cycle prior to cleaning
can be determined by a graphic technique.
complete the process within an allotted time
period may be established. Similar flow decay
studies can also be performed during sizing of a stopped. The time lost in cleaning is offset by a
filtration system for sterile operations. return to high filtration rates associated with the
In semicontinuous operations, decisions must new media. This point also can be calculated
be made on length of the cycle prior to shutdown from theoretic relationships for constant pres¬
for replacement of media. If the goal is maxi¬ sure or constant volume filtration.14 Data from
mum output from the filter per unit of overall laboratory equipment can be applied to produc¬
time, the graphic approach of Figure 7-8 is ap¬ tion units since the analysis is independent of
plicable. During productive time T, the filter dis¬ filter area.
charges a clear filtrate at a steadily decreasing The evaluation of coarse straining operations
rate. Nonproductive time T' is required to clean is limited to sizing a filter that will not have ex¬
the filter and replace media. For graphic analy¬ cessive pressure drop. The amount of impurity
sis, nonproductive time T' is plotted to the left of is usually small, and continued operation does
the origin of a volume V versus time curve. not significantly decrease filter capacity. The
When a line is drawn from T' tangent to the metal cartridge filters, either woven-mesh or
curve, the value of V and T at the point of tan- edge-type, and porous sintered stainless steel,
gency indicates where the filtration should be have replaced cheesecloth in most pharmaceuti¬
cal applications. Straining suspensions contain¬
ing gums or other viscous ingredients can be
accomplished with self-cleaning edge filters.
These suspensions frequently bridge the media,
and cleaning devices are needed to maintain
adequate flow.

Sterile Operations
Filtration may be used to clarify and sterilize
pharmaceutical solutions that are heat-labile.
Until the introduction of membrane media, un¬
glazed porcelain candles and the asbestos pad
were the accepted standards. The candle re¬
quires extensive cleaning and is a fragile me¬
dium. High flow rates are attained only through
use of multiple-element manifolds. The asbestos
pad has significant absorption and adsorption
properties, and chemical prewash and pH ad¬
justment are required to prevent interaction
with products. Failure to achieve sterility may
FIG. 7-7. Extrapolation of filtrate volume produced in a
occur with asbestos pads owing to blow-through
given time can be made from log-log plots of experimental and channeling of medium of organisms when
data. critical pressures are exceeded. Both asbestos

CLARIFICATION AND FILTRATION • 155

and porcelain are migratory media; fragments of of any growth-supporting medium, the following
a candle or asbestos fibers may be found in the precautions must be kept in mind:
filtrate unless serial filtration through secondary
media is used. Since membrane filters do not 1. Identify the potential sources of adverse bio¬
have these disadvantages, porcelain candles and chemical and chemical contamination at
asbestos pads are no longer considered media of each point of the system'.
choice for sterile filtration. 2. Identify the control points necessary to elimi¬
Membrane filters have become the basic tool nate possible contamination and decrease
in the preparation of sterile solutions and have cost.
been officially sanctioned by the United States
Pharmacopoeia (USP) and the U.S. Food and 3. Identify the hazards associated with each
Drug Administration (FDA). The available ma¬ control point, i.e., airborne contamination
terials permit selection so that absorption effects and protein denaturation.
are negligible and ionic or particulate contami¬ 4. Establish a protocol for monitoring the haz¬
nation need not occur. The membrane requires ards at control points of the system.
no pretreatment and may be autoclaved or gas-
sterilized after assembly in its holder. Figure 7-9 illustrates the basic filtration system
A sterility requirement imposes a severe re¬ for nonsterile filtration of serum, water, and
straint on filter selection. All sterility tests are salts to reduce the microbiologic and particulate
presumptive, and one must rely upon total confi¬ matter, followed by final filtration through the
dence in the basic process; economics becomes sterile membrane.13
a secondary factor. Membranes with porosity The use of filtration to remove bacteria, partic¬
ratings of 0.2 or 0.45 microns are usually speci¬ ulate matter from air, and other gases such as
fied for sterile filtrations. In this porosity range, nitrogen and carbon dioxide is widespread in the
membrane filters may clog rapidly, and a prefil¬ pharmaceutical industry.16 The following are
ter is used to remove some colloidal matter to some common applications employing initial gas
extend the filtration cycle. The FDA allows the filtration:
use of 0.45-micron filters only in cases of colloi¬
dal solutions in which 0.2-micron filters have
been shown to clog very rapidly. Vent filtration
Most pharmaceutical liquids are compatible Compressed air used in sterilizers
with one or more of the membrane filters now
available. High viscosity or abnormal contami¬ Air or nitrogen used for product and in-proc-
nant levels are the primary restraints to the use ess solution transfers and at filling lines
of membranes, since an extremely large filtra¬ Air or nitrogen used in fermentation
tion area is needed for practical flow rates. Oil
and viscous aqueous menstruums are therefore When sterile and under ideal conditions, tra¬
heat-sterilized whenever possible. These solu¬ ditionally packed fiberglass or cotton filters pro¬
tions are usually clarified through coarser, vide vent protection. The use of hydrophobic
nonsterilizing membranes, preferably prior to membrane filters is increasing. These filters
heat sterilization. Paraffin oils, however, may be guarantee bacterial removal in wet and dry air
successfully filtered through 0.2-micron mem¬ and do not channel, unload, or migrate the me¬
branes after heating to reduce viscosity.15 dium. These filters may need to be heated by
Simple formulations such as intravenous so¬ jacketing. Restrictions of airflow through the
lutions, ophthalmics, and other aqueous prod¬ vent filter can result in pump damage or tank
ucts may be filtered directly through mem¬ collapse.17
branes in an economical manner. Heat-labile Manufacturers of membrane filters provide
oils and liquids containing proteins require pre¬ extensive application data and detailed direc¬
treatment, e.g., centrifugation or conventional tions for assembly, sterilization, and use of their
filtration, prior to sterilizing filtration. The objec¬ filters.12,13,18~31 The basic elements of any ster¬
tive is removal of gross contamination that ile operation must be followed. All apparatus
would rapidly plug the finer membranes. Diffi¬ should be cleaned and sterilized as a unit. Filtra¬
cult materials, such as blood fractions, demand tion should be the last step in processing, and
serial filtration through successively finer mem¬ the filter should be placed as close as possible to
branes. The cost of multiple filtration may seem the point of use of final packaging. In serial
excessive, but it is often the only way to achieve filtrations, only the final unit need be sterile, but
sterility. minimal contamination in prior steps increases
In selecting a filtration system for sterilization the reliability of the total process. Sterile filtra-

156* The Theory and Practice of Industrial Pharmacy

 NonSterile Preparation in a Final Sterilizing Filtration in a
Clean Room Sterile Work Area

Re.*..
Grade GC90
1.0 am ) _ . .
0.46 am > stack
Water „ GC50

Valve

Balanced
Salt
Solution

OBJECTIVE: Reduce Bioburden and Chemical Burden to OBJECTIVE: Achieve Sterile Filtration
Sterile Membrane

FIG. 7-9. Schematic representation of operational sequence.

tions should always be a pressure operation; a structive test used to predict the functional per¬
vacuum is undesirable since bacteria may be formance of a filter. Each membrane has a char¬
drawn in at leaky joints and contaminate the acteristic bubble point, diffusion rate, or
product. diffusion rate of air through water in a wetted
After the successful introduction of a new fil¬ filter, which is a function of the porosity rating
tration process, manufacturing tolerances allow and predicts the performance of the filter. The
reasonable changes in flow rate so long as qual¬ common integrity tests used to predict the per¬
ity is met. Therefore, the most common produc¬ formance of the filter are the bubble point test,
tion problem is complete plugging of filter media the diffusion test, and the forward flow test. Prior
resulting in no productivity. Subtle changes in to filtration, the integrity test detects a damaged
raw material quality are often at fault. The level membrane, ineffective seals, or a system leak.
of an impurity need change only slightly to The test performed after filtration confirms that
create problems with the fine porosity media the filter is still intact and that the system is
used in polishing operations. For example, iron remaining leak-free throughout the run.12
contamination in an alkaline product can lead to
colloidal precipitates, which blind the media.
Raw material problems should always be sus¬ Bubble Point Test
pected when synthesis procedures have been Membrane filters, which have discrete uni¬
altered or when the vendor of a purchased com¬ form passages that penetrate from one side of
modity has changed. the media to the other, can be regarded as fine,
uniform capillaries. The bubble point test is
bctsed on the fact that when these capillaries are
Integrity Testing full of liquid, the liquid is held by surface ten¬
An important feature of a filtration system is sion. The minimum pressure required to force
its ability to be tested for integrity before and the liquid out of the capillary must be sufficient
after each filtration. This is especially true in to overcome surface tension. Figure 7-10 illus¬
sterilization filtration, where even a few micro¬ trates the principle in the bubble point test. As
organisms passing through a crack in the filter can be seen in this figure, the capillary pressure
could be disastrous. An integrity test is a nonde¬ is higher in the case of a small pore than in that

CLARIFICATION AND FILTRATION • 157

Surface Tension in Capillary Tubes equation (7), where the contact angle changes
with different liquids. Filtration should normally
be performed at pressures lower than the bubble
point of a membrane. This prevents gas from
passing through the filter at the end of a filtra¬
tion cycle and thereby prevents excessive foam¬
ing.
The bubble point is also a useful criterion for
testing membrane efficiency. Figure 7-11 is a
schematic diagram of a nondestructive test ap¬
paratus that may be used without loss of product
or a break in sterility. A bubble test may be run
during and after filtration as an in-process con¬
trol. After wetting the filter and venting the unit,
valve A is closed, and air pressure is imposed on
the filter through valves B and C. When valve C
is closed, the filter holder should retain the pres¬
sure on the pressure gauge, and no bubbles
should appear in the receiving vessel. Failure to
hold a rated pressure is evidence of an unrelia¬
ble membrane or improper holder assembly.
When such failure occurs, filtration should be
discontinued, and material already processed
should be refiltered. Although each membrane
has a specific bubble point, which is dependent
on the liquid wetting the membrane, a test at a
pressure of 20 pounds per square inch (psi) is
FIG. 7-10. Surface tension in capillary tubes. usually sufficient to detect leaks.
Figure 7-12 illustrates the apparatus for per¬
forming a bubble point test on cartridge filters.
of a large pore. The same is true for pores in a
membrane. The bubble point pressure is gov¬
erned by the following equation: Diffusion Testing
A diffusion test must be performed in high-
p = K 4y Cos 6 volume systems, e.g., cartridges or multistack
(7)
discs, where a large volume of downstream liq¬
uid must be displaced before bubbles can be de¬
where: tected. A diffusion test measures volume of air
that flows through a wet membrane from the
P = bubble point pressure pressurized side to the atmospheric side. The
K = shape correction factor (experimental test is based on the theory that in a wet mem-
constant)
D = pore diameter
y = surface tension of the liquid Hose Clamp

6 = liquid-to-membrane contact angle (angle

of wetting)

In performing a bubble point experiment, the

membrane is wetted and usually has a liquid
above and a gas below. Since the pores are full of
liquid, there is no passage of gas at zero pres¬
sure. There is still no passage of gas if the pres¬
sure is increased slightly. When the bubble
point pressure is reached, a small bubble forms
at the largest opening. As the pressure is further
increased, rapid bubbling begins to occur. Bub¬ FIG. 7-11. Connections for nondestructive bubble test to
ble point pressure for a given membrane is dif¬ assure that membrane filter is intact. The test does not
ferent for different liquids. This can be seen in affect sterility. (Courtesy of Millipore Corporation)

158 • The Theory and Practice of Industrial Pharmacy

 with elements in place in the system, before
or after autoclaving, by in situ steaming or by
ethylene oxide to verify tightness of any
valves in parallel with elements.
3. Measurement of forward flow of assembly
after completion of the filtration procedure to
verify the integrity of the element during fil¬
tration.

The test is performed by placing a given ele¬

ment in its holder and wetting the filter. A prese¬
lected air pressure is applied to the upstream
side of the filter system. Measurement of the
total rate of airflow through the filter system is
then made. The quality acceptance level for a
given filter is based on a maximum total airflow
FIG. 7-12. Apparatus for performing the visible bubble at which the filter appears, empirically, to retain
test for cartridge filters 26 (From Field Experience in Test¬
all bacteria.23
ing Membrane Filter Integrity by the Forward Flow Test
Methods, Bulletin AB7JO-1-75. Pall Corporation, NY.)
Filtration Equipment
brane filter, under pressure, air flows through and Systems
the water-filled pores at differential pressures
below the bubble point pressure of the filter by a Commercial Equipment
diffusion process. The process follows Fick’s law
Commercial filtration equipment is classified
of diff usion. In performing the diffusion test, the
by type of driving force (gravity, pressure, cen¬
filter is thoroughly wetted in place with water, or
trifugal, or vacuum), by method of operating
the membrane is tested after filtration. Pressure
(batch or continuous), and by end product de¬
is applied using air at 80% of the established
sired (filtrate of cake solids).2,4,26 The clarifica¬
bubble point pressure for the particular mem¬
tion demands of pharmaceutical processes are
brane. Pressure is held for 2 min, and the vol¬
usually met by batch pressure units. Compatibil¬
ume of the air displaced is recorded. The volume
ity with a wide range of products restricts mate¬
of air is determined by measuring the rate of
rials of construction to stainless steel, glass, and
flow of the displaced water. The pressure is in¬
inert polymers.
creased until the bubble point is reached at an
Gravity filters are common in water treat¬
increment of 2 psi. Applying pressure at 80% of
ment, where a sand filter may be used to clarify
the bubble point pressure validates filter integ¬
water prior to deionization or distillation. The fil¬
rity since there would be a significant increase
tering medium may consist of sand or cake beds,
in airflow (water flow) at lower pressures, indi¬
or for special purposes, a composition containing
cating damaged membranes, wrong pore size fil¬
asbestos, cellulose fibers, activated charcoal,
ter, ineffective seals, system leaks, or a broad
diatomaceous earth, or other filter aids. Small-
pore size distribution.
scale purification of water may use porous ce¬
ramics as a filter medium in the form of hollow
Forward Flow Test “candles.” The fluid passes from the outside
through the porous ceramics into the interior of
Forward flow testing is based upon measure¬
the hollow candles. Tray and frame filters are
ment of the diffusion rate of air through water in
best adapted for slow, difficult filtrations and for
a wetted filter at a pressure well below the bub¬
exceptionally soft- or fine-grained precipitates,
ble point pressure. The following three kinds of
which clog under the slightest pressure or pass
tests can be performed, but often, only one or
through the openings of a cloth. Gravity bag fil¬
two are deemed sufficient.23,24
ters also are applied to concentration of magmas,
such as milk of magnesia. More efficient meth¬
1. Measurement of forward flow of individual
ods, however, particularly with respect to space
elements prior to assembly to their housing to
requirements, are available. The gravity nutzck
verify the integrity of each element prior to
is a false-bottom tank or vessel with a support
use.
plate for filter media. Porcelain nutzches may be
2. Measurement of forward flow of the assembly used for collecting sterile crystals or in opera-

CLARIFICATION AND FILTRATION • 159

tions where slurries are incompatible with met¬ The disc filter overcomes some deficiencies of
als. Since they are frequently operated under the filter press (Fig. 7-14). Compactness, porta¬
pressure or vacuum, they are not truly gravity bility, and cleanliness are obvious advantages
filters. for pharmaceutical batch operations. The term
Vacuum filters are employed on a large scale, disc filter is applied to assemblies of felt or paper
but are rarely used for the collection of crystal¬ discs sealed into a pressure case. The discs may
line precipitates or sterile filtration. Continuous be preassembled into a self-supporting unit, or
vacuum filters can handle high dirt loads, and each disc may rest on an individual screen or
on a volume basis, are cheap in terms of cost per plate. Single plate or multiples of single plates
gallon of filtered fluid. In the operation of the may be applied. The flow may be from the inside
continuous drum filter system, vacuum is ap¬ out or the outside in. Figure 7-15 illustrates the
plied to the drum, and the fluid flows through flow schematics through a plate. Fluid flows
the continuous belt. Solids are collected at the from the outside along the thin flow channel in
end of the belt. the plate. The filtrate flows along similar chan¬
Pressure filtration is desired in handling large nels in the bottom plate, and then to the inside
quantities of material in order to accelerate the circumference.22 This type of filter is intended
filtration process. Liquids with high viscosity only for clarification operations. Flow rates are
can hardly be filtered at all by gravity. similar to plate and frame presses at operating
The plate and frame filter press is the simplest pressures of up to 50 psi. Pulp packs or filter-
of all pressure filters and is the most widely used masse may be used instead of disc sheets for
(Fig. 7-13). Filter presses are used for a high high-polish filtrations, but flow rates are then
degree of clarification of the fluid and for the appreciably lower. Maximum filtrate recovery by
harvesting of the cake. When clarity is the main air displacement of liquid is usually possible
objective, a “batch” mode operation is applied. with a disc filter. Pressure leaf filters utilize the
The filter media are supported by structures in a rotation of a pressure leaf to partially remove the
pressure vessel. When an unacceptable pres¬ cakes and extend the life of the filter media.
sure drop across the filter is reached during the When filter aids are required, a plate and
filtration process, the filter media are changed. frame press with sludge frames is generally ac¬
Methods of supporting the filter media include ceptable, but disposal of cake and cleaning be¬
horizontal plates, horizontal or vertical pressure comes time-consuming. The precoat pressure
leaf, and plate and frame. filter (Fig. 7-15) is designed to overcome this
As the name implies, the plate and frame filter objection. It consists of one or more leaves,
press is an assembly of hollow frames and solid plates, or tubes upon which a coat of filter aid is
plates that support filter media. When assem¬ deposited to form the filtering surface. The filter
bled alternately into a horizontal or a vertical area is usually enclosed within a horizontal or
unit, conduits permit flow of the slurry into the vertical tank, and special arrangements permit
frames and through the media. One side of the discharge of spent cake by backflush, air dis¬
plate is designed for the flow of the feed. After placement, vibration, or centrifugal action. This
passing the filter media, the filtrate is accommo¬ type of filter is desirable for high-volume proc¬
dated on the other side. The solids collect in the esses. Two or more units can be used alterna¬
frames, and filtrate is removed through place tively, or surge tanks for clear filtrate may permit
conduits. In cake filtration, the size of the frame intermittent operation of a single unit.
space is critical, and wide, sludge frames are
used.
The filter press is the most versatile of filters Cartridge Filters and Systems
since the number and type of filter sheets can be Cartridge filters have an integral cylindric
varied to suit a particular requirement. It can be configuration made with disposable or cleanable
used for coarse to fine filtrations, and by special filter media and utilize either plastic or metal
conduit arrangements, for multistage filtration structural hardware.26 With the discovery of
within a single press. The filter press is the most strong pleatable membranes such as cellulose
economical filter per unit of filtering surface, nitrate, polyamide, polyvinylidene chloride,
and material of construction can be chosen to PTFE, and nylon, cartridge filters have revolu¬
suit any process conditions. Labor costs in as¬ tionized the filtration industry. Cartridge filters
sembly and cleaning are a primary disadvan¬ provide maximum filtration area in the smallest
tage, and leakage between plates may occur possible package, allow quick changeout of the
through faulty assembly. The normal range of media, and save time and money. Cartridge fil¬
flow is three gallons per minute per square foot ters of different shapes, structures, forms, and
of filter surface at pressures of up to 25 psi. sizes for. different applications in the pharma-

160 • The Theory and Practice of Industrial Pharmacy

FIG. 7-13. The plate and frame filter press may have 10 to 100 filtering surfaces and may be filled with pumps, sanitary
fittings, sludge frames, or dividing plates for serial filtration. (Courtesy of Ertel Engineering and T. Shriver & Co. Inc.)

CLARIFICATION AND FILTRATION *161

FIG. 7-14. Disc filter casing (A) accommodates precompressed cartridges or disc media. Exploded view (B) shows liquid
flow through assembled disc. (Courtesy of the Cuno Engineering Corporation.)

FIG. 7-15. A precoat pressure filter with wedge wire elements (A) is part of all stainless steel filter systems (B). Special
pump and fittings allow cleaning and sterilization in minutes. (Courtesy of Croll-Reynolds Engineering Co., Inc.)

162 • The Theory and Practice of Industrial Pharmacy

ceutical industry are now available in disposable
and nondisposable forms.12,19'27-30 The hous¬
ings for cartridge filters come in a wide variety of
configurations for both micron and submicron
filtration. The major differences in various hous¬
ings are in the design, materials of construction,
seals that are used to install the cartridge in the
housing, and the application for which they are
used in the pharmaceutical industry. The hous¬
ing for cartridge filters are described in terms of
the height of the cartridge and in the number of
cartridge receptacles in the base end of the
housing. When a user purchases a housing from
one manufacturer, he is usually not “locked in”
to that manufacturer’s cartridges. Adaptors are
available that allow the cartridge filter of one
manufacturer to fit into virtually any other man¬
ufacturer’s housing.
Filter media can be formed into cartridge form
by either tubular-wound, string-wound, or
pleated formation. Alternate layers of filter
media and separator material are rolled into a
spiral configuration, and by potting the ends of
the cartridge, form the “dead-ended” or “cross- FIG. 7-16. A disposable wound cartridge is installed in
holder. Liquid flows through the element and is discharged
flow” type of flow channels. String-wound car¬
through the core. (Courtesy of the Filterite Corporation.)
tridges are the most commonly used and inex¬
pensive filters available. Pleated cartridges are
modified tubular configurations with a large fil¬
tration area. A single knife-edge flat gasket may
be a satisfactory seal for cartridge filters with
1.0-micron or larger pore size. For submicron fil¬
tration, the most satisfactory seal is an O-ring.
Disposable or permanent cartridge filters are
used for fluid clarification or sterilization. Stan¬
dard elements for nonsterile filtration may be
interchanged between cartridge holders offered
by several companies (Fig. 7-16). Increases in FLUID
OUTLET
capacity result from multi-element holders, and FLUID
12 element units are usually adequate for INLET

batches of 500 to 1000 gallons. The cost of dis¬

posable elements is offset by labor savings inher¬
ent in the simplicity of assembly and cleaning of
ROTATABLE STATIONARY
cartridge clarifiers. METAL » CLEANING
FILTER SLADE
The metallic edge filters, particularly those DISCS
with self-cleaning devices (Fig. 7-17), are excel¬
lent security filters for suspensions that may
plug or blind conventional Wire mesh. A clean¬
ing blade combs away accumulated solids,
which fall into a sump in the filter casing. A
quick-coupling metal cartridge filter with con¬
struction that prevents short-circuiting of the fil¬
ter element is also available (Fig. 7-18). The spe¬
cial design permits rapid disassembly as well as
interchange of reusable filter media. Metal ele¬
ments permit particle retention as low as 1.5
microns. Duo filters, two units connected in par¬ FIG. 7-17. An edge filter with automatic cleaning device
allel, are recommended where uninterrupted may be automated by replacing handle with motor. (Cour¬
service is required. A high-frequency vibrator, tesy of the Cuno Engineering Corporation.)

CLARIFICATION AND FILTRATION *163

 j/'MfU-S) .

FIG. 7-18. Quick-coupling cartridge filter for metallic media is readily cleaned. (Courtesy of the Ronnigen-Petter Corn
pany.)

acting only on the element, assists in filtration of

slurries that have blinding tendencies.
Vendor^ of membrane filters offer cartridge
units in single- and multiple-element configura¬
tions.2127-32 These cartridges have become the
unit of choice for high-volume, sterile filtrations
and are ideal for in-line, final polish prior to bot¬
tling of bulk parenterals. Cartridge filters having
absolute ratings of 0.04 microns are also avail¬
able (Fig. 7-19). The latter units have 5 to 10
square feet of effective filtering area per car¬
tridge of 10-inch height, and some can also be
steam-sterilized.27-32

Membrane Filters and Housings

The use of membrane cartridge filters and
housings has been discussed extensively in the
previous section. The following section deals
mainly with disc membranes and holders.
Membrane filter holders accept membranes
from 13 to 293 mm in diameter. A useful rule of
thumb for membrane media and holder sizes for
various volumes of low-viscosity liquid is shown
in Table 7-5. Although 90- or 142-mm units are FIG. 7-19. Multiple-cartridge holders permit high-volume
suitable for moderate volumes, the 293-mm processing. (Courtesy of the Pall Corporation.)

164 • The Theory and Practice of Industrial Pharmacy

Table 7-5. Membrane Disc Filter Sizes for Vari¬ Suction filters are greatly utilized in the labo¬
ous Volumes ratory. Usually, a conical funnel and the Buch¬
ner funnel are used for suction filtration, as are
Volumes Filter
immersion and suction-leaf filters.33 Immersion
10-100 ml 13- or 25-mm discs filter tubes, also known as filter sticks, are gen¬
100-300 ml 47-mm discs erally used for small-scale laboratory operations.
300-5.000 ml 90-mm discs Small-laboratory pressure filters have been
5,000-10,000 ml 142-mm discs used substantially in recent years for both sterile
20-1,000 L 293-mm discs and nonsterile filtration operations. Gravity and
1,000 L and up cartridges suction filters are used mostly for nonsterile fil¬
tration. For the pressure filtration of small
amounts of material, the filter medium may be
membrane holder is the usual production choice mounted in a filter tube, with the liquid poured
for small-batch sizes. Stainless steel holders for in and pressure applied to the upper surface of
the sterilizing filter have sanitary connections, the liquid.34
and the support screens are faced with Teflon to Filter paper in circular form is the most com¬
permit autoclaving with the membrane in place. mon medium for laboratory filtrations. Filter
Special compatibility problems may require pol¬ papers are available in a wide variety of textures,
yvinylchloride holders with stainless steel sup¬ purities, and sizes and are available for different
ports, or units that have only Teflon and polypro¬ uses. They may be circular (1 to 50 cm in diame¬
pylene contact parts.20 ter), folded, or arranged in sheets or rolls.
Serial filtration is often desired to fractionate Among the special types of laboratory filter
the particulates in a fluid. A membrane of large paper for pharmaceutical industry are:
pore size may often be used as a prefilter for a
final downstream membrane filter of a smaller
1. Filter papers impregnated with activated car¬
pore size.
bon for adsorption of colors and odors in
Pressure drop across the filter media is often
pharmaceutical liquids.
observed. This pressure drop may be contrib¬
uted by either the filter media, the holder, or the 2. Filter paper impregnated with diatomaceous
housing. In a properly designed system, the earth for removal of colloidal haze from liq¬
pressure drop due to housing should usually be uids with low turbidity.
insignificant except for high-flow liquids or
gases. Minimum laboratory equipment includes a
plate and frame press, a membrane filter holder,
and a single-element housing for disposable car¬
Laboratory Filtration Equipment tridges. A 6- or 8-inch, stainless steel filter press
Laboratory equipment catalogs offer a wide with four to eight filter surfaces and sludge
choice of funnels and flasks adaptable to phar¬ ffanies is adequate. This covers the flow range
maceutical filtration studies. Although a Buch¬ from 8 to 200 gallons per hour with minimum
ner funnel test permits analysis of the major dif¬ filtrate holdup in the press. Stainless steel con¬
ficulties in a filtration problem, development struction permits autoclaving for sterile opera¬
laboratories should have additional procedures tions. Auxiliary equipment for mixing filter aid
and apparatus that produce the qualitative con¬ and feeding the press (10- to 20-gallon tanks,
ditions expected in large-scale production. This agitators, and centrifugal pump) should also be
requirement can be met with a nominal capital available. A 90-mm, stainless steel membrane
investment. filter holder processes 1 to 15 gallons of sterile
For gravity filtration, conventional glass per¬ solutions per hour. The support plate should be
colators are applicable, in which case the bottom Teflon-lined to permit autoclave sterilization
tube is covered with fibrous material. The filter¬ with membranes in place; the gaskets should
ing funnel is the most common of all laboratory also be Teflon. Integrity testing apparatus and a
filter devices. Filter paper is used with funnels. stainless steel pressure vessel of 1- to 5-gallon
Sometimes, a plug of fibrous material may be capacity are essential auxiliaries. The same
used instead. Filter bags for laboratory use are pressure assembly may be used in cartridge fil¬
made of fabric and are mounted for gravity filtra¬ ter tests. A broad selection of media should be on
tion. The uncertainty of adequate clarification hand for each unit.
with glass beads or sand has restricted their use More flexibility is obtained by adding a metal
as gravity filters for certain operations in the lab¬ cartridge filter and a small, manually operated,
oratory. self-cleaning, edge filter. If processing of high-

CLARIFICATION AND FILTRATION • 165

volume cosmetic products is expected, a single¬ Membrane Ultrafiltration
leaf, precoat pressure filter should be available.
Units can be obtained with capacities as low as Membrane ultrafiltration has become a com¬
IVi gallons. mercially feasible unit operation in the past dec¬
ade.10,12'13’19’22'30'35-38 Unlike conventional fil¬
tration, ultrafiltration is a process of selective
Cake Filtration molecular separation. It is defined as a process
Cake filtration in which solids recovery is the of removing dissolved molecules on the basis of
goal is an important pharmaceutical process. membrane size and configuration by passing a
Personnel involved in synthesis or fermentation solution under pressure through a very fine fil¬
to produce bulk active ingredients consider cake ter. Ultrafiltration membrane retains most mac¬
filtration to be the primary aim of the unit opera¬ romolecules while allowing smaller molecules
tion. Engineering textbooks and current litera¬ and the solvent to pass through the membrane,
ture stress the theory, laboratory test methods, even though the membrane is not rated as abso¬
and equipment required for solids separa¬ lute. The difference between microfiltration and
tion.2,4^6 ultrafiltration is significant. The former removes
The plate and frame press and precoat pres¬ particulates and bacteria; the latter separates
sure filters used for clarification also are applied molecules. Application of hydraulic pressure
to solids recovery. The basic design is often reverses the normal process of osmosis, so that
modified to reduce the high labor factor. In gen¬ the membrane acts as a molecular screen
eral, these pressure filters are restricted to batch through which only those molecules below a cer¬
operation and recovery of moderate weights of tain size are allowed to pass.
expensive materials. Separation of a solvent and a solute of differ¬
For large-scale operations, continuous vac¬ ent molecular size may be achieved by selecting
uum filters are most widely used. The rotary- a membrane that allows the solvent, but not the
drum vacuum filter is divided into sections, each solute, to pass through. Alternatively, two sol¬
connected to a discharge head. The slurry is fed utes of different molecular size may be sepa¬
to a tank in which solids are held in suspension rated by choosing a membrane that passes the
by an agitator. As the drum rotates, each section smaller molecule, but holds back the larger one
passes through the slurry, and vacuum draws (Fig. 7-20). Ultrafiltration is similar in process to
filtrate through a filter medium at the drum sur¬ reverse osmosis; both filter on the basis of mo¬
face. The suspended solids deposit on the filter lecular size. Ultrafiltration is different from re¬
drum as a cake, and as rotation continues, vac¬ verse osmosis in the sense that it does not sepa¬
uum holds the cake at the drum surface. The rate on the basis of ionic rejection. Dialysis and
cake is washed and dried as it moves toward the ultrafiltration are similar in the sense that both
discharge point. It may be scraped from the processes separate molecules, but ultrafiltration
drum or it may be supported by strings until it is different in that it does involve the application
breaks free under gravitational forces. Many var¬ of pressure.
iants of the basic design are needed to accom¬ The selectivity and retentivity of a membrane
modate differences in cake formation, drying are characterized by its molecular weight cutoff.
rates, and discharge properties. It is difficult to characterize the porosity of an
Filtering centrifuges are another general class ultrafiltration membrane by means of precise
of solids recovery devices. In this method of fil¬ molecular weight cutoff. The configuration of
tration, centrifugal force is used to affect the the molecule and its electrical charge may also
passage of the liquid thrbugh the filter me¬ affect the separation properties of the mem¬
dium."3 This type of filtration is particularly ad¬ brane.30 Ultrafiltration membranes are therefore
vantageous when very fine particles are in¬ rated on the basis of nominal molecular weight
volved. This device is fitted with a perforated cutoff. The shape of the molecule to be retained
basket, which supports the filter media. The plays a major role in retentivity. Many of the
basket revolves inside the casing. Slurry is same techniques that are used in microfiltration
sprayed into the basket, in which centrifugal to increase flow rate and throughput are also
action forces the filtrate through the media on used for ultrafiltration. Ultrafiltration mem¬
which the cake deposits. Continuous discharge branes are available as flat sheets, pleated car¬
of solids is possible, but batch units that require tridges, or hollow fibers. The hollow fibers have
shutdown for removal of solids are also common. the selective skin on the inside of the fiber.
Whenever solids recovery is the primary goal, Industrial use of this procedure has followed
centrifuges must be considered as an alternative the development of anisotropic polymer mem¬
to filtration. branes in a variety of biologically inert, noncel-

166 • The Theory and Practice of Industrial Pharmacy

 Pressurized Solution
of X, Y
CONCENTRATED X

FIG. 7-20. Schematic diagram of membrane ultrafiltration process.

lulosic materials. These membranes are fragile ery techniques. The most important application
structures, however, and usually require a back¬ of ultrafiltration is the removal of pyrogens.
ing plate of porous material to withstand opera¬
tional pressure. During the processing of a solu¬
tion, a region of high solute concentration also References
develops at the surface of the membrane, resist¬ 1. Oulman, C., and Baumann, E.: Filtration as a labora¬
ing further passage of solvent. Providing essen¬ tory tool. In Separation and Purification. 3rd Ed. Ed-
tial support for the membrane and overcoming i ited by R. Perry and A. Weissberger. John Wiley and
concentration polarization through shear effects Sons, New York, 1978, p. 364.
2. Perry, R., and Chilton, C.: Chemical Engineers
have resulted in a wide variety of commercial
Handbook. 5th Ed. McGraw-Hill, New York, 1973.
apparatus, including tangential-flow cassette 3. Tiller, F.M.: Chem. Eng., 73:151, 1966,.
systems, process ultrafiltration cartridges, hol¬ 4. Encyclopedia of Chemical Technology, Vol. 9.
low fiber beakers, and collodion bags. Since the 2nd Ed. Interscience, New York, 1966, p. 264.
technology continues to change rapidly, reliance 5. Orr, C. (ed.): Filtration—Principles and Practices,
on technical expertise of the manufacturer is Part II. Marcel Dekker, New York, 1979.
6. Mais, L. G.: Chem. Eng., 78:49, 1971.
advisable.
7. London, A.: Engineering, 207:443, 1969.
Applications in the pharmaceutical industry 8. Purcas, D. B.: Chem. and Proc. Eng., 48:95, 1967.
are predominantly in the concentration of heat- 9. Smith, G. R. S.: Chem. Eng., 74:154, 1967.
labile products, such as vaccines, virus prepara¬ 10. Weissberger, A. (ed.): Techniques of Organic Chem¬
tions, and immunoglobulins. Ultrafiltration also istry. Vol. III.'Interscience, New York, 1950.
has been used to recover antibiotics, hormones, 11. Daniels, F., and Alberty, R. A. (eds.): Physical Chem¬
istry. 3rd Ed. John Wiley and Sons, New York, 1966.
or vitamins from fermentation broths, to sepa¬
12. Industrial Process Catalog. Millipore Corporation,
rate cells from fermentation broth, to clarify so¬ Bedford, MA, 1982.
lutions, and to remove low-molecular-weight 13. Micro Filtration Systems Catalog 1982. Micro Filtra¬
contaminants prior to using conventional recov¬ tion Systems, Dublin, CA, 1981.

CLARIFICATION AND FILTRATION *167

14. Sharbaugh, J. C.: Chern. Eng., 69:153, 1962. and Pressure Hold Test, Bulletin #PCF701. Pah
15. Mulvany, J. G.: Soap Perfum. Cosmet., 43:486,1970. Trinity Micro Corporation, Cortland, NY.
16. Duberstein, R., and Howard, G. J., Parenteral Drug 26. Porter, H. F.: Chem. Eng., 78:39, 1971.
Association 32:192, 1978. 27. Nickolaus, N.: Filtration and Separation, March-
17. Cole, J.: Pharm. Tech., 1:49, 1977. April, 1975.
18. Cole, J. C., and Shumsky, R.: Pharm. Tech., 1:39, 28. The Pall Pharmaceutical Filter Guide Bulletin AB-
1977. 200. Pall Trinity Micro Corporation, Cortland, NY:
19. Laboratory Filtration Microbiology Electrophoresia 29. Filtration Catalog and System Design Guide. Gelman
1929. Sartorius GmbH, West Germany, 1979. Sciences, Ann Arbor, MI, 1980.
20. Low Volume Sterilizing Filtration, Application Report 30. Filtration, Catalog Lab 50. Nuclepore Corporation,
AR-11. Milbpore Corporation, Bedford, MA, 1973. Pleasanton, CA, 1980.
21. High Volume Pharmaceutical and Biological Filtra¬ 31. Cartridge Filters and Housing, Catalog PD-180. Milli-
tion, Application Manual AM202. Millipore Corpora¬ pore Corporation, Bedford, MA, 1980.
tion, Bedford, MA, 1972. 32. Ultipor AB Bulletin AB-100A. Pall Trinity Micro Cor¬
22. Ballew, H., et al. (eds.): Basics of Filtration and Sepa¬ poration, Cortland, NY, 1972.
ration. Nuclepore Corporation, Pleasanton, CA, 1978. 33. Drown, C.: Technical Quarterly, 20:552, 1981.
23. Field Experience in Testing Membrane Filter Integ¬ 34. Orr, C. (ed.): Filtration Principles and Practices,
rity by the Forward Flow Test Methods, Bulletin Part I. Marcel Dekker, New York, 1977.
AB710-1-75. Pall Corporation, New York. 35. McDonald, D. P.: Mfg. Chem. and Aerosol News,
24. Forward Flow Test Instructions for Filter Element 42:73, 1971.
Integrity Using the Pall Portable Forward Flow Kit, 36. Stavenger, P. L.: Chem. Eng. Progress, 67:30, 1971.
Bulletin #PCF 700. Pall Trinity Micro Corporation, 37. Porter, M. C., and Michaels, A. S.: Chem. Tech., 3:56,
Cortland, NY. 1971.
25. Forward Flow Test Instructions for Filter Assembly 38. Blatt, W. F.: American Lab., 4:78, 1972.
Integrity Using the Pall Portable Pneusmatic Trough

168 • The Theory and Practice of Industrial Pharmacy

 8
Preformulation
EUGENE F. FIESE and TIMOTHY A. HAGEN

Preformulation commences when a newly syn¬ Preliminary Evaluation

thesized drug shows sufficient pharmacologic
promise in animal models to warrant evaluation
and Molecular Optimization
in man. These studies should focus on those Once a pharmacologically active compound
physicochemical properties of the new com- has been identified, a project team consisting of
poundjhat could affect drug performance and representatives from the disciplines indicated in
development nof an efficacious dosage form. A Figure 8-2 has responsibility for assuring that
thorough understanding of these properties may the compound enters the development process
ultimately provide a rationale for formulation in its optimum molecular form. While each dis¬
design, or support the need for molecular modi¬ cipline may have its own criteria for an “opti¬
fication. In the simplest case, these preformula¬ mized” molecule, the physical pharmacist must
tion investigations may merely confirm that focus on how the product will be formulated and
there are no significant barriers to the com¬ administered to patients. Commonly, stability
pound’s development and/or solubility shortcomings can adversely af¬
Prior to starting preformulation studies, the fect these aspects of drug performance.
physical pharmacist should meet with the prin¬ When the first quality sample of the new drug
cipal investigators involved in the drug’s devel¬ becomes available, probing experiments should
opment to obtain information on the known be conducted to determine the magnitude of
properties of the compound and the proposed each suspected problem area. If a deficiency is
development schedule as listed in Figure 8-1. detected, then the project team should decide on
Since drug research is usually targeted for a spe¬ the molecular modification(s') that would most
cific therapeutic area, potency relative to com¬ likely improve the drug’s properties. Salts,
petitive products as well as the probable human prodrugs, solvates, polymorphs, or even new
dosage form(s) may be known. Similarly, the analogs may emerge from this modification ef¬
medicinal chemists may have insight regarding fort.
the molecule’s weaknesses as a result of their Although each of these modification ap¬
efforts to synthesize the compound. In addition, proaches has proven beneficial, the salt and pro¬
a literature search should be conducted to pro¬ drug approaches axe the most common. Most
vide an understanding of the probable decay salts of organic compounds are formed by the
mechanism(s) and conditions that promote drug addition or removal of a proton to lorrrTan ion¬
decomposition. This information may suggest a ized drug molecule, which is then neutralized
means of stabilization, a key stability test, or a "with a counter ion. Kphedrine hydrochloride, for
stability reference compound (such as aspirin "example, is prepared by addition of a proton to
for a compound undergoing ester hydrolysis). the basic secondary nitrogen atom on ephedrine,
Information on the proposed mode of drug- ad¬ resulting in a protonated drug molecule
ministration as well as a literature review on the (ephedrine-H(+)), which is neutralized with a
formulation, bioavailability, and pharmacokinet¬ chloride anion (ephedrine-HCl). In general, or¬
ics of similar drugs often proves useful when ganic salts are more water-soluble than the cor¬
deciding how to optimize the bioavailability of a responding un-ionized molecule, and hence,
new drug candidate. offer a simple means of increasing dissolution

171
 I. Compound Identity: While salt formation is limited to molecules
with ionizable grounsTprodrugs may be formed
II. Structure: with any organic molecule having a chemically
reactive functional group. Prodrugs are syn¬
III. Formula and Molecular Weight: thetic^ derivatives (e.g., esters and amides) of
drug molecules that may have intrinsic pharma¬
cologic activity but usually must undergo some
IV. Therapeutic Indication:
transformation in vivo to liberate the active drug
molecule. Through the formation of a prodrug, a
Probable Human Dose:
variety of side chains or functional groups may
Desired Dosage Form(s): Beadded to improve the biologic and/or pharma¬
Bioavailability Model(s): ceutical properties ol a compound.2 Some of the
Competitive Products: biologic response parameters that may be altered
by prodrug formation are absorption due to in¬
V. Potential Hazards: creased lipophilicity or increased water solubil¬
ity, duration of action via blockade of a key meta¬
VI. Initial Bulk Lots: bolic site, and distribution to organs due to
changes in lipophilicity. Examples of biologic
Lot Number: improvements are abundant in the steriod and
Crystallization Solvent(s): prostaglandin prodrug literature.3 Pharmaceuti¬
Particle Size Range: cal improvements resulting from prodrug forma¬
Melting Point: tion include stabilization, an increase or de¬
% Volatiles: crease in solubility, crystallinity, taste, odor, and
Observations: reduced pain on injection.
Erythromycin estolate is an example of a pro-
VII. Analytical Methods: drug with improved pharmaceutical properties
(Fig. 8-3). In aqueous solutions, protonated
HPLC Assay: erythromycin is water-soluble, has a bitter taste,
TLC Assay: and is rapidly hydrolyzed in gastric acid
UV/VIS Spectroscopy: (t30% = 9 sec) to yield inactive decay products.
Synthetic Route: To overcome this problem, the water-insoluble
Probable Decay Products: lauryl sulfate salt of the propionate ester prodrug
(estolate) was formed for use in both suspension
VIII. Key Dates: and capsule dosage forms. Erythromycin propio¬
nate is inactive as an antimicrobial and must
Bulk Scale-Up: undergo ester hydrolysis to yield bioactive eryth¬
romycin. In an oral q.i.d. bioavailability comnar-
Toxicology Start Date:
ison between Upjohn’s enteric coated tablet for¬
Clinical Supplies Preparation:
mulation of erythromycin base E-Mycin and
IND Filing: Dista’s nonenteric Ilosone capsule formulation
Phase ITesting: of erythromycin estolate (Fig. 8-4), the lipophilic
ester prodrug was absorbed four times more effi¬
IX. Critical Development Issue(s): ciently than the formulated free base, but hydro¬
FIG. 8-1. Essential information helpful in designing the lyzed only 24% in serum to produce equivalent
preformnlation evaluation of a new drug. plasma levels of bioactive erythromycin base.4 5
Thus, a prodrug was used to overcome a phar¬
rates, and possibly improving bioavailability. maceutical formulation problem without com¬
During synthesis, salts are usually formed in promising bioavailabibty.
organic media to improve yield as well as purity. To date, most prodrugs have been esters or
Some of the problems commonly encountered in amides designed to increase lipophilicity Unfor¬
evaluating salt forms include poor crystallinity, tunately. this type of modification often de-
various degrees of solvation or hydration, hygro- creases water solubility and thus decreases the
.scopicity, and instability due to an unfavorable concentration gradient across the ..cell mem¬
pH in the crystalline microenvironment. Table brane, which controls the rate of drug absorp¬
8-1 lists a spectrum of pharmaceutical altera¬ tion. This trade-off between lipophilicity and
tions resulting from salt formation, while Table concentration gradient is generally assumed to
8-2 lists salts used in commercial pharmaceuti¬ result in a net improvement in absorption. In
cal products through 1974.1 1980, Amidon suggested the making of water-

172 • The Theory and Practice of Industrial Pharmacy

Time Increasing
DISCIPLINES

ch3 ch3

Erythromycin Base Erythromycin Estolate

P, = H lauryl sulfate salt of TIME (hour*)

M.W. = 733.9 erythromycin propionate
M.P. = 192 °C ester FIG. 8-4. Average plasma concentrations of free base and
PKa = 8.8 R, = C,HsCO esterified erythromycin in 16 patients following q.i.d.
R, = C,2H„S04H doses of 250 mg of erythromycin base (•) E-Mycin or
M.W. = 1056.4 erythromycin estolate (A, M) llosone. These products were
M.P. = 137 °C judged equivalent with respect to production of bioactive
Drug pKa = 6.9 erythromycin base plasma levels. (From DiSanto, A. ft., et
FIG. 8-3. Structures of erythromycin and its estolate pro- al.: ]. Clin. Pharmacol, 20:437, 1980. Reproduced with
drug. permission of the copyright owner.)

PREFORMUMTION • 173
Table 8-1. Examples of Modification of Pharmaceutical Agents Through Salt Formation

Salt-Forming Agent Compound Modified Modification

Acetylaminoacetic acid Doxycycline Solubility

N-Acetyl-1,-asparagine Erythromycin Solubility, activity, stability
N-Acetylcystine Doxycycline Combined effect useful in pneumonia
Adamantoic acid Alkylbiguanides Prolonged action
Adipic acid Piperazine Stability, toxicity, organoleptic
properties
N - Alkylsulfamates Ampicillin Absorption (oral)
Lincomycin Solubility
Anthraquinone-l,5-disulfonic acid Cephalexin Stability, absorption
Arabogalactan sulfate (arabino) Various alkaloids Prolonged action
Arginine Cephalosporins Toxicity
a-Sulfobenzylpenicillin Stability, hygroscopicity, toxicity
Aspartate Erythromycin Solubility
Betaine Tetracycline Gastric absorption
Bis(2-carboxychromon-5-yloxy)alkanes 7-(Aminoalkyl)theophyllines Activity, prolonged prophylactic effect
Carnitine Metformin Toxicity
4-Chloro-m-toluenesulfonic acid Propoxyphene Organoleptic properties
Decanoate Heptaminol Prolonged action
Diacetyl sulfate Thiamine Stability, hygroscopicity
Dibenzylethylenediamine Ampicillin Prolonged action
Diethylamine Cephalosporins Reduced pain on injection
Diguaiacyl phosphate Tetracycline Activity
Dioctyl sulfosuccinate Vincamine Organoleptic properties
Embonic (pamoic) acid Kanamycin Toxicity
2-Phenyl-3-methylmorpholine Toxicity
Fructose 1,6-diphosphoric acid Tetracycline Solubility
Erythromycin Solubility
Glucose 1-phosphoric acid, glucose b- Tetracychne Solubility
phosphoric acid Erythromycin Solubility
1-Glutamine Erythromycin Solubility, activity, stability
Hydroxynaphthoate Bephenlum Toxicity
2-(4-Imidazolyl)ethylamine Prostaglandin Prolonged action
Isobutanolamine Theophylline Stability
Lauryl sulfate Vincamine Organoleptic properties
Lysine a-Sulfobenzylpenicillin Toxicity, stability, hygroscopicity
Cephalosporins
Methanesulfonic acid Pralidoxime (2-PAM) Solubility
N-Methylglucamine a-Sulfobenzylpenicillin Toxicity, stability, hygroscopicity
Cephalosporins Reduced pain on injection
N-Methylpiperazine Phenylbutazone Toxicity, faster onset of action
Morphohne Cephalosporins Reduced pain on injection
2-Naphthalenesulfonic acid Propoxyphene Organoleptic properties
Octanoate Heptaminol Prolonged action
Probenecid Pivampicillin Organoleptic properties
Tannic acid Various amines Prolonged action
Theobromine acetic acid Propoxyphene Activity
3,4,5-Trimethoxybenzoate Tetracycline Organoleptic properties
Heptaminol Prolonged action
Tromethamine Aspirin Absorption (oral)
Dinoprost (prostaglandin F^,) Physical state

From Berge, S.M., et al.: J. Pharm. Sci., 66:1, 1977. Reproduced with permission of the copyright owner.

174 • The Theory and Practice of Industrial Pharmacy

Table 8-2. Salts Used in Pharmaceutical Products Marketed in the United States Through 1974.

Anion Percenta Anion Percent*

Acetate 1.26 Iodide 2.02

Benzenesulfonate 0.25 Isethionate' 0.88
Benzoate 0.51 Lactate 0.76
Bicarbonate 0.13 Lactobionate 0.13
Bitartrate 0.63 Malate 0.13
Bromide 4.68 Maleate 3.03
Calcium edetate 0.25 Mandelate 0.38
Camsylateb 0.25 Mesylate 2.02
Carbonate 0.38 Methylbromide 0.76
Chloride 4.17 Methylnitrate 0.38
Citrate $.03 Methylsulfate 0.88
Dihydrochloride $.51 Mucate 0.13
Edetate $.25 Napsylate 0.25
Edisylate0 0.38 Nitrate 0.64
Estolated 0.13 Pamoate (Emboriate) 1.01
Esylate® 0.13 Pantothenate 0.25
Fumarate 0.25 Phosphate/diphosphate 3.16
Gluceptatef 0.18 Polygalacturonate 0.13
Gluconate 0.51 Salicylate 0.88
Glutamate 0.25 Stearate 0.25
Glycollylarsanilate® 0.13 Subacetate 0.38
Hexylresorcinate 0.13 Succinate 0.38
Hydrabamineh 0.25 Sulfate 7.46
Hydrobromide 1.90 Tannate 0.88
Hydrochloride 42.98 Tartrate 3.54
Hydroxynaphthoate 0.25 Teoclate1 0.13
Triethiodide 0.13

Cation Percenta Cation Percent

Organic Metallic:
Benzathinek 0.66- Aluminum 0.66
Chloropro. aine 0.33 - Calcium 10.49
Choline 0.33 Lithium 1.64
Diethanolamine 0.98 Magnesium 1.31
Ethylenediamine 0.66 Potassium 10.82
Meglumine1 2.29 Sodium 61.97
Procaine 0.66 Zinc 2.95

“Percent is based on total number of anionic or cationic salts in use through 1974. bCamphorsulfonate. cl,2-Ethanedisulfonate. dLauryl
sulfate. “Ethanesulfonate. fGlucoheptonate. Sp-Glycollamidophenylarsonate. hN,N'-Di(dehydroabietyl)ethylenediamine. 12-Hydroxy-
ethanesulfonate. J8-Chlorotheophyllinate. kN,N'-Dibenzylethylenediainine. ‘N-Methylglucamine.
From Berge, S.M., et al.: J. Pharm. Sci., 66:1, 1977. Reproduced with permission of the copyright owner.

soluble prodrugs by adding selected amino acids drug of estrone, a potential increase of five or¬
that are substrates for enzymes located in the ders of magnitude in adsorption rate was found
intestinal brush border.6 Assuming that enzyme in yivo using perfused rat intestines.
cleavage was not rate-limiting, and that the lib¬ Although any of the modifications discussed
erated drug molecule would remain in the lipo¬ may provide an increase in bioavailability,
philic membrane, then the resulting membrane chemical instability or a lack of synthetic feasi¬
transport of the parent compound should be very bility may prohibit the commercial development
rapid, owing to the large concentration gradient of a modified drug molecule. Whatever the case,
of liberated drug across the membrane, as illus¬ the molecular form of the drug advancing from
trated in Figure 8-5. Using the lysine ester pro¬ this preliminary evaluation should have a sub-

PREFORMULATION *175
 Lumen Enzyme membrane I. Bulk Characterization

Crystallinity and Polymorphism

Hygroscopicity
Fine Particle Characterization
Bulk Density
Powder Flow Properties

II. Solubility Analysis

Ionization Constant-pKa
pH Solubility Profile
Common Ion Effect-Ksp
Thermal Effects
Solubilization
FIG. 8-5. Concentration (C) versus distance (X) profile for Partition Coefficient
the absorption of water-soluble prodrugs (PD*), which, are Dissolution
enzymatically (E) hydrolyzed in the intestinal brush bor¬
der to liberate the lipophilic parent compound (D). Key:
thickness of aqueous diffusion layer; SE, enzyme layer III. Stability Analysis
thickness; Sm, membrane thickness; and PC membrane-
enzyme layer partition coefficient. (From Amidon, G. L., et Stability in Toxicology Formulations
al: ]. Pharm. Sci., 69:1363, 1980. Reproduced with per¬ Solution Stability
mission of the copyright owner.)
pH Rate Profile
Solid State Stability
Bulk Stability
stantial chance of successfully progressing Compatibility
through the drug development process.
FIG. 8-6. Outline of the principal areas of preformulation
Once the optimum molecular form of a drug research.
has been selected, formulation development
commences, which prompts other disciplines to
begin their task in the drug development process
as depicted in Figure 8-2. The objective of this Crystallinity and Polymorphism
phase is the quantitation of those physical Crystal habit and the internal structure of a
chemical properties that will assist in developing drugTan~affect bulk and physicochemical prop-
a stable, safe, and effective formulation with erties, which range from flowabilitv to chemical
maximum bioavailability. Figure 8-6 lists the stability. Habit is the description of the outer
major areas of preformulation research in the appearance of a crystal whprpag thp internal
order in which they are discussed in the follow¬ structureJis the molecular arrangement within
ing text. Keep in mind that these topics vary in the solid. Several examples of different habits of
importance according to the type of formulation crystals are shown in Figure 8-7. A single inter¬
sought for each individual drug candidate. nal structure for a compound can have several
different habits, depending on the environment
for growing crystals. Changes with internal
Bulk Characterization structure usually alter the crystal habit while
In most instances, the synthetic process is such chemical changes as conversion of a so¬
developed in parallel with preformulation inves¬ dium salt to its free acid form produce both a
tigations. A drug candidate at this stage often change in internal structure and crystal habit.
has not had all of its solid forms identified, and Characterization of a solid form involves (1) ver¬
there is a great potential for new polymorphs to ifying that the solid is the expected chemical
emerge. Bulk properties for the solid form, such compound, (2) characterizing the internal struc¬
as particle size, bulk density and surface mor¬ ture, and then (3), describing the habit of the
phology, are also likely to change during process crystal.
development. Therefore, comprehensive charac¬ The internal structure of a compound can be
terization of all preformulation bulk lots is nec¬ classified in a variety of ways, as shown in Fig¬
essary to avoid misleading predictions of stabil¬ ure 8-8. The first major distinction is whether
ity or solubility, which depend on a particular the solid is crystalline or amorphous. Crystals
crystalline form. arecharacterized bv repetitious spacing-of con-

176 • The Theory and Practice of Industrial Pharmacy

 or within dosage forms, is a major disadvantage
for developing an amorphous form.
A crystalline compound may contain either a
Platy
stoichiometric or nonstoichiometric amount of
Equant or Massive
crystallization solvent.7 Nonstoichiometric ad¬
ducts, such as inclusions or clathrates, involve
entrapped solvent molecules within the crystal
€ lattice. Usually this adduct is undesirable, owing
Needle or Acicular Bladed to its lack of reproducibility, and should be
avoided for development. A stoichiometric ad¬
A duct, commonly referred to as a solvate, is a mo¬
lecular complex that has incorporated the crys¬
S’ tallizing solvent molecules into specific sites
within the crystal lattice. When the incorporated
Tabular
Prismatic solvent is water, the complex is called a hydrate,
and the terms .hemihydrate, monohvdrate. and
FIG. 8-7. Different habits of crystals. (Reprinted by per¬
mission of the publisher from Hartshome, N. H., and dihydrate describe hydrated forms with molar
Stuart, A.: Practical Optical Crystallography. American equivalents of water corresponding to half, one,
Elsevier, New York, 1964, p. 1, and courtesy of McCrone and two. A compound not containing any water
Research Institute, American Pharmaceutical Association within its crystal structure is termed anhydrous.
Academy of Pharmaceutical Sciences 33rd National Meet¬ Identification of possible hydrate compounds
ing, November 14, 1982, San Diego, CA.
is important since their aqueous solubilities can
15e~ilgmficanriy less than their anhydrous forms.
•^USnvefiion of an anhydrous compound to a hw
stltuent atoms or molecules in a three-dimen-
drate within the~dosage form may reduce~~the
sional~afrav. whereas amorphous forms have
dissolution rate and extent of drug absorption.
atoms or molecules randomly placed as in a liq¬
An example of the in vivo importance of sol¬
uid. Amorphous forms are typically prepared by
vate forms is shown in Figure 8-9, where the
rapid precipitation, lyophilization, or rapid cool-
mjTof liquid melts. Since amorphous forms are-
usually of higher thermodynamic energy than
corresponding crystalline forms, solubilities as
well as dissolution rates are generally greater.
Upon storage, amorphous solids tend to revert to
more stable forms. This thermodynamic insta¬
bility, which can occur during bulk processing

chemical compound

habit internal structure

crystalline amorphous

single entity molecular adducts

'-polymorphs | ^ |
nonstoichiometric stoichiometric
inclusion compounds solvates (hydrates)

channel layer cage

FIG. 8-9. Mean serum concentrations of ampicillin in
(clathrate)
human subjects after oral administration of250-mg doses
FIG. 8-8. Outline of differentiating habit and crystal of two solvate forms of the drug in suspension. Key: •,
chemistry of a compound. (From Haleblian, ]. K: anhydrous; and o, trihydrate. (From Poole, ]., et al: Cur¬
]. Pharm. Sci., 64:1269, 1975. Reproduced with permission rent Therapeutic Research, 10:292, 1968. Reproduced with
of the copyright owner.) permission of the copyright owner.)

PREFORMULATION • I 77
 anhydrous and trihydrate forms of ampicillin Table 8-3. Analytic Methods for
were administered orally as a suspension to Characterization of Solid Forms
human subjects.8 The more soluble anhydrous
Material Required
form (10 mg/ml) produced higher and earlier
Method per Sample
peaks in the blood serum levels than the less sol¬
uble trihydrate form. Microscopy 1 mg
Polymorphism is the ability of a compound (or Fusion methods 1 mg
element) to crystallize as more thanone distinct (hot stage microscopy)
crystalline species with different internal lat¬ Differentia) scanning calorimetry 2-5 mg
tices. Chemical stability and solubility changes (DSC/DTA)
'Hue'to polymorphism can have an impact on a Infrared spectroscopy 2-20 mg
drug’s bioavailability and its development pro¬ X-ray powder diffraction 500 mg
gram. Chloramphenicol palmitate exists in three Scanning electron microscopy 2 mg
crystalline polymorphic forms (A, B, and C) and Thermogravimetiic analysis 10 mg
an amorphous form.9 Aguiar and co-workers Dissolution/solubility analysis mg to gm
investigated the relative absorption of polymor¬
phic forms A and B from oral suspensions ad¬
ministered to human subjects.10 As summarized
in Figure 8-10, “peak” serum levels increased
substantially as a function of the percentage of methods for studying solid forms are listed in
form B polymorph, the more soluble polymorph. Table 8-3 along with the sample requirements
Many physicochemical properties -vary with for each test. In the following sections, three of
theTnternal structure of thesolid drug includ¬ these techniques are discussed in detail, with
ing melting point, density, hardness, crystal particular emphasis on polymorphism.
shape, optical properties, and vapor pressure.11 Microscopy. All substances that are trans¬
Characterization of polymorphic and solvated parent when examined under a microscope that
forms involves quantitative analysis of these dif¬ has crossed polarizingfilters are either isotropic
fering physicochemical properties. Several or anisotropic.. Amorphous substances) such as
supercoolea glasses and noncrystalline solid _or-
ganic compounds. or~substanceswith cubic
crystal lattices, such as sodium chloride, are iso-
24 tropic materials, which have a single refractive
mdexTWithcrossed polarizing filters, these iso¬
E tropic substances do not transmit light, and they
20 appear black. Materials with more than one re¬
o fractive index are anisotropic and appear bright
o with brilliant colors (birefringence) against the
black polarized background. The interference
u 16
X colors depend upon the crystal thickness and the
Q. differences in refractive indices. Anisotropic
substances are either uniaxial, having two re¬
i 12 fractive indices, or biaxial, having three princi¬
cc
O pal refractive indices.
_i Most drugs are biaxial, corresponding to ei¬
X 8
ther an orthorhombic, monoclinic, or triclinic
crystal system. Although one refractive index is
easily obtained for biaxial systems, proper orien¬
tation of the crystal along its crystallographic
axes is required to describe the crystalline form
completely. Owing to the many possible crystal
habits and their appearances at different orien¬
tations, these methods require a well-trained
optical crystallographer to characterize fully
even simple biaxial systems. Crystal morphology
FIG. 8-10. Correlation of "peak” blood serum levels (2 hr)
of chloramphenicol vs. percentage of concentration of
differences between polymorphic forms, how¬
polymorph B. (From Aguiar, A. ]., et al.: J. Pharm. Sci., ever, are often sufficiently distinct that the mi¬
56:847, 1967. Reproduced with permission of the copy¬ croscope can be used routinely by the less expe¬
right oumer.) rienced microscopist to describe polymorphic

178 • The Theory and Practice of Industrial Pharmacy

 TGA
crystal habits and observe transitions induced by
heat or solvents.
The polarizing microscope fitted with a hot
stage is a useful instrument for investigating
polymorphism, melting points, transition tem¬
peratures, and rates of transition at controlled
heating rates. In addition, the hot-stage micro¬
scope facilitates differentiation of DSC endo-
therms (explained in the next section) for poly¬
morphic transitions from desolvation processes
(when the sample is heated in degassed immer¬
sion oil). A problem often encountered during
thermal microscopy is that organic molecules
can degrade during the melting process, and
recrystallization of the melt may not occur, be¬
cause of the presence of contaminant degrada¬
tion products.
Thermal Analysis. Differential scanning
calorimetry (DSC i and differential thermal anal¬
ysis (l)TAi measure the heat loss or gain result¬
ing from physical or chemical changes within a
sample as a function of temperature. Examples
of endothermic (heat-absorbing) processes are
fusion, boiling, sublimation, vaporization, desol-
vation, solid-solid transitions, and chemical deg-
radation. Crystallization and degradation are
FIG. 8-11. Thermogravimetric (TGA) and differential
usually- exothermic processes. Quantitative scanning calorimetric (DSC) analysis for an acetate salt of
measurements of these processes have many an organic amine that has two crystalline forms, anhy¬
applications in preformulation studies including drous and dihydrate. Anhydrous/dihydrate mixture was
purity,12 polymorphism,13 solvation,14 degrada¬ prepared by dry blending. Heating rate was 5°/min.
tion, and excipient compatibility.15,16
For characterizing crystal forms, the heat of
fusion, AHf, can be obtained from, the ,.area-un- Thermogravimetric analysis (TGA) measures
der-the-DSC-curve for the 'meltiiig endotherm. changes in sample weight as a function of time
Similarly, the heat of transition from one (isothermal) or temperature. Desolvation and
polymorph to another may be calculated as decomposition processes are frequently-moni¬
shown by Guillory for several sulfonamides.13 A tored by TGA. Comparing TGA and DSC data
sharp symmetric melting endotherm can indi¬ recorded under identical conditions can greatly
cate relative purity, whereas broad, asymmetric aid in the interpretation of thermal processes. In
curves suggest impurities or more than one Figure 8-11, the dihydrate form of an acetate
thermal process. Heating rate affects the kinet¬ salt loses two moles of water via an endothermic
ics and hence the apparent temperature of solid- transition between 70° and 90oC. The second
solid transitions. endotherm at 155°C corresponds to the melting
A variable with DSC experiments is the at¬ process, with the accompanying weight loss due
mosphere in contact with the sample. Usually, a to vaporization of acetic acid as well as to decom¬
continual nitrogen purge is maintained within position.
the heating chamber; however, the loss of a vola¬ TGA and DSC analysis can also be used to
tile counter ion such as ethanolamine or acetic quantitate tfie presence of a solvated species
acid during a polymorphic transition may pro¬ Within a bulk drug sample. For the above exam¬
duce misleading data unless the transition oc¬ ple, 10% of the dihydrate form was easily de¬
curs within a closed system. In contrast, desol¬ tected by both methods (Fig. 8-11).
vation of a dihydrate species, as shown in Figure Both DSC and TGA are microtechniques and
8-11; releases water vapqr, which if unvented dependoh thermal equilibration within the sam¬
can generate degradation prior to the melting ple. Significant variables in these methods in-
point of the anhydrous form. During initial test¬ clude sample homogeneity, sample size, particle
ing, a variety of atmospheres should be tried size, heating rate, sample atmosphere, and sam¬
until the observed thermal process becomes ple preparation. Degradation during thermal
fully understood. analysis may provide misleading results, but

PREFORMULATION * 179
FIG. 8-12. Differential scanning calorimetric (DSC)
analysis and HPLC stability analysis of an organic amine
hydrochloride salt that undergoes decomposition upon
melting.

FIG. 8-13. X-ray intensity ratio as a function of composi¬

tion of forms A and B of chloramphenicol palmitate. (From
may be detected by high-performance liquid Aguiar, A. ]., et al.: J. Pharm. Sci., 56:847, 1967. Repro¬
chromatography (HPLC) analysis of samples duced with permission of the copyright owner.)
heated under representative conditions for re¬
tention of drug or appearance of decay products
(Fig. 8-12).
X-Rav. An important technique for establish- Polymorphism
ing*the batch-to-batch reproducibility of a crys- Polymorphs can be classified as one of two
talline form is x-raypowder diffraction. Random types: enatiotropic (one polymorph can be re¬
orientation of a crystal lattice in a powder sam¬ versibly changed into another by varying tem¬
ple causes the x-rays to scatter in a reproducible perature or pressure, e.g., sulfur) or monotrapic
pattern of peak intensities at distinct angles (9) (one polymorphic form is unstable at all temper¬
relative to the incident beam. Each diffraction atures and pressures, e.g., glyceryl stearates).
pattern is characteristic of a specific crystalline There is no general way of relating enatiotrophy
lattice for a given compound. 7 An amorphous and monotrophy to the properties of the poly¬
form does not produce a pattern. Mixtures of dif¬ morphs, except by locating the transition tem¬
ferent crystalline forms can be analyzed using perature or the lack of one. At a specified pres¬
normalized intensities at specific angles, which sure, usually 1 atmosphere, the temperature at
are unique for each crystalline form. A typical which two polymorphs have identical free ener¬
standard curve is shown in Figure 8-13 for poly¬ gies is the transition temperature, and at that
morphic forms A and B of chloramphenicol pal- temperature, both forms can coexist and have
mitate. identical solubilities in any solvent as well as
Single-crystal x-ray analysis provides a precise identical vapor pressures. Below the solid melt¬
identification and description of a crystalline ing temperatures, the polymorph with the lower
substance. Unit cell dimensions and angles con¬ free energy, corresponding to the lower solubil¬
clusively establish the crystalline lattice system ity or vapor pressure, is the thermodynamically
and provide specific differences between crystal¬ stable form.
line forms of a given compound. Other methods During preformulation, it is important to iden-
such as infrared spectroscopy, dilatometry, pro¬ tifythe polymorph that is stable at room temper¬
ton magnetic resonance (PMR), nuclear mag¬ ature and to determine whether polymorphic
netic resonance spectroscopy (NMR), and scan¬ transitions are possible within the temperature
ning electron microscopy (SEM) have additional range used for stability studies and during proc¬
applications for studying polymorphism and sol¬ essing (drying, milling, etc.). As discussed by
vation.11 Hal ebb an and McCrone, a polymorphic corn-

180 • The Theory and Practice of Industrial Pharmacy

pound is best characterized by a complete pres¬ morphism is determination of the relative stabil¬
sure-temperature phase diagram showing melt- ity of metastable polymorph and prediction of its
vapor, solid-vapor, and solid-melt curves.11 A rate of conversion within a dosage form. For sus¬
free energy-temperature curve at 1 atmosphere pension dosage forms, the rate of conversion can
should be constructed since temperature is usu¬ depend on several variables, including drug sol¬
ally a more critical variable than pressure in ubility within the vehicle, presence of nuclea¬
pharmaceutics. As previously discussed, chlor¬ tion seed for the stable form, temperature, agita¬
amphenicol palmitate has three known polymor¬ tion, and particle size. Solid dosage forms such
phic forms, which are thermodynamically de¬ as capsules and tablets have similar complica¬
scribed by a van’t Hoff plot of free energy (as tions due to the influence of particle size, mois¬
determined from solubility measurements) ver¬ ture, and excipients. In short, the most effective
sus temperature (Fig. 8-14). Transition temper- means for evaluating the stability of a metasta¬
atures are shown by intersection of the extrapo¬ ble polymorph in the dosage form is to initiate
lated hhdsTSCFC for forms A and C, and 88“C for prototype formulation work by screening a wide
forms A and B. f orm A is the, stable form at tem- range of factors, including the presence and ab¬
peratures less than 5(J"U.10 sence of seed crystals of the stable polymorphic
Transition temperatures obtained by extrapo¬ form. Essential to this approach is development
lation of van’t Hoff plots are susceptible to large of an analytic method that is sensitive to small
errors. Direct measurements of transitions are amounts of the stable polymorph in the presence
preferred to support the extrapolated intersec¬ of the metastable polymorphs and excipients. In
tion points in the solubility-temperature dia¬ most cases, the lower limit of detection for
grams. The most direct means for determining polymorph mixtures is in the range of 2 to 5%.
transition temperatures is microscopic observa¬ To screen for additional polymorphic forms'of
tion of samples held at constant temperatures. a particular drug, bridging solvents, supersatu¬
Unfortunately, these solid-solid or solid-vapor- rated solutions, supercooled melts and sub-
solid transitions usually occur slowly, owing to limination have proven useful.11 Observation of
large activation energies and slow nucleation. To the drug particles by light microscopy during or
facilitate the conversion rate, a single polymorph after processing by these techniques should pro¬
or a mixture of forms can be granulated in a vide substantial insight into the preferred crys¬
“bridging” solvent at various temperatures. The talline forms of the compound without consum¬
drug should be only sparingly soluble in the ing inordinate quantities of material.
bridging solvent, and solvate formation should
not occur. These experiments can be conducted
quickly with a polarizing microscope, or samples Hygroscopicity
can be stored in sealed containers at controlled Many drug substances, particularly water-sol¬
temperatures and periodically examined by uble salt forms, Jiave a tendency to adsorb at-
other suitable analytic methods. mospheric moisture. Adsorption and eciuilib-
A more difficult task in the study of poly- num moisture content can depend upon the
atmospheric humidity, temperature, surface
area, exposure, and the mechanism for moisture
uptake, as described by Van Campen and co¬
workers. 18 Deliquescent materials adsorb suffl-
cient waterto dissolve" completely, as is observed
with sodium chloride on a humid day. Other
hygroscopiclubstances adsorb water because of
hydrate formation or specific site adsorption.
With most hygroscopic materials, changes in
moisture level can greatly influence many im¬
portant parameters, such as chemical stability,
flowability, and compactibility.
—— x 10
Temp
Tfl test for hygroscopicity, samples of bulk
drug are placed in oven containers with a thin
FIG, 8-14. The van’t Hoff plot of solubility vs. reciprocal powder bed to assure maximum atmospheric
absolute temperature for polymorphs A, B, and C of chlor¬
amphenicol palmitate. Key: Polymorphs A (►—► );
exposure. These samples are then exposed to a
B (•—•); and C (o—o). (From Aguiar, A. ]., et al.: range of controlled relative humidity environ¬
]. Pharm. Sci., 58:983, 1969. Reproduced with permission ments prepared with saturated aqueous salf so¬
of the copyright owner.) lutions. a_Moisture uptake jfiou]iibe_monitored

PREFORMULATION • 181
at time points representative of handling (0 to 24 generated by displacing that particle’s volume of
hours) and storage (0 to 12 weeks). Analytic conducting medium. Given that the instrument
methods for monitoring the moisture level (i.e., has been calibrated with standard spheres, the
gravimetry, TGA, Karl Fischer titration, or gas counter provides a histogram output (frequency
chromatography) depend upon the desired pre¬ versus size) within the limits of that particular
cision and the amount of moisture adsorbed aperture tube. Several different sizes of aperture
onto the drug sample. tubes should be used to assure accurate count¬
Normalized (mg H20/g sample) or percent- ing of single particles. Other stream counters are
age-of-weight-gain data from these hygroscopic based on the principles of light blockage or laser
studies are plotted against time to justify special light scattering for sizing each particle.20
handling procedures kinetically. A plot of nor¬ Although the Coulter method is quick and sta¬
malized equilibrium versus relative humidity tistically meaningful, it assumes that each re¬
data may support the need for storage in a low- sistance arises from a spherical particle; thus,
humidity environment or for special packaging nonspheres are sized inaccurately. Other limita¬
with a desiccant. As these studies proceed, addi¬ tions with the Coulter counter are the tendency
tional testing of powder flow, dissolution, or sta¬ of needle-shaped crystals to block the aperture
bility of “wet” bulk may be warranted to lend fur¬ hole, the dissolution of compound in the aque¬
ther support to the need for humidity controls. ous conducting medium, and stratification of
particles within the suspension. Additional
methods of particle size analysis are image anal¬
Fine Particle Characterization ysis and sieve analysis. Sieve methods are used
Bulk flow, formulation homogeneity, and sur- primarily for large samples of relatively large
fate-area controlled processes such as dissolu¬ particles (—100 microns). Computer interfacing
tion and chemical reactivity are directly affected of image analysis techniques offers the greatest
by size, shape, and surface morphology of the promise for particle size analysis in the ’80s.21
drug particles. In general, each new drug candi¬ Kinetic processes involving drug in the solid
date should be tested during preformulation state, such as dissolution and degradation, may
with the smallest particle size as is practical to be more directly related to available surface area
facilitate preparation of homogeneous samples than to particle size. If drug particles have a
and maximize the drug’s surface area for inter¬ shape that can be defined mathematically, then
actions. light microscopy size analysis or Coulter counter
A light microscope with a calibrated grid usu¬ analysis with appropriate geometric equations
ally provides adequate size and shape character¬ may provide a reasonable estimation of surface
ization for drug particles.20 Sampling and prepa¬ area. ^
ration of the microscopic slide must be A more precise measurement of surface area
preformed carefully to obtain a representative is made by Brunauer, Emmett, and Teller (BET1
dispersion. Several hundred particles should be nitrogen adsorption, in which a layer of nitrogen
sized, and the resulting mean and range of sizes" molecules Is adsorbed to the sample surface at
reported as a histogram. The use of photomicro¬ 196°C. Once' surface adsorption has reached
graphs and a hemacytometer slide, as well as equilibrium, the sample is heated to room tem¬
other sizing techniques, may make this task perature, the nitrogen gas is desorbed, and its
slighdy less strenuous. Although it is time-con¬ volume is measured and converted to the num¬
suming, light microscopy has few restrictions on ber of adsorbed molecules via the ideal gas law.
particle shape. Since each nitrogen molecule (N2) occupies an
In conjunction with light microscopy, stream area of 16A2, one may readily compute the sur¬
counting devices, such as the Coulter counter. face area per gram for each preweighed sample.
and HIAC counter, often provide a convenient By determining the surface area at several par¬
"method for characterizing the size distribution tial pressures of nitrogen (5% to 35% N2 in He),
of a compound. Samples are prepared for analy¬ extrapolation to zero nitrogen partial pressure
sis by the Coulter counter by dispersing the ma¬ yields the true monolayer surface area. While
terial in a conducting medium such as isotonic BET measurements are usually precise and
saline with the aid of ultrasound and a few drops quickly obtained with current commercial
of. surfactant. A known volume (0.5 to 2 ml) of equipment, errors may arise from the use of
this suspension is then drawn into a tube impure gases and volatile surface impurities
through a small aperture (0.4 to 800 microns in (e.g., hydrates).
diameter), across which a voltage is applied. As Surface morphology may be observed by scan¬
each particle passes through the hole, it is ning electron microscopy (SEM), which serves
counted and sized according to the resistance to confirm qualitatively a physical observation

182 • The Theory and Practice of Industrial Pharmacy

related to surface area. For example, bulk lots of
drug recovered by different crystallization proc¬
esses that have been used in an attempt to im¬
prove yield may result in surface morphologies
that provide greater area for surface reactions
such as degradation, dissolution, or hygroscopi-
city.
During preparation for SEM analysis, the
sample is exposed to high vacuum during the
gold coating process, which is needed to make
the samples conductive, and concomitant re¬
moval of water or other solvents may result in a
false picture of the surface morphology. Variable
vacuum treatment of an identical sample prior
to the gold coating step may confirm the effects
of sample preparation on surface morphology.
Most modem SEM instruments also provide
energy dispersive x-ray spectroscopy analysis of
FIG. 8-15. Correlation between capsule size and packed
surface metal ions, which may prove beneficial density for different fill weights (200-600 mg).
in deciphering an instability or incompatibility
problem.
tures. After vigorous agitation, the samples are
centrifuged briefly and then left to stand undis¬
Bulk Density turbed until floatation or settling has reached
Bulk density of a compound varies substan¬ equilibrium. The sample that remains sus¬
tially with the method of crystallization, milling, pended corresponds to the true density of the
or formulation. Once a density problem is identi¬ material. Density of the test solution corre¬
fied, it is often easily corrected by milling, slug¬ sponding to the drug’s true density should be
ging, or formulation. Usually, bulk density is of checked with a calibrated pycnometer preferably
great importance when one considers the size of after the test to include any density changes due
a high-dose capsule product or the homogeneity to dissolved material.
of a low-dose formulation in vyhich there are
large differences in drug and excipient densi¬
ties. Powder Flow Properties
Apparent bulk density (g/ml) is determined by Pharmaceutical powders may be broadly clas¬
pouring presieved (40-mesh) bulk drag into a sified as free-flowing or cohesive (non-free-flow¬
graduated cylinder via a large funnel and meas¬ ing). Most flow properties are significantly af¬
uring the volume and weight “as is.” Tapped fected by changes in particle size, density,
density is determined by placing a graduated shape, electrostatic charge, and adsorbed mois¬
cylinder containing a known mass of drug or for¬ ture, which may arise from processing or formu-
mulation on a mechanical tapper apparatus, lationT^As a result, a free-flowing drug candi¬
which is operated for a fixed number of taps date may become cohesive during development,
(—1000) until the powder bed volume has thus necessitating an entirely new formulation
reached a minimum. Using the weight of drag strategy. Preformulation powder flow investiga¬
in the cylinder and this minimum volume, the tions should quantitatively assess the pharma¬
tapped density may be computed. Knowing the ceutical consequences of each process improve¬
anticipated dose and tapped formulation den¬ ment and provide direction for the formulation
sity, one may use Figure 8-15 to determine the development project team. This direction may
appropriate size for a capsule formulation. consist of a formulation recommendation such
In addition to bulk density, it is frequently as granulation or densification via slugging, the
desirable to know the true density of a powder need for special auger feed equipment, or a test
for computation-of void volume orporosity of system for evaluating the improvements in flow
packed powderPeds. Experimentally, the true brought about by formulation. This subject be¬
density is determined by suspending drag parti¬ comes paramount when attempting to develop a
cles in solvents of various densities and in which commercial solid dosage form containing a large
the compound is insoluble. Wetting and pore percentage of cohesive material.
penetration may be enhanced by the addition of Free-flowing powders may be characterized by
a small quantity of surfactant to the solvent mix- a simple flow rate apparatus consisting of a

PREFORMULATION • 18S
grounded metal tube from which drug flows Table 8-4. Compressibility and Flowability of
through an orifice onto an electronic balance, Pharmaceutical Excipients.
which is connected to a strip chart recorder.
Several flow rate (g/sec) determinations at each % Compressibility Flowability
of a variety of orifice sizes (Vs to V2 inches) Excellent
5-15
should be made. In general, the greater the stan¬ 12-16 Good
dard deviation between multiple flow rate meas¬ 18-21 Fair-passable
urements, the greater is the weight variation in 23-35 Poor
products produced from that powder. 33-38 Very poor
When several lots of a drug candidate are <40 Very, very poor
tested under dissimilar conditions, equation (1),
proposed by Jones and Pilpel, may be used to Material % Compressibility Flowability
show the dependence of flow rate (W) on true
Celutab 11 Excellent
particle density (p), gravity (g), and orifice di¬
Emcompress 15 Excellent
ameter (D0).23 Both (A) and (n) are constants
Star X-1500 19 Fair-passable
that are dependent upon the material and its
Lactose monohydrate 19 Fair-passable
particle size. 26-27
Maize starch Poor
Dicalcium phosphate,
/ 4W \1/n dihydrate (coarse) Poor
27
D0 = A (1)
' 60 TTp Vg ' Magnesium stearate 31 Poor
Titanium dioxide 34 Very poor
Another measurement of a free-flowing pow¬ Dicalcium phosphate,
der is compressibility, as computed from powder dihydrate (fine) 41 Very, very poor
density, equation (2): Talc 49 Very, very poor

From Jones, T.M.: Pharmazeutische Industrie, 39:469, 1977.

Reproduced with permission of the copyright owner.
% Compressibility = (-—&-) x 100 (2)
-\ Pt /

itly defined at this time, understanding the

where pt is the tapped bulk density and p0 is the
drug’s solubility profile and possible solubiliza¬
initial bulk density. Table 8-4 lists compressibil¬
tion mechanisms provides a basis for later for¬
ity data and flowability characterization for sev¬
mulation work. Preformulation solubility studies
eral pharmaceutical excipients.
usually include*^einrminationsTirpKa7ternpera-
While angle of repose determinations are usu¬
ture dependence. pH solubility profile, splnhilitv
ally useless because of their lack of precision,
products, solubilization mechanisms, ancfrate of
observation of powder flow from a glass funnel
dissolution.
and then a grounded metal funnel provides in¬
Analytic methods that are particularly useful
sight into the drug’s flow properties, electrostatic
for solubility measurements include HPLC, UV
properties, and tendency to brige in. a cone-
spectroscopy) fluorescence spectroscopy, and
shaped hopper.24
gas chromatography. For most drugs, reverse
Cohesive powders may be characterized by
phase HPLC offers an efficient and accurate
tensile testing or evaluated in a shear cell. Since
means of collecting solubility data. Its major
both methods require large samples of material
advantages are direct analysis of aqueous sam¬
(>20 g) for testing, these methods are not dis¬
ples, high sensitivity, and specific determinatiori
cussed in this section; rather, the reader is re¬
of drug concentration due to chromatographic
ferred to the works of York, Sutton, and Hiestand
separation of drug from impurities or degrada¬
for experimental details and application of cohe¬
tion products.
sive powder test results to hopper design.22,25-28
Solubility and dissolution experiments should
have all factors defined, including pH, tempera¬
ture, ionic strength, and buffer concentrations-.
Solubility Analysis For an equilibrium solubility determination,
Preformulation solubility studies focus on excess drug dispersed in solvent is agitated at a
drug-solvent systems that could occur during constant temperature. Samples of the slurry are
the delivery of a drug candidate. For example, a withdrawn as a function of time, clarified by
drug for oral administration should be examined centrifugation, and assayed to establish a pla¬
for solubiEtvTn media having isotonic chloride teau concentration. The solid precipitate is also
ion concentration and acidic pH. EvejLiliDugh characterized to establish the equilibrium solid
the routes of administration may not be explic¬ form of the drug.

184 • The Theory and Practice of Industrial Pharmacy

 Problems encountered with sample workup media of the intestine. For basic drugs such as
can involve adsorption or incomplete removal of erythromycin and papaverine, (pKa ~ 8 to 9),
the excess drug during filtration or centrifuga¬ the ionized form is predominant in both the
tion steps. In addition, if excess drug is not a stomach and intestine. In general, the un-ion¬
solid but an oil, sample preparation may be even ized drug molecule is the species absorbed from
more difficult. In particular, drugs capable of the gastrointestinal tract; however, rate of disso¬
ionization may require different methods of lution, lipid solubility, common ion effects, and
removing excess drug, owing to altered adsorp¬ metabolism in the GI tract can shift or reverse
tion properties. Filtered saturated solutions predictions of the extent and site of absorption
should be carefully examined using a high-in- based on pH alone.
tensity fight beam to detect the presence of a A pKa value can be determined by a variety of
finely dispersed oil or solid. Solutions can also be analytic methods. Buffer, temperature, ionic
examined conveniently with a fight microscope, strength, and cosolvent affect the pKa value and
with which particles or droplets of 1 fj. or greater should be controlled for these determinations.
can be distinguished if present in sufficient con¬ The preferred method is the detection of spectral
centration. shifts by ultraviolet (UV) or visible spectroscopy
Solubility values that are useful in a candi¬ since dilute aqueous solutions can be analyzed
date’s early development are those in distilled directly. A second method, potentiometric titra¬
water, 0.9% NaCl, 0.01M HC1, 0.1MHC1, and tion, offers maximum sensitivity for compounds
0.1M NaOH, all at room temperature as well as with pKa values in the range of 3 to 10 but is
at pH 7.4 buffer at 37°C. These early results are often hindered by precipitation of the un-ionized
useful in developing suspensions or solutions for form during the titration since a high drug con¬
toxicologic and pharmacologic studies. Further¬ centration is usually required to obtain a signifi¬
more, these studies identify those candidates cant titration curve. To prevent precipitation, a
with a potential for bioavailabifity problems. cosolvent such as methanol or dimethylsulfox-
Drugs having limited solubility (<1%) in the ide can be incorporated to maintain sufficient
fluids of the gastrointestinal tract often exhibit solubility for the un-ionized species, and the pKa
poor or erratic absorption unless dosage forms value is extrapolated from titration data col¬
are specifically tailored for the drug.30 Solubility lected for various cosolvent concentrations. As
profiles are not predictors of biologic perfor¬ shown in Figure 8-16, dependence of the disso¬
mance, but do provide rationale for more exten¬ ciation constant on cosolvent can be highly sig-
sive in vivo studies and formulation develop¬
ment prior to drug evaluation in humans.
10.0

pKa Determinations
Determination of the dissociation constant for
9.>5
a drug capable of ionization within a pH range of
1 to 10 is important since solubility, and conse¬
quently absorption, can be altered by orders of
magnitude with changing pH. The Henderson-
Hasselbalch equation provides an estimate of
the ionized and un-ionized drug concentration
at a particular pH.

For acidic compounds:

[ionized drug]
pH = pKa + log
[un-ionized drug]
For basic compounds: 8.0

[un-ionized drug]
pH = pKa + log (3)
[ionized drug] _i_i_i_i_i-1-1_i_i_i
10 20 30 40 50 60 70 80 90 100

For a weakly acidic drug with pKa value % Ethanol

greater than 3, the un-ionized form is present FIG. 8-16. The pKa determination for an organic amine
within the acidic contents of the stomach, but drug candidate whose un-ionized form is exceedingly in¬
the drug is ionized predominately in the neutral soluble in water.

PREFORMULATION *185
 nificant, and extrapolations provide only an esti¬ It therefore follows that the pHmax is defined as:
mate of the pKa value. In general, the use of
cosolvent yields higher pKa values for acids and
lower values for bases than does pure water. pHmax = PKa + log (8)
With insoluble drugs, the dependence of solu¬
bility on pH can also be used to obtain pKa val¬
At a solution pH equivalent to pHmax, both the
ues. For this third method, the pKa corresponds
free base and salt form can exist simultaneously
to the pH of the solution where the equilibrium
in equilibrium with a saturated solution. The
solu bility is twice the value for the intrinsic solu¬
pHmax is verified by sampling precipitated drug
bility of the un-ionized form. If other solubility
from the equilibrated solution and confirming
determining factors such as solute-solute associ¬
the presence of both drug forms. Solubility ex¬
ation or solubility products become significant
pressions for acidic drugs are derived in a simi¬
owing to the titrant used to adjust the pH, then
lar fashion.33
pKa values may be incorrectly determined by
When the ionized or salt form of a drug is the
this procedure. Many references are available
solubility-limiting species in solution, the con¬
containing composite lists of pKa values for vari¬
centration of the paired counter ion is usually
ous functional groups and organic molecules,
the solubility determining factor. For a hydro¬
which facilitate initial estimates for dissociation
chloride salt of a basic amine, the equilibrium
constants.31 In addition, Albert and Seijeant
between the solid and ionized species in solution
have provided detailed descriptions of several
is approximated by the following expression:
experimental methods for determining pKa val¬
ues.32
[BH+ Cl-jsolld & [BH+] + [C1-] (9)
pH Solubility Profile and
where KsP is the solubility product for the pro¬
Common Ion Effects
tonated species and chloride counter ion, or:
The solubility of an acidic nr basic drug de¬
pends on the pKa of theionizi n» functional KsP = [BH+][C1~] (10)
~Tffoup~ahd the intrinsic solubilities for both the
“Ionized and un-ionized forms. For a basic drug, If the contribution of the un-ionized species is
the total molar solubility, St, is equal to the fol¬ negligible as compared with the protonated
lowing summation: form, the total drug solubility decreases as the
chloride ion concentration increases. In this
^ St = [BH+] + [B] (4) case, the apparent solubility product is defined
as:
where BH+ is the protonated species and B is
the free base. The pH at which bbth base and
KsP = St [Cl-] (11)
salt species are simultaneously saturated is de¬
fined as the pHmax or:
Experimental determination of a solubility
product should include measurement of pH as
S„ pH = PHmax = [BH+]S + [B]s (5)
well as assays of both drug and counter ion con¬
centrations. To compute the thermodynamic sol¬
where the subscript (s) denotes saturation. For
ubility product, concentrations should be con¬
weak bases in the pH region where the solubility
verted to activities with appropriate corrections
of the protonated form is limiting, the molar sol¬
for activity coefficient dependence on ionic
ubility is:
strength.34,30
In summary, aqueous solubility profiles for
St, pH < PHmax = [BH+]S + [B] (6)
ionizable compounds over large pH ranges with
varying counter ion concentrations are func¬
= [BH+]S (l + -^r)
tions of many variables, as given by the follow¬
ing expression for an organic amine drug:
Similarly, the solubility.in the pH region where
the free base is limiting is expressed as: St = f (pH, pKj, [B]s, K*p, anions) (12)

St, pH > pHmax = [BH+] + [B]s (7) These parameters also depend on ionic strength,
/ \ temperature, and the aqueous media composi-
= [Bjs (1 + tion. Consequently, pH solubility profiles can

186 • The Theory and Practice of Industrial Pharmacy

appear dramatically different for compounds tion rates and solubilities were even less than
with similar functional groups. A particularly their respective free base forms in media con¬
useful reference by Kramer and Flynn for or¬ taining chloride ion.38 Consequently, the solu¬
ganic hydrochlorides highlights pH solubility bility product for each ionizable compound with
profile dependence on solvent composition.36 either sodium or chloride ions should be evalu¬
While most of this discussion has focused on ated to detect potential in vivo problems with
solubility product limitations of basic com¬ dissolution and/or absorption.
pounds, similar analyses may be made for acidic Another point illustrated with doxycycline is
drugs. that nonideal behavior of a solution species can
The pH solubility profile for doxycycline dramatically affect the solubility at certain pH
(pKa 3.4) reported by Bogardus and.Backwood values. Doxycycline was shown to form dimeric
illustrates a common ion effect for an amine species involving self-association of the proton-
hydrochloride salt.37 As shown in Figure 8-17, ated form. This mechanism accounted for the
the solubility in aqueous medium with pH 2 or large positive deviation from ideal behavior, in
less logarithmically decreased as a function of which actual solubility values are a factor of 10
pH (which was adjusted with hydrochloric acid) higher at pH 2.0. Therefore, actual solubility
because of corresponding increases in the chlo¬ profiles should be experimentally determined
ride ion concentration. In gastric juice, where within the pH region of interest.
the pH can range from 1 to 2 and the chloride
ion concentration is between 0.1M and 0.15M,
doxycycline hydrochloride dihydrate has a solu¬
Effect of Temperature
bility of ~4 mg/ml, which is a factor of 7 less
than its solubility in distilled water. For the hy¬ The heat of solution, AHS, represents the heat
drochloride salts of chlortetracycline, demeclo- releasecTbr absorbed' when a mole of solute is
cycline, and methacyeline, the apparent dissolu- dissolved in a large quantity 6f solvent. Most
commonly, the solution process is endothermic,
or AHS is positive, and thus increasing the solu¬
tion temperaturefrncreases the drug solubility.
Tor such solutes as lithium chloride and other
hydrochloride salts that are ionized when dis¬
solved, the process is exothermic (negative AHS)
such that higher temperatures suppress the sol¬
ubility.
Heats of solution are determined from solubil¬
ity values for saturated solutions equilibrated at
controlled temperatures over the range of inter¬
est. Typically, the temperature range should in¬
clude 5°C, 25°C, 37°C, and 50°C. The working
equation for determining AHS is:

+c (13)
where S is the molar solubility at temperature T
(°kelvin) and R is the gas constant. Over limited
temperature ranges, a semilogarithmic plot of
solubility against reciprocal temperature is lin¬
ear, and AHS is obtained from the slope. For non¬
electrolytes and un-ionized forms of weak acids
and bases dissolved in water, heats of solution
are usually in the range of 4 to 8 kcal/mole. Salt
FIG. 8-17. The pH-solubility profile for doxycycline in forms of drugs are often less sensitive to temper¬
aqueous hydrochloric acid at 25°C. At pH = 2.16, both ature and may have heats of solution between
doxycycline monohydrate and doxycycline hydrochloride -2 and 2 kcal/mole.
dihydrate were in equilibrium with solution. Theoretic
In Figure 8-18, examples of AHS determina¬
curves arc detailed by authors. (From Bogardus, J. B., and
Blackwood, R. K.: J. Pharm. Sci., 68:188, 1979. Reproduced tions are shown for the free base and hydrochlo¬
with permission of the copyright uumer, the American ride salt of an organic amine as reported by Kra¬
Pharmaceutical Association.) mer and Flynn.36 Although the AHS for the free

PREFORM CLATION • 187

 lize drug molecules by disrupting the hydropho¬
bic interactions of water at the nonpolar solute/
water interfaces. The extent of solubilization
due to the addition of cosolvent depends on the
chemical structure of the drug, that is, the more
nonpolar the solute, the greater is the solubiliza¬
tion achieved by cosolvent addition. This rela¬
tionship is illustrated in Figure 8-19 for hydro¬
cortisone and hydrocortisone 21-heptanoate.40
The lipophilic ester is solubilized to a greater
extent by additions of propylene glycol than by
the more polar parent compound.
Cosolvent effects for dissociated drag mole¬
cules are usually much less, as shown by Kra¬
mer and Flynn.36 Some poorly soluble drugs can
be solubilized in micellar solutions such as
0.01M Tween 20, or via molecular complexes as
with caffeine.41,42 These specific formulations
are usually not developed during the prefor¬
mulation phase, however.

Partition Coefficient
A measurement of a drug’s lipophilicity and
an indication of its ability to cross cell mem¬
branes is the oil/water partition coefficient in

FIG. 8-18. Plot of hydrochloride and free base solubilities

for etoxadrol, an organic amine, against reciprocal tem¬
perature. (From Kramer, S. F, and Flynn, G. L.: ]. Pharm.
Set, 61:1896, 1972. Reproduced with permission of the
copyright owner.)

base is somewhat large, a 10° change in temper¬

ature produces a fivefold change in solubility.
'This finding wouldTertainly affect solution dos¬
age form design and storage conditions. In addi¬
tion, solvent systems involving cosolvents, mi¬
celles, and complexation have very different
heats of solution in comparison to water.

Solubilization
For drug candidates with either poor water
solubility or insufficient solubility for projected
solution dosage forms, preformulation studies
should include limited experiments to identify
possible mechanisms for~solubilization. A gen¬
eral means of increasing solubility is The addi¬
tion of a cosolvent to the aqueous system The
solubility of poorly soluble nonelectrolytes can
FIG. 8-19. Solubility of hydrocortisone and hydrocorti¬
often be improved by orders of magnitude with sone 21-keptanoate in propylene glycol-water mixtures.
suitable cosolvents such as"ethanol, propylene (From Hagen, T. A.: Ph.D. dissertation, University of
glycol, and glycerin.39 These cosolvents solubi¬ Michigan, Ann Arbor, Michigan, 1979.)

188 • The Theory and Practice of Industrial Pharmacy

systems such as octanol/water and chloroform/ and W is the weight (mg) of drug dissolved in
water. The partition coefficient is defined as the time t.
ratio oLun-ionizeH drug distributed betweefffhe A plot of W versus t gives a straight fine with
phasesaTequilibnumT the slope equal to the intrinsic dissolution rate
constant k, 47 usually expressed in units of
p _ Cnil mg/cm2/min.
1 Cilw equilibrium (14)
Experimentally, a constant surface area is ob¬
tained by compressing powder into a disc of
For series of compounds, the partition coeffi¬ known area with a die and punch apparatus. Ei¬
cient can provide an empiric handle in screen¬ ther of the two systems shown in Figure 8-20
ing for some biologic properties.43 For drug de¬ can be used to maintain uniform hydrodynamic
livery, the lipophilic/hydrophilic balance has conditions (k constant). The rotating disc
been shown to be a contributing factor for the method or Wood’s apparatus permits the hydro¬
rate and extent of drug absorption.44,45 Although dynamics of the system to be varied in a mathe¬
partition coefficient data alone does not provide matically well-defined manner.48 The static disc
understanding of in vivo absorption, it does pro¬ method is used because it is conveniently avail¬
vide a means of characterizing the lipophilic/ able, but it contains an element of undefined
hydrophilic nature of the drug. turbulence, which necessitates calibration with
standards. Potential problems with this method
are transformations of the crystal form, such as
Dissolution polymorphic transformations or desolvation,
Dissolution of a drug particle is controlled by during its compression into a pellet or during the
severar~physicochemicai properties, including dissolution experiment. Since many drug candi¬
chemical form, crystal habit, particle size, solu¬ dates are weak acids and bases, pH and common
bility, surface area, and wetting properties. ion gradients at the solid-liquid interface can
When coupled with equilibrium solubility data, lead to erroneous conclusions, as discussed by
dissolution experiments can help to identify po¬ Mooney and co-workers.49,50
tential bioavadability problem areas. For exam¬ Dissolution experiments with drug suspen¬
ple, dissolution of solvate and polymorphic sions are further complicated by changing sur¬
forms of a drug can have a significant impact on face area, changing surface crystal morphology,
bioavailability and drug delivery. and interstitial wetting.51 However, dissolution
The dissolution rate of a drug substance in profiles with excess drug can be used to charac¬
which surface area is constant during dissolu¬ terize metastable polymorphs or solvates. In Fig¬
tion is described by the modified Noyes-Whitney ure 8-21, the conversion of the metastable form
equation: II to form I is shown to occur in an organic sol¬
vent medium, which clearly depicts form I as
dC DA the thermodynamically stable form at room tem¬
-(Cs-C) (15)
dt hV perature..Static pellet dissolution rates also sub¬
stantiated that form II was the higher energy
where D is the diffusion coefficient, h is the form since its dissolution rate was significandy
thickness of the diffusion layer at the solid-liq¬ greater (Table 8-5).
uid interface, A is the surface area of drug ex¬
posed to dissolution media, V is the volume of
media, Cs is the concentration of a saturated so¬ s
lution of the solute in the dissolution medium at
the experimental temperature, and C is trie con¬
centration of drug in solution at time t. The dis¬
solution rate is given by dC/dt. If the surface
area of the drug is held constant and Cs > > C,
then equation (15) can be rearranged and inte¬
grated to give the working equation:

(16)

where the constant k is defined as:

FIG. 8-20. Constant surface area dissolution apparatus.
Left: static disc dissolution apparatus. Right: rotating disc
k = ^-Cs (17) apparatus.

PREFORMULATION • 180
 Essential to a meaningful chemical stability
study are multiple samples and development of
a specific assay that quantitates intact drug as
well as decay products (thus assuring mass bal¬
ance accountability). Over the past decade,
high-performance liquid chromatography has
emerged as the analytic method of choice for
specificity and quantitation even in complex
systems. Development of a valid stability assay
requires authentic pure samples of each decay
product, which may be supplied by the synthetic
chemists or may be isolated from samples that
have been intentionally degraded by excessive
acid, base, or heat.
During drug development, several bulk lots
are produced, reflecting scale-up and process
improvements in yield, purity, and possibly crys¬
tallinity. The first lot used for preformulation
stability studies may not be representative of the
commercial bulk product, but it does provide
FIG. 8-21. Powder dissolution profiles for two polymor¬
phic forms of an organic acetate salt in acetonitrile at
baseline data. In subsequent evaluations, paral¬
25°C. lel testing of the initial bulk lot of drug with the
new bulk or formulation aids in forming conclu¬
sions about progress of the project.
Upon completion of the initial stability tests,
one or more challenge models indicating stabil¬
Stability Analysis ity may emerge that may be useful for limited
Preformulation stability studies are usually testing on future bulk lots or formulations.
•he first quantitative assessment of chemical Should a particularly difficult instability prob¬
stability of a new drug. These studies iilclude lem arise during drug development, then an in-
both solution and solid state' experiments under depth elucidation of the decay mechanism may
conditions typical for the handling, formulation, suggest a stabilization approach or underscore
storage, and administration of a drug candidate. the futility of the stabilization effort.
This section focuses on the evaluation of chemi¬
cal stability during preformulation research.
Test protocols and experimental methods are
emphasized in lieu of kinetic theory, which is Stability In Toxicology
presented later in this chapter. In addition, the
reader is referred to the literature for compre¬ Formulations
hensive reviews of drug stability.52-55 Since toxicology studies typically commence
early in drug development, it is often advisable
to evaluate samples of the toxicology prepara¬
tions for stability and potential homogeneity
Table 8-5. Comparison of Dissolution Rates*
problems. Usually, a drug is administered to the
and Solubility for Two Polymorphic Forms of animals ftrtheirfesd. or bv oral savage of a solu-
an Organic Acetate Salt. tion or suspension of the drug in an aqueous
vehicle^
Ratio Water, vitamins, minerals (metal ions), en-
Form I Form II mi zvmes and a multitude oiTunctional groups afe
present in feed, which can severely reduce the
Dissolution rate in 0.57 0.69 .83 shelf-life of a drug. Enzyme activity and mois-
ethanol, mg/cm2/min turiTlevels typically decrease with time while
Dissolution rate in 0.017 0.027 .62 feed composition varies with the “consumer”;
Acetonitrile, mg/cm2/min thus, a fresh sample of feed to be used in the
toxicology test provides the most relevant stabil¬
Solubility in Acetonitrile, .22 .29 .75
ity data. Since enzyme activity and mobility of
mg/ml
adsorbed water vary substantially with tempera¬
*Dissolution rates measured with a static-disc apparatus. ture, it is recommended that storage tempera-

190 • The Theory and Practice of Industrial Pharmacy

 ture typical of the toxicology laboratory be used may be used to confirm assay specificity as well
for this stability study. as to provide estimates for maximum rates of
Solution and suspension toxicologic prepara¬ degradation. This initial experiment should be
tions should be checked for ease of manufacture followed by the generation of a complete pH-rate
and then stored in flame-sealed ampules at vari¬ profile to identify the pH of maximum stability.
ous temperatures. In addition to chemical stabil¬ Aqueous buffers are used to produce solutions
ity, the suspensions should be subjected to an over a wide range of pH values with constant
occasional shaking to check dispersability. levels of drug, cosolvent, and ionic strength.
When analyzing the suspension data, drug solu¬ Since most solution pharmaceuticals are in¬
bility at the same temperature and pH may sug¬ tended for parenteral routes of administration,
gest that only drug in solution is undergoing this initial pH-rate study should be conducted at
decomposition. a constant ionic strength that is compatible with
physiologic media. The ionic strength (/a) of an
isotonic 0.9% sodium chloride solution is 0.15,
Solution Stability and several compendia contain recipes for iso¬
The primary objective of this phase of prefor¬ tonic buffer solutions. Ionic sttengthrfdr any
mulation research is identification of conditions new buffer solution may be calculated from the
necessary to form a stable solution. These stud¬ following equation:
ies should include the effects of pH, ionic
strength, ^sdlventThght, temperature, and oxy- ti = i Sm.Z,2 (18)
gen.
—Solution stability investigations usually com¬ where m, is the molar concentration of the ion,
mence with probing experiments to confirm which has valence Z,.-Note that all ionic species
decay at the extremes of pH and temperature (even the drug molecules) in the buffer solution
p Q1NHC1 water and O.lfVNaOH all at must be considered in computing ionic strength.
90°C). These intentionally degraded Samples Table 8-6 illustrates a comprehensive account-

Table 8-6. Comprehensive Accounting of Buffer Speciesa in Constant Ionic Strength (p. = 0.5) Solu¬
tions Used to Generate a pH-Rate Profile for Ampicillin

Total Total
pH Citrateb H3A x H2A~ X HA- x A" x Phosphatec H3P04 x H2POi x HP04= x bobs*
Obs. Required x 102 102 102 102 I02 x 102 102 102 10s 10s hr"'

2.05 2.0d 9.90 9.19 0.72 _ _ 0.20 0.09 0.10 _ 58.85.

2.34 2.4 9.40 7.87 1.53 — — 1.20 0.32 0.88 — 56.02
2.55 2.6 8.90 6.79 2.10 0.01 — 2.18 0.41 1.77 — 52.97
2.96 3.0 7.94 4.42 3.45 0.06 — 4.11 0.34 3.76 — 42.77
3.56 3.6 6.78 1.65 5.09 0.12 — 6.44 0.14 6.29 — 24.73
3.91 4.0 6.14 0.70 4.62 0.82 — 7.71 0.06 7.64 0.01 15.34
4.48 4.6 5.32 0.35 2.92 2.05 — 9.35 0.02 9.25 0.07 7.65
4.67 4.8 5.07 0.05 2.39 2.61 0.06 9.86 0.01 9.72 0.12 6.43
4.91 5.0 4.85 0.02 1.69 3.01 0.11 10.30 — 10.10 0.10 5.3V
5.31 5.4 4.42 0.01 0.75 3.34 0.32 11.15 — 10.62 0.53 5.53
5.71 5.8 3.95 0.01 0.26 2.97 0.71 12.09 — 10.74 1.35 6:80
5.86 6.0 3.68 — 0.19 2.52 0.96 12.63 — 10.53 2.10 11.23
6.25 6.4 3.07 — 0.07 2.68 0.32 13.85 — 9.25 4.62 13.61
6.44 6.6 2.72 — 0.05 1.07 1.63 14.55 — 8.11 6.44 17.79
6.85 7.0 1.76 — 0.01 0.37 1.39 16.47 — 5.50 10.97 26.81
7.19 7.2 1.30 — — 0.18 1.11 17.39 — 4.18 13.20 31.32
7.55 7.6 0.63 — — 0.04 0.59 18.73 — 2.10 16.63 32.79
7.94 8.0 0.27 — — 0.01 0.26 19.45 — 0.93 18.52 -53.78

"The Buffers were made from Mcllvaine, T.C.: J. Biochem., 49.183, 1921, and all citrate and phosphate ions are concentrations in
moles/L. *The ionization constants of citric acid and citrate ions at 35° are pK, = 3.11, pK2 = 4.75; pK3 = 6.42, from Bates, R.G., and
Pinching, G.D.; J. Am. Chem. Soc., 71:2374, 1949. 'The ionization constants of phosphoric acid and phosphate at 35° (ji = 0.5) are
pKj = 1.96; pK2 = 6.70, from Schwartz, M.A., Granatek, A.P., and Buckwalter, F.H , J. Pharm. Sci., 51:523, 1962. dThe buffer was made
by mixing 990 ml of 0.1 M citric acid with 10 ml of 0.2 M Na2HP04 to make a liter.
From Hou, J.P., and Poole, J.W.: J. Pharm. Sci., 58:447, 1969. Reproduced with permission of the copyright owner, the American
Pharmaceutical Association.

PREFORMULATION * 191
 ing of buffer molecules in constant ionic
strength solutions, which were used by Hou and
Poole in generating a pH-rate profile for ampicil-
lin.56
Cosolvents may be needed to achieve drug
concentrations that are necessary for analytic
sensitivity, or to produce a defined initial condi¬
tion-. Cosolvents selected from the alcohol family
could prove beneficial, as most pharmaceutical
solvents contain hydroxy groups. If several
cosolvent levels are used to prepare these initial
samples, then the apparent decay rates may vary
linearly with the reciprocal of the resulting solu¬
tion dielectric constant.57 The apparent pH of a
buffer solution also varies, owing to the presence
of cosolvent.
Once the stability solutions are prepared, ali¬
quots are placed ih flint glass ampules, flame-
sealed to prevent evaporation, and stored at con¬
stant temperatures not exceeding the boiling
point of the most volatile cosolvent or its azeo¬
trope. Some of the ampules may be stored at a
variety of temperatures to provide data for calcu¬
lating activation energies.
Some of these solution samples should be sub¬
jected to a light stability test, which includes FIG. 8-22. The pH-rate profiles for ampicillin degrada¬
protective packaging in amber and yellow-green tion in solution at 35°C and constant ionic strength
O = 0.5). Dotted line is the apparent rate profile in the
glass containers. 8 Control samples for this light
presence of buffer, while the solid line is the theoretic rate
test may be stored in cardboard packages or profile at zero buffer concentration. (From Hoit, J. P., and
wrapped in aluminum foil. Poole, J. W.:J. Pharm. Sci., 58:447, 1969. Reproduced with
Given that the potential for oxidation is ini¬ permission of the copyright owner.).
tially unknown, some of the solution samples
should also be subjected to further testing
with an excessive headspace of oxygen, stant versus the reciprocal of the absolute tem¬
Y^Twith a headspace of an inert gas such as he¬ perature at which each particular buffer solution
lium or nitrogen, with an inorganic antioxi¬ was stored during the stability n-st. To justify
dant such as sodium metabisulfite, andc(47 with extrapolation to “use” conditions, stability stor¬
an organic antioxidant such as butylated hy- age temperatures should be selected that incre¬
droxytoluene-BHT. Headspace composition can mentally (At ~ 10°C) approach the anticipated
be controlled if the samples are stored in vials for “use” temperature. If this relationship is linear,
injection that are capped with Teflon-coated one may assume a constant decay mechanism
rubber stoppers. After penetrating the stoppers over this temperature range and calculate an
with needles, the headspace is flooded with the activation energy (Ea) from the slope (-Ea/R) of
desired atmosphere, and the resulting needle the line described by:
holes are sealed with wax to prevent degassing.
To generate a pH-rate profile, stability data In k = ^ (y) + C (19)
generated at each pH and temperature condition
are analyzed kinetically to yield the apparent
decay rate constants. All of the rate constants at where C is a constant of integration and R is the
a single temperature are then plotted as a func¬ gas constant.
tion of pH as shown in Figure 8-22. The mini¬ A broken or nonlinear Arrhenius plot suggests
mum in this curve is the pH of maximum stabil¬ a change in the rate-limiting step of the reaction
ity. Often, this plot, as it approaches its limits, or a change in decay mechanism, thus making
provides insight into the molecular involvement extrapolation unreliable. In a solution-state oxi¬
of hydrogen or hydroxide ions in the decay dation reaction, for example, the apparent decay
mechanism.59 rate constant decreases with elevation of tem¬
An Arrhenius plot is constructed by plotting perature because the solubility of oxygen in
the logarithm of the apparent decay rate con- water decreases. At elevated temperatures, ex-

192 • The Theory and Practice of Industrial Pharmacy

cipients or buffers may also degrade to give decay product(s) appearance, and to establish a
products that are incompatible with the drug room-temperature shelf-life for the drug candi¬
under study. Often, inspection of the HPLC date.
chromatograms for decay products confirms a To study the many possible solid state reac¬
change in the decay mechanism. tions, one may need more than a specific assay
Shelf-life (t10%) for a drug at “use” conditions for the intact compound. Polymorphic changes,
may be calculated from the appropriate kinetic for example, are usually detected by differential
equation, and the decay rate constant obtained scanning calorimetry or quantitative infrared
from the Arrhenius plot. For a first-order decay analysis (IR). In the case of surface discoloration
process, shelf-life is computed from: due to oxidation or reaction with excipients, sur¬
face reflectance measurements on tristimulus or
_ -In 0.90 _ 0.105 diffuse reflectance equipment may be more sen¬
(20) sitive than HPLC assay. In any event, additional
. kj k,
samples are required in the solid state stability
where t10% is the time for 10% decay to occur study to accommodate these additional tests.
with apparent first-order decay constant kj. Fre¬ To determine the solid state stability profile of
quently, it is useful to present the pH-rate pro¬ a new compound, weighed samples are placed in
file as a plot of pH versus t10% shelf-life data. open screw cap vials and are exposed directly to
Results of these initial solution stability stud¬ a variety of temperatures, humidities, and light
ies dictate the subsequent course of action. If intensities for up to 12 weeks (Fig. 8-23). Sam¬
the compound is sufficiently stable, liquid for¬ ples usually consist of three 5- to 10-mg weighed
mulation development may commence at once. samples at each data point for HPLC analysis
If the compound is unstable, then further inves¬ and approximately 10 to 50 mg of sample for
tigations may be necessary. polymorph evaluation by DSC and IR (~2 mg in
KBr and —20 mg in Nujol). To test for surface
oxidation, samples are stored in large (25-ml)
vials for injection capped with a Teflon-lined
Solid State Stability rubber stopper and the headspace flooded with
The primary objectives of this investigation dry oxygen. To confirm that the decay observed
are identification of stable storage conditions for is due solely to oxygen rather than to reduced
drug in the solid state and identification of com¬ humidity, a second set of vials should be tested
patible excipients for a formulation. Contrary to in which the atmosphere is flooded with dry ni¬
the earlier solution stability profile, these solid trogen. After a fixed exposure time, these sam¬
state studies may be severely affected by ples are removed and analyzed by multiple
changeslrTpuritv and crystallinity, whidhoften
result from process improvements.60 Repetitive
testing of the initial bulk lot in parallel with
newer bulk lots should be expected, and ade¬
quate material should be set aside for these Storage Condition 4 Weeks 8 Weeks 12 Weeks
studies. 5°C—Refrigerator
In general, solid state reactions are much 22°C—Room Temperature
slower and more difficult to interpret than solu¬ 37°C—Ambient Humidity
tion state reactions, owing to a reduced number 37°C/75% R.H.
of molecular contacts between drug and excipi¬ Light Box
ent molecules and to the occurrence of multiple- Clear Glass
phase reactions.61,62 A kinetic analysis of slow Amber Glass •
solid state degradation based on retention of in¬ Yellow-Green Glass
tact drug may fail to quantitate clearly the com¬ No Exposure (Control)
pound’s shelf-life, as assay variation may equal 50°C—Ambient Humidity
or exceed the limited apparent degradation, par¬ —02 Headspace
ticularly at the low temperatures that are critical -N2 Headspace
to establishing a room-temperature shelf-life. 70°C—Ambient Humidity
90°C—Ambient Humidity
Usually, this situation may be corrected on anal¬
ysis of the appearance of decay product(s),
FIG. 8-23. Sample scheme for determining the bulk sta¬
which may total only 1 to 5% of the sample. Ad¬
bility profile for a new drug candidate. At each point, bulk
ditional analytic data from such studies as TLC, drug samples should consist of 3 x 10 mg for HPLC analy¬
fluorescence, or UV/VIS spectroscopy may be sis and a 50-mg sample for polymorph analysis by DSC
required to determine precisely the kinetics of or IR.

PREFORMULATION • 193
methods to check for chemical stability, poly¬ pound with bulk instability at high humidity
morphic changes, and discoloration. should be formulated with anhydrous excipi¬
Once the results of this initial screen are tabu¬ ents. Similarly, the pH of maximum drug stabil¬
lated, the decay process may be analyzed by ei¬ ity should match the pH of an aqueous suspen¬
ther zero-order or first-order kinetics, particu¬ sion or solution of the drug and excipient.
larly if the amount of decay is less than 15 to A list of the most common excipients is cre¬
20%. The same kinetic order should be used to ated along with the hypothetic formulations uti¬
analyze the data at each temperature if possible. lizing these excipients. Usually, the approxi¬
Samples exposed to oxygen, light, and humidity mate dose of the drug is known; thus, each
may suggest the need for a followup stability test excipient can be blended with the drug at levels
at three or more levels of a given parameter for that are realistic with respect to a final dosage
full quantitation of its involvement. form (e.g., 10:1 drug to disintegrant and 1:1
In the event that humidity is not a factor in drug to filler such as lactose). Each blend is then
drug stability, an Arrhenius plot may be con¬ divided into weighed aliquots, which are tested
structed; if linear, it may be extrapolated to for stability at some elevated temperature (50°C)
“use” conditions for predicting a shelf-life. If that is lower than the melting point of the in¬
humidity directly affects drug stability, the con¬ gredients. Early inspection (AT ~ 2 days) of
centration of water in the atmosphere may be these stability samples may allow culling of
determined from the relative humidity and tem¬ those samples with a phase change and allow for
perature by using psychrometric charts.63 Sta¬ retesting at a lower temperature. If possible, pel¬
bility data obtained at various humidities may be lets should be formed from the drug excipient
linearized with respect to moisture using the fol¬ blends to increase drug-excipient contact and
lowing apparent decay rate constant: accelerate testing.
In addition to excipient compatibility testing,
■ ko (21) small batches of hypothetic capsule or tablet for¬
mulations (2 or more) should be prepared and
where [gpl] is the concentration of water in the tested in the same stability protocol to check for
atmosphere in units of grams of water per liter of possible incompatibilities arising from a multi-
dry air, and ko is the decay rate constant at zero component formulation.
relative humidity. For example, a 75% relative Solid formulations often require granulation
humidity atmosphere at 37°C is equivalent to of the drug excipient blend to improve flow, den¬
0.0405 grams of water per liter (gpl) of dry air. sity, or homogeneity. Stability during the granu¬
When the effect of moisture on chemical stabil¬ lation process may be checked by excessive wet
ity is examined in detail, a comparison to solu¬ down and drying (in a 50°C forced air oven for
tion state stability and hygroscopicity data may 48 hours) of samples of the unformulated bulk,
suggest an aqueous reaction occurring in the excipient-drug blends and the hypothetic formu¬
drug-saturated water layer on the crystal sur¬ lations. These wet downs should utilize only
face. pharmaceutically acceptable solvents with and
Another useful relationship for analyzing solid without such approved binders as methylcellu-
state stability data assumes that a compound lose and polyvinylpyrrolidone. Often, the list of
must partially liquefy prior to decomposition. granulating solvents may be reduced after the
Given that the mole fraction of the solid that has drug’s solubility profile is considered. Besides
liquefied (Fm) is directly proportional to its decay chemical stability, the unformulated bulk sam¬
rate, then: ples exposed to each granulation solvent should
be checked for crystallinity, polymorph conver¬
1_ 1 sion, and solvate formation, all of which could
In kapp a In Fm =-p- (22)
LT T„ . severely alter dissolution or bioavailability.

where AHfus is the molar heat of fusion, Tm is

the absolute melting point (°kelvin), T is the ab¬ Formulation Recommendation
solute temperature of the stability study, and R Upon completion of the preformulation evalu¬
is the gas constant. ation of a new drug candidate, it is recom¬
Once bulk drug stability has been determined, mended that a comprehensive report be pre¬
compatibility with excipients commonly used to pared highlighting the pharmaceutical problems
produce solid dosage forms must be established. associated with this molecule. This report
The number of excipients may be reduced by should conclude with recommendations for de¬
considering the results of the solid state and so¬ veloping phase I formulations. These reports are
lution stability profiles. For example, a com¬ extremely important in preparing regulatory

1P4 • The Theory and Practice of Industrial Pharmacy

documents and aid in developing subsequent 26. Hiestand, E.N., et al.: J. Pharm. Sci., 62:1513,
drug candidates. 1973.
27. Hiestand, E.N., and Peot, C.B.: J. Pharm. Sci.,
63:605, 1974.
28. Hiestand, E.N., and Wells, J.E.: Proc. Intern. Powder
Acknowledgments
and Bulk Solids Handling and Processing Conf.,
The authors wish to thank Ms. D.M. Johnson, Rosemont, IL, 1977. Industrial and Scientific Confer¬
Ms. G. Mazzella, Mr. C.J. Kenney, Ms. N.M. ence Management, Inc., Chicago, 1977.
Ursitti, and Ms. L.E. Whitaker of Pfizer Central 29. Streng, W.H., et al.: J. Pharm. Sci., 73:1679, 1984.
30. Kaplan, S.A.: Drug. Metab. Rev., 1:15, 1972.
Research for their assistance in preparing this
31. Christensen, J.J., Hansen, L.D., and Izatt, R.M.:
chapter. Also, the editorial comments of the fol¬ Handbook of Proton Ionization Heats and Related
lowing individuals were greatly appreciated: Thermodynamic Quantities. John Wiley and Sons,
Dr. A.J. Aguiar (Pfizer, Inc.), Dr. D.L. Casey New York, 1976.
(Baxter Travenol), Dr. D.S. Dresback (Pfizer, 32. Albert, A., and Serjeant, E.P.: Ionization Constants of
Inc.), Dr. R.A. Upper (Bristol Laboratories), and Acids and Bases. Methuen, London, 1962.
33. Osol, A. (Ed.): Remington’s Pharmaceutical Science.
Dr. J.S. Turi (Boehringer Ingelheim Ltd.).
16th Ed. Mack Publishing, Easton, PA, 1980,
Chap. 16.
34. Martin, A., Swarbrick, J., and Cammarata, A.: Physi¬
References cal Pharmacy: Physical Chemical Principles in the
1. Berge, S.M., Bighley, L.D., and Monkhouse, D.C.: Pharmaceutical Sciences. 3rd ed. Lea and Febiger,
J. Pharm. Sci., 66:1, 1977. Philadelphia, 1983.
2. Higuchi, T., and Stella, V.: Prodrugs as Novel Drug 35. Kielland, J.: J. Amer. Chem. Soc., 59:1675, 1937.
Delivery Systems. American Chemical Society, 36. Kramer, S.F., and Flynn, G.L.: J. Pharm. Sci.,
Washington, DC, 1975. 61:1897, 1972.
3. Roche, E.B.: Design of Biopharmaceutical Properties 37. Bogardus, J.B., and Backwood, R.K.: J. Pharm. Sci.,
Through Prodrugs and Analogs. American Pharma¬ 68:188, 1979.
ceutical Association, Washington, DC, 1977. 38. Miyazaki, M., et al.: Chem. Pharm. Bull., 23:1197,
4. DiSanto, A.R., et al.: J. Clin. Pharmacol., 20:437, 1975.
1980. 39. Williams, N.A., and Amidon, G.L.: J. Pharm. Sci.,
5. Yakatan, G.J., et al.: J. Clin. Pharmacol., 20:625, 73.T8, 1984.
1980. 40. Hagen, T.A.: Ph.D. Thesis. University of Michigan,
6. Amidon, G.L., Leesman, G.D., and Elliott, R.L.: Ann Arbor, MI, 1979.
J. Pharm. Sci., 69:1363, 1980. 41. Mulley, B.A.: Solubility in systems containing sur¬
7. Haleblian, J.K.: J. Pharm. Sci., 64:1269, 1975. face-active agents. In Advances in Pharmaceutical
8. Poole, J., et al.: Curr. Ther. Res., 10:292, 1968. Sciences. Vol. 1. Edited by H.S. Bean, A.H. Beckett,
9. Aguiar, A.J., et al.: J. Pharm. Sci., 56:847, 1967. and J.E. Carless. Academic Press, London, 1964,
10. Aguiar, A.J., and Zelrher, J.E.: J. Pharm. Sci., 58:983, p. 87.
1969. 42. Higuchi, T., et al.: J. Am. Pharm. Assoc., Sci. Ed.,
11. Haleblian, J., and McCrone, W.: J. Pharm. Sci., 43:349, 1954.
58:911, 1969. 43. Hansch, C., and Dunn, W.J.: J. Pharm. Sci., 61:1,
12. Brennan, W.P., et al.: Purity Determinations by Ther¬ 1972.
mal Methods. ASTM STP 838. Edited by R.L. Blaine 44. Dressman, J.B., Fleisher, D., and Amidon, G.L.:
and C.K. Schoff. American Society for Testing and J. Pharm. Sci., 73:1274, 1984.
Materials, Philadelphia, 1984, p. 5. 45. Suzuki, A., Higuchi, W.I., and Ho, N.F.: J. Pharm.
13. Guillory, J.K.: J. Pharm. Sci., 61:26, 1972. Sci., 59:644, 1970.
14. Allen, P.V., et al.: J. Pharm. Sci., 67:1087, 1978. 46. Wurster, D.E., and Taylor, P.W.; J. Pharm. Sci.,
15. Jacobson, H., and Reier, G.: J. Pharm. Sci., 58:631, 54:169, 1965.
1969. 47. Hamlin, W.E., et al.: J. Pharm. Sci., 54:1651, 1965.
16. El-Shattawy, H.H.: Drug Dev. Ind. Pharm., 7:605, 48. Wood, J.H., et al.: J. Pharm. Sci., 54:1068, 1965.
1981. 49. Mooney, K.G., et al.: J. Pharm. Sci., 70:13, 1981.
17. Shibata, M„ et al.: J. Pharm. Sci., 72:1436, 1983. 50. Mooney, K.G., et al.: J. Pharm. Sci., 70:22, 1981.
18. Van Campen, L., Amidon, G.E., and Zografi, G.: 51. Hixson, A., and Crowell, J.: Ind. Eng. Chem., 23:923,
J. Pharm. Sci., 72.T381, 1983. 1931.
19. Weast, R.C.: CRC Handbook of Chemistry and Phys¬ 52. Carstensen, J.T.: J. Pharm. Sci., 63:1, 1974.
ics. 55th Ed. CRC Press, Cleveland, 1974, p. E-46. 53. Bym, S.R.: Solid-State Chemistry of Drugs. Academic
20. Kaye, B.H.: Chemical Analysis: Direct Characteriza¬ Press, New York, 1982.
tion of Fine Particles. Vol. 61. John Wiley and Sons, 54. Mollica, J.A., Ahuja, S., and Cohen, J.: J. Pharm. Sci.,
New York, 1981. 67:443, 1978.
21. Kaye, B.H.: Private communication. 55. Connors, K.A., Amidon, G.L., and Kennon, L.: Chem¬
22. York, P.: Intern. J. Pharm., 6:89, 1980. ical Stability of Pharmaceuticals. John Wiley and
23. Jones, T.M., and Pilpel, N.: J. Pharm. Pharmacol., Sons, New York, 1979.
18:429, 1966. 56. Hou, J.P., and Poole, J.W.: J. Pharm. Sci., 58:447,
24. Gold, G., et al.: J. Pharm. Sci., 55:1291, 1966. 1969.
25. Sutton, H.M.: Characterization of Powder Surfaces, 57. Graham, R.E., Biehl, E.R., and Kenner, C.T.:
Academic Press, London, 1976, p. 1, 7, 158. J. Pharm. Sci., 65:1048, 1976.

PREFORMULATION >195
58. Lachman, L., Swartz, C.J., and Cooper, J.: J. Am. 61. Carstensen, J.T., Osadca, M., and Rubin, S.H.:
Pharm. Assoc., Set. Ed., 49:213, 1960. J. Pharm. Sci., 58:549, 1969.
59. March, J.: Advanced Organic Chemistry: Reactions, 62. Bym, S.R.: J. Pharm. Sci., 65:1, 1976.
Mechanisms, and Structure. McGraw-Hill, New 63. Perry, R.H., and Chilton, C.H.: Chemical Engineers’
York, 1968, p. 199. Handbook. 5th Ed. McGraw-Hill, New York, 1973,
60. Pikal, M.J., et al.: J. Pharm. Sci., 67:767, 1978. p. 20.

196 • The Theory and Practice of Industrial Pharmacy

 9
Biopharmaceutics
K. C. KWAN, M. R. DOBRINSKA, J. D. ROGERS, A. E. TILL, and K. C. YEH

Biopharmaceutics is the study of physiologic , evaluation of drug dosage forms is illustrated.

and pharmaceutical factors influencing drug re¬ Other texts and monographs should be con¬
lease and absorption from dosage forms.1 sulted for historical perspective and more exten¬
Whereas physicochemical properties of the drug sive treatments of these topics.2-32
(and excipients) dictate the rate of drug release
from the dosage form and the subsequent trans¬
port across biologic membranes, physiologic and Pharmacokinetics
biochemical realities determine its fate in the
The primary goals of pharmacokinetics are to
body. The optimal delivery of the active moiety
quantify drug absorption, distribution, biotrans¬
to the site of action depends on an understand¬
formation, and excretion in the intact, living
ing of specific interactions between the formula¬
animal or man; and to use this information to
tion variables and the biologic variables. In drug
predict the effect of alterations in the dose, dos¬
product development, it is invariably an iterative
age regimen, route of administration, and physi¬
process whereby the pharmaceutical or the bio¬
ologic state on drug accumulation and disposi¬
logic system is systematically perturbed to yield
tion. The pharmacokinetics of a drug can be
specific information concerning the effect of one
deduced by studying the time courses of
on the other.
changes in drug or metabolite concentrations in
Whereas physicochemical parameters of the
body fluids. The drug concentration in plasma or
drug and the dosage form can be accurately and
urine at any time after the administration of a
precisely measured in vitro, meaningful quanti¬
known dose or dosage regimen is the net result
tative estimates of drug absorption can be ob¬
of its absorption, distribution, biotransformation
tained only through appropriate experiments in
(metabolism) and excretion. The task, therefore,
vivo. Pharmacokinetic techniques provide the
is to resolve the observed kinetic profiles into
means by which the processes of drug absorp¬
their component parts. The contribution of ab¬
tion, distribution, biotransformation, and ex¬
sorption, distribution, biotransformation, and
cretion are quantified in the intact organism
excretion can be individually isolated by appro¬
(animal or man). Equally important, pharmaco¬
priate experimental design and kinetic analysis
kinetic inferences can aid in the formation of
of the data, often with the aid of models. Quanti¬
test hypotheses and in the design of experi¬
tation is then achieved by maintaining material
ments. Alternative hypotheses can be examined
balance at all times.
in abstraction or through simulation to focus on
Drug disposition refers to events that occur
experiments that are necessary rather than
subsequent to absorption, whereas elimination
those that are simply data-gathering exercises.
refers to the irreversible loss of a drug from the
In this way, experiments with marginal informa¬
body by metabolism and excretion.
tional content can be deferred or eliminated.
In this chapter, the basic pharmacokinetic
concepts and techniques are reviewed; the phys¬
icochemical and biologic factors that influence Disposition
drug absorption, elimination, and accumulation Following an intravenous dose, plasma con¬
are discussed; and finally, the specific applica¬ centrations of a drug often decline exponentially
tion of these general principles to the design and with time. Such behavior suggests that the ki-

197
 DOSE

(U)

FIG. 9-1. One-compartment, open model. (See text for def¬

inition of symbols.)

netics of drug disposition may be described by

one or more first-order processes.

Elimination

A model consistent with monoexponential

decay in plasma levels is depicted in Figure 9-1.
This is the so-called one-compartment, open
model, in which Cj is plasma concentration, VV FIG. 9-2. A semilogarithmic plot of plasma concentration
is the apparent volume of distribution, k10 is the (C,) vs. time (t) for a one-compartment model.
overall elimination rate constant, fr is the frac¬
tion of the dose that is excreted in the urine un¬
changed, fm is the fraction metabolized, and fx is
the fraction eliminated by all other routes, e.g.,
bile. The rate of change in C, is therefore: rocal time. As such, its numerical value denotes
the fractional (or percentage) loss from the body
per unit time. For example, k10 = 0.25 hr-1 sig¬
dCj _ 1. p
(i) nifies that the instantaneous rate of elimination
dt kl°Ll
is 25% per hour.
The plasma half-life, t4, is the time required
which upon integration yields:
for a given plasma concentration to be halved.
For systems undergoing monoexponential
Cj = Ci(0)e_^lot
decay, q is a constant, independent of plasma
— _5Lp-kiot
concentration. Figure 9-2 shows a graphic solu¬
(2) tion for t*. Alternatively, it can be evaluated by
v,e
substituting D/2Vi for Cj in equation (3),
At time zero, i.e., t = 0, the plasma concentra¬ whereby:
tion C^O) is equal to the dose D divided by the
volume of distribution Vj. 2.303 log 2 0.693
Experimentally, a semilogarithmic plot of C2 —k—~= ~v~ (i
versus t is a straight line, as shown in Figure
9-2. Model parameters k10 and Vj can be calcu¬ The plasma half-life of a drug is inversely pro¬
lated from its slope and intercept, respectively. portional to its elimination rate constant.
Thus: Urinary Excretion. The rate expression for
urinary excretion, of unchanged drug according
to the model in Figure 9-1 is given by:
log C, - log (-2-) - (3)

= frkjoVA (5)
The volume of distribution is useful in relat¬
ing plasma concentration to the amount of drug
in the body at a given time; it is expressed in where U is the cumulative amount of drug ex¬
units of volume. Thus, the product of V4 and creted in urine to time t. The time course of uri¬
CjCt) is the amount of drug in the body at time t. nary excretion is obtained by integrating equa¬
The elimination rate constant has units of recip¬ tion (5) and substituting Cj from equation (2),

I
198 - The Theory and Practice of Industrial Pharmacy
 that is: mentally, fr can be obtained by the ratio of U(°°)
to D.
Clearance. According to equation (6), the
U(t) = frk10V1 fcjdt cumulative amount excreted in the urine to time
Jo
t is proportional to the area under the plasma
= frD(l - e~kl0t) (6) concentration curve from 0 to t. This relation¬
ship holds for all times such that the amount
The amount of drug ultimately recovered in the excreted over any interval between tj and t2 is
urine unchanged is obtained by evaluating also proportional to the corresponding area over
equation (6) at t = »: the same interval. In other words:

U(oo) = frD (7)

Cjdt (9)
The time course of urinary excretion is a mono¬
exponential that approaches U(<») asymptoti¬
cally. Its shape is, in fact, a mirror image of the Cjdt (10)
plasma concentration profile. Equation (6) can
be rearranged to show that:
f12
Ufe) i Cidt (ID
U(°°) - U(t)
log (8)
U(») The proportionality constant relating plasma
concentration and urinary excretion of a drug is
Thus, a semilogarithmic plot of the fractional
known as its plasma renal clearance rate, CLr, or
amount remaining to be excreted as a function
simply renal clearance.
of time should be a straight line with a slope
identical to that shown in Figure 9-2 for plasma
decay. Figure 9-3 is sometimes referred to as the U(ts) ~ U(ti)
CLr = frk10Vj f te (12)
deficit plot, or sigma-minus plot; it or equation
Cjdt
(8) can be used to estimate the overall elimina¬ A.
tion rate constant, k10, from urine data. The rate
constant for urinary excretion is frki0. Experi- Similarly, blood or serum renal clearance rates
would apply to situations in which drug concen¬
trations are measured in blood or serum. Ex¬
u»-ut plicit reference to blood, plasma, or serum is
u® usually unnecessary, except for emphasis or for
contrasting results from different experiments.
The renal clearance of a substance is the prod¬
uct of its urinary excretion rate constant, frk10,
and its volume of distribution, Vj. Dimension-
ally, CLr has units of volume per unit time, e.g.,
ml/min. Physiologically, the renal clearance rate
represents that volume of plasma from which
drug is completely eliminated per unit time as a
result of passage through the kidneys. A sche¬
matic illustration of this phenomenon is shown
in Figure 9-4, in which the density of shaded
areas denotes plasma concentrations before and

VOLUME OF
PLASMA CLEARED
OF DRUG

FIG. 9-3. Deficit plot, or sigma-minus plot, of the fraction

of drug remaining to be excreted in the urine vs. time. FIG. 9-4. Schematic illustration of renal clearance.

BIOPHARMACEUTICS • 199
 AUC*, may be obtained as the integral of equa¬
tion (2) evaluated from time zero to infinity, i.e.,
-j—~~—, or by suitable interpolation and extrapo-

lation techniques.32,33
The clearance concept applies to any body
organ or tissue capable of eliminating a drug.
For example, hepatic clearance refers to the rate
of elimination resulting from passage through
the liver, while biliary clearance refers to that
part of hepatic clearance that is due to excretion
in bile. Unlike measurement of renal clearance,
however, their direct experimental determina¬
tion in the intact animal or person is difficult,
and in some cases, impossible. Nevertheless,
insights concerning their contribution are often
obtained through pharmacokinetic inferences.
The overall elimination of a drug from the
body is composed of fractions that are excreted
in urine, metabolized, and eliminated by all
other means such that fr + fm + fx = 1.0. Since
renal clearance can be represented by frki0Vi,
the total clearance rate from plasma is k10Vi.
Multiplying both sides of equation (1) by Vj
yields:
FIG. 9-5. Graphic representation of renal clearance calcu¬
lation. The shaded areas represent a typical area under
the plasma concentration curve and the corresponding
amount of drug excreted in the urine.
~Vi^r=kioV)Ci = CLCi (15)

where CL is the total plasma clearance rate, or

simply plasma clearance. Equation (15) states
that CL is the proportionality constant relating
after passage through the kidneys (or any other the overall elimination rate and plasma concen¬
clearing organ). The clear zone represents a vol¬ tration at any time. Integrating equation (15)
ume that is completely devoid of drug. Experi¬ with respect to time:
mentally, the renal clearance of a substance can
be determined by dividing the amount of drug VjCj(O) - VA(t) = CL f C3dt (16)
present in a timed urine sample by the corre¬ Jo
sponding area under the plasma concentration
curve, as shown in equation (12). This is de¬ Inasmuch as V A(0) is the administered dose D
picted graphically in Figure 9-5. and V A(t) is the amount of drug in the body at
The numerical value of renal clearance can be time t, the left-hand side of equation (16) repre¬
applied in various ways. For example, a combi¬ sents the amount of drug already eliminated at t.
nation of equations (5) and (12), indicates that In other words, the product of plasma clearance
the rate of urinary excretion at any instance is and the cumulative area under the plasma con¬
equal to the product of renal clearance and the centration curve at t is equal to elimination by all
plasma concentration at that time: routes to that time:

Total amount eliminated at t = CL I Cjdt

~ = CLA (13) ■'0
(17)
In the absence of total urinary collection, U(®>),
When t = oo, C1(«=) = 0; therefore:
and therefore fr, can be estimated indirectly
from the product of CLr and the total area under
D = CL • AUC« (18)
the plasma concentration curve, AUC*:

Ultimately, elimination by all routes accounts

U(oo) = frk10Vi = CLrAUC„ (14) for the amount administered.

200 • The Theory and Practice of Industrial Pharmacy

 The experimental determination of plasma DOSE
I
clearance can be accomplished in various ways
following an intravenous dose. Given a reasona¬
bly complete set of plasma concentration data,
CL can be estimated by the ratio of D to AUC„ or fx kto
by the product of k10 and Vj obtained from the
C, V, f mkio
cr vr
slope and intercept in Figure 9-2. Given com¬
plete urine collection and an estimate of renal frkio kio
clearance, CL can also be calculated by:

or _ CLt _ CLrD FIG. 9-6. Disposition of drug and metabolite according to

(19) a one-compartment model for each.
fr U(»)

In summary, clearance is a proportionality con¬ notes plasma concentration, volume of distribu¬

stant that relates plasma concentration of a sub¬ tion, and elimination rate constant of the metab¬
stance to its elimination rate. It serves the same olite. The total area under the metabolite
purpose in relating area under the plasma con¬ concentration curve is therefore:
centration curve to the amount eliminated.
Plasma clearance can be readily determined f“ C?dt = -4_.
M (22)
from plasma concentration and urinary excre¬ Jo K10V1
tion data following an intravenous dose. Renal
clearance can be estimated directly from any The rate expression for metabolite concentra¬
conveniently timed plasma and urine sample tions in plasma following an intravenous dose D
irrespective of the mode of administration. of drug is:
The difference between plasma and renal
clearance is clearance by other routes;
-Sg- = fmk1(A - kfoCf ’ (23)

CLnr = CL - CLr (20)

The asterisk (*) distinguishes metabolite con¬
The dominant component of extrarenal clear¬ centrations following drug administration from
ance, CLnr, is usually biotransformation, al¬ those after metabolite administration. The
though biliary excretion, expiration, or perspira¬ plasma time course of the metabolite following
tion may also contribute. drug administration is obtained by substituting
Metabolism. The metabolic clearance of a Cj from equation (2) into equation (23) and inte¬
drug, CLm, is the sum of all processes that result grating, namely:
in the formation of primary metabolites, m,. If
extrarenal clearance is due solely to biotransfor¬ pm* = fmkloD_rp—kiot _ p _ L-mtl
mation, CLm can be estimated directly from Ll VYWo - k10) 16 6 klot]
equation (20). Otherwise, the contribution of (24)
each primary metabolic path must be examined
independently. The procedure outlined below Equation (24) can be further integrated and re¬
assumes a single metabolite but may be applied arranged to yield:
repeatedly for any specific precursor/successor
pairs. Note, however, that secondary or tertiary
metabolite formation has no impact on the meta¬ fmD = kr0\T Pcfdt (25)
Jo
bolic clearance rate of the parent drug.
Figure 9-6 depicts a situation where drug and
The left-hand side of equation (25) is the
metabolite disposition can each be described by
amount of metabolite formed, whereas the right-
a one-compartment open model. Thus, following
hand side is the amount of metabolite ultimately
an intravenous dose M of the metabolite, its
eliminated from the body. The plasma clearance
plasma concentrations decline monoexponen-
of metabolite, k'/JjV™. can be obtained from equa¬
tially with time:
tion (22) following an intravenous dose M of the
metabolite.
An alternative view of the same situation is
Cf = ^re - kf0t (21)
obtained by combining equations (22) and (25).
The fractional contribution of a specific meta¬
where the superscript m on C], V1; and k10 de¬ bolic pathway to the plasma clearance of a drug

BIOPHARMACEUTICS *201
is given by the dose normalized ratio of total
areas under the metabolite curve following the
intravenous administration of drug D and me¬
tabolite M, namely:

, AUC™*/D
(26)
™ AUC27M

By analogy to renal clearance:

CLm = fmCL (27)

A potential source of error occurs when the

metabolite formed undergoes further biotrans¬
formation before reaching the general circula¬
tion. This phenomenon, known as sequential
metabolism,34 causes an underestimation of the
area term in equation (25), and hence the
amount formed.

Distribution
Drug distribution is a reversible process. The
rates of exchange between plasma and tissues FIG. 9-7. Semilogarithmic plot of plasma concentration
(Cj) vs. time for a two-compartment model.
vary widely depending on the types of tissue and
the drug’s partition characteristics. With few
exceptions—notably plasma proteins and red
This technique, known as curve stripping, can
blood cells—experimental determination of drug
be repeated as often as necessary and is gener¬
distribution in humans is not feasible. Its mani¬
ally useful in obtaining the eigenvalues (slopes)
festations can be deduced, however, from the
and eigenvectors (intercepts) of a polyexponen¬
plasma concentration profiles. When distribu¬
tial function.
tion is rapid, the body behaves kinetically as a
A pharmacokinetic model consistent with bi¬
single homogeneous pool, and the plasma con¬
exponential decay is shown in Figure 9-8. The
centration time course may be adequately de¬
body is perceived to be divided into two kineti¬
scribed by a single exponential (Fig. 9-2). On the
cally distinct compartments. A central compart¬
other hand, the kinetics of drug disposition often
ment 1, which includes plasma and from which
exhibit multiexponential characteristics. Each
elimination occurs, is linked to a peripheral
additional exponential has been interpreted to
compartment 2 by first-order processes having
represent a group of tissues requiring progres¬
rate constants k12 and k21. Rate expressions ap¬
sively more time in which to achieve a steady
ropos to this model are:
state in drug distribution.
Figure 9-7 is a typical semilogarithmic plot of
biexponential decay corresponding to equation ^ = -k12C] + k21C2 - k1(A (30)
(28).

Cj = Ae-at + Be"*31 (28) DOSE

The profile shows an initial curvature that even¬
tually becomes log-linear with a terminal slope
—/3/2.303. The intercept B is obtained by extrap¬
olation back to time zero. Taking the logarithm
of the difference between plasma concentration
Cj and the value of Be-,3t yields another straight
line from which A and a can be evaluated; that
is:

log[Ci-Be-n=logA-(29)

202 • The Theory and Practice of Industrial Pharmacy

 ;'2_ — ki2Ci bining and rearranging equations (34) through
k2JC2 (31)
l (37).

dU V- - D (40)
= frkjoVA (32)
dt 1 A+ B

where C2 is a hypothetic concentration whose . A + B

(41)
product with V! equals the amount of drug pres¬ kl° A/a + B/0
ent in the peripheral compartment. The rela¬
tionship between the model parameters and the k (42)
experimentally determined slopes (a and /3) and Kai ~ K10
k
intercepts (A and B) is obtained by simultaneous
solution of equations (30) and (31), whereby: — a + p — k10 — k21 (43)

P(k2i a) _at , 0(^21 P) -at Obviously, the distributive process alters not
VK/3 - a) V,(a - fS) only the plasma concentration and urinary ex¬
(33) cretion profiles but also the interpretation of
many of the pharmacokinetic parameters. Nota¬
such that: bly, the terminal slope 0, or the corresponding
titj3 does not reflect the rate of drug elimination
D(k2] - a) from the body; it merely represents the slowest
(34) rate of drug disappearance from plasma. Also,
V,(0 - a)
the volume of distribution V) must be qualified
by reference to the central compartment. The
P .. D(k2i - 0)
(35) product of Vi and Cj is not sufficient to account
Vi(a - P)
for the quantity of drug in the body. The contri¬
bution from the peripheral compartment, i.e.,
(kio + k21 + k12)
VjC2, must be included.
The meaning of clearance remains un¬
+ A/(k]0 + k21 + k12)2 4k21k10 changed, however. Equation (33) can be inte¬
2 grated and rearranged to yield an expression for
plasma clearance, namely:
(36)

(kio + k21 + k12)

2
CL-k“V>-AU t (44)
_ V(kio + k21 + k12)a — 4k21k10 which is identical to that obtained for the one-
compartment open model. AUC„ may be ob¬
2
tained as the integral of equation (28) evaluated
(37)
from time zero to infinity, i.e., — + —, or by in-
The corresponding time courses of change in a 0
the amount of drug in the peripheral compart¬ terpolation and extrapolation techniques. Ac¬
ment and in urine are respectively: cording to equations (32) and (39), the product
of renal clearance and plasma concentration is
the instantaneous rate of urinary excretion,
kl2D -at , Jil2D_
V,C2 = (38) while the product of CIr and AUC„ is the
03 - a) (« - ft amount excreted in urine. Multiplying both
sides of equation (30) by Vj, the rate of drug dis¬
and:
appearance, from plasma is:
't
U = frkinV i C^dt
= kjoVA + k.aVA - kajVA
(/3 k10) (a k10) (45)
(fi-a) (a - 0)
The first term on the right-hand side of equation
(45) represents rate of drug loss from the body;
The model parame m can be evaluated by com- the second and third terms indicate drug distii-

BIOPHARMACEUTICS • 203
 DOSE where AUC* is the total area under the plasma
concentration curve following treatment x. The
estimation of bioavailability requires knowledge
of plasma clearance, which is obtained indepen-
dendy following an intravenous dose. See equa¬
tion (18) for determination of plasma clearance.
At any time t following the administration of a
dose, the amount absorbed, A(t), is equal to the
sum of that which is present in the body, Ab(t),
and that which is already eliminated from the
body. In other words:
FIG. 9-9. Mammillary model representing polyexponen¬
tial decay.
A(t) = Ab(t) + CL f Cidt (47)
•'o

Estimates of Ab(t) depend on how the drug is

bution. Again, this emphasizes the difference distributed in the body. When drug disposition
between drug elimination rate and plasma dis¬ can be adequately described by a one-compart¬
appearance rate except for monoexponential ment open model, Ab(t) = VjCj(t) and the time
decay. The differences in interpretation cited course of absorption is estimated by:
previously apply to all mammillary models (Fig.
9-9) and polyexponential functions.
A(t) = VAO) + k10Vj fcjdt (48)
Absorption
When a drug is not administered directly into This is known as the Wagner-Nelson method of
the vasculature, it must be transported to the estimating absorption.35 V] and k10 can be ob¬
general circulation before it can be counted. In tained following an i.V: dose (see Fig. 9-2).
pharmacokinetics, absorption is defined as the When a two-compartment open model ap¬
amount of drug that reaches the general circula¬ plies, the absorption profile can be constructed
tion unchanged. Hence, that which is metabo¬ from equation (49):
lized or chemically transformed at the site of
application or in transit is by definition not ab¬
sorbed. This definition arises mainly out of ne¬ A(t) = VACO + V]C2(t) + k^v, P C,dt
cessity because of experimental and physiologic Jo
(49)
limitations in quantitating the manifestations of
absorption in the intact animal or human. In
this context, the rate and extent of drug absorp¬ The amount of drug present in the body at any
tion is synonymous with its bioavailability. More time is the sum of the amounts in the central
generally, the term bioavailability may be used and the peripheral compartment. To evaluate
to indicate the delivery of the active moiety from equation (49), some method of estimating C2 is
the site of administration to the target tissue or needed. As a first approximation, Loo and
organ, whereas absorption often refers to the Riegelman proposed that Ci varies linearly with
overall transport of a drug and related sub¬ time between any two adjacent data points,36
stances into the body or parts thereof, e.g., the such that:
eyes or the skin. The more restrictive definitions
of absorption and bioavailability are used Ci(tj) = C^tj-,) + bT (50)
throughout this chapter.
Material balance dictates that total elimina¬ where b is the slope and T is the time between tj
tion must equal the amount absorbed, that is: and tj_! as shown in Figure 9-10. Integrating
equation (50) into equation (31) yields:
Amount absorbed = Amount eliminated

If F is the fraction absorbed following a ^+k21C2 = k12C1(tj-,) + bk12T (51)

nonintravascular dose Dx, then:

FDX = CL • AUCX (46) Integrating equation (51) with respect to T and

204 • The Theory and Practice of Industrial Pharmacy

 Starting at t = 0 when C2(tj_i) = C^t,-,) = 0,
the value of C2(tj) can be estimated sequentially
by the repeated application of equation (56). At
t= no more drug remains in the body, equa¬
tion (49) collapses to equation (46), and A(°°) =
FD as expected. Figure 9-11 is a typical absorp¬
tion profile constructed according to equation
(49) using the Loo-Riegelman approximation of
C2 given in equation (56).
In summary, to estimate the bioavailability of
a drug administered by a nonintravascular
route, knowledge of its plasma clearance is re¬
quired. The plasma clearance in an animal or a
person can be calculated following an intrave¬
nous dose. In essence:

AUC£/DX
(57)
AUCJD

Since AUCX and AUC„ can both be determined

FIG. 9-10. Relationship between two adjacent plasma directly by interpolation and extrapolation of the
concentration data points proposed by Loo and Riegel- terminal slope of the plasma concentration
man.3e
curve to infinity, the estimation of F is model-
independent. In contrast, determinations of the
absorption time course based on compartmental
noting that at T = 0, C2 = C2(tj-i), one obtains: analysis depend not only on plasma clearance
but also on estimates of the volume of distribu¬
tion and the rate constants for drug distribution.
C2 = C2(tj-i)e_k2lT + •pa-C1(tj_1)[l - e_k2lT] These values are obtained by interpreting the
kinetics of drug disposition following an intrave¬
nous dose in reference to specific models.
+ 7^%te-k2lT + k21T-l] (52)

Now define the relationships:

Accumulation
Suppose a drug is administered intravenously
AC, = C,(tj) - C,ft_,) (53) by infusion at a constant rate Ro (amount/time).
Plasma concentration (and the amount of drug
and

At = t, - tj_, (54)

At T = At,

C2 = C2(tj) and b= (55)

The substitution of equations (53), (54), and

(55) into equation (52) results in:

C2(tj) = C^VOe-^

+ - e~^]
*21

k12AC, ■ -fa,At , l. a. _ ]i
t
+ (k21)2At 6 +k2lAt 11
(56) FIG. 9-11. A typical Loo-Riegelman absorption profile.

BIOPHAKMACEUTICS • 205
in the body) would increase with time and ap¬
proach a plateau, which is called a steady state.
At steady state, the rate of input to the body, R0,
equals the rate of drug elimination from the
body, that is:

Ro = CL • Cf (58)

where Cf is the plasma concentration at steady

state. The value of Cf to be attained is propor¬
tional to the infusion rate. Equation (58) is ap¬
plicable to all linear mammillary models of drug
disposition. The rate of approach to steady state
depends on the manifestations of drug distribu¬
tion.
Where the one-compartment, open model (see
Fig. 9-1) applies, the rate of change in drug lev¬
els is given by:

v^-Ro-k«>vA (59)

which, upon integration, yields:

Ci= tVc1
K10vl
~e_kl0t) (6Q) FIG. 9-12. Relationship between plasma half-life and
approach to steady state for a one-compartment model
At t = oo, Ci = Cf. Thus, equation (60) reduces drug.
to equation (58). Subtracting equation (60) from
equation (58), one obtains:

Cf - Ct
= e-kl0t (61) half-life given in equation (4). Similarly, it can
c ss1 be shown that two half-lives would be required
to achieve 75% of steady state, 3.3 half-lives for
or:
90%, 6.6 half-lives for 99%, and so on. This rela¬
tionship between plasma half-life and approach
to steady state is shown in Figure 9-12. Note
that the approach to steady state follows exactly
the same time course as that for drug disappear¬
Therefore, a plot of the left-hand side of equa¬ ance from plasma following an intravenous in¬
tion (62) versus t should be a straight line with jection. For drugs that exhibit polyexponential
slope of -kio/2.303. Equation (62) also indicates decay, the approach to steady state would also be
that the rate of approach to steady state is di¬ polyexponential.
rectly related to the plasma half-life. For exam¬ Consider, for example, the situation whereby
ple, the time required to reach 50% of steady drug disposition can best be described by a two-
state can be determined by setting Ci = Cf/2 in compartment, open model (see Fig. 9-8). Tem¬
equation (62) whereupon: poral changes in plasma concentration attend¬
ant to a constant infusion of a drug are given by:

(63)
or:
C,
Ro
k10V rl1
(fi kio)
03 -a)
-at

(a k10)
2.303 log 2
(64)
(a - p)
At steady state, t = °°, equation (65) also col¬
which is identical to the definition of plasma lapses to equation (58), as it should. Subtracting

206• The Theory and Practice of Industrial Pharmacy

equation (65) from equation (58) one obtains: by:

Cr Ci _ (fi kjo) „t , (a k10) -m

Cf® = -^-(1 + e-klor)e-klot' (69)
Cf (fi -a) (a - 0) vi
(66)
where t' is time from the most recent dose. Simi¬
In this case, the approach to steady state results larly, after the third and subsequent doses, one
from two independent exponential processes, a can calculate:
and j8, each governed by its own half-life, tJ>a
and tJ>/3. The fractional contribution to the ob¬
= -^-(1 + e_kl0T + e-2k,OT)e~kl0t' (70)
served sum is given by the eigenvectors of equa¬ n
tion (66), because of the following relationship:
and:
(fi ~ kio) , (<* ~ kip) _
(67)
(fi “ «) (« - /3)
Cf > = -^-(1 + e-k,0T + e~2kl0T + • • •
M
For each component, times required to reach
_j_ g—(n- l)kioT^g-kiot'
50%, 90%, and 99% of steady state are still 1.0,
3.3, and 6.6 half-lives, respectively. According to = p (i - e~nkl0T)
equations (36) and (37), however, u1/3 is longer (71)
Vj (1 - e-kl0T)
than tim; thus, steady state for the a process
would be attained sooner. Figure 9-13 shows a
As n becomes large, the plasma concentration
biexponential approach to steady state. At all
profiles from one interval to the next become
times, the observed plasma concentration repre¬
indistinguishable. At steady state, n = », the
sents the sum of two processes.
plasma time course is represented by:
A steady state in drug accumulation can also
be achieved by dosing at regular intervals. In the
simplest case, consider the events following the D e~kl0t'
Cfs) = (72)
repeated intravenous administration at intervals Vj (1 - e~kK”)
t of a drug that undergoes monoexponential
decay. According to equation (2), plasma con¬
The mean plasma concentration over a dosage
centration after the first dose is represented by:
interval at steady state, Cfs), can be determined
by dividing the integral of equation (72) by r
Cf> = Jy-e-kl0t (68) such that:
vi

At t = t, a second dose is administered. Plasma

concentrations thereafter are then represented

D
(73)
Tk10V,

Mean plasma concentration at steady state, Cf5),

after intermittent dosage serves the same pur¬
pose as Cf after a constant infusion. They would
in fact be numerically identical if the rate of dos¬
age, D/t, given discretely were the same as the
infusion rate, R0, given continuously. A graphic
representation of drug accumulation after a con¬
stant infusion and intermittent oral dosage is
shown in Figure 9-14.
Equation (73) would also apply to the repeated
intravenous administration of drugs that un¬
dergo polyexponential decay, although the time
courses of change in plasma concentration
t would differ. For example, with biexponential
FIG. 9-13. Biexponential approach to steady state. decay, plasma concentrations during the nth

BIOPHARMACEUTICS • 207
 c,

t FIG. 9-15. Drug accumulation after intermittent oral

doses taken at unequal intervals.
FIG. 9-14. Drug accumulation after a constant infusion
and intermittent oral doses taken at equal intervals;
shaded areas illustrate the equality between AUC (J> and
AUC iss>.

Factors Affecting Drug

dosing interval are represented by:
Elimination
r<n) = D f(k21-a)(l -e-"") ,
1 Vjl 03-«)(l-e—) Binding to Plasma Proteins

+ (k21 zm - e~n/3r) Binding is usually a reversible interaction be¬

tween a small molecule such as drug or metabo¬
(« - m - e~pr)
lite and a protein or other macromolecule.39-42
Only unbound drug can be transported across
The rate of approach to steady state would on
capillaries, be distributed to tissues, gain access
average emulate a constant infusion.
to metabolizing enzymes, and interact with re¬
Two additional properties of repeated inter¬
ceptors to elicit a pharmacologic effect. Binding
mittent dosage should be considered. First, the
is a distributive process, which delays drug elim¬
area under the plasma concentration curve over
ination. Tissue binding cannot be measured
one dosage interval at steady state, AUC*S, is
directly in the intact, living animal or human
equal to the total area under the plasma concen¬
although its influence on drug distribution
tration curve after a single dose, that is:
and elimination has been deduced and dis¬
cussed.43-45
AUC<SS) = AUCW (75)
■ Binding is a function of the affinity of the pro¬
tein for drug as well as the concentration of drug
This identity is given by the shaded areas of Fig¬
and protein. By far. the most important binding
ure 9-14. At steady state, drug input to the body
proteins in plasma are albumin for acidic drugs
(FD) is equal to drug elimination from the
and aracid glycoprotein for basic drugs. The
body.37 Mathematically, these relationships can
interaction between drug and protein can be
be summarized by rearrangements of equations
represented by the law of mass action such that:
(44), (46) and (75) such that:

FD = CL • AUCl0 = CL • AUC?5) (76) Cu.l + Cl p ^5 Cb,!

drug + protein drug-protein
Second, a steady state can also be attained by
intermittent drug administration at unequal in¬ where Cu, and Cbl are, respectively, the plasma
tervals provided that the dosage sequence recurs concentrations of unbound and bound drug
regularly. For example, daily intervals of dosage such that the total drug concentration C! =
may be r1( t2, and t3 such that iq + r2 + r3 = Cu,i + Cb l. Cu p is the plasma concentration of
24 hr. If the same dosage schedule were main¬ free protein binding sites expressed in molar
tained from day to day, the plasma concentration equivalents of the drug. By definition, the con¬
profiles would in time become indistinguishable centration of total (free and bound) protein bind¬
from one day to the next. In general, the concept ing sites, Cp, is the sum of Cu p + Cb,. The equi¬
of a steady state applies whenever the dosage librium between free and bound drug can
regimen consists of recurring cycles. Within therefore be expressed as:
each cycle, the dose and the dosage interval
need not be uniform,38 as is shown in Figure Cb,
(77)
9-15. (CU,)(CU,P)

208 • The Theory and Practice of Industrial Pharmacy

where the equilibrium constant K is a measure be governed by either passive mechanisms (sim¬
of the affinity of the protein for drug. ple diffusion) or carrier-mediated mechanisms
Define fu as the fraction of the total drug con¬ (facilitated diffusion and active transport).
centration that is unbound so that fuCj = Cu ! While the renal processes serve primarily to
and (1 - fu)C) = Cb i. Substituting these rela¬ maintain extracellular fluid volume and osmo¬
tionships into equation (77), one obtains, after lality, to conserve important solutes, and to help
rearrangement: regulate acid-base balance, they are also impor¬
tant in controlling the excretion of exogenous
compounds such as drugs.
u 1 + KCu,p Glomerular Filtration. Approximately 25%
of the cardiac output goes to the kidneys, and
10% of this output to kidneys is filtered by the
= 1 + K(Cp - Cb-1) (78) glomerulus. A fluid conforming closely to that of
an ideal ultrafiltrate of plasma moves across the
When the fractional occupancy is small com¬ glomerular membrane. It has nearly the same
pared to total available binding sites, that is, composition as plasma with respect to water and
Cb,i < C„, the free fraction of drug is essentially low molecular weight solutes. Glomerular filtra¬
independent of changes in drug concentration. tion separates gross particulate matter and such
These circumstances often prevail within the colloidal materials as proteins from the ultrafil¬
therapeutic dosage range. trate. The availability of a drug for glomerular
filtration depends on its concentration in plasma
water; only free drug (drug not bound to macro¬
Renal Physiology molecules or red blood cells) can be filtered. The
filtrate contains the drug at a concentration
The mammalian kidney is composed of many
equal to that in plasma water, i.e., fuCj.
units called nephrons. A nephron consists of an
The rate at which plasma water is filtered is
individual renal tubule and its glomerulus. The
called the glomerular filtration rate (GFR); the
glomerulus is formed by the invagination of a
rate at which a drug is filtered is equal to the
tuft of capillaries into the dilated blind end of the
concentration of unbound drug in plasma multi¬
nephron (Bowman’s capsule). The capillaries
plied by GFR.48,49'52 The GFR can be measured
are supplied by an afferent arteriole and drained
in intact animals and humans by measurement
by an efferent arteriole. The renal tubule con¬
of the excretion and plasma concentration of a
sists of the proximal convoluted tubule (pars
substance that is freely filtered through the glo¬
convoluta), which drains into the straight por¬
meruli and is neither secreted nor reabsorbed by
tion of the proximal tubule (pars recta), which
the tubules. In addition, the substance should
forms the first part of the loop of Henle. The
be physiologically inert and nontoxic; neither
thick ascending limb of the loop of Henle
destroyed, synthesized nor stored within the kid¬
reaches the glomerulus of the nephron from
ney; and preferably, easily measured in plasma
which the tubule arose and passes close to its
and urine. Inulin, a fructose polymer of molecu¬
afferent arteriole. The final portion of the tubule
lar weight 5200, appears to meet all criteria, and
is the distal convoluted tubule. Distal tubules
its renal clearance provides an index of GFR.
coalesce to form collecting ducts that pass
Passive Transport Across the Renal
through the renal cortex and medulla and empty
Tubule. Passive transport of exogenous com¬
into the pelvis of the kidney. The vascular sup¬
pounds, such as drugs, in the renal tubule in¬
ply of the tubules is essentially a portal one in
volves simple diffusion along a concentration
that the blood that perfuses the peritubular cap¬
gradient.53-57 The concentration gradient be¬
illaries has initially traversed the glomerular
tween urine and plasma is the driving force for
capillaries46-51
diffusion. The rate of movement is also governed
by the diffusivity of the molecule through the
Renal Excretion Mechanisms tubular membrane, the membrane/aqueous
The nephrons carry out the vital functions of phase partition coefficient for the molecule, the
the kidney through three major processes: glo¬ thickness of the membrane at the site of diffu¬
merular filtration, tubular reabsorption of water sion, and the area of the membrane through
and filtered substances from the lumen of the which the molecule passes. Biologic mem¬
tubule into the plasma, and tubular secretion of branes, being lipid in nature, are more permea¬
substances from the plasma across the tubular ble to lipid soluble substances, and transmem¬
membrane into the tubular lumen. The proc¬ brane diffusion depends in part on the lipid
esses of tubular reabsorption and secretion may solubility of the diffusing compound. In the case

BIOPHARMACEUTICS • 209
of acids and bases, the un-ionized species exhib¬ excretion of many drugs and their metabolites.
its greater lipid solubility than the ionized spe¬ These processes are characterized by (1) suscep¬
cies and is either the sole diffusing species or tibility to interference by metabolic or competi¬
the more rapidly diffusing species. The diffusing tive inhibitors and (2) a maximal capacity of the
species of an acid or base is governed by the con¬ transporting mechanism (Tm). Although some
centration gradient across the membrane and organic ions undergo simultaneous active bidi¬
the pKa of the compound. In the specific case of rectional transport, i.e., reabsorption and secre¬
passive diffusion across the renal tubular mem¬ tion, the predominant transport of most organic
brane, the concentration gradient depends on ions in the renal tubule is secretory.59 Thus, ac¬
urinary pH since intracellular and blood pH are tive secretion usually adds substances to the fil¬
essentially constant. trate. Substances added to the filtrate in this
Diffusion across the tubular membrane is also manner may be subsequently reabsorbed. Active
affected by flow-related changes in urinary con¬ secretion occurs in the proximal portion of the
centration. The observation that excretion of N1- renal tubule; reabsorption can occur all along
methylnicotinamide (a quaternary ammonium the tubule.
compound) is enhanced by increases in urinary The existence of renal tubule transport sys¬
flow suggests that ionized substances diffuse tems for the secretion of organic acids and bases
passively across renal tubular membranes. is well documented. These systems involve sep¬
Although diffusion across the tubular mem¬ arate and independent mechanisms and are not
brane may occur in either direction for some subject to inhibition by the same competitive
organic bases, diffusion from blood to tubular inhibitors. There is not a high degree of specific¬
lumen is highly improbable for organic acids.55 ity within either system. Substances transported
Passive reabsorption from filtrate to blood occurs by the same system compete with each other.
for many drugs. The urinary excretion rate of Probenecid was synthesized in the early 1950s
amphetamine (pKa 9.77) fluctuates with as an inhibitor of renal transport mechanisms. It
changes in urinary pH; the total amount ex¬ has since been shown that probenecid itself is
creted under alkaline urine conditions is lower actively secreted by the organic acid mecha¬
than under acidic urine conditions. The renal nism. Probenecid has been used as the classic
clearance of phenobarbital (pKa 7.2) increases inhibitor of the organic anion transport system,
with increasing urinary flow. At any given rate and its ability to inhibit secretion of a compound
of flow, the clearance is higher when the urine is is taken as evidence for secretion of that com¬
alkaline than when it is acidic. In general, a pound through the acid transport system.
weak base whose pKa is 6 or below is expected to N1 -methylnicotinamide is the classic example
be extensively reabsorbed at all urinary pH val¬ of an organic base that is actively transported by
ues; little or no reabsorption is expected for a the renal tubule. It was one of the earliest bases
strong base whose pKa is close to 12 throughout for which secretion was demonstrated, and it
the range of urinary pH; reabsorption is ex¬ has been used throughout the years to define
pected to vary with changes in pH for bases with the characteristics of the organic cation trans¬
pKa values of 6 through 12. Reabsorption of port system. For drugs cleared by tubular secre¬
acidic drugs with pKa values between 3 and 7.5 tion, it makes no difference what fraction is
varies with urinary pH; acids with pKa < 2 are bound to plasma protein, provided that the bind¬
not reabsorbed, and those with pKa > 8 are ex¬ ing is reversible. Secretion can be so extensive
tensively reabsorbed throughout the range of that all of the drug, whether in red blood cells or
urinary pH. Urinary flow rate often affects the bound to plasma proteins, can be removed. Only
excretion of compounds whose tubular reab¬ the unbound drug is capable of crossing the cells
sorption is pH-sensitive.51,52 lining the tubule; transport of all drug out of the
Carrier-Mediated Transport Across the blood requires rapid dissociation of the drug-pro¬
Renal Tubule. Carrier-mediated transport is a tein complex and movement of drug out of the
term used to describe transfer across a biologic blood cells.
membrane that is at a higher rate than could be A compound may be subject to all of the renal
attributed to diffusion alone.58 Such transport excretion processes. Most organic acids and
may involve facilitated diffusion or active trans¬ bases, however, are thought to be excreted by a
port. The term active transport is usually applied three-component mechanism: glomerular filtra¬
only to those systems in which a substance is tion, active secretion, and passive reabsorption.
transported across a biologic membrane against The amount of a substance excreted by the kid¬
a concentration gradient at the expense of en¬ ney is equal to the amount filtered by the glo¬
ergy derived from cell metabolism. Active trans¬ merulus plus the net amount transferred by tu¬
port processes figure prominently in the renal bules. Observed renal clearance, therefore,

210 • The Theory and Practice of Industrial Pharmacy

essentially consists of two components: glomer¬ vantages of being technically easy, of enabling
ular filtration and net tubular transport. If a drug quantification of kidney function as a whole, and
is not bound to macromolecules in the plasma, of being applicable to humans. Limitations in¬
then its renal clearance either equals glomerular clude the inability to separate reabsorption from
filtration (GFR) if there is no net tubular secre¬ secretion for substances undergoing both proc¬
tion or reabsorption, exceeds GFR if there is net esses and the inability to define transport mech¬
tubular secretion, or is less than GFR if there is anisms or to localize function to specific neph¬
net tubular reabsorption. ron segments.
While a renal clearance equal to GFR indi¬ In the clearance techniques used to study the
cates the absence of a net tubular involvement, renal excretion of a compound, an appropriate
it does not preclude the involvement of compen¬ marker for GFR (e.g., inulin) is infused simulta¬
sating tubular processes. When a compound is neously with the compound. Blood and urine
bound to macromolecules, the degree of binding samples are collected and analyzed for the refer¬
must be determined at relevant concentrations ence material and compound being studied;
before meaningful statements can be made renal clearances of each are then calculated.
about its renal clearance. When a compound is When the ratio of the clearance of the com¬
excreted by glomerular filtration with possible pound being studied to that of the reference is
passive tubular reabsoiption, renal clearance greater than 1.0, net secretion is indicated;
should be calculated from the non-protein- when the ratio' is less than 1.0 (after correcting
bound fraction in plasma. For a compound with for plasma protein binding), net reabsorption is
renal clearance higher than GFR, e.g., one in¬ indicated. A change in the ratio with a change in
volving tubular secretion, the total plasma con¬ urinary pH implies some passive transport, as
centration of the compound is used in the calcu¬ does a change in ratio with changing urinary
lation of clearance. In those experimental flow rates. A change in the ratio with increasing
situations whereby the contributions of glomer¬ plasma concentration of the study compound, or
ular filtration and tubular secretion to the renal in the presence of a competitive or metabolic
clearance of a compound are separable, the fil¬ inhibitor of transport, indicates the presence of a
tration contribution should be corrected for pro¬ carrier-mediated transport process. Urinary ex¬
tein binding in all cases. cretion of the study compound due to glomerular
Changes in renal clearance may result in filtration is equal to the unbound plasma con¬
changes in plasma half-life (4), in the overall centration of the compound multiplied by the
elimination rate constant k]0, in the fraction of renal clearance of the marker (GFR); net tubular
renal elimination of a compound (fr), and in the transport is equal to the total urinary excretion
fraction metabolized (fm). A decrease in renal minus excretion due to glomerular filtration.
clearance (e.g., increased reabsorption, inhibi¬ In the absence of active reabsorption proc¬
tion of secretion, decreased glomerular filtra¬ esses, appropriate adjustment of urinary pH to
tion) may result in an increase in 4 and a de¬ preclude significant passive reabsorption of a
crease in k10. For a drug that is metabolized, as compound enables quantitation of the secretory
well as excreted, unchanged in the urine, de¬ component (i.e., “net tubular transport” equals
creased renal clearance may also result in a secretion). If there is no passive diffusion of
larger fraction of drug metabolized (ffm) and a compound from plasma to tubular lumen, the
smaller fraction recovered in the urine un¬ secretory component can be further evaluated in
changed (J,fr). Opposite changes in the respec¬ terms of saturation (Michaelis-Menten) kinetics.
tive parameters would occur for an increase in
renal clearance.
Biotransformation
Most drugs are cleared from the body, at least
Experimental Techniques partially, through biotransformation (metabo¬
A number of techniques have been employed lism). The maximum fraction of the dose that
for studying renal processes both in vitro and in may be metabolized is given by the relative dif¬
vivo. In vitro techniques used to examine renal ference between the plasma and renal clear¬
tubular transport mechanisms include renal ances of the drug, (CL — Clr)/CL. Biotransfor¬
slices, suspensions of renal tubules, perfused mations may be catabolic (e.g., hydrolysis,
isolated renal tubules, and perfused isolated kid¬ reduction, and oxidation) or anabolic (e.g., con¬
neys. In vivo methods for studying renal excre¬ jugations with glucuronic acid, glycine, or sul¬
tion processes include clearance techniques, the fate). Metabolism, unlike excretion, does not
stop-flow technique, micropuncture, and micro¬ result in the removal of drug mass from the
perfusion. Clearance techniques have the ad¬ body. Rather, new chemical entities are formed,

BIOPHARMACEUTICS • 21 i
and the distribution, metabolism, and excretion where CLint is constant and independent of the
of each metabolite are unique and usually inde¬ dose of drug administered.
pendent of the parent compound. When a me¬ In addition to the intrinsic metabolic activity
tabolite possesses intrinsic pharmacologic activ¬ of the liver, delivery of drug to the liver (i.e., per¬
ity, as with the N-demethylated metabolite of a fusion) may be an important determinant of the
number of antiepileptic drugs,60'61 characteriza¬ fiver’s ability to metabolize the drug: hepatic
tion of its pharmacokinetic profile as well as its drug clearance cannot exceed the rate at which
formation kinetics is essential to a complete the drug is delivered to the fiver. Flow rate to the
understanding of pharmacokinetic/pharmacody- fiver may limit full expression of the intrinsic
namic relationships. metabolic enzyme activity of the fiver, and he¬
patic drug clearance is then lower than CLint. A
Intrinsic Clearance and Effect of Blood Flow commonly used model that relates blood flow
and CLint to hepatic drug clearance (CLh) is the
Although the liver is the major metabolic perfusion-limited, or well-stirred, compartment
organ in the body, significant metabolic activity model of hepatic clearance.63-66
may also exist in the lungs, kidneys, blood, or
gut mucosa. A drug may be metabolized by com¬ fuCLint \
peting pathways in the liver. The overall hepatic CLh = (82)
Qh "F fuCLjnt /
clearance of a drug is then given by the summa¬
tion of clearances by each pathway. The ability
where fu is the fraction of unbound drug in
of the liver to metabolize a drug depends in part
on the intrinsic activity of the enzymatic system blood, Qh is the hepatic blood flow rate (normally
~1.5L/min in man), and CLh is the hepatic
associated with each metabolic pathway. The
drug clearance from blood. Equation (82) is de¬
overall intrinsic reaction velocity, vint, may be
fined in terms of blood since this is the fluid that
expressed in terms of the familiar Michaelis-
carries drug to the eliminating organ. If meas¬
Menton equation applied to each of the N enzy¬
urement of drug in blood is not experimentally
matic systems involved in hepatic drug removal:
feasible, the blood-to-plasma concentration ratio
N
can be determined and used to convert plasma
Vim S
Vm,jCu,i (79) concentration to blood concentration.
iti KmJ + CUil The quantity in equation (82) equivalent to
CLh/Qh is referred to as the hepatic extraction
where Cu>1 is the unbound concentration of drug ratio, E, of the drug. The effects of changes in
available to the liver enzymes, Vm is the maxi¬ Qh and in fu CLjnt on CLh are readily evident if
mum reaction velocity, and Km is the Michaelis compounds are classified on the basis of their
constant, which is equivalent to the Cu_i at extraction ratio. If a drug is highly extracted
which Vjnt = Vm/2. Since the instantaneous rate (E -» 1), then fuCLjnt » Qh, and equation (82)
of drug elimination is equal to the product of its reduces to:
clearance and concentration, as shown in equa¬
fim CLh = Qh (83)
tion (15), the intrinsic hepatic clearance, CLlnt,
is given by:
Hepatic drug clearance is then insensitive to in¬
N
v„ trinsic enzymatic activity or binding and is ap¬
CLin. — -2
i-i Km,i + Cu,j
(80) proximated by hepatic blood flow rate, i.e., it is
perfusion-limited. On the other hand, if the drug
is poorly extracted (E —* 0), then Qh » fuCLjnt
According to equation (80), if Cu l is signifi¬ and equation (82) reduces to
cant relative to the value of Km, then CLint is not
constant but varies with the dose of drug admin¬ fim CLh = fuCLint (84)
E—>0
istered. The CLjnt of either enantiomer of pro¬
pranolol, for instance, is reduced more than 50%
when the dosage of the racemate is increased and hepatic drug clearance is insensitive to
from 160 to 320 mg/day in humans.62 For most changes in Qh but sensitive to changes in both
drugs, however, Cu l is small relative to Km over drug binding to blood components and metabolic
the therapeutic dosage range and equation (80) enzyme activity in the fiver. Thus, induction of
reduces to equation (81): hepatic enzyme activity, for instance, would in¬
crease the hepatic clearance of a low extraction
compound but have little effect on a high extrac¬
CLin. = 2 (Cu,i « Kjn j) (81) tion compound. Finally, the hepatic clearance of
i= 1 ^m.i

212 • The Theory and Practice of Industrial Pharmacy

a drug with an intermediate extraction ratio (i.e., the extraction ratio E, is lost by extraction in the
E ~ 0.2 to 0.8) is affected by changes in Qh, fu, liver; the remaining fraction, F, reaches the gen¬
or CLjnt. eral circulation, i.e., it is bioavailable. If P is the
The above relationships are exemplified by fraction of the dose absorbed unchanged into the
the block diagram in Figure 9-16. Shown is the portal circulation, then F = P(1 - E). If drug is
effect on extraction ratio (block height) and he¬ totally absorbed in unchanged form from the
patic drug clearance of a ±0.5 L/min change gastrointestinal lumen and not metabolized in
from normal hepatic blood flow for a compound the gut wall, then P = 1 and the bioavailable
with CLj*,t equal to 0.1, 1, or 10 times normal fraction is:
hepatic blood flow. In all cases, the drug is not
bound in blood, i.e., fu = 1. When CLjnt is high F = 1 - E (85)
(15 L/min) relative to blood flow, drug is highly
extracted by the liver, and E = 0.94 when and according to equation (46), the amount of
Qh = 1 L/min. Substantial increases in Qh result bioavailable drug is:
in only slight decreases in E. Hepatic clearance,
on the other hand, increases almost proportion¬ FDP° = (1 - E)Dpo = CL • AUC£° (86)
ately with Qh and approaches Qh as E ap¬
proaches unity, as shown in equation (83). In If all of the drug eliminated from the body is
contrast, when CLim is low (0.15 L/min) relative cleared by the fiver, CL in equation (86) can be
to blood flow, the drug is poorly extracted by the replaced by CLh. Expressing E and CLh in terms
liver, that is, E = 0.13 when Qh = 1 L/min. In of the perfusion-limited model in equation (82)
this case, as blood flow increases, there is a pro¬ gives:
portionate decrease in extraction ratio. Hepatic
clearance is approximately equal to CLjnt and is fuCLin, \
DP°
independent of blood flow, as shown in equation Qh 4" fuCLjnt /
(84). For the intermediate case where CLint = / Qi fuCLlnt
Qh (1.5 L/min), there is a modest decrease in E -) AUC£° (87)
' Qh + fuCLjnt
and increase in hepatic clearance as blood flow
increases. which simplifies to:

Calculation of Intrinsic Clearance

The intrinsic clearance is obtained from blood CLint fuAUCg° (88)
concentration data following oral administration
of the drug. Before it reaches the general circu¬ Thus, the intrinsic hepatic clearance of a drug
lation, an orally administered drug is absorbed may be determined by the ratio of the dose and
into the portal circulation and must pass the AUC„ for unbound drug after oral adminis¬
through the liver. During this “first pass,” a frac¬ tration. The application of equation (88), how¬
tion of the portally available dose, equivalent to ever, requires that the entire administered dose
Dp° reaches the fiver unchanged and that the
liver is the sole organ for drug elimination. Ap¬
propriate use of equation (88) can be ensured by
infusing the drug directly into the hepatic portal
vein and by adjusting for extrahepatic elimina¬
tion. For example, if in addition to hepatic clear¬
ance, the drug is cleared renally, then CLh =
(1 - fr)CL, which upon substitution into
equation (86) would result in:

(i - yjy° (89)
Mnt fuAUCg°

The evaluation of equation (89) requires an esti¬

mate of fr, which can be obtained following an
FIG. 9-16. Relationship between extraction ratio (E),
intravenous dose of the drug.
blood flow (Qh), and hepatic drug clearance (CLh) for a Whereas changes in hepatic blood flow affect
compound with an intrinsic clearance (CLint) equal to 0.1, the hepatic clearance of most drugs (except
1, or 10 times normal hepatic blood flow. when E -> 0), the determination of intrinsic

BIOPHARMACEUTICS • 213
hepatic clearance is insensitive to changes in essential in assessing whether a given com¬
flow rate. The intrinsic hepatic clearance of total pound may be excreted in bile. Conjugation re¬
drug is given by fuCLint. Hence, the effect of actions increase the polarity as well as the mo¬
binding to plasma or blood proteins is to reduce lecular weight of the drug. Glucuronide
the overall elimination rate of drug from the conjugates, for instance, are strong acids with
body. pKa values of 3 to 4, are nearly completely ion¬
ized at physiologic pH, and have molecular
weights 176 daltons greater than the parent
Enterohepatic Circulation compound. Not surprisingly, therefore, many
compounds are excreted in bile in their conju¬
Biliary Excretion gated forms.
Drug elimination from the liver can occur by Many of these generalizations are illustrated
two distinct mechanisms: hepatic metabolism by the data from two nonsteroidal anti-inflam¬
and biliary excretion. Hepatic clearance is the matory agents, indomethacin and sulindac. In-
quantitative measure of the overall ability of the domethacin is pharmacologically active whereas
liver to eliminate the drug and is the sum of the sulindac is a prodrug that is metabolized reversi¬
hepatic metabolic clearance and the biliary bly to the active moiety, the sulfide metabolite.
clearance. Sulindac is also irreversibly biotransformed to
While all compounds may be excreted in bile, the inactive sulfone metabolite. Structures and
the importance of biliary clearance to the elimi¬ molecular weights are given in Figure 9-17.
nation of a compound depends on the degree to Both are arylacetic acids with molecular weights
which it concentrates in bile relative to plasma. of about 350 daltons. In addition, these com¬
Biliary clearance is given by equation (90): pounds undergo glucuronidation so that the ef¬
fective molecular weight is about 525. Biliary
Biliary Clearance = and renal clearances of each in various animal
species, including man, were determined from
„ Concentration in Bile .... the total (free plus conjugate) amount of drug
Bile Flow x —-——-:——- (90)
Concentration in Plasma present in bile and urine. The data, summarized
in Table 9-1, are expressed in terms of the renal
Since bile flow in man is relatively constant— to biliary clearance ratios as an index of the rela¬
between 0.5 and l.Oml/min—biliary clearance tive importance of the two routes of elimination.
is proportional to the ratio of bile to plasma drug A substantial species difference is evident for
concentration. Compounds are classified accord¬ both indomethacin and sulindac. Biliary clear¬
ing to the degree to which they concentrate in ance is by far the dominant route in the dog and
bile. Biliary clearance cannot exceed bile flow for rat, while renal clearance is slightly favored in
such compounds as electrolytes and proteins, the rabbit. Based on molecular weight alone, a
whose concentration ratios of bile to plasma are species difference is expe^ica; the conjugated
usually equal to or less than unity. On the other
hand, a biliary clearance of 500 ml/min is not
uncommon for drugs.
For the biliary clearance of a compound to be
significant, the compound must be actively se¬
creted into bile and achieve a concentration gra¬
dient relative to the blood. Separate secretory
mechanisms appear to exist for acids, bases, and
neutral compounds. Several physicochemical Sulindac
features of a molecule are important in deter¬
mining the extent to which it is secreted in bile.
First, compounds secreted in bile usually have
molecular weights exceeding 300 to 400 daltons.
Moreover, the molecular weight threshold ap¬
pears to depend on species: about 325 in the rat,
400 in the guinea pig, 475 in the rabbit, and 500
in man. Second, compounds excreted in bile are
usually polar in nature. Molecular structure may
also be important, but the nature of the depend¬
ence is not well understood.
Knowledge of the metabolic profile of a drug is FIG. 9-17. Sulindac and metabolites.

214 • The Theory and Practice of Industrial Pharmacy

Table 9-1. Renal to Biliary Clearance Ratios in Various Species67 70

Renal to Biliary Clearance Ratio

Species Indomethacin Sulindac Sulindac Sulfone Sulindac Sulfide

Dog <0.008 <0.004 — _

Rat 0.03 <0.03 — —

Rhesus monkey 1.36 0.11 0.11 -0

Man 0.73 0.12 0.10 <0.03
Rabbit 2.73 1.65 2.5 2.1

— Not available.

compounds exceed the “threshold” molecular may accumulate in the gallbladder. Since gall¬
weight by approximately 200 daltons in the rat bladder emptying is sporadic, different amounts
but by approximately only 50 daltons in the rab¬ of drug are released into the gut at uneven time
bit. intervals. If the drug is reabsorbed, gallbladder
The renal-to-biliary clearance ratios are of emptying serves as an additionajysource of drug
similar magnitude in the rhesus monkey and input into the body. The overall input function is
man, especially for sulindac and metabolites, complex in that neither the amount nor the time
and are intermediate between those of the rat course of reabsorption is known, and reabsorp¬
and rabbit. Only minimal amounts of the sulfide tion may overlap with part of the dose being ab¬
metabolite are excreted in urine. sorbed for the first time. Therefore, drugs that
Also, sulindac sulfide is an interesting exam¬ are recycled tend to exhibit unusual pharmaco¬
ple of structural dependence: while it differs kinetic properties. The overall effect of entero¬
from the parent drug and the sulfone metabolite hepatic recycling of drug is to delay its elimina¬
only in the oxidation state of the sulfur atom, its tion from the body and to prolong its phar
clearance into bile (or urine) of man is marginal macologic effect.
compared to either sulindac or the sulfone me¬ The effect of recycling on drug elimination
tabolite. may be described quantitatively; again, sulindac
is used to illustrate this point. The biliary clear¬
ance, CLb, of sulindac and its sulfone and sul¬
Biliary Recycling fide metabolites was studied in man by use of a
Following its secretion into bile, the drug is duodenal intubation technique70 and by direct
stored in the gallbladder. When the gallbladder collection of bile through a surgically implanted
contracts, the drug is released into the duode¬ T-tube.71 Results of both techniques were simi¬
num and may then be metabolized, reabsorbed, lar, with CLb averaging about 200 ml/min for
or excreted in feces. If reabsorbed back into the both sulindac and the sulfone and about 14 ml/
portal circulation, it once again is subject to bili¬ min for the sulfide. The total amount of drug
ary secretion in the liver and thus completes an secreted in bile, CLb • AUC«, as a percentage of
“enterohepatic cycle.” Biliary clearance is a the administered dose averaged 135% for sulin¬
route of drug elimination from the body only to dac, 186% for the sulfone metabolite, and 16.2%
the extent that drug is excreted in feces, bio- for the sulfide metabolite; the total biliary drug
transformed, or otherwise degraded in the intes¬ flux was 336% of the administered dose. Thus,
tinal lumen (i.e., it undergoes irreversible clear¬ on the average, a given dose of sulindac is recy¬
ance). If drug is reabsorbed, the hepatoportal cled approximately 3.4 times.
system is simply an organ of drug distribution Drug recycling may appear as secondary re¬
(ie., reversible clearance). As indicated previ¬ entry peaks in the plasma concentration profiles.
ously, compounds are often cleared in bile as In patients who have fasted, these peaks are typ¬
their conjugates. Commonly, these are hydro¬ ically seen 8 to 12 hours after administration of
lyzed within the lumen by the gut flora liberat¬ the dose coincident with gallbladder emptying
ing the original drug, which is then free to be following resumption of eating with the evening
reabsorbed. meal (Fig. 9-18). Figure 9-18 demonstrates that
With the notable exception of the rat, all com¬ a plasma half-life (t$) cannot be obtained in the
mon laboratory animals and humans have a gall¬ usual manner in that the terminal plasma con¬
bladder. Contraction of the gallbladder occurs centrations do not decline logarithmically. The
only intermittendy, usually in response to food degree of drug accumulation in plasma upon,
stimuli, so that considerable amounts of drug administration of multiple doses, however, is

BIOPHARMACEUTICS • 215
 behave in this way are said to obey linear elimi¬
nation kinetics. Occasionally encountered, how¬
ever, are drug concentrations that may not be
insignificant relative to the Km for one or more
processes, whereby the elimination rate be¬
comes disproportionate in relation to concentra¬
tion, and increasingly so with increasing dose or
concentration. Drugs that behave nonlinearly
within the therapeutic range include salicylic
acid, phenytoin, theophylline, diflunisal, aceta¬
minophen, and 5-fluorouracil.
The disposition of salicylic acid (SA) in hu¬
mans is schematically depicted in Figure 9-19.
Levy and co-workers have shown that capacity
limitations exist in the formation of salicylurate
(SU).74 Deviations from linear kinetics become
evident even after the administration of a single
aspirin tablet. With increasing dosage, the meta¬
bolic pathway leading to the formation of salicyl
phenolic glucuronide (SPG) also becomes non¬
Time (h)
linear. On the other hand, the renal excretion of
SA and biotransformation to salicyl acyl glucu¬
FIG. 9-18. Plasma concentration profile of sulindac (•) ronide (SAG) and gentisic acid (GA) appear lin¬
and its sulfone (A) and sulfide (O) metabolites demon¬
ear throughout the therapeutic range. There¬
strates secondary re-entry peaks due to biliary recycling in
humans. fore, the overall rate of salicylate elimination
from the body can be represented by equation
(92), which is based on the one-compartment,
remarkably consistent among studies.72 Thus, a open model:
mean effective t$ that is consistent with the ob¬
served drug accumulation may be obtained
from:

C<n) 1 - EXP(-.693nx/t})
1 - EXP(-.693r/tj) ^

where C?'1 and Cin> are the average drug concen¬ where C1( V1; and CLr refer to the plasrnaxon-
tration over the first and the nth dosage interval centration, the volume of distribution, and the
of t hours. The mean effective t$ for sulindac is renal clearance of SA while CLmAG, CL^A,
7.8 hours while that of its active sulfide metabo¬
lite is 16.4 hours.73 Thus, after three days of
therapy, effective mean steady-state conditions
should prevail.

Capacity Limitations
Drug removal from the body may be excretory
or metabolic. Either route may be further com¬
posed of multiple parallel pathways, each with
its own inherent capacity to remove the drug.
The overall elimination rate of the drug from the
body is the sum of these individual contribu¬
tions. The Michaelis constants, Km, for most
elimination processes are large relative to the
concentrations of drug following therapeutic
doses, as was shown by equation (81). Hence,
the rate of drug elimination is usually propor¬
tional to concentration; the proportionality con¬
stant is the plasma clearance CL. Drugs that FIG. 9-19. Disposition of salicylic acid.

216 • The Theory and Practice of Industrial Pharmacy

VmU/(KmU + CO. and V^PG/(K®PC + Cj) are the input rate (INPUT) to the body, namely:
metabolic clearances of SA leading to the forma¬
tion of SAG, GA, SU, and SPG, respectively. The dCt
plasma clearance, CL, of SA is the sum of the — INPUT (kSAG + k<3A + kSA)Ci
dt
individual clearances, that is:
Cj. V;su V;
SAG
+ (95)
CL = CL^ag + CLga + CLr Vi Km + Cj K*AG + Cj
VSU vSPG
_v m_l_vm_ where kSAG, kcA, and kSA are the first-order rate
(93)
K®u + C, K^PG + Cj constants for the formation of SAG, the forma¬
tion of GA, and the renal excretion of SA, respec¬
Thus, the plasma clearance of SA depends on tively. In the ensuing discussion, the total drug
concentration because of capacity limitations in input equals D/Vj, although the rate of introduc¬
the formation of SU and SPG. Representative tion may be fast or slow.
model parameters are shown in Table 9-2. Figure 9-20 shows the simulated plasma con¬
Plasma clearance decreases with increasing centrations of SA as a function of dose. Because
concentrations of SA. Consequendy, the overall plasma clearance decreases with increasing con¬
elimination rate of SA increases more slowly in centration, total area under the plasma concen¬
proportion to changes in concentration. On the tration curve, AUC*,, increases more rapidly in
other hand, as elimination proceeds, C] de¬ proportion to dose (Fig. 9-21). Regardless of
creases with time and eventually becomes insig¬ dose, the terminal phases of plasma concentra¬
nificant relative to K„u and K®fG. Thereafter, tion profiles are log-linear with identical half-
plasma clearance is independent of concentra¬ lives. The onset of the log-linear phase occurs at
tion; in other words: the same plasma concentration but is dispropor¬
tionately delayed with increasing doses (Fig.
ySU vSPG
CL = CL^G + CL^,A + CLr + -ptr + v-spg 9-22). Analogously, at identical doses, the faster
input rate produces a greater AUC«,. Because
(94) higher concentrations are achieved sooner, the
intensity and the duration of the nonlinear ef¬
when: fects of elimination are both magnified.

(C; « KmU and Ci « K^PG)

such that the elimination rate is proportional to

Ci and behaves linearly.
The effect of capacity-limited elimination on
salicylate plasma levels can be illustrated as a
function of dose and of the dosage regimen. The
time course of change in Ci following a dose of
salicylate can be described by dividing both
sides of equation (92) by Vj and providing a drug

Table 9-2. Representative Model Constants for

Salicylic Acid74,75

Model Parameter Numerical Value

CLr 41.3 ml/h

CL^AG 39.1 ml/h
CLGA 12.7 ml/h
v*u 60.3 mg/h
v-SU
61.5 mg/L
vsr° 32.3 mg/h
tfSPG
114.4 mg/L
Va 5.5 L FIG. 9-20. Simulated plasma concentrations of salicylic
acid as a function of dosage.

BIOPHARMACEUTICS "217
 E
O’

T?
O
CD

Time (Days)

FIG. 9-23. Disproportionate increases in salicylate accu¬

mulation with increasing doses. Key: lower curve = 1 tab¬
let; middle curve = 2 tablets; upper curve = 3 tablets.

Dose (mg) the salicylate plasma concentration curve over a

dosage interval at steady state always exceeds
FIG. 9-21. Disproportionate increase in AUC» following
increasing doses of salicylic acid (A). Curve B represents the total area after a single dose, except in the
the result if linear kinetics prevail. trivial case where there is no accumulation.
Finally, fractional contribution of individual
elimination pathways depends on dose. As each
The effects of capacity limitations in elimina¬ pathway approaches saturation, its contribution
tion on salicylate accumulation are shown in to total urinary excretion diminishes while those
Figure 9-23. At a given dosing frequency, higher of the remaining routes become relatively more
steady-state concentrations are achieved in pro¬ prominent. This effect is illustrated in Figure
portion to increases in dose. At a fixed total daily 9-24.
dose, decreasing the dosing frequency increases The nonlinearities exemplified by salicylate
the mean plasma concentration at steady state. kinetics apply to any drug whose elimination is
The time required to achieve steady state in¬ subject to capacity limitations.
creases with increasing doses at a given fre¬
quency or increasing frequency at a fixed dose.
Whereas AUCL15 equals AUC^ss) when linear Effects of Disease
kinetics prevail (see Fig. 9-14), the area under The pharmacokinetics of a drug may be mark¬
edly altered in the presence of disease.76 As dis¬
cussed earlier, the kidneys and the liver are the
major drug-eliminating organs in the body. Any
disease process that affects the functional integ¬
rity of an eliminating organ or delivery of drug
thereto (e.g., blood perfusion) may decrease the
rate at which the drug is cleared from the body.
In addition, a decline in organ function occurs
with advancing age. Cardiac output declines
with age and results in a reduced renal and
splanchnic blood flow. The effects of these and
other age-related physiologic changes on drug
pharmacokinetics have been reviewed.77 A re¬
duction in the usual recommended dose or a
change in dosage regimen may be required in
the diseased or elderly patient to avoid side ef¬
Time (h) fects due to excessive drug accumulation and
FIG. 9-22. The effect of dose on the onset of the log-linear yet achieve the desired therapeutic response.
phase of the salicylate plasma profile. Immature renal and metabolic function must be

218 • The Theory and Practice of Industrial Pharmacy

 where knr is the first-order rate constant of extra-
renal elimination, i.e., (1 - fr)k10.
For these drugs, a plot of k]0 versus CLcr
should be a straight line with slope a and inter¬
cept knt. As an example, Table 9-3 presents data
relating CLcr to plasma 4 of amiloride in renally
impaired patients.80 For a one-compartment
model drug, k10 = 0.693/t*. The plot of k10 ver¬
sus CLcr is linear (Fig. 9-25). Since amiloride is
not metabolized and is cleared from the body
exclusively by the kidneys, the intercept knr is
zero. The predicted 4 in subjects with normal
renal function, where CLcr is nominally 120 mil
min, is 6.3 hours, which is in excellent agree¬
ment with the value of 6 hours reported for
healthy subjects.80 All three observations sup¬
port the application of equation (97) in the indi¬
vidualized dosage adjustment for the renally
impaired patient. Thus, on the basis of a meas¬
ured CLcr, the patient’s predicted k!0 can be read
from Figure 9-25 and substituted into equation
(73) to determine how the dose or dosage fre¬
quency should be changed from the normal regi¬
men to maintain the same mean plasma concen¬
tration at steady state.
For drugs with a narrow therapeutic margin,
FIG. 9-24. Effect of dosage on urinary excretion of sali¬
cylic acid and its metabolites.

considered as well when devising dosage regi¬

mens for neonates.78
The effect of renal impairment on drug elimi¬
nation depends on the fractional contribution of
the kidneys to the total drug clearance. In gen¬
eral, if fr exceeds 0.3, a reduction in dosage is
warranted in the renally impaired patient. For
some compounds, the first-order rate constant
for renal excretion, kr (= frkJ0), is directly pro¬
portional to the creatinine clearance, CLcr, a
measure of renal function:

kr = aCLcr (96) Creatinine Clearance (ml/min)

FIG. 9-25. Relationship between k10 and tj of amiloride

The effect on the overall drug elimination rate and creatinine clearance in patients with varying degrees
constant k10 (= kr + knr) is then given by: of renal insufficiency (O). The mean in healthy subjects is
also represented (•). (Data from George79 and Weiss et
kjo = aCLcr + knr (97) a!80)

Table 9-3. Plasma Half-Life of Amiloride in Renally Impaired Patients79

Patient Plasma Half-Life (h) Creatinine Clearance (ml/min)

3 7.5 97
2 21.4 46
5 43.8 17
1 102.5 6
4 143.5 5

BIOPHARMACEUTICS • 219
 or when k10 at low CLcr cannot otherwise be stantial destruction of hepatic tissues occurs,
measured, a first approximation of the relation¬ drugs normally considered to be highly extracted
ship between k10 and CLcr can be obtained by by the liver may require reclassification in that
linear interpolation between the extremes hepatic clearance would no longer depend solely
(CLcr = 0 or 120 ml/min), with fr and k10 in on blood flow.
healthy subjects being the only known values At the opposite extreme, drugs whose hepatic
(knr = (1 - fr)kio)- This method has been suc¬ extraction ratio is low (E < 0.2) are insensitive
cessful in predicting the elimination rate con¬ to changes in blood flow. Their hepatic clear¬
stants for a number of antibiotics in severely ance is affected by drug binding to proteins and
uremic patients.81 intrinsic metabolic activity. In other words,
Implicit in equation (97), or its equivalent equation (98) reduces to equation (84), namely,
expressed in terms of clearances, is that volume CLh ~ fuCLlnt. Tolbutamide, a low extraction
of distribution and nonrenal elimination are drug cleared almost entirely by hepatic metabo¬
constant and independent of renal function. Bio¬ lism (CL ~ CLh), is an interesting example of
transformation and tissue or plasma protein this type of dependence.83 During the acute
binding of a drug, however, may be altered in phase of viral hepatitis, CL for tolbutamide is
the uremic state, and dosage adjustment is thus increased, volume of distribution is unchanged,
more complex. and plasma 4 is decreased (Table 9-4). However,
In contrast to renal impairment, the effect of the fraction of the drug unbound in plasma (fu)
hepatic dysfunction on drug elimination is not was higher during the active phase of the dis¬
well defined. This lack of definition is not sur¬ ease and the intrinsic clearance of unbound
prising, considering the host of diseases that af¬ drug (CLint) was similar during and after recov¬
fect blood flow, drug-metabolizing enzymes, and ery from the disease (Table 9-4). Since pharma¬
biliary secretion, all of which may be involved in cologic activity is related to free drug concentra¬
drug clearance by the liver.76 Generalizations, tion, no change in dosage is indicated in this
however, can be made based on equation (82), case, even though half-life was shorter and
that is: plasma concentrations were lower for total drug.
Binding may be altered because of changes in
protein composition, concentration, and confor¬
-'int (98)
CL„ - Q„E - mation. For example, changes in binding affin¬
uCL•int ity have been shown to occur with changes in
pH in patients with uremia and cirrhosis of the
Diseases that cause alterations in hepatic liver. Dehydration and hypoproteinemia would
blood flow, protein binding, and intrinsic clear¬ have opposing effects on protein concentration,
ance have an effect on hepatic drug elimination. and therefore on the free fraction, fu. Concentra¬
Drugs that are highly extracted (E -> 1) by the tions of a j-acid glycoprotein rise dramatically
liver are particularly sensitive to change in he¬ under stress, which is likely to affect the binding
patic blood flow (Qh). In other words, equation of basic drugs. The effect of binding is especially
(98) reduces to equation (83), namely, CLh ~ critical for drugs that are highly bound, because
Qh- For example, because of a reduced cardiac a small change in the fraction bound represents
output, the overall CL of lidocaine (E = 0.7) in a major change in the fraction unbound. Thus, a
patients with heart failure is 60% of that in change from 99% to 98% bound represents a
healthy subjects.82 In diseases in which sub¬ two-fold increase in fu.

Table 9-4. Mean Pharmacokinetic Parameters for Tolbutamide in Five Subjects During and After
Recovery from Acute Viral Hepatitis

During After Change

Volume of distribution (L/kg) 0.15 0.15 none

Plasma drug clearance (ml/h/kg) 26 18 increased
Half-life (h) 4.0 5.9 decreased
Free fraction in plasma (%) 8.7 6.8 increased
Clearance of unbound drug (ml/h/kg) 300 260 none

Adapted from Williams et al.83

. 220 • The Theory and Practice of Industrial Pharmacy

Factors Affecting Drug Physical Factors
Absorption
Solubility
In general, drug absorption from dermal, vagi¬
nal, rectal, parenteral, or gastrointestinal absorp¬ Drug absorption requires that molecules be in
tion sites into the systemic circulation occurs by solution at the absorption site. Dissolution of
a passive diffusion across biologic membranes. solid dosage forms in gastrointestinal fluids is a
These membranes form lipoidal barriers that prerequisite to the delivery of a drug to the sys¬
separate the body’s interior from its exterior en¬ temic circulation following oral administration.
vironment. The rate of diffusive movement, dA7 Dissolution depends in part on the solubility of
dt, across a homogeneous membrane is gov¬ the drug substance in the surrounding medium.
erned by Fields law, that is: Polar solutes are more soluble in water than in
organic phases, while the reverse is true for non¬
polar solutes. Ionized species have a greater
aqueous solubility than their un-ionized count¬
erparts. The total solubility of acids or bases in
aqueous medium is therefore pH-dependent.
where Dc is the diffusion coefficient of the drug For drugs absorbed by passive diffusion, those
through the membrane, Pc is the partition coeffi¬ exhibiting low aqueous solubility tend to have a
cient between the membrane and the donor slower oral absorption rate than those exhibiting
medium containing the drug, S is the membrane high aqueous solubility.
surface area, dC is the concentration differential For drugs intended for topical application
across the membrane, and dX is the membrane (e.g., vaginal, rectal, dermal), the solubility of
thickness. In actual practice, concentrations on the drug in the vehicle is important. For a given
the receptor side of the membrane are low be¬ vehicle, the highest driving force for absorption
cause of continuous blood flow. Thus, when the is obtained when the drug concentration in the
concentration on the donor side is relatively vehicle equals its solubility. Concentrations
high, equation (99) reduces to: below saturation decrease the absorption effi¬
ciency, while concentrations exceeding drug sol¬
ubility serve as reservoirs to maintain a satu¬
rated solution.

where C is the drug concentration at the absorp¬

tion site, and Pm is the permeability constant
defined by: Particle Size
Surface area of drug particles is another pa¬
D P rameter that influences drug dissolution, and in
pm = -^ (101) turn, drug absorption. Particle size is a determi¬
nant of surface area. Small particles with greater
surface area dissolve more rapidly than larger
For solid dosage forms, drug concentration at particles, even though both have the same in¬
the absorption site is a function of the dissolu¬ trinsic solubility. Particle size appears to have
tion rate of the drug in the medium at that site. little influence on the absorption of drugs with
The dissolution is given by the Noyes-Whitney high aqueous solubility, but it may have a pro¬
equation: nounced effect on the absorption of drugs with
low aqueous solubility. The absorption of griseo-
fulvin, a neutral compound with low aqueous
Iff = T(Cs - C) (102) solubility (15 pg/ml), is poor and erratic. In¬
creasing particle surface area through
micronization markedly improves absorption, as
where C is the concentration at time t, Dc' is the illustrated in Figure 9-26. Further reduction of
diffusion coefficient of drug in the medium, S is particle size by formation of fine solid disper¬
the surface area of drug particles, h is the thick¬ sions in polyethylene glycols results in an ap¬
ness of the diffusion layer surrounding the parti¬ proximate doubling of absorption efficiency,
cles, and Cs is the solubility of the drug in the compared with conventionally micronized for¬
diffusion layer. mulations.

BIOPHARMACEUTICS • 221
 pH range 1 to 8, the un-ionized fraction changes
dramatically for acids with pKa values between
2.5 and 7.5 (decreasing with increasing pH) and
for bases with pKa values between 5 and 11. For
these compounds, pH-dependent absorption is
expected. Weak acids with pKa values greater
than 7.5 and bases with pKa values less than 5
have pH-independent absorption.87 In general,
drugs with pKa values from 5 to 7 are more read¬
ily absorbed than acidic drugs with high pKa val¬
ues. Amphoteric compounds manifest the least
absorption difficulties when they are presented
as zwitterions, while neutral compounds do not
exhibit pH-dependent absorption.

0 0.5 1.0 1.5 2.0 2.5

Specific Surface Area (m2/gm)

Chemical Factors
FIG. 9-26. Effect of specific surface area on the absorp¬
tion of griseofulvin in humans.
Lipophilicity
Biologic membranes, being lipoidal in nature,
are usually more permeable to lipid soluble sub¬
Crystal Form stances. Transport across these membranes
therefore depends, in part, on the lipid solubility
Polymorphs are crystal forms caused by differ¬
of the diffusing species. Lipid solubility of a drug
ences in the packing and orientation of mole¬
is determined by the presence of nonpolar
cules under different crystallizing conditions.
groups in the structure of the drug molecule as
The physicochemical properties of these crystal well as by ionizable groups that are affected by
forms (e.g., density, solubility, melting point)
local pH. The un-ionized drug species exhibits a
are influenced by the intermolecular forces pres¬
greater lipid solubility than the ionized species.
ent. For example, polymorphs with weak attrac¬
The relative lipophilic to hydrophilic properties
tive forces (thus, in a high energy state) exhibit
of the entire molecule, described by the partition
greater solubility than those with strong attrac¬
coefficient, determine whether^the molecule
tive forces. Hence, differences in dissolution
readily undergoes passive diffusion across the
and absorption rates between polymorphs of a
gastrointestinal or other biologic membranes. In
given compound may also be observed. The rate
general, the lipid/water partition coefficient of a
of absorption of chloramphenicol appears to be
molecule is a useful index of its propensity to be
directly related to the solubility of the different
absorbed by passive diffusion. A high lipid solu¬
crystal forms of its palmitate ester.85 When dif¬
bility, however, does not necessarily favor ab¬
ferences in crystal energy are small, effects of
sorption unless the water solubility is relatively
polymorphism on absorption may not be ob¬
low so that the drug is not “trapped” in the aque¬
served. Three polymorphs of chlorpropamide
ous phase. On the other hand, when the water
have been shown to yield comparable serum
solubility is too low, a significant concentration
drug concentrations.86
cannot be achieved at the membrane surface,
and absorption may be inefficient despite a fa¬
Dissociation Constant vorable partition coefficient.
The un-ionized species of acidic or basic com¬ The absorption of a drug may often be en¬
pounds in solution penetrates lipoidal mem¬ hanced through appropriate structural modifica¬
branes of the gastrointestinal tract more effi¬ tions that serve to alter the relative lipophilicity/
ciently than the ionized species. The rate of hydrophilicity of the compound, e.g., esterifica¬
gastrointestinal absorption of a drug, therefore, tion of' a water-soluble acid. Another approach to
is directly related to the concentration of its un¬ enhanced absorption of compounds with poor
ionized species at the absorption site, which is a lipid solubility is that of inclusion of adjuvants in
function of the pKa of the compound and pH of the dosage form, which rather than altering the
the environment. The pH of the gastrointestinal lipid solubility of the drug in question, possibly
tract ranges from approximately 1.2 to 3.5 in the enhance absorption by altering the permeability
stomach, to 5.0 to 6.0 in the duodenum, to 6.5 to of the absorbing membrane. For example, salicy¬
8.0 in the jejunum and large intestine. Over the late may interact with calcium or magnesium

222 • The Theory and Practice of Industrial Pharmacy

ions in the rectal membrane and thus facilitate temic biotransformation when administered by
rectal absorption of theophylline.88 a nonintravascular route.

Stability Gastrointestinal Tract

Chemical integrity must be maintained until Presystemic elimination of drugs occurs most
the compound is delivered to its intended site of
often following oral administration. Biotransfor¬
absorption or application. Obviously, chemical
mation can occur in the gut lumen, the gut wall,
instability in the dosage form, or instability prior
or the liver. Drug metabolizing enzymes that are
to transport across the initial biologic barrier,
found in the upper intestine probably originate
invariably affects bioavailability. in secretions of Paneth’s cells, or from cells shed
Salt formation is a chemical modification that into the lumen from the mucosal lining. Such
usually enhances aqueous solubility; however, enzymes have been implicated in the hydrolysis
aqueous solubility per se may not be the sole de¬ of phthalate esters and pivampicillin. These en¬
terminant of bioavailability. For example, salts zymes are inactivated by gut flora in the lower
of weak acids may precipitate on initial contact
bowel.89
with the gastric environment following oral
The intestinal flora represent a highly diverse
administration. Hence, dissolution of the precip¬
and relatively potent source of drug metabolic
itate is a prerequisite to absorption. In a static
activity. At least 400 different species of bacteria
situation, the concentration and the partition
are present in the human intestinal tract. These
characteristics of the drug at the pH of the mu¬
bacteria are mostly anaerobes involved in reduc¬
cosal surface where absorption occurs can be
tive reactions. Drugs containing nitro-groups
independently studied. The dynamics of trans¬
may be reduced to amines, which can be toxic.
port along the gastrointestinal tract and across
Sulfa drugs, lactulose, and some cathartics may
the gastrointestinal membranes, however , are
be activated by these bacteria. These reactions
such That the effect of salt formation on the bioa¬
may be complementary to metabolism occurring
vailability of the sample drug is usually unpre¬ subsequently in the gut wall or liver, but they
dictable. The observed effect is a function of the
may also be regenerative (e.g., hydrolysis of glu-
dissolution rate of the salt or its precipitate, gas¬
curonide, sulfate or acylamide metabolites ex¬
tric pH, gastric emptying time, intestinal motil¬
creted in the bile).90 Diet, disease, and drugs
ity, pKa of the drug, and so on.
contribute to differences in the number, type,
Chemical instability is often a function of pH.
and location of these bacteria. Since most are
Compounds that are highly labile in the neutral
restricted to the lower bowel, the potential for
range are seldom useful as drugs. Whereas in¬
bacterial degradation is greatest for drugs ad¬
stability in the alkaline range is seldom encoun¬
ministered rectally. Drugs that are rapidly ab¬
tered under physiologic conditions, stability in
sorbed following oral ingestion may not be ex¬
acid is a concern, particularly for drugs intended
posed to bacteria in the lower intestine. On the
for oral administration. For example, gastric in¬
other hand, bio-inactivation by gut flora may
stability of penicillin G is a major factor in its
further decrease the bioavailability of com¬
poor and erratic bioavailability following oral
pounds that are not efficiently absorbed in the
administration. This problem led to the synthe¬ upper tract.89
sis of the acid-resistant phenoxyalkylpenicillins,
The metabolism of a drug during transit
of which penicillin V is a member.
through the gut wall also influences bioavailabil¬
Prodrug formation is commonly used to en¬
ity. Drug-metabolizing enzymes are known to be
hance absorption of a drug by chemical modifi¬
located in the endoplasmic reticulum, mitochon¬
cation. An ideal prodrug is one that is quantita¬
dria (monoamine oxidase), and cytosol (N-ace-
tively absorbed and biotransformed to the parent
tyltransferase). Some enzymes such as phenol
drug during its transport to the site of action
and estrone sulfokinases exist throughout the
(e.g., systemic circulation, brain, epidermis).
gastrointestinal tract, while others may be more
Prior chemical degradation, including the for¬
localized in the jejunal mucosa (steroid alcohol
mation of the active moiety, adversely affects
sulfokinase). These enzyme systems fall into
bioavailabiUty.
two categories: (1) those that catalyze such
preconjugation reactions as C-oxidation, hy-
droxylation, dealkylation, N- and S-oxidation,
Metabolic Factors reduction, and hydrolysis and (2) conjugative or
In addition to the physical and chemical fac¬ synthetic reactions. Since many of these reac¬
tors that may affect drug absorption are meta¬ tions may also occur in the liver, it is usually
bolic factors. Drugs may be exposed to presys- difficult to quantify the relative contribution of

BIOPHARMACEUTICS • 223
either site to the overall metabolic scheme of a through the liver before reaching the systemic
drug. It can be said, however, that preconjugat- circulation. Drugs absorbed from the intestinal
ive reactions that depend upon cytochromes tract into the lymphatic*System may bypass the
P450 or P448 are quantitatively unimportant in liver.
the gut wall, where synthetic reactions such as The types of metabolic reactions encountered
O-sulfation are more highly developed. Al¬ in the liver are similar to those occurring in the
though the pylorus, duodenum, and jejunum gut wall. Unlike the gut wall, mixed function
have the greatest metabolic activity, biotransfor¬ oxidases have a major role in preconjugative
mation can occur throughout the alimentary reactions in the fiver, where glucuronidation is
tract from the buccal mucosa to the rectum. the most prevalent conjugative or synthetic re¬
Metabolism is a major source of variation in bio¬ action. A drug or its metabolites may undergo
availability and therapeutic response.91,92 one or more of these reactions to form products
Physiologic changes in the gastrointestinal having different pharmacologic activity. The net
tract, other drugs, diet, or disease may alter effect of first-pass hepatic metabolism of a drug
drug-metabolizing enzyme activity in the gut is to reduce its bioavailabifity. Examples of drugs
wall. Monoamine oxidase activity is affected by that undergo significant first-pass hepatic me¬
thyroid activity, systemic progesterone levels, tabolism include antiarrhythmics (e.g., fidocaine
and iron deficiency.91 At the mucosal level, in¬ and verapamil), /J-blockers (e.g., propranolol and
duction of preconjugative reactions are usually metoprolol), centrally acting analgesics (e.g.,
unimportant, but drug competition for conjuga¬ propoxyphene and pentazocine), and antide¬
tion or enzyme inhibition is clinically relevant. pressants (e.g., imipramine and amitripty¬
Sulfation depends on the systemic supply of in¬ line).94 More comprehensive review of this sub¬
organic sulfate that can be depleted by such ject may be found in the literature.95-97
drugs as salicylamide. Interactions between
sympathomimetics, which are sulfated, and
other drugs similarly metabolized are potentially Lungs
dangerous. A classic example of enzyme inhibi¬ Since drug absorption following most routes of
tion involves tyramine, which is normally deam- administration (oral, rectal, inhalation, intra¬
inated in the gut wall by monoamine oxidase. muscular, buccal, transdermal, subcutaneous)
Antidepressant monoamine oxidase inhibitors places a drug in the venous side of the systemic
(e.g., iproniazid, isocarboxazid, nialamide, phen¬ circulation, the agent must pass through the
elzine) block this metabolic pathway and thus lungs before reaching the arterial portion of the
expose patients to severe hypertensive crisis fol¬ system. Drugs exposed to metabolic activity at
lowing ingestion of tyramine-rich foods.93 the site of application, during the absorption
Foodstuffs are known to contain several com¬ process, or upon first pass through the fiver risk
pounds that may induce microsomal drug oxida¬ further biotransformation upon entry into the
tion in the gut wall. Some plant indoles and poly¬ lungs. The extensive capill. r> network in the
cyclic aromatic hydrocarbons produced in meat lungs exposes the blood to an endothelial sur¬
cooked over charcoal have been implicated in face area of roughly 70 to 125 m2. Large num¬
the enhanced metabolism of ethoxycoumarin bers of pinocytotic vesicles containing drug-me¬
and phenacetin by O-deethylation.92 tabolizing enzymes are found in lung tissues.
Although litde is known about the effect of On a mass basis, the lungs represent a smaller
disease on the metabolic activity of the gut wall, organ and contain proportionately more fibrous
celiac disease has been shown to reduce the con¬ tissue than the fiver. Blood flow to the lungs,
jugation of ethinyl estradiol but to increase the however, is approximately three times that to
sulfation of methyldopa.91 the fiver. Thus, while the intrinsic clearance of
the lungs is normally smaller than that of the
fiver, total clearance by the lungs may be signifi¬
Liver cant because of blood flow.98
The most important site of presystemic drug The lungs have been implicated in the metab¬
metabolism is the liver. The liver receives its olism of a number of compounds. For example,
blood supply from the hepatic artery and the benzphetamine, aminopyrine, ethylmorphine,
hepatic portal vein. Approximately 75% of the and imipramine undergo demethylation, while
hepatic blood flow stems from the portal vein, ethoxycoumarin and coumarin undergo O-
which drains all but the lowest 10 cm and the deethylation and aromatic hydroxylation, re¬
uppermost 55 cm df the gastrointestinal tract. spectively. Reductive reactions in the lungs are
Hence, drugs absorbed from the intestinal tract not well understood, but dehydrogenation of ste¬
and the upper portions of the rectum must pass roids has been reported. The reduction of nitro

224 • The Theory and Practice of Industrial Pharmacy

groups to the corresponding amines is operative small intestine, may compensate for the de¬
ana is applicable for chloramphenicol. Hydro¬ crease in passive absorption.
lytic enzymes are numerous in the lungs and The buccal cavity is richly supplied with capil¬
play an important role in the metabolism of en¬ laries. Venous return bypasses the liver. Many of
dogenous compounds. Their role in the metabo¬ the chemical and metabolic processes encoun¬
lism of xenobiotics, however, is not well under¬ tered with oral administration are avoided when
stood. The major conjugative enzyme systems drugs are administered by the buccal route.
detected in the lungs are glutathione S-transfer- The rectal cavity has a surface area of 200 to
ase, UDP glucuronyltransferase, sulfotransfer- 400 cm2. In general, drugs absorbed in the lower
ase, and N-acetyltransferase, with glutathione region of the rectum enter directly into the sys-
conjugation being most important." .temic circulation. Those absorbed in the upper
region pass through the liver first. Anastomoses
Other Tissues among the rectal veins complicate this pic¬
ture.102
Little is known about the presystemic metabo¬
The nasal mucosa represents a site of drug
lism of drugs that are administered intramuscu¬
application that has absorption characteristics
larly, subcutaneously, nasally, or dermaily; how¬
similar to those of intramuscular administration.
ever, many of the enzymes identified in the
An ample blood supply, neutral pH, and low en¬
liver, gut wall, or lungs may be present at these
zymatic activity contribute to these characteris¬
sites of application as well and could contribute
tics.103 If other than local effects are intended,
to the presystemic elimination of agents so ad¬
drug potency is of prime concern since main¬
ministered. The metabolic potential of the skin
taining relatively large amounts of drug at the
has been extensively evaluated.100,101 The skin
absorption site is difficult.
contains many of the same enzymes found in
Until recently, dermal application of drugs
the liver and is capable of oxidative, reductive,
was intended for local effects only. As transport
hydrolytic, and conjugative-type reactions. Most
of substances through skin is better understood,
of the enzyme activity appears to be localized in
however, lipophilic drugs that are reasonably
the epidermal layer, which constitutes only
potent are being incorporated into transdermal
about 3% of the total skin. While enzyme activ¬
dosage forms with the intent of establishing
ity in whole-skin homogenates is low compared
therapeutic blood levels of drug. Since skin on
to the liver, if the enzymes are concentrated in
various portions of the body has been shown to
the epidermal layer, activities are actually close
have different permeability characteristics for a
to those of liver enzymes. Such activity may re¬
given drug, selection of a site of application is
sult in first-pass metabolism (during absorption)
important. The rate of penetration depends on
of topically applied drugs that are intended for
diffusion of drug in the vehicle to the skin sur¬
systemic action.
face, surface pH considerations, and diffusion
through the stratum comeum and supportive
Physiologic Factors tissues. Drug may also move along hair follicles,
sweat glands, sebaceous glands, or aqueous
The physiologic conditions at the site of drug
channels.104105
application, the residence time of the drug at the
Bioavailability is usually good following intra¬
site, and shunting through body fluids also in¬
muscular and subcutaneous drug administra¬
fluence drug entry into the systemic circulation.
tion. A large muscle mass is most often chosen
for intramuscular injection. Muscle is richly
Site of Application supplied with blood, and absorption of drug is
The large effective surface area of the gastro¬ efficient. Though usually not a problem, the po¬
intestinal tract exerts a great influence on the tential for metabolism at these injection sites
absorption of orally administered drugs. The exists. On the other hand, blood flow is more
gastrointestinal mucosal surface is a mass of restricted in subcutaneous tissue; therefore,
folded tissue covered by projections of columnar absorption from a subcutaneous injection is
epithelial cells called villi and microvilli. These likely to be sustained.
structures increase the effective surface area of
the intestinal tract 600-fold over its simple tube¬
like appearance. Surface area decreases in a dis¬ Residence Time
tal direction, suggesting that passive drug ab¬ The time for which a drug remains at its site
sorption is less efficient as the drug migrates of absorption may affect its bioavailability. The
toward the colon. Active transport processes, effect is minimal with intramuscular or subcuta¬
more prevalent in the ileum than in the upper neous injection, or with dermal application,

BIOPHARMACEUTICS" 225
since the drug is confined to the site of applica¬ administered orally, rectally, or intravenously
tion. Drug may be available for absorption from may be recycled through the bile.108
these sites for a protracted period. Because of Finally, the lymphatic system is a pathway
leakage, swallowing, or expectoration, absorp¬ through which the drug, having been absorbed
tion following the intranasal and buccal admin¬ gastrointestinally or parenterally, may be
istration may be more variable and less com¬ shunted, only to reappear later in the systemic
plete. circulation. Nearly all tissues of the body have
Drugs taken orally enter the stomach, where lymphatic channels that drain excess fluid di¬
gastric emptying regulates movement into the rectly from the interstitial spaces. The lymphatic
intestinal tract. Once drug has moved into the system is a major pathway for absorption of fatty
small intestine, transit should proceed unim¬ substances from the gastrointestinal tract. About
peded until drug reaches the colon. The mouth- one tenth of the fluid filtering from arterial capil¬
to-cecum transit time in healthy humans has laries enters the terminal lymphatic capillaries.
been shown to be as short as 1.5 to 3.5 hours.106 This shunt is particularly important for sub¬
Hence, within 3 hours of ingestion, drug may stances with high molecular weight because
enter the large intestine, where absorption may lymphatic capillaries are much more permeable
be inherently less efficient or impeded by the than venous capillaries. Lymph generated in the
presence of fecal material. Depending on the lower half of the body, and in the left half of the
dosage form and the presence of food, however, upper body, eventually re-enters the systemic
the stomach and small intestine may not be circulation at the juncture of the left internal
completely clear of drug for up to 5 and 20 hours jugular and subclavian veins, whereas lymph
respectively.107 The physicochemical nature of from the right half of the upper body re-enters
the drug, the type of formulation, and the sites of contralaterally. The flow of lymph is slow com¬
absorption along the gastrointestinal tract will pared to blood flow dynamics.10^ Hence, the ini¬
determine the effect of delayed gastric emptying tial effect of drug shunting through the lymphat¬
or decreased intestinal motility on drug bioavail¬ ics is a reduction of drug concentrations in
ability. blood, followed later by a sustaining effect.
With regard to rectal drug administration, res¬
idence time in the rectal cavity is governed by
leakage, defecation, or upward migration of the
Product Development
drug into the lower bowel. The first two factors Pharmacokinetic and biopharmaceutic con¬
would reduce or terminate drug absorption, cepts and techniques are used routinely
while the latter would increase drug exposure to throughout the life cycle of a drug. In the drug
first-pass metabolism in the liver. discovery phase, absorption, first-pass metabo¬
lism, active metabolites, and plasma half-lives
are common criteria in the selection of candi¬
dates for safety assessment. In the post-market¬
Shunting and Recycling ing phase, pharmacokinetic bases for important
The plasma concentration profile of a drug clinical drug-drug interactions may be sought,
may be altered by shunting, a process that may while interchangeability among multisource
occur following drug administration. Shunting drug products may be evaluated on the basis of
refers to the entry of a drug into a body fluid their relative bioavailability. The remainder of
(other than blood) before or after entry into the this chapter pertains to the application of phar¬
systemic circulation. Depending on the route of macokinetics and biopharmaceutics in the prod¬
administration and the efficiency of the shunt¬ uct development phase, with particular empha¬
ing process, the drug might conceivably never sis on dosage form design and evaluation.
appear systemically. Usually, however, the drug
is recycled, through absorption or mixing, into
the systemic circulation. One example of shunt¬
Preclinical Information
ing involves secretion of the drug from blood
into the parotid or submaxillary fluids. Pharmacology and Toxicology
The liver may also secrete the drug from blood When a drug candidate begins to undergo
into bile. Bile is then stored in the gallbladder, safety assessment, much is already known about
which empties periodically, albeit irregularly, its biochemical, pharmacologic, and/or anti-in¬
into the small intestine. Drug may then be reab¬ fective properties in vitro and in animals. Differ¬
sorbed, and the process recurs. A notable exam¬ ences in potency between routes of administra¬
ple of this is the drug indomethacin, for which it tion provide initial clues on drug absorption and
has been estimated that 50 to 60% of a dose -disposition. As a point of reference, data follow-

226 • The Theory and Practice of Industrial Pharmacy

ing the intravascular administration of the drug bly expired air are sampled and assayed
are preferred. Data from other parenteral routes, radiometrically. Accountability of the adminis¬
however (e.g., intramuscular, subcutaneous, or tered dose (i.e., mass balance) in the excreta is
intraperitoneal), may suffice if experimental determined, as is the profile of radioactivity in
limitations exist (e.g., drug solubility). Similar blood or plasma. Incomplete absorption or the
ED50 values following parenteral and other presence of significant biliary excretion of the
routes suggest comparable bioavailability. A drug may be detected.
higher ED50 following oral administration may If such studies are coupled with a sensitive
indicate poor absorption or the presence of lumi¬ analytic method specific for unchanged drug,
nal, gut wall, or hepatic inactivation. A lower valuable information may also be obtained on
ED50 following a nonintravascular route may oral bioavailability, first-pass metabolism, meta¬
indicate the presystemic formation of active bolic profile, routes of elimination of unchanged
metabolites. drug, plasma and renal drug clearances, and
Similar clues can be derived from toxicologic half-lives. Principal metabolites may also be iso¬
studies in animals. Comparative LD50 values in lated and identified. For compounds with a clear
the assessment of acute toxicity may be used in and measurable pharmacologic endpoint (e.g.,
the same manner as ED50 data. Dosages needed diuretic/saluretic agents), concomitant meas¬
to induce lethality, however, may be such that urements of pharmacologic responses in animal
capacity limits in absorption, protein binding, disposition studies may reveal correlations with
and biotransformation are approached or ex¬ drug concentration data and provide evidence
ceeded. For example, the fraction that is bio- for the presence of active metabolite(s). When
available may initially increase with dose be¬ metabolites contribute to the pharmacologic or
cause of saturation in first-pass metabolism and toxicologic profile of the drug, sensitive and spe¬
may subsequently decrease because of satura¬ cific analytic methods must be developed for
tion in transport. them prior to initiation of wide-scale clinical
Changes in apparent potency or toxicity on studies. Multiple-dose studies in animals to as¬
repeated administration of drug by the same sess the degree of accumulation of drug and ac¬
route suggest drug accumulation, enzymatic tive metabolite, as well as the possibility of enzy¬
induction, or inhibition. Support may be found matic induction or inhibition of the bioactivation
in results of studies on the effect of drug on process, may also be useful.
hexobarbitol sleeping time or specific enzymatic In general, drug disposition data in animals
systems in vitro. Specific disposition studies can cannot be directly extrapolated to man. Species
be designed to evaluate drug or metabolite accu¬ differences in metabolic pattern have been the
mulation. subject of extensive investigation.110 While
In the course of pharmacologic and toxicologic routes of drug metabolism are often similar in
testing, the process and scale by which the com¬ laboratory animals and man, metabolic rates fre¬
pound is synthesized evolves continually. These quently differ.210 In some cases, these quantita¬
tasks often involve different formulations as tive differences among species can be reconciled
well. Since these differences are known, signifi¬ on the basis of their intrinsic metabolic clear¬
cant changes in physicochemical properties can ances. 111 Hence, animal disposition data provide
be direcdy studied for their effect on absorption. the basis to design initial disposition studies in
The relative importance of process and formula¬ humans.
tion variables to the bioavailability of the test The following examples illustrate the applica¬
compound can be deduced from a systematic tion of preclinical metabolism data to product
examination of changes in indices of activity development.
and toxicity over time. Methyldopa. Methyldopa is an antihyper¬
tensive agent that is variably and incompletely
absorbed from the gastrointestinal tract of man.
Biotransformaticm A number of methyldopa esters were tested in
Before a drug candidate is tested in humans, the spontaneously hypertensive rat model to
information on its disposition in several species identify derivatives that had improved absorp¬
of laboratory animals is usually available. A thor¬ tion characteristics and that were readily hydro¬
ough knowledge of these preclinical data is nec¬ lyzed to methyldopa in vivo.112 Two compounds
essary for the rational design of pharmacokinetic having a longer duration of action and an appar¬
and bioavailability studies in humans. Typically, ent antihypertensive potency approximately
studies are performed in several species wherein three times that of methyldopa were selected for
radiolabeled drug is administered both intrave¬ further study: the pivaloyloxyethyl (POE) and
nously and orally; urine, feces, blood, and possi¬ succinimidoethyl (SIE) esters of methyldopa.

BIOPHARMACEUTICS • 227
Table 9-5. Disposition of Radioactivity after Oral Administration of Labeled Methyldopa or its Ester
Progenitors

Radioactivity Recovered
(% Dose) % Urinary Radioactivity

Compound Conjugated
Species Given* Urine Feces Methyldopa Methyldopa

Rat SIE 77 12 51 _
POE 61 33 65 —
Methyldopa 29 71 — —
Human SIE 70.7 8.5 4.2 24.9
POE 69.2 8.9 22.5 18.7

* Oral doses in terms of methyldopa equivalents were 40 mg/kg in rats and —100 mg in man.
— Not measured.
Adapted from Vickers et al.113

When radiolabeled doses of either ester were beled POE ester was also studied in man at
administered orally to rats,113 improved absorp¬ doses equivalent to 500 mg of methyldopa.116
tion characteristics were demonstrated: more of More than 90% of either label was recovered in
the label was excreted in urine and less in feces urine, indicating that absorption from the gas¬
than after a comparable dose of methyldopa trointestinal tract was nearly complete. About
(Table 9-5); over half of the urinary radioactivity 42% of the dose was excreted in urine as un¬
after either ester was due to methyldopa. A simi¬ changed methyldopa. When methyldopa itself is
lar excretion pattern of radioactivity was ob¬ given orally, -25% of the dose is available to the
served113 when the labeled esters were adminis¬ systemic circulation (i.e., is bioavailable), and
tered to humans (Table 9-5). -18% of the dose is excreted unchanged in
Since —40% of a labeled oral dose of methyl¬ urine.117 The higher urinary recovery of methyl¬
dopa is excreted in urine, and the remainder is dopa after the POE ester suggests that approxi¬
recovered in feces as unchanged drug,114115 mately 60% of the dose is bioavailable as methyl¬
higher absorption of the esters from the gastro¬ dopa.
intestinal tract is indicated. Based on urinary Different profiles were observed for the 3H
recoveries of methyldopa, however, the bioavail¬ and 14C labels in the systemic circulation, indi¬
ability of methyldopa from the SIE ester is con¬ cating that as in the animal studies, hydrolysis
siderably lower than that from the POE ester of the POE ester occurs presystemically. Plasma
(Table 9-5), or even from oral methyldopa.114 A was collected in the presence of an esterase in¬
six-fold higher ratio of conjugated to free meth¬ hibitor to quench in vitro hydrolysis of any ester
yldopa in urine after the SIE ester compared to present and was assayed specifically for the in¬
the POE ester suggests that the lower bioavaila¬ tact compound.118 No intact ester was detected,
bility is related to a greater first-pass conjugation which confirms that hydrolysis occurs presys¬
after the SIE ester. temically and is essentially complete. Only the
The POE ester labeled with 3H in the methyl¬ initial 2-hour urine collection in one of four sub¬
dopa moiety or 14C in the pivalic acid moiety was jects contained the intact ester equivalent to
given orally to rats, dogs, and rhesus monkeys at <0.001% of the dose.117 Since sampling of por¬
doses of up to 300 mg/kg.113 Profiles of 3H and tal blood is not feasible, the site of hydrolysis in
14C in the portal circulation differed, and.negli¬ man cannot be ascribed exclusively to the gut
gible amounts of the intact ester were present in wall; it may also include esterases in the portal
the portal plasma. When added to rat, dog, or blood and/or the liver.
human plasma, the ester is rapidly hydro¬ The POE ester at doses equivalent to 500 and
lyzed.113 These results indicate that the ester is 1000 mg of methyldopa was compared to oral
hydrolyzed in the. gut wall during the absorption and i.v. doses of methyldopa in a bioavailability
process and that the active therapeutic moiety, study in humans.119 The average value for and
methyldopa, is delivered to the portal circula¬ range of bioavailability of methyldopa after ad¬
tion. Intact ester that may survive gut wall me¬ ministration of the 500-mg equivalent doses are
tabolism is subject to rapid hydrolysis by plasma compared in Table 9-6. The bioavailability of
esterases in the portal and systemic circulation. methyldopa from the ester is —2.2 times higher
The metabolic disposition of 3H- and 14C-la¬ and is much less variable than that from an

228 • The Theory and Practice of Industrial Pharmacy

Table 9-6. Mean Systemic Availability of Methyldopa After Oral Administration of Methyldopa or Its
POE Ester Progenitor*

Systemic Availability of Methyldopa (% Dose) After

Species ' N Methyldopa POE Ester Prodrug

Dog (beagle) 4 91.4 (74.6-103)1 97.lt

Rhesus monkey 3 16.8 (10.9-28.5) 69.9 (66.8-75.1)
Cynomolgus monkey 3 19.4 (14.4-33.5) 39.7 (30.2-50.2)
Man 10 27.3 (11-59) 60.6 (53.3-69.7)

•Human data from Dobrinska et al.117

t Range.
•Non-crossover study.

equivalent dose of methyldopa itself. Also sum¬ availability occurs because of prehepatic metab¬
marized in Table 9-6 are results for bioavailabil¬ olism. Gastrointestinal metabolism of levodopa
ity of the two compounds in several species of has also been demonstrated in humans,121,122
animals. Considerable variation exists among and gastrointestinal side effects may be related
species. Results, in the rhesus monkey are clos¬ to the presence of metabolic products in the
est to those in man. stomach.121
Levodopa/Carbidopa. Parkinsonism is a Carbidopa is a dopa decarboxylase inhibitor
debilitating disease that is associated with a de¬ that does not penetrate the blood-brain barrier.
ficiency of dopamine in the brain. Levodopa is Coadministration of levodopa with carbidopa
used to treat the disease because unlike dopa¬ results in an increase in levodopa bioavailability
mine, it readily crosses the blood-brain barrier, and permits a significant reduction in dosage
and it is decarboxylated in the brain to dopa¬ requirements; gastrointestinal side effects are
mine. Effective treatment requires large oral correspondingly reduced. The effect of car¬
doses because levodopa bioavailability is limited bidopa pretreatment on the plasma concentra¬
by extensive metabolism. Presystemic and sys¬ tions of levodopa in humans are exemplified by
temic decarboxylation to dopamine causes nau¬ the data in Table 9-8. Levodopa was adminis¬
sea and vomiting, which limits further increases tered as a single 250-mg dose alone or following
in dose. pretreatment for 48 hours with 50 mg carbidopa
Studies in animals have established that pre¬ three times a day. Levodopa bioavailability, ex¬
systemic elimination of levodopa occurs in the pressed as the amount absorbed divided by its
gastrointestinal lumen and/or gut wall rather volume of distribution as given in equation (48),
than in the liver. In the dog and rat,119120 the and the plasma q of levodopa were compared
AUC of levodopa in the systemic circulation is between treatments. In the'presence of car¬
nearly identical after intravenous and intrapor¬ bidopa, A(°°)/V! of levodopa is increased by a fac¬
tal administration (Table 9-7), which indicates tor of 5 and q is twice as long. The increase in
that the liver does not contribute to first-pass bioavailability results from inhibition of presys¬
elimination of the drug. After oral administra¬ temic decarboxylation by carbidopa, whereas the
tion of 14C-labeled levodopa to the dog, the label prolonged q reflects the inhibition of decarboxyl¬
is completely absorbed,119 but the AUC for in¬ ation of levodopa in the general circulation. Con¬
tact drug is only ~40% that after an equivalent sequently, more levodopa is available for a
i.v. dose (Table 9-7). Thus, the low systemic bio- longer period of time for transport into the brain,
where it becomes a source of dopamine since
carbidopa itself does not pass the blood-brain
Table 9-7. Influence of Route of Administration
barrier.
on Systemic Plasma Concentrations of Levo¬
dopa69’120
Preformulation
Mean AUC (pug minimi) of Levodopa When
Equivalent Doses are Administered
Solubility
Species Intravenously Intraportally Orally Most drugs are administered orally in solid
Dog dosage forms. Following administration of such
1392 1272 584
Rat 433
dosages, the delivery of the active ingredient to
419 —
the systemic circulation requires initial trans-

BIOPHARMACEUTICS • 229
Table 9-8. Effects of Carbidopa on Levodopa in Humans

Levodopa

Treatment (pug/ml)" tj(h)

Levodopa 250 mg 0.44 ± 0.i9t 0.94 ± 0.28

Levodopa 250 mg + carbidopa 50 mg t.i.d. 2.19 ± 1.32 2.15 ± 1.02

‘Total amount of levodopa absorbed divided by volume of distribution,—see equation (48).

tMean ± S.D.; N = 4

port through the gastrointestinal membrane. well as in ophthalmic preparations. Similarly, an

Solubility characteristics play an important role injectable dosage solution of methyldopa is for¬
in this initial process. Hydiophificity favors drug mulated as the hydrochloride salt of its ethyl
dissolution in the aqueous milieu of the gastro¬ ester in order to increase solubility and stability.
intestinal lumen, while lipophilicity favors sub¬ These ester derivatives are distinct chemical
sequent penetration into the lipoidal membrane. entities, however, with properties different from
For efficient absorption, a proper balance be¬ those of the parent compound. Competing
tween these two opposing properties is required. biotransformational and excretory pathways
Because of the finite fluid volume within the may affect the quantitative in vivo hydrolysis to
gastrointestinal lumen, the efficiency of absorp¬ the active moieties. For example, while over
tion is also affected by the size of the dose. For 90% of the intravenously injected dexametha¬
example, dexamethasone is only slightly soluble sone sodium phosphate is bioavailable as dexa¬
in water (0.1 mg/ml), but it is highly soluble in methasone,125 the bioavailability of methyldopa
common organic solvents. Because of its rela¬ from injections of the ethyl ester hydrochloride
tively low dosage (<10 mg), it is well absorbed is less than 20%.126
orally.123 On the other hand, methyldopa re¬ Decreasing aqueous solubility by the forma¬
quires a high dosage and is more soluble in tion of insoluble esters may also be desirable
water (10 mg/ml), but its bioavailability is poor. under certain circumstances. A classic example
Pardy because of its lipophobicity, methyldopa is chloramphenicol palmitate, which minimizes
does not penetrate the gastrointestinal mem¬ the unpleasant taste of the drug in oral suspen¬
brane efficiendy. sions. Excessive suppression of solubility, how¬
For acidic or basic compounds that are poorly ever, may adversely affect bioavailability.
absorbed because of low solubility in both or¬
ganic and aqueous media, improved absorption
can be achieved by the formation of appropriate Polymorphism
soluble salts. These salts in general show faster Different crystal forms of a drug may be pro¬
dissolution, with their water solubility being duced in the course of chemical synthesis, isola¬
pH-dependent. For example, chlorpheniramine tion, and purification. At a specific temperature
base is an oily liquid with low water solubility. and pressure, only one form has the strongest
Formation of the maleate salt, which is crystal- intermolecular forces and is the most thermody¬
fine and easily handled at room temperature, al¬ namically stable. Metastable forms melt at lower
lows its incorporation into solid dosage forms. temperatures are more soluble, and are less
Indomethacin is practically insoluble in water at dense. Differences in these variables between
neutral or acidic pH. When incorporated into polymorphs are measures of their relative stabil¬
osmotically controlled drug delivery systems, ity. Less stable forms seek to revert to the more
indomethacin itself is incapable of generating stable ones. Because of this tendency to revert
the required osmotic pressure. The formation of on storage, the thermodynamically stable form is
the soluble sodium salt enables the drug to be preferred in dosages forms. For example, there
released from the dosage form at a predeter¬ are at least five known polymorphs of cortisone
mined rate.124 acetate, the caking of which in aqueous suspen¬
Formation of soluble ester derivatives is an¬ sions has been attributed to polymorphic rever¬
other approach to resolving the solubility issue. sion.127
Injectable dosage forms of dexamethasone em¬ Polymorphism is not a concern if the drug is
ploy a sodium phosphate salt that has enhanced inherently well absorbed or if the energy differ¬
solubility. The greater solubility of the sodium ences among polymorphs are small. For exam¬
salt also allows its incorporation in inhalation as ple, diflunisal exists in two nonsolvated enan-

230 • The Theory and Practice of Industrial Pharmacy

tiotropic forms. At temperatures below 90°C, the intramuscular injection may sustain absorption
more stable Form II has a lower aqueous solubil¬ sufficiently to permit a reduction in dosage fre¬
ity than Form I—0.014 versus 0.026 mg/ml at quency. This route of administration is a practi¬
25°C. Since both forms are equally well ab¬ cal alternative for drugs that are not used chron¬
sorbed,128 Form II is used in tablet formulations. ically, such as antibiotics. Absorption through
For drugs that are poorly absorbed because of the skin may be similarly rate-limiting and thus
solubility limitations, amorphous solids or meta¬ suitable for chronic drug administration. The
stable crystalline forms may be considered. For usefulness of transdermal drug delivery may be
example, different polymorphs of chlorampheni- limited by local irritation and site variations in
cal palmitate are known to influence its bioavail- skin permeability. As with oral administration,
ability following oral administration.85 If the both intramuscularly and transdermally admin¬
enhancement in bioavailability were to be repro- istered drugs may be subject to degradation or
ducibly maintained by these means, however, metabolism at the site of application.
methods must be found to prevent spontaneous Hepatic first-pass metabolism can be avoided
nucleation or reversion. or minimized by directing drug input to the sys¬
temic circulation away from the oral route of
administration. The buccal and sublingual
routes of administration completely circumvent
Design Variables
the liver and the gastrointestinal wall. These
routes are suitable for potent drugs that are rap¬
Mode of Administration idly absorbed; however, if the drug is retained at
Oral administration, which provides conven¬ the site of application for a protracted period of
ient access of drug to the systemic circulation, is time, part of the dose may be swallowed and
traditionally the preferred route of drug adminis¬ thus be subjected to presystemic hepatic metab¬
tration. The appropriateness of this route of olism. Rectal and intravaginal routes of adminis¬
administration for a given drug, however, is de¬ tration provide at least partial avoidance of the
termined by such factors as rate and extent of liver in the first pass, and in addition, are useful
gastrointestinal absorption, acid lability, first- for drugs whose unit dosage exceeds 1 g.
pass metabolism, gastrointestinal transit time, For drugs that are poorly absorbed by other
and duration of action. Acid lability can be mini¬ routes, subcutaneous injection and intranasal
mized or overcome by formulation. Buffering, instillation may be considered. Drug delivery to
however, usually adds considerable bulk to an the lungs may be intended for local or systemic
oral dosage form, and enteric coating invariably effects. The large surface area and rich blood
delays the onset of drug absorption. supply of the lungs provide a rate of systemic
The feasibility of optimizing drug deliver)7 by drug availability approaching that of intrave¬
alternative modes of administration depends on nous administration. Optimal drug delivery to
the physicochemical and pharmacokinetic prop¬ the bronchi and lungs by aerosol or insufflation
erties of the drug, its potency, and physiologic techniques requires a conscientious effort by the
conditions at the alternate site of application. patient. Even so, drug losses to the alimentary
Most of the potential disadvantages of oral ad¬ canal are inevitable.-
ministration can be circumvented by controlled When drugs are administered topically for
intravenous administration, provided that the local rather than systemic effect, selective
drug is sufficiently soluble in a vehicle for injec¬ chemical or metabolic lability may be desirable.
tion; however, chronic intravenous drug admin¬ For example, topical steroids should ideally be
istration is rarely considered. Usually, a compro¬ rapidly biotransformed before reaching the sys¬
mise is made between patient acceptance and temic circulation; highly reactive an¬
the technology that is available to deliver the tineoplastics may be injected into the arterial
drug reliably. supply of a tumor; intraocular delivery of the
Much of the convenience of oral administra¬ prodrug dipivalyl epinephrine favors corneal
tion is negated if the duration of a drug’s action penetration and reduces drug loss through the
is such that the frequency of administration is nasolacrimal duct, maximizing the local availa¬
unacceptably high. Compounds with this char¬ bility of the active agent epinephrine. In each
acteristic are candidates for controlled delivery, case, the goal is to effect a greater separation of
which is discussed later in this chapter. Intra¬ local activity in the target tissue from systemic
muscular and transdermal routes may also be side effects.
considered. Both routes involve sites from which Finally, parenteral routes such as intra-articu-
absorption may be the slowest and therefore the lar, intrathecal, and intracardiac administration
rate-limiting step. For rapidly eliminated drugs, are available for selected drugs, but restricted to

BIOPHARMACEUTICS • 231
critical situations in which immediate access to The peak and trough concentrations within a
a specific site is required. dosage cycle as well as the rate of approach to
steady state depend on the half-life. The shorter
Dosage Regimen the half-life is, the more the daily dose must be
subdivided to maintain peak and trough concen¬
The goal in the design of dosage regimens is to trations within the chosen limits. Furthermore,
achieve and maintain drug concentrations in approximately 7 half-lives in time must elapse to
plasma or at the site of action that are both safe achieve a steady state. To hasten the approach to
and effective. Maximum safe concentration and steady state, a loading dose of the drug may be
minimum therapeutic concentration are sche¬ given. An appropriate loading dose can be calcu¬
matically illustrated in Figure 9-27. Toxicity lated based on the mode of administration by
would result if doses were administered too fre¬ using the following equations.
quently, whereas, effectiveness would wane if For a continuous intravenous infusion, an ini¬
the dosage rate were too infrequent. The optimal tial loading bolus dose D* is administered:
regimens are combinations of dose and dosage
frequency that would result in steady-state con¬
D* = CfV, (103)
centrations within the chosen limits.
Acceptable plasma concentration profiles at
This initial dose followed immediately by an in¬
steady state can be devised with the aid of phar¬
fusion at a dosage rate prescribed by equation
macokinetic parameters derived from single¬
(58) results in the immediate attainment Cf for
dose experiments. The important parameters
a drug whose disposition is described by a one-
are plasma clearance, half-life, and bioavailabil¬
compartment pharmacokinetic model (see Fig.
ity. Suppose_that the desired mean plasma con¬
9-1). For drugs whose plasma concentration
centration, Cfs), for a drug is 2 pg/ml, and its
decays polyexponentially (see Fig. 9-9), a similar
plasma clearance is 125 ml/min. According to
approach causes plasma concentrations to fall
equations (58), or (73), the dosage rate by the
for a period of time before returning to Cf. To
intravenous route should be 250 pg/min, or
compensate for this initial fall in Cf, a loading
360 mg/day. The target concentration can be at¬
bolus dose D* equal to or greater than that given
tained by either a constant infusion or intermit¬
by equation (104) may be considered:
tent boluses (see Fig. 9-14). The dose and dos¬
age intervals need not be equally divided; a psspi
steady state may be obtained as long as the dos¬ D* = --1 - (104)
ing pattern recurs in regular cycles (see Fig. O)

9-15). If the same drug is to be given by a

nonintravascular route with a bioavailability of where w is the eigenvalue associated with the
50%, the same target concentration can be terminal slope. This dose is followed immedi¬
achieved with a dosage rate of 720 mg/day. ately by a continuous infusion at a rate pre¬
scribed by equation (58); however, this strategy
results in initial plasma concentrations higher
than Cf and may be inappropriate for drugs
having a narrow margin of safety.
For intermittent dosage at regular intervals, a
loading dose (D*) could be chosen such that the
mean plasma concentration following the first
dosage_interval, Cff would equal that at steady
state, Cfs). Combining equations (73) and (76)
yields:

n. rCfs)CL
(105)
F

where F represents the bioavailability of the

drug. Administration of D* followed by the
maintenance dose given every r hours immedi¬
Time ately establishes steady state plasma concentra¬
FIG. 9-27. Effect on plasma concentration of too frequent tions.
(A), proper (B), and inadequate (C) frequencies of drug Special consideration must be given to the
administration. design of dosage regimens when the disease

232 • The Theory and Practice of Industrial Pharmacy

state of the patient might affect drug disposition. tained with a zero-order input delivery system is
In patients with less than normal cardiovascular a function of both the input rate and the CL of
function, tissue perfusion is decreased. If he¬ the drug. The time required to reach Cf after
patic or renal function is compromised, drug the dose is administered, however, is governed
elimination is decreased because of a decrease primarily by the plasma half-life of the drug.
in metabolic or renal clearance, respectively. In Approximately 7 half-lives are required to ap¬
each case, plasma clearance decreases and half- proach Cf. If more rapid attainment of the
life is prolonged. These altered parameters steady-state level is desired, then an immediate
should be used in equations (58), (73), (103), release drug fraction (loading dose) can be ad¬
(104), and (105) to calculate the doses and dos¬ ministered with the zero-order delivery system.
age rates needed to achieve the desired Cf in Design strategies accompanying this approach,
patients. including the effects following multiple-dose
administration, have been reviewed.129
While advantages of controlled-delivery dos¬
Controlled Delivery
age forms are readily apparent, limitations must
The goals of controlled drug delivery are to also be addressed prior to and throughout the
conserve dose, maintain effective drug concen¬ development process. A convenient once-a-day
trations, eliminate nighttime dosage, improve dosage form is precluded, for instance, for a drug
compliance, and decrease side effects, thus opti¬ that is bulky or where daily dosage requirements
mizing drug therapy. Pharmacokinetic informa¬ are high. The length of time that an oral con¬
tion is essential in determining the feasibility trolled-delivery dosage unit remains functional
and design of a controlled delivery dosage form. within the gastrointestinal tract must be consid¬
Drugs with plasma half-lives of 6 hours or less, ered—functional in terms of transit time as well
inactive metabolites, well-defined minimum as the release of drug at the site of absorption.
therapeutic blood levels, and rapid absorption Certain drugs manifest “absorption windows”
are the most likely candidates for controlled de¬ whereby absorption is limited to a specific region
livery. Dosages for drugs with longer half-lives of the gastrointestinal tract. Others may be ab¬
can be calculated conventionally so that thera¬ sorbed, albeit nonuniformly, along the entire in¬
peutic blood levels are established and then self- testinal length. Once the dosage unit is embed¬
sustained, allowing for twice-daily dosage or ded in fecal matter, drug diffusion to the gut wall
less. A narrow margin of safety complicates this may become difficult.
approach, as does the fact that well-defined min¬ Controlled drug delivery systems for routes of
imum therapeutic drug levels are difficult to es¬ administration other than oral are becoming in¬
tablish even in the absence of active metabo¬ creasingly popular. Topical dosage forms such as
lites.107 ophthalmic delivery devices (e.g., Ocusert) and
A common approach has been to combine a dermal drug delivery patches are usually in¬
rapid-release dose fraction with a fraction hav¬ tended for local drug effects. Drugs with lipo¬
ing pseudo-first-order release characteristics. philic characteristics may also be delivered
When absorption is not rate-limiting, the ideal transdermally for their systemic effect. Once the
approach to this situation is zero-order delivery skin becomes saturated, the drug should enter
of drug to the absorption site. The amount of the systemic circulation at a constant rate as
drug reaching the absorption site changes with long as drug activity at the skin surface remains
time for first-order drug delivery, thus preclud¬ at unity. The rate of drug entry into the systemic
ing the desired constant blood level profile. Fol¬ circulation is governed by the inherent flux of
lowing administration of a zero-order-input de¬ drug through the skin or by the combined effect
livery system, steady-state blood levels (Cf) of of a rate-controlling membrane on the patch it¬
the drug are obtained: self and the skin flux. With the further advan¬
tage of being able to keep a transdermal device
in contact with the skin for days, this method
Cf = T/17 006) may be an ideal approach to the goals of con¬
V 1K10
trolled drug delivery. Hence, complete pharma¬
where Iq, is the zero-order input rate. The dose D cokinetic characterization of the drug and the
is a function of ko, the dosage interval t, and the delivery device becomes even more critical.
bioavailability:

kor = FD (107) Combinations131

Rational combination therapy may be divided
As indicated in equation (106), the Cf at¬ into three general categories: (1) those combina-

BIOPHARMACEUT1CS • 233
 tions whereby the individual components are ripheral dopa decarboxylase activity is
independently required in the treatment of a maximally inhibited..Above this threshold, a rel¬
specific illness or symptom complex (e.g., an atively large range in the ratio of L-dopa to car¬
analgesic may be combined with an antipyretic bidopa can be accommodated. Finally, the inhib¬
or an antihistamine to alleviate the symptoms of itory effect of carbidopa requires one or two days
influenza or allergy, while a /3-blocker may be of intermittent dosing to be fully manifested.
combined with a diuretic to control hyperten¬ The requirement is not a concern, however,
sion); (2) therapy whereby a second agent is since the combination is intended for chronic
needed to ameliorate an unwanted pharmacody¬ therapy.
namic effect of the primary agent (e.g., anticho¬ In contrast, there are physical and pharmaco¬
linergic/narcotic antidiarrheals reduce potential kinetic arguments against fixed combination
for narcotic abuse, while some diuretic combina¬ dosage forms of a /3-lactam antibiotic and pro¬
tions minimize potassium loss); and (3) combi¬ benecid. Like carbidopa, a threshold dose of pro¬
nations designed to effect an improvement in benecid is required for maximal blockade of the
pharmacokinetic properties, (e.g., the coadmin¬ renal secretory component of antibiotic elimina¬
istration of levodopa and a decarboxylase inhibi¬ tion, and mainly because probenecid is usually
tor greatly reduces dopamine formation in the given orally, some time must elapse before its
gastrointestinal lumen and outside the central effect is fully manifested. Since the optimal
nervous system, the net result being a reduction route for the antibiotic is often parenteral, how¬
in the dose and the dosing frequency of levodopa ever, and the effective dose of the components
and in side effects associated with peripheral often exceeds 500 mg each, their combination in
dopamine). a single dosage form is not usually considered.
Fixed combinations are dosage forms de¬ Secondarily, pharmacokinetic considerations
signed to effect a planned interaction between suggest pretreatment with probenecid to ensure
the components or to provide convenience to the -maximal conservation of the antibiotic. This pre¬
patient. Since each component is required for treatment is particularly relevant when only a
rational therapy, fixed combinations ensure single dose of the antibiotic is indicated, such as
compliance. Where the components interact, by in the treatment of gonorrhea.
design or otherwise, fixed combinations define Divergent pharmacokinetic properties among
the intensity and the duration of the net effect. individual components in fixed combinations of
In any event, clinical proof of safety and efficacy convenience are unimportant, even if incidental
is needed to support the usefulness of a pro¬ interactions exist. With planned interactions, on
posed combination. the other hand, the adjuvant (e.g., carbidopa
For convenience dosage forms, the primary and probenecid) should ideally be long-lived rel¬
biopharmaceutic concern is to ensure that the ative to the therapeutic moiety. This ensures a
bioavailability of each component in the fixed stable platform on which the pharmacokinetic
combination is equivalent to that following the behavior of the therapeutic moiety can be repro¬
concomitant administration of the single entities duced from one dose to the next. Without this
at the same dose by the same route. As long as stable platform, the kinetic behavior of the com¬
there is proof of safety and efficacy, incidental pound of primary interest may be difficult to as¬
pharmacokinetic interactions between the com¬ sess. '
ponents should not be a concern, but may in fact
be a strong argument for the fixed combination.
With planned pharmacokinetic interactions, Dosage Form Evaluation
biopharmaceutic considerations are to optimize The foregoing discussion pertains to factors
the dose of the individual components, their that contribute to the evolution of pharmaceuti¬
ratio, and the dosage regimen of the combina¬ cal products. The final step is to design appropri¬
tion. More often than not, the desired therapeu¬ ate studies for evaluating the resultant dosage
tic activity resides with one of the components forms in vivo. The following discussion applies
whose absorption or disposition characteristics equally to verterinary and human health prod¬
are improved by a second agent. For example, ucts.
carbidopa, a dopa decarboxylase inhibitor, is Studies for evaluation of dosage forms in vivo
given in combination to maximize the availabil¬ are conducted in' human subjects in a random¬
ity of L-dopa for transport to the central nervous ized complete-block design to minimize inter¬
system and to minimize dopamine formation in subject variations. The size of the study panel
the periphery. In designing this particular com¬ should be sufficient to produce statistically
bination, it became evident that there is a mini¬ meaningful results. Determination of sample
mum daily dose of carbidopa above which pe¬ size is often based on pilot studies conducted in

234 • The Theory and Practice of Industrial Pharmacy

smaller test panels. Washout periods between age form may be improved by reformulation.
treatments are incorporated into the study plan Low bioavailability from the oral solution, on the
to avoid carryover effects from the previous other hand, indicates that the drug is intrinsi¬
treatment. The analytic method must be specific cally poorly absorbed or is subject to significant
for the drug and validated with respect to sensi¬ first-pass metabolism and is not likely to be im¬
tivity, reproducibility, and linearity. proved by formulation.
In all cases, bioavailability of a test dosage
form x is obtained by comparison to a reference
Dose Dependence
standard s, which may be an intravenous or oral
To make reliable inferences based on blood solution, or in bioequivalence studies, another
and/or urine drug concentration data, some formulation of the same drug. Based on equation
basic pharmacokinetic properties of the drug (46), the bioavailability of dosage form x relative
must be known. At the minimum, it is necessary to that of s is defined as:
to determine whether absorption and disposition
kinetics are linear. Nonlinearity is indicated if Fx Ds CLX AUCX
absorption or disposition kinetics depend on the Fs Dx CLS AUCL
dose of drug administered. Proportionate in¬
crease in AUC and similarity of 4 following gra¬ Ds CLX CL) Ux
(109)
dated oral doses imply linearity in both absorp¬ Dx CLS CLX Ul
tion and disposition kinetics. Changes in 4 or
disproportionate increase in AUC with in¬ If the standard is an intravenous dose, then
creased doses may be manifestations of nonline¬ Fs = 1 and the absolute bioavailability of x is
arity in absorption or disposition. Intravenous determined; otherwise, a relative bioavailability
administration of the drug avoids the influence is obtained. In any event, an assumption must
of absorption, and any nonlinearity observed be made regarding body clearances between
with gradated intravenous doses is attributable treatments before bioavailability can be as¬
to disposition. sessed. Depending on the assumption, different
procedures may be employed.
If the assumption of CLX = CLS is adopted and
Bioavailability
substituted into equation (109), the relative bio-
Bioavailability is defined as the extent and the availability is given by the dose-corrected ratio of
rate at which the active ingredient is delivered to AUC values:
the general circulation from the dosage form.
Thus, by definition, intravenously administered Ds AUCX
drugs are completely bioavailable. The bioavaila¬ Fx/Fs = (110)
Dx AUC*
bility F following a nonintravenous dose Dx is
given by equation (46), which can also be ex¬
This method requires data defining the entire
pressed as:
area under the plasma concentration time curve
CT Ux for both treatments.
FDX = -^Ux = (108) On the other hand, for drugs excreted un¬
CL,- rr
changed in the urine, bioavailability may be ob¬
tained assuming that the renal to plasma clear¬
Estimation of the product FDX requires knowl¬
ance ratio remains constant between
edge of CL (or fr), which is obtained in a sepa¬
treatments. Equation (109) is reduced to:
rate treatment following an intravenous dose of
the drug (i.e., F = 1). When intravenous use of
Ds Ux
the drug is precluded, an oral solution of the Fx/Fs = (HD
drug may serve as the reference standard for a Dx Ui
solid oral dosage form. In principle, the bioavail¬
ability of the drug from an oral solution is the Thus, the bioavailability ratio equals the ratio of
maximum to be expected from a solid oral dos¬ dose-corrected total urinary recoveries of the
age form. Ideally, a solid dosage form is com¬ unchanged drug.
pared to both an intravenous and an oral solu¬ If both urine and AUC data are available, a
tion dose of the drug. In this manner, the effect third method may be employed.132,133 This
of formulation as well as the absolute bioavaila¬ method assumes that the change in plasma
bility can be determined. If bioavailability from clearance between two treatments is caused by
the solid dosage form is lower than that from an that of the renal clearance only, and that the
oral solution, then the performance of the dos¬ nonrenal clearance remains unchanged. The

BIOPHARMACEUTICS • 235
ratio of the two plasma clearances becomes: dependent means such as the Wagner-Nelson or
Loo-Riegelman methods given in equations (48)
CL* / U* FSDS - Ui \ // FSDS \ through (56).
CLS VAUC* + AUC* // l AUC),/
(112) Example
Test for Linearity. Simulated results for a
Substitution of equation (112) into equation subject in a typical dose-dependence pharmaco¬
(109) yields: kinetic study are used to illustrate the applica¬
tion of the methods described. The subject re¬
Ds AUC* ceived single 250-, 500-, and 1000-mg i.v.
boluses of the drug on separate occasions in a
D* AUCL randomized, three-way crossover study. Serial
4_1_(|jx _ ys AUC*) (113)
plasma samples were collected over 12 hours,
+ fsDx(u* u“AUCl/ and total urine was collected in intervals
through 48 hours after drug administration.
Equation (113) differs from equation (110) in Analytic results for the unchanged drug are
that it incorporates, in addition to the dose-cor¬ given in Table 9-9.
Plasma drug concentration-time profiles,
rected AUC ratio, a correction term to account
when plotted on semilogarithmic paper (Fig.
for the assumed change in plasma clearance.
9-28), show a rapid initial decline and then be¬
When s is an intravenous dose, Fs = 1 and equa¬
come linear after ~6 hours. Upon curve-strip¬
tion (113) reduces to:
ping, as given in equations (28) and (29), it is
clear that the data are best described by biexpo¬
AT IT*
F* = (CLS - CL) + CL*)--^p- (114) nential functions. Estimates of A, B, a, and p
can be obtained by curve-stripping, linear re¬
gression techniques,136,137 or nonlinear regres-
Thus, CL* is calculated from the sum of CL* and
the nonrenal clearance observed in the i.v. treat¬
ment, that is, CLS - CL®. If the bioavailability of
the reference standard is unknown, an approxi¬
mate solution to equation (113) may be obtained
by setting FSD* in the second term equal to D*.
The nature of this approximation has been de¬
fined, and an optimal solution suggested.133
A unique approach that obviates the need for
assumptions concerning CL between treatments
is to administer simultaneously an i.v. dose of
the drug labeled with a stable radioisotope and
the oral dose of the unlabeled drug.134'135
The foregoing methods of estimating the ex¬
tent of bioavailability apply only to drugs that
obey linear pharmacokinetics. For drugs follow¬
ing nonlinear pharmacokinetics, methodology
should be developed on a case-by-case basis. For
example, in the absence of first-pass metabo¬
lism, total urinary recovery is a measure of bioa¬
vailability if the unchanged drug and its metabo¬
lites are quantitatively excreted in the urine.
After a nonintravenous dose of the drug is
administered, the time to reach the maximum
plasma concentration, may be regarded as
a qualitative measure of the rate of absorption,
with the recognition that tmax is a function of not
only absorption but also elimination of the drug.
The preferred method is to use an intravenous
dose as a reference standard and to isolate the Time (h)
absorption profile for the nonintravenous formu¬ FIG. 9-28. Typical plasma drug concentration profiles of
lation by the use of deconvolution or model- drug in plasma following single intravenous doses.

236 • The Theory and Practice of Industrial Pharmacy

Table 9-9. Analytic Results for a Subject in a Typical Dose-Dependence Pharmacokinetic Study of a
Drug Given by Bolus Intravenous Injection at Doses of 250, 500, and 1000 mg

Plasma Drug Concentration (gg/ml) Urinary Drug Excretion (mg)

Time(h) 250 mg 500 mg 1000 mg Time(h) 250 mg 500 mg 1000 mg

O(predmg) 0 0 0 -2 to 0 0 0 0
(predrug)
0.1 10.8 21.0 40.9 0-2 80.2 179.2 293.7
0.25 9.2 18.1 35.2 2-4 28.8 59.0 112.1
0.50 7.3 14.3 27.9 4-6 18.7 36.4 74.5
0.75 5.8 11.5 22.6 6-8 13.2 25.6 53.2
1.0 4.8 9.4 18.7 8-12 16.1 30.1 65.7
1.5 3.4 6.7 13.7 12-24 14.4 27.0 60.6
2.0 2.7 5.1 10.9 24-36 1.90 2.90 8.4
3.0 1.9 3.5 8.1 36-48 0 0.4 1.2
4.0 1.6 2.7 6.5
6.0 1.1 1.8 4.6 Total 173.3 360.6 669.4
8.0 0.77 1.3 3.3
10.0 0.55 0.91 2.4
12.0 0.39 0.64 1.7

sion methods.138'139 Parameters given in Table according to equation (18), this finding also in-
9-10 were used to generate the solid fines in Fig- dicates that CL should be constant and indepen-
ure 9-28. These parameters are then used to cal- dent of the dose. Some variation in CL is ob-
culate pharmacokinetic parameters for the drug; served (Table 9-10) but there is no consistent
methods and results are also summarized in trend as dose increases.
Table 9-10. As indicated in Table 9-10, renal clearance of
Half-fives, rate constants, and volume of dis- the drug is the major component of CL; about
tribution are similar among the three doses. As 70% of the dose is excreted unchanged in urine
shown in Figure 9-29, AUC„ increases in pro- (fr). The average CLr differs somewhat between
portion to dose, indicating that the drug obeys treatments, but as with CL, there is no consist-
linear (first-order) disposition kinetics over the ent trend as the dose increases,
range of doses studied. Since AUG. = Div/CL Bioavailability. Suppose the same drug is to

Table 9-10. Pharmacokinetic Parameters Derived from Data in Table 9-9.

D„ Equation in Text or
Calculation
Parameter Units 250 mg 500 mg 1000 mg Method

A Mg/ml 9.01 18.0 33.1 28

B pg/ml 3.00 5.28 12.3 28
a h-1 1.39 1.28 1.39 28
p h-1 0.170 0.178 0.164 28

AUC^ p.g • h/ml 24.1 43.7 98.8 ~+—

a fi
t$>a h 0.50 0.54 0.50 0.693la
hip h 4.08 3.89 4.23 0.693//3
^•10 h-1 0.498 0.531 0.460 41
^21 h-1 0.476 0.428 0.496 42
^12 h-1 0.589 0.497 0.596 43
Vi L 20.8 21.5 22.0 40
CL ml/min 173 190 169 44
CLr ml/min 120 137 113 12 or 14
CL„r mlimin 53 53 56 20
% dose 69.3 72.1 66.9 7

BIOPHARMACEUTICS • 237
 250 500 1000

Dlv (mg)
FIG. 9-29. Relationship between AUC& and dosage.

0 2 4 6 8 10 12

be marketed in tablet formulations containing Time (h)

250-, 500-, and 1000-mg of the drug. The bioa¬ FIG. 9-30. Typical plasma concentration profiles after
vailability of the drug and therefore whether the oral administration of single doses of a drug.
amount of drug absorbed is proportional to the
administered dose (dose-proportionality) need to
be determined. Since it is already established dose treatments are given in Table 9-11. For
that the drug obeys linear disposition kinetics, convenience, suppose that the 500-mg i.v. dose
both objectives can be met by comparing the data axe identical to those used in the previous
three formulations with a single i.v. reference example (Table 9-9). As before, the i.v. data are
dose of the drug in a single-dose, randomized, analyzed, and the resulting pharmapokinetic
four-way crossover study. A 500-mg intravenous parameters for the 500-mg dose are as given in
dose is selected for the study since this is in the Table 9-10. Plasma drug profiles after the oral
middle of the oral dose range. doses are compared in Figure 9-30. The drug is
Simulated results for drug assay in plasma apparently rapidly absorbed, peak plasma con¬
and urine after the 250-, 500-, and 1000-mg oral centrations are observed within an hour of each

Table 9-11. Analytic Results for a Subject in a Typical Bioavailability Study Comparing Single 250-,
500-, and 1000-mg Oral Tablet Doses of a Drug

Plasma Drug Concentration (gg/ml) Urinary Drug Excretion (mg)

Time(h) 250 mg 500 mg 1000 mg Time(h) 250 mg 500 mg 2000 mg

0 0 0 0 -2 to 0 0 0 0
(predrug)
0.25 4.0 7.9 14.7 0-2 66.2 136.3 256.1
0.5 5.4 10.7 20.8 2-4 32.7 63.2 137.3
1.0 5.4 10.1 21.7 4-6 18.5 35.5 77.6
1.5 4.2 7.8 17.9 6-8 12.7 24.1 53.4
2.0 3.2 5.9 14.1 8-12 15.5 28.8 65.4
3.0 2.1 3.7 9.1 12-24 13.8 24.7 ‘ 59.7
4.0 1.5 2.7 6.7 24-36 1.8 3.0 8.1
6.0 1.0 1.8 4.4 36-48 0.27 0.30 1.1
8.0 0.71 1.2 3.1
10.0 0.51 0.87 2.2 Total 161.5 . 315.9 658.7
12.0 0.36 0.61 1.6

238 • The Theory and Practice of Industrial Pharmacy

A
Table 9-12. Summary of Results for a Subject in a Dose-Proportionality/Bioavailability Study Com¬
paring 250-, 500-, and. 1000-mg Oral Tablet Formulations With a 500-mg Intravenous Dose as the
Standard

• 0PO DTO
Source or Method
Parameter Units 250 mg 500 mg 1000 mg 500 mg of Calculation

c
'-'max . Mg/ml 5.4 10.7 21.7 — Table 9-11
^max h 0.5 0.5 1.0 — Table 9-11
4 h 4.08 3.88 4.10 — 0.693/terminal slope
3.89 Table 9-10
CLr ml/min 125 135 120 Equation (12): t! = Ojtj = 12
137 Table 9-10.
AUC„ /ig ■ h/ml 21.5 39.0 91.5 Equation (14): UJCLr
43.7 Table 9-10
U„ . % Dose 64.6 63.2 65.9 Table 9-11
72.1 Table 9-10
F % Dose 98.4 89.2 105 Equation (110)
89.6 87.7 91.4 Equation (111)
91.8 88.0 4 95.0 Equation (114)

dose and increase in proportion to the adminis¬ the total area under the curve. Dose-proportion¬
tered dose. After ~6 hours, plasma concentra¬ ality is observed with the three oral formulations
tions decline log-linearly with a terminal disposi¬ because AUC£° approximately doubles when the
tion half-life that is similar among all administered dose is doubled (Table 9-12).
treatments, including the i.v. dose (Table 9-12). Bioavailability estimates of the drug calcu¬
The renal clearance of the drug is calculated lated under the three alternative assumptions
by equation (12) where tx and 4 are times corre¬ expressed in equations (110), (111), and (114),
sponding to the beginning and the end of a urine regarding CL between treatments, are given in
collection interval; the area under the plasma Table 9-12. Without evidence to the contrary,
concentration curve over the same time interval, estimates based on equation (114) may be pre¬
J^Cjdt, is evaluated by the trapezoidal method ferred on the basis that plasma clearance in th,e
or by other suitable methods of interpolation.132 oral dose treatments is adjusted only for that
The average CLr observed in each oral dose portion that is experimentally observable, the
treatment (i.e., 0 to 12 hours) is given in Table renal clearance. The bioavailability of the drug,
9-12. Note that by design, urine collections are F, is independent of the dose, and the drug is
segmented into five discrete intervals over the nearly quantitatively absorbed over the 250- to
time plasma is being sampled (Table 9-11), and 1000-mg dosage range.
plasma samples are included at the beginning To obtain the rate of absorption, the intrave¬
and end of each urine collection period. Equa¬ nous dose data (see Table 9-10) are used as the
tion (12) can then be used to calculate CLr for reference, standard to define the disposition of
each of these intervals to compare these “incre¬ the drug, and the absorption profile is con¬
mental” values of CLr with the average value. In structed based on the Loo-Riegelman method, as
the present example, CLr is constant within a given in equations (49) through (56). The ab¬
treatment (calculations not shown) and thereby sorption profiles for the oral dose treatments are
is also independent of the plasma concentration given in Table 9-13. For this calculation, AUCg°
of the drug. Typically, there is some variation in values were estimated by the trapezoidal
mean CLr between treatments (Table 9-11). method, and CL was adjusted for the observed
Since CL|° is constant within a treatment, the change in CLr between the i.v. and p.o. routes of
total area under the curve, AUCg°, can be ob¬ administration consistent with the estimate of F.
tained from the ratio of total urinary recovery, Absorption of the drug is rapid and is nearly over
U£° and CL£°, as given in equation (14). This by 6 hours after the dose has been administered;
method is model-independent and does not re¬ by 12 hours, the total amount absorbed is nearly
quire extrapolation based on 4 of the plasma pro¬ identical to that calculated by the model-inde¬
file after the last data point (12 hours) to obtain pendent methods (Table 9-12).

BIOPHARMACEUT1.CS • 239
Table 9-13. Absorption Profiles for Drug After Single Oral Doses of 250, 500, and 1000 mg

Cumulative Amount of Drug Absorbed, A(t)

250 mg 500 mg 1000 mg

Time
(h) mg % Dose mg % Dose mg % Dose

0 0 0 0 0 0 0
0.25 96.5 38.6 191.2 38.2 354,1 35.4
0.5 150.6 60.2 300.2 60.0 574.5 57.4
1.0 202.2 80.9 389.6 77.9 794.4 79.4
1.5 217.4 87.0 418.8 83.8 881.0 88.1
2.0 222.8 89.1 429.2 85.8 917.0 91.7
3.0 228.6 91.4 436.3 87.3 941.2 94.1
4.0 228.5 91.4 437.5 87.5 947.7 94.8
6.0 229.3 91.7 440.4 88,1 952.8 95.3
8.0 229.5 91.8 438.8 87.8 952.1 95.2
10.0 229.7 91.9 439.1 87.8 950.8 95.1
12.0 229.7 91.9 439.2 87.8 951.2 95.1

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242 • The Theory and Practice of Industrial Pharmacy

 10

Statistical Applications in
the Pharmaceutical Sciences
SANFORD BOLTON-

Statisticians have become familiar faces in the quirements of all FDA submissions on new
research laboratories of industrial pharmaceuti¬ drugs or new dosage forms.
cal companies. Part of this recent upsurge has Applications of statistical techniques to phar¬
been due to the recognition by research scien¬ maceutical research are beginning to be more
tists that the-application of statistics can be a appreciated. Some statisticians and pharmaceu¬
useful tool in the design, analysis, and interpre¬ tical researchers, alone or in collaboration, have
tation of experiments. Also, governmental agen¬ had the foresight to recognize applications in
cies, principally the Food and Drug Administra¬ this area, and recent publications in the areas of
tion (FDA) have promulgated rules and optimization and experimental design indicate
regulations that virtually necessitate the appli¬ the activity in formulation research. ,2,3,4
cation of statistical techniques to fulfill the law Since this book deals with pharmaceutical
or its recommendations. technology, a chapter on statistics cannot be
The “Good Manufacturing Practices” (GMPs) expected to be in any way complete. Statisticians
and the “Good Laboratory Practices” (GLPs) are should be consulted for all but the simplest prob¬
more recent examples of FDA regulations that lems. Data from real experiments almost always
recommend statistical usage, formally or im¬ have unexpected wrinkles that need special con¬
plied, as part of the routine of careful implemen¬ sideration. The interaction should allow both the
tation and record-keeping of research and man¬ statistician and the pharmaceutical scientist to
ufacturing operations. For example, in learn and grow.
section 211.166 of the GMPs, the following There will always be more than one way to
statement appears with regard to stability test¬ examine, analyze, and interpret data. Statistics
ing and expiration dating of pharmaceuticals: is not an exact science; given a set ’of data, two
. . sample size and test intervals based on sta¬ statisticians may analyze and present the results
tistical criteria for each attribute examined to differently. Data that comes from a well-de¬
assure valid estimates of stability.” In .sec¬ signed experiment, however, should lead the
tion 58.120 of the GLPs regarding the protocol experimenter to the same conclusion, indepen¬
for nonclinical laboratory studies, the following dent of the analyses. In fact, if this is not the
statement implies both a prior statistical input case, something is amiss, and the data and/or
and the ultimate statistical analysis of the exper¬ analysis should be carefully re-examined.
imental results: “A statement of the proposed Computations in the statistical analysis of
statistical methods to be used [is to be included data are not difficult, but can be complicated,
in all protocols]. . . especially for the novice. Statistical packages are
Statistical input in sampling and testing for readily available, and if the data are compatible
quality control, stability testing, process valida¬ with software programs, they should be used.
tion, design of preclinical protocols, including Often, however, the analysis that should be used
statistical methods and appropriate statistical is not obvious except to the expert, and fre¬
analysis of the resulting data, are applications quently, there are situations in which only a
routinely applied by the pharmaceutical indus¬ custom-made program can fit the data. In addi¬
try to satisfy both internal requirements and tion, the statistician must sometimes improvise,
FDA recommendations. Both statistical treat¬ using creativity and ingenuity for a situation for
ment and interpretation of clinical data are re¬ which an analysis has yet to be devised. Never-

243
theless, anyone "who uses statistics should prac¬ Choosing Samples
tice some of the computations. This allows a
“hands-on” appreciation of what is involved, When 100 tablets are inspected for defects, or
helping the user to learn more about what he is when 20 tablets are assayed for potency, only a
doing. small proportion of the potentially available data
is being tested. Much of the work in statistics
Introductory Statistical Concepts involves examining relatively small samples and
then making inferences about the population
Statistics encompasses many areas of human from which the sample came. There are many
endeavor, and within each area is a scientific reasons why the totality of data cannot always be
field in itself. The statistical techniques most observed or tested. For instance, 100% sampling
applicable to pharmaceutical experimentation may be precluded because of practical time and
can be categorized broadly as follows: cost considerations. Situations in which 100%
sampling cannot be accomplished practically are
1. Descriptive statistics: Presentation of data
(1) destructive assays that may occur in analyti¬
including tabular and graphic representation cal procedures and (2) cases in which the popu¬
2. Hypothesis testing lation definition precludes 100% sampling, as
occurs in clinical studies in which the popula¬
3. Estimation
tion may include all patients with a particular
4. Experimental design disease.
The proper selection of samples is an essential
1. Although this chapter is mainly concerned part of a good experiment and is a consequence
with the latter three categories, descriptive sta¬ of the experimental design. A random sample is
tistics are important. Professional statisticians one in which each of all possible experimental
have expertise in this area, and collaboration units have an equal chance of being included in
between pharmaceutical scientist and statisti¬ the experiment or sample. Data derived from
cian should be complementary, using to full ad¬ random samples yield fair, unbiased estimates of
vantage the knowledge and experience of both population parameters such as the mean. To
parties. One should carefully consider various sample tablets randomly from a batch for visual
alternatives, presenting “pictures” of the data in inspection or assay, each tablet should have an
the most convincing manner. equal chance of being chosen. The method of
2. The possible overuse of hypothesis testing “random sampling” clearly must be modified to
in statistics has been debated, but at present it is apply to many real-life experimental situations.
certainly a popular standard statistical approach For example, if the experiment entails stratifica¬
to decision making. Government agencies, the tion, the random sampling is done within each
FDA in particular, rely on significance levels stratum. To obtain a random sample, a number
(5%) for drug-related claims. can be conceptually assigned to each potential
3. Estimation of unknown parameters such candidate, and then a table of random numbers
as a population mean or the slope of a line is can be used to select those units or individuals
often the objective of a statistical investigation. to be included in the experiment or to be as¬
This concept is illustrated and discussed in signed to a particular treatment group. Alterna¬
some detail in this chapter. tively, all possible experimental units can be
4. Statistical experimental design pervades all thoroughly mixed (literally or figuratively), and
areas, and some designs commonly used in samples can be chosen at random as in a lottery.
pharmaceutical experiments are presented. Poor One must be aware that bias can easily be in¬
or inadequate design can invalidate an other¬ troduced into the selection of samples if care is
wise carefully conducted experiment. not taken in randomization. Often, one must
Statistical analysis does not yield unequivocal compromise between theory and practice. In a
answers, nor can the analysis redeem a poor multicenter clinical trial where there is a choice
experiment. Good experimental design is essen¬ of large numbers of patients from perhaps thou¬
tial. The statistics presented here are concerned sands of clinical sites, the sample chosen may be
with probability. Observations by their very na¬ based more on convenience than randomness. If
ture are variable. By “variable,” we mean that if an effort is made, however, to choose sites based
an observation (an experiment) is repeated, the on relevant factors such as geographic location,
new outcome cannot be exactly predicted. Varia¬ for example, one might practically consider this
bility and unpredictability characterize most of a random sample. Certainly, choosing tablets for
our experience; here, the uncertainty is har¬ inspection cannot be done both conveniently
nessed and put to work. and strictly at random. How would one identify

244 • The Theory and Practice of Industrial Pharmacy

the 1,565,387th tablet if it was to be included in from the same small portion of material repeated
the sample? An alternative is to select samples over time, and (3) responses to a flavor prefer¬
stratified over various time periods during the ence from the same individual on multiple occa¬
production run. Ingenuity can often be used to sions. In these cases, the same experimental
devise a “pseudorandom” sampling procedure unit being used for more than one observation is
that can be satisfactory in difficult situations. responsible for the dependence, i.e.,-each obser¬
Systematic sampling is often used as an im¬ vation has a common component as part of its
provement over random sampling. Every nth variability. Note that in (2) the nature of the data
sample is chosen for inspection, testing, or anal¬ is different if the assay is performed on different
ysis, which ensures a regular sampling through¬ portions of material rather than on a single ho¬
out a process such as the manufacture of tablets. mogeneous portion.
If the process is cyclic or periodic in nature, and The same data may be treated as independent
if by chance the sampling corresponds to the in one situation and correlated in another. For
period, this method of sampling can lead to erro¬ example, to assess the stability of a product, a
neous conclusions. single bottle from a batch is assayed over time
Sampling for quality control should be care¬ with duplicate assays at each time period. Are
fully implemented to ensure that the samples the duplicates assayed at a given time period
selected are representative. A representative independent? If they are analyzed concurrently,
sample can be regarded as one that is carefully the duplicates are probably not independent be¬
chosen, and perhaps subsequently treated or cause of the common conditions existing at the
modified (e.g., by compositing in the case of time of the assay. These common conditions
bulk powders) so that the sample has the same could include, for example, the same analyst,
characteristics as the bulk material (powder) if it the same reagents, and the same instrument
were homogeneous. For example, sampling standardized with the same standard material.
from the top of a large container might not be Duplicates performed at two different laborato¬
representative and can result in samples that are ries by two different analysts or assays done at
different from those that might have been ob¬ different points in time are probably indepen¬
tained from the main bulk of material. It is not dent if proper care is taken. Since the tablets
easy to define exactly (statistically) a representa¬ come from a single bottle in which the material
tive sampling scheme for testing bulk materials. is more homogeneous than the batch as a whole,
The amount of material to be inspected, as well can any of the assays be considered indepen¬
as the number and kind of samples to be chosen, dent? These are rhetorical questions and serve
is often based on experience and empirical rules. to illustrate the complexity of a seemingly sim¬
One method of sampling bulk raw materials ple concept. If observations are correlated, spe¬
from drums, for example, is to sample VN con¬ cial analyses may be necessary to account for the
tainers (add one container if there is a remain¬ correlation.
der) where N is the number of containers. The Bias is another term common to statistics. If
material may then be taken from different parts samples are not carefully chosen, bias, which
of the container using a thief a sampling device may not be obvious, can easily be introduced.
that is basically a long hollow tube inserted into Human beings cannot always be objective, and
the powdered material. After collection, the vari¬ if some controls are not imposed, what is ob¬
ous samples are often thoroughly mixed, and served is often what one wishes to observe. Try
samples for assay are taken from this homogene¬ to make up a series of “random” numbers from 0
ous mixture. If carefully implemented, such pro¬ to 9 or letters of the alphabet quickly, without too
cedures for finished dosage forms or powdered much thinking, and you will observe your own
raw materials and intermediates should result in bias. Randomization and blinding are ways to
representative samples for analysis. overcome bias. In blinded experiments, the per¬
son observing and recording experimental re¬
sults is not aware of the source of the data. This
Independence and Bias procedure is especially important in experi¬
Many analyses and interpretation of data as¬ ments with subjective evaluations. Some exam¬
sume that the sample data points are indepen¬ ples of how bias may enter an experiment may
dent of one another, i.e., that the result of one seem obvious to an objective outsider, but may
observation does not influence the result of an¬ often not be obvious to the scientist closely in¬
other concurrent, future, or past observation. volved with his experiment. In an open (not
Examples of dependent or correlated observa¬ blinded) clinical trial, the more severely affected
tions are (1) blood pressure of the same individ¬ patients may be selected for the treatment that
ual taken on two or more occasions, (2) assays the inyestigator feels (perhaps erroneously) is

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 245

the better one. During duplicate assays, a knowl¬ Table 10-1. Frequency Distribution of Weights
edge of the results of the first assay may serve as of 200 Tablets
a criterion for accepting or rejecting the second
assay. Data used in curve fitting, e.g., as a func¬ Frequency Proportion of Tablets
Interval* (Number of Tablets) in Interval
tion of time, may be rejected because the fit is
not as good as expected. 176-180 3 0.015
180-184 6 0.03
184-188 12 0.06
188-192 17 0.085
192-196 26 0.13
Probability Distributions 196-200 33 0.165
Observations can be categorized as discrete or 200-204 36 0.18
continuous. A discrete observation is one of a 204-208 23 0.115
countable finite number, such as (1) a tablet cat¬ 208-212 22 0.11
egorized as either out of limits or within limits or 212-216 11 0.055
(2) the number of tablets in a bottle whose label 216-220 7 0.035
indicates 100 tablets. A continuous observation 220-224 4 0.02
is one that can be measured more and more pre¬
TOTAL 200 1.000
cisely according to the sensitivity of the measur¬
ing instrument. Weights of tablets and blood •Tablets included from the lower weight in interval up to, but
pressure are continuous measurements. Most of not including, the higher weight in interval.
the statistical problems in pharmaceutical re-
. search can be dealt with using the binominal
(discrete) and the normal (continuous) probabil¬ Normal Distribution—A Continuous Dis¬
ity distributions. The data that at least approxi¬ tribution. Examples of two normal distribu¬
mate these distributions are not mysterious as tions are shown in Figure 10-1. The reader may
suggested by the foregoing examples. These are find it helpful to visualize these distributions as
the ordinary data that are observed in real-life frequency distributions of tablet weights, as has
experiments: weight, blood pressure, intact'drug just been described. The two distributions in
in a formulation, dissolution, blood level of a Figure 10-1 have certain similarities and differ¬
drug, proportion of tablets out of specification, ences. Both curves are symmetric about a cen¬
tablet weights, or number of defective botdes. By tral value designated as p, the mean, and both
defining distributions of hypothetical data, infer¬ are bell-shaped. This shape indicates that most
ences can be made about samples of real data of the values in the distribution are near the
that are observed in the laboratory, the produc¬ mean, and as values are further from the mean,
tion area, or the clinic. they are less prevalent. Although theoretically
A probability distribution can be visualized as the data comprising a normal distribution can
a frequency distribution constructed from a take on values between —» and +°o, values suf¬
large number of observations. For example, the ficiently far from the mean have little chance of
weights of 200 tablets can be summarized in a being observed. For example, if the mean weight
frequency distribution, as shown in Table 10-1. of a batch of tablets were 200 mg, the chances of
The number of tablets that fall into a given inter¬
val is the frequency for that interval. The fre¬
quency distribution for the 200 tablets approxi¬
mates the true distribution. The weights of an
entire batch of 1,000,000 tablets can be thought
of as the universe, or true underlying distribu¬
tion, from which the 200 tablets were selected.
In Table 10-1, the tablets are placed in a discrete
number (12) of class intervals. If the intervals
were made small enough, resulting in a large
number of intervals of equal width, a plot of the
proportion of tablets in the batch falling into
each interval (as in a histogram) would result in
a smooth curve as the distinction between inter¬
vals disappears. Such a curve might look like FIG. 10-1. Examples of two normal curves with different
one of the normal curves shown in Figures 10-1 means and variances. The curve on the right has a smaller
or 10-2. variance and a larger mean.

246 • The Theory and Practice of Industrial Pharmacy

 deviations of each value from the mean divided
by (N - 1) is called the variance (S2). The
square root of the variance is the standard devia¬
tion. The number of observations minus one
(N - 1), is known as the degrees of freedom.
Many statistical calculations involve 2(X( - X)2,
and this expression appears often in this chap¬
ter, with examples of the calculations.*
As a simple illustration of the calculation of
the standard deviation, consider three data
points with values 2, 4, and 6. The mean is
12/3 = 4. The value for 2(X - X)2 is calculated
as follows:

X X (X - X) (X - X)2

WElGHT(Mg)
2 4,-2 4
4 4 0 0
FIG. 10-2. Distribution of tablet weights with mean = 6 4 2 4
200, and standard deviation = 10. The small shaded areas
in the tails each represent a probability of approximately 2(X - X)2 = 8
0.025.

The standard deviation of the numbers 2,4, and

6 is V8/2 = 2. The variance S2 is the square of
having a 100- or 300-mg tablet in a typical batch
the standard deviation and is equal to 22 = 4 in
would be small.
this example. The sample variance S2 is an un¬
In addition to normal curves being distin¬
biased estimate of the population variance a2.
guished by the mean or central value, they differ
The use of (N - 1) in the denominator of the
in their “spread.” The curve on the left-hand
expression for S2 ensures that the estimate is
side of Figure 10-1 is more spread out than the
unbiased. A shortcut and more accurate com¬
one on the right, a consequence of its larger
puting formula for 2(X - X)2 is 2 X2 - (2X)2/N
standard deviation (<r). Normal curves are ex¬
equal to 22 + 42 + 62 - ^2 = 8 in the above
actly defined by two parameters: the mean, a
example.
measure of location, and the standard deviation,
Another property of the normal distribution is
a measure of spread.
that the area under the normal curve as shown
The Greek letters p and a refer to the mean
in Figure 10-1, for example, is exactly one (1)
and standard deviation of the universe or popu¬
irrespective of the values p and cr. The area be¬
lation. The population is the totality of data from
tween any two points (Figure 10-2), e.g., 190 and
which sample data are derived. In the example
210, represents the probability of observing a
of 200 tablet weights, the 200 tablets are sam¬
value between 190 and 210. Because the theo¬
ples taken from a population of a batch of tablets
retic normal curve comprises an infinite number
that may consist of 1,000,000 tablets or more. In
of values, the probability of observing any single
general, p and a are unknown and are estimated
value is zero. However, in many statistical pro¬
from the data derived from the sample. The
cedures, there is a need to compute the probabil¬
sample mean, or average, X, is an unbiased esti¬
ity of observing values in some interval. For ex¬
mate of the true population mean p. That is, al¬
ample, suppose that the distribution of tablet
though the average obtained from any single
weights approximates a normal distribution as
experiment cannot be expected to equal p, if an
shown in Figure 10-2. The mean weight, p, of
experiment is repeated many times, and all the
this batch of tablets is 200 mg, and the standard
X’s are averaged, this overall average would
deviation, cr, is 10. The proportion of tablets
equal p. The average is calculated as 2 X/N,
weighing between 190 and 210 mg can be con¬
where 2 Xt is the sum of N data points. The av¬
sidered a measure of homogeneity of the batch
erage of the tablet weights in Table 10.1 is
and is equivalent to the probability of choosing a
200.32 mg. The average weight of the entire
tablet at random that weighs between 190 and
batch of tablets is probably _not equal to
210 mg. Probability can be conveniently thought
200.32 mg. The sample mean, X, however, is
the best estimate of the population mean, p. The
standard deviation. S, is calculated as ‘Future use of summation notation in this chapter does
V2(Xi - X)2/(N - 1). The sum of the squared not include the subscript i, although its use is implied.

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 247

of as the proportion of times a value or range of A
values is observed after many observations.
This problem can be solved by referring to a
table of “areas under the standard normal
curve.” Table 10-2 is a short version of such a
table that gives the area between -°° and Z,
where Z is a transformation that changes all nor¬
mal curves into the standard normal curve,
which has a mean of 0 and a standard deviation
190 200 210
of 1. This transformation allows the use of a sin¬
gle table, which can be used to calculate the area
between any two points for any normal curve.
The transformation is: B
Z = (X - fj.)/cr

To calculate the area between -» and X, com¬

pute Z and find the area in Table 10-2. The
reader may find it convenient to refer to Fig¬
ures 10-2 and 10-3 in the following discussion,
which describes the calculation for finding the
area between 190 and 210.
_J_I_L
-1 0 +1
1. Area between -» and 210: Z=
(X - fjL)/cr = (210 - 200)/10 = 1. Area be¬ z
tween -oo and 210 = 0.84 from Table 10-2.
2, Area between -oo and 190: Z=
(190 - 200)/10 = -1. Area between -oo and
c
190 = 0.16 from Table 10-2.

Table 10-2. Short Table of Cumulative Areas

Under the Standard Normal Curve

Z = (X- u)/(T Area From —<*> to Z

-2.576* 0.005 FIG. 10-3. A to C, Calculation of areas under a normal

-2.326 0.01 curve with u = 200 and a - 10 from table of areas under
-1.96* 0.025 the standard normal curve (see Table 10-2).
-1.645“ 0.05 Z = (X - u )!a.
-1.58 0.057
-1.28 0.10
-1.00 0.16 3. Area between 190 and 210 = (Area between
-0.50 0.31 —oo and 210) - (Area between —® and
0 0.50
190) = 0.84 - 0.16 = 0.68.
0.50 0.69
1.00 0.84
This computation is illustrated in Figure 10-3.
1.28 0.90
1.58 0.943
These calculations may also be made based on
1.645* 0.95 the symmetry of the normal curve; the portion of
1.96* 0.975 the curve below the mean is the mirror image of
2.326 0.99 that above the mean, and therefore the, area
2.576* 0.995 above and below the mean each equal 0.5 by def¬
inition. In this case, the area between 210 and
*Z = ± 2.576, ± 1.96, and ± 1.645 are the cutoff points used for
200 (fi) is 0.84 - 0.5 = 0.34. Therefore, the
a two-sided test at the 1%, 5%, and 10% levels respectively.
Z — 1.645 is the cutoff point for a one-sided test at the 5% level
area between 190 and 210 is 2 x 0.34 = 0.68
where H0 is \x ^ /x0 and HA is fx > /x0. (see Fig. 10-3C). Thus, 68% of the tablets weigh
Z = -1.645 is the cutoff point at the 5% level for a one-sided between 190 and 210 mg, or equivalently, the
test where H0: /u. /xq and HA: /x < fi0. probability of choosing a single tablet at random

248 • The Theory and Practice of Industrial Pharmacy

 that weighs between 190 and 210 mg is 0.68. the batch of tablets will have a normal distribu¬
(Chances are 68/100 that a tablet randomly tion with a mean weight, p, of 200 mg and a
taken from the batch will weigh between 190 standard deviation, a, equal to Vo-2/N =
and 210 mg.) Vl00/10 = 3.16. The value crx (or Sx =
What are the chances of finding a tablet cho¬
S/VN, the sample estimate) is commonly
sen at random that weighs 10% more or less
known as the standard error of the mean.
than the mean weight? This question is equiva¬
Figure 10-4 shows how the distribution of
lent to asking, “What is the probability that a
means (N = 10) compares with the original dis¬
tablet will weigh less than 180 mg or more than tribution.
220 mg?” As before, calculate Z for X = 220 To answer the foregoing question, the proba¬
and Z for X = 180. Z220 = (220 - 200)/10 = 2; bility of the mean being less than 195 is calcu¬
the area is approximately 0.975. Z180= lated, as before, with p = 200 and with
(180 — 200)/10 = -2; the area is approximately a = 3.16. Thus, Z = (195 - 200)/3.16 = -1.58.
0.025. The area between 180 and 220 is From Table 10-2, the probability of X being be¬
0.975 — 0.025 = 0.95. Therefore, 5% of the tab¬ tween -oo and 195 is 0.057. Using the symmetry
lets will weigh above 220 or less than 180 mg. of the normal curve, the probability of an aver¬
By using the area between 180 and -a> (0.025), age weight of 10 tablets beings above 205 is also
and the symmetric properties of the normal
0.057, and the probability of X being below 195
curve, the same result is obtained (see Fig.
or more than 205 is 0.057 + 0.057 = 0.114.
10-2).
Therefore, the probability that the mean of ten
Another, slightly different question is also ger¬
tablets will be between 195 and 205 mg is
mane: “What is the probability that the mean of
(1 - 0.114) = 0.886.
10 randomly chosen tablets is between 195 and
The distribution of tablet weights cannot be
205 mg?” An important result in statistical the¬
identically equivalent to a normal distribution
ory that relates to the distribution of means, the
because there is some upper limit on tablet
central limit theorem, must be considered before
weight, and the lower limit must be greater than
this question can be answered. This theorem
zero. Usually, real-life data does not conform
states that for any probability distribution (with
exactly to theoretic distributions, and an exact
finite variance), the distribution of means of N
analogy of the normal curve does not exist in
randomly selected samples will tend to be nor¬
real examples. This does not mean that we can¬
mal as N becomes large. Thus, if a new distribu¬
not make practical use of this well-known bell-
tion is formed, based not on the original data but
shaped symmetric distribution. Much of the raw
on means of size N drawn from the original data,
the distribution of means will tend to be normal.
This consequence of the central limit theorem
allows a comfortable application of normal curve
theory when dealing with means. A natural
question is, “WTiat is meant by large N?” If the
original data are normal, then means of any size
N will be normal. The sample sizes needed to
make means from non-normal distributions
close to being normally distributed vary depend¬
ing to a great extent on how aberrant the distri¬
bution of the original data is from a normal dis¬
tribution. A good guess is that the means of
sample sizes of 30 or more for the kind of data
that are usually encountered will closely approx¬
imate a normal distribution.
The distribution of means of N observations
will have the same mean as the original distribu¬
tion, but fhe variance will be smaller, equal to
o2/N where a2 is the variance of the original dis¬
tribution. The means of many samples of size A
10, for example, will tend to cluster more closely
together than the individual data because ex¬
treme values will be compensated for by the
other sample values composing the mean. FIG. 10-4. Normal distribution of single observations
Therefore, the mean of samples of size 10 from (N = 1) and means of size 10 (N = 10).

statistical, applications in the pharmaceutical sciences • 249

 median. The median, also known as the 50th
percentile, is the value that splits the data in
half, i.e., half of the observations are greater and
half are less than the median value. With an
even number of observations, the median may
be considered to be the average of the two obser¬
vations in the middle of the data set, the num¬
bers having been ordered from lowest to highest.
For example, if N = 10, the median is the aver¬
age of the fifth and sixth values. If a distribution
of data is perfectly symmetric (as in the normal
curve), the median equals the mean. The me¬
dian is often used to describe asymmetric distri¬
butions, e.g., the median income.
The spread, or dispersion of data, is commonly
FIG. 10-5. Histogram of assays of a sample of 100 tablets. expressed as the standard deviation, S =
V2(X - X)2/(N - 1). The larger the value of
S, the greater is the spread of the data. Another
or transformed data encountered in pharmaceu¬ common way of expressing the spread is the
tical sciences are close enough to normal distri¬ range, which is equal to the difference between
butions to allow adequate treatment, as if such the highest and lowest values in the data set.
data were normal. Usually, insufficient data are The coefficient of variation (C.V.) is a measure
available to define the probability distribution of relative variation and is equal to the standard
exactly since only a sample, a small part of the deviation divided by the mean, trip, or S/X, the
totality of data, is available. There are quantita¬ sample estimate.
tive methods of assessing if a sample of data is
likely to belong to some known distribution, e.g.,
the normal distribution;5 however, in this pres¬ Statistical Inference and
entation, the true distribution underlying the
Estimation
relative small data sets that are often subjected
to analysis will be assumed to be known, as a
result of experience or other available informa¬ t Distribution
tion. Practical examples of experiments in which
Data plotted in various ways, pictures of the data are derived from populations with a normal
data, are revealing, not only to help visualization distribution are commonplace. The examples in
of the possible underlying distribution from which probabilities have been calculated thus
which the data are drawn, but also to obtain far assume a prior knowledge of the parameters
some insight into the meaning and interpreta¬ of the distribution, that is, the mean and vari¬
tion of the data. A histogram, or bar graph, is a ance are known. In the great majority of cases,
useful way of displaying data. Figure 10-5 shows population parameters are unknown. In fact,
an example of a histogram of assays of a sample often the purpose of the statistical analysis is to
of 100 tablets from a pilot batch. The number of estimate these unknown parameters based on
tablets per mg interval is plotted such that the the sample statistics. The sample mean and var¬
area of each bar is proportional to the number of iance, X and S2, are unbiased estimates of these
tablets in the interval. Although the distribution parameters, and if the underlying distribution
of these tablets is slighdy skewed to the right, to (or population) is normal, probabilities of events
say that the distribution of tablets in this batch based on these estimates can be obtained from
is approximately normal would not be unrea¬ the t distribution in a manner similar to that de¬
sonable. scribed previously for the normal distribution.
The ratio t = (X - /x)/(S/VN) has a student’s
t distribution with N — 1 degrees of freedom
Measures of Centrality and (df), where N is the sample size. The value X is
Spread the mean of the N samples selected; p is the
The arithmetic average, or mean, is the most mean of the underlying population distribu¬
common measure of the “center” of a distribu¬ tion from which the samples were selected;
tion and is equal to 2 X/N, as previously noted. and S is the sample standard deviation,
Another often used measure of centrality is the V2(X - X)2/(N - 1). This formula for t is the

250 • The Theory and Practice of Industrial Pharmacy

 The process involves a hypothesis about one
or more parameters of a statistical model. An
example of a hypothesis is that the mean, /a, of a
population, e.g., abatch of tablets, is some value,
Mo. perhaps 200 mg. A sample is chosen, and the
estimate of the parameter X is calculated. If the
sample estimate is close to the hypothesized
value, the hypothesis is accepted. If die sample
estimate or statistic is sufficiendy far from the
hypothesized value, the hypothesis is rejected.
- 2.57 0 + 2.57
Rejection implies that the sample estimate of
the parameter is evidence that the population
parameter is different from that hypothesized.
FIG. 10-6. Illustration of “t” distribution with 5 degrees
of freedom. The area in each of the shaded portions at t = The conclusion in this case is that a statistically
±2.57 is 0.025. significant difference exists between the hy¬
pothesized parameter and the true parameter
estimated from the sample.
To illustrate this concept, suppose that a hy¬
same as thatfor Z for the normal distribution,
pothesis states that the average 90% dissolution
where Z = (X - /j.)/(ct/VN), except that for t,
time of a tablet batch is 30 min or less. A dissolu¬
the sample standard deviation, S, is used in the
tion test using 12 tablets from a new batch
denominator.
shows an average result of 33 min. Can one con¬
The t distribution is similar in shape to the
clude that the average dissolution time of the
normal distribution (Fig. 10-6), but is more
batch is greater than 30 min? If the average re¬
spread out with more area in the tails, the ex¬
sult of the 12 tablets were 50 min, the conclu¬
tremities of the curve comprising the smaller
sion might be reached more easily. Depending
and larger values. There are any number of t dis¬
on the individual tablet results, the decision
tributions, each defined by the degrees of free¬
would be more or less equivocal. Such decisions
dom. The mean of the t distribution is zero and
as whether to accept or reject the hypothesis,
the spread depends on the degrees of freedom.
based on the sample data, can be made using
With 1 df (N = 2), the curve is spread out, but
probabilities derived from the t distribution. The
as the degrees of freedom increase, the t distri¬
procedure followed in making such decisions, as
bution becomes tighter, with less spread, ap¬
well as sample computations, are given here for
proximating more closely the standard normal
some simpler problems, and the reader is en¬
distribution. When df = « (i.e., the standard
couraged to try as many computations as possi¬
deviation is known), the t distribution is identi¬
ble to gain insight into the statistical process.
cal to the standard normal distribution. The t
The procedure of hypothesis testing is exem¬
distribution is used to calculate probabilities
plified by a simple test that compares a sample
when the standard deviation is unknown and
mean with a hypothesized mean.
estimated from the sample. The use of the t dis¬
1. Initially, the hypothetical mean against
tribution is illustrated below in the testing of
which the mean of the sample data points is to
hypotheses involving continuous data derived
be compared is defined. This is the null hypothe¬
from a normal distribution.
sis. Statistically, the question being asked is,
“Does the mean being estimated from the sam¬
Hypothesis Testing (For ple come from a distribution described by the
hypothetical mean?” The null hypothesis is tra¬
Statistical Significance) ditionally written as:
Testing of hypotheses is a traditional use of
statistical methodology. Because many people H0: M = Mo
have been trained to understand the meaning of
these tests, hypothesis testing serves to commu¬ where mo is the hypothetical mean. Some exam¬
nicate clearly certain experimental conclusions ples of hypotheses follow, (a) The target weight
from a statistical point of view. This statistical of a batch of tablets is 325 mg (the specification
procedure is important for assessing differences weight). (H0: m — 325 mg.) (b) An antihyperten¬
in treatment effects for government submissions sive agent is hypothesized to lower the blood
involved with new drugs and dosage forms, in¬ pressure by 10 mm Hg on the average.
cluding results from clinical trials and bioavaila- (H0: A = 10 mm Hg, where A is the blood pres¬
bility studies. sure reduction.) (c) The specification for disinte-

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 251

gration time of tablets is not more than 15 min. Table 10-3. Short Table of Absolute Values of t
(H0: p < 15 min.) Corresponding to Various Probability Levels in a
2. The alternative to the null hypothesis Two-Sided Test*
should be stated, i.e., the domain of answers if
H0 is not true. This may be written as HA: p ^ Degrees of
Freedom (DF) P = 0.01 P = 0.02 P = 0.05 P = 0.20
Mo- In the previous example (a), the alternative
could be written as HA: g ^ 325 mg, i.e., the 1 63.66 31.82 12.71 6.31
mean weight of the batch is either less than or 2 9.93 6.97 4.30 2.92
greater than 325 mg. This is a two-sided alterna¬ 3 5.84 4.54 3.18 2.35
tive. A one-sided alternative, HA: /x < 325 mg, 4 4.60 3.75 2.78 2.13
suggests that if the true mean weight is not 5 4.03 3.37 2.57 2.02
325 mg (H0), only values of the mean less than 7 3.50 3.00 2.36 1.89
325 mg are relevant or possible. 10 3.17 2.76 2.23 1.81
3. Having defined the hypothesis and alterna¬ 11 3.11 2.72 2.20 1.80
tive, a level of significance (the a, or Type I, 12 3.06 2.68 2.18 1.78
error) is chosen, the probability of erroneous re¬ 13 3.01 2.65 2.16 1.77
jection of the null hypothesis. The statement 15 2.95 2.60 2.13 1.75
that a' result is statistically significant, e.g., 19 2.86 2.54 2.09 1.73
P < 0.05 or “significant at the 5% level,” refers 25 2.79 2.49 2.06 1.71
to the a error. A hypothesis tested at the 5% 40 2.70 2.42 2.02 1.68
GO 2.58 2.33 1.96 1.65
level means that if the test shows significance
(H0 is rejected), there is a 5% chance that the *For a one-sided test, use P/2. For example, at the 5% level,
decision to reject H0 is incorrect. In quality con¬ look in the column labeled P = 0.10.
trol plans, the a error can be thought of as the
manufacturer’s or producer’s risk. For example,
5. The next step in the hypothesis testing pro¬
at a = 0.05, a good batch of material is errone¬
cedure is to compute the t statistic, which leads
ously rejected 5% of the time.
to a decision of whether to accept or reject the
4. An appropriate sample is chosen, and the
null hypothesis.’
mean and standard deviation are calculated.
This is a simple concept, yet more complex than
it seems at first glance. What is an appropriate
t = |x - m|/(s/Vn)
sample? How many observations should one
The value of t determines whether or not the
make? (How many times should the experiment
null hypothesis will be rejected, rejection lead¬
be replicated?) How are samples chosen? Are
ing to a declaration of significance. If t is small,
the observations independent? If a sample of 20
the hypothesis is accepted. If t is large, that is, if
tablets is chosen from a batch, the mean weight
|X - p.\ is large compared to the standard error of
represents the mean of the entire batch, perhaps
X (S/VN), then X is said to be significantly dif¬
a million or more tablets. A large burden is
ferent from p. To make this decision, the com¬
placed on these 20 tablets. In this situation, in¬
puted value of t is compared to the value in a “t”
dependence means that the selection and/or
table under N - 1 d.f. at the stated a level, usu¬
weighing of any one tablet is not influenced by
or will not influence the weighing of the other ally 5% (Table 10-3). If the absolute value of t is
greater than the tabled value, the difference
tablets. Tablets should be selected at random or
in a known “designed” way so that the statistical (X - p.) is statistically significant. Significance
analysis will have a valid interpretation. One means that if the null hypothesis is true, the
method of sampling might be to take the 20 tab¬ chances of observing a t value equal to or greater
lets at regular intervals during the run. (Are than that observed is less than a, or 5% in this
there situations in which this method could lead case.
to bias?) Selection of twenty consecutive tablets The following example illustrates the hypoth¬
from any one part of a run would not be a good esis testing procedure just described. Table 10-4
procedure. Why should 20 tablets be sampled shows the weights of 20 randomly selected tab¬
rather than 10 or 30, for example? The sample lets arranged in ascending order. The null hy¬
size may be dictated by an official method, or by pothesis is H0: /x = 325 mg, and the alternative
cost, or to obtain sufficient power. In the case of
tablet weights, “power” might refer to the ability ’This is a two-sided test. There is no reason to believe
of the statistical test to correctly find a signifi¬ that the tablets will be either higher or lower in weight
cant difference if the tablets are truly out of than the target value; hence, the absolute value is the
specification. numerator.

252 • The'Theory and Practice of Industrial Pharmacy

Table 10-4. Tablet Weights (mg) of 20 Ran¬ H0. Large values of t lead to rejection of the null
domly Selected Tablets hypothesis; the test results in a decision of “sig¬
nificance.”
300 321 Interpretation. The conclusion based on this
306 321 sample of 20 tablets is that the average batch
310 322 weight is approximately 319.75 mg, which is
315 323 sufficiently far from the target weight of 325 mg
316 325 to declare a significant difference. In such an
316 325
experiment, one can never be certain that this
317 325
conclusion is correct. The statement that the dif¬
319 327
ference is significant at the 5% level means that
320 331
if, in fact, the batch mean were 325 mg, the
320 336
probability would be small (P < 0.05, or less
than 1 chance in 20) that a result as small as
319.75 or less (or greater than 330.25) would be
observed. The decision that the batch mean is
hypothesis is HA: g # 325 mg. Since the sample not 325 mg may be incorrect, but the chance
size is 20, the degrees of freedom are 19 that this error will occur is 5% or less.
(20 - 1). Calculations of the mean, standard No matter how small or large the sample size
deviation, and t statistic follow. The shortcut for¬ is, a declaration of significance rings true. There
mula for the variance or standard deviation, pre¬ is a small, but known, probability of erring in
viously illustrated, should always be used for coming to the conclusion that a difference
speed and accuracy. Also, when computing by exists. On the other hand, a verdict of nonsig¬
hand, it is important to retain as many decimal nificance is not conclusive. A decision of nonsig¬
places as possible. nificance can be virtually ensured by choosing a
sufficiently small sample size, resulting in weak
H0: g = 325 mg; HA: g # 325 mg power, i.e., a weak ability to obtain a statistically
significant difference. One should also be aware
X = (300 + 306 + . . . 336)/20 of the distinction between statistical and practi¬
cal significance. Just as a small sample size can
= 319.75 mg result in a large difference being statistically
nonsignificant, a large sample size can result in
S2 = 2(X - X)2/(N - 1) a small difference being statistically significant,
because the large sample size effectively re¬
= [(300 - 319.75)2 + ... (336 - 319.75)2]/19 duces the variance (S| = S2/N). In this exam¬
ple, the difference of 5.25 mg (325 -
= 67.2 319.75 mg) from the target weight is sta¬
tistically significant. The important question is,
Shortcut formula for S2 “Is the difference apt to cause a problem from a
therapeutic or regulatory point of view?” If the
= [N(Z X2) - (2 X)2]/[N(N - 1)] difference is not sufficiently large to reject the
batch, the next or other future batches should be
= [20(3002 + 3062 + . . . 3362) closely monitored. The use of the 5% signifi¬
cance level has no basis other than tradition and
- (300 + 306 + . . . 336)2]/(20)(19) the fact that the risk associated with the 5%
level seems reasonable; one time in twenty the
= [20(2046079) - (6395)2]/380 = 67.2 null hypothesis will be erroneously rejected.
The assumptions implicit in the t test, both in
S = VS2 = V672 = 8.20 this and in other examples, are (1) that the data
comes from a normal distribution, (2) that the
t« = |x - m|/(s/Vn) observations are independent, and (3) that the
variance of the observations is equal (weighing
= |319.75 - 325|/(8.20/V20) = 2.86 error in this case). In general, independence and
equality of variance are more stringent assump¬
From Table 10-3, for significance at a = 0.05, tions than normality. The central limit theorem
t19 must be greater than or equal to 2.09. Since helps to overcome non-normality of data when
the observed t is 2.86, the decision is to reject using averages.

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 253

 Comparison of Means of Two Independ¬ where the subscripts 1 and 2 refer to treatments
ent Samples. An important class of problems 1 and 2 respectively. Note the following:
in statistics is the comparison of the effects of
two treatments or conditions on experimental (N - 1)S2 = (N - 1)[2(X - X)2/(N - 1)]
outcomes. Examples of such experiments are
(1) the comparison of the effects of two thera¬ = 2(X - X)2
peutic treatments on blood pressure, (2) the
comparison of two disintegrants on drug dissolu¬ The following example illustrates the inde¬
tion of tablets, and (3) the comparison of two pendent two-sample t test. Two batches of tab¬
analytical methods. In these problems, the vari¬ lets were prepared using disintegrating agents A
ance is usually unknown and is estimated from or B. Dissolution was determined on randomly
the data. If the experimental units are not re¬ selected tablets with the following results: Disin-
lated, i.e., are independent, the statistical test is tegrant A: 45, 50, 47, 43, 41, 49, 35; X = 44.29
known as an independent two-sample t test. and S2 = 26.9. Disintegrant B: 38, 47, 42, 39,
In the case of a clinical trial in which two 32, 36, 41; X = 39.29 and S2 = 22.57. The vari¬
drugs are being compared, this statistical test ances are similar and are pooled to obtain an es¬
would be applicable if all of the patients taking timate of the common variance.
the two drugs are different. The null hypothesis
and alternative hypothesis are: S2 = [6(26.90) + 6(22.57)]/12 = 24.74

H0: M-} = M2 Ha: t = (44.29 - 39.29]/V24.74(1/7 + 1/7) = 1.88

The population means of the two treatments are The tabulated t at the 5% level with 12 df
assumed to be equal, and the null hypothesis is (Nj + N2 - 2 = 12) is 2.18 (Table 10-3). There¬
rejected only if the observed sample means are fore, the difference is not significant at the 5%
sufficiently different, based on the magnitude of level. One may conclude that although the data
the t statistic, which is computed as follows: are insufficient to prove an effect due to disinte¬
grants, the results are equivocal (P < 0.10), i.e.,
t = |Xj - X3|/(SpVl/N, + 1/N2) if the observed difference can be considered of
practical significance, further testing is indi¬
where Nj and N2 are the sample sizes associated cated. (Note that the tabulated t for significance
with Xj and X2 respectively, and t has at the 10% level with 19 df is 1.73.)
(Nj + N2 - 2) degrees of freedom. The hypoth¬ The sample sizes of the two groups need not
esis of equal means is tested by comparing the be equal in this design, although maximum effi¬
value of the calculated t to tabled t values with ciency for discriminating two means is obtained
appropriate df at the stated a level (Table 10-3). by use of equal sample sizes, given a fixed total
To estimate a2, the common variance of the number of observations. Thus, (1/Nj + 1/N2) is
two groups, the variance of each sample is calcu¬ minimized, and the value of t is thereby maxi¬
lated, and the results are pooled, with the as¬ mized.
sumption that the true variances of the two Comparison of Means of Paired Samples.
groups are equal. (If the variances of the two Observations from two groups to be compared
groups are different, other statistical techniques can often be paired in some natural way. The
are available.6) In general, to obtain an unbiased more alike the pairs are, the more precise the
estimate of cr when independent estimates of test is, and such pairing can be considered an
the common variance are available, a weighted example of a choice of experimental design.
average of the variance estimates is calculated Rather than different experimental units being
with df (N - 1) as the weights. In the case of chosen at random for the two groups, pairs are
two samples, the weighted average is: chosen to be as alike as possible. Examples of
pairing are (1) using the same individual for
(Ni ~ l)Si + (N2 - l)Sj more than one treatment, (2) using twins or lit¬
(Ni - 1) + (N2 - 1) ter-mates for two or more treatments, and
(3) providing similar samples of granulation for
which equals: comparison of assay methods. If a difference
between two groups exists and the pairs are cho¬
-2(X - X)2 +X(X - X)21 sen judiciously, the difference will be detected
- I_2_ more readily than if distinct individuals are ran¬
(Nj + N2 - 2) domly chosen for both treatments (given the

254 • The Theory and Practice of Industrial Pharmacy

same number of observations). Calculations for Confidence Intervals
the statistical test comparing means of paired
A confidence interval can be formed for a
data consist of first taking differences of the
mean, fi, or the difference between two means,
pairs and then performing a one-sample t test on
with confidence, 1 - a, as follows:
the differences. The null hypothesis is:
D ± (td.f.,o)(SD)
H0: /ij = p2 or p2 = A = 0
where D is a mean value or mean difference;
A comparison of two analytic methods was made
td.f.,a is the tabulated t value with appropriate
using five batches of material, and analysis was
degrees of freedom (Table 10-3) at the a level of
performed on each batch by each method. As
significance; and S5 is the standard error of the
shown in Table 10-5, the differences between
mean or mean difference.
methods for each batch is first computed, and
This procedure is related to hypothesis testing
the standard deviation of the differences is cal¬
in that if the confidence interval covers zero, the
culated, equal to 1.42. N is equal to 5 (there are
test of significance of the difference between
5 pairs). The calculated value of t is:
two means is not significant at the a level (two-
sided test). In the previous example, a 95% con¬
t = |0.50 - 0|/(1.42VT/5) = 0.79
fidence interval for the mean difference between
the two analytical methods is 0.50 ± 2.78 (1.42)
Since the tabulated value of t with 4 df at the 5%
(VT/5) or -1.26 to 2.26. A confidence interval of
level is 2.73, the difference is not significant at
1 - a (e.g., 95% if. a = 0.05) means that the
the 0.05 level.
probability is 95% that such intervals cover the
One-Sided Tests. The tests described thus
true mean value, or difference of means. There
far have been two-sided tests. Values of the ob¬
is no guarantee that in any single experiment the
served mean, or difference of means, that are
true value will be covered; however, on the aver¬
either too small or too large lead to rejection of
age, the true value will be included in the con¬
the null hypothesis. One-sided tests are used
fidence interval of 19 out of every 20 such ex¬
when the null hypothesis is rejected only for
periments. A lower degree of confidence is asso¬
unidirectional differences of the observed
ciated with a smaller interval. The smaller the
mean(s). Care should be taken in using one¬
interval is, the less is the confidence that the
sided tests since this choice implies that the al¬
true value is contained within the interval. The
ternative (values either too high or too low) is
confidence interval is a useful way of defining
not important or is of no interest. For example,
the region that contains the true mean or differ¬
in testing a new drug, H0 might be rejected only
ence; it is a statement having a probability asso¬
if a positive effect is observed; however, if a neg¬
ciated with it.
ative response (opposite of the expected effect)
In another example, a paired t test was used to
is possible and of interest, a two-sided test might
analyze the data from a bioavailability study in
be more appropriate.
which 12 volunteers were used to compare two
dosage forms. The average areas under the time
versus blood level curves were as follows: For¬
mula A = 524; Formula B = 486. The variance
Table 10-5. Comparison of Two Analytic Meth¬
computed from the 12 differences (A - B) was
ods
94. A 95% confidence interval is calculated
METHOD using the value 2.20 for t (see Table 10-3):
mg active/g
(524 - 486) ± tn 0.05 (SVl/N)
A
Batch A B A-B
= 38 ± 2.20(V94/12) = 31.8 to 44.2
1 100.8 100.1 0.7
2 101.9 99.3 2.6 A 90% interval is 38 ± tn>0.i (SVl/N)
3 98.7 100.0 -1.3
4 101.3 101.4 -0.1 = 38 ± 1.80(V94/l2) = 33.0 to 43.0
5 102.5 101.9 0.6
Some statisticians feel that in certain situa¬
AVERAGE 101.04 100.54 0.50
tions, such as bioavailability studies, confidence
S 1.46 1.07 1.42
intervals are a better way of expressing results

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 255

than stating only that one formula is or is not
significantly different from the other. By provid¬
ing upper and lower limits for the comparison,
the confidence interval allows the user or pre-
scriber of a product to make a judgment about
the practical equivalency of two products.

Comparison of Variances
In some experimental situations, a test of the
equality of two independent variance estimates,
Sf and S|, is of interest. In a one-sided test
where erf is hypothesized to be equal to or less
than o-f (H0: erf < of; HA: erf > of), the statisti¬
cal test consists of forming the ratio Sf/Sf. If Sf
is smaller than Sf, H0 is accepted as true. If Sf is
larger than Sf, a test of significance is performed
using the F distribution. The ratio Sf/Sf is com¬ FIG. 10-7. Illustration of“F” distribution with 4 and 10
pared to tabulated values of the F distribution degrees of freedom. The shaded portion represents values
from 3.48 to <*> and equals 5% of the area.
with vl and v2 degrees of freedom, where
vi ~ Nj - 1 and v2 = N2 - 1 (Nj and N? are
the sample sizes associated with Sf and Sf, re¬ than 1. The significance level using the cutoff
spectively). If the ratio exceeds the tabulated points in Table 10-6 is 10% in this test because
value at the specified a level, of is considered to the ratio has been deliberately constructed with
be significantly greater than of. The F distribu¬ the larger variance in the numerator. In a two-
tion is a probability distribution that is com¬ sided test, if the ratio Sf/Sf is formed whether or
pletely described by degrees of freedom in the not Sf is greater than Sf, tables with the lower
numerator and denominator of the F ratio cutoff points in addition to the upper points are
(Fig. 10-7). The values tabulated in Table 10-6 necessary. When the ratio is intentionally
are the upper cutoff points and are appropriate formed with the larger variance in the numera¬
for a one-sided test (H0: of £ of; HA: erf > of). tor, the F tables used to assess significance are
For a two-sided test (H0: erf = erf; HA: erf ^ simplified.
erf), form the ratio Sf/Sf if Sf is greater than Sf; An example follows to clarify the test proce¬
if Sf is the larger variance, form the ratio Sf/Sf. dure. The variances obtained from a formulation
That is, the ratio is formed with the larger vari¬ mixed in two different mixers will be compared.
ance in the numerator and is always greater Five samples were analyzed from Mixer A with a

Table 10-6. Short Table of Upper Points of the F Distribution at 5% Level of Significance

Degrees of Freedom in Numerator

Degrees of
Freedom
in
Denominator 1 2 3 4 6 7 10

3 10.10 9.55 9.28 9.12 8.94 8.89 8.79

4 7.71 6.94 6.59 6.39 6.16 6.09 5.96
5 6.61 5.79 5.41 5.19 4.95 4.88 4.74
7 5.59 4.74 4.35 4.12 3.87 3.79 3.64
8 5.32 4.46 4.07 3.84 3.58 3.50 3.35
10 4.96 4.10 3.71 3.48 3.22 3.14 2.98
13 4.67 3.81 3.41 3.18 2.92 2.83 2.67
20 4.35 3.49 3.10 2.87 2.60 2.51 2.35
40 4.08 3.23 2.84 2.61 2.34 2.25 2.08
120 3.92 3.07 2.68 2.45 2.18 2.09 1.91
CO 3.84 3.00 2.60 2.37 2.10 2.01 1.83

256 • The Theory and Practice of Industrial Pharmacy

variance of 2; eight samples from Mixer B had a judgment should be exercised before discarding
variance of 13. Does the use of the two mixers suspect data. For example, if replicate values
result in formulations of different homogeneity? from an analysis were 5.10, 5.11, 5.09, and 5.30,
This is a two-sided test, because a priori, it is not the last value would immediately be suspected
known which mixer will result in more variabil¬ with or without a statistical test. When doubt
ity, if a difference in variability exists. arises, Table 10-7, “Dixon criteria for Testing an
Extreme Mean,” can be used to decide if an ex¬
H0: o-a = o'! treme value belongs with the rest of the data.5
Ha: ai # 4 The data are first ordered numerically from low
a = 0.10 to high, Xj, X2,. . . Xk, where there are k values.
Fof example, if k is between 3 and 7, and Xk is
In a two-sided test, F = S§/SA = 6.5 (where S| is the extreme value, form the ratio
the larger variance estimate). Since 6.5 is (Xk - Xk_j)/(Xk - X,). If this ratio is greater
greater than the tabulated value than the tabulated value, the extreme value is
(F7,4,0.05 = 6.09), reject H0 at the 10% level. If considered aberrant (Table 10-7).
the variance from Mixer B is known a priori to In the foregoing example, 5.30 appears to be
be no less than that in Mixer A (HA: cr§ > af), a an outlier. Since k = 4, form the ratio
one-sided test would be appropriate, and the dif¬ (5.30 - 5.11)/(5.30 - 5.09) = 0.9. Table 10-7
ference would be significant at the 5% level. shows that at the 5% level with k = 4, a value of
0.765 or greater is significant. The value 5.30 is
deemed to be an outlier and is rejected.
Detection of Outliers An intelligent discussion dealing with outliers
Although many rules have been proposed to and various recommended procedures is pre¬
detect aberrant values, or outliers, considerable sented in ASTM, E178-75.7

Table 10-7. Dixon Criteria for Testing an Extreme Mean

Significance Level
k 5 percent

3 rI0 = (X2 - X,y(Xk - X!) if smallest value 0.941

4 is suspected; 0.765
5 = (Xk - Xk_i)/(Xk - Xfi if largest value 0.642
6 is suspected. 0.560
7 0.507

8 rn - (X2 - X^/fXis-,) if smallest value 0.554

9 is suspected; 0.512
10 = (Xk - Xk-!)/(Xk - X2) if largest value 0.477
is suspected.

11 r21 = (X3 - X,)/(Xk_i - X,) if smallest value 0.576

12 is suspected; 0.546
13 = (Xk - Xk_2)/(Xk - X2) if largest value 0.521
is suspected.

14 r22 = (X3 - X,)/(Xk_2 - Xj) if smallest value 0.546

15 is suspected; 0.525
16 = (Xk - Xk_2)/(Xk - X3) if largest value 0.507
17 is suspected. 0.490
18 0.475
19 0.462
20 0.450
21 0.440
22 0.430
23 0.421
24 0.413
25 0.406

From Dixon, WJ.: Processing data for outliers. Biometrics, 9:74-88, 1953. With permission from The Biometric Society.

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 257

Binomial Distribution Table 10-8. Binomial Probabilities For N - 18
and p = 0.3
The normal distribution is an example of a
continuous probability distribution. Although Number of Successes Probability
never exactly fitting this distribution, experi¬
mental data often approximate normality, and 0 0.002
inferences based on this assumption are reason¬ 1 0.013
ably accurate. Often, however, data are clearly 2 0.046
not continuous, and other distributions must be 3 0.105
found to accommodate these situations. The 4 0.168
binomial distribution is an example of a discrete 5 0.202
probability distribution that can be used to de¬ 6 0.187
7 0.138
scribe the outcome of experiments common in
8 0.081
the pharmaceutical sciences. It consists of di¬
9 0.039
chotomous data, data that can have one of two
10 0.015
possible outcomes. Examples of experiments
11 0.005
with a binomial outcome are (1) preference for 12 0.001
one of two formulations, (2) life or death (used to
compute the LD50), (3) acceptance or rejection
of dosage units in quality control, and (4) im¬
provement or worsening after treatment with a
drug. ity p, and a “failure” is the other outcome (prob¬
The binomial is a two-parameter distribution: ability of a failure = 1 - p = q). In this exam¬
(1) p, the probability of one of the two possible ple, p = 0.3 and q = 0.7. The sum of the
outcomes and (2) N, the number of trials or ob¬ probabilities of all N + 1 possible results from N
servations. If 100 tablets sampled from a batch binomial trials is one. There is a discrete num¬
have 5 rejects, p, the probability of rejection, is ber of possible results, (N + 1) in N trials. In 18
estimated as 0.05, and N = 100. Note that in trials, 0, 1, 2 ... or 18 successes are possible,
this example, probability is equated with the- but the probability of more than 10 successes is
proportion of rejects; the best estimate of the extremely small if p = 0.3. If a batch of tablets
unknown probability is the sample proportion. If were assumed to have 30% defects (p = 0.3),
the entire batch were inspected, the true proba¬ the probability of observing 10 or more defective
bility of a reject would equal the proportion of tablets (successes) in a random sample of 18 (N)
rejects in the batch. tablets would be so small that such an observa¬
An example of a binomial probability distribu¬ tion would probably lead to the conclusion that
tion for N = 18 and p = 0.3 is shown in Figure the batch really had more than 30% defects. The
10-8 and Table 10-8. The probability of observ¬ distribution shown in Figure 10-8 looks some¬
ing exactly 5 successes in 18 trials, for example, what symmetric. In fact, if Np and N
is 0.202. A “success” is one of the two possible (1 - p) = Nq are both greater than or equal to 5,
outcomes of a single binomial trial with probabil- the distribution is close enough to normal to
allow use of normal curve probabilities to ap¬
proximate the probability of binomial results.
As is the case for the normal distribution, the
binomial can be parsimoniously presented in
terms of its mean and standard deviation. The
mean corresponds to the true probability of suc¬
cess, p, and the standard deviation (a function of
p and N) is a = Vpq/N, where q = (1 - p). To
compute probabilities of events using the bino¬
mial, one can refer to binomial tables,8 using the
normal approximation when appropriate (see
next section, “Normal Approximation to the. Bi¬
nomial Distribution”), or calculate probabilities
using the binomial formula. The binomial for¬
mula gives the probability of X successes in N
trials.
FIG. 10-8. Binomial distribution with N = 18 and p = P(X) = QpxqN-x (1)
0.3.

258 • The Theory and Practice of Industrial Pharmacy

where P(X) is the probability of observing X suc¬ incidence of less than 10% in the 50 rats would
only be due to chance. A two-sided (two-tailed)
cesses in N trials and (^) = N!/(N - X)!(X!).
test allows for the possibility of results both
As an example of the use of the binomial for¬ greater and smaller than 10%, suggesting that
mula, consider the following. According to the the drug might improve the carcinogenic profile.
USP weight variation test for tablets weighing Since the value of Z is 1.89, less than 1.96, a
less than 130 mg, no single tablet out of 20 tab¬ two-sided test would fail to reach significance at
lets weighed should differ by more than ±20% the 5% level (see Table 10-2). Since Z is greater
from the average weight. For a batch of 100 mg than 1.65, a one-sided test would be significant
tablets, suppose 3% weigh less than 80 mg or at the 5% level; the drug increases the tumor
more than 120 mg. What is the probability of incidence. This example shows clearly that the
finding at least one aberrant tablet in a random choice of either one- or two-sided tests should be
sample of 20 tablets? If the average weight is seriously considered and justified a priori.
100 mg, the probability of finding one or more The calculation of Z as described above ap¬
bad tablets equals (1 - probability of finding 0 proximates cumulative binomial probabilities,
bad tablets out of 20). This probability equals: estimating the probability of 9" or more events in
50 animals if p = 0.10. A “continuity” correction
suggested by Yates6 improves the normal ap¬
j l - (2q)(0.03)° (0.97)20] = 0.46 proximation resulting in less significance. The
correction consists of subtracting 1/2N from the
absolute difference of the numerator of Z. For a
Note that (2^) = 201/2010! = 1 because 0! two-sided test, Conover describes an improved
correction.6 If the fractional part of |NP - Np0| is
equals 1 by definition.) Thus, there is a 46% greater than 0.5 but less than 1.0, the fractional
chance that one would find at least one bad tab¬ part is replaced by 0.5. If the fractional part is
let in this test if 3% of the batch were outside the greater than 0 but less than or equal to 0.5, the
limits. fractional part is deleted. If the value is an inte¬
Normal Approximation to the Binomial ger (i.e., die fractional part is 0), the value is
Distribution. If Np and Nq are both equal to or reduced by 0.5, which is equivalent to the Yates
greater than 5, cumulative binomial probabili¬ correction. The adjusted value of |Np - Np0| is
ties can be closely approximated by areas under divided by N for the numerator of die Z ratio.
the standard normal curve. The following exam¬ In the example, |Np - Np0| is equal to
ple illustrates this concept. It is known from past (0.18 x 50 - 0.10 x 50) = 4.00. According to
experience that the incidence of a specific ma¬ the foregoing rule, the value is decreased by
lignant tumor is 10% during the lifetime of a 0.50: 4.00 minus 0.50 = 3.50. The numerator of
certain strain of normal rats. A drug is adminis¬ Z is 3.50/50 = 0.07.
tered to 50 rats, and the tumor occurs in 9 (18%)
of the animals. Is this an unlikely event if the
drug is not carcinogenic? The probability of ob¬ Z = 0.07/Vpoqo/N
serving 9 or more afflicted animals can be com¬
puted if indeed the normal rate of 10% has not = 0.07/V(0.1)(0.9)/50
changed (H0: p0 = 0.10, where p0 is the hypoth¬
esized proportion). The normal approximation = 1.65
can be used since both Np and Nq are equal to or
greater than 5 (N = 50, p = 0.10, q = 0.90). Now, a one-sided test is just significant at the
Note that p0, the hypothetical population value 0.05 level.
of p, is used for this calculation. The probability Confidence Limits in the Binomial Case.
is computed using a normal curve with mean Confidence limits can be constructed for bino¬
0.10 and cr = V(0.1)(0.9)/50, calculating the mial data in a manner similar to that for the nor¬
area for_values greater than 0.18. mal distribution, as follows:
Z = (X - p)/<7x = (p - Po)/Vp0qo/N (where
p is the observed proportion) =
p ± ZVpq/N
(0.18 - 0.10)/V(0.10)(0.90)/50 = 1.89.
The interpretation depends on whether a one-
or two-sided test is used. The one-sided test The value of Z (see Table 10-2) depends on the
would be appropriate if the drug cannot truly degree of confidence. Suppose that of 1000 tab¬
decrease the proportion of cancerous events lets inspected, 25 were found to be defective.
below 10%; that is, an observation of a tumor The proportion of good tablets in the sample is

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES » 259

0.975 (975/1000). A 99% confidence interval for Comparison of Two Proportions. When
the true proportion of good tablets is:’ comparing the proportion of successes in two
groups, the data are often presented in the form
0.975 ± 2.58V(0.025)(0.975)/1000 of a “fourfold” table as shown in Table 10-9. Dis¬
eased animals were treated with either placebo
= 0.975 ± 0.013 (control) or drug. Sixty-one of 75 of the control
animals survived, whereas 69 of 75 animals
The width of the confidence interval is depend¬ given the drug survived. Is the drug more effec¬
ent on p and N, the number of observations, and tive than the control in preventing death? The
is independent of the size of the batch, provided null and alternate hypotheses are stated as fol¬
the number of observations is small relative to lows.
the batch size. A proportion (or any parameter
for that matter) can be estimated with any de¬ ■ placebo
1 placebo) Ha: Pdrug ^ P,
H(> Pdrug — P]
sired precision by appropriately increasing the
sample size. Realistically, time, expense, and where Pdrug is the probability that an animal will
accuracy of observations are limiting factors. survive the drug treatment, and PpiaCebo is the
probability that an animal will survive placebo
treatment.
Statistical Tests of Binomial Data This is the binomial analog of the indepen¬
Tests of hypotheses in the binomial case have dent groups two-sample t test. In the t test, the
a form similar to normal distribution tests, as variances were pooled under the assumption of
can be seen in the following examples. equal variability in the two groups. Here, all the
Comparison of a Sample Proportion to a data are pooled to estimate a common p, the best
Known Proportion. Quality control (QC) data estimate of the true probability under the null
gathered from many batches showed that 4% of hypothesis, which states that the two popula¬
tablets manufactured with a target weight of tions have the same proportion of survivors. The
200 mg weighed more than 220 mg or less than pooled p = p0 = 130/150 = 0.867. (130 of 150
180 mg, the upper and lower QC limits. Exami¬ animals survived and the overall proportion of
nation of a new batch shows that 32 of 500 tab¬ survivors is 0.867.) When the sample size (N) is
lets (6.4%) are out of specifications. Is this result equal in the two groups, the continuity correc¬
unexpected based on the previous history of the tion in the test of significance consists of sub¬
batch (4%, or 20 tablets, are expected to be out of tracting 1/N from the absolute value of the nu¬
limits)? As in the t test, the null hypothesis and merator. The Z ratio is computed as follows:
the alternative hypothesis are stated. A “Z” ratio
is then formed, using the continuity correction Z = [|pi - Pal - 1/N]/Vp0q0(l/Ni + 1/N2)
to compare the observed and hypothetical pro¬
portions: Z = [|0.92 - 0.813| - 1/75]

Hq: Po — 0.04 Ha: p0 # 0.04 h- V(0.867)(0.133)(l/75 + 1/75)

Z = [|p - Pol - l/(2N)]/Vp0qo/N = 1.68

Z = (|0.064 - 0.040| - 1/1000) where Nj = N2 = N. As in the t test, the Z ratio

is a “difference” divided by the variability of the
* V(0.04)(0.96)/500 difference, expressed as the standard deviation.
In this case, the difference is significant at the
= 2.62 10% level, not significant at the usual 5% level.
The new batch has significantly more tablets out
of limits than are normally observed (Table 10-2, Table 10-9. Fourfold Table Showing Number of
P < 0.01). A 95% confidence interval on the Animals Alive and Dead After Three Months
true proportion of out-of-limit tablets in this
batch is: Alive Dead Total

CONTROL 61 14 75
0.064 ± 1,96V(0.064)(0.936)/500
DRUG 69 6 75
= 0.064 ± 0.021
TOTAL 130 20 150
’For 95% confidence limits, substitute 1.96 for 2.58.

260 • The Theory and Practice of Industrial Pharmacy

Does this mean that the drug and control do not Table 10-10. Actual and Expected* Number of
differ? In all statistical tests, a nonsignificant Animals with Tumors After Drug Treatment and
difference does not imply sameness. The experi¬ Placebo
ment may not have had sufficient sensitivity to
pick up a difference that may have occurred Number with Number without
with a larger sample size. A significant differ¬ Tumors Tumors Total
ence, no matter how small or large the experi¬
DRUG 18 (16.18) 74 (75.82) 92
ment, means that a real difference probably
exists (with odds of 19-1 at the 5% level). The PLACEBO ll (15.82) 76 (74.18) 90
practical meaning of any difference must be in¬
terpreted in context, with an understanding of TOTAL 32 150 182
the implications of decisions based on experi¬
^Values in parentheses are expected values.
mental results. In this example, if increase in
survival due to the drug is small compared to
comparable marketed drugs, there might be lit¬ The chi-square statistic, which is used to as¬
tle interest no matter what the degree of signifi¬ sess significance, is calculated as 2(0 - E)2/(E),
cance. But if there is no drug on the market ef¬ where O is the observed count and E is the ex¬
fective in this disease, these results might be a pected count. In this example, chi-square is cal¬
stimulus for further work. culated as follows:

(1.82)2/16.18 + (1.82)2/75.82 + (1.82)a/15.82

Chi-Square Tests of Significance
Another way of testing for significance of the + (1.82)2/74.18
difference of two proportions is by means of the
X2 (chi-square) distribution. An example of this = 0.50
test is illustrated by a preclinical study per¬
formed to determine the carcinogenic potential The chi-square distribution is a probability
of a new drug in which 100 control animals were distribution defined by a single parameter, de¬
compared to a group of 100 animals given the grees of freedom. The chi-square test can also be
drug. At the end of the experiment, the animals used for experiments other than that described
were examined for tumors. Ten animals in the by the 2 x 2 table. If three drugs are being com¬
control group and eight in the drug group died of pared rather than two, a 3 x 2 table would de¬
nondrug related causes before the experiment scribe the results for a dichotomous response. In
was completed, and these animals were not in¬ an R x C (rows x columns) table, degrees of
cluded in the final count. The results are sum¬ freedom equal (R - 1) x (C - 1). For the 2x2
marized in Table 10-10. table illustrated here, df = 1. The cutoff point
The first step in the statistical analysis is to for significance for chi-square with one df is
compute the numbers of animals that would be equal to Z2, where Z is the standard normal de¬
expected to be observed in each of the four viate previously discussed (see Table 10-2). At
“cells” of the table if the null hypothesis were the 5% level, for example, X2 must exceed
true (i.e., if the treatments were the same). This (1.96)2 = 3.84 for significance, since 1.96 is the
is accomplished by multiplying the marginal to¬ cutoff point for a two-sided test at the 5% level.
tals for each cell and dividing by the grand total. Therefore, in the previous example, the differ¬
For example, in the upper left cell (animals on ence between drug and placebo is not signifi¬
drug with tumors) the expected number is cant. (Cutoff points for X2 tests with more than
(32 x 92)/182 = 16.18. Theoretically, this one d.f. can be found in most standard texts.5)
means that if the treatments were identical and As is the case for the normal approximation to
no variation occurred, “16.18” of 92 animals the binomial, the chi-square test is also approxi¬
would develop tumors in the drug group. For the mate. The expected count (E) in each cell
fourfold table, only one calculation is needed to should be equal to or greater than 5 for the ap¬
obtain the expected values for each cell, since proximation to be valid. In this example, all four
the cell totals must sum to the marginal totals as expected values are considerably greater than 5,
shown in Table 10-10. The expected numbers in as can be seen in Table 10-10.
row 1 must add to 92; therefore, the value in the As in the previously described binomial tests,
second column must be 75.82. Similarly, the a continuity correction can be used to improve
value in the second row, first column, must be the approximation. If the fractional portion of
15.82 to ensure that the column total is 32, and |0 - Ej is greater than 0 but less than or equal to
so forth. 0.5, delete the fractional portion (e.g., if

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 261

|0 - E| = 5.3, replace 5.3 by 5.0). If the frac¬ whereas an appropriate parametric test (such as
tional portion is greater than 0.5 but less than the t test) might show significance. The sign test
1.00, replace the fractional portion by 0.5 (e.g., if has the advantage of using simple binomial cal¬
|0 — E| = 6.98, replace 6.98 by 6.5). If the dif¬ culations, and it is useful for a quick assessment
ference |0 - E| is an integer, decrease the value of the results of an experiment. The procedure
by 0.5. In the above example, |0 - E| is 1.82. for performing the sign test follows:
Therefore, use 1.5 as the value of |0 - E|, rather 1. The differences of each of the paired sam¬
than 1.82. The recalculated value of X2 is 0.34. ples are tabulated, indicating only whether one
In this experiment, a comparison of the total treatment or factor has a higher or lower value
number of tumors found in the two groups may than the other. For example, a positive differ¬
also be of interest when tumors may be found in ence means that the second treatment gives
different organs, i.e., when a single animal may higher results, and a negative difference means
have more than one tumor. The analyses dis¬ that the first treatment gives higher results. In
cussed here, however, would be inappropriate case of a tie, the difference is ignored. With con¬
because of the lack of independence. Suppose in tinuous data, there should be no ties, but ties do
the above experiment that 18 animals on drug occur because of limitations of measuring tech¬
had at least one tumor with a total of 33 tumors, niques and/or because the data are not really
and that 14 animals on placebo had at least one continuous.
tumor with a total of 16 tumors. Clearly, one 2. After tabulation, the proportion of “wins”
would have to look carefully at both statistics: (positive differences, for example) is calculated.
(1) the proportion of animals with tumors and The observed proportion of “wins” is compared
(2) the total number, type, and location of tu¬ to that expected under the null hypothesis of
mors. However, the comparison of the total equality of treatments (H0: p0 = 0.5), using a
number of tumors, 16 versus 33, in the two one-sample binomial test.
groups must somehow take into account the In the following example (Table 10-11), tab¬
number of animals with and without tumors. lets were taken from two different punches of a
tablet press at various times during a run be¬
cause a difference in weight had been sus¬
The Sign Test pected. In 18 of 24 cases, the tablet from the left
The sign test is a popular nonparametric test side had a higher weight than that on the right
used to assess the significance of differences of side (a positive difference for the left side minus
paired data. The underlying distribution that right side). There is one tie (7:00), which is dis¬
represents the data need not be precisely de¬ regarded for the purposes of the statistical test.
fined, as opposed, for example, to the assump¬ The observed proportion p is 18/24 = 0.75, and
tion of normality necessary for the t test. The the hypothetical proportion p0 is 0.5.
sign test, however, has less power to differenti¬
ate the two treatments than a test in which the Z = (|0.75 - 0.5| - l/48)/V(0.5)(0.5)/24 = 2.25
actual distribution of data is taken into account.
This means that for a given set of data, the sign Since Z is greater than 1.96, the difference is
test may not result in a significant difference, significant at the 5% level. The tablets from the

Table 10-11. Weight Differences of Tablets Taken From Right and Left Sides of Tablet Press

Time Right Left A Time Right Left A

1:00 PM 220 221 +1 4:15 218 219 +1

1:15 221 220 -1 4:30 222 223 +1
1:30 219 223 +4 4:45 226 228 +2
1:45 218 221 +3 5:00 217 227 + 10
2:00 223 218 —5 5:15 219 220 +1
2:15 217 213 -4 5:30 215 218 +3
2:30 221 225 +4 5:45 220 224 +4
2:45 218 220 +2 6:00 219 220 +1
3:00 226 224 -2 6:15 223 221 -2
3:15 220 223 +3 6:30 216 220 +4
3:30 217 219 +2 6:45 222 226 +4
3:45 224 223 -1 7:00 221 221 0
4:00 222 225 +3

262 • The Theory and Practice of Industrial Pharmacy

left side tend to have higher weights than those
from the right side, suggesting that an adjust¬
ment on the tablet press should be made.

Sampling for Attributes and

Operating Characteristic Curves
The binomial distribution can be used to con¬
struct acceptance/rejection sampling plans in
quality control. MIL STD 105D is an excellent
document describing sampling plans for attri¬
butes.9 These plans recommend the number of
items to be inspected, and the number of rejects
that are observed determine whether or not the
lot will be accepted. The plans are more or less FIG. 10-9. Operating characteristic curve (OC) for Plan
stringent depending on the seriousness of a de¬ N, AQL = 0.25. (MIL STD 105D9)
fect and the risk of making a wrong decision. A
wrong decision is either (1) to pass a poor lot or accepting a lot for a specified plan, given the
(2) reject a good lot. true percentage of defects in the lot. Note that
As an example, Plan N from Mil Std 105D is the probability of rejecting a lot of specified qual¬
devised such that if there are 0.25% defects in a ity is simply (1 - probability of acceptance of
lot, there is a good chance of passing the lot.9 that lot). To construct the OC curve, it is suffi¬
This corresponds to an acceptable quality limit cient to calculate the probabilities of acceptance
(AQL) of 0.25. In this plan, 500 samples are at various “percent defective” values (as was
taken at random, and if 3 or fewer defects are done for 0.25%) and draw a smooth curve
found, the lot passes; otherwise, the lot is re¬ through these points. For example, if there are
jected. If 0.25% of the lot is defective, the proba¬ 1% rejects in the lot, the probability of accept¬
bility of the lot passing this inspection is equal to ance can be calculated from equation (1).
the probability of finding either 0, 1, 2, or 3 de¬
fects in the 500 samples inspected, since any
one of these observations will result in a decision X£ (5°°)(0.01)x (0.99)n_x = 0.26
to pass the lot. This probability can be calculated x=o v 0 '
using the binomial formula given in equa¬
tion (1): Note that p = 0.01 (probability of observing a
reject), and that q = 0.99 (1 - p). Since 0.26 is
the probability of accepting such a lot using
io (x) pV“X = P(0) + P(l) + P(2) + P(3) Plan N, the probability of rejecting the lot is
(1 - 0.26) = 0.74. The interpretation is that a
lot with 1% chipped tablets, for example, will be
where P(0), P(l), P(2), and P(3) are the prob¬ rejected about 3/4 of the time and will pass the
abilities of finding 0, 1, 2, and 3 defects, re¬ test 1/4 of the time using this plan.
spectively. The sum of these four probabili¬

ties is (5q0)(0-0025)° (0.9975)500 + . . . (5°°) Sample Size

(0.0025)3 (0.9975)497 = 0.29 + 0.36 + 0.22 + “What size sample do I need?” and “How
0.09 = 0.96. Therefore, the probability of pass¬ many patients should I recruit?” are common
ing the lot is at least 0.96 if there are 0.25% or questions that arise during planning of experi¬
less rejects in the batch. Conversely, the proba¬ ments. Estimation of the sample size needed to
bility of rejecting such a lot is 0.04 (1 - 0.96). show a statistically significant difference (if at
Four percent (0.04) is equivalent to the a error least some predetermined true difference exists)
in hypothesis testing, if 0.25% or less defects is an important problem in pharmaceutical and
characterize an acceptable lot. clinical studies. When testing means, the differ¬
What about the probability of accepting lots of ence to be detected (d) under HA, the a and p
bad quality? This is an important aspect of a errors, and the sample size, N, are closely re¬
sampling plan and is described by an operating lated. Given three of these values, the fourth is
characteristic (OC) curve as shown in Fig¬ fixed. To calculate the sample size, one must
ure 10-9. The OC curve shows the probability of specify (1) the variance; (2) a, the risk of errone-

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 263

ously declaring significance and rejection of the problem is more difficult because the value of t
null hypothesis; (3) /3, the risk of erroneously changes considerably with changes in sample
accepting the null hypothesis given an alterna¬ size (appropriate t values must be used in the
tive, and (4) the “difference to be detected.” As above formula, replacing Z). If an arbitrary value
the experienced researcher knows, these risks of t is chosen based on a preliminary guess of df,
and the meaningful differences are not easy to and the calculated N is substantially different
assess and are often a matter of good judgment. from the preliminary guess, the estimate of the
If the sample size is large or if a2 is known, sample size will be incorrect. Guenther has
the computation of a sample size, N, for a single shown that increasing the sample size as calcu¬
(or paired) sample experiment is:. lated from equation (2) by 0.5 Z2 gives a nearly
correct value for the sample size.10 Davies pro¬
N = <x2[(Za + Z^/d]2 (2) vides tables for the sample size needed for t tests
given a, (3, and d/cr.11
where d is the difference to be detected, and Za As an example of this calculation, consider a
and Zfj are the appropriate normal deviates for bioequivalency study in which the areas under
the a level and /3 level, respectively. For a two- the blood level versus time curves (AUC) for two
sided test, Za is the value of Z above which a/2% formulations are to be compared. What sample
of the area is found in the normal curve (see size would be needed to detect a difference in
Table 10-2). These are the same values used for the AUCs of ± 20 hour • mcg/ml with a power of
hypothesis testing, e.g., 1.96 at the 5% level of 90% at the 5% level in a situation in which the
significance, and 2.58 at the 1% level. Z^ is the average area is expected to be about 100 and the
value of Z above which /3 of the area is found in standard deviation is estimated to be 25? Bioe¬
the upper tail. For example, for /3 = 0.2, quivalency tests are usually designed so that
Z = 0.842; for /3 = 0.1, Z = 1.28; and for each subject receives each formulation on sepa¬
(i = 0.05, Z = 1.645. Although this may appear rate occasions (a paired design). According to
complicated, the examples that follow should equation (2), the sample size needed is:
clarify the use of this equation.
For example, a question regarding sample size N = (25)2[(1.96 + 1.28)/20]2 = 16.4
may be posed as follows. It is important to detect
a mean tablet weight that is 3 mg or more differ¬ Since cr2 is unknown, add 0.5 Z2 to 16.4:
ent from the target weight. If such a difference
exists, there should be a 90% chance that a sta¬ (0.5) • (1.96)2 + 16.4= 18.3
tistical test will show significance 03 = 0.10;
power = 1 — /3 = 0.90). The chance of conclud¬ Nineteen subjects will satisfy the requirements
ing that a difference of 3 mg or more exists for this study.
when in fact the batch is on target should be The above calculations are for a single-sample
small, e.g., 5% (a = 5%). The difference, 3 mg, or paired-sample test. The calculations for a two-
and the a and (3 risks described previously are sample test are slightly different. The sample
not preordained. These values are a result of size for the two-sample case, where
careful thought and experience, and are usually N] = N2 = N, (Nj and N2 are the sample sizes
“ball-park” figures, unless legal or official re¬ for the groups to be compared), is calculated as
quirements dictate exact limits and risks. If the follows:
standard deviation is 10, N is calculated from
equation (2): N = 2<r2[(Z* + Z^/d]2 (3)

N = 102[(1.96 + 1.28)/3]2 = 117 If cr2 is unknown, add 0.25 Z2 to N.10

For example, time to dissolution (50%) is to be
This means that 117 tablets should be sampled compared for two formulations of the same drug.
to determine the mean weight. A statistical test How many tablets of each formulation should be
comparing the observed mean weight versus the used if a true difference of 15 min or more is to
target weight would then have a and /3 risks of be detected with a power of 80% at the 10% level
0.05 and 0.10, respectively. The values of 1.96 of significance (two-sided test)? The standard
and 1.28 in the calculation of N refer to the stan¬ deviation is approximately 10. In comparison
dard normal deviate for a = 0.05 and /3 = 0.10. with the previous example, the experimenter is
A variation of equation (2) gives the approxi¬ willing to take greater risks of making errors of
mate sample size for binomial data, replacing a2 the first and second kinds (a and /3 are 0.1 and
appropriately with pq.6 0.2, respectively). When the risks of making
For small sample sizes and unknown a, the these errors are larger, the sample size needed to

264 • The Theory and Practice of Industrial Pharmacy

meet these criteria is smaller. Using equa¬ 12 - 0.5 Z2 ~ 10), and use this value in equa¬
tion (3), the sample size is: tion (4). (This is the inverse of the procedure
used previously in calculating the sample size.)
N = 2(10)2[(1.645 + 0.842)/15]2 = 5.5 The calculation using equation (4) follows:

Adding 0.25 Z2(0.25 X 1.652 = 0.7) to N results Zg = 0.2V10/0.252 - 1.96 = 0.57

in 6.2. Seven tablets from each formulation
should be sufficient to satisfy the above condi¬ P = 0.285 and the power is 71.5% as deter¬
tions. mined from Table 10-2.
For one-sided tests, the same formulas are In a two-sample test, the following is used:
used, but Za has a% of the area in the upper tail
(e.g., at the 5% level, Za = 1.645, and at the Zg = dVm? - Za (5)
10% level, Za = 1.28). In the previous example,
if a one-sided test were appropriate, using equa¬ Suppose, in a two-sample, two-sided test,
tion (3) results in the following calculation of N: Nj = N2 = 10, a = 0.05, d = 2, and cr2 = 3.
Again, subtracting 0.25 • Z2 from N as before
N = 2(10)2[(1.282 + 0.842)/15]2 (10 -1=9), and using equation (5):

+ 0.25(1.282)2 Zg = 2V9/(2)(3) - 1.96 = 0.49

= 4.4 Zg is 0.49 and the power is approximately 69%

(Table 10-2). This means that if a statistical test
Five tablets of each formulation would be ade¬ (t test) is performed comparing the means of the
quate. two groups at the 5% level with 10 experimental
units in each group, if the true difference (d)
between the group means is 2 or more, the sta¬
Power tistical test will show a significant result with a
The power of a test is its ability to detect a probability of at least 69%. The calculation of
difference if such a difference truly exists. The power is discussed more fully in Pharmaceutical
power can be calculated solving for Zg from Statistics by Bolton (see General References).
equations (2) or (3), specifying values for N, a,
and “d”. In the one-sample (or paired-sample)
test, for example, from equation (2):
Consumer Acceptance Testing
Before a product is introduced to the market,
Zg = d • VN/o2 - Za (4) it may be advisable to assess patient or con¬
sumer acceptability of one or more formulation
If N is small, substitute appropriate values of t attributes, such as taste, color, packaging, and
for Z, or make the inverse adjustment for N as physical characteristics (e.g. viscosity of a liquid
discussed previously, i.e., make the computa¬ suspension or thickness of an ointment). The
tions using Z, but subtract 0.5 Z2 from N. formulation section is often involved in imple¬
Consider a bioavailability study in which the menting and evaluating these tests, and a famil¬
average of the ratios of AUC of a tablet formula¬ iarity with common designs such as monadic
tion and solution of the same drug is to be as¬ tests, paired comparisons, and triangle tests is
sessed. If the bioavailabilities of the tablet and important.
solution are the same, the ratios of the areas
should be equal to 1, on the average. Therefore,
the null hypothesis is H0: Ratio = 1. The two- Monadic or Single-Product Test
sided alternative is HA: Ratio # 1. The FDA is In this test, the attributes of two or more prod¬
interested in knowing the power of such tests ucts are compared, and each individual evalu¬
because small sample sizes drat result in nonsig¬ ates only a single product. To analyze the result¬
nificant differences may have litde power. What ing data, some quantitative measurement must
is the power of the test with a sample size of 12 be associated with the test since such tests are
in which protection is to be provided against er¬ often qualitative in nature. A number or score
roneous acceptance of alternatives for which the may be assigned to a descriptive term related to
true ratio differs from 1 by 0.2 (20%) or more? the attribute being assessed. For example,
The test is performed at the 5% level, and the “excellent” = 1; “good” = 2; “fair” = 3; and
s.d. is approximately 0.25. Since N is small, “poor” = 4; or “I would buy this product” = 3, “I
subtract 0.5 Z2 from N (Z„ = 1.96; might buy this product” = 2; and “I would not

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 265

buy this product” = 1. The scoring systems are
often arbitrary, but research on the development
of such scoring schemes considers the follow¬
ing: (1) How many choices should be given to
the test panelist? (2) How should the evaluation
statements be expressed? (3) Are the intervals
between adjacent statements equal? For exam¬ superb
ple, is the difference between “poor" and “fair”
the same as the difference between “fair” and
“good”? Usually, an arbitrary equi-interval lin¬ excellent
ear scale is used despite its theoretical short¬
comings. very good
Use of six or seven reasonably spaced evalua¬
tion statements with a sufficiendy large panel
(30 or more) results in data that can be reliably good
analyzed. Snedecor and Cochran discuss such
scaled data and conclude that the ordinary t test
is applicable (with a small continuity correction) fairly good
provided a reasonable sample size is used.6 The
test for two products can be analyzed using a
fair
two-sample t test. For more than two products,
analysis of variance is used. The design, analy¬
sis, and interpretation of such experiments are fairly poor
the same as for other similar tests described in
this chapter, e.g., comparison of two drugs in
independent groups. Consider the following ex¬ poor
ample.
An antacid product is reformulated with a new
less expensive flavoring agent. Fifty subjects, very poor
users of this product, were randomly divided
into two groups of 25 each, with each subject
terrible
evaluating either the new or old formula. A
“thermometer” scale (Fig. 10-10) was used, and
the results are shown in Table 10-12. Testing
the hypothesis of equality of means,
H0: p-i = use the t test for two independent
groups at the 5% level. The procedure and cal¬
culations have been described in the section
“Hypothesis Testing for Statistical Significance”
for the case of the independent two-sample t
test.

t47 = |Xj - X2 - 0|/(SpVl/Ni + 1/N2)

FIG. 10-10. Typical thermometer scale for evaluating
Sp = V 24(1.94)* + 23(1,90)a]/47 = 1.917 consumer products.

t47 = |7.44 - 6.88j/[ 1.917V1/25 + 1/24] = 1.02

Although the old product received a higher rat¬

ing, the two formulations are not significantly Table 10-12. Comparison of Flavor Using Ther¬
different. The t value needed for significance is mometer Scale
2.01 (see Table 10-3).
The action based on these results depends on Old Product New Product
many factors, including common sense. In this
NUMBER OF SUBJECTS 25 24*
situation, the new product might be marketed
AVERAGE SCORE 7.44 6.88
because of the “nonsignificant” difference and 1.94 1.90
STANDARD DEVIATION
the decreased production costs. Alternatively,
the marketing group might feel that the existing 'One subject was ill and could not evaluate the product.

266 • The Theory and Practice of Industrial Pharmacy

franchise is so good that any product that is con¬ were the following:
ceivably not as good (as in the case here), or dif¬
ferent in any way for that matter, would not be a Prefer Prefer No
viable substitute. In the latter case, an experi¬ Formula A Formula B Preference
ment designed to test if products are distin¬
guishable might be preferred. 32 16 12
The independent two-sample t test described
in this section, sometimes known as a “mo¬ The question of what to do with “no prefer¬
nadic” test, may lack sensitivity because of large ence” decisions is controversial. Should subjects
intersubject variability. Nevertheless, this test is be forced to state a preference? Although there
often preferred, depending on product type as is no definitive answer, it appears best to allow
well as on cost and time restraints. Such tests subjects to give a “no preference” decision, but
can be completed more quickly than paired tests not to include this data in the statistical analysis.
in which each subject evaluates two products. Certainly, the "no preference” data should not
Also, the procedure used in this test may be be ignored when the recommended action is fi¬
more realistic when related to how products are nally made. It would certainly make a differ¬
actually used in the marketplace. ence, for example, whether either 90% or 10%
of the subjects made a “no preference” decision,
regardless of statistical significance.
These data can be analyzed by chi-square or
Paired Tests equivalent binomial techniques. The hypothesis
A paired test in which each subject compares to be tested is that among the subjects who ex¬
two or more products is often desirable because press a preference, there is equal preference for
of convenience and the improved sensitivity re¬ the two formulas.
sulting from the intrasubject comparison. Prod¬
ucts may be evaluated by (1) preference H0: p = 0.5 Ha: p # 0.5
whereby the subject notes which product is pre¬
ferred, (2) a ranking procedure, or (3) a scoring Percentage preferring A = 32/48 = 66.7%
or rating system as discussed under “monadic”
tests. If more than one product is to be com¬ Z = [|pA - 0.5| - 1/(2N)]/Vpq/N
pared, “round robin” tests can be used, whereby
each subject tests each and every possible pair of = (0.667 - 0.5 - l/96)/V(0.5)(0.5)/48
products. A variation is the incomplete block
design, in which a balanced subset of the prod¬ = 2.17
ucts are tested by each individual.11,12 In repeat
tests, products are evaluated sequentially, and There is a significant preference (P < 0.05) for
sufficient time should be allowed between as¬ Formula A among those who express a prefer¬
sessments for the subject to return to his normal ence. As just explained, when the results of
state. For example, in taste or smell tests, the such an experiment are reported, the number of
sensory organs can be overstimulated and a re¬ consumers who had no preference should be
covery period should be part of the experimental acknowledged. In this example, the conclusion
design. Order effects occur often in such tests is that of 48 subjects who expressed a prefer¬
because of unconscious bias as well as sensory ence, 2/3 preferred Formula A (P < 0.05), and
fatigue, and principles of good design including there were 12 subjects who had no preference.
blinding and randomization are particularly
important. Testing using a response scale (e.g.,
1 to 10) can be analyzed by paired t test proce¬
dures or by a two-way analysis of variance. Triangle Tests
If the number of subjects is small and the ex¬ Preference tests are primarily designed to pre¬
perimenter feels that assumptions such as nor¬ dict the proportion of the consumer population
mality that underly the statistical analysis are that will prefer one preparation to another. How¬
not valid, suitable nonparametric techniques ever, consumers may perceive two formulas as
(such as ranking tests) can be used (these tests being very different, but they could be seg¬
are described at the end of this chapter). As an mented into two equal groups, each of which
example consider a test in which 60 subjects prefers the alternate product. Thus, equality of
were asked to use two variations of a formula, A preferences does not distinguish between two
and B. Preference was indicated based on the possible situations: (1) the existence of two dis¬
formula’s “feel” in the mouth, and the results tinct but equal groups, each of which prefers one

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 267

or the other product and (2) one homogeneous The statistical analysis is based on a test of the
group that simply cannot differentiate the prod¬ following hypothesis:
ucts.
The triangle test is designed to assess if prod¬ H0: p = 1/3
ucts are in fact distinguishable. Three samples, Ha: p > 1/3
similar in appearance, are submitted for testing,
two of one product and one of another. The con¬ This means that if there is no difference, the
sumer is asked to choose the product that is dif¬ correct product will be chosen one third of the
ferent from the other two (optionally, a prefer¬ time by chance. This is a good example of a one¬
ence can also be requested). If there is a sided test, i.e., a difference can be tested for sig¬
“significant” number of correct guesses, the nificance only if correct choices are made by
products are considered distinguishable, and more than one third of the panelists. If less than
preference data, if requested, may be analyzed to one third choose the odd product, this result can
determine the preferred product. be due only to chance. If the experiment results
Order effects are important in such a test, and in significantly less than one-third correct
the order of presentation should be randomized choices, the experimental procedure should be
or balanced. There are six possible ways of pre¬ questioned. The test of hypothesis uses the bi¬
senting three products of which two are identi¬ nomial distribution with p = 1/3 and N = 30.
cal. If the products are called A and B, they can The test statistic is:
be presented in the following orders. (The prod¬
ucts should be labeled in some random manner, Z= [|Pobs - 1/3| - l/(2N)]/V(l/3)(2/3)/N
and the six orders should be randomized.)
where pobs is the observed proportion of correct
Subject 1st 2nd 3rd
choices, and N is the number of responses. For
this example:
1 ABB
2 A A B pobs = 15/30 = 0.50
3 B B A
4 BAA and
5 BAB
6 ABA Z = (| 1/2 - 1/3| - l/60)/V(2/9)/30 = 1.74

If order effects are present (e.g., the choice by At the 5% level (one-sided test), a value of Z
the panelist of the odd, or different, product equal to or greater than 1.65 is significant (see
tends to be the second product tested), the bal¬ Table 10-2). In this example, the conclusion is
anced design protects against bias. that the products are distinguishable at the 5%
Carry over effects cause a problem. For exam¬ level.
ple, in a taste test, if one or more products has so
strong a taste as to numb the taste buds, this
would influence the evaluation of the subse¬ Other Tests
quent products. Sufficient recovery time in be¬ Other designs used in consumer testing in¬
tween assessments would be an important part clude round-robin, sequential, and repeat paired
of the design. On the other hand, too long a time preference tests.13 The round-robin used for
interval between tastes could involve a “mem¬ more than two products compares all prepara¬
ory” factor, thus introducing excess variation. tions in all possible pairs. The sequential design
One could, however, reason that this situation is is based on the idea that results can be analyzed
more realistic in that consumers do not normally sequentially after each preference, so that if
compare products side by side. These are all large enough differences exist, a smaller sized
valid arguments to be individually assessed for panel can be used to come to a decision more
each product and marketing situation. quickly than if a fixed sample size is chosen in
Suppose that a variation of the base of a mar¬ advance. The advantage of this design depends
keted ointment is made to improve its kines¬ on many factors, including anticipated differ¬
thetic properties and that 30 panelists are to ences, the nature of the products, and the set¬
cpmpare the “feel” of the old and new products ting of the test. Repeat paired comparison tests
using a triangle test design. After proper ran¬ consist of a paired preference test repeated on a
domization of the products, 15 of the 30 panel¬ second occasion. The analysis can result in a
ists make the correct choice, i.e., choose the cor¬ segmenting of the population into two groups
rect “different” product. preferring each product as well as a group who

268 • The Theory and Practice of Industrial Pharmacy

 cannot distinguish the products. This test may more than two groups. In the t test, the following
be physically difficult to implement, however, statistic compares the difference of two sample
and the data are sensitive to deviations from the means to the standard deviation of the differ¬
model. ence (the denominator of the t statistic):

Analysis of Variance and (X, - X2)/VSp(l/N! + 1/N2)

Experimental Design The pooled variance, Sp, depends on the varia¬

Analysis of variance (ANOVA) is inextricably bility within each of the two groups. If the two
connected to experimental design. Experiments means come from the same normal distribution,
that are conceived to compare, estimate, and test the difference between these means (suitably
such effects as drug treatments, formulation dif¬ weighted) should also be a measure of the varia¬
ferences, and analytical methods can be de¬ bility of the data. Since the variance of a mean,
signed to yield an optimal return for effort ex¬ S|, is equal to S2/N, then S2 is equal to N(S|). A
pended. The experimental results may then be comparison of the the estimate of S2 from the
analyzed by ANOVA techniques. A good experi¬ difference of the two (or more) means to the
ment speaks for itself; the conclusions are often within group variability (S2 pooled) is a measure
obvious without complicated mathematical of the difference between means. If these two
treatment. With sophisticated calculators and estimates of variation are similar, one may con¬
computers readily available, however, most ex¬ clude that the means of the groups do not differ,
periments, if designed properly, can be easily i.e., that the difference between the means can
analyzed. In a poorly designed experiment, on be accounted for by ordinary variability. If the
the other hand, more than one factor may con¬ variability due to the difference between means
tribute to an experimental result with no way of is “significantly” larger than that within groups,
untangling the effects of the factors. (This is one can conclude that the means of the groups
called “confounding.”) Examples of obvious con¬ differ.
founding are (1) a clinical study in which pa¬ A large variability of the means is associated
tients are allowed to take various concomitant with large differences between the means. Since
drugs other than the test drug that affect the as noted previously, the variance of a mean is
condition being treated; and (2) a comparison of o-2/N (where N is the sample size), the sample
a new tablet formulation to the former formula¬ variance of the mean is weighted by N to obtain
tion for dissolution, with the tablets prepared on an estimate of cr2. Thus, a statistic that can be
two different tablet presses, one formulation on used to test treatment (group) differences is
each press. Differences in the performance of formed by the following ratio:
the presses (pressure, for example) can contrib¬
ute to differences in dissolution in addition to v Nj(Xj - X0)2/(G - 1) r
differences due to formulation changes.
Analysis of variance separates the total varia¬
tion in the data into parts, each of which repre¬
sents variation caused by factors imposed on the where the numerator is the variability (variance
experiment. A properly designed experiment al¬ estimate) due to the different means, and the
lows a clear unconfounded estimate of such var¬ denominator is the pooled within group vari¬
iation or, at least, can identify the confounding ance. Xj is the mean of the ith group, X0 is the
factors, if present. Consider an experiment to overall mean of all the groups, and G is the num¬
assess the effects of lubricating agent and disin¬ ber of groups.
tegrating agent on the dissolution of a tablet. The distribution of this F ratio under the hy¬
The final analysis of variance would separate the pothesis that the group means are equal is the
- effects of these factors by computing that part of same F probability distribution previously men¬
the total variation attributable to the lubricating tioned when testing for the equality of two vari¬
and disintegration agents isolated from that vari¬ ances. The F distribution has vj and v2 degrees
ation due to experimental error. This separa¬ of freedom, where v, is the degrees of freedom
tion serves as a basis for testing statistical hy¬ associated with the numerator (G — 1), and v2 is
potheses. the degrees of freedom associated with the de¬
nominator equal to 2(Nj) - G. For two groups,
analysis of variance results in exactly the same
One-Way Analysis of Variance probability level as the two-sample t test. (The F
One-way ANOVA can be considered an exten¬ statistic with 1 df in the numerator, which is the
sion of the independent two-sample t test to case for two groups, is the square of the t statistic

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 269

with degrees of freedom equal to that in the de¬ Table 10-13. Change Of Blood Pressure in Pre¬
nominator of the F ratio.) The following example clinical Study Comparing Two Drugs and Con¬
should clarify some of the foregoing concepts trol
and computations.
In a preclinical study, animals were treated Drug 1 Drug 2 Control
with two antihypertensive experimental drugs 8
15
and a control drug, with 12 animals randomly 12 14 16
assigned to the three groups, four per group. 19 13 20
One animal died from a nondrug related cause 11 6 22
and was lost to the experiment. The results
(change in blood pressure from baseline) are SUM 57 41 58
shown in Table 10-13. Are the treatment means MEAN (X) 14.25 10.25 19.33
different, or do the observed differences merely S 3.59 3.86 3.06
reflect the inherent variation of the animals’ re¬
sponse to such treatments? Under the assump¬
tions that the variances within each group are
equal, and that the data are independent and ratio is sufflciendy large to declare significance.
normally distributed, a test for equality of means The cutoff point for significance at the 5% level
can be performed using analysis of variance. for F2i8 is 4.46 (see Table 10-6). Since the calcu¬
The reader should refer to Table 10-13 as an aid lated F(5.54) is larger than 4.46, the conclusion
in following the calculations needed for the is that at least two of the means differ from each
ANOVA. other at the 5% level.
The overall mean is: Computations for ANOVA, when done by
hand, routinely use shortcut formulas, and the
Xq = 156/11 = 14.18 results are presented in an analysis of variance
table. For the above example, the calculations
The Between Treatment Mean Square (BMS) is: can be simplified as shown below (refer to
Table 10-13 to help in following the calcula¬
2Ni(Xi - X0)2/(G - 1) tions).
Total Sum (2X) =156
= [4(14.25 - 14.18)2
(2X)2/Nt = Correction Term (C.F.)
+ 4(10.25 - 14.18)2
= 1562/11
+ 3(19.33 - 14.18)2]/2
= 2212.36
= 70.74
2X2 = 2456
The Within Treatment Mean Square (WMS)
is the variance pooled from within each group. Total Sum of Squares = TSS

[3(Sf) + 3(S|) + 2(S§)]/(Nt - 3) = 102.167/8 = 2X2 - C.T.

= 12.77 = 2456 - 2212.36

where Nt = 2Nt =11. = 243.64

The F ratio with 2 and 8 df, a test of differ¬
ences among treatment means, is BMS/WMS. Between Treatment Sum of Squares

F2,8 = 70.74/12.77 = 5.54 = BSS

If the hypothesis that all three means are the = 2 T2/Ni - C.T.
same is true, the ratio BMS/WMS should be
equal to 1, on the average. If the computed F 572 412 582
2212.36
ratio is less than 1, the means are not signifi- 4 + 4 + 3
candy different. If the F ratio is greater than 1,
an F table should be used to determine if the = 141.47

270 • The Theory and Practice of Industrial Pharmacy

 ANALYSIS OF VARIANCE (ANOVA) TABLE
SOURCE DF SUM OF SQUARES (SS) MEAN SQUARE (MS)
Between Groups 2 (G - 1) 141.47 70.74 F2,8 = 5.54
Within Groups 8 (N - 3) 102.17 12.77

Total 10 (N - 1) 243.64

where T is the total sum of data in ith treatment Total Sum'Qf Squares = EX2 - C.T.
group.
= 1408 - 1280
Within Treatment Sum of Squares
= 128
= WSS = TSS - BSS
Between Labs Sum of Squares
= 102.17
The analysis is typically presented in an “anal¬ (Sum Column l)2 (Sum Column 2)2
ysis of variance (ANOVA) table/’ 3 ‘ + 3
The total variation is S(X - X)2 and is sepa¬
rated into two parts, that due to differences of + (Sum Column 7)2 _ c T
the means of the groups, and that due to the
pooled variation within the groups. If the groups
are not different, the variation among different
groups should be no greater than that due to var¬
iation among individuals within groups, the
“within” variation.
102
In general, there are “G” groups with replicate
measurements in at least one of the groups. Al¬
Within Labs Sum of Squares
though calculations are simplified and efficiency
is usually optimal when comparing means if the
= Total SS - Between SS
number of observations in each group is equal,
this is not a necessary condition for this analy¬
= 128 - 102
sis. In many experiments, especially in those
involving humans, the original plan usually pro¬
= 26
vides for equal numbers in each group, but life
circumstances intervene, resulting in dropouts
Table 10-6 shows F6 = 2.9 at the 5% level.
and lack of a symmetric design. The imbalance
Therefore, the ratio 8.5 is significant, and at
presents no problem, however, in the analysis of
least two of the laboratories are considered to be
this one-way design.
different (P < 0.05).
Consider another example of this design in
Confidence limits on the overall average can
which an analytical method is tested by sending
be constructed to give a range for the true mean
the same (blinded) sample to each of seven labo¬
of the analysis: X0 ± tCS^). For 95% confidence
ratories from the same company, located at dif¬
ferent sites. Each of laboratories 1 through 6 has
three analysts perform the analysis. Laboratory
Table 10-14. Assay Results for Seven Laborato¬
7 reports only two results because only two ana¬
ries
lysts are available. In this experiment, a problem
would result if one of the two analysts in labora¬ LABORATORY
tory 7 does a third analysis to present three re¬ 1 2 3 4 5 6 7
sults, since then the data for that laboratory
would not be independent. Independence, in 9 11 6 10 5 7 12
this example, refers to the fact that within each 8 9 9 10 3 7 10
laboratory, analysts perform their analyses inde¬ 7 13 9 7 4 7 —
pendently. The results are shown in Table 10-
AVERAGE 8 11 7 9 4 7 11
14. The computation is identical to that de¬
OVERALL AVERAGE = 8.0
scribed in the previous example.

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 271

 ANOVA
Source DF SS MS
Between Labs 6 102 17 F6,13 ~ 8.5
Within Labs 13 26 2

Total 19 128

limits, the value of t is 2.16 and S| = 2/20. The problem of multiple comparisons is com¬
(From the ANOVA Table, df = 13 and S2 = 2; plex, and many solutions have been proposed.
the total number of observations is 20.) The 95% The simplest method of dealing with multiple
confidence limits are 8 ± 2.16V2/20 = 8 ± 0.7. comparisons gives more significant results than
Note that the variance estimate for the computa¬ would be expected from the ANOVA a level. A t
tion is the within error, or variance. This is the test is constructed for differences between
correct error term because all of the laboratories means using the degrees of freedom and mean
of interest were included in the experiment (a square error from the ANOVA. If the sample
fixed model). If the laboratories were only a sam¬ sizes are the same in each group, a single least
ple of many possible laboratories, then the cor¬ significant difference (LSD) can be constructed:
rect error term would be the between mean
square with (C - 1) degrees of freedom. (This is LSD = tdf>0VSz(2/N)
known as a random model.) In general, the be¬
tween mean square is larger and has less de¬ where t is the tabled value of t with appropriate
grees of freedom than the within mean square, df at the a level of significance. Any difference
and confidence limits are wider in this case. exceeding the LSD can be considered to be sig¬
This less precise estimate is to be expected, be¬ nificant. The LSD test should be used only if the
cause in the random case, not all members of F test from the ANOVA is significant.
the population have been sampled. The overall In the above example of seven laboratories,
mean is estimated from a small sample of the comparisons of laboratories with three observa¬
possible laboratories. In the fixed model, each of tions (Laboratories 1 through 6) would result in
all of the possible laboratories (7) have been an LSD equal to 2.16V2(2/3) = 2.49, where
sampled with replicate determinations (ana¬ 2.16 is the value of t with 13 df at the 0.05 level,
lysts) obtained from each laboratory. If the num¬ and 2 is the within mean square. Laboratories 1
ber of observations in each group is not equal in and 2 are significantly different from each other,
the random model, construction of a confidence the difference of their means (11 - 8 = 3) ex¬
interval for the overall mean is difficult. ceeding the LSD (2.49). Laboratories 1 and 3,
for example, are not significantly different. In
comparing any of laboratories 1 dt.vugh 6 to lab¬
Multiple Comparisons oratory 7, an ordinary two-sample t test is used.
With more than two treatments, if the F test is For example, the comparison of laboratories 1
significant in the analysis of variance, one must and 7 is performed as follows:
determine which of the treatments differ. If a
separate test is done comparing each pair of t = (11 - 8)/V2(l/3 + 1/2) = 2.32
treatments, the chances of finding significance
when the treatments are really identical are Since the calculated t (2.32) is greater than the
greater than that indicated by the a level. If the tabulated t at the 5% level with 13 df (2.16), the
a level is 0.05, by definition, one time in twenty difference is significant.
a difference will be found to be significant when Other tests take into account the multiplicity
the treatments are truly identical. If more than of comparisons and impose a penalty so that dif¬
one pair of treatments are tested for significance ferences greater than that calculated for the t
in the same experiment, significant differences test are required for significance. One com¬
are found in more than 5% of such experiments, monly used method is Tukey’s multiple range
if treatments are truly identical. This concept method:
may be better understood if one thinks of a large
experiment in which 20 independent compari¬ Compute | Difference|/VS^/N = q (6)
sons are to be made at the 5% level. On the aver¬
age, one significant difference would be ex¬ Table A15 in the text by Snedecor and Cochran
pected in each experiment of this kind, if the shows significant values of q depending on the
hypothesis of equal treatment means is true. number of treatments, df and a level.6

272 • The Theory and. Practice of Industrial Pharmacy

 From equation (6) the minimum difference Table 10-15. Stability of Five Batches of Tablets
for significance for any pair of treatments is Using Three Kinds of Packaging Material
qVS'/N. Stricdy speaking, when using this for¬
Packaging Material
mula, N should be the same for each treatment.
In the laboratory example, laboratory 7 has two Batches ABC Mean
observations, compared to three observations in
the other 6 laboratories. A slight adjustment for 1 96 101 89 95.33
N would be necessary in this example,6 but for 2 89 99 80 89.33
purposes of illustration, assume that there are 3 82 88 83 84.33
three observations for all laboratories (N = 3). 4 94 94 90 92.67
For this example at the 5% level, q equals 5 93 90 89 90.67
4.88, and the minimum difference needed for
Mean 90.8 94.4 86.2
significance is:

4.88V2/3 = 3.98
for five batches of tablets using three different
kinds of packaging material, with the results
This difference is larger than that computed by
shown in Table 10-15. The computations for the
the LSD procedure. Laboratories 1 and 2 are not
ANOVA are shown below on page 274. Note that
significantly different using this method. Labo¬
the computation of the between batch and be¬
ratory 5 is significantly different from all the
tween packages sum of squares is performed in
other laboratories except for laboratories 3 and 6.
the same way as the one-way analysis of vari¬
Significant difference in laboratory results may
ance. The difference between the total sum of
require an action to determine and correct the
squares and the sum of the between packages and
cause; or, perhaps, it might be important just to
between batches sum of squares is the error sum
know that differences exist.
of squares.
Another commonly used method is Duncan’s
multiple range test, which is considered to have In this design, the error sum of squares is less
excellent properties.14 than that which would be computed from the
same data without the “blocking” factor of
batches. If the batches sum of squares were-not
Two-Way Analysis of Variance included in the analysis, the error sum of
(Randomized Blocks) squares would be increased by that amount. The
The two-way model is an extension of the inclusion of the batch, or blocking factor, usually
paired t test in which more than two groups or results in a smaller mean square for error, and
treatments are compared. As in the paired t test, thus a more precise experiment.
each individual (often referred to as a “block”) is
subjected to every treatment. Sometimes this Total SS
model is described as a design in which each
individual acts as his own “control.” = SX2 - C.T.
In general, the order in which treatments are
assigned to individuals is randomized unless a = 962 + 1012 + . . . + 892
special design such as a crossover is used, which
is discussed in a subsequent section of this _ (96 + 101 + . . . + 89)2
chapter. A table of random numbers can be used 15
to randomize the order of treatments to be tested
on each individual or experimental unit. = 123,259 - 122,763.27
The analysis of the two-way design is similar
to the one-way ANOVA except that an additional = 495.73
source of variation is present, that due to the dif¬
ferences among the blocks. For example, if three Between Package SS
assay methods are to be compared on six batches
of granular material, the variation due to blocks = R2(CS)2 - C.T.
(the batches) is associated with the differences
in concentration of active material in the six = 5(90.82 + 94.42 + 86.22)
batches.
The following example should clarify the de¬ - 122,763.27
sign and data analysis. The time to 10% decom¬
position at accelerated conditions was compared = 168.93

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 273

where R is the number of rows (batches), and C, fect, i.e., there is a concern in the results of only
is the column (packages) means. these five special batches (or the method by
which each was prepared), and all the batches of
Between Batch SS interest have been tested. Inferences about fu¬
ture batches made under unknown conditions
= CE(Ri)2 - C.T. are not of current interest.
If the batches are chosen randomly merely to
= 3(95.332 + 89.332 + . . . + 90.672) provide replication, however, then the batch dif¬
ferences per se are not of primary concern. In
- 122,763.27 this case, the ANOVA is referred to as a mixed
model: the batches are random and the packages
= 202.40 are fixed, i.e., in this experiment, possible differ¬
ences among the three packages are of interest,
where C is the number of columns (packages), and inferences about other yet untested pack¬
and Rj is the row (batch) means. ages are of no concern. If batches are random,
the F test for batches described previously may
Error SS = Total SS - Package SS - Batch SS be incorrect in the presence of batch X package
= 495.73 - 168.93 - 202.40 interaction. Interaction, in this example, would
= 124.40 be evident if package differences depended on
which batch was being tested. A more correct
As in the case of the one-way ANOVA, F ratios error term (the denominator of the F ratio) for
are referred to in F Table (see Table 10-6) with batch differences would come from replicate
appropriate degrees of freedom for tests of sig¬ determinations within each batch, e.g., a repeat
nificance. The F ratio for packages, with 2 and 8 determination obtained by assaying a duplicate
df, is 5.43 (Between Packages MS/Error MS), separate package. In any event, if batches are
which is significant at the 5% level. Therefore, random, serving only as replicates for assessing
at least two of the packages differ. The least sig¬ package differences, there is usually little inter¬
nificant difference (LSD) is tVS2(2/N) = est in whether or not baitches differ. In fact,
batch differences are known to exist, and that is
2.31 Vl5.55(2/5) = 5.76. In this case, packages
why each package is tested on the different
B and C are significantly different, with package
batches.
B resulting in the least degradation.
The two-way design is used in preclinical and
clinical studies in which two or more drugs and/
The Question of a Fixed or or placebos are to be compared. In these cases,
animals or humans represent the rows or blocks
Mixed Model that are considered to be random, i.e., the sub¬
The F ratio for batches, with 4 and 8 df, is jects are chosen as a means of replication to esti¬
3.25, which is significant at the 10% level but mate the error in the experiment. The question
not at the 5% level (see Table 10-6). A relevant of mixed and fixed effects models is an impor¬
question is, “Is the fact that these batches may tant consideration in the analysis of multicenter
differ from each other with regard to their stabil¬ clinical trials. Suppose a clinical study compar¬
ity an important consideration, or are the five ing the effect of an antihypertensive drug to pla¬
batches being used merely as a means of obtain¬ cebo included 20 patients (10 on drug and 10 on
ing replication for the assessment of the three placebo) at each of eight clinical sites, with re¬
packages?” If the batches were somehow spe¬ sults shown in Table 10-16. The difference be¬
cial, perhaps prepared so that they differed in tween treatments is not quite significant at the
some known way, it would be of interest to know 5% level as indicated by the (Treatment)/
if the stability of these batches were different. In (Sites x Treatment) ratio of 4.68. An F ratio of
these cases, “batches” is considered a fixed ef¬ 5.59 with 1,7 df is needed for significance.

ANOVA
Source DF SS MS
Between Batches (Rows) R- 1 = 4 202.40 50.6 F48 = 3.25
Between Packages (Columns) C - 1 = 2 168.93 84.5 F23 = 5.43
Error (Row x Column) (R - 1)(C - 1) = 8 124.40 15.55

Total 14 495.73

274 • The Theory and Practice of Industrial Pharmacy

Table 10-16. Multicenter Trial Of An Antihy¬ 37.82/5.49 = 6.89. This F has 1 and 144 df and
pertensive Drug and Analysis of Variance is significant at the 1% level. Which, then, is the
correct F test? Is the drug significandy better
Average Blood Pressure Change than the placebo or not? With the assumption
(mm Hg) that the interaction variance is not zero, (that is,
Site Placebo Active
interaction is present), the answer depends on
1 -2.6 -9.3 whether clinical sites are fixed or random. If
2 0.8 -6.4 fixed, the result is highly significant; if random,
3 -5.9 -5.4 the result misses significance at the 5% level, an
4 -3.2 -8.4 important significance level for governmental
5 2.5 -1.2 acceptance of data for a drug submission.
6 -8.2 -4:2 Practically speaking, the sites are not ran¬
7 -0.9 -6.8 domly selected; on the other hand, they may not
8 -10.0 -10.4 be considered fixed. A “fixed” effect means that
all members of the population have been sam¬
-3.44 -6.51 pled. In the present case, is not the purpose of
the experiment to make inferences to other clin¬
ical sites? Although rhetorical, this dilemma is
In this example, there is replication in each real, and two points should be carefully consid¬
cell of the two-way design. (A cell is defined as
ered and understood: (1) An assumption of a
the intersection of a row and column, e.g., site 3
fixed model makes it easier to obtain a signifi¬
and placebo in the 8x2 table, Table 10-16.) cant difference between drug and placebo, and
Each cell consists of ten patients. There are now
(2) If the mixed model shows no significance
two error terms in the analysis of variance, the and the fixed model shows significance, the pos¬
interaction term and the within error term, the
sibility exists that a significant interaction is
variability estimate from replicate determina¬
present. A significant interaction means that
tions within each cell. The variation due to repli¬ clinical sites do not differentiate treatments
cates (within mean square) can be estimated by equally, an important consideration if some clin¬
pooling the variance between patients within ical sites favor one treatment, and others favor
each treatment group at each center (N = 10).
the other treatment (as opposed to interaction in
This estimate has 144 df, 9 df within each treat¬
which one treatment is consistently favored, and
ment and 18df from each of the eight centers. only the degree of difference is different). The
If interaction is present, the “interaction” var¬
implication of interaction in this context is that
iance is a composite of the “within” variance and
the effect of the treatment is not consistent but
the interaction of sites and drug treatments, and
depends on the clinic, patient population, and so
thus is greater than the “within” error.* The in¬
forth.
teraction represents the degree to which the
sites differ in their ability to differentiate the
drugs. Interaction is great if some sites favor Missing Values
drug and others favor placebo. If a sites x treat¬
Although data may be inadvertently lost from
ment interaction exists, “within” error is the
any experiment, human clinical trials are partic¬
correct error term for treatments if sites are
ularly susceptible to data loss. Even the most
considered to be fixed; that is, the correct F
well-designed, well-intentioned study cannot
ratio for treatments in the fixed model is
enforce exact adherence to the plan, owing to
the usual vagaries of life. Patient dropouts due to
’Sampling variation can result in occasionally larger noncompliance, adverse effects, and missed vis¬
“within” error estimates. its due to illness or forgetfulness are part of al-

ANOVA
SOURCE DF SS MS F
Sites 7 137.05 19.58
Treatments 1 37.82 37.82 F,,7 = 4.68
Sites X'Treatments
(interaction) 7 56.52 8.07 ^7,144 ~ 1-47
Within Sites* 144 780.56 5.49*

* Between subject variance (see text), within sites and treatments, is adjusted to be comparable to other terms in the ANOVA.

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 275

most every clinical study. In cross-classified de¬ the drug under consideration.16 Although these
signs—e.g., two-way, factorial—the usual alternative analyses have much merit, bioavaila¬
analysis is not valid when pieces of data are bility data are usually reduced at present to the
missing. Various options for the analysis exist comparison of the three parameters just men¬
depending on the design, the quantity of miss¬ tioned; this procedure is acceptable to the FDA
ing data, and the nature of the data. Alternatives in most cases.
include estimation of the missing data, curve fit¬ The simplest analysis of bioavailability com¬
ting, and the use of special complex computer parisons uses an analysis of variance for a cross¬
programs, which make adjustments for the un¬ over design. Statistical tests of hypotheses may
balanced design. The analyses are usually not be done separately for each parameter, e.g., rela¬
simple and often are difficult to interpret. tive absorption, time to peak, and peak plasma
Herein lies much of the art of statistics, and an level. This method involves the easiest computa¬
experienced statistician should be consulted in tion and interpretation but does not take into
such matters. account multiple statistical tests and correlation
of the parameters. Thus, although a multivariate
test may be more appropriate, it may often be
Bioavailability and Crossover difficult to interpret. Some statisticians have
suggested that hypothesis testing is not appro¬
Designs priate in bioavailability tests, because accept¬
Evaluation and analysis of bioavailability and ance of the null hypothesis cannot logically lead
pharmacokinetic parameters are important con¬ to the conclusion that two formulations are ex¬
siderations for the pharmaceutical scientist. actly the same, since two different formulations
Usually, a finished dosage form is compared to cannot be identically equivalent. Rather, confi¬
some preliminary formulation or marketed for¬ dence intervals provide more useful informa¬
mulation regarding relative absorption. The tion.17,18 For example, if two formulas can be
usual method of comparison consists of a clini¬ said to be within 25% of each other with a high
cal study in normal volunteers in which single degree of confidence, the clinician can then de¬
doses of the experimental and comparative for¬ cide whether the two formulations are similar
mulations are taken in a crossover design. In from a practical point of view.
this design, half of the subjects are randomly The following example concerns the analysis
chosen to take either one or the other of two for¬ of only a single parameter for purposes of illus¬
mulations on the first experimental occasion tration. The bioavailability of a tablet formula¬
(also known as period, leg, or visit), and the re¬ tion of a new drug is to be compared to an equiv¬
maining formulation on the second occasion. A alent amount of drug given in solution. The
sufficient period of time should intervene be¬ values in Table 10-17 for area under the blood
tween the two periods so that “all” of the drug is level versus time curve were obtained from 12
eliminated before the second dose is adminis¬ subjects in a crossover design. The analysis of
tered. It is important that power considerations
be taken into account when determining sample
size; the FDA recommends that the experiment Table 10-17. Results of Bioavailability Study—
Area Under Blood Level vs. Time Curve
be of sufficient sensitivity to have 80% power to
detect a difference of 20% or more between for¬ Order of
mulations at the 5% level. Usually, 12 to 24 sub¬ Subject Tablet Solution Administration
jects satisfy these conditions using a crossover
design. 1 76 83 T-S*
Various parameters can be considered in the 2 59 54 T-S
comparison of formulas for bioavailability, in¬ 3 84 95 S-T
cluding (1) total amount of drug absorbed (from 4 96 81 T-S
area under the blood level versus time curve, for 5 50 64 S-T
6 61 66 S-T
example), (2) peak blood level, and (3) time to
7 48 57 S-T
peak. Analysis of the results at each plasma (or
8 68 61 T-S
urine) sampling time should be discouraged
9 74 70 S-T
because the multiplicity of tests and correlation
10 86 79 T-S
of data at proximal time points lead to confusion 11 91 88 S-T
regarding the true significance level of such 12 57 68 T-S
tests.15 Also, interpretation is difficult. Other AVERAGE 70.83 72.17
analyses for bioavailability data have been pro¬
posed that may be more relevant depending on *T-S = Tablet first, solution second.

276 • The Theory and Practice of Industrial Pharmacy

variance accounts for order of administration Error SS = Total SS - Subject SS
with 1 df as well as “subject” and ‘formulations”
variance. The error sum of squares is the total - Formulation SS - Order SS
sum of squares minus the sum of squares due to
order, subjects, and formulations. Otherwise, = 4708 - 4225 - 10.67 - 96
the computations are similar to those previously
described: = 376.33

Between Subject SS The F tests for formulations and order of ad¬

ministration are not significant (Fuo is 4.96 at
= ER?/2 - C.T. the 5% level), suggesting that the values of total
absorption from both formulations are similar. A
_ (1592 + 1132 + 1252) significant order effect would occur if the aver¬
age results of the first visit differed from the av¬
erage results of the second visit. Such a differ¬
17162 ence could be caused by systematic differences
24 in the experimental procedure, the assay proce¬
dure, or the state of the subjects. A significant
= 4225 order effect does not invalidate the experiment.
The design separates the variability due to order
Between Formulation SS of administration from the residual experimen¬
tal error.
EC? The crossover design is a special case of the
C.T. Latin square design, and the same deficiencies
12
(and advantages) are present in both. A discus¬
sion of Latin square designs can be found in
(8502 + 8662)
- 122,694 standard texts on experimental design. (See
12 “General References.”) If differential carryover
effects exist (i.e., the effect of one drug preced¬
= 10.67 ing the other has a carryover effect different
from that which occurs if the order of adminis¬
YO2
Order SS = - C.T. tration is reversed), the treatment effects are
confounded and inferences can be misleading.
In this case, confounding is interpreted as a con¬
8822 + 8342 fusion of treatment differences with differences
- 112,694
12 due to the different carryover effects. Also, if in¬
teractions exist, the error is inflated, and inter¬
= 96 pretation of the results is unclear. Therefore, if
either carryover effects or interactions are sus¬
where Oj is the sum of results of first visit and pected, crossover designs should not be used.
02 is the sum of results for second visit. Special Latin square designs can be used to esti¬
mate and account for carryover effects,19 or a
Total SS = EX2 - C.T. simple parallel group (one-way) design can be
used.
= 127,402 - 122,694 The advantage of the crossover design as com¬
pared with a parallel group design is that the
= 4708 sensitivity of the experiment is increased, owing

ANOVA
Source DF SS MS
Subjects 11 4225 384.1
Formulations 1 10.67 10.67 Fi.io — 0.3
Order 1 96 96 Fi.io = 2.6
Error 10 376.33 37.63

Total 23 4708

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 277

to the use of within subject variance as the error the data to the statistical model, or an improve¬
in the crossover design, which is smaller than ment in properties that satisfy the test assump¬
the between patient variance measured in the tions, such as variance homogeneity.
parallel groups design. Grizzle has proposed an Probably the most frequendy used transfor¬
analysis that detects carryover effects. If such mation is the logarithmic transformation, obvi¬
effects are present, the data from only the first ously restricted to data with positive values.
visit are used and then analyzed as a one-way Examples in which the log transformation is rec¬
ANOVA, disregarding the data obtained from the ommended include the following situations.
second visit. (In the case of two treatments, this (1) The data have a log-normal distribution.
analysis is the same as an independent two- (The transformation results in normally distrib¬
sample t test.) uted data.) (2) The coefficient of variation (S/X)
Incomplete block designs may be used for bio¬ of the observations, X, is constant. (Log X has
availability studies when more than two formu¬ approximately constant variance.) (3) If the data
lations are to be compared. For example, if three consist of a simple exponential function of the
formulations are included in a study, a full independent variable X (that is, Y = AeBX), then
crossover would require three .visits. An incom¬ log Y is linear with respect to X. One should con¬
plete block design would have each subject take sider the effects of the log transformation on the
only two of the possible three formulations in a variance as well as on the distribution of the
symmetric pattern. For formulations A, B, and data. The transformation may make skewed data
C, six subjects taking A-B, A-C, B-C, B-A, C-A, appear more normal, but at the same time, it
and C-B, in the order specified, results in an in¬ may result in nonhomogeneity of variance,
complete block design, balanced for order. Ele¬ heteroscedasticity. Ideally, the transformation
mentary discussions of incomplete block designs results in satisfying both the normality and vari¬
can be found in the works of Davies and ance homogeneity assumptions implicit in the
Cox.11,12 usual tests. Fortunately, this transformation
Bioavailability data are often analyzed by often results in data that approximately satisfy
using a log transformation or by computing a both of these assumptions.
ratio of parameter estimates (e.g., AUC^blet/ Other useful transformations are the arcsin
AUCsolution) as the test statistic. These tech¬ transformation, which is used for proportions,
niques usually result in similar conclusions al¬ and the square root transformation, which stabi¬
though the use of the log transformation results lizes the variance if the variance is proportional
in an asymmetric confidence interval when the to the mean.5
antilog is calculated to back transform the
data.2' An advantage of using ratios is that the
statistic may be more easily interpreted by the
Regression
clinical scientist. As previously noted, use of Regression is a form of curve fitting that can
confidence intervals may be a more appropriate be used for descriptive or predictive purposes.
way of expressing the difference between two The theory of regression analysis allows equa¬
formulations with regard to a given parame¬ tions relating variables to be established; it also
ter.16,18 For the example shown in Table 10-17, aids in understanding the behavior (reliability)
95% confidence limits on the difference be¬ of the estimated equation parameters.
tween the formulations for “area under the
curve” can be constructed as follows (t with
10 df = 2.23): Simple Linear Regression
Simple linear regression is concerned with the
(72.17 - 70.83) ± 2.23V37.63(1/12 + 1/12) fitting of straight lines, Y = A + BX, where A
and B are the parameters of the line, the inter¬
= 1.34 ± 5.58 cept, and slope, respectively. The dependent
variable Y is a response that is the outcome of an
= (-4.24 to 6.92) experiment and is variable, i.e., its outcome can¬
The true difference between the AUCs for the not be exactly predicted. The independent varia¬
two formulations lies between -4.24 and 6.92 ble is considered to be known precisely. For ex¬
ample, if blood pressure is the dependent
with a probability of 95%.
variable, any or all of the following may be inde¬
pendent variables, depending on the objective of
Transformations the experiment: dose of drug, length of treat¬
Data analysis can often be improved by means ment, and weight of patient. Some examples in
of transformations, which result in a better fit of which regression analysis would be appropriate

278 • The Theory and Practice of Industrial Pharmacy

are (1) cholesterol lowering as a function of straight line models and determination of varia¬
dose, (2) log plasma concentration as a function bility allow inferences and predictions of future
of time, (3) optical density as a function of con¬ potency, as well as of the time to a given level of
centration, (4) dissolution as a function of stea¬ degradation, to be made with probability qualifi¬
rate concentration, and (5) tablet assay as’ a cations. Proper design of such studies is ex¬
function of tablet weight. tremely important. Design considerations in¬
The objective of linear regression analysis is to clude the number of points in time at which the
fit the best straight line, Y = a + bX, from the drug will be analyzed, various storage condi¬
experimental data, using least squares. The tions, the number of samples to be analyzed at
least squares line is defined as the line that each point in time, and the source of these repli¬
makes [SfObserved Y - calculated Y)2] a mini¬ cates. FDA statisticians recommend that three
mum, where the “calculated Y” is obtained from batches at ambient conditions be used to esti¬
the least squares line. From the methods of cal¬ mate stability characteristics.23 Tablets should
culus, it can be shown that: be taken from more than one bottle at each time
period, especially during early development or
The slope, b = [2(X - X)(Y - Y)]/[2(X - X)2] marketing stages. Recommendations regarding
an optimal choice of time periods for assay to
The intercept, a = Y — bX reduce the variability of the regression line have
appeared in the literature; however, in practice,
Various significance tests may be performed the choice of time points seems to involve more
on the estimates of the parameters a and b if the than just this kind of optimality.24 Designs
following assumptions are met: should include appropriate observation intervals
to reveal possible lack of linearity in the stability
1. X is measured without error. (If both X and Y plots.
are subject to error, line fitting may be ac¬ Table 10-18 shows the concentration of intact
complished by other minimizing tech¬ drug in tablets as a function of time at 25°C.
niques.22) Three “randomly” selected tablets from a single
batch were assayed at each sample time. (In the
2. Y is a variable with a normal distribution at
case of tablets taken from each of three batches,
each X, and the observed Ys are statistically
the statistical analysis would take the different
independent.
batches into account, and would be more com¬
3. The variance of Y is the same at each X. plex than what is presented here.) The results
are plotted in Figure 10-11.
4. The true relationship between X and Y is a
Some pertinent questions are: (1) Do these
straight line.
data represent a straight line? (Does the decom¬
position follow zero-order kinetics?) (2) If so, at
With these assumptions, the least squares fit
what time will the product be 10% decomposed?
can be used to estimate the variance; the vari¬
(3) How much intact drug will be present in one
ance of the slope; the variance of the intercept; a
year? To answer these questions, estimates of
predicted value of Y; and confidence limits at a
the slope (b) and intercept (a) that define the
new value of X. It can also be used to determine
straight line, and the variance estimate are ob-
if the relationship is a straight line. (Multiple
observations of Y at at least one value of X are
needed for the latter test.) All of the statistical
tests and confidence intervals are based on nor¬ Table 10-18. Stability Data With Triplicate
mal curve theory. If the data are normal, it can Assays From A Single Batch
be shown that estimates of the parameters a and
b have normal distributions. The procedure for Time Concentration (% of Label)
fitting straight lines and some relevant statisti¬
0 weeks 102,102,104
cal tests are presented, using data derived from
8 weeks 100,99,101
stability studies for illustrative purposes. 16 weeks 98,99,98
24 weeks 94,97,96
32 weeks 97,95,93
Fitting Lines to Stability Data 2X = 240* 2Y = 1473
Because federal regulations now require expi¬ 2(X - X)2 = 1920 2(Y - Y)2 = 137.33
ration dating of pharmaceutical products, statis¬ ’Note that the sum of “time” values (X) equals 3 x 80 = 240
tical procedures play an important role in the because each “time” appears 3 times, one for each value of the
analysis of stability data. The fitting of data to concentration (Y).

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 279

 where Cx is the concentration of drug at time T.
The variance estimate, S2, is:

S2 = [2(Y - (a + bX))2]/(N - 2)

A shortcut formula is:

S2 = [S(Y - Y)2 - b2S(X - X)2]/(N - 2)

= [137.33 - (—0.246)2(1920)]/13 = 1.638

The variance, as computed here, is an esti¬

mate of the error in the line fitting, which in¬
cludes tabletting variation (weight variation,
mixing heterogeneity, and other random errors)
and assay error, as well as variation due to the
fact that a straight line might not be an accurate
representation of the data. In the present exam¬
ple, an independent estimate of the tablet varia¬
FIG. 10-11. Stability plot showing loss of drug with time tion is available from the replicates at each ob¬
in a tablet formulation.
servation point. A one-way ANOVA of these data
is the first step in separating the sum of squares
into its various components. There are five ob¬
tained using the least squares procedure as fol¬ servation times with three replicates at each
lows (see also Table 10-18). time.
The sample estimate of the slope, b, is: The Between Times sum of squares can be
further subdivided into two parts.
b = 2(X - X)(Y - Y)/2(X - X)2 The regression sum of squares is calculated
as:
A shortcut computing formula for b is:
b2S(X - X)2 = (-0.246)2 x (1920)
b = (N2XY - SX2Y)/(NSX2 - (SX)21
and is the sum of squares due to the slope of the
= 15 • [0(102) + 0(102) + . . . 32(93)1 ~ (240X1473) line. A slope of zero would result in a zero regres¬
[(15)(02 + 02 + . . . 322) - (240)*]
sion sum of squares; a large slope results in a
= (346,920 - 354,000)/(86,400 - 57,600) = 0.246 large sum of squares. The deviations sum of
squares is equal to between times sum of
The sample estimate of the intercept, a, is: squares minus regression sum of squares,
(119.33 - 116.03), and represents the variance
a = Y - bX = 98.33 - (—0.246)(16) = 102.27 due to the deviations of the average results at
each time period from the fitted line.
Therefore, the equation of the fitted line is: Test For Linearity. The F test for linearity
has 3 and 10 degrees of freedom (F3 10) and is
CT = 102.27 - 0.246T (7) equal to Deviations MS/Within Times MS, or

ANOVA
Source DF SS MS
Between Times 4 119.33 29.83
Within Times 10 18.00 1.80

Total 14 137.33

Source DF SS MS
Regression 1 116.03 116.03
Deviations from Regression 3 3.30 1.10

280 • The Theory and Practice of Industrial Pharmacy

1.10/1.80 = 0.61. This is not significant Prediction. Based on the data, the best pre¬
(F3 ]0 = 3.71 at the 5% level. See Table 10-6). diction for the time at which 10% of the drug is
There is no evidence for lack of linearity. The decomposed (or when 90% of the intact drug is
nonsignificant test for linearity in this context present) is determined by rearranging equa¬
suggests that the use of a straight line as a model tion (7).
for these data is reasonable. The F ratio com¬
pares the deviations of the means of the observa¬ T90 = (90 - 102.27)/(—0.246) = 49.9 weeks
tions from the fitted fine at each time period to
the error determined from replicates within where CT is 90 and T90 is the time when 10% of
each time period. If this ratio is small, there is no the drug is degraded.
reason to believe that the relationship is not lin¬ The amount of active drug predicted to be
ear. A lack of linearity would result in an inflated present after one year is calculated from equa¬
deviations mean square, because the data repre¬ tion (7):
senting a nonlinear function would be far re¬
moved from the least squares line. C52 = 102.27 - 0.246(52) = 89.5%
Test of Slope. It is of interest to test if the
slope differs from zero, i.e., the drug is indeed The estimates of both T90 and C52 just de¬
degrading. A zero slope means that no degrada¬ scribed are variable and have error associated
tion is occurring. The test compares the sample with them. The error of a predicted value of Y
estimate of the slope to its variance using a t (concentration, C52, for example), where a pre¬
test. The_ variance estimate of a slope is dicted value is an actual observation at time X,
S2/S(X - X)2. depends on the magnitude of the variance, and
how far away the new time is from the mean of
H0: B = 0 Ha: B ^ 0 the time values (X) used to compute the least
squares equation. The further the new value of
tj3 = |b - 0|/Vs2/2(X - X)2 X is from X, the more variable is the estimate of
the predicted value. The variance of a predicted
= 0.246/Vl.638*/1920 value is:

= 8.416 Sp = S2(Predicted Value)

(Equivalently, Fu3 = Regression MS/Error MS = S2[l + 1/N + (XT - X)2/S(X - X)2]

= 70.84 = t2.) The slope is significant (see
Table 10-3); the drug is degrading. where XT is the time of prediction. The pre¬
Test of Intercept. Although it may not be of dicted value, an assay actually determined at the
special interest in this example, a test for the time of prediction, has a variance that consists of
significance of the intercept may also be per¬ the error due to the estimation involved in the
formed. In this example, one might wish to test line fitting plus the error associated with the
if the intercept is different from 100. A t test is new assay at the predicted time. A 95% confi¬
performed comparing the difference between dence interval for a single assay performed at 52
the intercept estimate, a, and 100 to its standard weeks can be computed once the variance esti¬
deviation. mate of the predicted value is calculated. A 95%
confidence interval equals C52 ± tdfo05(Sp). In
H0: A = 100 HA; A # 100 the example, the confidence interval is:

t13 = |a - 100|/VS2[1/N + X2/S(X - X)2] 89.5 ± t13,o.o5Vl.638[l + 1/15 + (52 - 16f/1920]

= 89.5 ± 2.16V2H5 = 89.5 ± 3.65

= (2.27)/V 1.638(1/15 + 256/1920)
A confidence interval for the “true” potency at
= 3.97 52 weeks (a sample would not actually be as¬
sayed at this point) is:
Thus, the intercept, 102.27, (potency at time 0)
is significantly greater than 100, P < 0.05 (see C52 ± tia.o.osVs^l/N + (XT - X)2/2(X - X)2]
Table 10-3).
= 89.5 ± 2.38
*1.638 is the variance estimated from the original least
squares fit. A safer estimate of error is the within mean The time at which 90% remains, for example,
square with 10 df equal to 1.80. is known as inverse prediction, or a linear cali-

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 281

bration problem, in which it is of interest to esti¬ a result of the log transformation if the coeffi¬
mate the time, T = (CT - C0)/b, with an associ¬ cient of variation, S/X, of the original untrans¬
ated confidence interval. It can be shown that formed data is approximately constant. If a log
the confidence interval for T is: transformation is inappropriate (as in zero-order
reactions), and the variance is not constant but
[(T - gT) ± (tS/b) depends on the magnitude of the value (e.g., the
coefficient of variation is constant), a weighting
x V[(N + 1)/N](1 - g) + (T -'t)2'/2(T - T)2] procedure should be used when fitting the least
squares line, with weights equal to the inverse of
+ [(1 - g)l (?) the variance.25
The weighting procedure is used for any least
where g = (t2)(S2)/[b2S(T - T)2] and ms fhe squares fit in which the variance is not constant,
appropriate tabled “t” value for the. confidence but the procedure is more complex than the ex¬
interval. In the present example, the time for amples considered here. When fitting lines to
10% decomposition, T90, is 49.9 weeks. For a the Arrhenius relationship, log k = -HA/T + K,
95% confidence interval: a weighted least squares procedure should be
used, because in general, the log k’s do not have
g = (2.16)2(1.638)/(0.246)2( 1920) = 0.0658 equal variance. A nonlinear approach to the sta¬
tistical analysis of stability data combining the
(t13 for a = 0.05 is 2.16) first order and Arrhenius equations has recently
been described.26
(Note that if the slope b is not significantly dif¬
ferent from zero, g will be greater than 1 and
confidence limits cannot be obtained.) A 95% Correlation
confidence interval for T90, the time for 10% Figure 10-12 is a scattergram showing the re¬
decomposition, using equation (8) is: lationship of change in blood pressure after
treatment and the pretreatment blood pressure
[48.85 ± (2.16 x 1.28/0.246) measurement. If both variables are subject to
error and are distributed bivariately normal, a
x V(16/15)(0.9342) + (49.9 - 16)^/1920] correlation coefficient r can be computed and
tested for significance:
- [0.9342] = 37.1 to 67.5
r = 2(X - X)(Y - Y)/V2(X - X)2S(Y - Y)2
Thus, the time for 10% decomposition probably
occurs between 37.1 and 67.5 weeks. A conserv¬ where the X’s and Y’s are paired values, e.g.,
ative expiration date based on the time for 10% change of blood pressure and baseline blood
decomposition is 37.1 weeks, according to the pressure values. The value of r lies between +1
lower limit of the confidence interval. and -1 and measures the linear relationship
Allocation of X. The slope is estimated bet¬ between two variables, X and Y. A correlation
ter if the X values are maximally spread apart.
This can be seen from inspection of the variance
of the slope, which is equal to cr2 divided by
2(X - X)2. This quantity is maximized if the
assay points are equally divided between points
at zero time and the last assay time. This is not
usually done, however, because considerations
are important in addition to this “optimal” allo¬
cation. For example, in stability testing, data are
usually obtained at intermediate points to ob¬
serve the functional relationship between con¬
centration and time.
Weighting in Regression. If the reaction is
first order, a least squares procedure is followed
using log C for concentration. This transforms
the exponential equation, C = C0e~kt, to a linear
function, log C = log C0 - kt/2.303. If the data FIG. 10-12. Scattergram showing the relationship of
are log-normal, i.e., if log C is normal, then the post-treatment change in blood pressure to pretreatment
variance homogeneity assumption is satisfied as blood pressure.

282 • The Theory and Practice of Industrial Pharmacy

coefficient of +1 and -1 indicates that all points cautiously and intelligendy. This approach is
fall exactly on a straight line of positive slope or further elucidated in the following discussion of
negative slope, respectively. A correlation of 0 the simplex method, one of several techniques
indicates independence of the two variables, a used in formulation optimization procedures,
zero slope (if they are bivariately normal). In which are useful in designing dosage forms.
practice, an exact fit (r = ± 1) or a zero correla¬
tion rarely occur, and one must decide if the ob¬
served r is large enough to be taken seriously. Simplex Lattice
The test of the correlation coefficient This procedure may be used to determine the
(H0: p = 0) is a t test: t = r/V(l - ^/(N - 2) relative proportion of ingredients that optimizes
with N - 2 df. For data in Figure 10-12, where a formulation with respect to a specified varia¬
N = 19 and r = 0.478, the test of significance ble^) or outcome.27 A common problem in phar¬
(17 df), t = (0.478 - 0)/V(l - 0.228)/(17) = maceutics occurs when the components of a for¬
2.24, shows a significant correlation at the 5% mulation are varied in an attempt to optimize its
level (see Table 10-3). performance with respect to such variables as
Correlations should be carefully considered drug solubility, dissolution time, and hardness.
since a significant correlation does not necessar¬ Application of a simplex design can be used to
ily indicate cause and effect. For example, a help solve this problem 28,29 The method is illus¬
strong correlation between plasma uric acid in¬ trated using data estimated from a publication
crease and potassium decrease in patients on by Fonner and co-workers, in which a different
diuretics does not mean that one causes the approach, a constrained optimization, is de¬
other. Also, it should be appreciated that a small, scribed.2 In the present example, three compo¬
perhaps meaningless, correlation coefficient nents of the formulation will be varied—stearic
may be statistically significant when dealing acid, starch, and dicalcium phosphate—with
with large sample sizes. In general, one should the restriction that the sum of their total weight
interpret correlations with caution and'use such must equal 350 mg. The active ingredient is
results as clues for further experiments. kept constant at 50 mg; the total weight of the
formulation is 400 mg. The formulation can be
optimized for more than one attribute, but for
Empiric Models and the sake of simplicity, only one effect, dissolu¬
tion rate, is considered.
Optimization The arrangement of the three variable ingre¬
For the last 30 years in the chemical industry, dients in a simplex is shown in Figure 10-13.
relatively simple empiric equations associated Note that this simplex is represented by a tri¬
with optimizing techniques have been used to angle. With more than three ingredients, the
describe otherwise complicated response rela¬ representation of the simplex is more difficult.
tionships. Recently, these techniques have been The simplex, in general, is represented by an
shown to be useful in developing pharmaceuti¬ equilateral figure, such as a triangle for the
cal dosage forms.1-4 Usually, least squares pro¬ three-component mixture and a tetrahedron for
cedures are used to obtain an empirical polyno¬ a four-component system. Each vertex repre-
mial equation from experimental data that
adequately describes the system within the
range of the test variables, the levels of which SA 180 MG
ST 4 MG
are fixed in advance. Predictions and optimiza¬ DCP 166 MG

tion are then based on the polynomial equation.

Any set of data can be fit exactly by a polynomial
of sufficient degree. For example, an equation of
the form y = a + bx + cx2 can be fit exactly to
three points (x,y pairs). This does not mean that
such an equation has physical meaning in de¬
scribing the system or that it will accurately
predict responses at extra-design points, i.e.,
combinations of factors not included in the ex¬
periment. These procedures usually result, how¬ DCP 166 MG DCP 246 MG DCP 326 MG

ever, in equations that closely approximate the

FIG. 10-13. Special cubic simplex design for a three-com¬
response as a function of the variables being ponent mixture. Each point represents a different formula¬
studied, and although the procedure may seem tion. SA = stearic acid; ST = starch; DCP = dicalcium,
chancy, it has good predictive properties if used phosphate.

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 283

sents a formulation containing either (1) a pure two ingredients represented by the two vertices.
component or (2) the maximum percentage of The composition of these seven formulas in the
that component, with the other two components present example, a three-component system, is
absent or at their minimum concentration. The shown in Table 10-19.
choice of upper (maximum) and lower (mini¬ If the vertices in the design are not single pure
mum) concentrations of the variable ingredients substances (100%), as is the case in this exam¬
is usually based on judgment, experience, or ple, the computation is made easier if a simple
data from preliminary experiments, and repre¬ transformation is initially performed to convert
sents concentrations within which a viable prod¬ the maximum percentage of a component to
uct can be manufactured. In this example, the 100%, and the minimum percentage to zero
vertices represent mixtures of all three compo¬ (0%), as follows.
nents, with each vertex representing a formula¬
tion with one of the ingredients at its maximum Transformed %
concentration. The reason for not using pure
components is that a formulation containing (Actual % - Minimum %)
only one of the three components (350 mg of (Maximum % - Minimum %)
only starch, for example) would result in an un¬
acceptable product. Careful preliminary thought In the case of stearic acid, for example, the
must be given to the choice of the upper and transformation is (Actual % — 5.7)/(51.4 - 5.7).
lower concentrations of the three ingredients, An actual concentration of stearic acid of 28.6%
under the constraint that the total weight of the is transformed to a concentration of 50%, using
components is fixed. In this case, the lower and this formula. Figure 10-13 shows that the sim¬
upper limits are stearic acid 20 to 180 mg (5.7 to plex points nicely cover the space in a symmet¬
51.4%*); starch 4 to 164 mg (1.1 to 46.9%); ric fashion. This simplex arrangement allows
dicalcium phosphate 166 to 326 mg (47.4 to easy construction of an equation that exactly fits
93.1%). Thus, as shown in Figure 10-13, the the resulting data, a polynomial equation with
vertex associated with the maximum percentage seven terms.
of starch would be represented by a formulation
containing 164 mg of starch (46.9%), 166 mg of Response = bjX, + b2X2 + b3X3 + b12XiX2
dicalcium phosphate (47.4%), and 20 mg of ste¬
aric acid (5.7%). + bi3XiX3 + b23X2X3 + b123XaX2X3
Various formulations can be studied in this 0)
triangular simplex space. One basic simplex
design includes formulations at each vertex, where X1( X2, and X3 represent transformed per¬
halfway between the vertices, and at one center centage concentrations of stearic acid, starch,
point as shown in Figure 10-13. Note that a for¬ and dicalcium phosphate, respectively. This em¬
mulation represented by a point halfway be¬ pirical equation represents the data in the con¬
tween two vertices contains the average of the fines of the simplex space, and the coefficients
minimum and maximum concentration of the can be calculated as simple linear combinations
of the responses as follows, using In Y, the re¬
‘The percentage is based on a total of 350 mg of excipi¬ sponse variable recommended by Fonner.2 As
ents, and the total percentage of the three ingredients shown in Table 10-19, the responses are Y(l),
must necessarily equal 100%. Y(2), and so forth where, for example, Y(l) is the

Table 10-19. Seven Formulas To Be Tested—Actual and (Transformed) Values

Stearic Acid Starch DCP Response

% % % (min) In Response

51.4 (100) 1.1 (0) 47.4 (0) 292 Y(l) 5.68

5.7 (0) 46.9 (100) 47.4 (0) 5.6 Y(2) 1.72 .
5.7 (0) 1.1 (0) 93.1 (100) 50.4 Y(3) 3.92
5.7 (0) 24.0 (50) 70.2 (50) 15.6 Y(2,3) 2.75
28.6 (50) 24.0 (50) 47.4 (0) 25.6 Y(l,2) 3.24
28.6 (50) 1.1 (0) 70.2 (50) 124.5 Y(l,3) 4.82
20.9 (33) 16.4 (33) 62.6 (33) 37 Y(l,2,3) 3.61

284 • The Theory and Practice of Industrial Pharmacy

response for the formulation with X! (stearic simplex) and noting if the equation accurately
acid) at a maximum concentration. predicts the results. In the analysis of their ex¬
periment, Fonner and co-workers included data
bj = Y(l) = 5.68 from four experiments not covered by the sim¬
plex.2 Using equation (10), the prediction of the
b2 = Y(2) = 1.72 results for these four formulations is good, as
can be seen in Table 10-20. The last point in
b3 = Y(3) = 3.92 Table 10-20 represents a formulation outside of
the region of the simplex, and the prediction is
b12 = 4Y(1,2) - 2Y(1) - 2Y(2) = -1.83 good in this case. In general, predictions outside
of the simplex space might not be reliable, and
b13 = 4Y(1,3) - 2Y(1) - 2Y(3) = 0.10 caution should be exerted when extrapolating
into extra-design regions. When possible, repli¬
b23 = 4Y(2,3) - 2Y(2) - 2Y(3) = -0.30 cation is recommended in simplex experiments
to estimate the variance, which can be used to
b123 = 27Y(1,2,3) ~ 12 [Y(l ,2) + Y(l,3) assess the “fit” of the model by comparing the
predicted and actual results from extra-design
+ Y(2,3)] + 3[Y(1) + Y(2) + Y(3)] points.
Computer programs can be used to construct
= 1.71 contour maps and identify optimal regions once
the response equation has been established.
Substituting these values of the coefficients into
equation (9), the following response equation is
obtained. Nonparametric Statistics
Most of the statistical tests described in this
Dissolution Time chapter are based on an assumption that the
underlying distribution of the data is known (bi¬
= Y nomial or normal, for example). Although tests
based on the normal distribution give valid re¬
= 5.68Xi + 1-72X2 + 3.92X3 sults in face of a moderate degree of non-nor¬
mality, especially when inferences about means
- 1.83XjX2 + O.IOX1X3 are made, situations arise in which data should
be analyzed with limited assumptions about the
- 0.30X2X3 - 1.71XiX2X3 data distribution. One such nonparametric test
(10) has already been described, the sign test. Many
nonparametric tests assume only that the under¬
This is an empirical equation that should rep¬ lying distribution is continuous. In addition,
resent the response surface in the simplex analysis of data using nonparametric methods
space. Its adequacy can be tested by running has the advantage of using simple calculations
one or more experiments at other experimental that are often based on ordering or ranking pro¬
points (different formulations from those in the cedures. Thus, these methods can be used to

Table 10-20. Prediction of Dissolution Results of Extra-Design Points Using Equation Derived From
Simplex Experiment

Extra-Design Formulations Observed Dissolution

(Transformed) Dissolution Predicted from Eq (10)

Stearic Starch DCP

Acid (%) (%) (%) (antilog)*

20.4 21.6 58.2 33.4 38.9

20.4 65.3 14.4 12.9 12.7
64.1 21.6 14.4 72.8 72.9
64.1 65.3 -29.3 19.9 22.1

"Fonner and associates recommend use of In (response) for the optimization using their method. This transformation is used here.

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 285

obtain a quick look before a full-fledged analysis Nj = Smaller sample size
is undertaken.
A disadvantage is that these tests lack power N2 = Larger sample size
compared with corresponding parameteric tests;
nevertheless, some nonparametric tests are sur¬ T = Sum of ranks for smaller sized sample
prisingly powerful. (As noted previously, power
is the ability of a test to find significance, should In this example:
a true difference exist.) Also, in more complex
designs, nonparametric tests may not give the E(T) = (8)(8 + 9 + l)/2 = 72
variety of analyses and interpretations given by
parametric analyses. Several popular methods of S| = (8)(9)(8 + 9 + 1)/12 = 108
analysis are presented in this discussion; more
detail is given by Wilcoxon and Wilcox.30 For a two-sided test:

Z = [|94 - 72|]/Vl08 = 2.12

Wilcoxon Rank Sum Test According to Table 10-3, a value greater than
This test is used to compare the averages of 1.96 is needed for significance at the 5% level.
two treatments and has excellent power com¬ Therefore, the drug is significantly different
pared with the more powerful t test if the data from the control (P < 0.05); the drug group
are normally distributed. Consider the example showed a greater weight loss. Wilcoxon and Wil¬
in Table 10-21 showing changes in weight of cox provide a table that can be used to assess
control animals compared with animals given an significance, given the sample sizes of the two
anorexic drug. Values for drug and control groups and the rank sum.30
groups are ranked in order of magnitude. A rank For paired data, the non-zero differences (zero
is assigned to each value; average ranks are as¬ differences are not included in the analysis) of
signed in case of ties. The ranks are then the pairs are first ranked in order, disregarding
summed within each treatment group. In most sign. Then, the sum of the ranks of the positive
cases, a significance test may be used based on differences and the sum of the ranks of the neg¬
an approximation to the normal distribution: ative differences are computed and tested for
significance. The data in Table 10-22 were ob¬
Z = [T - E(T)]/VS? tained from a bioavailability study using 15 sub¬
jects. The peak serum concentration is com¬
has a distribution that is approximately normal pared for the two products. The sum of the
with variance equal to 1. positive ranks is 68.5, and the sum of the nega¬
tive ranks is 36.5. An approximate “normal” test
E(T) = Nj(Ni + N2 + l)/2 and is:

S| = N^aCNj + N2 + 1)/12 Z = [T - (N)(N + l)/4]/VN(N + 1)(2N + l)/24

Table 10j21. Weight Change in Drug and Control Groups and Ranks

Control Drug

Weight Change Rank Weight Change Rank

0 14 -2 10.5
-3 9 -8 3
+9 17 +1 15
-1 12.5 -19 1
-4 7.5 -4 7.5
+3 16 -2 10.5
-1 12.5 -11 2
-5 5.5 -5 5.5
-7 4
Sum of Ranks = 94 Sum of Ranks = 59

286 • The Theory and Practice of Industrial Pharmacy

Table 10-22. Results of Bioavailability Comparison Peak Height of Serum Concentration

Subject Test Product Control Product Difference Rank

1 9.6 9.4 +0.2 1.5

2 3.3 3.3 0 Omit
3 2.8 2.4 +0.4 5.5
4 5.0 4.1 +0.9 10
5 6.4 4.7 + 1.7 14
6 2.8 3.5 -0.7 8
7 4.0 3.7 +0.3 3.5
8 3.2 3.0 +0.2 1.5
9 4.3 3.3 + 1.0 11
10 4.7 6.2 -1.5 13
11 3.3 2.9 +0.4 5.5
12 4.6 3.8 +0.8 9
13 4.0 5.1 -1.1 12
14 5.9 5.3 +0.6 7
15 3.6 3.9 -0.3 3.5

where N Is the number of pairs, and T is the In this example:

sum of the ranks (either positive or negative).
X| = [12/(10)(11)][208.33 + 65.33 + 64.0]
Z = [68.5 - (14)( 15)/4]/V(14)(l5)(29)/24
- (3)(11)
= 1.00
= 3.84
Since Z is less than 1.96, the test product is not
significandy different from the control at the 5% For significance at the 5% level, a X2 value with
level. Wilcoxon and Wilcox have a table for sig¬ 2 degrees of freedom must exceed 5.99.5 There¬
nificance testing,30 and for small sample sizes, fore, the differences among the three formula¬
this table rather than the foregoing approximate tions are not significant at the 5% level.
formula should be used. Friedman’s Two-Way Analysis. Fried¬
man’s analysis for related samples with more
than two groups is also based on ranking of
One-Way and Two-Way Designs data.31 This test is analogous to a two-way
Nonparametric tests are available for one- and ANOVA.
two-way ANOVA type designs. In the case of Four batches of tablets were produced on
more than two independent groups arranged in three tablet presses (machines), and the average
a one-way design, the data are first ranked in weight of the tablets was estimated as the mean
order over all groups, disregarding group desig¬ of 20 randomly selected tablets. To test for ma¬
nation. The sum of the ranks for each group is chine differences, the machines are ranked
then calculated. A statistic with an approximate
X2 distribution can be computed as shown in the
Table 10-23. Hardness (Rank) of Tablets From
following example, in which the hardness of tab¬
Three Formulations
lets of three different formulations of the same
drug are compared (Table 10-23). The replicates Formula
are randomly selected tablets. The X2 test, with
C - 1 = 3 - 1 = 2 df, is: 1 2 3

8.3 (6) 7.9 (4) 8.4 (7)

X£_! = [12/N(N + IMXRf/Ni - 3(N + 1)
10.0 (10) 7.1 (2) 8.0 (5)
9.7 (9) 8.5 (8) 6.5 (1)
where C is the number of treatments, R, is the
7.3 (3)
sum of ranks in ith treatment, Nj is the number
Rj = SRanks 25 14 16
of observations in ith treatment, and N is the
(2R?yNi 208.33 65.33 64.0
total number of observations.

STATISTICAL APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 287

 Table 10-24. Data Showing Comparison of Tablet Weights From Four Machines Using Three Batches
With Ranks

Machine

1 2 3

Batch Weight Rank Weight Rank Weight Rank

1 202 (3) 199 (2) 197 (1)

2 203 (3) 199 (2) 198 (1)
3 205 (3) 200 (2) 196 (1) }
4 202 (3) 197 (1) 198 (2)

within each batch as shown in Table 10-24. An 9. MIL STD 105D, Military Sampling Procedures and
approximate X2 test can be used to assess signif¬ Tables for Inspection by Attributes. U.S. Government
icance using the following formula. Printing Office, Washington, DC, 1963.
10. Guenther, W. C.: The American Statistician, 35:243,
1981.
X2 _! = [12/(RC(C + 1))]2C2 - 3R(C + 1) 11. Davies, O.: Design and Analysis of Industrial Experi¬
ments. Hairier, New York, 1963.
where C is the number of groups (machines), R 12. Cox, D. R.: Planning of Experiments. John Wiley and
is the number of blocks (batches), and Cj is the Sons, New York, 1965, p. 221.
sum of ranks in the jth group. 13. Ferris, G.: Biometrics, 14:39, 1958.
14. Steele, R. G. D., and Torre, J. H.: Principle and Proce¬
In this example:
dures of Statistics. McGraw-Hill, New York, 1960,
p. 107.
\l = [12/(4 • 3 • 4)j • 218 - (12)(4) = 6.5 15. Albert, K. S. (Ed.): Drug Absorption and Disposition:
Statistical Considerations. Am. Pharm. Assoc., Wash¬
Since 6.5 is greater than the tabulated value of ington, DC, 1980.
X§ (5.99) at the 5% level,5 the result is signifi¬ 16. Westlake, W. J.: Int. J. Clin. Pharmacol., 11:342,
1975.
cant; the first machine shows the higher aver¬
17. Westlake, W. J.: J. Pharm. Sci., 61:1340, 1972.
age weight. (Wilcoxon and Wilcox provide a dis¬ 18. Shirley, E. J.: J. Pharm. Pharmacol, 28:312, 1976.
cussion of comparisons that involve more than 19. Cochran, W. G., and Cox, G. M.: Experimental De¬
two groups.30) signs. 2nd Ed. John Wiley and Sons, New York, 1957,
The tests described in this section, as well as p. 117.
other nonparametric tests, are described in more 20. Grizzle, J. E.: Biometrics, 21:467, 1965.
21. Westlake, W. J.: Biometrics, 32:741, 1976.
detail by Siegel,31 Wilcoxon and Wilcox,30 and
22. Mandel, J.: The Statistical Ar”w: ri Experimental
Hollander and Wolfe.32 Tables for tests of signifi¬ Data. Interscience, New York, 1964, p. 288.
cance are also provided by these sources. 23. O’Neill, R. T., and Scbuinnann, D. J.; Presentation at
meeting of Am. Statistical Assoc. Meeting, Washing¬
ton, DC, August 13-16, 1979.
References 24. Tootill, J. P. R.: J. Pharm. Pharmacol. (Suppl.),
1. Schwartz, J. B., Flamholz, J. R., and Press, R. H.: 13:75T, 1961.
J. Pharm. Sci., 62:1165, 1973. 25. Williams, E. W. J.: Regression Analysis. John Wiley
2. Fonner, D. E., Buck, ]. K., and Banker, G. S.: and Sons, New York, 1964.
J. Pharm. Sci., 59.1587, 1976. 26. King, S. P., Kung, M., and Fung, H.: J. Pharm. Sci.,
3. Dincer, S., and Ozdurmus, S.: J. Pharm. Sci., 73:657, 1984.
66:1070, 1978. 27. Gorman, J. W., and Hinman, J. E.: Technometrics,
4. Bolton, S.: J. Pharm. Sci., 72:362, 1983. 4:463, 1962.
5. Dixon, W. J., and Massey, F. J., Jr.: Introduction to 28. Shek, E., Gharri, M., and Jones, R.: J. Pharm. Sci.,
Statistical Analysis. 3rd Ed. McGraw-Hill, New York, 69:1135, 1980.
1969. 29. Anik, S. T., and Sukamer, L.: J. Pharm. Sci., 70:897,
6. Snedecor, G. W., and Cochran, W. G.: Statistical 1981.
Methods. 7th Ed. Iowa State Univ. Press, Ames, IA, 30. Wilcoxon, F., and Wilcox, R.: Some Rapid Approxi¬
1980. mate Statistical Procedures. Lederle Labs., Pearl
7. American Society for Testing Materials (ASTM), River, NY, 1964.
E 178-75, Standard Recommended Practice for Deal¬ 31. Siegel, S.: Non-Parametric Statistics for the Behav¬
ing with Outlying Observations. April 1975, p. 183. ioral Sciences. McGraw-Hill, New York, 1956, p. 166.
8. Tables of the Binomial Distribution. National Bureau 32. Hollander, M., and Wolfe, D. A.: Nonparametric Sta¬
of Standards, U.S. Government Printing Office, tistical Methods. John Wiley and Sons, New York,
Washingon, DC, 1952. 1973.

288 • The Theory and. Practice of Industrial Pharmacy

 Davies, O. (Ed.): Design and Analysis of Industrial Ex¬
General References periments. Hafner, New York, 1963.
Albert, K. S. (Ed.): Drug Absorption and Disposition, Sta¬ Dixon, W. J., and Massey, F. J., Jr.: Introduction to Statis¬
tistical Considerations. Am. Pharm. Assoc., Washing¬ tical Analysis. 3rd Ed. McGraw-Hill, New York, 1969.
ton, DC, 1980. Siegel, S.: Nonparametric Statistics for the Behavioral
Bolton, S.: Pharmaceutical Statistics. Marcel Dekker, Sciences. McGraw-Hill, New York, 1956.
New York, 1984. Snedecor, G. W., and Cochran, W. G.: Statistical Meth¬
Buncher, C. R., and Tsay, J. (Eds.): Statistics in the Phar¬ ods. 7th Ed. Iowa State Univ. Pres, Ames, IA, 1980.
maceutical Industry. Marcel Dekker, New York, 1981.
Cox, D. R.: Planning of Experiments. John Wiley and
Sons, New York, 1965.

APPLICATIONS IN THE PHARMACEUTICAL SCIENCES • 289

 11

Tablets
GILBERT S. BANKER and NEIL R. ANDERSON

Role in Therapy designed to contain one dose of medication in 5

The oral route of drug administration is the most to 30 ml. The patient is then asked to measure
important method of administering drugs for his or her own medication using a teaspoon, ta¬
systemic effects. Except in cases of insulin ther¬ blespoon, or other measuring device. Such dos- •
apy, the parenteral route is not routinely used age measurements are typically in error by ajac-
for self-administration of medication. The topi¬ tor ranging from 20 to 50% when the drug is
cal route of administration has only recently self-administered by the patient.
been employed to deliver drugs to the body for Liquid oral dosage forms have other disadvan¬
systemic effects, with two classes of marketed tages and limitations when compared with tab¬
products: nitroglycerin for the treatment of an¬ lets. They are much more expensive to ship (one C§?
gina and scopolamine for the treatment of mo¬ liquid dosage weighs 5 g or more versus 0.25 to l
tion sickness. Other drugs are certain to follow, 0.40 g for the average tablet), and breakage or \
but the topical route of administration is limited leakage during shipment is a more serious prob-J
in its ability to allow effective drug absorption for lem with liquids than with tablets. Taste mask¬
systemic drug action. The parenteral route of ing of the drug is often a problem (if the drug is
administration is important in treating medical in solution even partially). In addition, liquids
emergencies in which a subject is comatose or are less portable and require much more space
cannot swallow, and in providing various types per number of doses on the pharmacist’s shelf.
of maintenance therapy for hospitalized pa¬ Drugs are in general less stable (both chemically
tients. Nevertheless, it is probable that at least and physically) in liquid form than in a dry state
90% of all drugs used to produce systemic .ef¬ and expiration dates tend to be shorter. Careful
fects are administered hv the oral route. When a attention is required to assure that the product
new drug is discovered, one of the first questions will not allow a heavy microbiologic burden to
a pharmaceutical company asks is whether or develop on standing or under normal conditions
not the drug can be effectively administered for of use once opened (preservation requirements).
its intended effect by the oral route. If it cannot, There are basically three reasons for having liq¬
the drug is primarily relegated to administration uid dosage forms of a drug: (1) The liquid form
in a hospital setting or physician’s office. If pa¬ is what the public has come to expect for certain
tient self-administration cannot be achieved, the types of products (e.g., cough medicines).
sales of the drug constitute only a small fraction (2) The product is more effective in a liquid form
of what the market would be otherwise. (e.g., many adsorbents and antacids). (3) The
Of drugs that are administered orally, solid drug(s) are used fairly commonly by young chil¬
oral dosage forms represent the preferred class dren or the elderly, who have trouble swallowing
of product. The reasons for this preference are the solid oral dosage forms.
as follows.
Tablets and capsules represent unit dosage
forms in which one usual dose of the drug has Advantages
(£) been accurately placed. By comparison, liquid Of the two oral solid dosage forms commdnly
oral dosage forms, such as syrups, suspensions, employed in this country, the tablet and the cap¬
emulsions, solutions, and elixirs, are usually sule, the tablet has a number of advantages. One

293
 , r&A',W<?
_,c>> oAv^
G> 'T'"""1
of the major advantages of tablets over capsules, 6. They may provide the greatest ease of swal¬
which has recendv proved significant, is that the lowing with the least tendency for “hang-up”
tablet is an essentially tamperproof dosage form. above the stomach, especially when coated,
IfTrecent episodes of tampering with pharma¬ provided that tablet disintegration is not ex¬
ceutical products, products have been altered cessively rapid.
- i. ino-^'4 5'
after leaving the manufacturer and the whole¬ 7. They lend themselves to certain special-
saler or distributor. A number of deaths and seri¬ release profile products, such as enteric or
ous injuries have resulted from such tampering, delayed-release products.
with the result that the FDA has found it neces¬
sary to impose new standards for tamper-resis¬ 8. They are better suited to large-scale produc¬
tant packaging.1 3 The major advantage of cap¬ tion than other unit oral forms.
sules—their ability to hide their contents from 9. They have the best combined properties of
sight and to mask or hide the taste or odor of chemical, mechanical and microbiologic sta¬
their contents—makes them the most vulnera¬ bility of ail the oral forms.
ble to tampering of all dosage forms. In contrast,
any adulteration of a tablet after its manufacture The development pharmacist should know
is almost certain to be observed. Addition of any fully what the potential advantages of tablets are
liquid to a tablet would produce disintegration if as a dosage form class. If these general advan¬
the liquid is aqueous, or would produce visible tages together with the specific criteria specifi¬
changes if the liquid is nonaqueous. Addition of cations for the product are not met, an optimum
extraneous powder to a tablet is not readily feasi¬ or even near-optimum product may not have
ble. Even though improved packaging provides been achieved.
some consumer protection for such dosage
forms as capsules, which are susceptible to tam¬
pering, no packaging is completely tamperproof.
A major disadvantage of capsules over tablets
is their higher cost. Capsules, whether hard gel¬
atin or “soft elastic capsules, employ a capsule Disadvantages
shell to contain the drug contents. The cost of The disadvantages of tablets include the fol¬
this shell is approximately several tenths of a lowing.
cent or more, depending on whether the capsule 1. Some drugs resist compression into dense
is banded, printed with identification, or other¬ compacts, owing to their amorphous nature or
wise treated. In addition to this is the cost of flocculent, low-density character.
filling. This fitting cost is higher than the typical 2. Drugs with poor wetting, slow dissolution
total cost of tablet production, now that direct properties, intermediate to large dosages, opti¬
compression methods of tablet manufacture mum absorption high in the gastrointestinal
exist, since the capsule fitting operation is far tract, or any combination of these features may
slower than the tablet compression operation. be difficult or impossible to formulate and man¬
In consideration of these few comparisons to ufacture as a tablet that will still provide ade¬
capsules, the following may be cited as the pri¬ quate or full drug bioavailability.
mary potential advantages of tablets. 3. Bitter-tasting drugs, drugs with an objec¬
tionable odor, or drugs that are sensitive to oxy¬
1. They are a unit dose form, and they offer the gen or atmospheric moisture may require encap¬
greatest capabilities of all oral dosage forms sulation or entrapment prior to compression (if
for the greatest dose precision and the least feasible or practical), or the tablets may require
content variability. coating. In such cases, the capsule may offer the
best and lowest cost approach.
2. Their cost is lowest of all oral dosage forms.
In summary of the foregoing advantages and
3. They are the lightest and most compact of all disadvantages of tablets in comparison to other
oral dosage forms. oral dosage forms, tablets do provide advantages
to the pharmacist, in minimal storage space re¬
4. They are in general the easiest and cheapest
quirements as well as ease of dispensing and
to package and ship of all oral dosage forms.
possibly control; to the patient in convenience of
5. Product identification is potentially the sim¬ use, optimum portability, and lowest cost; and to
plest and cheapest, requiring no additional the physician in flexibility of dosage (with bi¬
processing steps when employing an em¬ sected tablets), and in accuracy and precision of
bossed or monogrammed punch face. dosage in general.

294 • The Theory and Practice of Industrial Pharmacy

Challenges in Product Design, for a mathematical optimization approach.
Whether or not such an approach may be war¬
Formulation, and Manufacture ranted depends on how simple and straight¬
As a class, tablets are one of the most chal¬ forward the design/manufacturing processes
lenging of all pharmaceutical products to design appear to be; however, using statistical
and manufacture. The difficulty of achieving experimental design procedures readily avail¬
full and reliable drug bioavailability for drugs able today, the generation of a model for the sys¬
with poor wetting and slow dissolution, for ex¬ tem may be little additional work, if any, espe¬
ample, has previously been mentioned, as has - cially with computer assistance. It is preferable
th.e difficulty of achieving good cohesive com- to stumbling through three or four levels of trial
pacts of amorphous or flocculent drugs. How¬ and error experimentation.
ever, eveiTfinr drugs with good compression
characteristics, good dissolution, and no bioa¬
vailability problems, tablet product design and
The Pharmaceutical Tablet
manufacture can be challenging because of the
many competing objectives of this dosage form. Dosage Form
That is, any action that is taken to improve one
objective or set of objectives may cause another
objective Or set of objectives to degrade. For ex¬ Properties
ample, tablets should have a smooth surface, The objective of the design and manufacture
good appearance, and perhaps some surface of the compressed tablet is to deliver orally the
gloss, and be cohesive ancTcompact so that they correct amount of drug in the proper form, at or
do not undergo friability, powdering, or chipping over the proper time and in the desired location,
in the bottle during shipping or handling. What¬ and to have its chemical integrity protected to
ever step is taken to achieve this first set of ob¬ that point. Aside from the physical and chemical
jectives, whether it is using more binder or ad¬ properties of the medicinal agent(s) to be formu¬
hesive, increasing compression pressure or lated into a tablet, the actual physical design,
punch dwell time, or using precompression, it manufacturing process, and complete chemical
may be expected to have a negative effect on makeup of the tablet can have a profound effect
another set of objectives, tablet disintegration on the efficacy of the drug(s) being adminis¬
time, drug dissolution rate, and possibly bioa¬ tered.
vailability. Depending on a drug’s degree of A tablet (1) should be an elegant product hav¬
compressibility, its dose, its solubility and solu¬ ing its own identity while being free of defects
bility rate, its site of absorption along the GI such as chips, cracks, discoloration, contamina¬
tract, and other factors, finding a satisfactory tion, and the like;'(2) should have the strength
compromise between competing sets of objec¬ to withstand the rigors of mechanical shocks
tives may be simple or extremely complex. encountered in its production, packaging, ship¬
When finding the correct compromise is not ping, and dispensing; and (3) should have the
straightforward and simple, the pharmaceutical chemical and physical stability to maintain its
scientist should seriously consider use of optimi¬ physical attributes over time. Pharmaceutical 5)
zation procedures to design the best compromise scientists now understand that various physical
product.2-4 Trial and error methods of formula¬ properties of tablets can undergo change under
tion do not allow the formulator to know how environmental or stress conditions, and that
close any particular formulation is to the opti¬ physical stability, through its effect on bioavaila¬
mum solution, and without a model to define the bility in particular, cttn be of more significance
relationships between formulation and manu¬ and concern in some tablet systems than chemi¬
facturing variables, and levels of values for the cal stability. <
quality features of the product, it is not possible On the other hand, the tablet (1) must be able
to investigate play-off decisions between objec¬ to release the medicinal agent(s) in the body in a
tives. Once the product is mathematically/statis¬ predictable and reproducible manner and
tically modeled, one can compute how much a X‘2)_must have a suitable chemical stability over
secondary objective or set of objectives suffers or time so as not to allow alteration of the medicinal
gains if a primary objective specification is agent(s). In many instances, these sets of objec¬
slightly relaxed (or tightened). As a result of the tives are competing. The design of a tablet that
various competing objectives that are encoun¬ emphasizes only the desired medicinal effects
tered in tablet product design, the formulation may produce a physically inadequate product.
and manufacture of this product class are ideal The design of a tablet emphasizing only the

TABLETS • 295
 physical aspects may produce tablets of limited ured with a sliding caliper scale. This method is
and varying therapeutic effects. As one example much more rapid than measurement with a
of this point, Meyer and associates present infor¬ micrometer in providing an overall estimate of
mation on 14 nitrofurantoin products, all of tablet thickness in production operations, but it
which passed the compendial physical require¬ does not as readily provide information on varia¬
ments, but showed statistically significant bio¬ bility between tablets; however, if the punch and
availability differences.5 die tooling has been satisfactorily standardized
and the tablet machine is functioning properly,
this method is satisfactory for production work.
Evaluation Tablet thickness should be controlled within a
To design tablets and later monitor tablet pro¬ ±5% variation of a standard value. Any variation
duction quality, quantitative evaluations and Tn tablet thickness within a particular lot of tab¬
assessments of a tablet’s chemical, physical, and lets or between manufacturer’s lots should not
bioavailability properties must be made. Not be apparent to the unaided eye for consumer
only could all three property classes have a sig¬ acceptance of the product. In addition, thickness
nificant stability profile, but the stability profiles must be controlled to facilitate packaging. Diffi¬
may be interrelated, i.e., chemical breakdown or culties may be encountered in the use of unit
interactions between tablet components may dose and other types of packaging equipment if
alter physical tablet properties, gready changing the volume of the material being packaged is not
the bioavailability of a tablet system. consistent. A secondary packaging problem with
General Appearance. The general appear¬ tablets of variable thickness relates to consistent
ance of a tablet, its visual identity and overall fill levels of the same product container with a
’‘elegance,” is essential for consumer accept¬ given number of dosage units.
ance, for control of lot-to-lot uniformity and gen¬ The physical dimensions of the tablet, along
eral tablet-to-tablet uniformity, and for monitor¬ with the density of the materials in the tablet
ing trouble-free manufacturing. The control of formulation and their proportions, determine
the general appearance of a tablet involves the the weight of the tablet. The size and shape of
measurement of a number of attributes such as the tablet can also influence the choice of tablet
a tablet’s size, shape, color, presence or absence machine to use, the best particle size for the
of an odor, taste', surface texture, physical flaws granulation, production lot sizes that can be
and consistency, and legibility of any identifying made, the best type of tablet processing that can
markings. be used, packaging operations, and the cost to
Size and Shape. The size and shape of the produce the tablet! The shape of the tablet alone
tablet can be dimensionally described, moni¬ can influence the choice of tablet machine used.
tored, and controlled. A compressed tablet’s ShapedTabletsTequiring “slotted punches” must
shape and dimensions are determined by the be run at slower speeds than are possible with
tooling dunng the~compression process. The round tablets, using conventional punches. Be¬
thickness of a tablet is tEeonly dimensional var¬ cause of the nonuniform forces involved within
iable related to the process. At a constanFcom- a tablet during compression, the more convex
pressive load, tablet thickness varies with the tablet surface, the more likely it is to cause
changes in die fill, with particle size distribution capping problems, forcing the use of a slower
and packing of the particle mix being com¬ tablet machine or one with precompression ca¬
pressed, and with tablet weight, while with a pabilities.6
i constant die fill, thickness varies with variations Unique Identification Markings. Pharma¬
in compressive load. Tablet thickness is consist¬ ceutical companies manufacturing tablets often
ent batch to batch or within a batch only if the use some type of unique markings on the tablet
tablet granulation or powder blend is adequately in addition to color, to aid in the rapid identifica¬
A consistent in particle size and size distribution, tion of their products. These markings utilize
if the punch tooling is of consistent length, and some form of embossing, engraving, or printing.
if the tablet press is clean and in good working A look into the product identification section of
order. the current Physician’s Desk Reference (PDR),7
The crown thickness of individual tablets may provides a quick reference to the multitude of
be measured with a micrometer, which permits marking variations, both artistic and informa¬
accurate measurements and provides informa¬ tional, that can be produced.
tion on the variation between tablets. Other The type of informational markings placed on
techniques employed in production control in¬ a tablet usually includes the company name or
volve placing 5 or 10 tablets’in a holding tray, symbol, a product code such as that from the
where their totsil crown thickness may be meas¬ National Drug Code (NDC) number, the product

296 • The Theory and Practice of Industrial Pharmacy

name, or the product potency. In the future, specification, but the visual inspection tech¬
these identifying marks, in conjunction with a niques used for detecting or evaluating these
greater diversity of tablet sizes and shapes, may characteristics are subjective in nature. Elec¬
provide the sole mpans of identification of tab¬ tronic devices that are currently being developed
lets, if the pharmaceutical industry continues to hold promise for making inspection a more
lose the use of approved Food, Drug, and Cos¬ quantitative and reproducible operation.
metic (FD&C) colors. Hardness and Friability. Tablets require a
Organoleptic Properties. Many pharma¬ certain amount of strength, or hardness and re¬
ceutical tablets use color as a vital means of sistance to friability, to withstand mechanical
rapid identification and consumer acceptance. shocks of handling in manufacture, packaging,
The color of a product must be uniform within a and shipping. In addition, tablets should be able
single tablet (nonuniformity is generally re¬ to withstand reasonable abuse when in the
ferred to as “mottling”), from tablet to tablet, and hands of the consumer, such as bouncing about
from lot to lot. Nonuniformity of coloring not in a woman’s purse in a partially filled prescrip¬
only lacks esthetic appeal but could be associ¬ tion bottle. Adequate tablet hardness and resist¬
ated by the consumer with nonuniformity of ance to powdering and friability are necessary
content and general poor quality of the product.8 requisites for consumer acceptance. More re¬
The eye cannot discriminate small differences cently, the relationship of hardness to tablet dis¬
in color nor can it precisely define color. The eye integration, and perhaps more significantly, to
has limited memory storage capability for color, the drug dissolution release rate, has become
and the storage of visually acquired data is diffi¬ apparent. The monitoring of tablet hardness is
cult, which results in people perceiving the especially important for drug products that pos¬
same color differently and a single person de¬ sess real or potential bioavailability problems or
scribing the same color differently at different that are sensitive to altered dissolution release
times. In addition, visual color comparisons re¬ profiles as a function of the compressive force
quire that a sample be compared against some employed.
color standard. Color standards themselves are Historically, the strength of a tablet was deter¬
subject to change with time, thus forcing their mined by breaking it between the second and
frequent redefinition, which can lead to a grad¬ third fingers with the thumb acting as a ful¬
ual and significant change in acceptable color.8 crum. If there was a “sharp” snap, the tablet was"
Efforts to quantitate color evaluations have used deemed to have acceptable strength. More re¬
reflectance spectrophotometry, tristimulus col¬ cently, however, tablet hardness has been de¬
orimetric measurements, and the use of a fined as the force required to break a tablet in a
microreflectance photometer to measure the diametric compression test. To perform this test,
color uniformity and gloss on a tablet sur¬ a tablet is placed between two anvils, force is
face.8-10 applied to the anvils, and the crushing strength
The presence of an odor in a batch of tablets that just causes the tablet to break is recorded.
could indicate a stability problem, such as the Hardness is thus sometimes termed the tablet
characteristic odor of acetic acid in degrading crushing strength. Several devices operating in
aspirin tablets; however, the presence of an odor this manner have been and continue to be used
could be characteristic of the drug, (vitamins to test tablet hardness: the Monsanto tester, the
have a characteristic odor), added ingredients Strone-Cobh tester, the Pfizer tester, the Erweka
(flavoring agents have pleasant odors), or the tester, and the Schleuniger tester.11-115
dosage form (film-coated tablets usually have a One of the earliest testers to evaluate tablet
characteristic odor). hardness was the Monsanto hardness tegtpr
Taste is important in consumer acceptance of which was developecT approximately fifty years
chewable tablets. Many companies utilize taste ago. The tester consists of a barrel containing a
panels to judge the preference of different fla¬ compressible spring held between two plungers.
vors and flavor levels in the development of a The lower plunger is placed in contact with the
product. Owing to the subjectiveness of “taste” tablet, and a zero reading is taken. The upper
preference, however, the control of taste in the plunger is then forced against a spring by turn¬
production of chewable tablets is often simply ing a threaded bolt until the tablet fractures. As
the presence or absence of a specified taste. the spring is compressed, a pointer rides along a
A tablet’s level of flaws such as chips, cracks, gauge in the barrel to indicate the force. The
contamination from foreign solid substances force of fracture is recorded, and the zero force
(e.g., hair, drops of oil, and “dirt”), surface tex¬ reading is deducted from it. To overcome the
ture (“smooth” versus “rough”), and appearance manual nature of the Monsanto tester and the
(“shiny” versus “dull”) may have a zero-defect minute or longer time required to make an indi-

TABLETS • 297
vidual test, the Strong-Cobb tester was devel¬ pointer moving along a scale provides the break¬
oped about twenty years later. The original de¬ ing strength value in kilograms. As shown in
sign employed a plunger activated by pumping a Figure 11-1, the Schleuniger tester operates in a
lever arm, which forces an anvil against a sta¬ horizontal position. An anvil driven by an elec¬
tionary platform by hydraulic pressure. The tric motor presses the tablet at a constant load
force required to fracture the tablet is read from rate against a stationary anvil until the tablet
a hydraulic gauge. Later modifications of the breaks. A pointer moving along a scale indicator
Strong-Cobb tester were built with the force ap¬ provides the breaking strength value. The in¬
plied by air-pressure rather than by a manual strument reads in both kilograms and Strong-
pump. Cobb units. This instrument is currently the
Approximately one decade later, the Pfizer most widely employed and has the advantage of
tester was developed and made available to the being both fast and reproducible.
industry: This tester operates on the same me¬ Unfortunately, these testers do not produce
chanical principle as a pair of pliers. As the pli- the same results for the same tablet. Studies
er’s handles are squeezed, the tablet is com¬ have shown that operator variation, lack of cali¬
pressed between a holding anvil and a piston bration, spring fatigue, and manufacturer varia¬
connected to a direct force reading gauge. The tion contribute greatly to the lack of uniformity.
dial indicator remains at the reading where the Even those testers designed to eliminate opera¬
tablet breaks and is returned to zero by depress¬ tor variability have been found to vary.15’16
ing a reset button. The Pfizer tester became ex¬ Operators must be aware of these variations,
tensively used in comparison to the earlier test¬ especially when the tablets are to be evaluated
ers, based on its simplicity, low cost, and the by other persons or in other labs. For accurate
rapidity with which it could be used. comparison, each instrument should be care¬
Two testers have been developed to eliminate fully calibrated against a known standard.
operator variation. In the Erweka tester, the tab¬ The, hardness of a tablet, like its thickness, is a
let is placed on the lower anvil, and the anvil is function of the die fill and compression force. At
then adjusted so that the tablet just touches the -a'boristant dieTili, the hardness values increase
upper test anvil. A suspended weight, motor and thickness decreases as additional compres¬
driven, moves along a rail, which slowly and sion force is applied. This relationship holds up
uniformly transmits pressure to the tablet. A to a maximum value for hardness and a mini-
mum value for thickness, beyond which in¬
creases in pressure cause the tablet to laminate
or cap, thus destroying the integrity of the tablet.
At a constant compression force (fixed distance
between upper and lower punches), hardness
increases with increasing die fills and decreases
with lower die fills.
When uniform tooling is used, the die-fill/
force relationship makes control of tablet hard¬
ness a useful method of physically controlling
tablet properties during a production operation,
particularly when this measurement is com¬
bined with measurements of tablet thickness.
The fill/force relationship is also the basis for
instrumenting tablet machines.
In general, tablets are harder several hours
after compression than they are immediately
after compression. Lubricants can affect tablet
hardness when they are used in too high a con¬
centration or mixed for too long a period. Large
tablets require a greater force to cause fracture
and are therefore “harder” than small tablets. FIG. 11-2. The Roche type friabilator. (Courtesy of Van-
For a given granulation, a flat beveled tool pro¬ Kel Industries, Chatham, NJ.)
duces a tablet harder than a deep cup tool.
Tablet hardness is not an absolute indicator of
strength since some formulations, when com¬ when the punches are in poor condition or worn
pressed into very hard tablets, tend to “cap” on at their surface edges, the tablets produced re¬
attrition, losing their crown portions. Therefore, sult in “whiskering” at me tablet edge. Such tab¬
another measure of a tablet’s strength, its friabil¬ lets have higher than normal friability values
ity, is often measured. Tablets that tend to pow¬ because the “whiskers” are removed in testing.
der, chip, and fragment when handled lack ele¬ Tablet friability may also be~mfluenced by the
gance and consumer acceptance, and can create moisture content of the tablet granulation and
excessively dirty processes in such areas of finished tablets. A low but acceptable moisture
manufacturing as coating and packaging. They level frequently acts as a binder. Very dry7 granu¬
can also add to a tablet’s weight variation or con¬ lations that contain only fractional percentages
tent uniformity problems. of moisture often produce more friable tablets
The laboratory friability tester is known as the than do granulations containing 2 to 4% mois¬
Roche friabilator.17 This device, shown in Fig¬ ture. For this reason, the manufacture of chemi¬
ure 11-2, subjects a number of tablets to the cally stable tablets that contain some hydrolyz¬
combined effects of abrasion and shock by utiliz¬ able drugs' that are mechanically sound is
ing a plastic chamber that revolves at 25 rpm, difficult.
dropping the tablets a distance of six inches with The traditional hardness and friability evalua¬
each revolution. Normally, a preweighed tablet tions performed on tablets involve only a small
sample is placed in the friabilator, which is then sample of tablets. How the tablets withstand the
operated for 100 revolutions. The tablets are mechanical shocks of a production environment
then dusted and reweighed. Conventional com¬ is related to the large number of tablets involved,
pressed tablets that lose less than 0.5 to 1.0% of the production equipment used, and the skill of
Their weight ~are generally considered accepta¬ the production personnel. Rough handling tests
ble. borne chewabie tablets and most efferves- can be performed to give an indication of how
cent tablets undergo high friability weight well a tablet will hold up in its specified package
losses, which accounts for the special stack and shipping container during shipment. Rough
packaging that may be required for these types handling tests usually include a vibration test, a
of tablets. When capping is observed on friability drop test, and an incline plane impact test.18
testing, the tablet should not be considered for Some investigators have actually shipped bottled
commercial use, regardless of the percentage of products across the country and back again to
loss seen. estimate the strength of the new tablet product
When concave and especially deep concave in shipment.
punches are used in tabletting, and especially Drug Content and Release. As mentioned

TABLETS • 299
earlier, a physically sound tablet may not pro¬ average tablet weight is close to the theoretic
duce the desired effects. To evaluate a tablet’s average weight. The weight variation test is
potential for efficacy, the amount of drug per clearly not sufficient to assure uniform potency
tablet needs to be monitored from tablet to tablet of tablets of moderate- or low-dose drugs, in
and batch to batch, and a measure of the tablet’s which excipients make up the bulk of the tablet
ability to release the drug needs to be ascer¬ weight.
tained. The potency of tablets is expressed in terms, of
Weight Variation. With a tablet designed to gramsTmilligrams,~or micrograms (for some po¬
contain a specific amount of drug in a specific tent drugi) of drug per tablet and is given as the
amount of tablet formula, the weight of the tab¬ label strength of the product. Official compendia
let being made is routinely measured to help or other standards provide an acceptable po¬
ensure that a tablet contaihs the proper amount tency range around the label potency. For highly
of drug. In practice, composite samples of tablets potent, low-dose drugs such as digitoxin, this
(usually 10) are takenand weighed throughout range is usually not less than 90% and not more
the compression process. The composite weight than 110% of the labeled amount. For most
divided by 10, however, provides an average other larger-dose drugs in tablet form, the offi¬
weight but contains the usual problems of aver¬ cial potency range that is permitted is not less
aged values. Within the composite sample that than 95% and not more than 105% of the la¬
has an acceptable average weight, there could be beled amount.
tablets excessively overweight or underweight. In general, official potency analytic methods
To help alleviate this problem the United States require that a composite sample of the tablets be
Pharmacopeia (USP)/National Formulary (NF) taken, ground up, mixed, and analyzed to pro¬
provides limits for the permissible variations in duce an average potency value. In composite
the weights of individual tablets expressed as a assays, individual discrepancies can be masked
percentage of the average weight of the sam¬ by use of the blended sample. Even though the
ple.19 The USP weight variation test is run by average assay result looks acceptable, it could
weighing 20 tablets individually, calculating the mask a wide variation in potency, with the result
average weight, and comparing the individual that a patient could be variably underdosed or
tablet weights to the average. The tablets meet overdosed. With such a drug as digitoxin, in
the USP test if no more than 2 tablets are out¬ which the safe and effective level and the toxic
side the percentageTimit aricTIf no tableFdiffers level are close (or even overlapping), exceeding
by more tlian~2limes~the percentage limit. The the official or accepted potency range is not only
weighrvanaHun toierancesfor uncoated tablets undesirable, but possibly dangerous.
differ depending on average tablet weight Three factors can directly contribute to con¬
(Table 11-1). tent uniformity problems in tablets: (1) nonuni¬
The weight variation test would be a satisfac¬ form distribution of the drug substance through¬
tory method of determining the drug content out the powder mixture or granulation,
uniformity of tablets if the tablets were all or es¬ (2) segregation of the powder mixture or granu¬
sentially all (90 to 95%) active ingredient, or if lation during the various manufacturing proc¬
the uniformity of the drug distribution in the esses, and (3) tablet weight variation. As noted
granulation or powder from which the tablets in the previous section, the use of weight cannot
were made were perfect. For tablets such as as¬ be used as a potency indicator, except perhaps
pirin, which are usually 90% or more active in¬ when the active ingredient is 90 to 95% of the
gredient, the ±5% weight variation should come total tablet weight. In tablets with smaller dos¬
close to defining true potency and content uni¬ ages, a good weight variation does not ensure
formity (95 to 105% of the label strength) if the good content uniformity, but a large weight vari¬
ation precludes good content uniformity.
Table 11-1. Weight Variation Tolerances for To assure uniform potency for tablets of low-
Uncoated Tablets dose drugs, a content uniformity test is ap¬
plied.19 In this test, 30 tablets are randomly se¬
Average Weight Maximum Percentage lected for the sample, and at least 10 of them are
of Tablets (mg) Difference Allowed assayed individually. Nine of the 10 tablets must
contain not less than 85% or more than 115% of
130 or less 10 the labeled drug content. The tenth tablet may
130-324 7.5 not contain less than 75% or more than 125% of
More than 324 5
the labeled content. If these conditions are not
Copied from USP XX—NF XV, © 1980, U.S. Pharmacopeia! met, the tablets remaining from the 30 must be
Convention, Inc. Permission granted. assayed individually, and none may fall outside

300 • The Theory and Practice of Industrial Pharmacy

of the 85 to 115% range. In evaluating a particu¬
lar lot of tablets, several samples of tablets
should be taken from various parts of the pro¬
duction run to satisfy statistical procedures.
The purity of official tablets is usually assured
by utilizing raw materials, both active drug and
all excipients, that meet official or other rigid
specifications. Extraneous substances present
in a raw material or a drug that are not specifi¬
cally allowed by compendial specifications or
well-defined manufacturer’s specifications may
render the product unacceptable for pharmaceu¬
tical use. These extraneous substances may be
toxic on acute or long-term use or may have an
unpredictable or deleterious effect on product
stability or efficacy. Certain well-defined impuri¬
ties often appear in the specification of raw ma¬
terials or drug substances, or if they are the
product of unavoidable decomposition of the
drug, they mav be listed with an upper tolerance
limit. For example, aspirin tablets as specified
5y~the USP may contain no more than 0.15% of
free" salicylic acid relative to thtTamount of aspi-
rm_present.
'Disintegration. A generally accepted maxim
is that for a drug to be readily available to the
body, it must be in solution. For most tablets, the
first important step toward solution is break¬
down of the tablet into smaller particles or gran- FIG. 11-3. Tablet disintegration tester. (Courtesy ofVan-
ules, a process known -as disintegration. The Kel Industries, Chatham, NJ.)
time that it takes a tablet to disintegrate is meas¬
ured in a device described in the USP/NF.19 assembly containing the tablets up and down
Wagner has written an excellent review of the through a distance of 5 to 6 cm at a frequency of
disintegration test,20 to which the reader is re¬ 28 to SZ cycles'per minute. Perforated plastic
ferred for a more detailed study. "discs may also be used in the test. These are
Research has established that one should not placed on top of the tablets and impart an abra¬
automatically expect a correlation between dis¬ sive action to the tablets. The discs may or may
integration and dissolution. However, since the not be meaningful or impart more sensitivity to
dissolution of a drug from the fragmented tablet the test, but they are useful for tablets that float.
appears to control partially or completely the To be in compliance with the USP standards,
appearance_of.the.drug in the blood, disintegra¬ the tablets must disintegrate, and all particles
tion is still used as a guide to the formulator in must pass through the 10-mesh screen in the
the preparation of an optimum tablet formula tame specified. IFany residue remains, it must
and as an in-process control test to ensure lot-to- have a soft mass with no palpably firm core. Pro¬
lot uniformity. cedures are stated for running disintegration
The USP device to test disintegration uses 6 times for uncoated tablets, plain-coated tablets,
glass tubes that are 3 inches long, open at the enteric coated tablets, buccal tablets, and sublin¬
top, and held against a 10-mesh screen at the gual tablets. Uncoated USP tablets have disinte¬
bottom end of the basket rack assembly (Fig. gration time standards as low as 5 min (aspirin
11-3). To test for disintegration time, one tablet tablets), but the majority of the tablets have~a
is placed in each tube, and the basket rack is maximum disintegration time of 30 min. En¬
positioned in a 1-L beaker of water, simulated teric coated tablets are to show no evidence of
gastric fluid, or simulated intestinal fluid, at disintegration after 1 hour in simulated gastric
37°C ± 2°C, such that the tablets remain 2.5 cm fluid. The same tablets are then tested in simu-
below the surface of the liquid on their upward lated intestinal fluid and are to disintegrate in 2
movement and descend not closer than 2.5 cm hours plus the time specified in the monograph.
from the bottom of the beaker. A standard Dissolution. The original rationale for using
motor-driven device is used to move the basket tablet disintegration tests was the fact that as

TABLETS 301
 the tablet breaks down into small particles, it of¬ tion testing. They determine compliance with
fers a greater surface area to the dissolving the limits on dissolution as specified in the indi¬
media and therefore must be related to the avail¬ vidual monograph for a tablet (or a capsule). The
ability of the drug*to the body. The disintegra¬ USPXX/NFXV, Supplement 3, specifies that ei¬
tion test, however, simply identifies the times ther of two apparatuses be used for determining
required for thd tablet to break up under the con¬ dissolution rates.21
ditions of the test and for all particles to pass Apparatus 1. In general, a single tablet is
through a 10-mesh screen. The test offers no placed in a small wire mesh basket fastened to
assurance that the resultant particles will re¬ the bottom of the shaft connected to a variable
lease the drug in Solution at 3n appropriate rate. speed motor (Fig. 11-4A). The basket is im¬
For this reason, dissolution tests and test speci¬ mersed in the dissolution medium (as specified
fications have now been developed for nearly all in the monograph) contained in a 100-ml flask_
tablet products. The rate of drug absorption for The flask is cylindric with a hemispherical bot¬
acidic drug moieties that are absorbed high in tom. The flask is maintained at 37°C ± 0.5°C by
the GI tract is ofte’n determined by the rate of a constant temperature bath. The motor is ad-
drug dissolution from the tablet. If the attain¬ justed to turn at the specified speed, and sam¬
ment of high peak'blood levels for the drug is a ples of the fluid are withdrawn at intervals to
product objective, obtaining rapid drug dissolu¬ determine the amount of drug in solution.
tion from the tablet is usually critically impor¬ Apparatus 2. The same equipment as in appa¬
tant. The rate of “dissolution may thus be directly ratus 1 is used, except that the basket is replaced
related to the efficacy of the tablet product, as by a paddle, formed from a blade and a shaft, as
well as to bioavailability differences between for¬ the stirring element (Fig.4B). The dosage form
mulations. Therefore, an evaluation as to is allowed to sink to the bottom of the flask be¬
whether or not a tablet releases its drug contents fore stirring. Dosage forms may have a “small,
when placed in the environment of the gastroin¬ loose piece of nonreactive material such as not
testinal tract is often of fundamental concern to more than a few turns of wire helix” attached to
the tablet formulator. prevent them from floating.20 Description of a
The most direct assessment of a drug’s release dissolution test in a USP/NF monograph speci¬
from various tablet formulations or products is fies the dissolution test medium and volume,
accomplished through in vivo bioavailability which apparatus is to be used, the speed (rpm)
measurements. The use of in vivo studies is re¬ at which the test is to be performed, the time
stricted, however, for several reasons: the length limit of the test, and the assay procedure. The
of time needed to plan, conduct, and interpret test tolerance is expressed as a percentage of the
the study; the highly skilled personnel required Jabeled amount of drug dissolved in the time
for human studies; the low precision and high limit. For example, for methyldopa tablets, the
variability typical of the measurements; the high dissolution test calls for a medium of 900 ml of
cost of the studies; the use of human subjects for 0.1N HC1, apparatus 2 mining at 50 rpm, and a
“nonessential” research; and the necessary as¬ time limit of 20 min. The accepted amount dis¬
sumption that a perfect correlation exists be¬ solved in 20 min is not less than 80% of the la¬
tween diseased patients and the healthy human beled amount of methyldopa (based on the cited
subjects used in the test. Consequently, in vitro assay procedure).
dissolution tests have been extensively studied, Dissolution testing and interpretation can be
developed, and used as an indirect measure¬ continued through three stages if necessary. In
ment of drug availability, especially in prelimi¬ stage l(Si), six tablets are tested and are accept¬
nary assessments of formulation factors and able if all of the tablets are not less than the
manufacturing methods that are likely to influ¬ monograph tolerance limit (Q) plus 5%. If the
ence bioavailability. As with any in vitro test, it tablets fail S]; an additional six tablets are tested
is critically important that the dissolution test be (S2). The tablets are acceptable if the average of
correlated with in vivo bioavailability tests. the twelve tablets is greater than or equal to Q
Two objectives in the development of in vitro and no unit is less than.Q minus 15%. If the
dissolution tests are to show (1) that the release tablets still fail the test, an additional 12 tablets
of the drug fromlhe. tablet is as close as possible are tested. The tablets are acceptable if the aver¬
iol 00%"ancT(2) that therate ot drug releasels age of all 24 tablets is greater than or equal to Q
uniform batch to fiatch and is~the same as the and if not more than 2 tablets are less than Q
reIeaseratefromThdse“batches proven to be bio- minus 15%.
availableandclinicailyeSecfive. Since 1970, the Industrial pharmacists routinely test their for¬
United States Pharmacopeia and the National mulations for dissolution. Their results are plot¬
Formulary have provided procedures for dissolu¬ ted as concentration versus time. Values for

302 • The Theory and Practice of Industrial Pharmacy

 [D
ppi
9.4 to 10.1 mm diameter
before coating

NOTES-
(1) Shaft and blade material-.
303 (or equivalent}
stainless steel.
(2) A and B dimensions are
not to vary more than
0.5 mm when part is
rotated on t axis.
(3) Tolerances are ±1.0 mm,
unless otherwise stated.

41.5 mm radius.

FIG. 11-4. A, USP dissolution apparatus 1. B, USP dissolution apparatus 2. (Reproduced from the Third Supplement to
USP XX-NF XV, © 1982, USP Convention, pages 310 and 311. Permission granted.)

t50%, t90%, and the percentage dissolved in 3. Punches for compressing the granulation
30 min are used as guides. The value for t50% is within the dies.
the length of time required for 50% of the drug
4. Cam tracks for guiding the movement of the
to go into solution. A value for t90% of 30 min is
punches.
often considered satisfactory and is an excellent
goal since a common dissolution tolerance in the 5. A feeding mechanism for moving granulation
USP/NF is not less than 75% dissolved in from the hopper into the dies.
45 min.
Tablet presses are classified as either single¬
punch or multi-station rotary presses. Figure
Tablet Compression Operation
11-5 illustrates in cross-section the compression
process on a single punch machine. Note that all
Tablet Compression Machines of the compression is applied by the upper
punch, making the single punch machine a
Tablets are made by compressing a formula¬
“stamping press.”
tion containing a drug or drugs with excipients
Multi-station presses are termed rotary be¬
on stamping machines called presses. Tablet
cause the head of the tablet machine that holds
compression machines or tablet presses are de¬
the upper punches, dies, and lower punches in
signed with the following basic components:
place rotates. As the head rotates, the punches
are guided up and down by fixed cam tracks,
1. Hopper(s) for holding and feeding granula¬
which control the sequence of filling, compres¬
tion to be compressed.
sion, and ejection. The portions of the head that
2. Dies that define the size and shape of the tab¬ hold the upper and lower punches are called the
let. upper and lower turrets respectively, and the

TABLETS • 303
 FIG. 11-5. The compression cycle of a single-punch tablet press. (Courtesy of Vector Corporation, Marion, IA.)

portion holding the dies is called the die table. At time, the lower punches re-enter the pulldown
the start of a compression cycle (Fig. 11-6), cam (C), and the cycle is repeated.
granulation stored in a hopper (not shown), Many production tablet machines are de¬
empties into the feed-frame (A), which has sev¬ signed so that the compression cycle is accom¬
eral interconnected compartments (Fig. 11-7). plished more than once (requiring additional
These compartments spread the granulation granulation hoppers, feed frames, cam tracks,
over a wide area to provide time for the dies (B) and compression rolls) while the machine head
to fill (Fig. 11-6). The pull-down cam (C) of Fig¬ makes a single revolution.
ure 11-6 guides the lower punches to the bottom All other parts of a tablet press are designed to
of their vertical travel, allowing the dies to over¬ control the functioning of the components just
fill. The punches then pass over a weight- listed. Such features as capacity, speed, maxi¬
control cam (E), which reduces the fill in the mum weight, and pressure vary with the design
dies to the desired amount. A wipe-off blade (D) of the equipment, but the basic elements remain
at the end of the feed-frame removes the excess essentially the same.
granulation and directs it around the turret and Although tablet compressing machinery has
back into the front of the feed-frame. Next, the undergone numerous mechanical modifications
lower punches travel over the lower compres- over the years, the compaction of materials be¬
o sion roll (F) while simultaneously the upper tween a pair of moving punches within a sta¬
Q 3^-punches ride beneath the upper compression tionary die has remained unchanged. The prin¬
* roll (G). The upper punches enter a fixed dis¬ cipal modification from earlier equipment has
tance into the dies, while the lower punches are been an increase in production rate rather than
raised to squeeze and compact the granulation any fundamental change in the process. Better
within the dies. To regulate the upward move¬ control and simplification have been corollary
ment of the lower punches, the height of the benefits.
lower pressure roll is changed. After the moment In recent years, there has been a change by
of compression, the upper punches are with¬ manufacturers from activities concerned with
drawn as they follow the upper punch raising production rate to problems of process improve¬
cam (H); the lower punches ride up the cam (I), ment and control. Growth of governmental and
which brings the tablets flush with or slightly pharmacopeia tests related to intertablet weight
above the surface of the dies. The exact position and potency variation, as noted earlier in the
is determined by a threaded bolt called the ejec¬ chapter, have created some of the new require¬
tor knob. The tablets strike a sweep-off blade af¬ ments for tablet compressing machinery. As tab¬
fixed to the front of the feed-frame (A) and slide let production rates have increased with modem
down a chute into a receptacle. At the same equipment, for example, the need for automatic

304 • The Theory and Practice of Industrial Pharmacy

11 .
FIG. 11-6. The compression cycle of a rotary tablet press. (See text for explanation of lettered labels.) (Courtesy of Thomas
Engineering, Hoffman Estates, IL.)

FRESH POWDER
FROM HOPPER

RECIRCULATE

FIG. 11-7. Granulation flow in an open feed frame of a rotary tablet press. (Courtesy of Vector Corporation, Marion, IA.)

tablets • 305
tablet weight control independent of operator pressure. Either of these alternatives gives a
vigilance has become a matter of increasing con¬ smoother pressure or compressive load force
cern. This topic is discussed later, in the section over a longer period of time. Hydraulic or pneu¬
“Auxiliary Equipment.” matic pressure is much more accurate and can
Tabletting presses vary principally in the be set with closer tolerances, which do not
number of tooling stations available for compres¬ change with time or fatigue.
sion and in special application features. Table Special adaptations of tablet machines allow
11-2 tabulates the maximum and minimum tab¬ for the compression of “layered” tablets and
let manufacturing output capable within the coated tablets. Precompression stations are also
various press models of several manufacturers. available to help in compressing difficult granu¬
A tablet machine’s output is regulated by lations. Available with certain Fette machines is
three basic characteristics of its design: a device that chills the compression components
to allow for the compression of low-melting-
point substances such as waxes, thereby making
Number of tooling sets
it possible to compress products with low melt¬
Number of compression stations ing points, such as suppositories.
Rotational speed of the press There are many basic and optional features
available in tablet machines, including some not
In general, all rotary presses are engineered mentioned in this text. Manufacturers’ bro¬
for fast and economical productionofall kinds of chures should be closely checked for available
tablets. Larger machines can readily produce features. One should attend equipment shows, if
several million tablets each in a working day, possible, to obtain up-to-date information on
and their performance can be geared to continu¬ equipment developments. In some instances,
ous low-maintenance operation. Figure 11-8 is test runs on machinery may be made before a
an example of a modem high-speed tabletting final decision to purchase new high-speed tablet
machine. equipment or specialized granulation or drying
There are many modifications and options equipment.
that can be obtained from various manufactur¬
ers. One modification, which is found on most
modem high-speed tablet presses, is the use of Compression Machine Tooling
hydraulic or pneumatic pressure to control the As mentioned earlier, the size and shape of a
pressure rolls in place of the older spring type tablet as well as certain identification markings

Table 11-2. Selected Rotary Tablet Press Characteristics

Number of Stations Rated Output, Tablets
Available per Minute (TPM)
Manufacturer Min Max Min Max U.S. Representative

Colton 12 90 480 16,000 Vector Corp.

Marion, IA 52302

Wilhelm Fette, Gmbh 20 55 300/900 3300/8250 Raymond Automation Company, Inc.

Hamburg, W. Germany Norwalk, CT 06856

Kilian & Co., Gmbh 14 67 140/383 1083/10,000 INPPEC

Koln, W. Germany Fairfield, CT 06430

Manesty Machines Ltd. 1.6 69 600/1500 3330/10,000 Thomas Engineering

Liverpool, England Hoffman Estates, IL 60172

Stokes-Merrill 33 65 1200/3300 3500/10,000 Stokes-Merrill Division

Penwalt Corp.
Oak Brook, IL 60521

Korsch Maschinenfabrik 20 55 540/1100 1640/5500 Aeromatic

Berlin, W. Germany East Towaco, NJ 07082

Hata Ironworks 28 71 420/1420 1960/7100 Elizabeth-Hata International Inc.

Hori Engineering Co., McKeesport, PA 15132
Osaka, Japan

306 • The Theory and Practice of Industrial Pharmacy

FIG. 11-8. The Manesty Nava rotary tablet press. (Courtesy of Thomas Engineering, Hoffman Estates, IL.)

are determined by the compression machine 1-inch barrel diameter, 1 Vi-inch head diameter,
tooling. Each tooling set consists of a die and and 5.25-inch length. The dies that are used
upper and lower punches. Since each tablet is with the above punches are either a 0.945-inch
formed by a tooling set, the tooling must meet outside diameter (OD) die capable of making a
many requirements to satisfy the needs of dos¬ 7/ie-inch round tablet or 9/i6-inch capsule-shaped
age uniformity, production efficiency, and es¬ tablet; or a 13Ae-inch OD die capable of handling
thetic appearance. a 9/i6-inch round or 14-inch capsule shaped tab¬
The terminology used with tooling is illus¬ let.
trated in Figure 11-9. The most common tools Several types of steel are normally used in the
employed are referred to as BB tooling and are manufacture of compression tooling. These
5.25 inches in length, and have a nominal barrel steels differ in toughness, to withstand the cy¬
diameter of 0.75 inches and 1-inch head diame¬ clic compacting forces, (ductility), and in wear
ter. B tooling is identical to the BB type except resistance. Unfortunately, no single steel type
that the lower punch is only 39/ie inches long. D has a high resistance to abrasive wear and a
tooling is popular for large tablets, utilizing a high ductility. Therefore, the selection of the

TABLETS • 307
 PUNCH BODY best steel for a specific application must be
based on experience and an accumulated history
of the product being tabletted. In the selection of
Tip Straight^
the proper steel for a specific use, one should
also consider the shape of the punch tip,
Relief—' whether or not debossing is to be employed on
Barrel To—. the tooling, the expected compression forces
Stem Radius involved, and whether the materials to be proc¬
essed are abrasive or corrosive
The size, shape, and contour of a tablet is al-
Length

^ most unlimited within the given limits of the

j specified die size. A survey of the PDR Product
J Identification section reveals numerous varia-
’ tions on tablet size and shape.4 In addition, tool-
Overall

| ing can be made with certain other information

E to aid in producing a visibly unique tablet prod¬
uct. Company names or symbols, trade names,
Barrel To dosage strength, or National Drug Code (NDC)
Neck Radius-^ numbers can be cut or engraved into a punch
Neck To face, or the punches may be scored, to produce
Head Radius- uniquely embossed or engraved tablets. Even
Inside Head —
Anqle
Head OO-^
_ , -
though tooling design would appear to be limit-
less, certain practical aspects do limit design
implementation. Because of the movement of
-Head Flat
Outside Head- tooling during a compression operation, certain
Angle tablet shapes or contour configurations perform
better than others. Round tablets perform better
than irregularly shaped tooling since they do not
PUNCH TIP require “keying” to maintain the proper upper
punch orientation with the die. When the tip on
Tip straight 311 upper punch is not round, it must not rotate,
or it will strike the edge of the die hole as it dg;
spends for compression. To prevent this, a slot is
cut longitudinally into the barrel of the punch,
a key is inserted. This key protrudes a short
' distance so that it engages a similar slot cut into
the upper punch guides on the tablet press.
Lower punches do not need keys because their
, tips remain within the die bore, which controls
the axial movement of the punch. Because
keyed punches cannot rotate, wear is distributed
unevenly, and punch life is shortened.
When a press is set up with keyed punches,
the upper punches are inserted first to deter¬
mine the placement of the dies. Once the dies
Chamfer
are properly aligned and seated, they are locked
in place, and the lower punches are inserted.
The more curvature that is built into a tablet
r contour, the more difficult it is to compress, es¬
pecially if the tablet tends to laminate or cap.
M \,e The engraving or embossing on a tablet must be
vsk“j designed to be legible, must not add to compres-
jj* sion problems, 'and must fit on the tablet sur- sur¬
FIG. 11-9. Tablet press tooling nomenclature. (Courtesy face. Many considerations, at close tolerances,
of Thomas Engineering, Hoffman Estates, IL.) must be incorporated in tooling design to pro¬
duce tablets that are uniform and esthetic. Man¬
ufacturing specifications for tooling have been
standardized by the Industrial Pharmaceutical

308 • The Theory and Practice of Industrial Pharmacy

Technology Section of the Academy of Pharma¬ tablet compression operation. In many cases,
ceutical Sciences in its Standard Specifications the speed of the die table is such that the dwell
of Tabletting Tools.22 time of a die under the feed frame is too short to
Because of its hard steel structure, tablet tool¬ allow for adequate or consistent gravity filling of
ing may appear to be indestructible. During nor¬ the die with granulation. Improper filing of the
mal use, however, the punches and dies become dies with granulation results in unsatisfactory
worn, and the cyclic application of stress can weight variation and content uniformity of the
cause the steel to fatigue and break. Improper resulting tablets. A similar result can occur with
storage and handling can readily result in a poorly flowing granulation. To help alleviate
damage that necessitates discarding of an entire these problems, mechanized feeders can be
tooling set. The punch tips are especially deli¬ employed to force granulation into the dies
cate and susceptible to damage if the tips make (Fig. 11-10).
contact with each other, the dies, or the press The high tablet output rates of modem
turret upon insertion or removal of the tools presses demand that the granulation hoppers be
from the tablet machine. A good tool control sys¬ refilled at frequent intervals; the larger the tablet
tem must be employed to maintain the history of is, the more frequently the hopper needs to be
each tool set, not only to maintain a constant replenished. Allowing a tablet machine to ran
surveillance of critical tolerances altered by “dry” results in a series of rapidly degenerating
wear, but also to eliminate product mixups by and unacceptable events. First, low-weight tab¬
preventing the wrong tooling from being used lets and tablets with poor weight variation are
for a product. produced. Then, the soft granulation is unable
To avoid tooling damage, compressive loads or to be formed into tablets. Finally, the tooling is
pressures at the pressure rolls must be trans¬ usually ruined, particularly with thin tablets, by
lated into a calculation of pressure at the punch the punches being forced together without any
tips. As tablet punch diameter decreases, less granulation between them. Because of the rela¬
force is required to produce the same pressure at tively low volume of press hoppers, the filling of
the punch face, since the face represents a hoppers by hand on high-speed presses is ineffi¬
smaller fraction of a unit area (square inch). The cient, increases the risk of punch damage, and
formula for the area of a circle is irr2 where r is can contribute to weight variation problems.
the radius of the circle. Given a flat punch face, Therefore, mechanized equipment has been
the area of a Vi-inch-diameter punch would thus developed to load granulation into the press hop¬
be 3.14 x (Vs)2 or 3.14 x Vm, or approximately pers.
V20 square-inch. If a 1-ton load is being applied A popular method of handling large quantities
by the pressure roll, this area is translated as of material is to place bulk granulation con¬
2000 pounds on V20 square inch, or 40,000 tainers directly above tabletting machines to
pounds on 1 square inch, a gross overload. gravity-feed the granulation into hoppers. This
The following are manufacturers of tablet can be accomplished by several means. Bulk
compression tooling: granulation containers can be placed on floors
above a tablet machine, and granulation can
Thomas Engineering, Hoffman Estates, IL then be directed through openings in the floor
Stokes, Warminster, PA into the hoppers. In a similar fashion, granula¬
tion containers can be held on mezzanine?
Natoli Engineering Company, Chesterfield, above tablet machines. If such overhead room is
MO unavailable, hoists and mechanical lifts can be
Elizabeth Carbide Die Co., McKeesport, PA used to elevate granulation containers or mate¬
Key Industries, Englishtown, NJ rial transfer devices directly in position above
the press. Granulation level sensors can be used
Advance Engineering and Manufacturing Co., to stop the press automatically when the granu¬
St. Louis, MO lation level drops to a critical level in the hopper.
Aeromatic Inc., Somerville, N.J. The high rate of tablet output with modem
Carle and Montanan Inc., Hackensack, NJ presses calls for a higher frequency or even con¬
tinuous monitoring of tablet weight. Electronic
I. Holland Ltd., Nottingham, U.K. monitoring devices, such as the Thomas Tablet
Sentinel (Fig. 11-11), Pharmakontroll, and the
Kilian Control System-MC, monitor the force at
Auxiliary Equipment each compression station, which correlates with
There are some common auxiliary pieces of tablet weight. These monitors are also capable of
equipment that increase the efficiency of the initiating corrective actions, altering the amount

TABLETS • 309
FIG. 11-10. A, Manesty granulation feeding device. (1) Granulation input port from tablet machine feed hopper. (2) Ro¬
tating feed fingers. (3) Compressed tablet scrape-off blade. B, Manesty granulation feeding device mounted on a rotary
tablet machine. (1) Tablet machine turret. (2) Tablet machine hopper. (3) Feeding device. (4) Compressed tablet output
chute. (Courtesy of Thomas Engineering, Hoffman Estates, IL.)

310 ’The Theory and Practice of Industrial Pharmacy

FIG. 11-11. Thomas Table Sentinel II. (Courtesy of Thomas Engineering, Hoffman Estates, IL.)

of die fill to maintain a fixed force, ejecting tab¬ tion is verified, along with the set-up of the
lets that are out of specification, counting, and proper tabletting machine and proper tooling.
documenting the machine operation throughout
the run.
In almost all cases, tablets coming off a tablet Processing Problems
machine bear excess powder and are run In the normal process of developing formula¬
through a tablet deduster to remove that excess. tions, and in the routine manufacture of tablets,
various problems occur. Sometimes, the source
of the problem is the formulation, the compres¬
In-Process Quality Control sion equipment, or a combination of the two.
During the compression of tablets, in-process Capping and Lamination. Capping is. a
tests are routinely run to monitor the process, term used to describe the partial or complete
including tests for tablet weight, weight varia¬ separatiorroFthe top or bottom crowns of a tablet
tion, hardness, thickness, disintegration, and from the main body of the tablet. Lamination is
various evaulations of elegance. The in-process the separation of a tablet into two or more dis-
tests are performed by production and/or quality tinct layers. Usually, these processing problems
control (QC) personnel. In addition, many in- are readily apparent immediately after compres¬
process tests are performed during product de¬ sion; however, capping and lamination may
velopment by the formulator. Such testing dur¬ occur hours or even days later. Subjecting tab¬
ing development has become increasingly im¬ lets to the friability test described earlier is the
portant in recent years for process validation quickest wav of revealing such problems. Cap¬
purposes. The data supplied by the formulator is ping and lamination have in the past been attrib¬
usually employed by QC personnel to establish uted to air entrapment. During the compression
the test limits. At the start-up of a tablet com¬ process, air is entrapped among the particles or
pression operation, the identity of the granula¬ granules and does not escape until the compres-

TABLETS• 311
 sion pressure is released. Research has shown, compressed in standard tooling under identical
however, that capping and lamination are due to compression conditions.
the deformational properties of the formulation Tablet tooling can also be a cause of capping.
during and immediately following compres¬ The concave or beveled edge faces of punches
sion.^3 . gradually curve inward with use and form a
"During compaction, particles undergo suffi¬ “claw” that can pull off the crowns of a tablet.
cient plastic deformation to produce die-wall Wear in the upper punch guides accelerates this
pressures greater than can be relieved by elastic glaw formirionb^perinitfihg the punch tips to
recovery when the punch pressure is removed. strike the edges of the die holes. Also, the greater
In some materials, this die-wall pressure causes the radius of"curvature of the punch face, the
enough internal stress to cause a crack to propa¬ greater is the force exerted on the edges and the
gate and initiate fracture of the compact in the less on the center of the tablet at tfte moment of
die. If the excess stresses do not initiate fracture compression.
upon decompression in the die, the compact Dies develop a wear “ring” in the area of com¬
may laminate or cap upon ejection from the die. pression. As the ring develops, and enlarges, the
As the compact is ejected, the die-wall pressure tablets that are compressed in the rings have a
falls to zero. The emerging portion of the com¬ diameter that is too large to pass easily through
pact expands while the confined portion cannot, the narrower portion of the die above the ring.
thus concentrating shear stresses at the edge of Upon ejection, this constriction causes the tab¬
the die and causing a break to develop. Tablets let to cap or laminate. A simple solution of this
that do not fracture have the ability to relieve the particular problem is to turn the die oyer so that
shear stresses developed during decompression compression occurs in an unworn area above
and/or ejection by plastic deformation. This the ring. On some presses, the depth of penetra¬
stress relaxation is time-dependent; therefore, tion of the upper punch can be regulated so that
the occurrence of tablet fracture is also time- compression may be performed over some range
dependent. Intact tablets of acetaminophen, of locations within the die. There are also dies
methenamine, and erythromycin can be made if available with tungsten carbide inserts. The car¬
the decompression is extended for several bide is so durable that the casing wears out be¬
hours. Rapid decompression results in tablets fore the insert does. Wear on tablet tooling in¬
that fracture. Stress relaxation could be the ex¬ creases as the hardness of the material being
planation for some practical tabletting problems. compressed increases. Most organic materials
Tablet lamination or capping problems are often are soft; certain inorganic materials such as
eliminated by precompression, slowing die magnesium trisilicate are relatively hard and
Tabletting rate, and reducing the final compres¬ abrasive.
sion pressure. As the stress relaxation time is Another cause of capping is an incorrect'set-
increased, the amount of stress needing to be np at the press. When a compressed tablet is
relieved is reduced, allowing an intact compact ejected from a die, the lower punch must rise
to be formed. flush with or protrude slightly above the face of
Often, deep concave punches produce tablets the die at the point where the tablet strikes the
that cap. "The curved part of such tablets ex¬ sweep-off blade. If the punch remains below the
pands radially while the body of the tablet can¬ face of the die, the sweep-off blade cuts off the
not, which establishes a shear stress that pro¬ tablet, leaving the bottom in the die. A less se¬
duces the fracture. Flat punches may plimin-atp vere result of this incorrect adjustment is that
jhis additional shear stress. the edge of the tablet catches on the die and
A certain percentage of moisture is often es¬ chip. An incorrect adjustment of the sweep-off
sential for jtqoff compaction._ A granulation that blade can also result in tablet fractnre. If the
isTtbo dryTendstocap or laminate for lack of blade is adjusted too high, tablets can start to
cohesion. For moisture-critical granulations, the travel under it, become stuck, and break off. The
addition of a hygroscopic substance, e.g., sorbi- resulting broken pieces of tablets then enter the
tol, methylcellulose, or polyethylene glycol 4000. feed frame; if they are large enough, they can
"can helpTIo rtiaintain a proper moisture level. cause a disruption of the granulation feed, as
Capping and lamination may also be encoun¬ well as affect the weight and hardness of subse¬
tered in direct compression product develop¬ quent tablets.
ment. fjome powder or fine particulate materials Picking and Sticking. “Picking” is a term
may not be compressible or may have poor com¬ used to describe the surface material from a tab¬
pression properties. Relative compressibility of let that is sticking to and being removed from
various materials may be reflected by their de¬ the tablet’s surface by a punch. Picking is of par¬
gree of consolidation (crown thickness) when ticular concern when punch tips have engraving

312 • The Theory and Practice of Industrial Pharmacy

 or embossing. Small enclosed areas such as drying. To overcome this difficulty, the formula-
those found in the letters “B,” “A,” and “O” are tor may change the solvent system, change the
difficult to manufacture cleanly. Tablet materi¬ Tinder system, reduce the drying temperature,
als that stick to the punches can accumulate to or grind to a smaller particle size. The usrj of
the point of obliterating the tip design. “Stick-. colorants in direct compression formulations
ing” refers to tablet material adhering to the die can lead to mottling if the dye is not well disper¬
wall When sticking occurs. additionaTforce is sed or if its particle size is too large.
required to overcome the friction between the Certain colored adhesive gel solutions may not
tablet and the die wall during ejection. Serious be distributed well because they must be hot
sticking at ejection can cause chipping of a tab¬ when added to much cooler powder mixtures.
let’s edges and can produce a rough edge. Also, a The adhesive then precipitates from solution
sticking -problem does not allow the lower and carries most of the color with it. Further
punches free movement and therefore can place wetting, even overwetting, is needed to disperse
unusual stresses on the cam tracks and punch the binder and the color. The additional mixing
heads, resulting in their damage. Sticking can and increased activation of the binder, however,
also apply to the buildup of material on punch may result in tablets with increased disintegra¬
faces. tion times. Therefore, a better practice may be to
These flaws have many remedies. Lettering incorporate fine powder adhesives such as
should be designed as large as possible, particu¬ acacia and tragacanth into the product before
larly on punches with small diameters. The tab¬ adding the granulating fluid, or to disperse a dry
let can perhaps be reformulated to a larger size. color additive during the powder blending step.
Plating of the punch faces with chromium is a Weight Variation. In previous sections,
method for producing a smooth, nonadherent weight variation of tablets has been mentioned
face! as an important in-process control measure¬
"TFTsome cases, colloidal silica added to the for¬ ment, and weight variation specifications have
mula acts as a polishing agent and makes the been given. The weight of a tablet being com-,
. punch faces smooth so that materiaTdoes not pressed is determined by the amount of granula¬
^rb^'pling to them On the other hand the frictional tion in the die prior to compression. Therefore,
nature of this material may require additional anything that can alter the die-filling process
lubrication to facilitate release of the tablet from can alter tablet weight and weight variation.
\ the die. Sometimes, additional binder or a Granule Size and Size Distribution Before
change in binder may make the granules more Compression. Variations in the ratio of small to
cohesive, and therefore less adherent, than be¬ large granules and in the magnitude of differ¬
fore. ence between granule sizes influence how the
Low-melting-point substances, either active void spaces between particles are filled. Thus,
ingredients or additives such as stearic acid and although the apparent volume in the die is es¬
Polverhvlcne glycol, may softeiTsufficientlv from sentially the same, different proportions of large
the heat oTcompression to cause sticking. Dilu¬ and small particles may change the weight of fill
tion of the active ingredient with additional in each die. Furthermore, if large granules are
higher-melting-point materials and a conse¬ being used to fill a small die cavity, relatively few
quent increase in the size of the tablet may help. granules are required, and the difference of only
The level of low-melting-point lubricants may be a few granules around the average may repre¬
reduced, or higher-melting-point replacements sent a high percentage weight variation. If hun¬
may be substituted. When a low-melting-point dreds of granules are required on the average for
medicament is present in high concentration, die fill, a variation of a few granules around the
refrigeration of the granulation and the press average would produce a minor weight varia¬
may be in order. Excessive moisture may be re¬ tion, given a narrow particle size range.
sponsible for sticking, and further drying of the Poor Flow. The die-fill process is based on a
granulation is then required. continuous and uniform flow of granulation
Mottling. Mottling is an unequal distribution from the hopper through the feed frame. When
of color on a tablet, with light or dark areas the granulation does not flow readily, it tends to
standing out in an otherwise uniform surface. move spasmodically through the feed frame so
One cause of mottling is a drug whose color dif¬ that some dies are incompletely filled. Similarly,
fers from the tablet excipients or a drug whose dies are not filled properly when machine speed
degradation products are colored. The use of col¬ is in excess of the granulation’s flow capabili¬
orants may solve the above problem but can ties. With poor flow, the addition of a glidant
create others. A dye can cause mottling by mi¬ such as talcum or colloidal silica, or an increase
grating to the surface of a granulation during in the amount already present, may be helpful.

TABLETS *313
Also available are induced die feeders, which of particles is then impaired, and the granules
mechanically “force” the granulation down into do not move efficiendy into the dies. There is a
the die cavities as they pass beneath the feed tendency to minimize the mixing time during
frame. lubricant addition to prevent or reduce granule
Poor flow through the feed frame is usually a friability; however, inadequate mixing at this
sign that the granulation is not flowing properly stage can result in unsatisfactory granulation
out of the hopper. As particulate solids move flow.
under the force of gravity through progressively Punch Variation. When lower punches are
smaller openings, they are subjected to uneven of unequal lengths—the difference may be only
pressures from the mass above and alongside. a few thousandths of an inch—the fill in each
Depending on the geometry of the hopper, this die varies because the fill is volumetric. Only a
situation may give rise to one or another of two good punch and die control program can provide
causes for poor flow: “arching” or “bridging,” tooling of uniform dimensions.
and “rat-holing." Figure H-12 illustrates these Hardness Variation. Hardness variation is
phenomena. When poor hopper flow occurs, it a problem that has the same causes as weight
may be controllable with vibrators attached to variation. Hardness depends on the weight of
the hopper sides to induce the granulation flow. material and~tKe~space between the upper and
Devices designed to improve poor flow char¬ Tower punches at the moment of compression. If
acteristics of materials often introduce another Therolume of material or the distance between
problem, however. Since most tablet granula¬ punches varies, hardness is likewise inconsist¬
tions consist of materials with a range of particle ent.
sizes, the vibration or mixing action of the flow- Double Impression. A last problem for dis¬
promoting devices may induce segregation and cussion is that of double impression. This in¬
stratification of the particles. The larger particles volves only punches that have a monogram or
tend to drift upward while the smaller particles other engraving on them. At the moment of
sift downward. Not only can the resulting “clas¬ compression, the tablet receives the imprint of
sification” of particle sizes cause appreciable the punch. On some machines, the lower punch
changes in tablet weight and weight variation as is free to drop and then travel uncontrolled for a
described earlier, but it can also lead to poor con¬ TTiori distance before! t rides up the eiectioncam
tent uniformity, since drug is often not uni¬ to push the tablet out of the die. During its free
formly distributed between the larger and travel, it rotates. At this point, the punch may
smaller particles. Poor particulate flow may be make a new, although lighter, impression on the
caused not by the granulation, but by poor de¬ bottom of the tablet, resulting in a double im¬
sign of the granulation hopper, which can be print. Similar problems can be encountered with
exaggerated by dents that effectively cut off the engraved upper punches and tablet machines
flow. Poor weight variation can also be caused that utilize two compression stages to compress
by surges of excessive flow. Direct compression a tablet. The first stage, precompression, uses a
granulations fed through typical wet-granulation lower compactionforce.than the final compres-
hoppers and feed frames are prone to this type of sTdhsTige, but the tablet does receive thelm-
flow. Often, restricting the flow out of the hop¬ print of the punch. If the upper punch is uncon¬
per corrects the problem. Recently, a patent was trolled, it can rotate during the short travel to the
issued for a new feed frame design that accom¬ final compression stage and thus create a double
modated excessive flow from the hopper with¬ imprint. The newer presses have antituming
out compromising uniform weight variation.24 devices as an integral part of their design and
Poor Mixing. Sometimes, the lubricants and construction.
glidants are not thoroughly distributed. The flow

Tablet Granulations

Basic Characteristics
The characteristics of a tablet that make it a
popular dosage form, e.g., compactness, physical
stability, rapid production capability, chemical
stability, and efficacy, are in general dictated
primarily by the qualities of the granulation
from which it is made. Basically stated, materi¬
FIG. 11-12. Bridging (left); rat-holing (right). als intended for compaction into a tablet must

314 • The Theory and Practice of Industrial Pharmacy

possess two characteristics: fluidity and com¬ these can affect the characteristics of the granu¬
pressibility. To a great extent, these properties lations produced. Therefore, methods to mea¬
are required by the compression machine de¬ sure certain granulation characteristics have
sign. As previously discussed, good flow proper¬ been developed to monitor granulation suita¬
ties are essential for the transport of the material bility for tabletting.
through the hopper, into and through the"feed Particle Size and Shape. The particle size
frame, and into the dies. Tablet materials should of a granulation is knovpi to affect the average
therefore be in a physical form that flows tablet weight, tablet weight variation, disintegra- ,
smoothly and uniformly. The ideal physical form tion time, granule friability, granulation
for this plirpose is spheres, since these offer flowability, andythe^drymg /fate kinetics of wet
minimum contact surfaces between themselves granulations.26-28 The exact effect of granule
and with the walls of the machine parts. Unfor¬ size and size distribution on processing require¬
tunately, most materials do not easily form ments, bulk granulation characteristics, and
spheres; however, shapes thajt approach spheres final tablet characteristics depends upon the for¬
improve flowability. Therefore granulation is in mulation ingredients and their concentrations, ^
part the pharmaceutical process that attempts to as well as the type of granulating equipment and ”
improve the flow of powdered materials by form¬ processing conditions employed. Therefore, the
ing spherelike or regularly shaped aggregates formulator should-determine for each formula-
called granules. The need to assess the shape of tion and manufacturing process the effects of
particles and their relative regularity or approxi¬ granule size and size distribution on processabil-
mation to spheres has led to the development of ity and tablet quality features. The methods for/e-fr^^A^
equations whereby certain “factors” can be cal¬ measuring and interpreting particle size andl ^
culated to provide quantitative comparisons of particle size distribution are discussed in Chap- ^
different particle shapes. By measuring particle •ter 2, “Milling.” vionvJe-**
surface area (S), volume (V) and a projected Surface Area. The determination of the sur¬
equivalent diameter (dp), a volume shape factor face area of finely milled drug powders may be of
(av), a surface shape factor and a shape value for drugs that have only limited water sol¬
coefficient (avs) can be calculated tjsing equa¬ ubility. In these cases, particle size, and espe¬
tions (1) to (3) for quantitative work.25 cially the surface area of the drug, can have a
significant effect upon dissolution rate. The de¬
termination of the surface area of granulations is
not a common practice. In general, if one is in¬
terested in effects of granulation surface upon
measurable properties of the final dosage form,
<*, = 4- (2) particle size of the granulation is measured. An
up
inverse relationship normally exists between
particle size and surface area: however, granula¬
«vs = — (3) tions can have convoluted structures with con¬
av
siderable internal surface. Technology available
The shape coefficient for a sphere is 6. As a par¬ for determining the surface area of coarse pow¬
ticle becomes more irregular in shape, the value ders or agglomerates (granulations) is not as
of Oyg increases. For a cube, ave is equal to 6.8. advanced as that available for fine powders. The
The other desirable characteristic, compressi¬ two most common methods for determining sur¬
bility, is the property of forming a stable, com¬ face area of solid particles are gas adsorption and
pact mass when pressure is applied. The requi¬ air permeability. In the first rrtelhod (gas adsorp¬
site physical properties and the forces that hold tion), the amount of gas that is adsorbed onto
the tablet together are discussed in Chapter 4, the powder to form a monolayer is measured and
“Compression and Consolidation of Powdered then used to calculate the surface area of the
Solids.” The consideration of compressibility in powder sample. Air permeability, the rate at*
this discussion is limited to stating that granula¬ which air permeates a bed of powder, is used to
tion is alsojthe pharmaceutical process that con¬ calculate the surface area of the powder sample.
verts a mixture of powders, which have poor These methods are described in Chapter 4.
cohesion, into aggregates capable of compaction. Density. Granule density may influence
compressibility’~tablet porosity, dissolution, and
other properties. Dense, hard granules may re-
Granulation Properties quire higher compressible loads to produce a
There are many formulation and process vari¬ cohesive compact, let alone tablets of acceptable
ables involved in the granulation step, and all of appearance that are free from visible granule

TABLETS *315
boundaries. The higher compression load, in where pu is the untapped bulk density (often
turn, has the potential of increasing the tablet called loose or aerated bulk density). In theory,
disintegration and drug dissolution times. Even the more compressible a bed of particulates is,
if the tablets disintegrate readily, the harder, the less flowable the powder or granulation will
denser granules may dissolve less readily. At the be. Conversely, the less compressible a material
same time, harder, denser granules are usually is, the more flowable it will be.
less friable. Basically, two methods are used to Bulk density largely depends on particle
determine granule density. Both involve the use shape. As the particles became more spherical in
of a pycnometer. In one, the intrusion fluid is shape, bulk density is increased. In addition, as
mercury, aiicTin the other, it is a solvent of low granule size increases, bulk density decreases.
surface terrsioiTTe.g., benzene) in which the The smaller granules are able to form a close,
granules are not soluble. The accuracy of these more intimate packing than larger granules.
pycnometer methods depends on the ability of Strength and Friability. A granule is an
the intrusion fluids to penetrate the pores of the aggregation of component particles that is held •
granules. Density is calculated from the volume together by bonds of finite strength. The
of intrusion fluid displaced in the pycnometer - strength of a wet -granule is due mainly to the
by a given mass of granulation:25 jurfaciPtensidn of liquldand capillary forces.
y These forcesare responsible lorTnitial agglomer-
D = MA'p - ^ (4) ation of the wet powder. Upon drying, the gran¬
ule has strong bonds resulting from fusion or
recrystalhzation of particles and curing of the
where D is density, Vp is the total volume of the
adhesive or binder. Under these conditions, van
pycnometer, and V, is the volume of intrusion
der Waals forces are of sufficient strength to pro¬
fluid containing that mass of granules (M) that
duce a strong, dry granule. Measurements of
is required to fill the pycnometer.
granule strength are therefore aimed at estimat¬
The term bulk density refers to a measure
ing the relative magnitude of attractive forces
used to describe a packing of particles or gran¬
seeking to hold the granule together. The resul¬
ules. The equation for determining bulk density
tant strength of a granule depends, of course, on
(Pb) is:25
base material, the kind and amount of granulat¬
ing agent used, the granulating equipment used,
and so forth. Factors affecting granule strength
are discussed in this section.
Granule strength and friability are important,
where M is the mass of the particles and Vb is as they affect changes in particle size distribu¬
the total volume of packing. The volume of the tion of granulations, and consequently, com¬
packing can be determined in an apparatus con¬ pressibility into cohesive tablets. When deter¬
sisting of a graduated cylinder mounted on a mining a relative measure of granule strength,
mechanical tapping device that has a specially two distinct types of measurements can be
cut rotating cam. An accurately weighed sample made. Perhaps, the one most commonly used is
of powder or granulation is carefully added to that of compression strength. In this test, a
the cylinder with the aid of a funnel. Typically, granule is placed between anvils, and the force
the initial volume is noted, and the sample is required to break the grannie is measured 29’30
then tapped until no further reduction in vol¬ Other common methods of studying granule
ume is noted. The volume at this tightest pack¬ strength are those that relate to. friability meas-
ing is then used in equation (1) to compute bulk mgemgnts. Most of these methods are variations
density Pb. A sufficient numberof taps should be oftKe American Society for Testing Materials
employed to assure reproducibility for the mate¬ (ASTM) tumbler test for the friability of coal,
rial in question. The tapping should not produce
and provide a means of measuring the propen¬
particle attrition or a change in the particle size
sity of granules to break into smaller pieces
distribution of the material undergoing testing.
when subjected to disruptive forces.31
See Chapter 4 for further details.
Flow Properties. The flow properties of a
An important measure that can then be ob¬
material result from many forces. Solid particles
tained from bulk density determinations is the
attract one another, and forces acting between
percent compressibility, C, which is defined as
particles when they are in contact are predomi¬
follows:25
nately surface forces. There are many types of
# forces that can act between solid particles:
C = ^-(lQO) (6) (1) frictional forces, (2) surface tension forces,
Pb (3) mechanical forces caused by interlocking of

316 • The Theory and Practice of Industrial Pharmacy

 particles of irregular shape, (4) electrostatic static angle of repose, and the angle arrived at in
forces, and (5) cohesive or van der Waals forces. the last method is commonly called the kinetic
All of these forces can affect flow properties of a or dynamic angle of repose. Values for angles of
solid. They can also affect granule properties repose <30° usually indicate a free-flowing ma¬
such as particle size, particle size distribution, terial and angles >40° suggest a poorly flowing
particle shape, surface texture or roughness, material. As mentioned previously, flow of
residual surface energy, and surface area. With coarse particles is also related to packing densi¬
fine powders (< 150/am), the magnitude of the ties and mechanical arrangements of particles.
Tricfional and van der Waals forces usually pre¬ For this reason, a good auxiliary test to run in
dominate.'for larger particles (a 150/am) such conjunction with the repose angle test is the
’asgranuTes'produced by a wet granulation tech¬ compressibility test, discussed previously. From
nique, frictional forces~hormally predominate the angle of repose and compressibility values, a
over van der Waals forces. Also, as particles in- reasonable indication of a material’s inherent
crease in size, mechanical or physical properties flow properties should be possible.
of particles and their packings become impor¬ Hopper Flow Rates. Hopper flow rates have
tant. While an evaluation of some of the funda¬ been used as a method of assessing flowability.
mental properties of particles discussed earlier Instrumentation to obtain hopper flow rates
(e.g., shape and bulk density) is important, there continually monitors the flow of material out of
are tests that can be employed as flow measure¬ conical hoppers onto a recording balance device.
ments of the effect of all the interparticulate Instrumentation of this kind is quite simple, and
forces acting at once. Two of the most common results are easy to interpret, making the method
methods are (1) repose angle, and (2) hopper attractive from a pragmatic standpoint. Unfortu¬
flow rate measurements. nately, the two methods used for-studying flow,
Repose Angle. The fixed funnel and free¬ hopper tests and repose angles, do not correlate
standing cone methods employ a funnel that is well.
secured with its tip at a given height, H, above Compaction. The process of consolidating
graph paper that is placed on a flat horizontal and compacting powder or granule materials to
surface. Powder or granulation is carefully form a tablet is complex, owing to the numerous
poured through the funnel until the apex of the internal events that act simultaneously (see
conical pile just touches the tip of the funnel. Chap. 4). The basic tool that has been developed
Thus, with R being'the radius of the base of the for studying the compression process is the in¬
conical pile: strumented tablet press. Tablet presses are in¬
strumented by affixing transducers to measure
the forces applied during the compression proc¬
tan a = -p- ^ (7) ess. The signals produced by the transducer sys¬
tem are then monitored by some means—most
recently, by computer. Properly instrumented
or
and monitored tablet presses have been shown
to be of great assistance in studying the mecha¬
a = arctan-=— (8) nism of compaction, the relationship of compac¬
K tion mechanism to tablet properties, and various
formulation evaluations. Such studies have also
where a is the angle of repose. The fixed cone allowed for the development of compression pro¬
method establishes the diameter of the cone file references for comparison, the development
base by using a circular dish with sharp edges. of automatic control systems, and the monitor¬
Powder is poured onto the center of the dish ing of tooling wear.32
from a funnel that can be raised vertically until a
maximum cone height, H, is obtained. The re¬
pose angle is calculated as before. In the tilting Manufacture of Granulations
box method, a rectangular boxTs filled with pow¬
der and tipped until the contents begin to slide.
In the revolving cylinder method, a cylinder Dry Manufacturing Methods
with a transparent end is made to revolve hori¬ The manufacture of granulations for tablet
zontally when half filled with powder. The maxi¬ compression may follow one or a combination of
mum angle that the plane of powder makes with three established methods: the dry methods of
the horizontal surface on rotation is taken as the direct compression, compression granulation,
angle of repose. The angle determined by these and wet granulation. Table 11-3 compares the
first three methods is often referred to as the type and number of processing steps commonly

TABLETS *317
required with each technique. A consideration process, fewest processing steps) there are some
of the important aspects of these processes illus¬ limitations to the technique.
trates the advantages and disadvantages of each. 1. Differences in particle size and bulk den¬
Direct Compression. There are a few crys¬ sity between the drug and diluent may lead to
talline substances, such as~sodium chloride, so- stratification within the granulation. The strati¬
dlumjbromide, and potassium chloride, that may fication may then result in poor content uni¬
be~compressed directly, the vast mBoritv of formity of the drug in the compressed tablet.
Tnedlcinal agents are rarely so easy to tablet, The stratification and resultant content uni¬
however. In addition, the compression of a sin¬ formity problems are of special concern with
gle substance may produce tablets that do not low-dose drugs.
disintegrate. If disintegration is a problem, other 2. A large-dose drug may present problems
components are needed, which in turn may in¬ with direct compression if it is not easily com¬
terfere with the compressibility of the active in¬ pressible by itself. To facilitate compression,
gredient and thus minimize the usefulness of noncompressible large-dose drugs, which are
the method. Most materials possess relatively usually restricted to about 30% of a direct com¬
weak intermolecular attraction or are covered pression formula, could require an amount of
with films of adsorbed gases that tend to hinder diluent so large that the resultant tablet is costly
compaction. Thus, most large-dose drugs do not and difficult to swallow.
lend themselves to this process. With many 3. In some instances, the direct compression
other drugs having small doses, uniform blends diluent may interact with the drug. A good ex¬
of the drug and coarser direct compression dilu¬ ample of such a reaction is that which occurs
ents cannot be achieved, which makes this proc¬ between amine compounds and spray-dried lac¬
ess impractical. However, the use of compressi¬ tose, as evidenced by a yellow discoloration.
ble diluents with many moderate-dose drugs 4. Because of the dry nature of direct com¬
makes this process the most streamlined pression, Static charge buildup can occur on the
method of tablet manufacture (Table 11-3). drug during routine screening and mixing,
A directly compressible diluent is an inert which may prevent a uniform distribution of the
substance that may be compacted with little dif¬ drug in the granulation.
ficulty and may compress even when quantities The equipment and procedures used in direct
of drugs are mixed with it. Compression capac¬ compression are basically screening or milling
ity is still maintained when other tablet materi¬ and mixing. These topics are covered in Chapter
als necessary for flow, disintegration, and so 1, “Mixing,” and Chapter 2, “Milling.”
forth are blended in. Directly compressible vehi¬ Compression Granulation. Compression
cles are examined in detail later in this chapter. granulation has been used for many years, and
Direct compression materials, in addition to pos¬ is a valuable technique in situations where the
sessing good flow and compressibility, must be effective dose of a drug is too high for direct
inert, tastejess, reworkable, able to disintegrate, compaction, and the drug is sensitive to heat,
and inexpensive. moisture, or both, which precludes wet granula¬
Even though direct compression has some tion. Many aspirin and vitamin formulations are
important advantages (low labor input, a dry prepared for tabletting by compression granula¬
tion.
Compression granulation involves the com¬
Table 11-3. Processing Steps Commonly Re¬
paction of the components of a tablet formula¬
quired in the Various Tablet Granulation Prepa¬
tion by means of a tablet press or specially de¬
ration Techniques
signed machinery, followed by milling and
Processing Step Wet Dry Direct screening, prior to final compression into a tab¬
let. When the initial blend of powders is forced
Raw material X X X into the dies of a large-capacity tablet press and
Weigh X X X is compacted by means of flat-faced punches,
Screen X X X the compacted masses are called slugs, and the
Mix X X process is referred to as “slugging.” The slugs
Compress (slug) X are then screened or milled to produce a granu¬
Wet mass X lar form of tabletting material, which now flows
Mill X more uniformly than the original powder mix¬
Dry X
ture. When a single slugging process is insuffi¬
Mill X X
cient to confer the desired granular properties to
Mix X X
the material, the slugs are sometimes screened,
Compress X X X
slugged again, and screened once more.

318 • The Tneory and Practice of Industrial Pharmacy

 Slugging is just an elaborate method of sub¬
jecting a material to increased compression
time. The act of slugging followed by screening
and subsequent compression of the particles is
roughly equivalent to an extended dwell time
during compression in a tablet machine. The
two or more times that the material is subjected
to compaction pressures causes a strengthening
of the bonds that hold the tablet together. The
resultant granules also increase the fluidity of
these powder mixtures, which by themselves do
not flow well enough to fill the dies satisfacto¬
rily.
As shown in Table 11-3, the compression
granulation method requires less equipment
and space than other methods, and eliminates
the addition of moisture and the application of
heat, as found in the wet massing and drying
steps of the wet granulation method.
On a large scale, compression granulation can
also be performed on a specially designed ma¬
chine called a roller compactor. Roller compac¬
tors are capable~of~producing as much as 500 kg
per hour or more of compacted ribbon-like mate¬
rial, which can then be screened or milled into a
granulation suitable for compression into tab¬
lets.
Roller compactors, utilize two rollers that re¬
volve toward each other (Fig. 11-13). By means FIG. 11-13. Schematic diagram of a Chilsonator roller
of a hydraulic ram forcing one of the rollers compactor irTa granulation production system. (Courtesy
of the Fitzpatrick Company, Elmhurst, IL.)
against the other, the machine is capable of ex¬
erting known fixed pressures on any powdered
material that flows between the rollers. Pow¬
dered material is fed between the rollers by a changes in the compact. The vertical feed screw
screw conveyor system. After passing through is usually set so that it delivers more material
the rollers, the compacted mass resembles a thin than the compaction rolls accept, assuring con¬
wide ribbon that has fallen apart into large seg¬ stant loading during the compaction process.
ments. These are equivalent to the slugs pro¬ The speed of the compaction rolls controls the
duced by the slugging process. The segments pressure dwell time, which has a great effect on
are then screened or milled for the production of the density and hardness of the compact.
granules. A standard procedure for testing compaction
The compaction force of the roller compactor uniformity and machine capacity is to select a
is controlled by three variables: (1) the hydraulic hydraulic pressure in the mid-ranges of the
pressure exerted on the compaction rolls, (2) the equipment. Set the compaction roll at the slow¬
rotational speed of the compaction rolls, and est speed, and set the feed screw at the highest
(3) the rotational speed of the feed screws. The speed. If the powders are compactible in the first
roll speed and the feed-screw speed have the pass, the machine will overload. When this hap¬
greatest effect on the compaction process. The pens, the compaction roll speed should be in¬
feed screws on most modem compactors consist creased until the loading is constant. Maximum
of a variable-speed horizontal and vertical screw. throughput is achieved at this setting for the
The horizontal screw picks up the powder from material being tested. If no overloading occurs,
the hopper and maintains a continuous flow to the powder should be passed through a second
the vertical screw. The vertical screw delivers time, using the same procedure. The roller com¬
the powder to the compaction rolls. The vertical pactor offers the advantages over the slugging
screw speed is critical for uniform compaction. process of increased production capacity, greater
It serves to deaerate the powder and maintains a control of compaction pressure and dwell time,
constant flow onto the compaction rolls. Any and no need for excessive lubrication of the pow¬
variation in deaeration or load causes extreme der.

TABLETS* 319
 There are many modifications available on roll of time depends on the wetting properties of the
compactors. Roll designs cover a complete range powder mixture and the granulating fluid, and
from smooth to sign curves and serrated sur¬ upon the efficiency of the mixer. A rough way of
faces. The shapes and sizes of the screw feed determining the end point is to press a portion of
assembly are available in a wide range of de¬ the mass in the palm of the hand; if the ball
signs. Most compactors can be fitted with liquid- crumbles under moderate pressure, the mixture
cooled rolls and chambers. All manufacturers of is ready for the next stage in processing, which
roller compactors have pilot plant facilities and is wet screening.
offer complete testing programs. Trial runs are The wet screening process involves convert¬
advisable, so that the compactor is suitable for ing the moist mass into coarse, granular aggre¬
the materials to be compacted. gates by passage through a hammer mill or oscil¬
lating granulator, equipped with screens having
large perforations. The purpose is to further con¬
Wet Granulation solidate granules, increase particle contact
The wet granulation technique uses the same points, and increase surface area to facilitate
preparatory and finishing steps (screening or drying. Overly wet material dries slowly and
milling, and mixing) as the two previously dis¬ forms hard aggregates, which tend to turn to
cussed granulation techniques. The unique por¬ powder during subsequent dry milling. There
tions of wet granulation process involve the wet are many instances in which wet milling may be
massing of the powders, wet sizing or milling, omitted, with a considerable saving of time. The
and drying. The theory, equipment, and meth¬ formulator should be alert to these opportunities
ods associated with drying are discussed in and not follow the old method blindly.
Chapter 3. A drying process is required in all wet granu¬
Methods. Wet granulation forms the gran¬ lation procedures to remove the solvent that was
ules by binding the powders together with an used in forming the aggregates and to reduce
adhesive, instead of by compaction. The wet the moisture content to an optimum level of con¬
granulation technique employs a solution, sus¬ centration within the granules. During drying,
pension, or slurry containing a binder, which is interparticulate bonds result from fusion or re¬
usually added to the powder mixture; however, crystallization and curing of the binding agent,
the binder may be incorporated dry into the pow¬ with van der Waals forces playing a significant
der mix, and the liquid may be added by itself. role.
The method of introducing the binder de¬ After drying, the granulation is screened
pends on its solubility and on the components of again. The size of the screen depends upon the
the mixture. Since, in general, the mass should grinding equipment used and the size of the tab¬
merely be moist rather than wet or pasty, there let to be made.
is a limit to the amount of solvent that may be The use of volatile or inflammable solvents for
employed. Therefore, when only a small quan¬ wet granulation creates other problems. Safety
tity is permissible, the binder is blended in with considerations demand that at a minimum, the
the dry powders initially; when a large quantity work areas be well-ventilated to reduce direct
is required, the binder is usually dissolved in the toxic effects or to keep the solvent vapor concen¬
liquid. The solubility of the binder also has an tration below explosion limits. Also, all equip¬
influence on the choice of methods, since the ment should be electrically grounded to prevent
solution should be fluid enough to disperse sparks that could initiate explosions. Explosion-
readily in the mass. proof or explosion-resistant motors may also be
The liquid plays a key role in the granulation required. If solvent granulating systems are to
process. Liquid bridges are developed between be used, the entire process should be thoroughly
particles, and the tensile strength of these bonds discussed, and the facilities should be inspected
increases as the amount of liquid added is in¬ by the company’s safety engineer.
creased. These surface tension forces and capil¬ Exhausting solvent vapors or drying granula¬
lary pressure are primarily responsible for initial tions made with solvents also requires special
granule formation and strength. Once the gran¬ precautions. Environmental Protection Agency
ulating liquid has been added, mixing continues (EPA) regulations limit the amount of solvent
until a uniform dispersion is attained and all the vapors that can be exhausted into the atmos¬
binder has been activated. During granulation, phere. Such EPA limits could require recovery
particles and agglomerates are subjected to con¬ or burning of the solvent vapors, which axe ex¬
solidating forces by action of machine parts and pensive operations. Ovens employed for drying
of interparticulate forces. Granulation in large granulations wetted with explosive solvents
blenders requires 15 min to an hour. The length should employ high airflow rates, to stay well

320 • The Theory and Practice of Industrial Pharmacy

below vapor explosive limit concentrations in ulating. Examgles_aie_sigmabladeand_planetary
aii. Such ovens should also contain appropriate mixers. Granulating mixers are slow, are gener¬
controls to prevent explosions due to accumula¬ ally poor powder mixers, and require care for
tion of vapors folio .ring a power outage or during even addition of granulating liquids. Also, con¬
later resumption of power. siderable time is needed to distribute the binder
Equipment. When traditional equipment is properly throughout the mass.
used in the conventional wet granulation While some tablets are still made in the tradi¬
scheme (Table 11-4), the entire process is labor- tional manner, newer equipment has been de¬
intensive and time-consuming. The equipment veloped that can accomplish both dry mixing
used for granulation is not highly effective for and wet granulation efficiently and in much less
dry mixing. Therefore, in many instances, a dif¬ time. These new mixers are classified as high¬
ferent mixer is used for dry mixing prior to gran¬ speed mixer/granulators.

Table 11-4. Some Common Tablet Excipients

Diluents

Lactose USP Mannitol USP

Lactose USP. anhydrous Sorbitol
Lactose USP, spray-dried Sucrose USP powder
Directly compressible starches Sucrose-based materials
Hydrolyzed starches Calcium sulfate dihydrate NF
Microcrystalline cellulose NF Dextrose
Other cellulose derivatives
Dibasic calcium phosphate dihydrate NF

Binders and Adhesives

Acacia Starch, pregelatinized

Cellulose derivatives Sodium alginate and alginate
Gelatin derivatives
Glucose Sorbitol
Polyvinylpyrrolidone (PVP) Tragacanth
Starch, paste

Disintegrants

Starch Cellulose derivatives

Starch derivatives Alginates
Clays PVP, cross-linked
Cellulose

Lubricants

Stearic acid Polyethylene glycols

Stearic acid salts Surfactants
Stearic acid derivatives Waxes
Talc

Glidants and Flow Promoters

Silica derivatives
Talc
Cornstarch

Colors, Flavors and Sweeteners

FD & C and D & C dyes and lakes

Spray-dried and other flavors
Natural sweeteners
Artificial sweeteners

TABLETS • 321
 The Littleford Lodige mixer was one of the ized condition and provide a high-volume rate of
first high-shear powder blenders capable of rap¬ transfer of material back and forth across the
idly blending pharmaceutical powders and wet blender. When liquid granulating agents are
massing within the s?me equipment. With some added to dry powders, the liquid enters the
formulations, the equipment may also be capa¬ mixer under pressure through the liquid nozzle
ble of producing agglomerated granular particles immediately above the chopper assembly, or as¬
that are ready for fluid bed or other drying meth¬ semblies, and is immediately dispersed.
ods without further processing. Figure 11-14 il¬ Using this type of high-shear powder mixing
lustrates a conventional Lodige mixer and de¬ equipment, complete mixing may be obtained in
scribes the various assemblies of the unit. The as little as 30 to 60 sec. A temperature rise of 10
unit consists of a horizontal cylindric shell to 15° may be expected if dry blending is contin¬
equipped with a series of plow-shaped mixing ued over a period of 5 to 10 min. When a high¬
tools and one or more high-speed blending chop¬ speed, high-shear mixer of the Litteford Lodige
per assemblies mounted at the rear of the mixer. type is used for wet granulation, the power used
When the chopper blades are operated during by the mixer increases as the powder mass be¬
dry mixing, dry lumps of powder are effectively comes increasingly wet. Power usage is often
dispersed so that sieving is no longer an essen¬ reflected in the readings of an ammeter or watt¬
tial prerequisite of powder blending when this meter mounted on the equipment and may be
type of equipment is employed. For the addition useful in helping to identify the proper end point
of liquids, an injection tube terminating in one for the wet granulation process.
or more spray nozzles is provided. The nozzles The Diosna mixer/granulator is another type
are located immediately above the chopper as¬ of high-speed powder mixer and processor (Fig.
sembly. 11-15). The mixer utilizes a bowl (1) mounted in
In operation, the plow-shaped mixing tools the vertical position. A high-speed mixer blade
may be revolved at variable speeds to maintain (2) revolves around the bottom of the bowl. The
the contents of the mixer in an essentially fluid¬ blade fits over a pin bar at the bottom of the mix-

UTTLEFORD

VENT- SAFETY SWITCHES LOADING HOPPER-1 /—LANCE TYPE LIQUID

CONSTRUCTED OF STAINLESS TOTALLY CONSTRUCTED OF) / INJECTORS
STEEL. SUPPLIED WITH EXTENSION STAINLESS STEEL J / COMPLETELY REMOVABLE FOR
AND FILTER BAG <NOT SHOWN) FOR CLEANING
RELEASE OF SEAL PURGE AIR OR
OTHER GASES.

PLOW SHAPED MIXING TOOLS

SANITARY CONSTRUCTED AS ONE •AIR PURGE SEALS
INTEGRAL PART OF WAIMMAFT. [SPLIT GLAND TYPE)
AuwemeacoksTmjcnon- PREVENT CONTAMINATION OF
UflUZMG LARGE RADIUS PRODUCT FROM SEAL AREA BY
FILLETS PROVIDING A POSITIVE INGRESS
OF AIR AT ALL TIMES ALONG THE
SHAFT INTO THE MIXEB, SPLIT
SEAL GLANDS ARE EASILY
SHAFT OR TOOT MOUNTED REMOVABLE TO COMPLETELY
REDUCER EXPOSE INTERIOR GLAND AREA
DRIVEN BY GUARDED V-BELTS FOR INSPECTION AND CLEANING
MOTOR IS T.&FC. OR EXPLOSION
ntoofo&m IARD BEARINGS
FREE SPACE BETWEEN SEAL AND
BEARING PREVENTS PRODUCT
CONTACT WITH BEARINGS. ALSO
MAKES SEALS READILY
ACCESSIBLE FOR INSPECTION AND
MAINTENANCE.

78 P.SJ.G. JACKET
STAINLESS STffL HINGE (HEATING OR COOLING/
WITH NON-LUBRICATED TEFLON DESIGNED AND CONSTRUCTED TO
•CARING ASMC CODE ALL INTERIOR
SURFACES STAINLESS STEEL AND
POLISHED TO A tM FINISH
PRODUCT DISCHARGE-
CONTOURED TO BOTTOM OF
DRUM TO ELIMINATE MAO AREAS REMOVABLE HEAD
AND FOSSIBLE CONTAMINATION

HIGH SPEED CHOPPERS

owe* OPINING CAM-LOCK
LARGE CONTOURED SIDE
OPENING ACCESS -
CLEANOUT DOOR
EXPOSES INTERIOR OF MIXER FOR
INSPECTION AND CLEANING MANUAL OPERATED-
GASKET MATERIAL - t/2" P-GASKET, DISCHARGE
GRAY CLOSEO CELL NEOPRENE PNEUMATIC OPERATED ALSO
(REMOVABLE) AVAILABLE

FIG. 11-14. The Littleford Lodige mixer. (Courtesy of Littleford Brothers, Florence, KY.)

322 • The Theory and Practice of Industrial Pharmacy

 FIG. 11-15. Schematic diagram of the Diosna mixer. (1) Mixer bowl. (2) High-speed mixer blade. (3) High-speed chopper
blade. (4) Pneumatic discharge port. (5) Mixed lid. (6) Exhaust air sleeve. (7) Mixer control panel. (Courtesy of Dierks and
Sohne, Osnabriick, West Germany.)

ing bowl, which powers the blade. The blade is operation, however, is the same as that de¬
specially constructed to discourage material scribed previously for the Diosna mixer.
from getting under it. The mixer also contains a When a high-shear solids mixer is used in a
high-speed chopper blade (3), which functions production operation, mounting the mixer in a
as a lump and agglomerate breaker. A pneu¬ position that allows the bowl from a fluid bed
matic discharge port (4) provides the unit with dryer to be placed under the mixer facilitates
automatic discharge. The unit is provided with a materials transfer. Most fluid bed dryers for pro¬
lid (5) and the larger units employ a counter¬ duction operations have wheeled assemblies to
weight to assist in raising and lowering the lid. facilitate materials transfer to and from the fluid
The lid has three openings: one to accommodate bed unit. Since wet granular material may resist
a spray nozzle, a second larger opening for an air transfer by air conveyor systems such as the
exhaust sleeve (6), and a third opening for a Vacumax, a gravity type of transfer provision
viewing port. The units are also equipped with may be especially helpful. The need to raise the
an ammeter on the control panel, (7) which may equipment to an appropriate working height in
be employed to determine the end point of gran¬ order to discharge directly into a bowl of a fluid
ulation operations. Typical time sequences for bed dryer is not regarded as a major disadvan¬
the use of a Diosna mixer are as follows: mixing, tage, provided that powder can be conveniendy
2 min or less; granulating, 8 min or less; dis¬ charged into the unit when it is in a raised posi¬
charge, 1 min with the discharge capable of tion.
being preset when the pneumatic discharge sys¬ Figure 11-17 illustrates the Gral mixer/
tem is in place. granulator. This equipment is a modification of
Figure 11-16 describes the Littleford MGT the industrial planetary mixers. The difference
mixer/granulator, which has been developed to between the Gral mixer/granulator and a
meet granulation needs more specifically. For standard planetary mixer is that the new unit
comparison, the horizontal configuration of the contains two mixing devices. A large mixing arm
Lodige unit (Fig. 11-15) has been rotated 90° to is shaped to the rounded configuration of the
a vertical configuration, the drum assembly has bowl and provides the large-scale mixing motion
been converted to a bowl assembly, and a dis¬ on the powder. A smaller chopper blade enters
charge port has been added to facilitate empty¬ off-center from the mixing arm and is located
ing and cleaning of the bowl. The principle of above it. The larger mixing blade and a second-

TABLETS • 323

L.
FIG. 11-16. The Littleford MGT mixer-granulator. (1) Bowl. (2) Lid with counter weight. (3) Exhaust sleeve. (4) Dis¬
charge port. (5) Control panel. (Courtesy of Littleford Brothers, Florence, KY.)

ary chopper blade system is therefore similar to necessary with the two previously mentioned
the Lodige and Diosna units previously de¬ high-shear mixers. Another advantage of the
scribed. The difference, however, is that the unit is that the main mixing blade is not a part of
Gral unit has the configuration of a planetary the bowl, thus making cleanup easier. Fluid may
top-entering mixer. The mixing bowl may be be injected into the mixer bowl. The equipment
loaded at floor level, as in Figure 11-17, and is available with time control.
then raised to the mixing position by the hy¬
draulic bowl elevator cradle. The bowl is brought
into contact with a cover providing a tight seal. Tablet Design and Formulation
An advantage of the unit is that it may be dis¬ The three basic methods of tablet manufac¬
charged by its hydraulic port while in the raised ture have been previously detailed, the desirable
position, offering sufficient space for a container properties and required features of granulations
to be placed beneath the discharged port. The and tablets defined, and the interrelationships
entire mixer unit does not have to be elevated to between many of these properties and the proc¬
provide this vertical discharge distance as is essing and machine variables noted. Regardless

324 • The Theory and Practice of Industrial Pharmacy

 perhaps 120 to 700 mg for standard density or¬
ganic materials. By using oval tablets, which
may be easier to swallow, tablets weighing up to
800 mg or more may be produced. Tablet formu¬
lations may contain a diluent for secondary rea¬
sons: to provide better tablet properties such as
improved cohesion, to permit use of direct com¬
pression manufacturing, or to promote flow.
Regardless of why a diluent is selected, dilu¬
ents and all other tablet excipients must meet
certain criteria in the formulation. These in¬
clude the following:

1. They must be non toxic and acceptable to

the regulatory agencies in all countries
where the product is to be marketed.
2. They must be commercially available in an
acceptable grade in all countries where the
product is to be manufactured.
3. Their cost must be acceptably low.
4. They must not be contraindicated by them¬
selves (e.g., sucrose) or because of a compo¬
nent (e.g., sodium) in any segment of the
population.
5. They must be physiologically inert.

FIG. 11-17. The Oral mixer-granulator. (1) Mixing arm. 6. They must be physically and chemically
(2) Bmvl. (3) Chopper blade. (4) Bowl cover. (S) Hydraulic stable by themselves and in combination
discharge port. (6) Mixer control panel. (7) Bowl elevator with the drug(s) and other tablet compo¬
cradle. (Courtesy of Machines Collette, Wheeling, IL.) nents.
7. They must be free of anv unacceptable mi-
of how tablets are manufactured, conventional crobiologicP’loacL^
oral tablets for ingestion usually contain the 8. They must be color-compatible (not produce
same classes of components in addition to the any off-color appearance).
active ingredients, which are one or more agents
functioning as (1) a diluent, (2) a binder or an 9. If the drug product is also classified as a
adhesive, (3) a disintegrant, and (4) a lubricant. food, (certain vitamin products), the diluent
Some tablet formulations may additionally re¬ and other excipients must be approved di¬
quire a flow promoter. Other more optional com¬ rect food additives.
ponents include colorants, and in chewable tab¬ 10. They must have no deleterious effect on the
lets, flavors and sweeteners. All nondrug bioavailability of the drug(s) in the product.
components of a formula are termed excipients.
There are cited cases of pharmaceutical man¬
ufacturers actually producing products in which
Diluents - an excipient reduced the bioavailability of a
Diluents are fillers designed to make up the drug, or in which chemical incompatibilities ex¬
required bulk of the tablet when the drug dosage isted. The former situation occurred with the
itself is inadequate to produce this bulk. The marketing of an antibiotic that utilized a calcium
dose of some drugs is sufficiently high that no salt as the diluent. The tetracycline product
filler is required (e.'g., aspirin and certain antibi¬ made with a calcium phosphate filler had less
otics). Round tablets for ingestion are usually in than half' the bioavailabilitv of the~ standard
a size range of 3/is to Vi inch. Tabiets below Vie product.'5'3 Divalent and trivalent cations form
men may be difficult tor the elderly to handle, insoluble complexes and salts with a number of
and those larger than Vi inch become difficult to amphoteric or acid functionality antibiotics,
swallow. This provides a tablet weight range of which greatly reduces their absorption (which is

TABLETS • 325
 also why milk should not be coadministered lactose are commonly available commercially: a
with these drugs). A classic case of a chemical 60- to 80-mesh (coarse) and an 80- to 100-mesh
incompatibility that went unrecognized for sev¬ (regular) grade. In general, lactose formulations
eral years was the interaction of certain amine show good drug release rates, their granulations
drugs with the commonly used diluent lactose. are readily dried, and the tablet disintegration
in the presence of a metaTstearate lubricant times of lactose tablets are not strongly sensitive
(such as magnesium stearate^ the resulting tab: to variations in tablet hardness. Lactose is a
lets were gradually discolored with time.34-30 low-cost diluent, but it may discolor in the pres¬
TableFformulators should remember that physi¬ ence of amine drug bases or salts of alkaline
cal and chemical interactions between formula¬ compounds.
tion components may be promoted by the inti¬ Spray-dried lactose is one of several diluents
mate contact between potential reactants that now available for direct compression following
are tightly compressed together in a tablet com¬ mixing with the active ingredient, and possibly,
pact. Thus, materials that are capable of forming a disintegrant and a lubricant. If this form of lac¬
a eutectic mixture, for example, may pose no tose is allowed to dry out and the moisture con¬
problem when lobsely packed as a powder in a tent falls below the usual 3% level, the material
capsule, while the same formulation when com¬ loses some of its direct compressional character¬
pressed in a tablet forms a compact that quickly istics. In addition to its direct compression prop¬
softens and becomes unacceptable. erties, spray-dried lactose also has good flow
Table 11-4 lists some of the commonly used characteristics. It can usually be combined with
tablet diluents. Note that several of the diluents as much as 20 to 25% of active ingredient with¬
listed exist as hydrates (dibasic calcium phos- out losing these advantageous features. Spray-
phate and calcium sulfate). Diluents that exist dried lactose is especially prone to darkening in
TnTheir common salt form as hydrates, contain¬ the presence of excess moisture, amines, and
ing appreciable bound water as water of crystal¬ other compounds, owing to the presence of a
lization, may nevertheless be excellent for very furaldehyde. A neutral or acid lubricant should
water-sensitive drugs, provided that the bound be used whcn sprar-dried Tactose is employed.
water is not released under any elevated storage Starch, which may come from com, wheat or
condition to which the product might be ex¬ potatoes, is occasionally used as a tablet diluent.
posed. Dibasic calcium phosphate and calcium The USP grade of starch, however, has four flow
sulfate 'have the advantages of possessing low and compression characteristics and possesses a
concentrations of unbound moisture and having high typical moisture content of between 11 and
a low afrinity for atmosphcric moisture. These 14%. Specially dried types of starch that have a
‘are^reqlhfedfeatures^ for any excipient material standard moisture level of 2 to 4% are available,
STbe combined with a water-sensitive drug. The but at a premium price. Use of such starches in
bound water of calcium sulfate is not released wet granulation is wasteful since their moisture
until a temperature of approximately 80°C is levels increase to 6 to 8% following moisture
reached. Such bound water is usually unavaila¬ exposure. _
ble for chemical reaction. Such excipients con¬ Various directly compressible starches are
taining tighdy bound water but having a low now available commercially. Sta-Rx 1500 is one
remaining moisture demand may be vasdy su¬ _ such free-flowing, directly compressible starch;
perior to an anhydrous diluent, which has a it may be used as a diluent, binder, and/or disin¬
moderate to high moisture demand. tegrating agent. Since it is self-lubricating, it
Lactose is the first diluent listed in Table 11-4 may be compressed alone, but when combined
because it is still the most widely used diluent in with as little as 5 to 10% of drug, it typically re¬
tablet formulation. Lactose is an excipient that quires addition of a lubricant, and possibly a
has no reaction with most drugs, whether it is flow promoter such as 0.25% of a colloidal sili¬
used in the hydrous or anhydrous form. Anhy¬ cone dioxide. Sta-Rx 1500 contains about 10%
drous lactose has the advantage over lactose in moisture and is reportedly prone to softening
that it does not undergo the Maillard reaction. when combined with excessive amounts (more
WhiclTcan lead to browning and discoloration than 0.5%) of magnesium stearate.
with certain drugs, as’ noted previously. The Two hydrolyzed starches are, Emdex and
anhydrous form, however, picks up moisture .Celutab. which are basically 90 to 92% dextrose
when exposed to elevated humidity. Such tab¬ andjibout.3 to 5% maltose. They are free-flnw-
lets may have to be carefully packaged to pre¬ mg and directly compressible. These materials
vent moisture exposure. When a wet granula¬ TnavTie~7ised in-pjace of-mannitol in chewable
tion process is employed, the hydrous form of taBleti because of their sweetness and smooth
lactose should generally be used. Two grades of -TeeltngTn^the mouth. These materials contain

326 • The Theory and Practice of Industrial Pharmacy

 about 8 to 10% moisture and may increase in advocated as tablet diluents, those listed in
hardness after compression. Table 11-4 probably represent 80 to 90% of cur¬
Dextrose is also used as a tablet diluent. It is rently used diluents.
available from one supplier under the name
Cerelose and comes in two forms: as a hydrate,
*and in anhydrous form for when low moisture Binders and Adhesives
Contents are required. Dextrose is sometimes These materials are added either dry or in liq¬
combined in formulation to replace some of the uid form during wet granulation to form gran¬
spray-dried lactose, which may reduce the ten¬ ules or to promote cohesive compacts for directly
dency of the resulting tablets to darken. compressed tablets. Acacia and tragacanth are
Mannitol is perhaps the most expensive sugar natural gums (listed in Table 11-4), and are
used as a tablet diluent, hut because of its nega¬ employed in solutions ranging from 10 to 25%
tive heat of solution, its slow solubility, and its concentration, alone or in combination. These
pleasant feeling in the mouth, it is widely used materials are much more effective when they
irrrhewabie tablets. It is "relatively nonhygro- are added as solutions in the preparation of
scopic and can be used in vitamin formulation, granulations than when they are added dry to a
-irrwhich moisture sensitivity may be a problem. direct compression formula. These natural
Mannitol formulations typically have poor flow gums have the disadvantage of being variable in
characteristics and usually require fairly high their composition and performance based on
lubricant levels. their natural origin, and they are usually fairly
Sorbitol is an optical isomer of mannitol and is heavily contaminated with bacteria. When these
sometimes combined in mannitol formulations materials are used, their wet granulation masses
to reduce diluent cost: however, sorbitol is hy¬ should be quickly dried at a temperature above
groscopic at humidities above 65%. Both of 37° to reduce microbial proliferation.
these sugars have a low caloric content and are Gelatin is a natural protein and is sometimes
noncariogenic. used in combination with acacia. It is a more
Sucrose, or sugar, and various sucrose-based consistent material than the two natural gums,
diluents are employed in tablet making. Some is easier to prepare in solution form, and forms
manufacturers avoid their use in products that tablets equally as hard as acacia or tragacanth.
would subject a diabetic to multiple gram quan¬ Starch paste has historically been one of the
tities of sugar. Some of the sucrose-based dilu¬ most common granulating agents. It is prepared
ents have such tradenames as Sugartab (DO to by dispersing starch into water, which is then
&37o sucrose plus 7 to 10% invert sugar), DiPac heated for some prescribed time. During the
(97% sucrose plus 3% modified dextrins), and heating, the starch undergoes hydrolysis to
TSlu lab (9U% sucrose and 4% invert sugar with dextrin and to glucose. A properly made paste is
a small amount of com starch and magnesium translucent rather than clear (which would indi¬
stearate). All of these diluents are available for cate virtually complete conversion to glucose)
direct compression, and some are also employed, and produces cohesive tablets that readily disin¬
with or without mannitol, in chewable tablets. tegrate when properly formulated. Liquid glu¬
All have a tendency to pick up moisture when cose. which is a 50% solution in water, is a fairly
exposed to elevated humidity. common wet granulating agent. Its properties
Microcrystalline cellulose, often referred to by are similar to those of sucrose solutions, which
the tradename Avicel, is a direct compression are commonly employed in concentrations be¬
material. Two tablet grades exist: PH 101 (pow¬ tween 50 and 74%. These sugar solutions are
der) and PH 102 (granules). The flow properties capable of producing wet granulations, which
of the material are generally good, and the direct when tabletted, produce hard but somewhat
compression characteristics are excellent. This brittle compacts. These materials have the ad¬
is a somewhat unique diluent in that while pro¬ vantage of being low-cost adhesives. Unless the
ducing cohesive compacts, the material also acts sugar solutions are highly concentrated, bacte¬
as a disintegrating agent. It is, however, a rela¬ rial proliferation may be a problem.
tively expensive material when used as a diluent Modified natural polymers, such as the algi¬
in high concentration and is thus typically com¬ nates and cellulose derivatives (methylcellulose,
bined with other materials. As in the case of Hrydroxypropyl melhylcellulose, and hydroxyp'ro-
starch, microcrystaUine cellulose is often added pyl cellulose), are common binders and adEe-
to tablet formulation for several possible func¬ sives. Used dry for direct compression, they
tions. It is a commonly employed excipient. have some binder capabilities, while their aque¬
While a careful search of the literature reveals ous solutions have adhesive properties. Hydroxy-
over 50 chemicals that have been evaluated and propyl cellulose may also be used as an alcohol

TABLETS • 327
solution to provide an anhydrous adhesive. bricant, with some glidant properties as well.
Ethylcellulose may be used only as an alcoholic The differentiation between these terms is as
solution, and it may~5e~expected to retard disin¬ follows: Lubricants are intended to reduce the
tegration and dissolution time of drugs in the friction during tablet ejectioffbetween the walls
resulting tablets when wet granulation is em¬ of the tablet and the walls of the die cavity in
ployed. Pplyyinylpyrrolidone-4s a synthetic poly- which the tablet was formed. Antiadherents-
mer that mav be used as an adhesive in either have the purpose of reducing sticking or adher
an aqueous solution or alcohol. It also has some ston ot any of the tablet granulation or powder to
capaBiEties as a drv binder. the faces ot the ]punches or to the die wall.
Glidants are intenc ed to promote flow of the tab-
let granulation or powder materials by reducing
Disintegrants friction between the particles. •
A disintegrant is added to most tablet formula¬ In addition to the lubricants listed in Table
tions to facilitate a breakup or disintegration of 11-4, hydrocarbon oils such as mineral oil have
the tablet when it contacts water in the gastroin¬ been employed by application to granulation as a
testinal tract. Disintegrants may function by fine spray, either directly or in a solvent solu¬
drawing water into the tablet, swelling, and tion. The problem with using this type of lubri¬
causing the tablet to burst apart. Such tablet cant is the production of oil spots. The most
fragmentation may be critical to the subsequent widely used lubricants have been stearic acid
dissolution of the drug and to the attainment of and various stearic acid salts and derivatives.
satisfactory drug bioavailability. Starch USP and Calcium and magnesium stearate are the most
various starch derivatives are the most common common salts employed. Stearic acid is a less
disintegrating agents. They also have the lowest effectiveTubricant than these salts and also has
cost. Starch is typically used in a concentration a lower melting point. Talc is probably the sec¬
range'oF5 to 20% of tablet weight. Such modi¬ ond most commonly used tablet lubricant, his-
fied starches as Primogel and~Explotab, which Tnricaily. Most talc samples are found to contain
are low substitutedcarboxyimethyl starches, are trace quantities of iron, and talc should be con¬
used in lower concentrations (1 to 8%, with 4% sidered carefully in any formulation containing
usually reported as optimum). Various pre¬ a drug whose breakdown is catalyzed by the
gelatinized starches are also employed as disin¬ presence of iron. The higher-molecular-weight
tegrants, usually in a 5% concentration. polyethylene glycols and certain polymeric sur¬
Clays such as Veegum HV and bentonite have factants have been used as water-soluble lubri-
been used as disintegrants at about a 10% level. cants. These materials are much less effective as
Such use of these materials is limited unless the lubricants, however, than the materials previ¬
tablets are colored, since the clays produce an ously cited. Since lubrication is basically a coat¬
off-white appearance. The clays are typically ing process, the finer the particle size of the lu¬
less effective as disintegrants than some of the bricant, the more effective the lubricant action is
newer modified polymers and starches, which likely to be.
can increase in volume in the presence of water As previously noted, most of the materials
by 200 to 500%. The disintegrating characteris¬ listed as lubricants, with the possible exception
tics of microcrystalline cellulose have been re¬ of those that are water-soluble, also function as
ported previously in this chapter; however, in antiadherents. Talc, magnesium stearate, and
the cellulose class, a new material known as starch as well as starch derivatives possess an¬
Ac-Di-Sol is now available and is effective in low tiadherent properties. In addition, various colloi¬
concentration levels, iris ah internally cross- dal silicas have been used as antiadherents.
linked form of sodium carboxymethylcellulose. Materials used as glidants, or flow promoters,
Another cross-linked polymer that is available as are typically talc at a 5% concentration, com
a disintegrant is cross-linked polyvinylpyrroli¬ starch at a 5 to 10% concentration, or colloidal
done. silicas such as Cab-O-Sil, Syloid, or Aerosil in
0.25 to 3% concentrations.

Lubricants, Antiadherents, and

Colors, Flavors and Sweeteners
Glidants The use of colors and dyes in tablet making
These three classes of materials are typically has served three purposes over the years: dis¬
described together because they have overlap¬ guising of off-color drugs, product identification,
ping functions. A material that is primarily de¬ and production of a more elegant product. With
scribed as an antiadherent is typically also a lu¬ the continual decertification of many synthetic

328 • The Theory and Practice of Industrial Pharmacy

 dyes, pharmaceutical manufacturers are becom¬ Examples of tablet formulations are shown in
ing quite concerned as to how future tablet for¬ the Appendices to this chapter. Not only do the
mulations will be colored. The availability of nat¬ formulations illustrate the use of common in¬
ural vegetable colors is limited, and these colors gredients, but they also illustrate the use of the
are often unstable. Two forms of color have typi¬ ingredients in tablets to be made by wet granula¬
cally been used in tablet preparation. These are tion, dry granulation, and direct compression
the FD&C and D&C dyes—which are applied as processes.
solutions, typically in the granulating agent— It has previously been noted that while the
and the lake forms of these dyes. Lakes are dyes excipients are the inactive part of a tablet formu¬
that have been absorbed on a hydrous oxide and lation, they have a direct influence on the qual¬
usually are employed as drv powders for color¬ ity and effectiveness of the final product. Figure
ing. In addition to concerns regarding possible 11-18 describes, for example, the influence of
delisting in the future, several other precautions compression force on disintegration time for var¬
should be considered when colors are employed. ious direct compression materials. Some materi¬
When using water-soluble dyes, pastel shades als have a maximum disintegration time of no
usually show the least mottling from uneven higher than 200 to 250 sec, regardless of the
distribution in the final tablet. When wet granu¬ compression force applied over the range stud¬
lation is employed, care should be taken to pre¬ ied. One material rapidly increased in disinte¬
vent color migration during drying. In any col¬ gration time to over 500 sec at a compression
ored tablet, the formulation should be checked force of less than 1000 kg. Similar relationships
for resistance to color changes on exposure to between important tablet properties and pro¬
light. Various artificial light sources are available cessing characteristics can be shown for many
that simulate the ultraviolet spectrum of sun¬ other tablet excipients.
light. Methods of quantifying color are given ear¬ Another important consideration that many
lier in the chapter under the heading, “Organo¬ pharmaceutical formulators must consider in
leptic Properties.” tablet formulation is the worldwide acceptability
Flavors are usually limited to chewable tablets of. their formulation components. An excipient
or other tablets intended to dissolve in the used in the United States, for example, may not
mouth. In general, flavors that are water-soluble be permitted in a major market area such as
have found little acceptance in tablet making Japan or Europe, or vice-versa. Companies with
because of their poor stability. Flavor oils are major international markets strive to have tablet
added to tablet granulations in solvents, are dis¬ formulations that are equally acceptable around
persed on clays and other absorbents, or are the world and that contain components that are
emulsified in aqueous granulating agents. Vari¬ not likely to be delisted in any country.
ous dry flavors for use in pharmaceutical prod¬
ucts are also available from flavor suppliers.
Usually, the maximum amount of oil that can be Types and Classes of Tablets
added to a granulation without influencing its Tablets are classified by their route of admin¬
tabletting characteristics is 0.5 to 0.75%. istration or function, by tlie type of drug delivery
The use of sweeteners is primarily limited to system they represent within that route, and by
chewable tablets to exclude or limit the use of their form and method of manufacture. Table
sugar in the tablets. Various sugars used as tab¬ 11-5 lists the various classes of tablets, with the
let excipients have been described earlier. Man¬ primary classification being the route of admin¬
nitol is reportedly about 72% as sweet as su¬ istration or function.
crose. Until recendy, saccharin was the only
artificial sweetener available. This material is
about 500 times sweeter than sucrose. Its major
Tablets Ingested Orally
disadvantages are that it has a bitter aftertaste Well over 90% of the tablets manufactured
and has been reported to be carcinogenic. A new today are ingested orally. Orally ingested tablets
artificial sweetener that is expected to largely axe designed to be swallowed intact, with the
replace saccharin is aspartame. The primary dis¬ exception of chewable tablets.
advantage of aspartame is its lack of stability in Compressed Tablets or Standard Com¬
the presence of moisture. When aspartame is pressed Tablets. This category refers to stan¬
used in a formulation, e.g., a chewable tablet dard uncoated tablets made by compression and
with hygroscopic components, it will be neces¬ employing any of the three basic methods of
sary to determine its stability under conditions manufacture: wet granulation, double compac¬
in which the product can adsorb atmospheric tion, or direct compression. Tablets in this cate¬
moisture. gory are usually intended to provide rapid disin-

TABLETS • 329
FIG. 11-18. Disintegration time vs. applied force for tablets prepared from various direct compression diluents. (Re¬
printed from Banker, G. S., Peck, G. E., and Baley, G.: Tablet formulation and design. In Pharmaceutical Dosage Forms:
Tablets. Vol. 1. Edited by H. Lieberman and L. Lachman. Marcel Dekker, New York, 1980, p. 75, by courtesy of Marcel
Dekker, Inc.)

tegration and drug release. Most tablets drugs designed to produce systemic effects. As
containing drugs intended to exert a local effect the solubility of the drug decreases, especially
m the gastrointestinal tract are of this tvoe. with acidic drug moieties that are absorbed best
These drugs are typically water-insoluble and in the upper GI tract, rapid tablet disintegration
include such therapeutic categories as the ant¬ becomes increasingly important, even critical,
acids and adsorbents. Other drugs in this group for this tablet category.
are intended to produce a systemic effect. These Multiple Compressed Tablets. There are
drugs have some aqueous solubility, dissolve two classes of multiple compressed tablets: lay¬
from the tablet and disintegrated tablet frag¬ ered tablets and compression-coated tablets.
ments in GI contents, and are then absorbed and Both types may be either two-component or
distributed in the body. As described earlier in three-component systems: two- or three-layer
this chapter, proper disintegration of the tablet tablets, a tablet within a tablet, or a tablet within
and deaggregation of the tablet fragments or a tablet within a tablet. Both types of tablets usu¬
granular particles are often critical to the proper ally undergo a light compression as each compo¬
performance of the dosage form. The locally act¬ nent is laid down, with the main compression
ing drugs mentioned perform in accordance being the final one. Tablet machine production
with their state of deaggregation, since adsorb¬ speeds for multiple compressed tablets are ap¬
ents and antacids both involve surface activity preciably slower than for standard compressed
that increases as their surface area increases. tablets, especially in the case of compression-
Dissolution is also a surface-related phenome¬ coated tablets.
non, with dissolution rates increasing as a drug’s Tablets in this category are usually prepared
surface area is increased. Thus, tablet breakup for one of two reasons: to separate physically or
and particle deaggregation is also important for chemically incompatible ingredients, or to pro-

330 • The Theory and Practice of Industrial Pharmacy

Table 11-5. Types and Classes of Tablets relatively few repeat-action or controlled-release
products using this approach are marketed.
Oral Tablets for Ingestion Repeat-Action Tablets. The mode of opera¬
Compressed tablets or standard compressed tablets (CT)
tion of repeat-action tablets, and their hmita-
Multiple compressed tablets (MCT) tions based on uncontrolled and unpredictable
Layered tablets gastric emptying, have just been mentioned. In
Compression-coated tablets addition to multiple compressed tablets being
Repeat-action tablets used for this effect, sugar-coated tablets may
Delayed-action and enteric coated tablets also be employed. The core tablet is usually
Sugar- and chocolate-coated Tablets coated with shellac or an enteric polymer so that
Film-coated tablets it will not release its drug load in the stomach.
Chewable tablets The second dose of drug is then added in the
sugar coating, either in solution in the sugar
Tablets Used in the Oral Cavity syrup or as a part of the dusting powder added
for rapid coat buildup. More uniform drug addi¬
Buccal tablets
tion occurs if the drug is in solution or fine sus¬
Sublingual tablets
Troches and lozenges
pension in the sugar solution, especially if an
Dental cones automated-spray sugar-coating operation is
employed. Even so, the coating operation will
Tablets Administered by Other Routes probably require interruption one or more times
while the partially coated tablets are assayed to
Implantation tablets establish that the correct amount of drug has
Vaginal tablets
been applied in the coating.
Tablets Used to Prepare Solutions
Delayed-Action and Enteric Coated
Tablets. The delayed-action tablet dosage form
Effervescent tablets is intended to release a drug after some time
Dispensing tablets (DT) delay, or after the tablet has passed through one
Hypodermic tablets (HT) part of the GI tract into another. The enteric
Tablet triturates (TT) coated tablet is the most common example of a
delayed-action tablet product. All enteric coated
tablets (which remain intact in the stomach but
duce repeat-action or prolonged-action products. quickly release in the upper intestine) are a type
In some cases, a two-layer tablet may provide of delaved-action tablet. Not all delayed-action
adequate surface separation of reactive ingredi¬ tablets are'entenc or are intended to produce the
ents; if complete physical separation is required enteric effect. In veterinary product develop¬
for stability purposes, the three-layer tablet may ment, tablets may be designed to pass through
be employed. TTie layered tablet is preferred to the stomach (or several stomachs) of an animal
the compression-coated tablet; surface contact or through all or most of the small intestine be¬
between layers is lessened, and production is fore releasing—or even into the cecum or large
simpler and more rapid. bowel, as in the case of treating worm parasites
Multiple compressed tablets readily lend located in this lower region. In a human drug
themselves to repeat-action products, wherein application, a product may be designed to pass
one layer of the layered tablet or the outer tablet through the stomach intact and then release
of the compression-coated tablet provides the gradually for several hours or longer in the intes¬
initial dose, rapidly disintegrating in the stom¬ tines.
ach. The other layer or the inner tablet is formu¬ The compendial specifications for an enteric
lated with components that are insoluble in gas¬ coated tablet are that all of the six tablets placed
tric media but are released in the intestinal in separate tubes of the USP disintegration ap¬
environment. The shortcoming of this category paratus (using discs) remain intact after 3Q min
of dosage form for repeat-action products is that of exposure in simulated gastric fluid at
its performance is highly dependent on gastric 37°C±2°C and then disintegrate within the
emptying. If the second layer or core tablet ~TIme~ specifjed~foFTHat product’s monograph.
quickly leaves the stomach following release of plus 30 min. If one or two tablets fail to disinte¬
the initial fast-release dose, an entirely different grate completely in the intestinal fluid, the test
blood level profile results than if there is a sev¬ is repeated on 12 additional^tablets; not less than
eral-hour or longer delay before the second frac¬ 16 of the total 18 tablets tested must disintegrate
tion is emptied. It is probably for this reason that completely. Prior to gastric exposure, the tablets

TABLETS *331
 niiiiuica. same disadvantage. Their primary historical role
The coatings that are used today to produce was to produce an elegant, glossy, easy-to-swal-
enteric effects are primarily mixed acid func¬ low tablet dosage form. Also, they permit separa¬
tionality and acid ester functionality synthetic or tion of incompatible ingredients between coat¬
modified natural polymers. Cellulose acetate ing and core, and this fact has been widely
^ phthalate has the longest history of use as an utilized in preparing many multivitamin and
enteric coating. More recently, polyvinyl acetate multivitamin mineral combinations. The proc¬
phthalate and "HycTroxypropyl methylcellulose ess as originally developed was time-consuming
' phthalate have' come into use. All three poly- and required skilled coating artisans to be con¬
mers have the common feature of containing the ducted properly. Earlier sugar coatings typically
dicarboxylic acid, phthalic acid, in partially es- doubled tablet weight. Today, water-soluble pol¬
terfied form. These polymers, being acid esters, ymers are often incorporated in the sugar solu¬
are insoluble in gastric media that have a pH of tion, automated-spray coating equipment is
up to about 4; they are intended to hydrate and employed, and high-drying-efficiency side-
begin dissolving as the tablets leave the stom¬ vented coating pans are used. The result is that
ach, enter the duodenum (pH of 4 to 6), and the coatings are more elastic and mechanically
move further along the small intestine, where stable, coat weight may be 50% or less of the
the pH increases to a range of 7 to 8. The pri¬ core weight, and the process may be completed
mary mechanism by which these polymers lose in a day or less.
their film integrity, thereby admitting intestinal Film-Coated Tablets. Film-coated tablets
fluid and releasing drug, is ionization of the re¬ were developed as an alternative procedure to
sidual carboxyl groups on the chain and subse¬ the preparation of coated tablets in which drug
quent hydration. The presence of esterases in was not required in the coating. The initial film-
the intestinal fluid that break down .ester link¬ coating compositions employed one or more pol¬
ages of the polymer chains may also play some ymers, which usually included a plasticizer for
role, as may surface activity effects of bile salts the polymer and possibly a surfactant to facili¬
and other components in bile that enter the tate spreading, all delivered to the tablets in so¬
upper small intestine via the bile duct. lution from an organic solvent. The film-coating
Enteric coatings are employed for a number of process was an attractive tablet coating method
therapeutic, safety, and medical reasons. Some since it permitted the completion of the tablet
drugs are irritating when directly exposed to the coating operation in a period of one or two hours.
gastric mucosa, including aspirin and strong An airless spray coating procedure was typically
electrolytes such as NH„C1. While for most peo¬ employed for such film-coating compositions,
ple the occasional aspirin tablet may not cause using either conventional coating pans or side-
irritation, those on daily doses of aspirin, such as vented equipment. During the decade of the
arthritics, may find gastric upset a major prob¬ 1970s, several factors began to make solvent-
lem. Enteric coating is one method of reducing based film coating less attractive. These factors
or eliminating irritation from such drugs. There were the increase in cost of the organic solvents,
are other drugs that if released in the stomach OSHA restrictions on worker exposure to solvent
may produce nausea and vomiting/The low pH vapors, and EPA limitations on solvent vapor
of the stomach destroys otRer dru gs (for exam¬ discharge to the atmosphere. As a result of these
ple. ervthromvcinY and hence enteric coating influences, many companies have now con¬
may be necessary to bring the drug through that verted their earlier film-coating process to a
environment to the more neutral intestinal con¬ totally aqueous-based procedure. Polymers such
tents. Yet another reason for enteric coating may as hvdroxvpropyl cellulose and hvdroxvpropvl
be the desire to release the drug undiluted and methylcellulose, which are dissolved in water
in the highest concentration possible within the wifh an appropriate plasticizer, are now widely
intestine. (Examples are intestinal antibacterial used to produce immediate-release film coat¬
or antiseptic agents and intestinal vermifuges.) ings. The recent development of a colloidal dis¬
As in the case of repeat-action-and other con- persion of ethylcellulose in water also makes it
trolled-release dosage forms, the influence of possible to produce slow- or controlled-release
altering the release profile of the drug on total film coatings without the use of organic sol¬
drug bioavailability, distribution, and pharmaco¬ vents. _A_30%_ethylcellulose_disperaonJsjnar-
kinetics must be investigated. keted under the trade name Aquacoat bv the
Sugar- and Chocolate-Coated Tablets. FMC Corporation
Chocolate-coated tablets are nearly a thing of Film-coated tablets offer a number of advan¬
the past. They are too easily mistaken for candy tages over sugar-coated tablets. These advan-

332 • The Theory and Practice of Industrial Pharmacy

 _C----- an^Ug.U.1 U1 LUC xeis). urugs administered by this route are in¬
coating based on the elasticity and flexibility of tended to produce systemic drug effects, and
the polymer coating, little increase in tablet consequently, they must have good absorption
weight, the ability to retain debossed markings properties through the oral mucosa. Drug ab¬
oh~aTabIet-through the thin film coating, the' sorption from the oral mucosa into the blood¬
: avoidance of sugar, which is contraindicated in stream leads direcdy to the general circulation.
the diets of a significant segment of the popula¬ Drug absorption from the gastrointestinal tract
tion, and the employment of a process that may leads to the mesenteric circulation, which con¬
be continuous, or that readily lends itself to au¬ nects directly to the liver via the portal vein.
tomation. The primary disadvantage of film Thus, drug absorption from the oral cavity
coating compared with sugar coating is that it is avoids first-pass metabolism. The oral route of
difficult to produce film-coated tablets that administration from these two classes of tablet
match the physical appearance and elegance of dosage form thus offers several possible advan¬
thejsugancdated product. Film coating in the tages: The gastric environment, where decom¬
future will assume increasing importance as a position may be extensive (for certain steroids
means of controlling drug delivery release rates and hormones), may be avoided for drugs that
from both tablets and bead particles as well as are well absorbed in the mouth. A more rapid
from drug crystals. Film-coated tablets, which onset of drug action occurs than for tablets that
are basically tasteless, also offer the advantage are swallowed (an advantage with vasodilators
over sugar-coated tablets of being less likely to given by this route). The first-pass effect may be
be mistaken for candy. avoided as noted previously, and for certain
Chewable Tablets. Chewable tablets are drugs (e.g., methvltestosteronei. the nausea pro¬
intended to be chewed in the mouth prior to duced when the product is swallowed is avoided.
swallowing and are not intended to be swallowed Buccal and sublingual tablets should be for¬
intact. The purpose of the chewable tablet is to mulated with bland excipients, which do not
provide a unit dosage form of medication which’’ stimulate salivation. This reduces the fraction of
can be easily administered to infants and chil¬ the drug that is swallowed rather than being
dren or to the elderly, who may have difficulty absorbed through the oral mucosa. In addition,
swallowing a tablet intact. The types of sugars these tablets should be designed not to disinte¬
and other components employed in chewable grate but to slowly dissolv^/typically over a 15-
tablets have been designated in this chapter tcTBOTmn period, tolrrovideTbr effective absorp¬
trader the heading “Table Design and Formula- tion.
tion.” The most common chewable tablet on the ""Troches and Lozenges. These are two
market is the chewable aspirin tablet intended other types of tablets used in the oral cavity,
for use in children. Bitter or foul-tasting drugs where they are intended to exert a local effect in
are not good candidates for this type of tablet, the mouth or throat. These tablet forms are com¬
and this fact restricts the use of the chewable monly used to treat sore throat or to control
tablet dosage form. Many antacid tablet products coughing in the common cold. They may con¬
are of the chewable type. The chewable tablet tain local anesthetics, various antiseptic and
offers two major advantages to the delivery of a antibacterial agents, demulcents, astringents,
solid antacid dosage form. First, the dose of most and antitussives. Lozenges were originally
antacids is large, so that the typical antacid tab¬ termed pastilles, but are more commonly called
let would be too large to swallow. Second, as cough drops. They are usually made with the
noted previously, the activity of an antacid is re- drug incorporated in a flavored hard-candy
^ lated to its particle size. It the tablet is chewed sugar base. Lozenges may be made by compres¬
^ pnoFTo swallowing, better acid neutralization sion but are usually formed by fusion or by a
may be possible from a given antacid dose. candy-molding process. Troches, on the other
hand, are manufactured by compression as are
other tablets. These two classes of tablets are
Tablets Used in the Oral Cavity designed not to disintegrate in the mouth but to
Buccal and Sublingual Tablets. These two dissolve or slowly erode over a period of perhaps
classes of tablets are intended to be held in the 30 min or less.
mouth, where they release their drug contents Dental Cones. Dental cones are a relatively
for absorption directly through the oral mucosa. minor tablet form that are designed to be placed
These tablets are usually small and somewhat in the empty socket remaining following a tooth
flat, and are intended to be held between the extraction. Their usual purpose is to prevent the
cheek and teeth or in the cheek pouch (buccal multiplication of bacteria in the socket following
tablets), or beneath the tongue (sublingual tab- such extraction by employing a slow-releasing

TABLETS • 333
antibacterial compound, or to reduce bleeding favorable to the action of a given antiseptic
by containing an astringent or coagulant. The agent. The buffer pH, however, should not be
usual vehicle of these' tablets is sodium bicar¬ greatly removed from physiologic pH. The vehi¬
bonate, sodium chloride, or an amino acid. The cle of these tablets is typically a slowly soluble
tablet should not be formulated with a compo- material similar to agents described for the prep¬
nent that might provide media for bacterial pro¬ aration of buccal and sublingual tablets. The
liferation. The tablet should be formulated to tablets should be designed to be compatible with
dissolve or erode slowly in the presence of a some type of plastic tube inserter, which is usu¬
small volume of serum or fluid, over a 20- to ally employed to place the tablet in the upper
40-min period, when loosely packed in the ex¬ region of the vaginal tract.
traction site.

Tablets Used to Prepare Solutions

Tablets Administered by Other Effervescent Tablets. Effervescent tablets
are designed to produce a solution rapidly with
Routes the simultaneous release of carbon dioxide. The
Implantation Tablets. Implantation or tablets are typically prepared by compressing the
depot tablets are designed for subcutaneous im- active ingredients with mixtures of organic
plantation in animals or man. Their purpose is acids—such as citric acid or tartaric acid—and
to provide prolonged drug effects, ranging from sodium bicarbonate. When such a tablet is
one month to a year. They are~usuallv designed chopped into a glass of water, a chemical reac¬
to provide as constant a drug delivery release tion is initiated between the acid and the sodium
rate as possible. These tablets are usually small. bicarbonate to form the sodium salt of the acid,
cylindric, or rosette-shaped forms and are typi¬ and to produce carbon dioxide and water. The
cally not more than 8 mm in length. Since there reaction is quite rapid and is usually completed
areTwo major safety problems with this form of within one minute or less. In addition to having
drug administration, this class of dosage form the capability of producing clear solutions, such
has achieved little use in humans. The safety tablets also produce a pleasandy flavored car¬
problems include the need for a surgical tech¬ bonated drink, which assists in masking the
nique to discontinue therapy, and tissue toxicity taste of certain drugs. For many years, various
problems in the area of the implantation site. A saline cathartics were prepared as effervescent
special injector utilizing a hollow needle and mixtures and powders. The most widely pro¬
plunger (the Kern injector) may be used to ad¬ duced effervescent tablet today is one that con¬
minister rod-shaped tablets. Surgical techniques tains aspirin. If a clear solution is to be pro¬
may be required for administering tablets of duced, the drug that is incorporated in the tablet
other shapes. Implantation tablets have been must be soluble at a neutral or slightly alkaline
largely replaced by other dosage forms, such as pH, and any lubricant or other additive em¬
diffusion-controlled silicone tubes filled with ployed to facilitate tablet compression must be
drug ofTiiodegradable polymers that contain en¬ water-soluble.
trapped drug in a variety of forms. The primary The advantage of the effervescent tablet as a
application of current implantation tablets and dosage form is that it provides a means of extem¬
depot forms is to the administration of growth poraneously preparing a solution containing an
hormones to food-producing animals. In this accurate drug dose. As in the case of aspirin, this
case, the implant or depot should be made in an dosage form may provide other advantages as
animal structure that is not consumed. The ear well. The solution produced by the most widely
of the animal is typically used, and appropriate marketed effervescent aspirin tablet has a pH of
drug release to the animal from the ear site must about 8. If the volume of the solution and the pH
be achieved. of the solution are adequate to raise the gastric
Vaginal Tablets. Vaginal tablets or inserts contents to neutral or near-netural pH, the aspi¬
are designed to undergo slow dissolution and rin remains in solution and is rapidly available
drug release in the vaginal cavity. The tablets upon emptying from the stomach. Some litera¬
are typically ovoid or pear-shaped to facilitate ture has been published to indicate that this
retention in the vagina. This tablet form is used form of aspirin is less irritating to the stomach
to release antibacterial agents, antiseptics, or mucosa. In addition, neutralization of gastric
astringents to treat vaginal infections, or possi¬ contents may be rapidly obtained from solutions
bly to release steroids for systemic absorption. of this type of tablet. The product does, however,
The tablets are often buffered to promote a pH represent a “systemic” antacid effect, with an

334 • The Theory and Practice of Industrial Pharmacy

appreciable dose of sodium or potassium, and water of known quality to produce sterile solu¬
thus does not represent a recommended method tions. Another difficulty with dispensing tablets
of producing routine gastric neutralization. is that some of the components previously used
The disadvantage of the effervescent tablet, in this dosage form are highly toxic and are ex¬
and one reason for its somewhat limited utiliza¬ tremely hazardous, and even lethal, if mistak¬
tion, is related to the difficulty of producing a enly swallowed. Great care must be taken in the
chemically stable product. Even the moisture in packaging and labeling of such tablets to attempt
the air during product preparation may be ade¬ to prevent their oral consumption. In the past,
quate to initiate effervescent reactivity. During bichloride of mercury was usually prepared in
the course of the reaction, water is liberated coffin-shaped tablets, with an embossed skull
from the bicarbonate, which autocatalyzes the and crossbones to emphasize its toxicity.
reaction. Providing adequate protection of effer¬ Hypodermic tablets (HT). Hypodermic
vescent tablets in the hands of the consumer is tablets are composed of one or more drugs with
another problem. The moisture to which tablets other readily water-soluble ingredients and are
are exposed after opening the container can also intended to be added to sterile water or water for
result in a rapid loss of product quality in the injection. Such extemporaneous preparation of
hands of the consumer. It is for this reason that an injectable solution was once widely used in
effervescent tablets are specially packaged in medicine, because the physician, especially the
hermetic-type foil pouches or are stack-packed rural physician, could carry many vials of such
in cylindric tubes with minimal air space. An¬ tablets in his bag with only one bottle of sterile
other reason for such packing is the fact that the water for injection, to prepare a great many
tablets are usually compressed to be soft enough types of injectable medications as the need
to produce an effervescent reaction that is ade¬ arose. Hypodermic tablets are little used today in
quately rapid. this country because their use increases the
A number of investigators have looked at alter¬ likelihood of administering a nonsterile solution,
native effervescent components in recent years even though portable sterile filtration equip¬
in an attempt to produce a more chemically ment exists to help assure the sterility and free¬
stable system. Such studies have included in¬ dom from particulate matter in such a product.
vestigation of malic acid, fumaric acid, and vari¬ Furthermore, since physicians today practice
ous acid anyhdrides, in combination with newer most of their medicine from an office or a hospi¬
carbonate sources such as sodium glycine car¬ tal, the advantage of portability of tablets for in¬
bonate and various sesquicarbonates. If, in the jection is far outweighed by the hazards and dis¬
future, more chemically stable effervescent mix¬ advantages of this dosage form in most medical
tures are identified that continue to provide situations.
rapid reactivity in water, the effervescent tablet Tablet Triturates (TT). Tablet triturates
system may expand as a method of producing are small, usually cylindric, molded, or com¬
extemporaneous drug-containing solutions. pressed tablets. Though rarely_used today, they
Dispensing Tablets (DT). Dispensing tab¬ provided an extemporaneous method of prepara¬
lets are intended to be added to a given volume tion by the pharmacist. The drugs employed in
of water by the pharmacist or the consumer, to such products were usually quite potent and
produce a solution of a given drug concentra¬ were mixed with lactose and possibly a binder,
tion. Materials that have been commonly incor- such as powdered acacia, after which the mix¬
porateffirTdispensihg ta"Blets include mild silver ture was moistened to produce a moldable, com-
protemate, bichloride of mercury, merbromin, pactable mass. This mass was forced into the
and quaternary ammonium compounds. The holes of a mold board fabricated from wood or
dispensing tablet must typically comprise totally plastic, after which the tablets were ejected
soluble components, and the excipient ingredi¬ using a pegboard, whose pegs matched the holes
ents of the tablet must not produce deleterious in the mold. The tablets were then allowed to dry
effects in the intended application of the solu¬ and were available for dispensing. Since virtu¬
tion or undesirable physical or chemical interac¬ ally every conceivable drug that would be useful
tions with the active agent. In some cases, as in in a tablet dosage form is available in that form,
applications where the solution is to be used in or in capsule form, there is virtually ho need
contact with mucous membranes or on wounds, today for pharmacists to prepare tablets extem¬
the tablet may also contain components to pro¬ poraneously. Since in preparing this form of
vide buffering or isotonicity. Dispensing tablets molded tablet, alcohol was commonly used to
are less commonly used than formerly, since wet the powder mass to expedite drying of the
they cannot be employed on a routine basis with tablets, tablet triturates were usually soft and

TABLETS • 335
quite friable. Many of the drugs employed in available, as noted in the previous section on
these tablets were highly potent, and drug mi¬ tablet design and formulation. A number of
gration could occur as the alcohol evaporated, so these newer excipient materials are polymeric,
content uniformity of such tablets was often such as the cross-linked form of carhoxymethyl-
questionable. Because of these problems and the cellulose. which is sold under the trade name
question of producing bioavailable dosage forms AtxDi-SoI. IFis predicted that the majority of the
from such extemporaneous preparations, the new future excipients will be polymers, based on
tablet triturate is rarely seen today. their ability to produce a wide range of materials
and properties according to molecular structural
alterations. The majority of these polymer deriv¬
Future Trends atives are of natural origin, based on their better
regulatory approval status.
Coatings. Solvent-based film coating will
Formulation and Product Trends continue to decline, based on high solvent costs
Uncoated Tablets. Future design, formula¬ and EPA and OSHA restrictions. They will be
tion, and manufacture of conventional uncoated virtually replaced by completely water-based
tablets will follow the existing trend to more effi¬ systems. Polymer solutions in water may be
cient processing, combining or eliminating proc¬ used to produce water-soluble film coatings.
essing steps where possible, reducing handling, Colloidal dispersions of polymers (such as the
reducing processing variables, minimizing pro¬ ■$0% ethylcellulose dispersion marketed as
duction time, and further reducing total produc¬ Aquacoat), which produce dense films by parti-
tion costs. Where possible, direct compression cie coalescence, not only will make the forma¬
will continue to expand as a preferred method of tion of water-soluble film coating a highly effi¬
tablet manufacture, and new and improved ex¬ cient process, (virtually equal to earlier
cipient materials that are especially compatible solvent-based methods), but will show the way
with direct compression and extend its utility, to produce totally water-based enteric and sus¬
reliability, or simplicity as a process will find tained-release coatings. Side-vented coating
favor in pharmaceutical solid dosage form devel¬ pans, and pan designs with improved drying ef¬
opment. Where direct compression is not the ficiencies will virtually replace the conventional
process of choice, use of^high-shear mixer/ solid-pan design. Improved methods of fabricat¬
granulators will continue to expand, followed by ing small spherical drug-containing particles
efficient and rapid fluid-bed drying of the ag¬ will continue to develop, as will more reproduci¬
glomerates. More progressive companies wil- ble methods of coating such particles. Air sus¬
loptimize formulations andprocessing conditions pension coating will continue to play a role in
to produce the highest-quality agglomerates coating such small particles; it is not likely that
(granulations) at the lowest cost, employing re¬ air suspension coating will grow appreciably as a
gression and other mathematical approaches. tablet coating method.
Optimizing binder efficiency and processing Controlled-Release Tablets. Theoretically,
conditions for reliable production of consistent tablets offer the lowest-cost approach to sus¬
agglomerates in a single high-shear mixer/ tained- and controlled-release solid dosage
granulator will be a major goal in such studies. forms. Currently, the vast majority of such prod¬
Automation and computer control will rapidly ucts are coated pellets placed in capsules. This
expand in monitoring and controlling tablet pro¬ particulate approach to sustained release has
duction operations and entire tablet production offered several advantages: metered particle
facilities. Some type of continuous system to emptying from the stomach, utilization of a plu¬
monitor tablet weight, utilizing instrumented rality of coatings, and several release profiles for
tablet presses or high-speed electro-balances the various populations of coatings, thereby per¬
tied in to press operation, will become routine mitting an immediate release fraction followed
good manufacturing practice for high-speed by a sustaining fraction. Matrix slow-releasing
tablet production. tablets cannot match these characteristics. For
Excipient Materials. New and improved this reason, and based on public expectations (or
excipients will continue to be developed to meet those of marketing specialists) that controlled-
the needs of advancing tablet manufacturing release products are expected to be beads in a
technology. In recent years, new improved dis- capsule, relatively few ‘sustained-release oral
integrants have been marketed that are ex¬ products have been in tablet form.
tremely efficient in lower concentrations, and A major recent break in that trend is the
that have good compressional properties. New highly successful sustained-release theophylline
direct compression diluents have also become product of Key PharmaceuticalsT~Inc.. Theo-

336 • The Theory and Practice of Industrial Pharmacy

Dur. This is a unique type of sustained-release constant drug release rate profiles as the tablet
Tablet that overcomes some of the limitations of dosage form moves along the GI tract are also
earlier matrix tablets. Under gastric pH condi¬ under active development. Such a system offers
tions, the Theo-Dur tablet slowly erodes; how¬ the potential ultimate dosage form as a simple,
ever, at a pH corresponding to the upper small low-cost, and reproducible physicochemical ap¬
intestine,- the tablet disintegrates rapidly to re¬ proach to oral controlled and sustained drug re¬
lease coated particles, which in turn slowly re¬ lease.
lease drug. Two different release mechanisms
are operative, neither of which is zero-order—
erosion and decreasing surface area, and disso- Manufacturing Improvements
lutionTircoatedparlicles—but the overall tablet Basic Improvement Areas. Wet granula¬
release pFofile comprising the two mechanisms tion has traditionally been a highly labor-inten¬
irfsequence is nearly linear for most of the dose sive and time-consuming process (see Table
in the tablet. The result is the ability to control 11-3). In the last 20 years, however, significant
theophylline blood levels in a narrow range, improvements in tablet manufacturing effi¬
above the minimum effective level and below ciency have taken place. These can be attributed
the toxic level. This type of sustained-release to four basic areas: the elimination or combina¬
tablet has clearly shown the potential of the tab¬ tion of processing steps, the improvement of
let as a reliable sustained-release dosage form specific unit operations, the design of new
with good release profile precision.36®' More equipment specifically oriented to granulation
sustained-release tablet forms of this type are objectives, and the improvement of materials
sure to follow. handling techniques and systems. Illustrating
A prolonged gastric retention coated tablet the use of these improvement areas, Table 11-6
system has been reported.38 The tablet utilizes a compares the processing steps of Lederle’s old
cross-linked polymer coating that has the capac¬ tablet-manufacturing process to its new tablet¬
ity to swell greatly and rapidly in the stomach manufacturing process.
and be restricted there by physical size. Gastric Elimination or Combination of Steps. Ta¬
fluid that penetrates the hydrated swollen film bles 11-3 and 11-6 indicate the processing steps
dissolves the drug within the sac enveloping the that may be omitted on conversion from wet
tablet, and drug is released from solution by dif¬ granulation to direct compression. As noted,
fusion across the hydrated membrane/film. new mixer/granulators allow several processes
Drug release is at a constant rate so long as the of wet granulation to be conducted in rapid suc¬
concentration of drug within the sac exceeds the cession or to be combined in one piece of equip¬
capacity of the membrane to deliver the drug, ment.
and the film/membrane is thus providing the Unit Operation Improvement. The effi¬
rate-limiting step. If the dimension of the fluid- ciency of new tablet manufacturing methods, as
filled sacs exceeds approximately 2 cm, these exemplified by the new process, was achieved by
dosage units consistently remain in the stomach enhancing the efficiency of three specific unit
for at leo„t 6 to 8 hours, releasing drug in solu¬ operations. First, material blending was im¬
tion to the gastric contents at a constant rate. proved by replacing slow-speed planetary type
This gastric retention tablet dosage form reflects mixers with high-speed mixer/granulators. Sec¬
the type of innovation to control not only the rate ond, the tablet compression operation was im¬
of drug release, but also the site of release, that proved by replacing old single-fill-station,
will undoubtedly continue in the years ahead to gravity-fed compression machines with newer
further improve and enhance drug delivery ca¬ high-speed, multi-station presses, with induced
pabilities. die feed and automated weight control. Third,
The Pros product of the Alza Corporation is the coating operation was brought into better
another new zero-order sustained-release tablet compliance with EPA standards by switching
product; it is based on osmotic pressure as the from organic-solvent based systems to aqueous
rate-controlling process. This concept will also systems, which were further aided by side-
expand the use of tablet dosage forms in con¬ vented coating equipment having greatly im¬
trolled release. The first such products are al¬ proved drying efficiencies.
ready being marketed in Europe, and the drug Materials Handling. A major labor-saving
indomethacin is about to be marketed in the change made in equipment designs allowed
United States in an Oros system, at the time of material to be moved by gravity. A granulation
this writing. gravity feed system was designed that elimi¬
Film coatings that may be applied to tablets to nated the manual feeding of granulation into the
provide diffusion-controlled “membranes” for presses.

TABLETS • 337
Table 11-6. Unit Processing of Solid Dosage Forms (Tablet Manufacturing)—Lederle Laboratories
Old Process New Process
(Wet Granulation) (Direct Compression)

Raw Materials Raw materials

Weighing and measuring Weighing and measuring (automatic weigher and recording system)*
Screening Gravity feeding
Manual feeding Blending (Littleford blender)
Blending (slow-speed planetary mixer) Gravity feeding from the storage tank*
Wetting (hand addition) Compression (high-speed rotary press)*
Subdivision (comminutor) Aqueous coating (Hi-Coater)
Drying (fluid bed dryer)
Subdivision (comminutor)
Premixing (barrel roller)
Batching and lubrication (ribbon blender)
Manual feeding
Compression (Stokes rotary press)
Solvent film coating (Wurster column)
Tablet inspection (manual)

*In planning phase, to be installed later.

Courtesy of Lederle Laboratories, Pearl River, NY.

With use of similar techniques, even wet binder, disintegrant, and lubricant may be sus¬
granulation operations have been made more pended and/or dissolved in a suitable vehicle
efficient, and a hypothetical state-of-the-art pro¬ according to their nature. The solids should rep¬
cessing scheme is presented in the flow chart in resent at least 50 to 60% of the suspension.
Figure 11-19. All processing steps including dry¬ Under constant stirring to maintain good distri¬
ing might be combined in a single processor in bution, the slurry is pumped to an atomizing
the wet granulation method of the future. Such wheel, which whirls the material into a stream
equipment will minimize materials handling, of hot air. The heat removes the liquid carrier,
labor requirement, and human variables. and the solids fall to the bottom of the dryer as
Equipment. Various equipment improve¬ fine, spherical granules ranging from as low as
ments that would combine several of the wet 10 to as high as 250 microns in diameter, the
granulation processing steps are being investi¬ size depending on the speed of the wheel and
gated. One such method is the use of the sprayer the flow rate of the feed. The drug may be mixed
dryer. The components of the formula-diluent, with this “base” in proportions as high as 1:1. If

Mix, mass, and Dry

Weigh Load agglomerate (fluid bed
ingredients mixer > ingredients .“L* dryer) Lubricate
Transfer
(high-speed mixer) (gravity)

Compress Drum
(high-speed presses) <■ Transfer- (store)
A

Mix, mass,
Weigh Load agglomerate, dry,
ingredients processor > and lubricate Tiansfer > Compress
(store)

FIG. 11-19. Flaw charts depict state-of-the-art wet granulation processing of the 1980s (A), and projected wet granulation
processing methods of the future—1990 and beyond (B). (Adapted from Anderson, N.R., Banker, G.S., and Peck, G:E.:
Principles of improved tablet production system design. In Pharmaceutical Dosage Forms: Tablets. Vol. 3. Edited by
H. Lieberman and L. Lachman. Marcel Dekker, Inc., New York, 1982, p. 14, by courtesy of Marcel Dekker, Inc.)

338 • The Theory ami Practice of Industrial Pharmacy

the drug remains stable with the temperatures to be processed is shown in the material con¬
and solvents used, it may also be included in the tainer just below the spray inlet. The liquid
slurry. granulating agent is pumped from its container
Fluid Bed Spray Granulators. The first and is sprayed as a fine mist through a spray
equipment reported in the pharmaceutical liter¬ head onto the fluidized powder. The wetted par¬
ature to provide continuous-batch wet granula¬ ticles undergo agglomeration through particle-
tion was fluid bed drying equipment, which was particle contacts. Exhaust filters are mounted
modified by the addition of spray nozzles or fluid above the product retainer to retain dust and
injectors to provide addition of liquid binding fine particles. After appropriate agglomeration is
and adhesive agents to dry-powdered materials achieved, the spray operation is discontinued,
for powder agglomeration, followed by drying in and the material is dried and discharged from
the same equipment. the unit.
Figure 11-20 presents a schematic cross- The advantages of such rapid wet massing,
section of such a fluid bed spray granulator. The agglomeration, and drying within one unit are
airflow necessary for fluidization of these pow¬ obviously attractive. Excluding equipment
ders is generated by a suction fan mounted in cleanup, the process may readily be sequentially
the top portion of the unit, which is directly completed within 60 to 90 min or less.
driven by an electric motor. The air used for flu¬ There are several difficulties in the fluid bed
idization is heated to the desired temperature by spray granulating process. Fluid bed systems
an air heater, after first being drawn through may not provide adequate mixing of powder
prefilters to remove any jmpurities. The material components. In fact, there is a tendency for

FIG. 11-20. Schematic diagram of a fluid bed granulator dryer. (1) Material container. (2) Air suction fan. (3) Fluid spray
head. (4) Inlet air heater. (5) Inlet air filter. (6) Exhaust air filters. (7) Explosion relief panels. (Courtesy ofAeromatic,
lowaco, N].)
demixing to occur when there are disparities in wall construction to provide circulation of a
particle size or density in the materials being heating medium; in other cases, the systems are
processed. Particles with granulating agents on designed to operate at room temperature and
their surfaces tend to stick to the equipment fil¬ use vacuum as the sole source of water or liquid
ters, reducing the effective filter surface area, removal.
causing product loss, and increasing cleanup Figure 11-21 provides a cutaway view of a
difficulties. Special attention is also needed for double-cone mixer-dryer processor. As in any
safety in any fluid bed processor. Dust explo¬ vacuum-drying operation, equipment and dry¬
sions can occur in a fluid bed dryer, with flam¬ ing costs are relatively high. Drying times are
mable solvents or with dry materials that de¬ considerably longer than with the fluid bed
velop static charges, and all production size granulator processor. The double-cone or twin-
fluid bed equipment must contain explosion re¬ shell processor would be considerably easier to
lief panels. clean, however. The attractiveness today of the
Double-Core and Twin-Shell Blenders double-cone or twin-shell mixer, granulator, and
With Liquid Feed and Vacuum-Drying dryer as a continuous-batch processor of wet
Capabilities. A number of manufacturers of granulation products hinges on the use of nona-
both double-cone and twin-shell blenders have queous granulating liquids. Standard auxiliary
produced equipment modifications that provide equipment is available to condense solvent va¬
the potential for sequencing the operations of pors and provide substantially complete solvent
powder mixing, wet massing, agglomeration, recovery. This is important from two stand¬
and drying. The specialized equipment typically points: solvent vapors are not discharged to the
includes a liquid feed through the trunnion of atmosphere, an environmental consideration,
the machine, leading to a spray dispenser lo¬ and efficient solvent recovery is achievable, an
cated above the axis of rotation of the unit; a economic consideration,
vacuum inlet through the same or the opposing Day-Nauta Mixer-Processor. The Nauta
trunnion leading to a vacuum intake port cov¬ mixer is a vertical screw mixer (Fig. 11-22). A
ered by a nylon or other appropriate fine-filter screw assembly is mounted in a conical cham¬
sleeve, which is also located above the axis of ber, with the screw lifting the powder to be
rotation and out of the direct path of powder blended from the bottom to the top. The screw
motion; and agitating elements capable of rota¬ assembly orbits around the conical chamber wall
tion within the powder mass contained in the to ensure more uniform mixing. The Nauta
blender. The blender may also employ a double¬ mixer was originally designed not as a wet gran-

ray head for liquids coating Protective cover for

nylon filter sleeve Flexible connections for
Circulating baffles ^ irculating heating medium
for heating medium
J Flexible connection
Flexible connections for / for vacuum line
irculating heating medium
Flexible connection
for liquid spray

Packing glands

FIG. 11-21. A cutaway view of a double-cone mixer-dryer processor. (Courtesy of Paul 0. Abbe, Little Falls, NJ.)

340 • The Theory and Practice of Industrial Pharmacy

 breaker, which may be attached at the bottom of
the conical chamber; a temperature monitor; a
nuclear, noncontact density gauge; an ammeter
or wattmeter; an infrared moisture analyzer; and
a sampling system.
Topo Granulator. The Topo granulator was
developed in Austria for the preparation of gran¬
ules and coated particles under high vacuum.
The machine is illustrated in Figure 11-23. The
material to be granulated or coated is placed in
the chamber, which may be accomplished by
dust-free suction. A granulating compartment is
then loaded by vacuum, and each granulating
fluid or addition product (liquid or solid) is
added as desired by imploding the added ingred-
ient(s) upon the components already in the
chamber. When granulating agents are thus
added to the chamber under vacuum, the granu¬
lation forces are reportedly greatly increased to
produce the necessary compaction. The resul¬
tant agglomerated particles can then be dried
under vacuum in the chamber. Some of the ad¬
vantages reported for this granulation process
are a reduction in the required volume of granu¬
lating fluid; a unique agglomeration mechanism

FIG. 11-22. Schematic diagram of the Nauta processor.

(1) Screw assembly. (2) Conical chamber. (3) Source of
hot, dry air. Hot air moves up through the material (verti¬
cal arrows), which is kept in motion by the orbiting screw
assembly (circular arrows). (Courtesy of Day Mixing, Cin¬
cinnati, OH.)

ulation mixer-granulator but as a powder and

semisolids mixer. The basic operation following
power mixing includes incorporation of the
liquid-granulating agent, wet massing, and dry¬
ing as hot, dry air is passed through the wet ma¬
terial. The hot air moves up through the mate¬
rial, which is kept in a state of motion by the
orbiting screw assembly. It dries the granulation
and exits the top of the processor. If additional
help is required for particular drying needs, the
Nauta can be constructed to utilize vacuum dry¬
ing. Accessory equipment designed to monitor FIG. 11-23. The Topo granulator. (Courtesy of Machines
and control processor operation includes a lump Collette, Wheeling, IL.)

tablets* 341
 for the granulation process as it occurs under
vacuum; a reduction in the amount of excipient
materials that may be required to produce a sat¬
isfactory granule, owing to the intensified com¬
paction of the granulation process; and genera¬
tion of a granulation that produces tablets of
, exceptional hardness and stability.
By imploding coating materials on existing
granulations, coating within the unit is report¬
edly possible. It has also been reported that by
alternately imploding various drug and excipient
materials, the equipment is capable of effec¬
tively separating incompatible drugs or of pro¬
ducing effervescent products of improved stabil¬
ity to moisture. Unfortunately, little published
scientific or technical information is available
regarding products produced by this equipment.
CF Granulator. The CF granulator utilizes a
cylindric bowl with a rotating base plate (Fig.
11-24). Passing through the space between the
bowl and base pla|e is fluidizing and drying air.
A feeding device feeds powders, granules, or
other solids into the machine. The rotating base
and air form the material into rounded particles,
a doughnut-like ring along the wall of the cham¬
ber, in a twisted-rope motion. While the material
is thus formed, binding or coating solutions and
powders can be sprayed onto the material. Oper¬
ating in this fashion, materials can be granu¬
lated, agglomerated or coated, and dried within a
reasonably limited time. The equipment is also
used to produce spherical beads of drug applied
to sugar beads, which may then be coated in the
equipment for controlled-release purposes.
Computer Process Control. As the tablet
manufacturing processes continue to be im¬
proved in the four areas indicated, human FIG. 11-24. The CF granulator. (Courtesy of Vector
worker involvement will continue to decline. As Corporation, Marion, IA.)
human involvement requirements are reduced,
computer control of the process is inevitable.
There are many good reasons for implementing
computer process control. under computer control with limited human in¬
tervention is possible in a continuous mode.
Rigid control enforcement In the common batch mode of tablet produc¬
tion, individual unit operations such as coating
Operational information processes, fluid bed dryers and tablet press
Documentation of the process monitors are becoming automated by microcom¬
Security of the process and its control puters. There are obstacles to computer control,
including the need for smaller and more power¬
Increased consistency ful computer devices, better process interfacing
Increased flexibility sensors, particularly of the “composition” type,
Increased reliability and better man/machine interfacing. Therefore,
as the price and size of computers continue to
Increased productivity decrease, as the availability of sensors increases,
and as our knowledge of tablet processes in¬
Merck, Sharp and Dohme’s computer-controlled creases, the computer control of tablet, batch
Aldomet plant has shown that tablet production operations will rapidly grow in the future.

342 • The Theory and Practice of Industrial Pharmacy

 Mannitol 180 mg 1.8 kg

Appendices (fine powder)

Polyvinylpyrrolidone
(10% solution)
30 mg 0.3 kg

Appendix A Mix the first four ingredients, and moisten with a 10% PVP
-solution in 50% ethanol. Granulate by passing through a 14-mesh
screen. Dry at 140 to 150T. Size through a 20-mesh screen, a.dd
Common Tablet Ingredients in the oil of peppermint mixed with the Cab-O-Sil and finally the
Wet Granulation Formulas magnesium stearate; mix well and compress using '/2-in. flat-face
beveled-edge punches.
Reprinted from reference 39, p. 109, by courtesy of Marcel Dek-
Phenobarbital Tablets ker, Inc.

Quantity per Quantity per Chewable Laxative Tablets

Ingredient Tablet 10,000 Tablets
Quantity per Quantity per
Phenobarbital 65 mg 650 g Ingredient Tablet 10,000 Tablets
Lactose (fine powder) 40 mg 400 g
Starch (paste) 4 mg 40 g Phenolphthalein 64 mg 0.64 kg
Starch (dry) 10 mg 100 g Powdered sugar 750 mg 7.5 kg
Talc 10 mg 100 g Powdered cocoa (defatted) 350 mg 3.5 kg
Mineral oil, 50 cps 4 mg 40 g Gelatin (10% solution) q.s. q.s.
Calcium stearate 12 mg 0.12 kg
Mix the phenobarbital and lactose, and moisten with 10%
Talc 60 mg 0.60 kg
starch paste to proper wetness. Granulate by passing through a
14-mesh screen, and dry at MOT. When dry, pass through a Mix the phenolphthalein, sugar, and cocoa, and moisten with
20-mesh screen; add the dry starch and talc; mix well. Finally, the gelatin solution. Pass through an 8-mesh screen, and dry in a
add the mineral oil, mix again, and compress using %2-in. stan¬ tray oven at 120 to 130°F. When dry, reduce granule size by pass¬
dard cup punches.
ing through a 16-mesh screen. Mix the calcium stearate and talc,
Reprinted from reference 39, p. 109, by courtesy of Marcel Dek-
pass through a 100-mesh screen, add to the granulation, and com-
ker, Inc.
press to weight using 5/8-in. flat-face punches.
Reprinted from reference 39, p. 109, by courtesy of Marcel Dek-
Aminophylline Tablets ker, Inc.

Quantity per Quantity per Ferrous Sulfate Tablets

Ingredient Tablet 10,000 Tablets
Quantity per Quantity per
Aminophylline 100 mg 1.0 kg Ingredient Tablet 10,000 Tablets
Tricalcium phosphate 50 mg 0.5 kg
Pregelatinized starch 15 mg 0.15 kg Ferrous sulfate (dried) 300 mg 3.0 kg
Water q.s. q.s. Com starch 60 mg 0.60 kg
Talc 30 mg 0.3 kg 20% Sugar solution q.S. q.s.
Mineral oil, light 2 mg 0.02 kg Explotab 45 mg 0.45 kg
Talc 30 mg 0.30 kg
Mix the aminophylline, tricalcium phosphate, and starch;
Magnesium stearate 4 mg 0.04 kg
moisten with water. Pass through a 12-mesh screen, and dry at
100°F. Size the dry granules through a 20-mesh screen; add the Mix the ferrous sulfate and cornstarch; moisten with sugar
talc and mix. Add the mineral oil, mix for 10 min, and compress syrup to granulate through a 12-mesh screen. Dry in a tray oven
using 5/i6-in. deep cup punches for enteric coating. overnight at 140 to 150°F. Size through an 18-mesh screen; add
Reprinted from reference 39, p. 109, by courtesy of Marcel Dek- the Explotab, talc, and magnesium stearate, and compress to
ker, Inc. weight using 3/s-in. deep cup punches in preparation for sugar-
coating.
Chewable Antacid Tablets Reprinted from reference 39, p. 109, by courtesy of Marcel Dek-
ker, Inc.
Quantity per Quantity per
Ingredient Tablet 10,000 Tablets

Aluminum hydroxide 400 mg 4.0 kg

(dried gel)
Magnesium hydroxide 80 mg 0.8 kg
(fine powder)
Sucrose 20 mg 0.2 kg
(confectioner’s)

TABLETS • 343
Appendix B Appendix C

Common Tablet Ingredients in Common Tablet Ingredients in

Dry Granulation Formulas Direct Compression Formulas
Aspirin Tablets (5-Grain) Acetaminophen Tablets (USP)

Quantity per Quantity per Quantity Quantity

Ingredient Tablet 10,000 Tablets per per
Ingredient Tablet 10,000 Tablets
Aspirin (20-mesh) 325.0 mg 3.250 kg
Starch USP (dried 32.5 mg 0.325 kg Acetaminohpen USP 325.00 mg 3.25 kg
Cab-O-Sil 0.1 mg 0.010 kg (granular or
large crystal)*
Combine the aspirin, starch, and Cab-O-Sil, and mix in a P-K
Avicel PH 101 138.35 mg 1.3835 kg
twin-shell blender for 10 min. Compress into slugs using 1-in.
Stearic acid 1.65 mg 0.0165 kg
flat-face punches. Reduce the slugs to granulation by passing
through a 16-mesh screen in a Stokes Oscillating Granulator or (fine powder)
through a Fitzpatrick Mill with a #2B screen, at medium speed,
*If smaller crystalline size acetaminophen is desired to improve
and with knives forward. Transfer the granulation to a tablet ma¬
dissolution, it is necessary to use a higher proportion of Avicel, to
chine hopper, and compress into tablets using l3/a2-in. standard
use PH 102 in place of PH 101, and to use a glidant. All lubricants
concave punches.
should be screened before being added to blender.
Note: All operations should be carried out in a dehumidified
Blend the acetaminophen and Avicel PH 101 for 25 min
area at a relative humidity of less than 30% at 70°F.
Screen in the stearic acid, and blend for an additional 5 min
Reprinted from reference 39, p. 109, by courtesy of Marcel Dek-
Compress tablets using 7/i6-in. standard concave or flat beveled
ker, Inc.
tooling.
Reprinted from reference 39, p. 109, by courtesy of Marcel Dek-
Effervescent Aspirin Tablets (5-Grain) ker Inc.

Quantity Quantity
Vitamin B, Tablets (Thiamine Hydrochloride
per per
USP; 100 mg)
Ingredient Tablet 10,000 Tablets
Quantity Quantity
Sodium bicarbonate 2.050 g 20.500 kg
per per
(fine granular)
Ingredient Tablet 10,000 Tablets
Citric acid (fine granular) 0.520 g 5.200 kg
Fumaric acid (fine granular) 0.305 g 3.050 kg Thiamine hydrochloride 100.00 mg 1.0 kg
Aspirin (20-mesh, granular) 0.325 g 3.250 kg USP
Mix the above ingredients in -a P-K twin-shell blender for Avicel PH 102 83.35 mg 0.8335 kg
20 min; transfer to a tablet machine equipped with l1/}-in. flat- Lactose (anhydrous) 141.65 mg 1.4165 kg
face punches, and compress slugs to approximately %-in. thick. Magnesium stearate 6.65 mg 0.0665 kg
Grind the slugs through a 16-mesh screen. Mix for 5 min in a Cab-O-Sil 1.65 mg 0.0165 kg
twin-shell blender, and compress into tablets using %-in. flat-face
beveled-edge punches. Blend all ingredients except the magnesium stearate for
Note: All operations should be carried out in a dehumidified 25 min. Screen in the magnesium stearate and blend for an addi¬
area at a relative humidity of less than 30% at 70°F. tional 5 min. Compress using 13/32-in. standard concave tooling.
Reprinted from reference 39, p. 109, by courtesy of Marcel Dek- Note: Anhydrous lactose could be replaced with Fast Flo lactose
ker, Inc. with no loss in tablet quality. This would reduce the need for a
glidant (which is probably present in too high a concentration in
most of these formulations). Usually, only 0.25% is necessary to
optimize fluidity.
Reprinted from reference 39, p. 109, by courtesy of Marcel Dek-
ker, Inc.

344 • The Theory and Practice of Industrial Pharmacy

Chlorpromazine Tablets USP (100 mg) 18. Annual Book of ASTM Standards. Part 20. American
Society for Testing and Materials, Philadelphia, 1978,
Quantity Quantity (D775) p. 180, (D880) p. 229, (D999) p. 282.
per per 19. The United States Pharmacopeia XX/National For¬
Ingredient Tablet 10,000 Tablets mulary XV. U. S. Pharmacopeial Convention, Rock¬
ville, MD, 1980, pp. 958, 990.
Chlorpromazine hydro- 100.00 mg 1.0 kg 20. Wagner, J. G.: Biopharmaceutics and Relevant Phar¬
chloride USP macokinetics. Drug Intelligence Publications, Hamil¬
Avicel PH 102 125.00 mg 1.25 kg ton, IL, 1971, p. 64.
Dicalcium phosphate 21. The United States Pharmacopeia XX/National For¬
125.00 mg 1.25 kg
mulary XV. Supplement 3. U.S. Pharmacopeial Con¬
(unmilled) or Emcompress
vention, Rockville, MD, 1982. p. 310.
Cab-O-Sil 1.74 mg 0.0174 kg 22. Tabletting Specification Manui, Industrial Pharma¬
Magnesium stearate 5.25 mg 0.0525 kg ceutical Technology Standard Specifications for
Tabletting Tools. 1981 revision. American Pharma¬
Blend all Ingredients except the magnesium stearate for
ceutical Association, Washington, D.C.
25 min. Screen in the magnesium stearate, and blend for an addi¬
23. Hiestand, E. N.: Paper presented at the International
tional 5 min. Compress into tablets using 1V&t-in. tooling.
Conference on Powder Technology and Pharmacy,
Reprinted from reference 39, p. 109, by courtesy of Marcel Dek-
Basel, Switzerland, 1978.
ker, Inc.
24. White, G.: U.S. Patent 4,157,148 (1979).
25. Fonner, D. E., Anderson, N. R., and Banker, G. S.:
Granulation and tablet characteristics. In Pharma¬
ceutical Dosage Forms: Tablets. Vol. 2. Edited by
References H. Lieberman and L. Lachman. Dekker, New York,
1. Federal Register, 47(Nov. 5):50441, 1982. 1982, p. 202.
2. Fonner, D. E., Buck, J. R. and Banker, G. S.: 26. Marks, A. M., and Sciarra, J. J.: J. Pharm. Sci.,
J. Pharm. Sci„ 59:1578, 1970. 57:497, 1968.
3. Schwartz, J. B.: Optimization techniques in pharma¬ 27. Forlano, A. S., and Chavkin, L.: J. Am. Pharm.
ceutical formulation and processing. In Modem Assoc., Sci. Ed., 49:67, 1960.
Pharmaceutics. Edited by G. Banker and C. Rhodes. 28. Pitkin, C., and Carstensen, J.: J. Pharm. Sci.,
Marcel Dekker, New York, 1978. 62T215 1973.
4 Buck, J. R., Peck, G. E., and Banker, G. S.: Drug De¬ 29. Harwood, C. F., and Pilpel, N.: J. Pharm. Sci., 57:478,
velop. Commun., J;89, 1974/1975. 1968.
5. Meyer, M. C., Slyka, G. W. A., Dann, R. E., and 30. Gold, G., Duvall, R. N., Palarmo, B. J., and Hurtle,
Whyatt, P. L.: J. Pharm. Sci., 63.1693, 1974. R. L.: J. Pharm. Sci., 60:922, 1971.
6. Hiestand, E. N., Well, J. E., Pool, C. B., and Ocks, 31. Fonner, D. E„ Banker, G. S„ and Swarbrick, J.:
J. F.: J. Pharm. Sci., 66:510, 1977. J. Pharm. Sci. 51:181, 1966.
7. Physician’s Desk Reference. 36th Ed. Medical Eco¬ 32. Schwartz, J. B.: Pharm. Tech., 5:102, 1981.
nomics, Oradell, NJ, 1982, p. 403. 33. Boger, W. P., and Gavin, J. J.: New Engl. J. Med.,
8. Matthews, B. A., Matsumota, S., and Shibata, M.: 261:827, 1959.
Drug Dev. Commun., 1:303, 1974/1975. 34. Costello, R., and Mattocks, A.: J. Pharm. Sci., 51:106,
9. Bogdansky, F. M.: J. Pharm. Sci.: 64:323, 1975. 1962.
10. Goodhart, F. W., Everhand, M. E., and Dickcius, 35. Duvall, R. N., et al: J. Pharm. Sci. 54:607, 1965.
D. A.: J. Pharm. Sci., 53:338, 1964. 36. jonkman, J.H.G., Schoenmaker, R., Grunberg, N.,
11. Smith, F. D., and Grosch, D.: U. S. Patent 2,041.869 and DeZeeuw, R.: Intemat. J. Pharm. 8:153, 1981.
(1936). 37. McGinity, J. W., Cameron, C. G., and Cuff, G. W.:
12. Albrecht, R.: U.S. Patent 2,645,936 (1953), Drug Develop, and Ind. Pharm., 9:57, 1983.
13. Michel, F.: U.S. Patent 2,975,630 (1961). 38. Banker, G.: Bioadhesive Polymers for Oral and Rectal
14. Brook, D. B., and Marshall, K. J.: Pharm. Sci., 57:481, Administration in Sumposium Proceedings on
1968. “Emploi des Polymeres dans L’elaboration de Nou-
15. Goodhart, F. W., Draper, J. R., Dancz, D., and velles Formes Medicamenteuses,” p. 129, School of
Ninger, F. C.: J. Pharm. Sci., 62.297, 1973. Pharmacy, University of Geneve, 1980.
16. Newton, J. M., and Stanley, P.: J. Pharm. Pharmacol., 39. Seth, B. B., Bandelin, F. S., and Shangraw, R. F.:
29:4 IP, 1977. Compressed tablets. In Pharmaceutical Dosage
17. Shafer, E. G. E., Wollish, E. G., and Engel, C. E.: Forms: Tablets. Vol. 1. Edited by H. Lieberman and
J. Am. Pharm. Assoc., Sci. Ed., 45:114, 1956. L. Lachman. Marcel Dekker, New York, 1980.

TABLETS • 345
 12

Tablet Coating
JAMES A. SEITZ, SHASHI P. MEHTA, and JAMES L. YEAGER

Historical Perspective papers on the subject were published. The in¬

vention by Dr. Wurster showed the merits of
No discussion on tablet coating would be com¬
plete without a brief historical review of pharma¬ high airflow in the coating process-, and eventu¬
ceutical coating to provide an appropriate per¬ ally, a series of perforated coating pans (Accela-
spective to the evolutions in the coating process Cota,* Hi-Coater,t Dnacoaterj) were developed
that have occurred over the past thousand years. as replacements for the coating pans of the 30s
One of the earliest references to coated solid and 40s (Figs. 12-1, 12-2, and 12-3).
dosage forms appears in early Islamic drug liter¬ In this chapter, the current state of tablet
ature, where coated pills were mentioned by coating and the opportunities for continued im¬
Rhazes (850-923).1 The use of coating on drugs provement are presented.
was probably an adaptation from early food pres¬
ervation methods, and French publications in Tablet Coating Principles
the 1600s described coating as a means of mask¬
ing the taste of medicines. Sugar coating of pills The application of coating to tablets, which is
was developed to a considerable extent by the an additional step in the manufacturing process,
French in the mid-1800s, and patents issued in increases the cost of the product; therefore, the
1837 and 1840 utilized sugar compositions for decision to coat a tablet is usually based on one
coated pills of cubeb and copaiba. Subsequently, or more of the following objectives:
there was rapid acceptance of sugar-coated pills
as the preferred solid dosage form for both pre¬ 1. To mask the taste, odor, or color of the drug.
scription and patent medicines in Europe and 2. To provide physical and chemical protection
the United States. It soon was recognized that for the drug.
quality sugar coating on a large scale could be
3. To control the release of the drug from the
accomplished more readily in coating pans, and
tablet.
several early pharmaceutical companies in the
United States were established, with coated pills 4. To protect the drug from the gastric environ¬
as a major part of their product line. ment of the stomach with an acid-resistant
Except for the substitution of compressed tab¬ enteric coating.
lets for pills, the sugar coating equipment and
5. To incorporate another drug or formula adju¬
process remained essentially unchanged for the
vant in the coating to avoid chemical incom¬
next 75 years. In 1953, a dramatic change was
patibilities or to provide sequential drug re¬
made in tablet coating when Abbott Laboratories
lease.
marketed the first film-coated pharmaceutical
tablet. Concurrently, in the early 1950s, Dr. 6. To improve the pharmaceutical elegance by
Dale Wurster, a professor at the University of use of special colors and contrasting printing.
Wisconsin, patented an air suspension coater
that efficiently applied film coating composi¬
'Thomas Engineering, Hoffman Estates, IL.
tions.2-4 This stimulated renewed interest in f Vector Corporation, Marion, IA.
tablet coating technology, and for the next 12 to + Driam MetaUprodukt GmbH & Co. KG, Eriskirch, West
15 years, several hundred patents and research Germany.

346
FIG. 12-1. Accela-Cota system. (Courtesy of Thomas
Engineering Inc., Hoffman Estates, IL.)

The coating process can best be described by

initially discussing the key factors that it com¬
prises and then showing their complex interac¬
tions. There are three primary components in¬
volved in tablet coating:
FIG. 12-3. Driacoater system.. (Courtesy of Driam
1. Tablet properties. Metallprodukt GmbH & Co. KG, Eriskirch, West Ger¬
many.)
2. Coating process.
Coating equipment.
Parameters of the coating process. discussed in the section entitled “Tablet
Facility and ancillary equipment. Coating Processes.”)
Automation in coating processes.
Tablet Properties. Tablets that are to be
3. Coating compositions. (Specific examples are coated must possess the proper physical charac¬
teristics. In the coating, process, the tablets roE
in' a coating pan or cascade in the air stream of
an air suspension coater as the coating composi¬
tion is applied. To tolerate the intense attrition of
tablets striking other tablets or walls of the coat¬
ing equipment, the tablets must be resistant to
abrasion and chipping. Tablet surfaces that are
brittle, that soften in the presence of heat, or
that are affected by the coating composition tend
to become rough in the early phase of the coat¬
ing process and are unacceptable for film coat¬
ing. Film coatings adhere to all exposed sur¬
faces so that anv surface imperfection is coated
and not eliminated, lhequality of thin film coat-
ings applied to compressed tablets usually de¬
pends much more on the quality of the starting
tablet than on the time at which sugar coatings
are applied. Sugar coatings, with their high sol¬
ids content, dry more slowly and can fill many of
the minor tablet surface imperfections that may
occur in the early phase of the coating process.
In addition to a smooth surface, the physical
FIG. 12-2. Hi-Coater system. (Courtesy of Vector Corpo¬ shape of the tablet is important. When a coating
ration, Marion, IA.) composition is applied to a batch of tablets in a

TABLET COATING • 347

coating pan, the tablet surfaces become covered pan is 8 to 60 inches in diameter and is rotated
with a tacky polymeric film. Before the tablet on its horizontal axis by a motor (Fig. 12-4).
surface dries, the appbed coating changes from Heated air is directed into the pan and onto the
a sticky liquid to a tacky semisolid, and eventu¬ tablet bed surface, and is exhausted by means of
ally to a nontacky dry surface. The tablets must ducts positioned through the front of the pan
be in constant motion during the early drying (Fig. 12-5). Coating solutions are applied to the
phase or tablet agglomeration can occur. The tablets by ladling or spraying the material onto
ideai tablet shape for coating is a sphere, which the rotating tablet bed. Use of atomizing systems
allows tablets to roll freely in the coating pan, to spray the liquid coating material onto the tab¬
with minimal tablet-to-tablet contact. The worst lets produces a faster, more even distribution of
shape is a square flat-faced tablet, in which case the solution or suspension. Spraying can signifi¬
coating materials would collect between the sur¬ cantly reduce drying time between solution ap¬
faces to glue them together, like a stack of plications in sugar coating processes and allows
dominos or poker chips. For this reason, coated for continuous application of the solution in film
tablets have rounded surfaces; the more convex coating.
the surface is, the fewer difficulties will be en¬ A significant improvement in the drying effi¬
countered with tablet agglomeration. ciency of the standard coating pan is achieved
A compressed tablet formulation includes bythe Pellegrini gjn (Fig. 12-61. the immersion-
many ingredients besides the active drug to pro¬ sword (Fig. iz-/i and the immersion-tube sys¬
vide a readily compressible, resilient, and rap¬ tems (Fig. 12-8). The Pellegrini system has a
idly dissolving dosage form. The resulting sur¬ baffled pan and a diffuser that distributes the
face properties of the tablet depend on the drying air uniformly over the tablet bed surface.
chemical nature of the ingredients utilized in Newer models are completely enclosed, which
the formulation. For the coating to adhere to the further increases their drying efficiency and fa¬
tablet, the coating composition must wet the cilitates automated control. With the immer¬
surface. Hydrophobic tablet surfaces are diffi¬ sion-sword system, drying air is introduced
cult to coat with aqueous-based coatings that do through a perforated metal sword device that is
hot wet the surface. The composition of the coat¬ immersed in the tablet bed. The drying air flows
ing formulation can be adjusted, however, upward from the sword through the tablet bed.
through the addition of appropriate surfactants Since the air is more intimately mixed with the
to reduce the surface tension of the coating com¬ wetted tablets, a more efficient drying environ¬
position and improve coating adhesion. ment is provided. Coating solutions are applied
Coating Process. The principles of tablet by an atomized spray system directed to the sur¬
coating are relatively simple. Tablet coating is face of the rotating tablet bed. With the immer¬
the application of a coating composition to a sion-tube system, a tube is immersed in the tab¬
moving bed of tablets with the concurrent use of let bed. The tube delivers the heated air, and a
heated air to facilitate evaporation of the solvent. spray nozzle is built in the tip of the tube. Dur¬
The distribution-of-the-eoating is accomplished ing this operation, the coating solution is applied
by the movement of the tablets either perpendic¬ simultaneously with the heated air from the
ular (coating pan) or vertical fair suspension immersed tube. The drying air flows upward
coater) to the application of the coating composi¬ through the tablet bed and is exhausted by a
tion. conventional duct. Relatively rapid processing
Equipment. Most coating processes use one times have been reported for both film and sugar
of three general types of equipment: (1) the coating with this system.5
standard coating pan, (2) the perforated coating Both the immersion-sword and the immer¬
pan, or (3) the fluidized bed (air suspension) sion-tube systems have been introduced in Eu¬
coater. The general trend has been toward en¬ rope, and they are adaptable to conventional
ergy-efficient, automated systems to shorten the coating pans.
total coating time and reduce operator participa¬ Perforated Pan Systems. In general, all equip¬
tion in the coating process. In addition, several ment of this type consists of a perforated or par¬
pharmaceutical companies have developed their tially perforated drum that is rotated on its hori¬
own coating equipment or made modifications zontal axis in an enclosed housing. In the
in standard equipment to accommodate their Accela-Cota and Hi-Coater systems, drying air is
particular coating processes. Most of the sys¬ directed into the drum, is passed through the
tems, however, are based on three basic designs. tablet bed, and is exhausted through perfora¬
Conventional Pan System. The standard coat¬ tions in the drum (Figs. 12-9 and 12-10). The
ing pan system consists of a circular metal pan Driacoater introduces drying air through hollow
mounted somewhat angularly on a stand. The perforated ribs located on the inside periphery of

348 • The Theory and Practice of Industrial Pharmacy

FIG. 12-4. Standard coating pans. A, B, Pan shapes. C, D, Air sources. (Courtesy of Thomas Engineering Inc., Hoffman
Estates, IL.)

the drum (Fig. 12-11). As the coating pan ro¬ bed and out an exhaust duct; alternatively, with
tates, the ribs dip into the tablet bed, and drying an optional split-chambered plenum, drying air
air passes up through and fluidizes the tablet can be directed in the reverse manner up
bed. Exhaust is from the back of the pan. through the drum perforations for partial fluidi¬
The Glatt coater is the latest perforated pan zation of the tablet bed. Several airflow configu¬
coater to be introduced in the industry (Fig. rations are possible.
12-11 A). In the Glatt coater, drying air can be In all four of these perforated pan systems, the
directed from inside the drum through the tablet coating solution is applied to the surface of the

TABLET COATING • 349

 INLET AIR SUPPLY

INLET AIR SUPPLY

PAN COVER

PERFORATED SWORD

FIG. 12-7. Simplified diagram of Glatt immersion-sword

system.
FIG. 12-5. Diagram of standard coating pans.

rotating bed of tablets through spraying nozzles in the center. The movement of tablets is up¬
that are positioned inside the drum. ward through the center of the chamber. They
Perforated pan coaters are efficient drying sys¬ then fall toward the chamber wall and move
tems with high coating capacity, and can be downward to re-enter the air stream at the bot¬
completely automated for both sugar coating and tom of the chamber. In some units, a smaller
film coating processes. column(s) is used to direct tablet movement
Fluidized Bed (Air Suspension) Systems. Flu¬ within the main column. Coating solutions are
idized bed coaters are also highly efficient drying continuously applied from a spray nozzle located
systems. Fluidization of the tablet mass is at the bottom of the chamber or are sprayed onto
achieved in a columnar chamber by the upward the top of the cascading tablet bed by nozzles
flow of drying air (Figs. 12-12 and 12-13). The located in the upper region of the chamber.
airflow is controlled so that more air enters the Tablet cores that are friable and prone to chip¬
center of the column, causing the tablets to rise ping and edge abrasion may be difficult to coat
even under optimum conditions in the fluidized

FIG. 12-6. Pellegrini pan (enclosed) system. (Courtesy of FIG. 12-8. Diagram of immersion-tube system. (From
Nicomac, Milan, Italy.) Demmer et al.5)

350 • The Theory and Practice of Industrial Pharmacy

 AIR SUPPLY AIR SUPPLY

EXHAUST

SPRAY
PERFORATED COATING PAN
EXHAUST PLENUM

TABLET BED

FIG. 12-9. Simplified diagram of Accela-Cota system.

bed systems, owing to the relatively rough

tablet-to-tablet impact and tablet-chamber con¬
tact.
Spray Application Systems.* The two basic FIG. 12-10. Simplified diagram of Hi-Coater system.
types of systems used to apply a finely divided
(atomized) spray of coating solutions or suspen¬
sions onto tablets are (1) high-pressure, airless inch gauge (psig)) through a small orifice (.009
and (2) low-pressure, air-atomized. The princi¬ inch to .020 inch id) in the fluid nozzle (Fig.
pal difference in the two types is the manner in 12-14), which results in a finely divided spray.
which atomization of the liquid is achieved. The degree of atomization and the spray rate are
In the airless spray system, liquid is pumped controlled by the fluid pressure, orifice size, and
at high pressure (250 to 3000 pounds per square viscosity of the liquid. Because of the small ori¬
fice, suspended solids in the coating composi¬
tion must be finely milled or filtered to prevent
‘Suppliers of spray application systems include (1)
orifice blockage.
Spraying Systems Co., Wheaton, IL; (2) Graco Inc., Min¬
neapolis, MN; (3) Vector Corp., Marion, IA, (4) Binks In the low-pressure air-atomized system, liq¬
Manufacturing Co., Franklin Park, IL; (5) Nordson Corp., uid is pumped through a somewhat larger orifice
Amherst, OH. (0.020 inch to 0.060 inch id) at relatively low

FIG. 12-11. A, Diagram of Driacoater pan. B, Glatt coater. (Courtesy of Glatt Air Techniques Inc., Ramsey, NJ.)

TABLET COATING • 351

 EXHAUST AIR DUCT

COATING CHAMBER

FUNNEL-LIKE MODIFICATION

SUPPORT SCREEN
AIR ATOMIZING NOZZLE
LIQUID FEED FOR NOZZLE
ATOMIZNG AIR SUPPLY
FLUIDIZING AIR SUPPLY

FIG. 12-12. Diagram of a fluidized bed coater.

pressures (5 to 50 psig) (Fig. 12-15). Low-pres¬

sure (10 to 100 psig) air contacts the liquid
stream at the tip of the atomizer, and a finely
divided spray is produced. The degree of atomi¬
zation is controlled by the fluid pressure, fluid
cap orifice, viscosity of the liquid, air pressure,
and air cap design.
Both airless and air atomizing systems can be
used effectively. Originally/airless systems were
primarily used in air suspension coaters, but
now the choice depends on the coating solution
formula and on the process developed for a par¬
ticular product.
Parameters. The following discussion of the
coating process focuses primarily on perforated
coating pans, as they are the most widely used
equipment in the industry. However, the princi¬
ples of the coating pan method are equally appli¬ FIG. 12-13. Fluidized bed coater. (Courtesy of Abbott
Laboratories, North Chicago, IL.)
cable to air suspension coating, with the ex¬
ception that a portion of the air in the air
suspension coater is used to suspend or move
the tablets.
During the coating process, the tablets move
through an application zone in which a portion
of the tablets receive some coating. Outside this
zone, a portion of the applied coating composi¬ FIG. 12-14. Simplified diagram of a high-pressure, air¬
tion may be physically transferred from the less nozzle.
coated tablets to adjacent ones, or even to the
surface of the coating equipment. Most of the
time, the tablets are in a drying mode moving AIR STREAM
away from the application zone and are recycled
repeatedly through the application zone. The LIQUID FEED

coating application and heated airflow can be AIR STREAM

continuous or intermediate, depending on the
coating composition and drying conditions. In a FIG. 12-15. Simplified diagram of a low-pressure, air-
continuous coating operation, the coating opera- atomized nozzle.

352 • The Theory and Practice of Industrial Pharmacy

tion is maintained essentially at equilibrium, essentially removed during the coating process.
where the rate of application of the coating com¬ The inlet air provides the heat to evaporate the
position equals the rate of evaporation of the vol¬ water. The exhaust air becomes cooler and con¬
atile solvents. Deviation from this equilibrium tains more water, owing to the evaporation of the
results in serious coating problems. Mathemati¬ solvent from the coating composition (see pre¬
cal modeling of the aqueous coating process has ceding example). If water is applied to a nonpen¬
been accomplished by Stetsko and associates,6 etrating surface, the relationship between inlet
and by Reiland and associates.7 These basic air (temperature/humidity) and exhaust air at a
studies have formed the basis for the automated given spray rate can be clearly demonstrated.
coating systems described later in the chapter. Tablet surfaces are permeable to the applied
A better appreciation of the balancing act that coating solution, which can cause coating diffi¬
must be maintained in the coating process can culties. Most of the coating composition is sol¬
be visually shown as follows: vent, so that rapid removal is necessary to pre¬
vent adverse effects on tablet integrity; however,
Inlet A(T1( Hj) + Cj(S) + pSAj high temperatures needed to achieve rapid dry¬
ing may be detrimental to the stability of the
—S>A (T2, H2) + C2 + pSA2 Exhaust drug in the tablet and may prevent partial distri¬
bution of the coating that occurs with movement
where A(T, H) is the air capacity, C(S) is the of the tablets outside the application zone. The
coating composition, pSA is the tablet surface drying characteristic of the film must also be
area, and E is the equipment efficiency. considered in determining the rate of applica¬
Air Capacity, A(T, H). This value represents tion. In general, more viscous, aqueous-based
the quantity of water or solvent that can be re¬ coating compositions use movement of the tab¬
moved during the coating process, which de¬ lets outside the application zone to produce par¬
pends on the quantity of air flowing through the tial distribution of the coating; longer drying pe¬
tablet bed (CFM), the temperature of the air (T), riods are required so that intermittent coating
and the quantity of water that the inlet air con¬ application may be used. Thin, rapidly drying
tains (H). This relationship can best be illus¬ formulations dry quickly on the tablet surface,
trated by using a psychrometric chart from an allowing constant application by efficient atomi¬
engineering handbook. The chart graphically zation of the coating solution.
shows the relationship between air tempera¬ Tablet Surface Area, pSA. The quality of the
tures and the quantity of water that air can con¬ tablets needed for coating has already been con¬
tain at various relative humidities (RH). sidered, but the size of the tablet and the pres¬
For example, if the temperature of the inlet air ence of debossed features also affect the coating
is 100°F at about 10% RH it contains 30 g H20 conditions. The total surface area per unit
per pound of dry air. During the coating opera¬ weight decreases significantly from smaller to
tion, water is evaporated from the applied aque¬ larger tablets. Application of a film with the
ous coating solution, and the air temperature same thickness requires correspondingly less
falls. The temperature of the exit air depends on coating composition. For example, when film
the amount of water it contains. If the exit tem¬ coating a small pan load (20 kg) of tablets, a
perature is 75°F, the fall in temperature of 25°F 0.281-inch round convex tablet that has a thick¬
is primarily due to evaporation of water, and the ness of 0.114 inch requires 40% more coating
exit air contains 70 g of H20 per pound of dry air than when the same coating thickness is applied
(about 55% RH). Saturating the exit air yields a to a 0.438-inch round convex tablet of 0.202-
wet bulb temperature of 63.5°F. inch thickness.
Given the operating conditions, it is possible In the coating process, only a portion of the
to know if the application rate is approaching the total surface area (pSA) is coated. The balance
capacity of the drying system. Only a small por¬ consists of partially coated tablets being dried or
tion of the tablet bed (pSA) receives coating at dried tablets to be further coated in the applica¬
any given time; the exit temperature therefore tion zone. Continuous partial coating and recy¬
measures the average of temperature conditions cling eventually results in fully coated tablets.
associated with tablets that are completely dry to The addition of small product identity mark¬
those of tablets partially coated with the coating ings or intagliations further complicates the
composition. coating process. The size of the atomized coating
Coating Composition, C(S). The coating con¬ droplet must be smaller and better controlled as
tains the ingredients that are to be applied on the features to be coated become smaller.
the tablet surface and the solvents, which act as Equipment Efficiency, E. Tablet coaters use
earners for the ingredients. These solvents are the expression “coating efficiency,” a value ob-

TABLET COATING • 353

tained by dividing the net increase in coated tab¬ sion of insoluble solids in the liquid coating mix¬
let weight by the total nonvolatile coating weight ture. Jacketed tanks may be needed for keeping
applied to the tablets. Ideally, 90 to 95% of the some solutions at an elevated temperature.
applied film coating should be on the tablet sur¬ The coating liquid can be supplied to the noz¬
face. Any quantity less than that suggests that zle system of the coating equipment by means of
improvements in the coating operation should portable pressure tanks or various pumping sys¬
be sought. Coating efficiency for conventional tems.
sugar coating is much less, and 60% would be Automation. There is little published infor¬
acceptable. This significant difference in coating mation providing details of automated coating
efficiency between film and sugar coating re¬ processes. A review article by Thomas discusses
lates to the quantity of coating material that col¬ details of a programmable- controller for pan
lects on the pan walls. With an efficient film coating systems. Within the last 6 to 8 years,
coating process, little coating material accumu¬ automation has been achieved in sugar coating
lates on the wall, but with sugar coating, the pan and film coating (nonaqueous and aqueous) sys¬
walls become thickly covered with coating. A tems. Through a series of sensors and regulating
common cause of low film coating efficiency is devices for temperature, airflow, spray rate and
that the application rate is too slow for the coat¬ pan speed, a feedback control of the process is
ing conditions (large tablet surface area, high maintained. Precise automated control of such a
airflow, and high temperature). This results in dynamic process is possible only with the help of
drying part of the coating composition before it the programmable controller. As in all auto¬
reaches the tablet surfaces, so that it is ex¬ mated processes, a manual bypass should be
hausted as dust. built into the system to accommodate any spe¬
Facility and Ancillary Equipment. The cial applications or equipment malfunctions. For
facility required for any coating operation should process automation, the perforated pans are pre¬
be designed to meet the requirements of current ferred over the old conventional coating pans
Good Manufacturing Practices (GMPs) as set because of their better efficiency. Figure 12-16
forth in the latest revision of the Code of Federal represents a completely automated system used
Regulations, Title 21, Part 211. Adequate space for film or sugar coating. As new tablet manufac¬
is needed not only for the coating equipment, turing plants are built by major pharmaceutical
but also for solution preparation and in-process companies, varying degrees of automation are
storage. The specific safety requirement for built into the tablet coating process. These auto¬
coating areas depends on the nature of the sol¬ mated coating systems are either designed by
vent. Where explosive or toxic concentrations of coating equipment manufacturers or developed
organic solvent could occur, during either solu¬ by individual companies and tailored to their
tion preparation or the coating operation, electri¬ specific equipment and/or products. A detailed
cal explosion-proofing and specialized ventila¬ description of such a system is provided by
tion are required. V. Sharma et al.9.
Treatment of the exhaust air from the coating
operation may be desired to recover expensive
organic solvents or to prevent solvents and par¬
ticulate from entering the atmosphere. Local, Tablet Coating Processes
state, and federal Environmental Protection In most cases, the coating process is the last
Agency (EPA) regulations define the limits of critical step in the tablet production cycle. The
organic solvent and particulate allowed in the successful application of the coating solution
atmosphere. formula to a tablet provides the visual character¬
Compliance with the regulations can be ex¬ istics for the product; thus, the quality of the
tremely expensive, and this cost factor should be product may be judged on this final production
considered in developing a new coating. A major step. The type of process chosen depends on the
advantage of totally aqueous-based film coating type of coating that is to be applied, the durabil¬
is that all direct and indirect expenses relating to ity (toughness) of the tablet core, and the eco¬
the purchase, handling, and environmentally nomics of the process. Because of the ever-
acceptable removal, of the organic solvent are increasing cost of energy and labor, the cost of
circumvented. organic solvents, and the associated environ¬
Other equipment is needed to support the mental constraints, the economics of the process
coating operation. Solution preparation requires is receiving greater emphasis. Sugar coating is
tanks, filters, and mixers. A colloid mill or ball still a widely used coating process because of the
mill may be needed for the homogeneous disper¬ excellent tablet appearance it achieves.

354 • The Theory and Practice of Industrial Pharmacy

Sugar Coating The tablet cores preferably have deep convex
surfaces with thin rounded edges to facilitate
The sugar coating process involves several
sugar coating. Since sugar Coating tends to be
steps, the duration of-which ranges from a few
long and vigorous, the cores should be relatively
hours to a few days. A successful product gready
resistant to breakage, chipping, and abrasion.
depends on the skill of the coating operator. This
is especially true in the pan-ladling method, in
which the coating solutions are poured over the Seal Coating^
tablet cores. The operator determines the quan¬ To prevent moisture penetration into the tab¬
tity of solution to add, the method afid rate of let core, a seal coat is applied. This is especially
pouring, when to apply drying air, and how long needed in pan-ladling processes, in which local¬
or how fast the tablets should be tumbled in the ized werwetting of a portion of the tablet bed
pan. Newer techniques utilize spraying systems occurs. Without a seal coat, the overwetted tab¬
and varying degrees of automation to improve lets would absorb excess moisture, leading to
coating efficiency and product uniformity. Re¬ tablet softening or disintegration and affecting
gardless of the methods used, a successful sugar the physical and chemical stability of the fin¬
coating process yields elegant, highly glossed ished product. In spray processes, it is possible
tablets.. to adjust the application of the subcoats and fur¬
The basic sugar coating process involves the ther coats so that localized overwetting does not
following steps: (1) sealing, (2) subcoating, (3) occur. This adjustment thus eliminates the seal
syruping (smoothing), (4) finishing, and (5) pol¬ coating step. Shellac is an effective sealant, but
ishing. tablet disintegration and dissolution times tend

TABLET COATING • 355

 to lengthen on aging because of the polymeriza¬
tion of the shellac, ^ein is an alcohol-soluble
protein derivative from com that has also been
used as an effective sealant. Lengthening disso¬
lution times have not been reported on aging of
zein seal coated tablets.

Subcoating ^
The subcoating is applied to round the edges
<S and build up the tablet size. Sugar coating can
increase the tablet weight by 50 to 100%. The
subcoating step consists of alternately applying a
sticky binder solution to the tablets followed by a
dusting of subcoating powders and then drying.
Subsequent subcoats are applied in the same
manner until the tablet edges have been covered
and the desired thickness is achieved. For spray
processes, a subcoating suspension containing
both the binder and the insoluble powder is
sprayed intermittently on the tablet bed. With
both methods of application, control of the dry¬
ing rate is critical to obtaining a rapid applica¬
tion of the subcoat.

Syrup (Smoothing/Color) Coatings

The purpose of this step is to cover and fill in
<2? the imperfections in the tablet surface caused by
the subcoating step, and to impart the desired FIG. 12-17. Canvas-lined, polishing pan. (Courtesy of
color to the tablet. This step perhaps requires Warner-Lambert Co., Morris Plains, NJ.)
the most skill. The first, syrup coats usually con¬
tain some suspended powders and are called
“grossing syrups.” Dilute colorants can be added tions in the materials and processes are possible;
to this phase to provide a tinted base that facili¬ however, the complexity of the process can be
tates uniform coloring in later steps. In general, appreciated by the following example.
no color is added until the tablets are quite
smooth; prematur(; applicatl()ri to rough tahlets 1. Materials and Equipment
can produce aTnottl&d appearance in the final Coating pans—Stainless steel, 40 inches in
coated"'tablets. In suBsequenTsyruping steps, diameter, with variable speed control; or
syrup solutions containing the dye are applied 48-inch Accela-Cota, with 2 to 3 air atom¬
until the final size and color are achieved. In the izing nozzles. Nozzles should have a fluid
final syruping or finishing step, a few clear coats orifice of .040 to .060 inch. Set atomizing
of syrup may be applied. air to 30 to 40 psig.
N
Tablet cores—55 to 70 kg of 3/8-inch stan¬
Polishing dard convex tablets.
The desired luster is obtained in this final step NOTE: If desired, coating solutions may be
of the sugar coating process. The tablets can be poured or ladled onto the tablets. If this
polished in clean standard coating pans, or method is chosen, apply the solutions in a
canvas-lined polishing pans (Tig. 12-17), by steady flow, with even distribution over
carefullyappjying powdered wax fbeeswax or the rotating tablet bed.
camauba)~or warm solutionsTif these waxes in II. Process
naphtha or other suitable.volatile solvents. A. Seal Coat
1. The specific advantage of using a
Example* spray system described in this exam¬
The basic sugar coating process is illustrated ple is that a faster and more even dis¬
in this example. An infinite number of varia- tribution of the coating materials is
obtained. Start the tablets rolling (pan
*See Table 12-1 for formulations used in this process. speed: 10 rpm). Set supply air to 30°C.

356 • The Theory and Practice of Industrial Pharmacy

Table 12-1. Formulations Usedin Sugar Coating

Seal Coating Solutions Formula Variation

I II

Cellulose acetate phthalate 175 g

Zein -Sr 480 g
Oleic acid, USP 60 g
Propylene glycol, USP 52.5 g
Polyethylene glycol 4000 144 g
Methylene chloride 480 ml 840 ml
Alcohol SD 3A 200-proof q.s. to 2.4 L q.s . to 1.75 L

Subcoating Solutions Formula Variation

I II III IV

Gelatin _ 60 g 5.4 kg 60 g
Acacia- 60 g 2.7 kg 450 g 60 g
Sugar, cane - 1500 g 53.7 kg
Syrup, com 450 g 1500 g
Syrup, USP 3.785 L
Water, distilled 1,0 L 44.3 kg 1.0 L

Subcoating Powders Formula Variation

1 II III IV V VI VII

Kaolin 225 kg
Dextrin 112 kg 185 kg
Cocoa powder 60 kg
Calcium carbonate, pptd 480 kg 7.72 kg
Sugar, cane, powdered 4.1kg 112 kg 240 kg 40 kg 0.9 kg 180 g 8.62 kg
Acacia, powdered 0.12 kg 6 kg lg 0.86 kg
Starch, com 1.35 kg 0.9 kg 60 g
Talc, USP 0.23 kg 1 g
Calcium sulfate, NF 8.62 kg

Syrup Solutions Grossing Syrups Heavy Syrups Regular Syrups

/ II III I II I II

Colorant q.s. ad q.s. ad q.s. ad q.s. ad q.s. ad q.s. ad q.s. ad

Subcoating powder 22.7 kg
Calcium carbonate,
light 7.75 kg 69 g
Sugar, cane, powder 136 kg 22.7 kg 572 g 2.73 kg 181 kg 85 g 1.2 kg
Starch, com 1.36 kg 69 g
Syrup, USP 22.7 L 3.785 L 256 kg
Water, distilled 76 kg 290 ml q.s. 100 ml 1.0 L

Polishing Solutions Formula Variation

I II

Wax, camauba, yellow 0.09 kg 10 g

Beeswax, white 0.09 kg 90 g
Wax, paraffin 0.02 kg
Naphtha 3.785 L 1.0 L
1

TABLET COATING • 357

 Apply 3 applications of zein solution 4. Turn off heat, and reduce inlet and
(see Table 12-1), 800 ml per applica¬ exhaust air.
tion. Allow 15 to 20 min between ap¬ 5. Apply several coats of the regular-
plications to ensure that the tablets are colored syrup solution to achieve a
dry. If tablets become tacky between final smoothness, size, and color de¬
applications, apply just enough talc to velopment.
prevent sticking to the pan and to each 6. Each coat of regular-colored syrup is
other. Make sure that the solution is applied as soon as the tablets exhibit a
well distributed. Additional mixing by slightly frosted appearance. Do not
hand may be necessary to achieve this allow them to become dusty.
if pan design and baffling are ineffi¬ D. Finishing
cient. 1. Make sure that the pan is clean.
B. Subcoat 2. Operate pan with the heat turned off,
Use any of the gelatin/acacia solutions no supply, and greatly reduced ex¬
and subcoating powders listed in haust air. Set pan speed at 12 rpm.
Table 12-1. 3. Apply 3 or 4 coats of regular-colored
1. Turn heat and inlet air off. Use ex¬ syrup rapidly, without permitting the
haust only. Start pan speed at 10 rpm. tablet bed. to frost or become dusty.
2. Apply 3 to 9 coats. Use 1.5 L of warm- 4. The last coats of regular syrup can be
gelatin/acacia solution for the first applied without colorant. This gives
coat. Reduce subsequent amounts “depth” to the color and enhances the
accordingly to obtain the correct thick¬ elegance of the coat.
ness. Be sure that edges are covered. 5. Shut off exhaust air before applying
Thickness is checked volumetrically. the last coat. Apply coat; mix uni¬
3. Allow at least 20 min between coats to formly and shut off pan while the tab¬
permit adequate drying. Be sure the lets are still damp. A quick jog every
solution is rapidly and uniformly dis¬ few minutes prevents sticking. After
persed in the tablet bed. Dust with 15 to 30 min, stop jogging and leave
subcoating powder when tackiness tablets in pan to dry slowly overnight.
develops. Apply subcoating powder E. Polishing
until tablets roll freely and show no Polishing can be done in the same pan as
signs of tackiness. the sugar coating, but better results are
4. After the last coat, jog the pan periodi¬ obtained in canvas-lined pans.
cally for at least 2 to 4 hours to ensure 1. Supply air, exhaust air, and heat
dryness. should be turned off. Pan speed
C. Syrup (Smoothing/Color) Coat 12 rpm.
The syruping coat usually involves three 2. Apply 3 to 4 coats of warm polishing
basic phases: grossing syrup (a syrup so¬ solution, approximately 300 ml per
lution with subcoating powders dispersed application.
in it), heavy syrup, and regular syrup. 3. Let solvent evaporate completely be¬
Apply each step in the sequence outlined. tween coats.
1. Remove excess dust in pan before
starting. Turn on exhaust outlet air. Tablet coatings achieve their luster during the
Set inlet air temperature to provide an polishing phase. In the canvas-lined pans, the
exhaust temperature of 45 to 48°C. Set lining is used to transfer the waxes to the tablet
pan speed at 12 rpm. surface and to provide a buffing action. The wax
2. Apply 5 to 15 coats of the grossing polishing solutions are usually poured onto the
syrup, just enough to wet the entire canvas, and the tablets pick up the wax shine as
bed. Because this solution dries rela¬ they tumble in the pan. The waxes can also be
tively quickly, uniform, rapid distribu¬ dusted onto the tablets. Care must be exercised
tion must be provided. Apply succes¬ to distribute the wax evenly to avoid wax spots
sive amounts of grossing syrup on some tablets. Application of warm air can fa¬
immediately after each preceding ap¬ cilitate distribution.
plication is drying and slightly dusty. The techniques used to obtain the desired
3. Apply several heavy-colored syrup product, especially in the pan-ladling process,
coats in a similar manner until a spe¬ are complex and can only be learned through
cific tablet volume is attained. practice. The beginner is advised to consult

358 • The Theory and Practice of Industrial Pharmacy

the listed literature for specific techniques, ma¬ systems so that the entire width of the tablet bed
terials, and precautions of the sugar coating can be covered by the spray from 2 to 5 nozzles.
processes.10-15 The use of modem efficient
automated systems is rapidly making man¬
ual techniques obsolete. Several automated Process Variables
processes have been described in the litera¬ Whether the coating process is in a conven¬
ture.8,16-18 tional pan system or in one of the perforated pan
Through the addition of cellulosic polymers, systems previously described, certain elements
and other coating ingredients normally associ¬ of the process need to be controlled to ensure
ated with film coating, much thinner sugar coat¬ consistent product quality. The process is as
ings have been attained.19,20 important as the coating solution formulation;
consequently development of a well-defined and
well-controlled process should be a major con¬
Film Coating cern of the formulator.
Since film coating originated from the pan The variables to be controlled in pan-spray
sugar coating era, it is not surprising that the film coating processes are:
film coating process today still contains some of
the process features associated with the early 1. Pan Variables
work. With the possible exception of the air sus¬ pan design/baffling
pension coater, film coating and sugar coating speed
share the same equipment and process parame¬ pan load
ters.
2. Process Air
air quality
Pan-Pour Methods temperature
Pan-pour methods have been used for many airflow rate/volume/balance ^
years for film coating, but they have been sup¬
3. Spray Variables
planted by newer coating techniques that are
spray rate
faster and more reproducible. Coating composi¬
degree of atomization
tions used in the earlier pan-pour methods were
spray pattern
usually too viscous to be sprayed effectively.
nozzle-to-bed distance
Tablets coated by pan-pour methods are sub¬
jected to alternate solution application, mixing
Since each listed variable is important to the
and drying steps similar to pan-pour sugar coat¬
overall success of the coating, further discussion
ing. The method is relatively slow and relies
is warranted.
heavily on the skill and technique of the opera¬
Pan Variables. Pan shape, baffling, rota¬
tor to balance the steps to produce an acceptable
tional speed, and loading all affect the mixing of
product. Tablets that are film coated by pan-pour
the tablet mass. Uniform mixing is essential to
processes almost always require additional dry¬
depositing the same quantity of film on each tab¬
ing steps to remove latent solvents. Aqueous-
let. The tablet coating adds an approximate in¬
based film coatings are not suitable for this
crease in weight of only 2 to 5% to the tablet.
method of application because localized over¬
Unacceptable color uniformity or enteric film
wetting inherent with the pan-pour process
integrity is encountered if the tablets are inade¬
causes numerous problems ranging from sur¬
quately coated because of poor tablet movement
face erosion to product instability due to unac¬
in the coating pan.
ceptably high latent moisture content in the
Tablet shape can also affect mixing. Some tab¬
cores.
let shapes may mix freely while other shapes
may require a specific baffling arrangement to
Pan-Spray Methods ensure adequate mixing. Baffles, however, pro¬
The introduction of spraying equipment was vide a source for chipping and breakage if they
the next evolution in improving the efficiency of are not carefully selected and used. •
film coating processes. Spraying lends versatility Pan speed affects not only mixing, but also the
to the process and allows for automated control velocity at which the tablets pass under the
of liquid application. Spray patterns are selected spray. Speeds that are too slow may cause local¬
to provide a continuous band across the tablet ized overwetting, resulting in the tablets stick¬
bed surface. Broad, flat spray patterns are usu¬ ing to each other or to the pan. Speeds that are
ally chosen by selection of appropriate nozzle too high may not allow enough time for drying

TABLET COATING • 359

before the same tablets are reintroduced to the The relationships between the orifice size, noz¬
spray; again, this results in a rough coating ap¬ zle configuration, fluid pressure, atomizing air
pearance on the tablets. Pan speeds of 10 to pressure, air volume, and fluid viscosity vary
15 rpm are commonly used in the large pan with each coating formulation. Manufacturing
coaters for nonaqueous film coating. Slower pan literature may provide the droplet size range
speeds (3 to 10 rpm) are used for aqueous film expected from a particular nozzle type based on
coating primarily to accommodate shower appli¬ water; however, this type of data is inadequate
cation rate and drying of the coating liquid. Se¬ for optimizing the nozzle performance in rela¬
lection of pan operating conditions depends on tion to the variety of solutions and suspensions
the equipment availability, type of tablets being used to coat tablets.
coated, and the characteristics of the coating so¬ The degree of atomization, at present, can
lution. only be controlled empirically. Adjustments of
Spray Variables. The spray variables to be either the fluid pressure on the airless high-
controlled are the rate of liquid application, the pressure systems or the atomizing air pressure
spray pattern, and the degree of atomization. and air volume on the low-pressure systems
These three variables are interdependent. In the change the degree of atomization. Higher pres¬
airless, high-pressure system, all three variables sures yield greater atomization. Atomization that
are direcdy affected by fluid pressure and nozzle is too fine causes some droplets to dry before
design. In the air-atomized, low-pressure sys¬ reaching the tablet bed. This “spray-drying” ef¬
tem, the rate of liquid flow is most directly af¬ fect can be readily detected as roughness on the
fected by the liquid pressure and liquid orifice tablet surface, especially in intagliations or as
size. The degree of atomization and spray pat¬ excess dust in the pan. Insufficient atomization
tern are most directly affected by atomizing air may result in droplets that are too large reaching
pressure, air volume, and the shape and design the tablet surface and causing localized overwet¬
of the air jets in relation to the fluid stream. ting, which could lead to sticking, picking, or a
The proper rate at which the coating solution rough “orange-peel” effect.
should be applied depends on the mixing and Process Air Variables. The temperature,
drying efficiency of the system, in addition to volume, rate, quality, and balance are parame¬
the coating formula and core characteristics. ters of the process air that need to be controlled
There is a range in which the coating rate must to obtain an optimum drying environment for a
operate to achieve the desired product quality or particular coating process. The sensitivity of the
processing time. Overwetting and underwetting film former and product core to heat largely de¬
must be avoided in all coating operations. termines the upper temperature at which the
A band of spray should be spread evenly over coating process is successful. In general, higher
the tablet mass. In larger pans, more nozzles tablet bed and coating chamber temperatures
must be added to cover the tablet bed width. A are more conducive to rapid solvent evaporation,
spray pattern that is too wide could result in the and consequently to faster coating rate. The lim¬
application of coating directly to the pan surface, its to the air volume and rate depend on the
producing lower coating efficiency and wasted overall design of the air-handling system and
material. If the spray pattern is too narrow, local¬ coating equipment. The upper end of the sys¬
ized overwetting may result, and the tablet-to- tem’s range is used most often. The more effi¬
tablet coating uniformity will be poor. Thus, tab¬ cient the equipment design, the less air volume
lets need to make many more passes through the is needed for drying.
spraying area to be adequately coated. During Supply air should have some degree of dehu¬
the coating operation, the spray width can be midification. Seasonal fluctuations in the mois¬
adjusted by moving the nozzles closer or farther ture content of incoming air can alter coating
away from the tablet bed. In the air-atomized, and drying conditions and possibly have adverse
low-pressure systems, adjusting the air pressure affects on the quality of the coating.
and/or direction accomplishes the same effect. The balance between supply and exhaust air¬
The distance that the nozzle is from the tablet flow should be such that all dust and solvent are
bed affects not only the spray width, but also the contained within the coating system.
quantity of coating applied to individual tablets
per pass under the spray.
Atomization is the process whereby the liquid Fluidized Bed Process
stream is finely subdivided into droplets. The The fluidized bed systems have been success¬
degree of atomization—the size and size distri¬ fully used for rapid coating of tablets, granules,
bution of the droplets—obtained from the spray and capsules. The coating solution formulations
nozzle is not an easily controllable parameter. used with these processes are similar to those

360 • The Theory and Practice of Industrial Pharmacy

used for the pan processes. Since air is used to 2. Turn on heat, drying air, exhaust, and
move the tablets in the coating process, there atomizing air.
are some specific process controls unique to air 3. Intermittently jog the pan while tablets
suspension coaters. axe warming,
The chamber design, together with the proc¬ 4. When exhaust temperature reaches 30°C,
ess air, controls the fluidization pattern. Tablet start spraying.
shape, size, density, and quantity of load affect 5. Apply 3.0 to 4.0 L of color solution at a
the ability of the tablet mass to be fluidized. rate of 70 to lOOml/iinin. Adjust rate
Adequate fluidization and drying depend on downward if tablets become tacky.
the volume and rate of the process air. Control of 6. Apply 1.5 to 2.5 L of clear solution at a
the process air is achieved by adjusting a varia¬ rate of 70 to 100 ml/min. Adjust rate
ble speed blower or by using dampers to keep the downward if tablets become tacky. Allow
tablet mass in a constant “fluid” motion inside tablets to dry in pan with air and heat on
the chamber. Too high an airflow results in ex¬ for 5 to 10 min.
cess tablet attrition and breakage. If the airflow
rate is too low, the mass does not move fast One of the simplest film compositions would
enough through the spray region, and overwet¬ have all of the ingredients solubilized in the sol¬
ting may occur. Fluidization may also be af¬ vents, as in example 1.
fected by the increase in weight or by changes in
the frictional characteristics of the tablets dur¬ Example 1: Hydroxypropyl Methylcellulose
ing coating application. Consequently, periodic Nonaqueous Formula
adjustment of the rate and volume will be neces¬
(This formula can be applied by spraying or
sary to maintain optimum fluidization.
pouring systems.)
During the coating operation, both the inlet
and exhaust air temperatures are monitored. Hydroxypropyl methylcellulose 2910, USP, 15 cps 4%
Evaporation of the solvent causes the exhaust Propylene glycol, USP 1.2%
air temperature to be cooler than the inlet. Any Ethyl alcohol 200-proof 45%
change in the rate of application of the coating Methylene chloride q.s. ad r00%
solution can be monitored by the difference be¬
tween the inlet and exit air temperatures. The polymer is gradually added to the ethyl
alcohol while the solvent is continuously agi¬
Examples - tated. A portion of the methylene chloride is
added to this suspension, to solubilize the poly¬
Representative examples of organic and
mer. The propylene glycol is then added, and the
aqueous-based film coating formulations for use
remainder of the methylene chloride is added to
in laboratory perforated coating pan are pro¬
obtain the proper volume.
vided.
The addition of insoluble colorants, opa-
quants, or flavors requires a milling step to facil¬
I. Materials and Equipment
itate their adequate dispersal.
Standard 24-inch Accela-Cota with 2 baffles.
Spray system—Air-atomized spray nozzle
Example 2: Cellulose Acetate
with a .040-inch fluid orifice and a flat Phthalate/Carbowax Nonaqueous
spray air cap.
Formula
Pumping system—Pressure tanks.
Coating materials—Description to follow (This formula should be poured, or diluted with
(see example 1). appropriate solvents for spraying.) 1 II.
Pan load—12 kg of 1/2-inch standard convex Nonenteric Formula
tablets.
Operating conditions—Set pan speed at 12 Cellulose acetate phthalate, NF 5.0%
to 15 rpm. Adjust supply air temperature Polyethylene glycol 8000, NF ' 15.0%
to give an exhaust air temperature of 30°C Sorbitan monooleate, NF 0.3%
during spray application. Use 40 to 50°C Dye yellow, D&C Lake #5 0.05%
for the aqueous coating systems. Atomiz¬ Titanium dioxide 0.5%
ing air pressure should equal 30 to 50 psig. Vanillin 0.1%
Castor oil 0.25%
II. Process Ethyl alcohol 200-proof 12.0%
1. Load tablets into pan. Attach and adjust Acetone q.s. ad 100.0%
i
the spray nozzle to spray on upper half of
tablet bed. The cellulose acetate phthalate is dissolved in

TABLET COATING • 361

the ethyl alcohol, sorbitan monooleate, and part This solution is prepared in a manner similar
of the acetone. To ensure proper dispersion, the to example 2. The cellulose acetate phthalate is
dye, titanium dioxide, and vanillin are milled in dissolved in solvent mixture, and acetone is
a ball or high-energy mill, or are dispersed in added to obtain the proper volume after polymer
acetone using a colloid mill. After the particle solvation is obtained.
size reduction or dispersion has occurred, the The literature available from pharmaceutical
colorants are added to the solution containing polymer manufacturers provides numerous
the polymer. The polyethylene glycol 8000 is coating formulas utilizing their particular poly¬
melted and added with the castor oil to the poly¬ mers. These formulas require the effective utili¬
mer dispersion. The composition is brought to zation of the favorable properties of the various
proper volume with acetone. This preparation polymers, plasticizers, and additives in the final
must be kept slighdy warm and must be prop¬ coating composition to acquire a quality coated
erly agitated to assure proper distribution of the tablet.
polyethylene glycol 8000 and the colorants in
suspension.
Development of Film Coating
Examples 3, 4, 5, and 6: Cellulose^ Aqueous
Formula
Formulations
The decision to coat a tablet is usually the
(Aqueous systems should be sprayed.)
simplest one in the sequence that converts a
compressed tablet to a coated tablet. The follow¬
3 4 5 6
ing questions must be answered concurrently
Hydroxypropyl with the decision to coat.
methyl-
cellulose
1. What is the purpose of the coating? Is it nec¬
2910, 15 cps 4.0% 2.0% 5.0%
essary to mask objectionable taste, color, or
Hydroxypropyl
odor, or is it necessary to control drug re¬
methyl-
lease?
cellulose,
6 cps 6.0% 4.0% 2. What tablet size, shape, or color constraints
Hydroxypropyl must be placed on the developmental work?
cellulose 1.0%
Propylene In the pharmaceutical industry, the color,
glycol, USP 1.0% 1.0% shape, and size of the final coated tablet is im¬
Polyethylene portant to marketing, and these properties have
glycol 400 0.5% 2.0% 1.0%
a significant influence on the decisions. Quality
Water q.s. 100.0% 100.0% 100.0% 100.0%
assurance is another function that exercises
control over the product appearance. Quality
These polymers are soluble in water. Slowly
assurance personnel evaluate the properties of
add the polymer(s) to vigorously stirred water.
the new product against the characteristics of
Continue the agitation until the polymer(s) are
existing products. In general, companies avoid
solubilized, add propylene glycol or polyethylene
marketing different products with the same ap¬
glycol or both, then bring to proper volume with
pearance. There are a relatively limited number
water. Colorants and pigments may be added
of colors available to the formulator, so that the
after milling or dispersion in water.
product lines of many major pharmaceutical
Cellulose acetate phthalate was the primary
companies contain several coated tablets with
synthetic enteric polymer used in the industry
various shades of red, yellow, green, and blue.
for many years. Now enteric acrylic resins and
Fortunately, tablet sizes and shapes can be eas¬
phthalate derivatives of polyvinyl acetate or hy¬
ily varied; thus, the ability tb select a tablet with
droxypropyl methylcellulose are also available.
a distinctive appearance is unlimited.
Example 7: Cellulose Acetate Phthalate Enteric An experienced formulator usually takes the
Solution pragmatic approach and develops a coating for¬
mulation as a modification of one that has per¬
(This system could be sprayed or poured.)
formed well in the past. The inexperienced
Cellulose acetate phthalate, NF 12.0% coater or the formulator seeking a better coating
Propylene glycol 3.0% system needs to start from a more basic position
Sorbitan monooleate, NF 1.0% and essentially builds his coating composition
Ethyl alcohol 200-proof 45.0% from a primary film former. The effect of the
Acetone q.s. ad 100.0% addition of plasticizers, opaquants, colorants,

362 • The Theory and Practice of Industrial Pharmacy

and the solvent system can then be individually plasticizers or additives is being evaluated. Coat¬
and collectively assessed. ing compositions that yield brittle films must be
Film formulations can be preliminarily plasticized to obtain a more flexible film that is
screened by spraying or casting films. Through acceptable for tablet coating. Tensile-strength
the preparation of a series of films with slight testing is one of the better ways to optimize the
changes in formula ingredients, it is possible to level of additives in the formulation.
eliminate the obvious physical incompatibilities
and poor film combinations rather quickly. One
should recognize that this is only a screening
study. Cast films and sprayed films can have dif¬ Coated Tablet Evaluations
ferent characteristics. In fact, some coating Once the preliminary screening of formula¬
compositions yield poor cast films yet are effec¬ tion variables has been accomplished, the candi¬
tive tablet-coatings. date coating must now be studied under tablet
Cast films can be prepared by spreading the coating conditions. Frequently, these studies are
coating composition on a Teflon, glass, or alumi¬ conducted on placebo tablets or on a group of
num foil surface using a spreading bar to get a placebo tablets with a limited number of drug
uniform film thickness. Many cast films adhere' tablets. The drug tablets must be of essentially
so well to glass that the film cannot be removed the same shape, size, and density as the place¬
intact, but glass is certainly suitable for evaluat¬ bos, so that their patterns of movement in the
ing the appearance of the film. Many investiga¬ coating pan are comparable. Obviously, there
tors who conducted water vapor permeability should be some distinctive tablet feature to per¬
studies prepared their films by pouring their mit separation of the tablets and allow evalua¬
coating composition on mercury in petri dishes. tion of the two coated tablets. The technique of
This is convenient, as the surface area is con¬ coating two different tablets at the same time
stant, and the film can be readily removed from has merit only if the surface properties of the
the liquid surface. two are equivalent. If two formulations, one hav¬
Sprayed films can be obtained by mounting a ing a hydrophilic surface and the other a hydro-
plastic-coated surface in a spray hood or coating phobic surface, are aqueous-coated, the coating
pan. Care must be used in spraying the film to may preferentially adhere to one of the formula¬
obtain a uniform film representative of the type tions.
achieved in tablet coating. Evaluation of the quality of coating on a tablet
The physical appearance of these films can involves studying not only the film per se, but
provide evidence of potential colorant or opa- also the film-tablet surface interactions. A num¬
quant separation. Lack of color uniformity ber of test methods can be employed.
within the film could suggest that the insoluble 1. Adhesion tests with tensile-strength testers
additives have not been properly suspended or have been used to measure the force required to
that some interaction has occurred between the peel the film from the tablet surface.25-2, Rowe
ingredients. In addition, the films can be sub¬ has been a prolific investigator in the area of film
mitted for the following tests. coating evaluation and the factors affecting film
strength.28,29
2. Diametral crushing strength of coated tab¬
Water Vapor Permeability lets can be determined with a tablet hardness
If the coating is going to be used as a seal coat tester. Obviously, the resistance of the uncoated
or to provide some physical protection for a tab¬ tablet to crushing will be a major factor in the
let containing a water-unstable drug, then test results. With this test, one is seeking infor¬
knowledge of the film’s water vapor permea¬ mation on the relative increase in crushing
bility should be assessed. (Detailed descriptions strength provided by the film and the contribu¬
of the test procedure can be found in the litera¬ tion made by changes in the film composition.
ture.21-24) 3. The rate of coated tablet disintegration
and/or dissolution must also be assessed. Unless
the coating is intended to control drug release,
Film Tensile Strength the coating should have a minimal effect on tab¬
Strips of the film are tested on a tensile- let disintegration or dissolution.
strength tester by applying a known force at a 4. Stability studies must be conducted on
constant rate. The elasticity and tensile coated tablets to determine if temperature and
strength/breaking stress of the films are evalu¬ humidity changes will cause film defects. Expo¬
ated. This test is particularly good when the ef¬ sure of coated tablets to elevated humidity and
fect of varying the concentration of a series of measurement of tablet weight gain provide rela-

TABLET COATING • 363

tive information on the protection provided by lar property in free films should always be con¬
the film. firmed by the performance and appearance of
5. Some investigators have attempted to quan¬ the coated tablet.
tify film surface roughness, hardness, and color The literature and patents cite numerous film
uniformity through instrumental means, but in coating compositions. The selection of a specific
general, visual inspection is sufficient to define formulation depends on the coating equipment
relative coated tablet quality. A practical qualita¬ and conditions available, the intended purpose
tive measure of the resistance of a coated tablet of the coating, and total solid load desired in the
to abrasion can be obtained by merely rubbing coating.
the coated tablet on a white sheet of paper. Re¬
silient films remain intact, and no color is trans¬ Materials Used in Film Coating
ferred to the paper; very soft coatings are readily
“erased.” from the tablet surface to the paper. The coating materials may be a physical depo¬
sition of the material on the tablet substrate, or
they may form a continuous film with a wide
Coating Formula Optimization variety of properties depending upon the compo¬
sition of the coating formulations. Examples of
Optimization is usually associated with minor
physical deposition of the coating materials are
modifications in a basic formula. As discussed
the techniques of sugar,1011 shellac,30 and wax
earlier, the basic or starting formula is obtained
coatings.31 During the last 40 years, a wide vari¬
from past experience or from various sources in
ety of polymers have been evaluated and are
the literature. Modifications on this basic for¬
being used commercially for tablet coating. Fur¬
mula may be necessary to improve adhesion of
ther discussion of coating materials in this chap¬
the coating to the core; to decrease bridging of
ter is limited to synthetic polymers, solvents,
intagliations; to increase coating hardness; or to
plasticizers, colorants, opaquant-extenders, and
improve any property of the coating that the for-
miscellaneous coating solution components.
mulator deems deficient. Colorant and opaquant
An ideal film coating material should have the
concentrations are usually fixed to achieve a
following attributes:
predetermined shade. Changes of the poly-
mer(s)-to-plasticizer ratio, however, or the addi¬
tion of different plasticizers or polymers, are 1. Solubility in solvent of choice for coating
preparation.
common modifications made in optimization of
the coating. 2. Solubility required for the intended use,
This type of experimentation can be best e.g., free water-solubility’, slow water-solu¬
achieved by conducting a fractional factorial bility, or pH-dependent solubility (enteric
type of study,* in which the concentration of a coating)
few plasticizers or polymers are evaluated in the
3. Capacity to produce an elegant looking prod¬
same general coating formulation. Factorial
uct.
studies allow evaluation of more variables with
fewer experiments. The evaluation of each coat¬ 4. Stability in the presence of heat, light, mois¬
ing composition, however, must be conducted ture, air, and the substrate being coated.
by a readily quantifiable criterion. For example, The film properties should not change with
if the coating compositions are to be applied to aging.
tablets, can the coating conditions be effectively
5. Essentially no color, taste or odor.
repeated? Can the properties of the film be
measured by an objective testing system? The 6. Compatibility with common coating solu¬
conditions used in the coating process fre¬ tion additives.
quently have as great an effect on the quality of
7. Nontoxicity with no pharmacologic activity,
the tablet coating as the coating composition.
and ease of application to the particles or
Studies on free films are much easier to conduct
tablets.
because there are test methods that can be used
to evaluate changes in film properties with mod¬ 8. Resistance to cracking, and provision of ade¬
ifications in coating composition. Bonding of a quate moisture, light, odor, or drug sublima¬
film to a tablet surface or bridging of an intaglia- tion barrier when desired.
tion can be measured, but the experimental
9. No bridging or filling of the debossed tablet
error is much higher. Optimization of a particu-
surfaces by the film former.
10. Ease of printing procedure on high-speed
* Plackett-Burman statistical method. equipment.

364 • The Theory and Practice of Industrial Pharmacy

 No commercially available material fulfills all it is soluble in fewer organic solvents, it is not
requirements of an ideal coating material. A used as frequently as hydroxypropyl methylcel¬
pharmaceutical scientist usually formulates a lulose.
coating solution to achieve certain desired prop¬
erties for the film-coated product. The available ETHYLCELLULOSE, NF
film formers can be classified into nonenteric
Ethylcellulose is manufactured by the reac¬
and enteric materials.
tion of ethyl chloride or ethyl sulfate with cellu¬
lose dissolved in sodium hydroxide. Depending
on the degree of ethoxy substitution, different
Film Formers viscosity grades are obtained and available com¬
mercially. This material is completely insoluble
Nonenteric Materials in water and gastrointestinal fluids, and thus
cannot be used alone for tablet coating. It is usu¬
It is not possible to mention all polymers that
ally combined with water-soluble additives, e.g.,
have been investigated for filmcoating. The fol¬
hydroxypropyl methylcellulose, to prepare films
lowing discussion describes only some of the
with reduced water solubility properties. A com¬
materials most commonly used by the pharma¬
bination of ethylcellulose with water-soluble
ceutical industry and is intended as a guide for
additives has been widely used in preparing sus¬
the student or pharmaceutical scientist.
tained-release coatings of fine particles and tab¬
lets. The polymer is soluble in a wide variety of
HYDROXYPROPYL METHYLCELLULOSE, USP
organic solvents and is nontoxic, colorless, odor¬
The polymer is prepared by reacting alkali- less, tasteless, and quite stable to most environ¬
treated cellulose first with methvl chloride to mental conditions. Unplasticized ethylcellulose
introduce methoxy groups and then with gropyl- films are britde and require film modifiers to
rme~Tixrde~To rntrcxTuce propylene glvcol ether obtain an acceptable film formulation. Banker
groups. The resuiting products are commercially and co-workers from Purdue University have
available in different viscosity grades. This poly¬ developed aqueous polymeric dispersions utiliz¬
mer is a material of choice for air suspension ing ethylcellulose. These pseudolatex systems
and pan-spray coating systems. The reasons fpr are high-solids,* low-viscosity compositions that
its widespread acceptance include (1) solubility have coating properties quite different from the
characteristics of the polymer in gastrointestinal regular ethylcellulose solutions. The material is
fluid, and in organic and aqueous solvent sys¬ commercially available through FMC Corpora¬
tems, (2) noninterference with tablet disintegra¬ tion as Aquacoat:*
tion and drug availability, (3) flexibility, chip
resistance, and absence of taste or odor, (4) sta¬ HYDROXYPROPYLCELLULOSE, FCC
bility in the presence of heat, light, air, or rea¬
This material is manufactured by treatment of
sonable levels of moisture, (5) ability to incorpo¬
cellulose with sodium hydroxide, followed by a
rate color and other additives into the film
reacfion with propylene oxide at an elevated
without difficulty. The interaction of this poly¬
temperature and pressure. It is soluble in water
mer with colorants is rare.32 Hydroxypropyl
below 4D°C (insoluble above 45°C), gastrointesti¬
methylcellulose closely approaches the desired
nal fluids, and many polar organic solvents. This
attributes of an ideal polymer for film coating.
polymer is extremely tacky as it dries from a so¬
When used alone, the polymer has the tendency
lution system and may be desirable for a
to bridge or fill the debossed tablet surfaces. A
subcoat, but not for a color or gloss coat. The
mixture of hydroxypropyl methylcellulose with
polymer yields very flexible films. It is usually
other polymers or plasticizers is used to elimi¬
not used alone, but it is used in combination
nate bridging or filling problems. This polymer
with other polymers to improve the film charac¬
is also used considerably in glossing solutions.33
teristics.

METHYL HYDROXYETHYLCELLULOSE
POVIDONE, USP
This polymer is prepared by reacting alkali-
Povidone is a synthetic polymer consisting of
treated cellulose first with methyl chloride and
linear l-vinyl-2-pyrrolidinone groups. The de¬
then with ethylene oxide. A wide variety of vis¬
gree of polymerization results in materials of
cosity grades are available. Because of its struc¬
tural similarity to hydroxypropyl methylcellu¬
lose, this polymer is expected to have similar *FMC Corporation, 2000 Market Street, Philadelphia, PA
properties. It is marketed in Europe, but because 19103.

TABLET COATING • 365

various molecular weight range. Povidone is waxes with cellulose acetate phthalate provide
usually available in four viscosity grades identi¬ films that are soluble in gastric fluids. Such sys¬
fied by their K values, which approximate K-15, tems constituted one of the first commercially
K-30, K-60, and K-90. The average molecular used nonenteric film coating processes.35 Coats
weight of these grades are 10,000, 40,000, produced with the use of high-molecular-weight
160,000, and 360,000 respectively. The most PEGs can be hard, smooth, tasteless, and non¬
common uses of povidone in pharmaceuticals toxic, but are somewhat sensitive to elevated
(frequendy K-30) are as a tablet binder and a temperatures.
tablet coating. It has excellent solubility in a
wide variety of organic solvents, in water, and in
gastric and intestinal fluids. When dry, povidone ACRYLATE POLYMERS

films are clear, glossy, and hard. The material is A series of acrylate polymers is marketed
extremely tacky, but it is possible to modify the under the trademark Eudragit.* Eudragit E is a
polymer properties by use of appropriate plasti¬ cationic copolymer based on dimethyl-
cizers, suspended powders, or other polymers. aminoethyl methacrylate and other neutral
Although povidone is soluble in both acidic and methacrylic acid esters, and is the only Eudragit
basic fluids, it can be cross-linked with other material that is freely soluble in gastric fluid up
materials to produce films with enteric proper¬ to pH 5, and expandable and permeable above
ties. Povidone has been used to improve the dis¬ pH 5. This material is available as (1) organic
persion of colorants in coating solutions to ob¬ solution (12.5%) in isopropanol/acetone,
tain a more uniformly colored film. ' (2) solid material, or (3) 30% aqueous disper¬
sion. Eudragit RL and RS are copolymers syn¬
SODIUM CARBOXYMETHYLCELLULOSE, USP thesized from acrylic and methacrylic acid esters
This material is a sodium salt of carboxy- with a low content of quaternary ammonium
groups. These are available only as organic solu¬
methylcellulose and is manufactured by the re¬
tions and solid materials. These polymers pro¬
action of soda cellulose with the sodium salt of
monochloroacetic acid. It is available in low, duce films for the delayed-action (pH-indepen-
medium, high, and extra high viscosity grades. dent) preparations similar to ethylcellulose
formulations. These materials are widely used in
Sodium carboxymethylcellulose is easily disper¬
sed in water to form colloidal solutions, but it is Europe, but have limited use so far in the
insoluble in most organic solvents, and therefore Uriited States.
is not a material of choice for coating solutions
based on organic solvents. Films prepared with
Enteric Materials
sodium carboxymethylcellulose are brittle, but
adhere well to tablets. Partially dried films are Enteric coating of pills and compressed tablets
tacky, however, so coating compositions must be has existed for more than a century.36 Some of
modified with additives. Conversion to aqueous- the most important reasons for enteric coating
based film coating with high coating efficiency are as follows:
equipment probably increases the usefulness of
this polymer in coating systems. 1. To protect acid-labile drugs from the gastric
fluid, e.g., enzymes and certain antibiotics.
POLYETHYLENE GLYCOLS 2. To prevent gastric distress or nausea due to
Polyethylene glycols (PEG) are manufactured irritation from a drug, e.g., sodium salicylate.
by the reaction of ethylene glycol with ethylene 3. To deliver drugs intended for local action in
oxide in the presence of sodium hydroxide at the intestines, e.g., intestinal antiseptics
elevated temperature and under pressure. In could be delivered to their site of action in a
addition to their other uses in formulations, they concentrated form and bypass systemic ab¬
are used in film coating for which a wide variety sorption in the stomach.
of molecular weights are available. The materi¬
als with low molecular weights (200 to 600 se¬ 4. To deliver drugs that are optimally absorbed
ries) are liquid at room temperature and are in the small intestine to their primary absorp¬
used as plasticizers for coating solution films. tion site in their most concentrated form.
The materials with high molecular weights (se¬ 5. To provide a delayed-release component for
ries 000 to 8,000) are white, waxy solids at room repeat-action tablets.
temperature. These polymers are used in combi¬
nation with other polymers to modify film prop¬
erties. Combinations of polyethylene glycol *Rohm and Haas Co. Inc., Pharma. Gmbh., Germany.

366 • The Theory and Practice of Industrial Pharmacy

 An ideal enteric coating material should have the absorption of drug from enteric coated tab¬
the following properties: lets. The pH of the stomach contents may vary
from 1.5 to 4.0, with about 10% of the patients
1. Resistance to gastric fluids. having achlorhydria. The amount of gastric fluid
may vary between individuals, and for the same
2. Ready susceptibility to or permeability to in¬ individual from time to time. Gastric residence
testinal fluids.
time for the dosage form may range from less
3. Compatibility with most coating solution than half an hour to more than 4 hours depend¬
components and the drug substrates. ing on the time of its administration, whether it
was consumed with food, and if so, the type and
4. Stability alone and m coating solutions. The
quantity of food. The USP disintegration test
films should not change on aging.
does not require a qualitative or quantitative test
5. Formation of a continuous (uninterrupted) for the active drug after agitation in artificial
film. gastric fluid for 1 hour. Several commercially
available enteric products passed the USP en¬
6. Non toxicity.
teric test, but released varying amounts of drugs '
7. Low cost. in simulated gastric fluid.3' Most acid-labile
drugs need protection between pH values 1 and
8. Ease of application without specialized
5. The pH of material approaching pylorus is
equipment.
expected to be about 5. An ideal enteric polymer
9. Ability to be readily printed or to allow film to should dissolve or become permeable near and
be applied to debossed tablets. above pH 5.
A common problem associated with the re¬
Pharmaceutical formulators have a wide tardant type of polymers (non-pH dependent sol¬
choice of materials for use in developing an en¬ ubility), which act by mechanical hydrophobic -
teric coated granule, pellet, or tablet product. ity, is that to provide enteric effect, the film
These materials range from water-resistant might be so thick that if the dosage form travels
films to pH-sensitive materials. Some are di¬ too fast through the gastrointestinal tract, solu¬
gested or emulsified by intestinal juices, and bilization in intestinal fluids may never be
some slowly swell and fall apart when solvated. achieved. Commercial products have failed the
Many formulators use a combination of the ac¬ enteric test both for lack of gastric protection
tions just fisted to achieve the desired objective. and for lack of solubility in intestinal fluids.38,39
Most commercially available enteric materials Many others passed these in vitro tests, but
fail to display two or more of the ideal properties failed to perform adequately when studied in
of an enteric coating material. The following sec¬ vivo.40
tion discusses some of the difficulties encoun¬ A review of tablet coating by Porter summa¬
tered in enteric formulations. rizes the commercially available enteric poly¬
The United States Pharmacopeia (USP) disin¬ mers.41
tegration test for enteric coated tablets requires
that the tablets tolerate agitation in simulated
gastric fluid test solution at 37 ± 2°C (no discs). CELLULOSE ACETATE PHTHALATE (CAP)

After 1 hour of exposure in simulated gastric CAP has been widely used in the industry. It
fluid, tablets should show no evidence of disinte¬ has the disadvantage of dissolving only above
gration, cracking, or softening. Then a disc is pH 6, and possibly delaying the absorption of
added to each tube, and the test is continued drugs. It is also hygroscopic and relatively per¬
using simulated intestinal fluid maintained at meable to moisture and gastric fluids, in com¬
37 ± 2°C as the immersion fluid, for a period of parison with some other enteric polymers. CAP
time equal to 2 hours or to the time limit speci¬ films are susceptible to hydrolytic removal of
fied in the individual monograph. If all the tab¬ phthalic and acetic acids, resulting in a change
lets disintegrate, the product passes the test. If 1 of film properties. CAP films are brittle and usu¬
or 2 tablets fail to disintegrate completely, the ally formulated with hydrophobic-film forming
test is repeated on 12 additional tablets. To pass materials or adjuvants to achieve a better enteric
the disintegration test, at least 16 out of 18 tab¬ film. FMC Corporation has developed a patented
lets should disintegrate. aqueous enteric coating called Aquateric.42
All enteric coated tablets must meet these re¬ Aquateric coating is a reconstituted colloidal dis¬
quirements. Passing the USP enteric test does persion ot latex particles (not a solvent solution
not guarantee optimal bioavailabifity of a partic¬ coating system). It is composed of solid or semi¬
ular dosage form. Several situations complicate solid polymer spheres of cellulose acetate

TABLET COATING • 367

phthalate ranging in size from 0.05 to 3 microns 1. It should either dissolve or disperse the poly¬
with an average particle size of 0.2 micron. This mer system.
material is currently being offered for potential
2. It should easily disperse other coating solu¬
industrial applications.
tion components into the solvent system.

ACRYLATE POLYMERS 3. Small concentrations of polymers (2 to 10%)

should not result in an extremely viscous so¬
Two forms of commercially available enteric
lution system (>300 cps), creating process¬
acrylic resins are Eudragit L and Eudragit S.
ing problems.
Both resins produce films that are resistant to
gastric fluid. Eudragit L and S are soluble in in¬ 4. It should be colorless, tasteless, odorless, in¬
testinal fluid at pH 6 and 7, respectively. expensive, nontoxic, inert, and nonflamma¬
Eudragit L is available as an organic solution ble.
(Isopropanol), solid, or aqueous dispersion.
5. It should have a rapid drying rate (the ability
Eudragit S is available only as an organic solu¬
to coat a 300 kg load in 3 to 5 hours).
tion (Isopropanol) and solid.
6. It should have no environmental impact.
HYDROXYPROPYL METHYLCELLULOSE PHTHALATE*
The most widely used solvents, either alone or
Shin-Etsu Chemical Company has made in combination are water, ethanol, methanol,
three enteric polymers ayailable commercially. isopropanol, chloroform, acetone, methylethyl-
These are derived from hydroxypropyl methyl- ketone, and methylene chloride. Because of en¬
cellulose, N.F., by esterification with phthaiic vironmental and economic considerations, water
anhydride, and are marketed as HPMCP 50, 55,
is the solvent of choice; however, several poly;'
and 55S (also known as* HP-50, HP-55, and mers cannot be applied from aqueous systems.
HP-55-S). HPMCP is the trade name for hydrox¬ Drugs that readily hydrolyze in the presence of
ypropyl methylcellulose phthalate. These poly¬ water can be more effectively coated with nona-
mers dissolve at a lower pH (at 5 to 5.5) than queous-solvent-based coatings. Such a process
CAP or acrylic eopoiymers, and this solubility might require applying an initial sealing coat
characteristic may result in higher bioavailabil- from an organic-based subcoating, followed by
ity of some specific drugs.43 For general enteric aqueous color and gloss coating. The use of or¬
preparations, HP-55 is recommended by Shin- ganic-solvent-based film coatings will undoubt¬
Etsu; HP-50 and HP-55S are recommended for edly decrease as better aqueous systems are de¬
special situations. These polymers are quite
veloped. It, is unlikely, however, that organic
stable compared with CAP because of their ab¬ solvents will be entirely supplanted.
sence of labile acetyl groups.

POLYVINYL ACETATE PHTHALATE (PVAP)|

Plasticizers
PVAP is manufactured by the esterification of The quality of a film can be modified by the
a partially hydrolyzed polyvinyl acetate with
use of “internal” or “external” plasticizing tech¬
phthaiic anhydride. This polymer is similar to
niques. Internal plasticizing pertains to the
HP-55 in stability and pH-dependent solubility.
chemical modification of the basic polymer that
It is supplied as ready-to-use or ready-to- alters the physical properties of the polymer.
disperse enteric systems.
This aspect has been discussed earlier under
different polymeric materials. By controlling the
Solvents degree of substitution, the type of substitution,
and the chain length, polymer properties can be
The primary function of a solvent system is to altered significantly.' Most often, the formulator
dissolve or disperse the polymers and other addi¬ uses external plasticizers as additives to the
tives and convey them to the substrate surface. coating solution formula so that the desired ef¬
All major manufacturers of polymers for tablet fects are achieved for the film. An external plas¬
coating provide basic physical-chemical data on ticizer can be a nonvolatile liquid or another
their polymers. These data are usually helpful to polymer, which when incorporated with the pri¬
a formulator. Some important considerations for mary polymeric film former, changes the flexi¬
an ideal solvent system are as follows: bility, tensile strength, or adhesion properties of
* Distributed by Biddle Sawyer Corporation, 2 Penn Plaza, the resulting film.
New York, NY 10121. As the solvent is removed, most polymeric
tSupplied by Colorcon, Inc., West Point, PA 19486. materials tend to pack together in three-dimen-

368 • The Theory and Practice of Industrial Pharmacy

 sional honeycomb arrangements.44 The choice may be soluble in the solvent system or sus¬
of plasticizer depends upon the ability of plasti¬ pended as insoluble powders. They are used to
cizer material to solvate the polymer and alter provide distinctive color and elegance to a dos¬
the polymer-polymer interactions. When used in age form. To achieve proper distribution of sus¬
correct proportion to the polymer, these materi¬ pended colorants in the coating solutions re¬
als impart flexibility by relieving the molecular quires the use of fine-powdered colorants (<10
rigidity. The type of plasticizer(s) and its ratio to microns). Repetitive production of colored coat¬
the polymer can be optimized to achieve the de¬ ing solutions from different lots of the same col¬
sired film properties. One should also consider orant can be particularly difficult if colorant lots
the viscosity of the plasticizer; its influence on have different dye content, crystal form of dye,
the final coating solution; its effect on film per¬ or particle size distribution. In general, the sus¬
meability, tackiness, flexibility, solubility, and pended colorants must be milled in the coating
taste; and its toxicity, compatibility with other solvent or solution to attain a uniform dispersion
coating solution components, and stability of the of the colorants. Color variation in a product can
film and the final coated product. be readily detected by the pharmacist and pa¬
A combination of plasticizers may be needed tient; therefore, the colors must be reproducible
to achieve the desired effeet. The concentration and stable.
of the plasticizers depends on many factors, in¬ The most common colorants in use are certi¬
cluding the polymer chemistry, method of appli¬ fied Food Drug and Cosmetic (FD&C) or Drug
cation, and the other components present in the and Cosmetic (D&C) colorants. These are syn¬
system. Even changes in the drying rate or use thetic dyes or lakes of dyes. Lakes are derived
of elevated temperatures may alter the influence from dyes by precipitating with carriers, e.g.,
of the plasticizer in the coating process. The alumina or talc. Lakes have become the color¬
presence of titanium dioxide, colorants, flavors, ants of choice for sugar or film-coating systems,
and other additives also affect the film former. as more reproducible tablet colors are attainable.
Most film formers tolerate only a certain additive Most commercially available lakes contain 10 to
load, and beyond that limit, the film properties 30% of the pure dye content, but some lakes
are adversely affected. approach up to 50%. An occasional problem with
The amount and type of plasticizers to be used the lake system might be the use of a solvent
for any given polymer can be based on the poly¬ system that dissolves the dye, thereby establish¬
mer manufacturer’s recommendations. Optimi¬ ing a time- and temperature-dependent equilib¬
zation of the plasticizer concentration must be rium for leaching the dye from the lake system.
based on the presence of the other additives. Use of pure dye is recommended in such cases.
Concentration of a plasticizer is expressed in re- The concentration of colorants in the coating
lation to the polymer'being plasticized. Kecom- solutions depends on the color shade desired,
mended levels of plasticizers range from 1 to the type of dye (i.e., dye versus the lake of the
50% by weight of the film former. Some of the dye), and the concentration of the opaquant-
commonly used plasticizers are castor oil; pro¬ extenders. If a very fight shade is desired, a con¬
pylene glycol; glycerin; low-molecular-weight centration of less than 0.01% may be adequate.
polyethylene glycols of ZUU and 4o(Tseries: and On the other hand, if a dark color is desired, a
surfactants, e.g., polysorbates (Tweens), sorbi- concentration of more than 2.0% may be re¬
tan esters fSpans). and organic acid esters. With quired. Since lakes contain less colorant, a larger
the increasing interest in aqueous coating, concentration in solution is generally required.
water-soluble plasticizers, e.g., polyethylene gly¬ The inorganic materials (e.g., iron oxides) and
cols and propylene glycol, are used. Conversely, the natural coloring materials (e.g., antho-
castor oil and Spans are used primarily for or- cyanins, caramel, carotenoids, chlorophyll, in¬
ganic-solvent-based coating solutions. For an digo, flavones, turmeric, and carminic acid) are
-external plasticizer to be effective, it should be also used to prepare coating solutions.
soluble in the solvent system used for dissolving A new fine of colorants is being developed.45
the film former and plasticizer. The plasticizer These colorants are nonabsorbable in the bio¬
and the film former must be at least partially sol¬ logic system. This is accomplished-by attaching
uble or miscible in each other. dyes to polymers that are too large to be absorbed
in the gastrointestinal tract and yet are resistant
to degradation in the gastrointestinal tract. A
Colorants magenta red dye is projected to be the first dye to
Coating solution formulations may contain a be cleared for use.
wide variety of components in addition to the A variety of products that are commercially
film former, solvents, and plasticizers. Colorants available permit preparation of coating solution

TABLET COATING • 369

without additional milling equipment.* Some are particularly prone to microbial growth, and
examples are: prolonged storage of the coating composition
should be avoided.
Opalux—Opaquant color concentrate for
sugar coating.
Quality Control
Opaspray—Opaque color concentrate for film
After coating, the tablets should be inspected
coating.
and tested for appearance and performance. In¬
Opadry—Complete film coating concentrate. spection should include checks for color (both
hue and continuity), size, appearance, and any
All of these concentrates are promoted as physical defects in the coating, which could af¬
achieving less lot-to-lot color variation. fect the performance or stability of the product.
The in vitro performance of the coated prod¬
uct is evaluated by disintegration and dissolu¬
Opaqua n t-Ex tend e rs
tion testing. A standard disintegration test meas¬
These are very fine inorganic powders used in ures the time required for the tablet to break up
the coating solution formulations to provide into particles small enough to fall through a
more pastel colors and increase film coverage. 10-mesh screen. Dissolution testing measures
These opaquants can provide a white coating or the amount of active drug in solution over time.
mask the color of the tablet core. Colorants are A description of the standard equipment and
much more expensive than these inorganic ma¬ methods used for each test is given in the
terials, and effectively less colorant is required USP/NF. Standards of acceptance for drug prod¬
when opaquants are used. The most commonly ucts can be found in the USP/NF or the Code of
used material for this purpose is titanium diox¬ Federal Regulations, Title 21.
ide. Some other materials are silicates (talc, alu¬ To be a valid quality control method, the in
minum silicate), carbonates (magnesium car¬ vitro test should be discriminating. This means
bonate). sulfates^ (calcium sulfate), oxides that it should be sufficiently sensitive to reflect
(magnesium oxide), and Hydroxides (aluminum variation in the product caused by improper proc¬
hydro xfijej essing or by the effects of storage and aging. For
'—Rowe' and associates have observed differ¬ this reason, modifications of the test media and
ences in the refractive indices of polymer film rates-of agitation are commonly adjusted to ac¬
formers, pigments, and other additives com¬ commodate each specific product.
monly used for film coating.46,47 These observa¬ Ideally, the in vitro performance should re¬
tions have implications for the use of pigments flect in vivo performance. This correlation is
and additives in the production of opaque films rare, owing to the difficulty of devising an in
with good hiding power and film-coated tablets vitro testing method to mimic the complex and
with highlighted intagliations. dynamic nature of the physiologic system. Drug
availability can be affected by apparently minor
changes in the concentration of ingredients in
Miscellaneous Coating Solution either the core or film formulation. Therefore,
Components for most drug products, bioavailability testing
To provide a dosage form with a unique char¬ remains the only valid assessment of the prod¬
acteristic, special materials may be incorporated uct’s in vivo performance.
into the coating solution. Flavors or sweeteners Additional testing of coated tablets may also
are added to mask objectionable odors or to en¬ include tests for mechanical strength and for
hance a desired taste. Surfactants are used to resistance to chipping and cracking during han¬
solubilize otherwise immiscible or insoluble in¬ dling. Methods and devices for these tests are
gredients, or to facilitate faster dissolution of the similar to those used for uncoated tablets.
coating. Antioxidants are incorporated to stabi¬
lize a dye system to oxidation and color change. Stability Testing
Antimicrobials are added to prevent microbial
growth in the coating composition during its Stability testing is conducted to determine the
preparation and storage, and on the coated tab¬ effect of time and storage conditions on the
lets. Sdfne aqueous cellulosic Coating solutions physical and chemical stability of the coated
product. The stability program should be de¬
signed to determine the shelf-life or expiry dat¬
* Colorcon, Inc., West Point, PA. 19486. ing of the coated product under normal storage

370 • The Theory and Practice of Industrial Pharmacy

conditions in its intended package. As a rule, pigment concentration and polymer concentra¬
tablet products should have at least a two-year tion in the coating solution. 8
expiration date, which means that the product Orange-Peel Effects. Inadequate spreading
must conform to all standards of performance of the coating solution be'fore drying causes a
and potency for at least two years after manufac¬ bumpv^or “orange-peel” effect on the coating.
ture. This indicates that spreading is impeded by too
The testing program may also be designed to rapid drying or by high solution viscosity. Thin¬
test the product’s stability at elevated or acceler¬ ning the solution with additional solvent may
ated storage conditions. This type of program correct this problem.
may help to establish acceptable storage condi¬ Bridging and Filling. During drying, the
tions for the product in relation to temperature, - film may shrink and pull away from the sham
humidity, and light exposure, or it may help to ^comers of an intagliation or bisect, resulting in a
study the rate of degradation of the active ingre¬ “bridging” of the surface depression. This defect
dient under various conditions. Potency data can be so severe that the monogram or bisect is
from tablets stored at elevated temperatures can completely obscured. This mainly represents a
be evaluated by using the Arrhenius relation¬ problem with the formulation. Increasing the
ship to project a degradation rate for the active plasticizer content or changing the plasticizer
ingredient and to project an expiration date for can decrease the incidence of bridging.49 Filling
the product stored under ambient conditions. is caused by applying too much solution, result-
In the development stage, the stability pro¬ ing in a thick film that fills and narrows the
gram may be used to test variations in the for¬ monogram or bisect. In addition, if the solution
mulation or process. On aging, or under various is applied too fast, overwetting may cause the
conditions of storage, a particular variation may liquid to quickly fill andije retained in the mono¬
result in physical instability of the film, color gram. Judicious monitoring of the fluid applica¬
changes, or chemical degradation of the active tion rate and thorough mixing of the tablets in
ingredient. the pan prevent filling.
Blistering. When coated tablets require fur¬
ther drying in ovens, too rapid evaporation of the
solvent from the core and the effect of high tem¬
Film Defects perature on the strength, elasticity, and adhe¬
Variations in formulation and processing con¬ sion of the film may result in blistering. Milder
ditions may result in unacceptable qualitV de¬ drying conditions are warranted in this case.
fects in the film coating. The source of these de¬ Hazing/Dull Film. This is sometimes called
fects and some of their probable causes are bloom. It can occur when too high a processing
described in the following sections. temperature is used for a particular formulation.
Sticking and Picking. Overwetting or ex¬ Dulling is particularly evident when cellulosic
cessive film tackiness causes tablets to stick to polymers are applied out of aqueous media at
each other or to the coating pan. un drying, af high processing temperatures. It can also occur
the point of contact, a piece of the film may re¬ if the coated tablets are exposed to high humid¬
main adhered to the pan or to another tablet, ity conditions and partial solvation of film re¬
giving a “picked” appearance to the tablet sur¬ sults.
face and resulting in a small exposed area of the Color Variation. This problem can be
core. W reduction in the liquidapplication rate or caused by processing conditions or the formula¬
increases in the drying air temperature and air tion. Improper mixing, uneven spray pattern,
volume usually solve this problem. Excessive and insufficient coating may result in color vari¬
tackiness may be an indication of a poor formu¬ ation. The migration of soluble dyes, plasticiz¬
lation. ers, and other additives during drying may give
Roughness. A rough or gritty surface is a the coating a mottled or spotted appearance. The
defect often observed when the coating is ap¬ use of lake dyes eliminates dye migration. A re¬
plied by a spray. Some of the droplets may dry formulation with different plasticizers and addi¬
too rapidly before reaching the tablet bed, result¬ tives is the best way to solve film instabilities
ing in deposits on the tablet surface of “spray- caused by the ingredients.
dried” particles instead of finely divided droplets Cracking. Cracking occurs if internal
of coating solution. Moving the nozzle closer to stresses in the film exceed the tensile strength
the tablet bed or reducing the degree of atomiza¬ of the film. The tensile strength of the film can
tion can decrease the roughness due to “spray¬ be increased by using higher-molecular-weight
drying.” Surface roughness also increases with polymers or polymer blends.50 Internal stresses

TABLET COATING • 371

in the film can be minimized by adjusting the Future Tablet Developments
plasticizer type and concentration, and the pig¬
Much progress has been achieved in tablet
ment type and concentration.51
coating through significant equipment improve¬
ments. The expanded use of microprocessors for
Specialized Coatings process control and improved spraying systems
are likely.
Compression Coating. This type of coating The advent of the pseudo-latex coating sys¬
requires a specialized tablet machine. The fin¬ tems has shown that high solids containing
ished product is a tablet within a tablet, as de¬ coating formulations are attainable. Most film
scribed in Chapter 11. Compression coating is coating formulations still are primarily volatile
not widely used, but it has advantages in some solvents. Reducing the quantity of solvent that
cases in which the tablet core cannot tolerate must be removed in the coating process would
organic solvents or water and yet needs to be dramatically improve coating efficiency.
coated for taste masking, or to provide delayed or With the exception of the polymers used
enteric properties to the product. In addition, for enteric coating, most polymers available for
incompatible ingredients can be conveniently pharmaceuticals were primarily developed for
separated by this process. nonpharmaceutical use. There is a need for pol¬
Electrostatic Coating. Electrostatic coating ymers developed specifically to meet the phar¬
is an efficient method of applying coating to con¬ maceutical coating requirements. Polymers that
ductive substrates. A strong electrostatic charge can be applied in high concentration from
is applied to the substrate. The coating material aqueous-based solvents would be desirable.
containing conductive ionic species of opposite Their films should be flexible, adhere well to all
charge is sprayed onto the charged substrate. tablet surfaces, and be nontacky.
Complete and uniform coating of comers and
intagliations on the substrate is achieved. The
adaptability of this method to such relatively
nonconductive substrates as pharmaceutical References
tablets is limited, although one process has been 1. Sonnedecker, G., et al.: Pharm. Technol., 4:77, 1980.
proposed.52 2. Wurster, D.E. (Wisconsin Alumni Research Founda¬
Dip Coating. Coating is applied to the tablet tion). U.S. Patent 2,648,609 (1953).
cores by dipping them into the coating liquid. 3. Wurster, D.E. (Wisconsin Alumni Research Founda¬
The wet tablets are dried in a conventional man¬ tion): U.S. Patent 2,799,241 (1957).
4. Wurster, D.E.: J. Am. Pharm. Assoc., Sci. Ed.,
ner in coating pans. Alternate dipping and dry¬
48:451, 1959.
ing steps may be repeated several times to obtain 5. Demmer, F., et al.: Drugs Made in Germany, 24:30,
the desired coating. This process lacks the 1981.
speed, versatility, and reliability of spray-coating 6. Stetsko, G., et al.: Pharm. Technol., 7:50, 1983.
techniques. Specialized equipment has been 7. Reiland, T., et al.: Drug Dev. Ind. Pharm., 9:945,
developed to dip-coat tablets, but no commercial 1983.
8. Thomas, R.: Pharm. Eng. 1:16, 1981.
pharmaceutical application has been obtained.
9. Sharma, V.K., Lippmann, I., and Mangold, G.W.: The
Vacuum Film Coating. Vacuum film coat¬ Aster Guide to Tablet Coating Automation. Aster
ing is a new coating procedure that employs a Publishing, Springfield, OR, 1984.
specially designed baffled pan.53 The pan is hot 10. Lachman, L.: Manuf. Chem. Aerosol News, 37:35,
water jacketed, and it can be sealed to achieve a 1966.
vacuum system. The tablets are placed in the 11. Tucker, S.S., et al.: J. Am. Pharm. Assoc., Sci. Ed.,
49:738, 1960.
sealed pan, and the air in the pan is displaced by
12. Abbott Laboratories: Brit, Patent 760,403 (1956).
nitrogen before the desired vacuum level is ob¬ 13. Rowell, T.R.: Drug Cosmet. Ind., 64:300, 1949.
tained. The coating solution is then applied with 14. Martin, E.W.: Remington’s Pharmaceutical Sciences.
an airless (hydraulic) spray system. The evapo¬ 13th Ed. Mack Publishing, Easton, PA, 1965, p. 595.
ration is caused by the heated pan, and the va¬ 15. Ellis, J.R., Prillig, E.B., and Amann, A.H.: Tablet coat¬
pors are removed by the vacuum system. Be¬ ing. In The Theory and Practice of Industrial Phar¬
cause there is no high-velocity heated air, the macy. 2nd Ed. Edited by L. Lachman et al. Lea &
Febiger, Philadelphia, 1976, pp. 386-388.
energy requirements are low and coating effi¬ 16. Krause, G.M., et al.: J. Pharm. Sci., 57:1223, 1968.
ciency is high. Organic solvents can be effec¬ 17. Heyd, A., et al.: J. Pharm. Sci., 59:1171, 1970.
tively used with this coating system with mini¬ 18. Kunze, K- H., Drugs Made in Germany, 9:42, 1966.
mal environmental or safety concerns. 19. Cretu, G.Y., Radulescu, N.K., Sirbu, C., et al.

372 • The Theory and Practice of Industrial Pharmacy

 (Institutui de Cercetari Chimico-Farmaceutice): 37. Madan, P.L.: Indian J. Pharm. Sci., 41:99, 1979.
Rom. Patent RO 81576B (1983). 38. Payne, M.: Pharm. J., 196:657, 1966.
20. Shin-Etsu Chemical Industry., Ltd., Jpn. Kokai Tok- 39. Couvreur, A., et al.: Modem Coating of Tablets and
kyo Koho Japanese Patent 58/201724 A2 [83/201724] Pills. A partial translation distributed by Distillation
(1983). Products Industries, Div. of Eastman Kodak Cc-.,
21. The American Society for Testing and Materials, Test Rochester, New York, 1958.
No. E96-66. 1 40. Maney, P.V., et al.: Manuf. Chem., 36:55, 1965.
22. Parker, J.W., et al: J. Pharm, Sci., 63:119. 1974. 41. Porter, S.C.: Drug Cosmet. Ind. 128:44, 1981-.
23. Woodruff, C.W., et al.: J. Pharm. Sci., 61:1956, 1972. 42. McGinley, E.J., and Tuason, D.C. (FMC Corp.): U.S.
24. Porter, S.: Pharm. TechnoL, 4:67, 1980. Patent 4,462,839 (1984).
25. Wood, J.A., et al.: Can. J. Pharm. Sci., 5:18, 1970. 43. Kriesel, D., and Mehta, S.P. (Abbott Laboratories):
26. Nadkami, P.D., et al.: I. Eharm Sci., 64:1554, 1975. U.S. Patent 4,340,582 (1982).
27. Fisher, D.G., et al.: J. Pharm. Pharmacol., 28:886, 44. Doolittle, A.K.: The Technology of Solvents and Plas¬
1976. ticizers. John Wiley and Sons, New York, 1954, p.
28. Rowe, R.C.: Acta Pharm. Terchnol., 29:205, 1983. 869.
29. Rowe, R.C.: Int. J. Pharm. Technol. t’rod. Mdnuf., 45. Meggos, H.N.: Pharm. Technol. 5:41, 1981.
3:67, 1982. 46. Rowe, R.C.: j. Pharm. Pharmacol. 35:43, 1983.
30. Wruble, M.S.: Am. J. Pharm., 102:318, 1980. 47. Rowe, R.C., et al.: J. Pharm. Pharmacol. 35:205,
31. Gans, E.H., et al.: J. Am. Pharm. Assoc., Sci. Ed., 1983.
43:483, 1954. 48. Rowe, R.C.: J. Pharm. Pharmacol., 30:669, 1978.
32. Prillig, E.B.: J. Pharm. Sci., 58:1245, 1969. 49. Rowe, R.C., et al.: J. Pharm. Pharmacol. 33:174,
33. Singiser, R.E. (Abbott Laboratories): U.S. Patent 1981.
3,256,111 (1966) 50. Rowe, R.C., et al.: J. Pharm. Pharmacol. 32:583,
34: Banker, G.S., et al,: Pharm. Technol., 5:54, 1981. 1980.
35. Endicott, C.J., Dallavii, A.A., and Dickinson, H.M.N. 51. Rowe, R.C.: J. Pharm. Pharmacol., 33:423, 1981.
(Abbott Laboratories): U.S. Patent 2,881,085 (1959). 52. Tanabe, S., et al.: Brit. Patent 1,075,404 (1967).
36. Am. J. Pharm., 39:467, 1867. 53. Wehrle, K.: Drugs Made in Germany, 25:66, 1982.

TABLET COATING • 373

 13
Capsules

be used for highly efflorescent or deliquescent

PART ONE materials. Efflorescent materials may cause the
capsules to soften, whereas deliquescent pow¬
ders may dry the capsule shell to excessive brit¬
Hard Capsules tleness. In some cases, this dehydration may be
retarded or prevented by the use of small
amounts of inert oils in the powder mixture.
Van Hostetler

ivhtterials
Telescoping capsules are made principally of
Mothes and Dublanc, two Frenchmen, are gen¬ gelatin blends and may contain small amounts
erally credited with the invention of the gelatin of certified dyes, opaquing. agents, plasticizers,
capsule. Their patents, granted in March and and preservatives. Capsules have been made
December of 1834, covered a method for pro¬ with methylcellulose, polyvinyl alcohols, and
ducing single-piece, olive-shaped, gelatin cap¬ denatured gelatins to modify then Mubility or
sules, which were closed after filling by a drop of produceTanentericefiect. Theylneformed by
concentrated warm gelatin solution. The two- dipping cool stainless steel mold pins into a gela¬
piece telescoping capsule, invented by James tin solution, a process described in this chapter.
Murdock of London (1848), was patented in Other methods, such as centrifugal casting,
England in 1865. have been used, but the pin method is the only
In addition to having the advantages of ele¬ one used in large-scale commercial production.
gance, ease of use, and portability, capsules Gelatin is a heterogeneous product derived by
have become a popular dosage form because irreversible hydrolytic extraction of treated ani¬
they provide a smooth, slippery, easily swal¬ mal collagen, and as such, it never occurs natu¬
lowed, and tasteless shell for drugs; the last ad¬ rally. Its physical and chemical properties are
vantage is particularly beneficial for drugs hav¬ mainly functions of the parent collagen, method
ing an unpleasant taste or odor. They are of extraction, pH value, thermal degradation,
economically produced in large quantities and in and electrolyte content. Common sources of col
a wide range of colors, and they generally pro¬ lagen are animal bones, hide portions, and fro¬
vide ready availability of the contained drug, zen pork skin. Bone and skin gelatins are readily
since minimal excipient and little pressure are available in commercial quantities in most areas
required to compact the material, as is necessary of the world.
in tabletting. Type A gelatin is derived from an acid-treated
Capsules are not usually used for the adminis¬ precursor and exhibits an isoelectric point in the
tration of extremely soluble materials such as region of pH 9, whereas type B gelatin is from an
potassium chloride, potassium bromide, or alkali-treated precursor and has its isoelectric
ammonium chloride since the sudden release of zone in the region of pH 4.7. Although capsules
such compounds in the stomach could result in may be made from either type of gelatin, the
irritating concentrations. Capsules should not usual practice is to use a mixture of both types
as dictated by availability and cost considera¬
Some of the material in this chapter has been retained tions. Differences in the physical properties of
from the previous edition, to which Mr. J. Q. Bellard con¬ finished capsules as a function of the type of gel¬
tributed. atin used are slight.

374
 Blends of bone and pork skin gelatins of rela¬ Method of Production
tively high gel strength are normally used for
hard capsule production. The bone gelatin pro¬ The three major suppliers of empty gelatin
duces a tough, firm film, but tends to be hazy capsules are Elililly and Company, Jndianapo-
and britde. The pork skin gelatin contributes hs, IN: Capsugel, Greenwood. SC; and the R. P.
plasticity and clarity to the blend, thereby reduc¬ Scherer Corporation, Troy, MI. Several smaller
ing haze or cloudiness in the finished capsule. volume suppliers exist throughout the world,
An abbreviated flowchart for the manufacture some of which process for their own use only.
of gelatin for use in capsules is presented in Fig¬ The completely automatic machine most com¬
ure 13-1. monly used for capsule production consists of
Two recent developments have taken place in mechanisms for automatically dipping, spin¬
the gelatin supply area. First, “green” (fresh) ning. drying, stripping, trimming, and joining
bones are being used commercially as a source the capsules. The stainless steel mold piriTTig.
of Type B gelatin. Aside from additional pretreat - 13-1), on which the capsule is formed, controls
rrrenrto'femove residual tissues and fat, the pro¬ some of the final critical dimensions of the cap¬
cessing coincides with that used for aged bones, sule, and tolerances must be held within frac¬
and the gelatins obtained are indistinguishable tions of a thousandth of an inch.
from each other in practical use. One hundred and fifty pairs of these pins are
The second development is the processing of dipped, as shown in Figure 13-2, into a gelatin
an “acid-bone” gelatin preparecTfrom bone by sol of carefully controlled viscosity to form caps
techniques essentially comparable to those for and bodies simultaneously. As shown in Figure
Type A gelatins. The resulting gelatin shows an 13-3, the pins are usually rotated to distribute
altered isoelectric point (pH 5.5-6.0), and gen¬ the gelatin uniformly (1), during which time the
erally, intermediate physical characteristics for gelatin may be set or gelled by a blast of cool air
the film. The acid extraction technique for (2). The pins are moved through a series of con¬
bones is valuable to processors of gelatin be¬ trolled air drying kilns for the gradual and pre¬
cause of the decreased extraction time required. cisely controlled removal of water (3 to 6). The
Both of the aforementioned materials are capsules are stripped from the pjns by bronze
commercially available and are used in hard jaws and trimmed to length by stationary knives
capsule production. (7) while the capsule halves are being spun in

FIG. 13-1. The process of manufacturing gelatin used in capsules.

capsules • 375
FIG. 13-2. Mold pin dipping.

chucks or collets. After being trimmed to exact areas to provide computer control of viscosity
length, the cap and body sections are joined and (and consequent wall thickness) during either
ejected from the machine. The entire cycle of machine operations or gelatin solution make-up.
the machine lasts approximately 45 min. Inspection processes—to remove imperfect
Thickness of the capsule wall is controlled by capsules—which historically have been done
the viscosity of the gelatin solution and the visually, have recently been automated follow¬
speed and time of dipping. Other matters critical ing the development and patenting of a practical
to the final dimensions are mold pin dimen¬ electronic sorting mechanism by Eli Lilly and
sions, precise drying, and machine control relat¬ Company. This equipment mechanically orients
ing to cut lengths. Precise control of drying con¬ the capsules and transports them past a series of
ditions is essential to the ultimate quality of the optical scanners, at which time those having
cast film. detectable visual imperfections are automati¬
At the least, in-process controls include peri¬ cally rejected.
odic monitoring, and adjustment when required, Empty capsules are subject to size variation as
of film thickness, cut lengths of both cap and a result of moisture content variation. This can
body, color, and moisture content. be caused by exposure to extreme variations in
Recent strides have been made in several absolute humidity or elevated temperature.

FIG. 13-3. Hard capsule manufacturing machine. See text for explanation of labels 1 through 7.

376 • The Theory and Practice of Industrial Pharmacy

 Unopened shipping containers are usually ade¬ Lilly/Parke-Davis
quate protection against these changes, but stor¬
Each of these capsule filling machines re¬
age in unopened containers should not be sub¬
quires an individual operator and may achieve a
jected to temperature conditions of over 100°F.
daily output of up to 200,000 capsules.
Open storage under either high or low humidity
The Lilly machine is shown in Figure 13-4.
conditions should be minimized. Empty cap¬
The empty capsules are fed from the storage
sules as usually received range in moisture con¬
hopper (1) and through the rectifying unit (2),
tent between 12% and 15%. Below 10% mois¬
into the two-piece filling ring (3A and 3B). Recti¬
ture content, they become brittle and may
fication is bas'ed on dimensional differences be¬
shrink to the point of not fitting into the filling
tween the outside diameters of the cap and body
equipment. Above 16% moisture content, they
portions of the capsule. As the ring (3A and 3B)
may cause size problems in the filling equip¬
is rotated, a vacuum is applied on its underside.
ment, plus a loss of mechanical strength. Expo¬
This vacuum seats the bodies into the lower half
sure to either heat or moisture extremes can dis¬
of the ring, while the caps are retained in the
tort empty capsules to the extent that they
upper portion. The two pieces of the ring are
cannot be handled by automatic filling equip¬
separated, and the cap-containing portion is
ment.
placed aside. The body-containing portion of the
ring is placed on a variable speed turntable and
is mechanically rotated under the powder hop¬
Filling Equipment per (4), which contains an auger for the forced
At present, at least nine manufacturers of cap¬ delivery of the powder. After one (or more) com¬
sule filling equipment are either located in or plete rotations of the ring, the powder hopper (4)
selling their products within the United States. is removed, and the two segments of the ring
Most of the units manufactured outside the (3A and 3B) are rejoined. The intact ting is posi¬
United States have local representatives. The tioned in front of the peg ring (5), and the clos¬
nine individual companies are: ing plate (6) is pivoted to a position approxi¬
mately 180 degrees from that shown in Figure
Eli Lilly and Company, Indianapolis, IN 13-4. Pneumatic pressure is applied to the peg
Farmatic SNC, Bologna, Italy
Hofliger and Karg, Waiblingen, Germany
Macofar SAS, Bologna, Italy
mG2 S.p.A., Bologna, Italy
Osaka, Osaka, Japan
Parke-Davis and Company, Detroit, MI
Perry Industries, Green Bay, WI
Zanasi Nigris, S.p.A., Bologna, Italy

Each machine type is briefly discussed in the

following sections, but no attempt is made to
quantify or compare weight variation figures
among the various types because of obvious de¬
pendence on such factors as the conditions of
the equipment, formulas, methods of operation,
operator competence, machine rates, and sizes
of capsules. Along with suitable consideration of
all other details, adequate statistical weight
checks or the use of 100% check-weighing
should be employed to ensure compliance with
regulatory requirements.
The largest number of total machines are sup¬
plied by Lilly and Parke-Davis. Since the ma¬
chines of both manufacturers .have essentially FIG. 13-4. Lilly capsule filling machine. See text for ex¬
the same method of operation, only one descrip¬ planation of labels 1 through 7. (Courtesy of Eli Lilly &
tion is given. Co., Indianapolis, IN.)

CAPSULES• 377
 f

ring (5), which forces the capsule body into the must be such that a constant amount of pow¬
cap, and the closing plate (6) holds the caps in der is available for delivery from the auger.
position. Ejection of the filled capsules from the Diluents and glidants should be selected with
rings cannot occur with the plate in the closing this phase of the operation in mind.
position. For ejection of the capsules, the pres¬
sure is released, the closing plate is restored to Pelletized or granular materials may be readily
its original position, and the capsules are ex¬ filled using this equipment. It is desirable to
pelled through the upper portion of the ring. remove the auger to avoid crushing. It may also
Normal closing and ejection occur with the peg be desirable to perform the closing operations in
ring in a vertical position, as shown in Figure a position other than the vertical position usu¬
13-4, with the filled capsules being collected ally used for powder. In a vertical position, pel¬
through a chute (7) into a collection chamber. lets or granules may escape from the body ring,
In this equipment, the powder is filled to the and this may cause damage to the capsules.
upper surface of the body-containing ring, and Since filling is best accomplished without an
the fill is therefore primarily volumetric. Al¬ auger in these cases, minimal change in fill
though changes in the total amount of powder weight can be achieved by alteration of rota¬
can be caused by changes in the rotational speed tional speed. Additional ring rotations do not
of the turntable (which changes the amount of increase the fill, but usually cause actual
time for which each hole is under the auger), damage to the pellets or granules.
there is no way to produce a partially filled cap¬ In addition to the semiautomatic machines
sule consistently. Although slower speeds usu¬ described previously, a relatively high-speed,
ally produce less weight variation, they also usu¬ automatic, continuous-motion machine called
ally result in heavier total fill weights, which the ROTOFIL is available from Eli Lilly and
may not be economical because of the resultant Company (Fig. 13-5). This machine is specifi¬
decrease in productivity. cally designed to fill pellets.
Minimum total fill weights (but usually maxi¬ The machine uses a rotary rectification sys¬
mum weight variation) axe achieved with the tem, which orients the capsules into a turret.
highest turntable speed. After the capsules are seated, the blocks contain¬
Maximum total fill weights (but generally ing the caps are retracted, and the bodies are
minimum weight variation) are achieved at the gravity-filled from the recirculating bed of pel¬
lowest rotational speed. lets.
Some of the variables that must be properly
controlled in order to achieve minimum weight
variation and proper uniformity of the finished
capsules are given in the following list:

1. The body-containing ring (3A) must be flat

across its surface to avoid creating volumetric
differences from one area of the ring to an¬
other.
2. The powder hopper (4) must be properly po¬
sitioned during the filling operation to avoid
uneven powder distribution from the auger.
The proper location includes consideration of
both the centering of the auger over the ring
holes and the parallelism between the lower
surface of the hopper and- the upper surface
of the ring.
3. Extreme variations in powder level in the fill¬
ing hopper (4) can cause uneven powder
flow, resulting in excessive fill weight varia¬
tion.
4. The individual rods in the peg ring must fit
the rings being used, be of uniform length,
and be perpendicular to the closing plate (6).
FIG. 13-5. Lilly ROTOFIL capsule filling machine.
5. Flow properties of the powder being filled (Courtesy of Eli Lilly & Co., Indianapolis, IN.)

378 • The Theory and Practice of Industrial Pharmacy

 The excess pellets are rolled from the surface Farmatic
of the turret and are transported back to the hop¬
per by vacuum. The cap blocks are realigned Farmatic offers three models of filling equip¬
over the turret, and a simple continuous cam ment for sale: 2000/15, 2000/30, and 2000/60,
motion provides the closing action. Filled cap¬ with rated outputs of up to 40,000, up to 80,000,
sules are ejected by compressed air, and both and up to 160,000 capsules per hour, respec¬
cap and body cavities are cleaned by compressed tively. A Farmatic capsule filling machine is pre¬
air and vacuum prior to the next use. Fill weight sented in Figure 13-6.
may be adjusted while the machine is in opera¬ The machines feature continuous motion
tion. with dosator-type powder feeding units, and are
The machine is rated as filling 1200 capsules totally enclosed for dust and noise control. Ad¬
per minute. r justable vacuum is used for separating the"cap-

FIG. 13-6. Farmatic Model 2000/60 capsule filling machine. (Courtesy of G.B. Gundi Bruno S.p.A., Bologna, Italy.)

capsules * 379
sules after rectification, and any defective or ity of shearing off long or improperly seated bod¬
unopened capsules are automatically rejected. ies.
Powder is moved from the product hopper by a Powder is auger-fed from the supply hopper to
screw conveyor to the operating tower, where its the filling chamber, which completely sur¬
level is continuously monitored. rounds the filling disc and in which the powder
Dosators measure and deliver the powder as a height is level-controlled. Tamping of powder
slug to the capsules. A digital display indicates into the holes of the filling disc is performed at
the status of the weight and compression. Ad¬ five successive stations. Tamps are externally
justments are made externally. adjustable at each individual station while the
The powder slug is ejected into the capsule machine is in operation. An additional station is
body, after which the capsule is closed. In the available for the insertion of tablets or pellets, so
case of a missing capsule, the slug is ejected in that mixed fills can be achieved.
such a way as to avoid its being carried into the Safety features built into the system include
completed capsules! Following ejection, all an empty capsule feed interruption signal with
bushings are cleaned by a combination of vac¬ automatic rejection of crushed and unjoined
uum and air. - capsules, and automatic clearance of empty cap¬
Various options are available, including auto¬ sule feed tubes after a predetermined number of
matic feeders for both capsules and powder, cycles. If no body is present in the body seg¬
counters, and automatic sampling with feedback ment, the powder is discharged through the seg¬
to the closing units to adjust incorrect weights. ment into a collecting container.
Farmatic does not have U.S. representation. Closing of filled capsules is performed in two
successive operations to allow for slower closing.
Closing is accomplished by the use of both upper
and lower closing rods.
Hofliger and Karg Figure 13-8 shows Model GKF-1200/1500,
The Hofliger and Karg (H & K) line consists and Figure 13-9 shows Model GKF-2400.
basically of four machines—Models GKF'-303, All Hofliger and Karg machines are com¬
GKF-602, GKF-1500, and GKF-2500; the num¬ pletely automatic and require only compressed
bers represent the approximate output of filled air and a power for operation.
capsules per minute. All models can be modified Hofliger and Karg is represented in the
to accept powders, pellets, or tablets. In addition, United States by Robert Bosch Packaging Ma¬
the first three models may be equipped to handle chinery Division, Piscataway, NJ.
the filling of thixotropic liquids into hard gelatin
capsules, at some reduction of output.
Labels appearing in Figure 13-7, which de¬
picts H & K Model GKF-602, signify the follow¬ Macofar
ing: 1, empty capsule storage hopper; 2, recti¬ The Macofar fine of capsule filling equipment
fier; 3, bulk powder storage hopper; 4, capsule consists of three models: MT-12, MT-13/1, and
body transport segment; 5, closing station; and MT-13/2. Model MT-12 is shown in Figure
6, filled capsules ejection station, 13-10. All three models are low-to-medium-
In Models GKF-602, GKF-1500, and GKF- capacity machines, ranging from 5,000 filled
2500, capsules are handled 6, 15, and 25, at one capsules per hour (MT-13/1) and 10,000 cap¬
time, according to the respective model number. sules per hour (MT-13/2) to over 35,000 cap¬
The empty capsule feed provides for the removal sules per hour (MT-12).
of faulty capsules, and is checked by a vacuum All units are based upon a similar method of
system, which provides a signal upon feed inter¬ rectification and filling. The empty capsules are
ruption. The rectified empty capsules are in¬ rectified into bushings in a central plate. Separa¬
serted into individual cap and body segments tion of cap from body is accomplished by vac¬
bolted to the transport wheel. The segments are uum, and the body-carrying bushings are posi¬
then transported to the various work stations tioned under the dosator unit.
carrying the caps and bodies. Thus, only these The dosator units pick up powder to a prede¬
segments, along with the rectifier and the termined level from a level-controlled powder
tamps, require replacement for size change. hopper. The powder is lightly tamped within the
Removal of capsule bodies to the carrier is dosators, following which the units are raised,
mechanical with a vacuum assist, to ensure gen- the body-carrying bushing is aligned under
de handling of the capsules. After separation of them, and the powder is ejected into the open
cap and body, the cap segment is lifted before bodies.
retraction of the segment to remove the possibil¬ The body bushings are retracted to the central

380 • The Theory and Practice of Industrial Pharmacy

 FIG. 13-7. H & K Model 602 capsule filling machine. See text for explanation of labels 1 through 6. (Courtesy of Robert
Bosch GmbH, Waiblingen, West Germany.)

plate beneath the cap blocks, and closing of the G36/4 is rated at 150 capsules per minute, G36/2
capsule occurs. Prior to reuse, the capsule¬ at 300, G36 at 600, G37N at 1600, and G38 at
holding bushings are cleaned of powder by 1000. All models utilize the same general meth¬
means of air/vacuum. ods for both powder and capsule handling. In
Various filling options are available for materi¬ the following section, Models G36, G37N, and
als other than powders. G38 are briefly discussed.
The distributor for Macofar in the United The following identifications apply to the la¬
States is Production Equipment, Inc., Rochelle bels in the illustration of Model G36 (Fig. 13-
Park, NJ. 11): 1, empty capsule hopper and rectifier; 2,
cap holder removal station; 3, cleaning station;
4, powder dosing head; 5, bulk powder hopper;
mG2 6, cap holder replacing station; 7, capsule clos¬
Five models of continuous-motion filling ma¬ ing and ejection station.
chines are currently offered by mG2. Model In Model G36, the capsules are fed from the
r

CAPSULES • 381
 neously to all dosing units while the machine is
in operation. The cap container is repositioned
over the body block (6), and closing is accom¬
plished by both upper and lower closing pins (7).
Ejection is accomplished by compressed air.
Each station is equipped with a safety device
that automatically stops the machine in the
event of an irregularity. Capsule carrying hold¬
ers are cleaned by air prior to being returned to
the rectifier station.
Model G37 has recently been modified
(G37N) to provide several new and/or improved
features: the handling of empty capsules has
been improved, the powder handling system has
been modified to lessen powder dusting, several
noise-reduction features have been incorpo¬
rated, and both cleanup and size changing have
been simplified. Adjustments of weight control
and powder compression can be made externally
while the unit is operating.
Model G37N, shown in Figure 13-12, is a con¬
tinuous-motion turret machine that provides
approximately two and one-half times the filling
rate of the G36. As indicated previously, it also
employs a different capsule handling mecha¬
nism. It is composed of two main units. The first
unit provides capsule feeding, rectifying, and
opening in a manner similar to that of the G36,
but with a greater number of elements. The sec¬
ond unit provides capsule separation, dosage,
closure, and ejection. The higher output is ob¬
tained by providing 40 dosing nozzles and 40
pairs of capsule transfer holders. Dosage adjust¬
FIG. 13-8. K & K Model 1200/1500 capsule filling ma¬ ment is the same as for Model G36, providing
chine. (Courtesy of Robert Bosch GmbH, Waiblingen, West simultaneous control of the position of all dosing
Germany.) pistons.
Model G38 (Fig. 13-13) is a newly introduced
machine that is slightly slower than the G37N
storage hopper through individual tubes and (with 20 filling tubes versus 40), but is totally
rectified (1) into individual two-piece side hold¬ enclosed. As with the G37N, all weight adjust¬
ers on a continuous chain. The capsules are sep¬ ments can be made through external controls
arated within the two-piece holders by applying with the machine in operation. Several features
vacuum to the lower portion, which pulls the have been added to allow machine jogging,
body into it while the cap is retained in the powder-level control, and photoelectric shutoff
upper holder. As the chain and retaining blocks (if more than three successive unopened cap¬
progress through the cycle, the cap-containing sules are encountered), as well as automatic
upper holder (2) is moved aside to a recess at the ejection of certain other empty capsule defects.
outer end of the conveying holder, exposing the All mG2 models either run or can be fitted
lower holder containing the body. The powder is with attachments to allow them to run with pow¬
continuously mixed within the powder hopper ders, granules, or pellets. Models G37N and G38
(5) and is maintained at a constant level prior to can be supplied with auxiliary equipment to pro¬
discharge. The body-carrying units now are car¬ vide for presorting of the empty capsules, auto¬
ried under a series of 12 volumetric dosing noz¬ matic sampling of filled capsules, and an inspec¬
zles (4), each of which picks up the product from tion unit, based upon weight, for filled capsules.
a rotating container, first compressing and then The representative for mG2 in the United
ejecting the powder into the capsule bodies. Pre¬ States is Supermatic Packaging Machinery, Inc.,
cise weight adjustments may be made simulta¬ Fairfield, NJ.

382 • The Theory and Practice of Industrial Pharmacy

FIG. 13-9. H & K Model 2400 capsule filling machine. (Courtesy of Robert Bosch GmbH, Waiblingen, West Germany.)

Osaka method of powder feed, correct powder formula¬

The Osaka filling machine is a high-capacity, tions are essential, and limitations exist in the
continuous-motion machine recently introduced possible amounts with which to fill a given size
in the United States. The only model currently capsule.
available is the R-180 (Fig. 13-14), which has a Provision is made to remove unjoined cap¬
rated capacity of 70,000 to 165,000 capsules per sules during the rectification process and empty
hour. The unit handles either powder or granu¬ or broken capsules after filling.
lar materials. The Osaka equipment can be supplemented
The unit is totally enclosed, with external ac¬ with several pieces of auxiliary equipment, in¬
cess to the capsule and powder hoppers. cluding a cleaner/polisher unit that has a rated
The powder-filling principle utilized is unique capacity of up to 400,000 capsules per hour.
in that vibration is used to move the powder The Osaka distributor in the United States is
from the powder hopper to powder shoes and the Sharples-Stokes Division of the Pennwalt
from the powder shoes into the capsule bodies. Corporation, Warminster, PA.
Capsule bodies pass under the powder-filling
area, in two rows. Each row is fed by two vibra¬
tory units. The vibrators are externally con¬ Perry
trolled so that fill-weight adjustments can be The Model CF ACCOFIL machine offered by
made during machine operation. Because of this Perry utilizes the well-established ACCOFIL

CAPSULES • 383
 is doctored from the sides and tips of the nee¬
dles. The vacuum is held as the needle is posi¬
tioned over an empty body, at which time the
vacuum is broken and a light surge of air is ap¬
plied to expel the powder.
Following filling, the chain links are properly
realigned, and the body is moved into the cap by
the slow cam action of the 24 closing pins. Fol¬
lowing closing, the capsule is ejected by air from
the conveyor, at which time it is counted, and
the count is recorded by a digital readout on the
front panel. Cleaning of all bushings, as well as
the powder needles, is accomplished by high-
pressure air.
The Model CF ACCOFIL machine is available
through Perry Industries, Inc., Green Bay, WI.

Zanasi
The line of Zanasi equipment currently avail¬
able includes nine different units in four model
lines. With suitable change parts, all may be
capable of handling powders, pellets, or tablets.
Some models may be purchased with attach¬
ments to allow the insertion of smaller capsules,
and some may be capable of paste or liquid fill¬
ing.
FIG. 13-10. Macofar Model MT-12 capsule filling ma¬ Two models, the LZ-64 (Fig. 13-16) and
chine. (Courtesy of Macofar, Bologna, Italy.) AZ-20 (Fig. 13-17), retain the familiar intermit¬
tent operation of past Zanasi machines. The
LZ-64 is rated at about 4,000 capsules per hour,
method of powder dose control, which is unique while the AZ-20 speed is variable—from approx¬
in capsule filling (Fig. 13-15). The machine is a imately 9,000 to 20,000 capsules per hour.
continuous-motion rotary machine with a rated Two newer series consist of continuous-
output of up to about 60,000 capsules per hour; motion machines, but retain the dosator princi¬
it fills powder mixtures only. ple. The BZ series consists of four machines:
Capsules are rectified from 24 vertical tubes, BZ-40 (30,000/hour), BZ-72 (60,000/hour),
and are cammed into a body downward position BZ-110 (110,000/hour), and BZ-150 (150,000/
in a plate, from which they are dropped with a hour). The BZ-40 and BZ-72 can handle pow¬
vacuum assist into a conveyor chain of two ders, pellets, and tablets, while the BZ-110 han¬
parts, the lower containing the bodies and the dles only powders and granules. The BZ-150
upper containing the caps. A sensor system is handles powders only. A variety of auxiliary
present, which provides for rejection of un¬ equipment is available with the BZ series of
separated capsules and prevents ejection of pow¬ machines, including an empty capsule
der in the absence of a capsule body. The cap- presorter, a powder recovery system, a filled-
containing portion is caused to swing away from capsule sampling system, and a check weighing
the body portion by a guide rail. Filling is accom¬ system.
plished while the cap links are displaced, follow¬ Zanasi’s newest series is the Z-5000 (Fig.
ing which the chain links are repositioned over 13-18), consisting of the Z-5000-R1, rated at up
each other. to 70,000 capsules per hour; the Z-5000-R2,
Powder is supplied from a bulk supply hopper rated at up to 110,000 capsules per hour; and
to a powder pan via a screw feeder. The level in the Z-5000-R3, rated at up to 150,000 capsules
the pan is controlled to a constant level. In the per hour. With change parts, all are capable of
continuously rotating powder turret, 24 verti¬ filling powders, granules, and tablets. Special
cally operating, cam-controlled empty needles attention has been paid to safety devices and
are immersed into the powder, and a vacuum is acoustical treatments for operator protection.
applied, sucking the powder up (in a predeter¬ Zanasi equipment is available in the United
mined amount) into the needle. Excess powder States from Z-Packaging Systems, Monsey, NY.

384 • The Theory and Practice of Industrial Pharmacy

FIG. 13-13. mG2 Model G38 capsule filling machine. (Courtesy of mG2 Macchine Automatiche, Bologna, Italy.)

Operations conditions encountered before use, Table 13-1

gives an approximation of the volume that may
Empty Capsules be contained in the various sizes, along with the
Empty capsules are sold by sizes. The ones amounts of some powders that can be contained
most commonly employed for human use range in these sizes. The powder weights listed are
from size 0, the largest, to size 5, the smallest. approximate and vary with the amount of pres¬
Size 00 capsules may occasionally be required sure employed in hand filling, or with the type of
because of the volume of material to be filled, equipment utilized in machine filling.
but this size is not used commercially in large Much consideration should be given to tech¬
volume. Although capsules change dimensions niques for handling and storage of empty cap¬
to some extent with varied moisture content and sules in any production facility. This is of great

Table 13-1. Filling Capacity of Empty Capsules

Approx. Acetyl-
Capsule Volume Quinine Sodium salicylic Bismuth
Size (ml) Sulfate (g) Bicarbonate (g) Acid (g) Subnitrate (g)

0 0.75 0.33 0.68 0.55 0.8

1 0.55 0.23 0.55 0.33 0.65
2 0.4 0.2 0.4 0.25 0.55
3 0.3 0.12 0.33 0.2 0.4
4 0.25 0.1 0.25 0.15 0.25
5 0.15 0.07 0.12 0.1 0.12

386 • The Theory and Practice of Industrial Pharmacy

T^X~I
FIG. 13-15. Perry Model CF ACCOFIL capsule filling machine. (Courtesy of Perry Industries, Green Bay, WI.)

388 • The Theory and Practice of Industrial Pharmacy

 Regarding the empty capsules only, handling
is ideally carried on in areas within the relative
humidity range of approximately 30 to 45%,
since major moisture content changes do not
occur within these limits. If conditions drier
than these are necessitated because of the in¬
gredients being Med, exposures of the empty
capsules prior to filling should be minimized.
Strong consideration should be given to the use
of air-conditioned facilities to control both tem¬
peratures and humidity when high-speed filling
equipment is being operated.

Formulations
The problems encountered in handling pow¬
ders during mixing and filling operations are so
diverse as to preclude any but general com¬
ments. Although some problems are common to
all types of filling equipment, certain machines
themselves represent unique situations. Among
the general problems, two major ones can be
listed.
1. After the powder ingredients have been
homogeneously blended by any suitable tech¬
nique, the flow of the resultant mixture must be
adequate to ensure delivery of sufficient powder
to the capsules at the time of filling. De-mixing
must not occur during the powder handling in
the filling equipment itself.
2. Physical incompatibilities between active
ingredients, between diluents, or between active
ingredients and/or diluents and the capsule shell
may create problems.
The capsule seldom contains only the active
FIG. 13-16. Zanasi Model LZ-64 capsule filling machine. ingredient(s); most capsule formulations require
(Courtesy of Zanasi, S.p.A., Bologna, Italy.) the use of some diluent material. Because of the
wide range of materials encapsulated, no at¬
tempt can be made to outline specific criteria for
importance when use rates are high, as when the choice of suitable diluents. The following are
high-speed Ming equipment is used. three major general considerations.
Capsules as received from the supplier gener¬ 1. The powder mix must provide the type of
ally have moisture content between 12 and 15%, flow characteristics required by the equipment,.
and these levels are maintained during storage In the case of the^ifhv Parke-Davis. Hofliger
in the original container. Storage under high- ancTKarg. Osaka. andPerrv machines, powders
temperature conditions (above 100°F) must not musTTie freeTIowniE In the case of Zanasi,
be prolonged. Exposure to extremely high or ex¬ Macofar, Farmatic, and mG2 equipment, the
tremely low humidity conditions for extended powder must have sufficient cohesiveness to
periods after the containers are opened causes retain its slug form during delivery to the cap¬
the capsules to either gain or lose moisture. At sules. For example, when one is filling with ace-
high moisture levels, the capsules absorb mois¬ tylsalicylic acid, an excipient such as a flowable
ture, and may soften and become tacky. In se¬ cornstarch allows filling in the former case,
vere cases, the capsules may absorb sufficient whereas compactible excipients such as micro¬
moisture to cause them to deform under their crystalline cellulose are required in the latter
own weight. At low moisture levels, they become case. In all cases, the powder mixture must re¬
brittle and suffer dimensional changes, which tain its homogeneous composition without
may cause handling problems in the filling de-mixing during the machine handling opera¬
equipment. tions. Lubricants, such as a metallic stearate,

CAPSULES• 389
FIG. 13-17. Zanasi Model AZ-20 capsule filling machine. (Courtesy of Zanasi, S.p.A., Bologna, Italy.)

may be used in the former case; binders, such as ipated with each new mixture of materials. Re¬
mineral oil, are sometimes used in the latter. actions at elevated temperatures and humidities
Particle sizes and powder densities of all ingredi¬ should be studied, for effects not only on the
ents should be matched as closely as possible to contained powder mixture, but also on the gela¬
assist in the prevention of de-mixing. tin capsules. Studies such as these should in¬
2. Potential incompatibilities should be antic¬ clude an evaluation in the presence of probable

390 • The Theory and Practice of Industrial Pharmacy

 FIG. 13-18. Zanasi Model Z-5000 capsule filling machine. (Courtesy of Zanasi, S.p.A., Bologna, Italy.)

packaging materials. Evaluation of any test pro¬ materials other than the aforementioned, first
cedure should be based on sound statistical consideration should be given to materials that
techniques. are given a “Generally Recognized As Safe” des¬
- 3. The choice of excipients should be made ignation by the FDA. Obtaining approval of ma¬
with a view toward current Food and Drug Ad¬ terials that are not in this category can be an
ministration (FDA) regulations as they apply to expensive and time-consuming process, al¬
Investigational New Drug and New Drug appli¬ though there are occasions when it cannot be
cations. Any applicable foreign regulations also avoided.
should be considered. Some materials that may Materials that may be considered for improve¬
be useful as excipients are bentonite, calcium ment of flow characteristics (glidants and/or lu¬
carbonate, lactose, mannitol, magnesium car- bricants, as indicated earlier) may include the
bonafeTmagnesium oxide, silica gel, starch, talc, following: glycol esters, silicones, silicon diox¬
and tapioca powder. ide, metallic stearates, stearic acid, and talc.
TFTt is desirable for any reason to consider Oils that may be considered for use in assist-

CAPSULES • 391
 ing in the control of dusting, as well as in provid¬ to reclaim portions of a batch as it is processed,
ing additional cohesiveness to a powder mix, or off-line to weigh and sort a complete batch
could include any inert, edible, FDA-approved that has been shown statistically to have unac¬
material. ceptable weight variation.
The determination of amounts of diluents to The ROTOWEIGH is a high-speed capsule
be used is based on (1) the total amount of mate¬ weighing machine sold by Eh Lilly and Com¬
rial that can possibly be put in the capsule in pany (Fig. 13-19). The capsules are gravity-fed
relation to the amount of active ingredients to be onto vacuum pins for presentation to a unique
supplied by the capsule, and (2) the amounts of weight detection system, which measures the
lubricant and/or oil ('generally iriTfie order of 2%~ reflected energy (backscatter) of a low power
orTess) that can be used. Experimentation with x-ray beam directed at each capsule. This re¬
the”actual materials is the only positive way to flected energy is proportional to the weight of
arrive at these figures. the.filled capsule, permitting automatic rejec¬
Serious consideration should be given to the tion of any individual capsule above or below
choice of suitable control procedures for the fill¬ preset weights. The machine operates at 73,000
ing operations. In addition, it may be desirable to capsules per hour, and its accuracy is more than
provide 100% weight checking after filling. The adequate to assure compliance with the USP
control procedures must ensure that the fin¬ weight requirements.
ished, filled capsules meet the appropriate cur¬ The second unit is the Vericap 1200 machine
rent regulatory tests, e.g., weight variation, con- (Fig. 13-20), which is sold by Modem Controls,
tent uniformity, solubility, and/or disintegration^ IntrTEIk River, MN. It operates by detecting
Current legal requirements should Be ade¬ capacitance variation as filled capsules are pro¬
quately explored since there are wide differ¬ pelled at high speed by compressed air between
ences between countries. The weight variation two charged plates. The measured change in
test in USP XX has been replacedrirr USP XXI dielectric constant thus produced is correlated to
with the Uniformity of Dosage’ Units Tests the weight of the capsule. Capsules that are
However, the weight variation test, as official in overweight or underweight are then automati¬
USP XX, is still useful in machine set-up and cally separated from the acceptable capsules.
evaluation. The machine operates at a rate of 73,000 cap¬
The iveight variation test defined by USP XX sules per hour.
is a sequential test, in which 20 intact capsules A second test in USP XX that may apply to
are individually weighed and the average weight capsules is that for content uniformity, which is
is determined. The test requirements are met if performed when specified by individual mono¬
none of the individual weights are less than graphs. In this case, 30 capsules are selected, 10
90%, or more than 110%, of the average. If the of which are assayed by the specified procedure.
'original 2u do not meef these criteria, the indi¬ The requirements are met if 9 of the 10 are
vidual net weights are determined. These are within the specified potency range of 85 to
averaged, and differences are determined be¬ 115%, and the tenth is not outside 75 to 125%.
tween each individual net content and the aver¬ If more than 1, but less than 3, of the first 10
age. The test requirements are met (1) if not capsules fail outside the 85 to 115% limits, the
more than two of the individual differences are remaining 20 are assayed. The requirements axe
greater than 10% of the average, or (2) if in no met if all 30 capsules are within 75 to 125% of
case any difference is greater than 25%. the specified potency range, and not less than 27
If more than 2 but less than 6 net weights de¬ of the 30 are within the 85 to 115% range.
termined by the test deviate by more than 10% Broad generalizations about stability test pro¬
but less than 25%. the net contents are deter¬ grams cannot be made, since the question has to
mined for an additional 40 capsules, and the be answered according to each user’s criteria.
average is calculated for the entire 60 capsules. The tests should be based on adequate statistical
"Sixty deviations from the new average are calcu¬ design, however, and should include evaluation
lated. The requirements are met (1) if the differ¬ of not only active ingredient stability, but also
ence does not exceed 10% of the average in visual and mechanical aspects of the finished
more than6of the 60 capsules, and (2) if in no dosage form. These tests must include extended
case any difference exceeds 25%. storage at various elevated temperatures with
“Two new pieces of equipment determine the different humidity levels. Tests should include
weight of individual capsules, providing for the the filled capsules, both by themselves and in
automatic rejection of overfilled and underfilled the presence of all contemplated packaging ma¬
capsules. These machines may be used in-line terials.

392 * The Theory and Practice of Industrial Pharmacy

 FIG. 13-19. ROTOWEIGH capsule -weighing machine. (Courtesy of Eli Lilly & Co., Indianapolis, IN.)

Finishing 1. Pan polishing. Because of its unique design

Finished capsules from all filling equipment (primarily in the area of airflow), the Accela-
'. require some sort of dusting and/or polishing Cota tablet coating pan may be used to dust and
operation before the remaining operations of polish capsules.. A polyurethane or cheese cloth
inspection, bottling, and labeling are completed. liner is placedin the pan, and the liner is used to
Dusting or polishing operations vary according trap the removed dust as well as to impart a gloss
to the type of filling equipment used, the type of to the capsules.
powder used for filling, and the individual de¬ 2. Cloth dusting. In this method, the bulk-
sires for the finished appearance of the com¬ fillecfcapsules are rubbed with a cloth that may
pleted capsules. The following are the methods or may not be impregnated with an inert oil.
most commonly used, based on desired output, This procedure is a hand operation, but one that
formulation, required final appearance, and can handle reasonable volumes, and that results
so on. in a positive method for removal of resistant

CAPSULES • 393
FIG, 13-20. Vericap 1200 capsule weighing machine. (Courtesy of Modem Controls, Elk River, MN.)

materials. In addition, it imparts a somewhat

improved gloss to the capsules.
3. Brushing. In this procedure, capsules are
fed under rotating soft brushes, which serve to
remove the dust from the capsule shell. This
operation must be accompanied by a vacuuming
for dust removal. Some materials are extremely
difficult to remove by brushing, even to the
point of impregnating the brushes and causing
scratches or deformation of the capsules.
Commercial capsule sort/polish equipment
has become available. Some of the units, in addi¬
tion to the Accela-Cota pan, are as follows.
ROTOSORT is a new filled capsule sorting
machine sold by Rli Lilly, and Company (Fig.
Li-21). It is a mechanical sorting device that
removes loose powder, unfilled joined capsules,
filled or unfilled bodies, and loose caps. It can
handle up to 150,000 capsules per hour, and it
can run directly off a filling machine or be used
separately.
The Erweka KEA dedusting and polishing FIG. 13-21. ROTOSORT capsule sorting machine. (Cour¬
machine for hard gelatin capsules is sold in the tesy of Eli Lilly & Co., Indianapolis, IN.)

394 • The Theory and Practice of Industrial Pharmacy

United States by Key Industries, Engbshtown, capsules arises from the fact that the imprinting
NJ (Fig. 13-22). The unit is designed to handle operation may occasionally damage some cap¬
the output from any capsule filling machine. It sules. When filled capsules are imprinted, con¬
moves the capsules between soft plastic tassels tamination, poor print quality, and actual
against a perforated plastic sleeve, under vac¬ damage to the imprinting equipment result. Var¬
uum. Any residual powder is removed by the ious types and capacities of equipment are com¬
vacuum. mercially available for this purpose in the
Seidenader Equipment. Totowa, NJ, offers United States. The three major suppliers of this
two units that may be used separately or may be equipment are' Ackley Machine Corporation,
combined in the finishing of filled gelatin cap¬ Moorestown, inj,TT. W. Hartnett Company. Phil-
sules! ~A~b~eIt is available that presents capsules adelpfilaHPA; and the MarkemMacmne Com¬
for visual inspection, and it may include a vac¬ pany, Keene, NH.
uum system to automatically remove unfilled ^Hartnett offers a variety of machines with out¬
capsules. Cleaning and polishing machine puts as high as 500,000 capsules per hour
PM60 (Fig. 13-23) may be used to polish fin¬ (model B, Fig. 13-24). Also available is a unit
ished capsules. It consists of two lamb’s wool that prints around the circumference of the cap¬
belts moving in opposite directions. The cap¬ sules, as opposed to a longitudinal imprint; how¬
sules are carried on the lower belt, and both belts ever, this machine operates at a slower rate. A
are under suction. lower-capacity unit (up to 250,000 capsules per
hour) allows printing on both sides of the cap¬
sule, in different colors if desired.
Special Techniques Markem offers three models, which range
Some special techniques that may be applied from approximately 60,000 to 250,000 capsules
to the capsules as a dosage form include the fol¬ per hour (Model 280A, Fig. 13-25). All three
lowing. models allow for two-sided printing, but not cir¬
1. Imprinting is a convenient method by cumferential.
which company and/or product identification Ackley offers a straight-line imprinter with an
information can be placed upon each capsule. output rate of about 500,000-capsules per hour,
Thd\fmpnntIng)operation is best performed on and has recently announced a new circumferen¬
the empty capsules, although fffled capsules can tial printer rated at about the same output.
be printedTThe~preference for imprinting empty In addition, several firms, including the major
empty capsule suppliers, offer custom imprint¬
ing services.
All imprinting machines operate on a rotogra¬
vure process, and a wide variety of colors of edi¬
ble inks, both water- and solvent-based, are com¬
mercially available.
2. Special purpose capsules are capsules to
which a special treatment has been given in an
attempt to retard the solubility in some manner.
This may be done in an attempt to delay absorp¬
tion of the active ingredient, or to provide en¬
teric properties. Normal solubility for gelatin
capsules, either empty or filled, is not defined by
the USP XX. However, the General Service
Administration, in Federal Specification #U-C-
115b (2/10/58), defines solubility limits for
empty capsules as follows: (a) water resistance—
fails to dissolve in water at 20 to 30°C in 15 min;
(b) acid solubility—dissolves in less than 5 min
in 0.5% aqueous HC1 (w/w) at 36 to 38°C.
None of the following is used for any commer¬
cial products as far as is known and cannot be
seriously recommended except for experimental
purposes, because of generally unpredictable
FIG. 13-22. Erweka KEA capsule dedusting and pol¬
results.
ishing machine. (Courtesy of Erweka-Apparatebau, a. Formalin treatment has been employed to
Heusenstamm, West Germany.) modify the solubility of gelatin capsules. Expo-

CAPSULES • 395
FIG. 13-23. Seidenader Model PM60 capsule polishing machine. (Courtesy of Seidenader Maschinenbau Munchen, West
Germany.)

sure to formalin vapors or treatment with aque¬ of insolubilization, or indeed, to prevent ulti¬
ous formalin results in an unpredictable de¬ mate complete insolubility.
crease in solubility of the gelatin film, owing to b. Various coatings have been used in an ef¬
cross-linkage of the gelatin molecule initiated by fort to provide similarly modified solubility char¬
the aldehyde. This result may also be noted if acteristics. These coatings include salol, shellac,
the product being filled contains aldehydic ma¬ cellulose acetate phthalate, and certain resins
terials, or if aldehyde flavorants are added. Be¬ that have usually been applied by usual pan
cause of the nature of the reaction initiated in coating techniques.
this manner, it is difficult to control the degree Gelatin capsules do, however, provide a con-

396 • The Theory and Practice of Industrial Pharmacy

 venient way to deliver pellets or granular mate¬
rial when delayed or prolonged release proper¬
ties have been incorporated in all or portions of
the material to be filled.
3. Separation of incompatible materials (a
technique used for some commercial products)
is carried out by the use of a two-phase fill in the
capsule. One phase consists of either a soft cap¬
sule, a smaller hard capsule, a pill, or a suitably
coated tablet that is filled into each capsule. Fol¬
lowing this as a second phase, a powder fill is
added in the usual manner. If this technique is
used on commercial filling equipment, modifica-
- tions must be made to the filling cycle of the
machine. These changes would include, at min¬
imum, the necessary changes in the machine
operation to allow materials to be loaded at two
points during the filling cycle. Tamp type pow¬
der filling machines require the disabling of the
tamp cycle.
4. Recently, there has been a revival of inter¬
est in the filling of conventional two-piece gela¬
tin capsules with liquids and semisolids. Hard
gelatin capsules were commonly used as early as
the 1890s for oils, ethereal extracts, and pill
masses,1 but the ability to fill the capsules on
semiautomatic and automatic equipment is a
FIG. 13-24. Hartnett Model B capsule imprinting ma¬ recent development. The formulations used for
chine. (Courtesy of R. H. Hartnett Co., Philadelphia, PA.) filling are usually semisolids at ambient temper-

FIG. 13-25. Markem Model 280A capsule imprinting machine. (Coursety of Markem Co., Keene, NH.)

capsules • 397
atures, which are melted to allow Ming.2 Or 5. A recent series of developments—
they are thixotropic formulations in which the primarily in Europe—have resulted in allowing
shear developed in Ming allows pumping, but the use of a liquid M into two-piece hard cap¬
whose high viscosity when shear is absent pre¬ sules. The Ms are either thermosetting (and
vents leakage after Ming. Quantitative assess¬ Med warm) or thixotropic. Modified commercial
ment of the gastric emptying of hard gelatin cap¬ equipment is available for filling.
sules Med with thixotropic liquids can be made
in terms of the lag time prior to emptying, and
the slope of the first order emptying curve. Re¬ References
sults have shown that the viscosity of the M has
1. Francois, D., and Jones, B.E.: Man. Chem. Aerosol
no significant influence on the emptying charac¬
News, 37:37, 1979.
teristics of these dosage forms.3 Machines for 2. Hunter, E., Fell, J.T., Sharma, H., and McNeilly, A.M.:
filling semisolid materials are currently available Die Pharm. Ind., 44:90, 1982.
from Robert Bosch GmbH, Elanco, Harro 3. Hunter, E., Fell, J.T., Sharma, H., and McNeilly, A.M.:
Hofliger, and Zanasi. Die Pharm. ind., 45:443, 1983.

becoming more acceptable for pediatric and geri¬

PART TWO atric use. Vaginal use is confined to applications
that require the medication to be inserted at
bedtime. Because of the action of the sphincter
muscle, rectal use is not similarly limited.
Soft Gelatin 3. As a specialty package in tube form, for

Capsules human and veterinary single dose application of

topical, ophthalmic, and otic preparations, and
rectal ointments.
J. P. Stanley
In the cosmetic industry, these capsules may
be used as a specialty package for breath fresh¬
eners, perfumes, bath oils, suntan oils, and vari¬
ous skin creams.

Many pharmaceutical companies have the

equipment and facilities for the development Methods of Manufacture
and production of tablets, liquids, and hard-shell Soft gelatin capsules have been available
capsule products, but they usually depend upon since the middle of the nineteenth century.
custom manufacturers for the development and Originally, they were made one at a time: leather
production of soft gelatin capsules. The custom molds—and later, iron molds—were used for
manufacturers are specialists in this field, owing shaping the capsule. The capsules were Med by
primarily to economic, patent, and technologic medicine dropper and sealed by hand with a
factors. Although few become directly involved “glob” of molten gelatin. Since those early days,
in the manufacture of soft capsules, pharmaceu¬ many methods of capsulation have been pro¬
tical chemists must be prepared to investigate posed and patented, but this discussion is con¬
this dosage form and to participate in its devel¬ fined to equipment of commercial significance
opment, either in their own laboratories or in in present use.
cooperation with the technical personnel of a As technology advanced, the individual iron
custom manufacturer. molds gave way to multiple molding units, and
Owing to their special properties and advan¬ these eventually led to sets of plates containing
tages, soft gelatin capsules are used in a wide die pockets. The ylate process is the oldest com¬
variety of industries, but they are used most mercial method of manufacture, but today this
widely in the pharmaceutical industry. Billions equipment can no longer be purchased, and
of capsules are made each year in various sizes consequently, only a few companies still use this
and shapes (Fig. 13-26), and in a variety of col¬ ' process. The plate process—a batch process that
ors and color combinations. Their pharmaceuti¬ requires two or three operators for each ma¬
cal applications are: chine—has given way to the more modem con¬
1. As an oral dosage form of ethical or proprie¬ tinuous processes, which require considerably
tary products for human or veterinary use. less manpower for operation.
2. As a suppository dosage form for rectal The continuous processes became a commer¬
use,1 or for vaginal use. Rectal dosage forms are cial reality in 1933, when the late R. P. Scherer

398 • The Theory and Practice of Industrial Pharmacy

 1 2 3 4 5 6 7 ±3%. The Scherer machine cannot be pur¬
o o O o o o o chased or leased, but the Scherer organization
9 28 40 40T 80T 90 provides plant and laboratory facilities for the
o o cy o
o

ROUND
O’ manufacture of this dosage form in the United
States and nine foreign locations.
The early success of the rotary die process led
others to develop continuous methods of soft
gelatin capsule manufacture. One such method,
1 2 3 4 5 6 7.5 10 12
known as the reciprocating die process, was an¬
0 O o 0 0 0 0 0 0 nounced in 1949 and was developed by the
Norton Company, Worchester, MA. Another
16 20 30 40 60 80 85 110 continuous process, also announced in 1949,
0 0 0 0 0 0 o 0 was developed by the Lederle Laboratories Divi¬
sion of the American Cyanamid Company and
OVAL has been used solely in the manufacture of that
company’s products. This equipment, known as
the Accoqel machine, is unique in that it is the
3 4 5 6 8 9.5 only equipment that accurately fills powdered
* ^ $ dry solids into sott gelatin capsules.
11
II 14
l*t 16
IU 20
ZU 90 360 A discussion of the comparative advantages
and disadvantages of the foregoing four proc¬
^ ^ ^ ^ esses—plate, rotary die, reciprocating die, and
Accogel machine—is beyond the scope of this
OBLONG chapter and would have little instructive value,
since the pharmaceutical chemist seldom has
the opportunity to choose between the four types
5 6 17.5 30A 30B 35 45 of equipment. One must consider, however, that
for maximum production efficiency, the contin¬
uous processes demand almost 24 hours per
day, 5 (preferably 7) days per week, of continu¬
ous operation. Thus, medicament formulations
55 65 90 160 250 320 480
must be so designed as to maintain their desired
physical characteristics during this period of
operation as well as during periods of weekend
shutdowns, should they occur. The production
capacity of each of these machines is deter¬
mined by (1) die size, which determines the
number of die pockets on the standard-sized die
plate, rotary die, or reciprocating die; (2) the
6 17 30 35 80 speed of the machine (of the operators for the
MISC. plate process); and (3) the physical characteris¬
tics of the material to be capsulated. Formula¬
tions are designed to achieve maximum produc¬
FIG. 13-26. Sizes and shapes of soft gelatin capsules tion capacity consistent with maximum physical
(1 cc = 76.23 m). Numbers represent the nominal capac¬ and ingredient stability and therapeutic efficacy
ity in minims. (Courtesy of R.P. Scherer Corporation, All of the aforementioned equipment is lim¬
Troy, Ml.) ited to the production of gelatin capsules. Other
films and film-forming polymers have not as yet
been successfully adapted for use on these ma¬
invented the rotary die process. Prior to this in¬ chines. An interesting review of the patent liter¬
vention, soft gelatin capsules were not looked on ature, covering capsule technology, has been
favorably by the pharmaceutical industry, owing published.2
to the relatively large amount of the capsulated
material (15 to 20%) lost during manufacture,
and to the variation in the net content of the The Nature of the Capsule Shell
capsule (possibly 20 to 40%). The rotary die The capsule shell is basically composed of gel¬
process reduced manufacturing losses to a negli¬ atin, a plasticizer, and water; it may contain ad¬
gible figure and content variation to less than ditional ingredients such as preservatives, color-

CAPSULES * 399
ing and opacifying agents, flavorings, sugars, prove the ingredient and physical stability of the
acids, and medicaments to achieve desired ef¬ product.7
fects. \Iron is always present in the raw gelatin, and
Gelatin’s chemical, physical, and physiologi¬ its concentration usually depends on the iron
cal properties make it an ideal substance for the content of the large quantities of water used in
capsulation of pharmaceutical products.3-6 The its manufacture. Gelatins used in-the manufac¬
gelatin is USP grade with additional specifica¬ ture of soft gelatin capsules should not contain
tions required by the capsule manufacturer. The more thanT5~ppm of this element, because-of its
additional specifications concern the Bloom effect on Food, Drug, and Cosmetic (FD&C) cer¬
strength, viscosity, and iron content of the gela¬ tified dyes and its possible color reactions with
tins used. organic compounds.
The Bloom or ael strength of gelatin is a mea¬ The plasticizers used with gelatin in soft cap¬
sure of the cohesive strength of the cross-linking sule manufacture are relatively few. Glycerin
that occurs between gelatin molecules and is USP, Sorbitol USP, Pharmaceutical Grade Sorbi¬
proportional to the molecular weight of the gela- tol Special, and combinations of these are the
tnTHBloom is determined by measuring the most prevalent. The ratio by weight of dry plasti¬
weight in grams required to move a plastic cizer to dry gelatin determines the “hardness” of
plunger that is 0.5 inches in diameter 4 mm into the gelatin shell, assuming that there is no effect
a 6%% gelatin gel that has been held at 10°C for from the capsulated material. (Some examples
17 hours. Bloom may vary with the require¬ of glycerin/gelatin ratios are shown in Table 13-2
ments of the individual custom manufacturer along with their typical usage.) The ratio by
but ranges from 150 to 250 g. In general, with all weight of water to dry gelatin can vary from 0.7
other factors being equal, the higher the Bloom to 1.3 (water) to 1.0 (dry gelatin) depending on
strength of the gelatin used, the more physically the viscosity of the gelatin being used. For most
stable is the resulting capsule shell. The cost of formulations, however, it is approximately 1 to
gelatin is directly proportional to its Bloom nr gel 1. Since only water is lost during the capsule
strength and thus is an important factor in the drying process, the percentage of plasticizer and
cost of soft capsules. Consequently, the higher gelatin in the shell is increased, but the impor¬
Bldomgelatins are only used when necessary to tant plasticizer to gelatin ratio remains un¬
improve the physical stability of a product or for changed.
large capsules (over 50 minims), which require In general, the additional components of the
greater structural strength during manufacture. gelatin mass are limited in their use by (1) the
Viscosity of gelatin, determined on a 6%%
concentration of~gelatin in water at 6Q°C, is a
measure of the molecular chain length and de- Table 13-2. Typical Shell “Hardness” Ratios
termines the manufacturing characteristics of and Their Uses
the gelatin film. The desired film characteristics
Ratio
are usually based on standard gelatin formula¬
Dry Glycerin/
tions, which allow production at a set sealing
Hardness Dry Gelatin Usage
temperature and definite drying conditions, and
produce a firm, nontacky, nonbrittle, pharma¬ Hard 0.4/1 Oral, oil-based, or
ceutically elegant product. The viscosity for gel¬ shell-softening pro¬
atin can range from 25 to 45 millipoise, but the ducts and those des¬
individual manufacturer sets a narrow range, tined primarily for
e.g., 38 ± 2 millipoise, for a particular type of hot, humid areas.
gelatin, to make use of a standard formulation
Medium 0.6/1 Oral, tube, vaginal oil-based,
and thus conform to standard production condi¬
water-miscible-based,
tions. or shell-hardening pro¬
Lowjudscositv—(25 to 32 millipoise), high- ducts and those destined
Bloom H 80 to 250 gj gelatins are used in con¬ primarily for temperate
junction with the capsulation of hygroscopic areas.
vehicles'or solids, and standard gelatin formulas
Soft 0.8/1 Tube, vaginal, water-
can be modified so as to require up to 50% less
miscibfe-based or shell¬
water for satisfactory operation on the capsulat¬
hardening products and
ion machine. These modified formulas afford
those destined primarily
less opportunity for the hygroscopic fill materials
for cold, drv areas^
to attract water from the shell and thereby im¬

400 • The Theory and Practice of Industrial Pharmacy

amounts required to produce the desired effect; size. Also, before a color is chosen, mixtures
(2) their effect on capsule manufacture; and (3) should be checked in the laboratory by addition
economic factors. Examples of ingredients fall¬ of water to ascertain if reactions take place to
ing into the first two categories are shown in cause the mixture to darken, gs in the case of
Table 13-3. ascorbic acid and iron salts in vitamin and min¬
The addition of medicaments to the gelatin eral formulations, or as in the case of reactions
mass usually is not recommended, for economic between iron and compounds of a phenolic na¬
reasons, since only 50% of the gelatin mass is ture. Since iron is present in gelatin, dark spots
incorporated into the capsules. This results in a may occur in the shell owing to~the migration of
50% loss of the added medicament. However, water-soluble iron-sensitive ingredients from
certain highly active, relatively inexpensive the fifhrnatenal Into the shell. As a rule, clear
compounds such as benzocaine (3 mg/capsule colors~Qsually are employed with clear type fill
shelf) in chewable cough capsules mav be used materials, and opaque colors are used with sus¬
successfully. pensions, but the reverse of this rule can be cho¬
Additional comments relative to the color of sen to achieve a particular appearance or for in¬
the gelatin shell are in order, since color is such gredient stability purposes. For special effects or
an important aspect of all products. This is par¬ identification purposes, two colors, both opaque
ticularly true of soft gelatin capsules, in which or one opaque and one clear, may be chosen
the color of the capsule can be definitely affected since the manufacturing process involves two
by the color or type of material capsulated. As a gelatin films.
general policy, the color of the capsule shell A publication by Horn and co-workers de¬
should never be lighter in hue than the capsu¬ scribes a gelatin disk method for the determina¬
lated material. tion of the effects of agitation, temperature, dis¬
More specifically, darker colors are more ap¬ solution medium, and shell composition on the
propriate for large-size (14 to 20 minim oblong) dissolution rate of soft gelatin capsules.8 This
oral products, since they will not accentuate the information should be helpful in the formulation
of gelatin capsules for various purposes.
From the foregoing discussion on the gelatin
Table 13-3. Additional Components of the Gela¬ shell, one may conclude that the pharmaceutical
tin Mass chemist must rely heavily on the experience of
Ingredient Concentration Purpose
the custom capsule manufacturer. However, in
order to choose the proper gelatin, gelatin for¬
Category I mula, and color, the custom manufacturer must
Methylparaben, 1 rely on the technical and product information
4 parts; Propyl- } 0.2% Preservative designed and developed by the pharmaceutical
1
paraben, part J chemist. With such mutual cooperation and free
FD&C and D&C
exchange of information, new products or dos¬
water-soluble dyes, age forms can be efficiently developed.
certified lakes,
q.s. Colorants
pigments, and vege¬
table colors, alone The Nature of the Capsule
or in combination
Content
Titanium dioxide 0.2 to 1.2% Opacifier Soft gelatin capsules can be used to dispense a
Ethyl vanillin 0.1% Flavoring for variety of liquids and solids. Requirements and
odor and taste specifications of these materials vary, depending
on the equipment of the manufacturer, but
Essential oils to 2% Flavoring for
there are basic precepts that may be used as a
odor and taste
guide for the formulation and production of
Category II commercially and therapeutically acceptable
Sugar (sucrose) to 5% To produce chew- capsules, regardless of method of capsulation.
able shell and The formulation of the capsule content for each
taste product is individually developed to fulfill the
specifications and end-use requirements of the
Fumaric acid to 1% Aids solubility;
product.
reduces aldehydic
Except for the Accogel process, which is pri¬
tanning of gelatin
marily concerned with the capsulation of dry

CAPSULES • 401
powders, the content of a soft gelatin capsule is a dient oils as fish oil may also function as a sol¬
liquid, or a combination of miscible liquids, a vent, or as the suspending medium for one or
solution of a solid(s) in a liquid/s), or a suspen- more additional active ingredients, as in vitamin
siofl of a solid( s) in a liquid(s). All such materials capsules.
for capsulation are formulated to produce the All liquids, solutions, and suspensions for cap¬
smallesTpossible capsule consistent with maxi¬ sulation should be homogeneous and air-free
mum ingredient and physical stability, thera¬ (vide infra), and preferably should flow by grav¬
peutic effectiveness, and production efficiency. ity at room temperature, but not at a tempera¬
Once the smallest capsule size is determined, ture exceeding 35°C at the point of capsulation,
personnel in the sales Or marketing departments since the sealing temperature of the gelatin
usually choose the color, shape, and ultimate films is usually in tfte range of 37 to 4Q°C. In
size of the retail product, unless there is a tech¬ general, liquids ranging in viscosity from ethyl
nical or production reason for the development ether (0.222 cp at 25°C)9 to heavy adhesive mix¬
chemist to specify a particular size, shape, and tures (exceeding 3000 cp at 25°C) may be en¬
color. The maximum capsule size and shape for capsulated, but there are some exceptions since
convenient oral use in humans is the 20 minim the property of viscosity alone is not the sole cri¬
oblong, the 16 minim oval, or the 9 minim round terion. Liquids that exhibit the rheologic prop¬
as shown in Figure 13-26. erty of tack or tackiness, such as glycerin
Liquids are an essential part of the capsule (954 cp at 25°C),9 are exceptions, since such liq¬
content. Only those liquids that are both water- uids can eventually cause the binding of slide
miscible and volatile cannot be included as valves and pumps in the capsule filling mecha¬
major constituents of the capsule content since nism. Also, preparations for encapsulation
therein migrate' into the hydrophilic gelatin should have a pH between 2.5 and 7.5, since
shell and volatilize from its surface. Water, ethyl preparations that are more acidic can cause hy¬
alcohol, and, of course, emulsions fall into this drolysis and leakage of the gelatin shell, and
category. Similarly, gelatin plasticizers such as preparations that are more alkaline can tan the
glycerin and propylene glycol cannot be major gelatin and thus affect the solubility of the shell.
constituents of the capsule content, owing to The capsulation of water-immiscible liquids is
tfaeirsoftening effect on the gelatin shell, which the simplest form of soft gelatin capsulation and
thereby makes the capsule more susceptible to usually requires little or no formulation. The
the effects of heat and humidity. As minor con¬ minimum size capsule depends on the dosage
stituents (up to about 5% of the capsule con¬ desired, the minimum fill volume being calcu¬
tent), water and alcohol can be used as cosol¬ lated from the specific gravity of the liquid. A die
vents to aid in the preparation of solutions for size and shape may then be chosen from those
capsulation. Also, up to 10% glycerin and/or pro¬ shown in Figure 13-26. The nearest die size
pylene glycol can be used as cosolvents with pol¬ above the calculated fill volume may be used, or
yethylene glycol or other liquids that have a any larger die may be chosen if the active ingre¬
shell-hardening effect when capsulated alone. dient is to be diluted for some reason. For exam¬
There are a large number of liquids that do not ple, a 25,000-unit vitamin A capsule using vita¬
fall into the foregoing category and thus can min A palmitate (1,000,000 units A/g) as a
function as active ingredients, solvents, or source for the vitamin A would have a minimum
vehicles for suspension-type formulations. fill volume of about 0.45 minims, and thus could
Thesejiquids include aromatic anij_alip.hatic be diluted to any size capsule desired. On the
hydrocarbons, chlorinated hydrocarbons, and other hand, the same potency capsule using fish
high-molecular-weight alcohols. estersTafld or¬ oil (50,000 units A/g) as a source for the vitamin
ganic acidsTMany of these are used in veteri¬ A would have a minimum fill volume of about
nary, cosmetic, and industrial products. For 8.8 minims.
human use, however, the pharmaceutical chem¬ The minimum fill volume for water-miscible,
ist is often limited in his selection or use of a nonvolatile liquids, such as polysorbate 80, is
particular liquid because of government regula¬ determined in the same manner. Because of
tions, product performance specifications, ingre¬ their hygroscopic nature, however, they cause
dient incompatibilities, and liquid-solid adsorp¬ water to migrate from the gelatin shell into the
tion characteristics. The most widely used fill material. This migration is rapid and could
liquid’s for human use are oily active ingredients amount to 20% of the weight of the miscible liq¬
(clofibrate), vegetable oils /soybean oil), mineral uid. During the drying period of the capsule,
oil, nonionic surface~active agents fpolvsorhate most of this water returns to and passes through
SO), and polyethylene glvcols f400 and 600Y ei- the gelatin shell, but up to 7.5% of the original
ther alone or in combination. Such active ingre¬ water can remain in the fill material, depending

402 • The Theory and Practice of Industrial Pharmacy

 on the hydrophilic properties of the liquid. Thus, (liquid or solid) that reduces their effect on the
for liquids of this type, a safety factor must be shell. Examples of such solids are strong acids
used in establishing the minimum fill volume (citric), strong alkalies (sodium salts of weak
and in choosing the die.* acids), salts of strong acids and bases (sodium
Although oily liquids do not retain moisture, chloride, choline chloride), and ammonium
water does pass from the shell of the capsule salts. Also, any substance that is unstable in the
into the fill material and out again during the presence of moisture (e.g., aspirin) would not
manufacture and drying of these capsules. This exhibit satisfactory chemical stability in soft gel¬
is important for the formulator to remember, atin capsules.
since such water transfer can and does have a The capsulation of suspensions is the basis for
bearing on formulations in which oily liquids are the existence of a large group of products. Again,
used as solvents or as vehicles for suspensions. the design of suspension type formulations and
If such suspensions contain hydrophilic solids, the choice of the suspending medium are di¬
water may be retained up to 3% by weight of the rected toward producing the smallest size cap¬
hydrophilic material. sule having the characteristics previously de¬
Combinations of miscible liquids often are scribed, i.e., maximum production capacity
used to produce desired physiological results consistent with maximum physical and ingredi¬
such as increased or more rapid absorption of ent stability and therapeutic efficacy.
active ingredient (vitamin A and polysorbate The fonnulation of suspensions for capsula¬
80); or to produce desired physiochemical re¬ tion follows the basic concepts of suspension
sults, such as improved flow properties (dilution technology. Formulation techniques, however,
or partial substitution with a thinner liquid), or can vary depending on the drug substance, the
improved solubility (steroid with oil and benzyl desired flow characteristics, the physical or in¬
alcohol). gredient stability problems, or the biophar¬
Except for when the Accogel process is used, maceutical properties desired. In most in¬
solids are filled into soft gelatin capsules, in the stances, these techniques must be developed
form of either a solution or a suspension. The through the ingenuity of the formulating chem¬
preparation of a suitable solution of a solid me¬ ist; however, in the formulation of suspensions
dicament should be the first goal of the pharma¬ for soft gelatin encapsulation, certain basic in¬
ceutical chemist. Usually, a solution is more formation must be developed to determine mini¬
easily capsulated and exhibits better uniformity, mum capstile'size.
stability, and biopharmaceutical properties than One laboratory tool for this puipose is known
does a suspension. For oral products, the medic¬ as the “base adsorption’' of the sohd(s) to be sus¬
ament must have sufficient solubility in the sol¬ pended. Base adsorption is expressed as the
vent system so that the necessary dose is con¬ number of grams of liquid base required to pro¬
tained in a maximum fill volume of 16 to 20 duce a capsulatable mixture when mixed with
minims (1 to 1.25 cc). one gram of solid(s). The base adsorption of a
Solids that are not sufficiently soluble in liq¬ solid is influenced by such factors as the solid’s
uids or in combinations of liquids are capsulated particle size and shape, its physical state (fi¬
as suspensions. Most organic and inorganic sol¬ brous, amorphous, or crystalline), its density, its
ids or compounds may be capsulated. Such ma¬ moisture content, and its oleophilic or hydro¬
terials should be 80 mesh or finer in particle philic nature.
size, owing to certain close tolerances of the cap¬ In the determination of base adsorption, the
sulation equipment and for maximum homoge¬ solid(s) must be completely wetted by the liquid
neity of the suspension. Many compounds can¬ base. For glycol and nonionic type bases, the
not be capsulated, owing to their solubility in addition of a wetting agent isls^dom required,
water and thus their ability to affect the gelatin but for vegetable oil bases, complete wetting of
shell, unless they are minor constituents of a the sohcKsThTnotachieved withouTanadditive.
formula or are combined with a type of carrier Soy lecithin. atlTconcentration of 2 to 3% by
weight of the oil, serves excellentlylvr this pur
pose, ancTbeing a natural product, is universally
* For example, a capsule to contain 500 mg of Polysorbate
.. ... , , , / 0.5g x 16.23 minim \
accepted for food and drug use. Increasing the
80 would have a calculated -r-rr-/ concentration above 3% appears to have no
v 1.08g /
fill volume of about 7.5 minims. Assuming, how¬ added advantage.
ever, that there is 5% residual water in the dry A practical procedure for determining base
capsule, the final fill volume would be about 8 minims adsorption and for judging the adequate fluidity
.525g x 16.23minimi of a mixture is as follows. Weigh a definite
1.08g I' amount (40 g is convenient) of the solid into a

CAPSULES • 403
 150-ml tared beaker. In a separate 150-ml taxed concentrations of 50 mg or less, since the small¬
beaker, place about 100 g of the liquid base. Add est capsules can accommodate such quantities.
small increments of the base to the solid, and If such material is to be used in combination,
using a spatula, stir the base into the solid after however, the data become necessary to allow for
each addition until the solid is thoroughly wet¬ its inclusion in the formulation. The conven¬
ted and uniformly coated with the base. This ience of using M/g factors is particularly evident
should produce a mixture that has a soft oint¬ in the vitamin field, where there may be many
ment-like consistency. Continue to add liquid ingredients and numerous combinations. Since
and stir until the mixture flows steadily from the the minim per gram factors are additive, they
spatula blade when held at a 45-degree angle can be used for a more rapid calculation of cap¬
above the mixture. The flow is even and contin¬ sule size than can be given by the preparation of
uous, and not in “globs.” Attention also should the many possible mixtures in the laboratory.
be given to the nature of the “cut-off” quality of See Table 13-4 for BA and M/g data on some typ¬
the mixture. As the mixture tends to stop flow¬ ical solids.
ing, proper cut-off is exhibited when the stream The final formulation of a suspension invaria¬
contracts rapidly upward toward the spatula bly requires a suspending agent to prevent the
blade rather than “stringing out” in intermediate settling of the solids and to maintain homogene¬
flow. ity prior to, during, and after capsulation. The
At the conclusion of the foregoing test, the nature and concentration of the suspending
base adsorption is obtained by means of the fol¬ agent vary, depending on the job to be done.
lowing formula: Also, a rather delicate balance must be achieved
between the requirement for a stable suspension
Weight of Base _ and the requirement for the mixture to have the
Base Adsorption proper flow characteristics. There is evidence,
Weight of Solid
\>5 too, that the proper suspending agent coats the
suspended solids, imparting a certain lubricity
The base adsorption mixture is milled or ho-
to them and thereby aiding capsulation. Also,
^Yjmogenized, and deaerated (a desiccator under
the coating can prevent contact with possible
yj] vacuum is suitable), and the specific gravity is
incompatible components in the mixture. Of the
taken. The specific gfSVlfyisthe weight of mlx-
examples shown in Table 13-5, the most widely
^ ture (W) per cubic centimeter or per 16.23 min¬
used suspending agent for oily bases is wax mix¬
ims (V). As in the case of liquids and solutions,
ture, and in nonoily bases, the polyethylene gly¬
the specific gravity may be used to determine
cols 4000 and 600(1
the die size required for a given quantity of the
In all instances, the suspending agent used is
particular mixture.
melted in a suitable portion of the liquid base,
The base adsorption is used to determine the
and the hot melt is added slowly, with stirring,
“minim per gram” factor (M/g) of the solid(s).
into the bulk portion of the base, which has been
The minim per gram factor is the volume in
preheated to 40°C prior to the addition of any
minims that is occupied by one gram (S) of the
solids. The solids are then added, one by one,
solid plus the weight of liquid base (BA) required
with sufficient mixing between additions to en¬
to make a capsulatable mixture. The minim per
sure complete wetting. Incompatible solids are
gram factor is calculated by dividing the weight
added as far apart as possible in the mixing order
of base plus the gram of solid (BA + S) by the
to prevent interaction prior to complete wetting
weight of mixture (W) per cubic centimeter or
by the base.
16.23 minims (V). A convenient formula is:
Additional aids to formulation involve the
physical and ingredient stability of the capsules.
There should be little concern with oxidation or
the effects of fight as a cause of ingredient insta¬
bility, since the gelatin shell is an excellent oxy¬
Thus, the lower the base adsorption of the gen barrier and may be opacified.10,11
solid(s) and the higher the density of the mix- Most ingredient stability problems are associ¬
Ture, the smaller the capsule will be. This also ated with the available moisture from the gelatin
indicates the importance of establishing specify shell, which when absorbed into the capsule
cations for the control of those physical proper¬ content, can cause areas of high concentration
ties of a solid mentioned previously that can af¬ of water-soluble solids, leading to ionization and
fect its base adsorption. interaction of the solids. Such problems may be
The BA and M/g data need not be obtained on alleviated or eliminated by employing a less sol¬
any material that is to be capsulated alone at uble salt (procaine penicillin instead of potas-

404 • The Theory and Practice of Industrial Pharmacy

Table 13-4. BA and M/g Factors of Some Typical Solids

Ingredient Base* BA M/g

Acetaminophen Veg. oil 0.76 25.97

Acetaminophen PEG 400 0.75 23.07
Ascorbic acid Veg. oil 0.60 20.60
Ascorbic acid Polysorbate 80 1.10 26.92
Al(OH)3—MgC03 (FMA 11) Veg. oil 1.90 41.30
Al(OH)3—MgC03 (FMA 11) PEG 400 2.44 42.10
Danthron Veg. oil 1.30 33.75
Danthron Glyceryl monooleate 1.39 33.94
Danthron Polysorbate 80 1.38 31.28
Danthron PEG 400 1.60 33.62
Danthron Triacetin 1.83 36.02
Ephedrine S04 Veg. oil 1.30 36.80
Ferrous S04 exsiccated Veg. oil 0.30 10.60
Ferrous S04 exsiccated Polysorbate 80 0.47 12.90
Guaifenesin7 Veg. oil 1.28 34.68
Lactose Veg. oil 0.75 23.87
Desiccated liver Veg. oil 0.80 25.70
Mephenesin Veg. oil 2.50 57.38
Mephenesin PEG 400 2.13 44.77
Meprobamate Veg. oil 1.59 42.55
Meprobamate PEG 400 1.30 32.52
Niacinamide Veg. oil 0.80 25.63
Neomycin sulfate Veg. oil 0.60 20.66
Phenobarbital Veg. oil 1.20 33.60
Procaine penicillin G Veg. oil 0.91 28.63
Sodium ascorbate Veg. oil 0.76 22.40
Salicylamide Veg. oil 0.80 25.80
Sulfathiazole Veg. oil 0.43 17.90
Sulfanilamide Veg. oil 1.03 28.55
Tetracycline (amphoteric) Veg. oil 0.61 21.63

•Vegetable oil bases contain 3% soy lecithin.

sium), employing coatings (gelatin-coated B12), Usually, the physical stability of a product is
adjusting pH with appropriate small quantities associated primarily with the type of gelatin and
of citric, lactic, or tartaric acids or with less re¬ gelatin formulation used but can be aided by
strictive quantities of sodium ascorbate or mag¬ proper fill formulation. If a particular solid may
nesium oxide, or salting-out with appropriate have a deleterious action on the gelatin shell,
small quantities of sodium chloride or sodium the form of the solid that is least water-soluble
acetate. and the most oleophilic would be the form of

Table 13-5. Typical Suspending Agents

Concentration Concentration
Type of Oily Base (%) Type of Nonoily Base (%)

White wax, NF 5 Polyethylene glycol 4000 1-15

gnd 6000
Paraffin wax, NF 5 Solid nonionics 10
Animal stearates 1-6 Solid glycol esters 10
Wax mixture* 10 and 30 Acetylated monoglycerides 5
Aluminum monosterate, NFt 3-5
Ethocel (100 cps)f 5-10

* 1 part hydrogenated soybean oil; 1 part yellow wax, NF; 4 parts vegetable shortening (melting point 33 to 38°C); used at 10% on the
adsorption oil and at 30% on any filler oil required.
tUsed with volatile organic liquids such as butyl chloride; toluene; tetrachlorethylene; benzene.

CAPSULES• 405
choice for an oil-based suspension. An example sample of the resulting fluid mass is visually
would be the use of calcium salicylate rather compared with a color standard, and additional
than the sodium or magnesium salts. Also, the colorants are blended into the mass if adjust¬
type of liquid base used can have an effect on ments are required. The mass is then main¬
physical stability. For example, the proteolytic tained at a temperature of 57 to 60°C before and
effect of chloral hydrate on the gelatin shell is during the capsulation process.
greatly reduced when a polyethylene glycol base The materials preparation department will
is used in place of an oily base. have a weigh-off and mixing area containing the
With the proper selection of materials and for¬ necessary equipment and facilities for the prep¬
mulation techniques, the pharmaceutical chem¬ aration of the variety of mixtures that may be
ist can prepare solutions or suspensions for com¬ capsulated. Typical equipment would include
parisons of stability' and dissolution rate with printomatic scales for exacting measurements
formulations of other solid dosage forms. By ac¬ and control records; stainless-steel jacketed
curately filling two-piece gelatin capsules with tanks for handling from 10- to 450-gallon
such formulations, comparative absorption, uri¬ batches of mix; and mixers, such as the Cowles,
nary excretion, and metabolic studies can be for the initial blending of solids with the liquid
made prior to the actual preparation of the soft base. After the initial blending is completed, the
gelatin capsule dosage form. Today the product mixture is put through a milling or homogeniz¬
development laboratory must evaluate all poten¬ ing process, using equipment such as the
tial formulations for a new drug substance or for homoloid milEjjtone mill, hopper mill, or the
product improvement. UrscKeFComitrol. The purpose of the milling
operation is not to reduce particle size, but to
break up agglomerates of solids and to make cer¬
Capsule Manufacture, tain that all solids are “wet” with the liquid car¬
rier, so as to achieve a smooth and homogenous
Processing, and Control mixture.
Although this aspect of soft gelatin capsules is Following the milling operation, all mixtures
the primary responsibility of the custom manu¬ are subjected to deaeration, and particularly so if
facturer, the pharmaceutical chemist should the capsulation machine is equipped with a pos¬
have an understanding of the materials and itive displacement pump. Deaeration is neces¬
equipment involved in the capsule’s manufac¬ sary to achieve uniform capsule fill weights; it
ture, processing, and quality control. The sev¬ also protects against loss of potency through oxi¬
eral methods of capsulation referred to in the dation prior to and during capsulation. When
early part of this chapter, although differing small amounts of volatile ingredients are in¬
somewhat in mechanical principles, do require cluded in a formulation, they axe carefully added
the use of similar materials, processing steps, and blended into the bulk mixture after deaera¬
and equipment, and the use of equivalent con¬ tion. Most liquids and suspensions may be de¬
trol procedures. aerated by means of equipment designed to ex¬
Except for the gelatin preparation depart¬ pose thin layers of the material continuously to a
ment, the manufacturing areas of a typical plant vacuum (29.5" Hg) and at the same time trans¬
are air-conditioned to assure the proper condi¬ fer the material from the mixing tank to the con¬
tioning of the gelatin films, the proper drying of tainer that will be used at the capsulation ma¬
the capsules, and the consistent low moisture chine. Suspensions or liquid mixtures
content of raw materials and mixtures. The tem¬ containing volatile liquids or liquid surface ac¬
perature is usually in the range of 20 to 22°C, tive agents as chief constituents of the formula
and the humidity is controlled to a maximum of may be deaerated by subjection to temperatures
40%'in the^perating areas and a range of 20 to up to 60°C for the period required to achieve the
30% in the 'drying areas- results desired. After deaeration, the mixture is
In the gelatin preparation department of a typ¬ ready to be capsulated.
ical manufacturer, the gelatin is weighed on At this point, samples of the mixture are often
printomatic scales and mixed with the accu¬ sent to the quality control laboratory for various
rately metered (printomatic) and chilled (7°C) tests, such as ingredient assays and specific
liquid constituents'in suitable equipment, such gravity, and tests for homogeneity of suspen¬
as a Pony Mixer. The resultant fluffy mass is sion, moisture content, or air entrapment. This
transferred to melting tanks and melted under in-process quality control step may or may not
vacuum (29.5" Hg) at 93°C. The mixing process be routine, depending on the product or antici¬
requires about 25 min for 270 kg of mass, and pated problems, but should always occur with
the melting procedure requires about 3 hours. A new products until the process is validated.

406 • The Theory and Practice of Industrial Pharmacy

 Owing to space limitations, a detailed descrip¬ mechanical pressure on the die rolls and the
tion of each capsulation process is not possible. heating (37 to 40°C) of the ribbons by the wedge.
A schematic drawing of the rotary die process is During manufacture, capsule samples are
presented, however, to acquaint the pharmaceu¬ taken periodically for seal thickness and fill
tical chemist with the fundamental aspects of weight checks. The seals are measured under a
capsulation (Fig. 13-27). The gelatin mass is fed microscope, and changes in ribbon thickness,
by gravity to a metering device (spreader box), heat, or die pressure are made if necessary. Ac¬
which controls the flow of the mass onto air¬ ceptable seal thickness is one half to two thirds
cooled (13 to 14°C) rotating drums. Gelatin rib¬ of the ribbon thickness. Fill weight checks are
bons of controlled (±10%) thickness are formed. made by weighing the whole fresh capsule, slit¬
The wet shell thickness may vary from 0.022 to ting it open, and expressing the contents. The
0.045 inch, but for most capsules, it is between shell is then washed in a suitable solvent (petro¬
0.025 and 0.032 inch. Thicker shells are used on leum ether), and the empty shell is reweighed. If
products requiring greater structural strength. necessary, adjustments in the pump stroke can
Product cost is direcdy proportional to shell be made to obtain the proper fill weight.
thickness. The ribbons are fed through a min¬ Immediately after manufacture, the capsules
eral oil lubricating bath, over guide rolls, and are automatically conveyed through a naphtha
then down between the wedge and the die rolls. wash unit to remove the mineral oil lubricant.
The material to be capsulated flows by gravity The washed capsules may be automatically sub¬
into a positive displacement pump. The pump jected to a preliminary infrared drying step,
accurately meters the material through the leads which removes 60 to 70% of the water that is to
and wedge and into the gelatin ribbons between be lost, or may be manually spread directly on
the die rolls,. The bottom of the wedge contains trays. Capsules from the infrared dryer are also
small orifices lined up with the die pockets of spread on trays, and all capsules are allowed to
the die rolls. The capsule is about half sealed come to equilibrium with forced air conditions of
when the pressure of the pumped material 20 to 30% relative humidity at 21 to 24°C.
forces the gelatin into the die pockets, where the Capsules at equilibrium .with 20 to 30% RH at
capsules are simultaneously filled, shaped, her¬ 21 to 24°C are considered “dry,” and the shell of
metically sealed, and cut from the gelatin rib¬ such a capsule contains 6 to 10% water, depend¬
bon. The sealing of the capsule is achieved by ing on the gelatin formula used. The moisture
content of the shell is determined by the toluene
distillaOon method, collecting the distillate over
riLL TAN*
a period of one hour. Additional water may be
removed from “dry’’ capsules by further heating,
e.g., at 40°C, but such a manufacturing step has
not been found to be practical or necessary.
After drying, the capsules are transferred to
the inspection department and held until re¬
leased by the quality control department. The
inspection and quality control steps in the proc¬
essing of capsules are much the same as with
other dosage forms and must conform to good
manufacturing practice. Control tests specifi¬
cally applicable to the quality of soft gelatin cap¬
sules may involve seal thickness determina¬
tions, total or shell moisture tests, capsule
•- fragility or rupture tests, and the determination
of freezing and high temperature effects.
Also, capsules may be sent after drying to a
finishing department for heat branding or ink
printing for purposes of identification.
Final physical control processing and packag¬
ing may be accomplished by the following in¬
line continuous operations.
1. A capsule diameter sorter allows to pass to
the next unit any capsule within ±0.020 inch of
FIG. 13-27. Schematic drawing of rotary die process. the theoretic diameter of the particular capsule
(Courtesy of R.P. Scherer Corporation, Troy, MI.) being tested. Overfills, underfills, and “foreign”

CAPSULES • 407
capsules are discarded. The unit is fed from a midities (<20% RH), low temperatures (<2°C)
hopper, and the capsules are passed through a and high temperatures (>38°C) or combinations
final naphtha washing unit just prior to the of these conditions have only transient effects.
sorter. The unit employs a syntron vibrator, The capsule returns to normal when returned to
which is a series of divergent wire lanes, and can optimum storage conditions. The transient ef¬
be used for capsule diameters ranging from fects are primarily brittleness and greater sus¬
0.200 to 0.500 inch. ceptibility to shock, requiring greater care in
2. A capsule color sorter is the next unit in handling or a return to proper storage conditions
line. The capsules are fed to it automatically prior to further handling.
from the diameter sorter by a pneumatic con¬ As the humidity is increased, within a reason¬
veyor. In this unit, any capsule whose color does able temperature range, the shell of the unpro¬
not conform to the reference color standard for tected control capsule should pick up moisture
that particular product is discarded, while satis¬ in proportion to its glycerin and gelatin content
factory capsules pass immediately to an elec¬ in accordance with the curves shown in Figure
tronic counting and packaging unit. 13-28. The total moisture content of the capsule
3. The electronic counting unit can count as shell, at equilibrium with any given relative
many as 8,000 capsules per minute (depending humidity within a reasonable temperature
upon size) directly into the bulk shipping carton. range, should closely approximate the sum of
A printout of the content of each carton and a the moisture content of the glycerin and the gel¬
printout of the number of cartons are automati¬ atin when held separately at the stated condi¬
cally produced and made a part of the produc¬ tions. For example, the shell of the described
tion record. Following this step, the cartons are control capsule contains 400 mg of dry' gelatin
labeled, sealed, and palletized and are then and 200 mg of dry glycerin per gram. At equilib¬
ready for shipment. rium with 30% RH at room temperature (21 to
24°C), the curves show that the gelatin should
retain about 12% (48 mg) of water, and the glyc¬
Capsule Physical Stability and erin 7% (14 mg) of water. Thus, the “dry” shell
Packaging
Unprotected soft gelatin capsules (i.e., cap¬

g ■m E H ■I■1■ ■1■ ■ ■H
m■
sules that can breathe) rapidly reach equilib¬
rium with the atmospheric conditions under

r Hi■■I■ ■1■1■■1■ ■
which they are stored. This inherent character¬
istic warrants a brief discussion of the effects of
temperature and humidity on these products,
and points to the necessity of proper storage and
packaging conditions and to the necessity of
choosing an appropriate retail package. The va¬
riety of materials capsulated, which may have
■ ■■ ■ ■ ■ ■■ ■ 11 ■■■
an effect on the gelatin shell, together with the
■ ■■■ ■ ■ ■■■ 1 N ■■ ■
■■■ ■ ■■ ■■■ K m ■ ■ ■
many gelatin formulations that can be used,
makes it imperative that physical standards are
established for each product.

■■
General statements relative to the effects of
temperature and humidity on soft gelatin cap¬
sules must be confined to a control capsule that
contains mineral oil, with a gelatin shell having

m■
a dry glycerin to dry gelatin ratio of about 0.5 to 1
and a water to dry gelatin ratio of 1 to 1, and that
is dried to equilibrium with 20 to 30% RH at 21 mM
to 24°C. The physical stability of soft gelatin cap¬
ii n
sules is associated primarily with the pick-up or
Mii
■■■ ■■■!■■
loss of water by the 'capsule shell. If these are
prevented by proper packaging, the above con¬ 40 50 60
m
70 80 90 100
trol capsule should have satisfactory physical PER CENT DRY COMPONENTS

stability at temperatures ranging from just above

FIG. 13-28. Equilibrium content by weight of dry glyc¬
freezing to as high as 60°C. erin (20 to 100°C ) and dry gelatin (25°C) at various rela¬
For the unprotected control capsule, low hu¬ tive humidities. 1,3

408 • The Theory and Practice of Industrial Pharmacy

would contain about 9.4% water (62 mg H20/ and subtle effects of the storage conditions on
662 mg of shell). the capsule shell are noted and recorded. The
If the conditions are changed to 60% RH (21 control capsule should not be affected except at
to 24°C), the moisture content should be approx¬ the 80% RH station, where the capsule would
imately 17.4%. In actual practice, however, such react as described under the effects of high
calculated moistures are considered maximum, humidity.
since moisture assays (toluene distillation In the case of a newly developed product, the
method) of the shells of oil-filled capsules give gross effects such as disintegration, leakers,
results somewhat lower than the theoretical val¬ unusual brittleness or softening, apparent color
ues. The deviation most likely is due to an inter¬ fading, or discoloration are obvious. The more
action between the plasticizer and gelatin, par¬ subtle changes may be the loss of a volatile in¬
tially satisfying their respective water-binding gredient as detected by slight capsule indenta¬
capacities and thereby causing a lower moisture tion, or the slight darkening or widening of the
content than would be theoretically expected. capsule seams, or slight changes in color hue.
Nevertheless, the curves serve to illustrate the Capsules often show a “soft spot” at the site at
hygroscopic nature of capsule shells, the relative which they lie next to the tray or against another
effect of changes in the glycerin to gelatin ratio capsule. This spot is the result of slower drying
on the hygroscopicity of the shell, and the poten¬ and is of no consequence in the control capsule,
tial effects of humidity on the chemical and since such areas firm up and are not flaws in the
physical stability of the product. capsule shell. On the other hand, if such areas
High humidities (>60% RH at 21 to 24°C) do not become firm, usually because of action by
produce more lasting effects on the capsule the capsule content, then physical stability prob¬
shell, since as moisture is absorbed, the capsules lems can be anticipated during the shelf-life of
become softer, tackier, and bloated. The cap¬ the product. Such defects must be corrected be¬
sules do not leak unless the increased moisture fore the product can be considered for produc¬
has allowed a deleterious ingredient in the cap¬ tion. Correction of such defects depends upon
sule content to attack the gelatin. On return to identifying their cause. Most defects can be cor¬
optimum storage conditions, the capsules are rected by appropriate changes in gelatin or fill
dull in appearance and most likely inseparably material formulations, but in some cases, differ¬
stuck together. An increase in temperature ent colorants, machine speeds, and machine
(>24°C), together with humidity (>45%), re¬ dies may have to be used. The experience and
sults in more rapid and pronounced effects and mature judgment of the custom manufacturer is
may even cause the unprotected capsules to invaluable in the solution of such problems.
melt and fuse together. Capsules containing Chemists conducting the physical stability
water-soluble or miscible liquid bases may be tests in their own laboratories should keep two
affected to a greater extent than oil-based cap¬ important points in mind: (1) Prior to testing,
sules, owing to the residual moisture in the cap¬ the capsules should be equilibrated to known
sule content and to the dynamic relationship atmospheric conditions, preferably 20 to 30%
existing between capsule shell and capsule fill RH at 21 to 24°C. (2) Evaluation of the results of
during the drying process. the previously described heat tests should be
The capsule manufacturer routinely conducts made only after the capsules have returned to
accelerated physical stability tests on all new equilibrium with room temperature.
capsule products as an integral part of the prod¬ After the capsules have passed the shell integ¬
uct development program. The following tests rity tests, additional physical studies should be
have proved adequate for determining the effect conducted using the various types of retail pack¬
of the capsule content on the gelatin shell. The ages being considered for the product. These lat¬
tests are stricdy relevant to the integrity of the ter tests should be designed to determine the
gelatin shell and should not be construed as sta¬ shelf-life of the product and may conform to
bility tests for the active ingredients in the cap¬ most of the standard testing procedures em¬
sule content. The results of such tests are used ployed by a company for its other solid dosage
as a guide for the reformulation of the capsule forms. Exceptions may involve those tests con¬
content or the capsule shell, or for the selection ducted at temperatures exceeding 45°C for time
of the proper retail package. The test conditions periods exceeding a month.
are (1.) 80% RH at room temperature in an open The soft gelatin capsule manufacturer takes
container; (2) 40°C in an open container; (3) great care in the production of capsules to meet
40°C in a closed container (glass bottle with tight the specifications of the product set forth by the
screw-cap). The capsules at these stations are customer. When bulk shipments of capsules are
observed periodically for 2 weeks. Both gross made by the manufacturer, they are temporarily

CAPSULES• 409
protected from normal changes in humidity by a For these studies, the NF XII (second supple¬
suitable moisture barrier such as a 0.003-inch ment, 1967) rotating-bottle method was used.
polyethylene bag within a standard fiber board A rationale for using a rotating-bottle method
carton. Since such packaging is not a permanent for dissolution studies on soft gelatin capsules is
moisture barrier, the capsules should be retail expressed, and examples are given by Withey
packaged as soon as possible after receipt. If and Mainville.17 Their dissolution studies on
immediate packaging is not practical, the bulk thirteen brands of commercial chloramphenicol
capsules in their original unopened cartons capsules, using their modified USP apparatus,
should be stored in an air-conditioned area in showed the soft gelatin capsule brand to release
which the humidity does not exceed 45% RH at only 22.3 to 24.8% of its chloramphenicol con¬
21 to 24°C. The retail packaging of these cap¬ tent in 30 min, while hard-shell capsule brands
sules should be done under similar conditions, B2 and D released 100.7% and 87.2% respec¬
for the maximum physical and chemical stabil¬ tively. Upon change to a rotating-bottle method,
ity of the product. the 30-min recoveries were 100% from the soft
Soft gelatin capsules may be retail packaged gelatin capsule brand, 82% from brand B2, and
using any modem packaging equipment, includ¬ 70% from brand D. None of these studies have
ing the electronic type. Capsules may be pack¬ been correlated with bioavailability data, and
aged in glass or plastic containers or may be thus, the significance of the difference in results
strip-packaged, so long as such packaging in¬ between the two dissolution methods is not
volves tight closures and plastics having a low clear. The difference could be attributed to
moisture vapor transfer rate. Suppliers of rigid greater agitation by the bottle method and less
plastics and plastic films can be of immeasura¬ opportunity for the capsule to adhere to the sides
ble service in suggesting the proper types of or bottom of the apparatus. The effect of several
packaging for testing. Since strip packaging usu¬ variables on capsule dissolution is discussed by
ally is done by specialists in this field, their ad¬ Horn and associates,8 who indicate that the de¬
vice should be solicited, and test strips should be gree of agitation, the pH of the dissolution me¬
made and tested for adequacy. dium, and the presence or absence of pepsin in
the medium are important to the dissolution of
soft gelatin capsules.
Pharmaceutical Aspects 4. The physiologic availability of drugs is
The pharmaceutical chemist should be cogni¬ often improved since these capsules contain the
zant of the inherent properties of soft gelatin drug in Liquid form, i.e., as a liquid drug sub¬
capsules. Essentially, these capsules are solid stance, drug in solution, or drug in suspension.
dosage forms containing liquid medication and Nelson, in his review,18 points out that the avail¬
therefore offer certain advantages: ability of a drug for absorption, from various
1. They permit liquid medications to become types of oral formulations, usually decreases in
easily portable. the following order: solution, suspension,
2. Accuracy and uniformity of dosage, cap¬ powder-filled capsule, compressed tablet, coated
sule to capsule and lot to lot, are predominant tablet. A study by Wagner and co-workers seems
advantages. These capsules easily pass the ap¬ to confirm both Nelson’s observation and the ef¬
propriate compendial tests and surpass other fective absorption from soft gelatin capsules.19
solid dosage forms in this respect, because liquid Their study involved the effect of dosage form
formulations can be more accurately and pre¬ on the serum levels of indoxole (solubility in
cisely compounded, blended, homogenized, and water 0.1 pg/'ml) and showed the serum level
measured or dispensed than can dry solid for¬ decreased in the following order: emulsion =
mulations. soft gelatin capsule (drug in polysorbate 80 solu¬
3. The pharmaceutical availability of drugs tion), aqueous suspension, powder-filled cap¬
formulated for this dosage form, as measured by sule.
disintegration time,14 or by dissolution rate,15,16 Maconachie, in his review article on soft gela¬
often shows an advantage over other solid dos¬ tin capsules,20 gives some specific examples of
age formulations. how this dosage form can improve drug absorp¬
In the dissolution rate studies of twenty drugs, tion. His examples involve acetaminophen,1
presented previously, which included a wide chlormethiazole,21 and temazepam.22 The
variety of chemical types and pharmacologic 4-hour urinary recovery of acetaminophen from
classes, the authors showed that in the majority three soft gelatin rectal suppository formulations
of cases, the drugs were more rapidly and com¬ (oil base and water-miscible type base) was
pletely available from the soft gelatin capsule found to be five to eight times greater than from
than from the commercial tablets or capsules. the traditional fatty type suppository formula-

410 'The Theory and Practice of Industrial Pharmacy

tion. The switch from a tablet to a soft gelatin This is an example of the capsule providing a
capsule form not only improved the stability of convenient portable dosage form for a liquid
chlormethiazole by protecting the drug from oxi¬ medication. The capsule also effectively masked
dation, but increased its bioavailability as evi¬ the bitter taste of theophylline.
denced by comparative blood levels and by ear¬ Papaverine hydrochloride bioavailability from
lier onset of a minor side effect (nose tingling). soft gelatin capsules was studied by Arnold et
Major side effects of the tablet dosage form were al.35 These authors found that the peak blood
also eliminated or ameliorated. The capsule for¬ level and area under the blood-level-time curve
mulation allowed the use of the liquid drug sub¬ from soft gelatin capsules were equal to those
stance (chlormethiazole base) rather than the obtained from an elixir and superior to those
solid derivatives used in the tablet formulations. from a sustained release hard-shell capsule for¬
A temazepam soft gelatin formulation, when mulation. Healthy volunteers were used in this
compared with hard gelatin capsule formula¬ study. Lee et al. found not only high blood levels
tions of temazepam, nitrazepam, amobarbital of papaverine 120 min after a 150-mg dose in
sodium, and a placebo, gave superior bioavaila¬ soft gelatin capsules, but a higher degree of vas¬
bility as indicated by “onset of sleep.” Further¬ odilation after four doses (150 mg x 4) of the
more, this was achieved at a lower dosage soft capsule dosage form when compared with
(20 mg per soft capsules versus 30 mg per hard equivalent doses from a sustained-release dos¬
capsule). age form.36 Patients with severe arteriosclerosis
In an article on soft gelatin capsules,23 Ebert obliterans were used in the study. Both studies
discusses and reports on the bioavailability and conclude that the soft gelatin capsule dosage
content uniformity of digoxin solutions in soft form shows significant advantage over the sus¬
gelatin capsules. The capsulated solutions were tained release tablet form of the drug.
0.05 mg, 0.10 mg and 0.20 mg of digoxin dis¬ The bioavailability of diazepam (structurally
solved in a base consisting of polyethylene glycol similar to that of temazepam, mentioned previ¬
400, USP (89.4% w/w); alcohol, USP (6.5% ously) was studied by Yamahira et al.37 They
w/w); propylene glycol, USP (3.4% w/w); and compared diazepam, capsulated in soft gelatin
purified water, USP (0.6% w/w). These capsules using a medium-chain triglyceride base, with a
were tested by various investigators for bioavail¬ tablet dosage form. They report that when these
ability in comparison with brand name tablets, dosage forms were repeatedly orally adminis¬
digoxin solution, and digoxin elixir.24"31 In all tered to an individual subject, the capsule dos¬
studies, the bioavailability of the soft gelatin cap¬ age form showed a tendency toward faster drug
sule formulation was found to be superior to the absorption and superior reproducibility of the
commercially available tablets. The most sur¬ plasma-level-time curve than the tablet dosage
prising finding of all these studies, according to form. This suggests that capsule dosage forms
Ebert, was that the capsulated solution exhib¬ have a more uniform drug absorption rate than
ited a more rapid and complete absorption than tablets. The authors suggest that diazepam,
did the same solution not encapsulated. The though it is a weak base, was emptied from the
commercially available tablets contain 20% stomach while mostly retained in the lipid, and
more drug than the capsulated solutions. Thus, this was affected by the movement of the triglyc¬
the capsule dosage form allows for a significant eride in the gastrointestinal tract.
reduction in dose for this relatively toxic drug. 5. The pharmaceutical chemist should cer¬
Another comparative bioavailability study of tainly consider the bioavailability potential of
digoxin soft gelatin capsules and tablets was re¬ soft gelatin formulations. The biopharmaceuti-
ported by Astorri and co-workers.32 They found cal characteristics of such formulations can be
that in heart patients using digoxin, the absorp¬ altered or adjusted more easily than those of
tion of digoxin from the capsulated solution was other solid dosage forms. Through the selection
36% higher than from the tablet, while in and use of liquids and combinations of b'quids
healthy volunteers absorption from the capsule that range from water-immiscible through emul-
was 20% higher than from the tablets. sifiable to completely water-miscible, and by al¬
The bioavailability of theophylline from soft tering the type or quantity of thickening or sus¬
gelatin capsules in comparison to a commer¬ pending agents, capsule formulations allow the
cially available liquid aminophylline preparation formulating chemist more flexibility in the de¬
and to a nonalcoholic aminophylline solution sign of a dosage form to fit the biopharmaceuti-
was studied by Ebert,33 and by Lesko and co- cal specifications of a particular therapeutic
workers.34 Both studies found that the two dos¬ agent.
age forms were bioequivalent as measured by 6. Orally administered drugs, particularly if
the area under the plasma-level-time curves. used chronically, can be irritating to the stom-

CAPSULES* 411
ach. The dosage form of such drugs can affect 13. Bull, H. B.: J. Am. Chem. Soc., 66:1949, 1944.
14. Eckert, V. T., Widmann, A., and Seidel, R.: Arz.
gastric tolerance, as indicated by the studies of
neim-Forsch, 19:821, 1969.
Caldwell et al.38 These authors compared the 15. Horn, F. S., and Miskel, J. J.: J. Pharm. Sci., 59:827,
degree of irritation or ulcerogenic potential of 1970.
soft gelatin capsule formulations of dexametha- 16. Horn, F. S., and Miskel, J. J.. Lex Et. Scienta, 8:18,
sone with a tablet formulation of the drug. Sev¬ 1971.
eral liquid formulations and tablet formulations 17. Withey, R. J., and Mainville, C. A.: J. Pharm. Sci.,
58:1120, 1969.
were administered to rats, and both ulcerogenic
18. Nelson, E.: Clin. Pharmacol. Ther., 3:673, 1962.
potential and bioavailability were determined. 19. Wagner, J. G., Gerard, E. S., and Kaiser, D. G.: 7:610,
The authors concluded that the liquid or capsule 1966.
formulations had a reduced ulcerogenic poten¬ 20. Maconachie, S.: Mfg. Chemist and Aerosol News,
tial when compared to the tablet formulation, Aug. 1977, p. 35.
and that this effect is apparently not a reflection 21. Frisch, E. P., and Ortengren, B.: Acta Psych. Scand.,
42(Suppl.):35, 1969.
of reduced bioavailability.
22. Hindmarch, I.: Arzneimittel-Forsch., 25:1836, 1975.
23. Ebert, W. R.: Pharm. Tech., 1:44, 1977.
24. Binnion, P. F., and Klopp, R. W.: Lancet, 1.1422,
References 1975.
1. Widmann, A.: Drugs Made in Germany, 3:167,1960. 25. Mallis, G. I., Schmidt, D. H., and Lindenbaum, J.:
2. Gutches, M.: Capsule Technology and Microen¬ Clin. Pharmacol. Ther., 18:761, 1975.
capsulation. Noyes Data Corp., Park Ridge, Nj, 1972. 26. Marcus, F. I., Dickerson, J., Pippin, S., et al.: Clin.
3. Idson, B., and Braswell, E.: Advances in Food Re¬ Pharmacol. Ther., 20:253, 1976.
search. Vol. VII. Academic Press, New York, 1957, p. 27. Binnion, P. F.: J. Clin. Pharmacol., 16:461, 1976.
235. 28. Johnson, B. J., Bye, C., Jones, G., and Sabey, G. A.:
4. Gelatin. Gelatin Manufacturer’s Institute of America, Clin. Pharmacol. Ther., 19:746, 1976.
New York, 1962. 29. Ghirardi, P., Catenazzo, G., Mantero, O., et al.: J.
5. Traub, W., and Piez, K.: Advances in Protein Chemis¬ Pharm. Sci., 66:267, 1977.
try. Chemistry and Structure of Collagen. Vol. 25. 30. Lindenbaum, J.: Clin. Pharmacol. Ther., 21:278,
Academic Press, New York, 1971. 3977.
6. Ramachandvan, G. N.: Treatise on Collagen. Chem¬ 31. Johnson, B. F., Smith, G., and French. J.: Br. J. Clin.
istry of Collagen. Vol. 1. Academic Press, New York, Pharmacol., 4:209, 1977.
1967. 32. Astorri, E., Bianchi, G., La Canna, G., et al.: J.
7. Stanley, J. P., and Bradley, C. W.: U S. Patent Pharm. Sci., 68.T04, 1979.
2,870,062, January 20, 1959. 33. Ebert, W. R.: Pharm. Tech., 3:61, 1979.
8. Horn, F. S., Veresh, S. A., and Miskel, J. J.: J. Pharm. 34. Lesko, L. J., Canada, A. T., Eastwood, G., et al.: J.
Sci., 62:1001, 1973. Pharm. Sci., 68:1392, 1979.
9. Handbook of Chemistry and Physics. 44th Ed. Chem¬ 35. Arnold, J. D., Baldridge, J., Riley, B., and Brody, G.: J.
ical Rubber Publishing Co., Cleveland, OH, 1963. Clin. Pharmacol., 15:230, 1977.
10. Lieberman, E. R., Gilbert, S. G., and Srinvasa, V.: 36. Lee, B. Y., Sakamoto, H., Trainor, F., et al.: J. Clin.
Trans. N.Y. Acad. Sci., 34:694, 1972. Pharmacol., 16:32, 1978.
11. Horn. F. A., Veresh, S. A., and Ebert, W. R.: J. Pharm. 37. Yamahira, Y., Noguchi, T., Takenaka, H., and Maeda,
Sci., 64:851, 1975. T.: Chem. Pharm. Bull., 27:1190, 1979.
12. Miner, C. A., and Dalton, N. N.: Glycerol. ACS Mono¬ 38. Caldwell, L., Cargill, R., Ebert, W. R., and
graph Series No. 117. Reinhold, New York, 1953, p. Windheuser, J. J.: Pharm. Tech., 3:52, 1979.
269.

ids or droplets of liquids and dispersions. For the

PART THREE purpose of this chapter, microencapsulation is
arbitrarily differentiated from macrocoating
techniques in that the former involves the coat¬
Microencapsulation ing of particles ranging dimensionally from sev¬
eral tenths of a micron to 5000 microns in size.
As the technology has developed, it has be-
J. A. Bakan
2*
trial pharmacist a new working tool. Microen¬
capsulation provides the means of converting
liquids to solids, of altering colloidal and surface
properties, of providing environmental protec¬
tion, and of controlling the release characteris-
Microencapsulation is a rapidly expanding tech- tics or availability of coated materials. Several of
nology. As a process, it is a means of applying these properties can be attained by macropack-
relatively thin coatings to small particles of sol- aging techniques; however, the uniqueness of

412 • The Theory and Practice of Industrial Pharmacy

microencapsulation is the smallness of the
coated particles and their subsequent use and
adaptation to a wide variety of dosage fonns and
product applications, which heretofore might
not have been technically feasible. Because of
the smallness of the particles, drug moieties can
be widely distributed throughout the gastroin¬
testinal tract, thus potentially improving drug
sorption. Figure 13-29 shows microencapsu¬
lated barium sulfate being released from a dis¬
solving gelatin capsule shortly after ingestion.1
Figure 13-30 shows the microcapsules distrib¬
uted throughout the intestines.1
The applications of microencapsulation might
well include sustained-release or prolonged-
action medications, taste-masked chewable tab-
lets, powders and suspensions, single-layer tab¬
lets containing chemically incompatible ingredi¬
ents, and new formulation concepts for creams,
ointments, aerosols, dressings, plasters, suppos¬
itories, and injectables. Pharmaceutically re¬
lated areas, such as hygiene, diagnostic aids,
and medical equipment design, also are amena¬
ble to microencapsulation applications.
This new technology does not exclude prob¬ FIG. 13-30. After a few hours, the same microencapsu¬
lem areas; for instance, no single microen¬ lated barium sulfate pellets as in Fig. 13-29 broadly dis¬
tributed throughout intestines. (From Galeone, M., et al:
capsulation process is adaptable to all core
Current Therapeutic Research, 31:456, 1982.
material candidates or product applications. Dif-

faculties, such as incomplete or discontinuous

coating, inadequate stability or shelf-life of sen¬
sitive pharmaceuticals, nonreproducible and
unstable release characteristics of coated prod¬
ucts, and economic limitations often are en¬
countered in the attempt to apply a particular
microencapsulation method to a specific task.
Many times, successful adaptation is, in part, a
result of the technical ingenuity of the investiga¬
tors.
Microencapsulation is receiving considerable
attention fundamentally, developmentally, and
commercially. In view of this interest, it is the
purpose of this chapter to present a description
of the more prominent microencapsulation
methods and some of their capabilities and limi¬
tations. The microencapsulation methods to be
discussed are air suspension, coacervation-
phase separation, spray drying and congealing,
and polymerization techniques. A survey of the
ever-expanding patent and published literature
reveals that not all microencapsulation tech¬
niques are included within the methods cited in
this chapter; however, the methods described
represent the currently established, most highly
FIG. 13-29. Microencapsulated barium sulfate releasing
from hard gelatin capsules a few minutes after ingestion. developed and widely used commercial proc¬
(From Galeone, M., et al: Current Therapeutic Research, esses, although some may not be applicable to
31:456, 1982.) pharmaceuticals at this time.

CAPSULFS -413
Fundamental Considerations ture. The composition of the core material can
be varied, as the liquid core can include disper¬
The realization of the potential that microen¬
sed and/or dissolved material. The solid core can
capsulation offers involves a basic understand¬
be a mixture of active constituents, stabilizers,
ing of the general properties of microcapsules,
diluents, excipients, and release:rate retardants
such as the nature of the core and coating mate¬
or accelerators. The ability to vary the core mate¬
rials, the stability and release characteristics of
rial composition provides definite flexibility and
the coated materials, and the microencapsula¬ utilization of this characteristic often allows ef¬
tion methods. One should note, however, that
fectual design and development of the desired
the method employed in the manufacture of
microcapsule properties.
microcapsules may well result in products of
It is not possible to discuss, or even list, all of
varied composition, quality, and utility.
the potential core materials and product applica¬
tions that are or may be amenable to microen¬
Core Material capsulation. However, to aid in illustrating the
The core material, defined as the specific ma¬ diversity of the materials and their applications,
terial to be coated, can be liquid or solid in na¬ some of these products are listed in Table 13-6.

Table 13-6. Properties of Some Microencapsulated Core Materials

Characteristic Purpose of
Core Material Property Encapsulation Final Product Form

Acetaminophen Slighdy water- Taste-masking Tablet

soluble solid

Activated Adsorbent Selective Dry powder

charcoal sorption

Aspirin Slighdy water- Taste-masking; Tablet or capsule

soluble solid sustained release;
reduced gastric
irritation;
separation of incom¬
patibles
Islet of Viable cells Sustained normal¬ Injectable
Langerhans ization of diabetic
condition
Isosorbide Water-soluble Sustained release Capsule
dinitrate solid

Liquid crystals Liquid Conversion of liquid Flexible film for

to solid; stabili¬ thermal mapping
zation of anatomy
Menthol/methyl Volatile solution Reduction of Lotion
salicylate camphor volatility; sus¬
mixture tained release
Progesterone Slighdy water- Sustained release Varied
soluble solid

Potassium Highly water- Reduced gastric Capsule

chloride soluble solid irritation
Urease Water-soluble Permselectivity of Dispersion
enzyme enzyme, substrate,
and reaction products
Vitamin A Nonvolatile Stabilization to Dry powder
palmitate liquid oxidation

414 • The Theory and Practice of Industrial Pharmacy

Coating Materials are difficult to simulate with existing film-cast¬
ing methods.
The selection of a specific coating material
3. The coating substrate or core material may
from a lengthy list of candidate materials pres¬
have a decisive effect on coating material prop¬
ents the following questions to be considered by
erties.
the research pharmacist.
1. What are the specific dosage or product
Hence, the selection of a particular coating
requirements—stabilization, reduced volatility,
material involves consideration of both classic
release characteristics, environmental condi¬
free-film data and applied results.
tions, etc?
As previously stated, the uniqueness of micro¬
2. What coating material will satisfy the prod¬
capsules in their properties and use involves
uct objectives and requirements?
their characteristic smallness. Consequently,
3. What microencapsulation method is best
the protective coatings that are applied are quite
suited to accomplish the coated product objec¬
thin. Although the active content of many mi¬
tives?
croencapsulated products can be varied from a
The selection of the appropriate coating mate¬ few percent to over 99%, the effective coating
rial dictates, to a major degree, the resultant thickness that can be realized, regardless of the
physical and chemical properties of the micro¬
method of application employed, varies from
capsules, and consequently, this selection must tenths of a micron to a few hundred microns,
be given due consideration. The coating mate¬ depending on the coating-to-core ratio and the
rial should be capable of forming a film that is particle size (surface area) of the core material.
cohesive with the core material; be chemically Figure 13-31 illustrates the theoretic film thick¬
compatible and nonreactive with the core mate¬ ness that can be applied to small spherical parti¬
rial; and provide the desired coating properties, cles.2 The thinness of microencapsulation coat¬
such as strength, flexibility, impermeability, op¬ ings, although not necessarily limiting, must be
tical properties, and stability. The coating mate¬ of prime consideration. Just as the smallness of
rials used in microencapsulation methods are microcapsules allows unique properties and for¬
amenable, to some extent, to in situ modifica¬ mulations to be accomplished, the thinness of
tion. For example, colorants may be added to the resultant coatings also can present unique
achieve product elegance or masking, or coat¬
ings may be plasticized or chemically altered
through cross-linking, for instance, to achieve
controlled dissolution or permeability'. A partial
listing of typical coating materials commonly
used in the various microencapsulation methods
is suggested in Table 13-7.
It is not within the scope of this discussion to
describe the physical and chemical properties of
coatings per se. It is pointed out, however, that
typical coating properties such as cohesiveness,
permeability, moisture sorption, solubility, sta¬
bility, and clarity must be considered in the se¬
lection of the proper microcapsule coating mate¬
rial. The selection of a given coating often can be
aided by the review of existing literature and by
the study of free or cast films, although practical
use of free-film information often is impeded for
the following reasons.
1. Cast or free films prepared by the usual
casting techniques yield films that are consider¬
ably thicker than those produced by the
microencapsulation of small particles; hence,
the results obtained from the cast films may not
be extrapolatable to the thin miciocapsule coat¬
ings.
2. The particular microencapsulation method FIG. 13-31. Theoretic coating thickness for spherical core
employed for the deposition of a given coating material having various amounts of coating. (From Her-
produces specific and inherent properties that big.2 Courtesy John Wiley and. Sons.)

CAPSULES' 415
Table 13-7. Representative Coating Materials and Applicable Microencapsulation Process

Processes

Spray
Phase Drying Solvent
Multiorifice— Separation— Pan and Air Evapor¬
Coating Materials Centrifugal Coacervation Coating Congealing Suspension ation

Water-soluble resins
Gelatin X X X X X X
Gum arabic X X X X X
Starch X X X X
Polyvinylpyrrolidone X X X X X
Carboxymethylcellulose X X X X
Hydroxyethylcellulose X X X X X
Methylcellulose X X X X
Arabinogalactan X X X X
Polyvinyl alcohol X X X X X X
Polyacrylic acid X X X X X
Water-insoluble resins
Ethylcellulose X X X X X
Polyethylene X X X
Polymethacrylate X X X X X
Polyamide (Nylon) X X
Poly [Ethylene-Vinyl acetate] X X X X X
Cellulose nitrate X X X X X
Silicones X X
Poly (lactide-co-glycolide) X X X
Waxes and lipids
Paraffin X X X X X
Camauba X X X
Spermaceti X X X X
Beeswax X X X
Stearic acid X X
Stearyl alcohol X X X
Glyceryl stearates X X X
Enteric resins
Shellac X X X X
Cellulose acetate phthalate X X X X X
Zein X X

problems. For example, most polymers exhibit ability of core materials, and separation of chem¬
microscopic discontinuities and some degree of ically reactive ingredients within a tablet or pow¬
ordered or random crystallinity. The total thick¬ der mixture.
ness of the coatings achieved with microen¬ The following examples illustrate the concept
capsulation techniques is microscopic in size, of improved stabilization. Microencapsulation of
and therefore, what might be a minor non¬ certain vitamins to retard degradative losses has
homogeneity occurring on the surface of a 5-mil been practiced for many years. The potency re¬
coating can penetrate the entire thickness of a tention properties of a microencapsulated vita¬
microencapsulation coating. min A palmitate oil are illustrated in Figure
13-32.3 The conversion of volatile liquids to dry,
free-flowing powders with subsequent retention
Selected. Stability, Release, and of the liquid core material during extended stor¬
age is another example of stabilization. Figure
Other Properties 13-33 depicts typical microcapsule stabilities of
Three important areas of current microen¬ an anthelmintic (carbon tetrachloride), methyl
capsulation application are the stabilization of salicylate, and a flavor.4 An example of stability
core materials, the control of the release or avail¬ enhancement, accomplished by mieroen-

416 • The Theory and Practice of Industrial Pharmacy

FIG. 13-32. Stability of a microencapsulated vitamin A
palmitate com oil prepared by phase-separation/coacerva-
tion technique, compared with an unencapsulated control.
(From Bakan.3) FIG. 13-34. Stability, enhancement of incompatible aspi¬
rin mixture by microencapsulation. A, Aspirin hydrolysis
capsulation of incompatible admixed constitu¬ of chlorpheniramine maleate-aspirin mixture; B, aspirin
hydrolysis of microencapsulated mixture; and C, hydroly¬
ents, is given in Figure 13-34. Compared in the
sis of aspirin control. (From Bakan.3)
graph is the formation of the aspirin hydrolysis
product, salicylic acid, occurring with a mixture
of aspirin and chlorpheniramine maleate.3 coated material must be released in a predictable
The release properties of microencapsulated and reproducible manner. A wide variety of
materials require detailed consideration, as the mechanisms is available to release encapsulated
core materials. Disruption of the coating can
occur by pressure, shear, or abrasion forces, any
of which affords a release mechanism. Other
mechanisms involve permeability changes
brought about enzymatically. Also, release can
be achieved from inert coatings by diffusion or
leaching of a permeant fluid. lire rate of release
is a function of the permeability of the coating to
the extraction fluid; the permselectivity, if any,
of the coating to core material solute; the disso¬
lution rate of the core material; the coating
thickness; and the concentration gradient exist¬
ing across the coating membrane.
Prolonged-action or sustained-release formu¬
lations are obvious examples of controlled re¬
lease from microencapsulated products, and
Figures 13-35 and 13-36 demonstrate the versa¬
tility of two diverse microencapsulation proc¬
esses and coating materials. The in vitro release
patterns achieved by applying varied amounts of
an ethylcellulose coating to small aspirin crys¬
tals using coacervation phase-separation encap¬
sulation techniques are shown in Figure 13-35.
Release of the aspirin is accomplished in this
case by a leaching or diffusion mechanism from
the inert, pH-insensitive ethylcellulose coating.
Depicted in Figure 13-36 are the in vitro release
FIG. 13-33. Stability of microencapsulated volatile liq¬ responses of amphetamine sulfate pellets, that
uids, prepared by phase-separationlcoacervation tech¬ have been microencapsulated with varying
niques. (From The NCR Corporation.4) amounts of a wax-fat coating applied by a pan-

CAPSULES *417
 coating process.5 Figure 13-36 illustrates the re¬
lease rate effects of varied amounts of coating as
well as the enteric nature of the coatings when
subjected to the simulated gastrointestinal ex¬
traction conditions. The nonlinearity of the re¬
lease curves plotted semilogarithmically sug¬
gests that the release of the amphetamine is
accomplished initially by a leaching action
through a gastric fluid-resistant coating followed
by release from a dissolvable or disintegratable
coating accomplished by the action of simulated
intestinal fluid. Also shown in Figure 13-36 is
the resultant release pattern (segmented curve)
for an appropriate sustained release blend of two
of the coated materials and a noncoated fraction
of the amphetamine.
The in vitro release properties of the microen¬
capsulated product forms already described—a
rapidly disintegrating tablet containing coated
particles, a microencapsulated powder, and a
blend of coated pellets—all illustrate, in vitro,
apparent first-order release kinetics, although
diverse mechanisms are involved. Conse¬
quently, the rate of release of the drugs from
these examples is proportional to the amount of
Fig. 13-35. In vitro release patterns of crystalline aspirin drug remaining - da/dt = k^, or after integra¬
coated with various amounts of ethylcellulose using phase- tion, a = aoe_krt or In (a/a^) = -krt, where ao is
separation!coacervation techniques. A, 52% coating; B, the total dose in the preparations, a is the frac¬
29%’coating; C, 16% coating; D, 13% coating. (From The tion of the total dose remaining in the coated
NCR Corporation.4) preparation at time t (if ao is unity), and kr is the
apparent first-order release constant. For sus¬
tained-release preparations formulated to re¬
lease a fraction (fs) of the dose immediately, and
another fraction (fr) exponentially as equated
previously, the amount of drug release (ar) by
any time thereafter is therefore:

ar = aof + aofr(l - e_k,t)

Many sustained-release products release all or

part of their drug content exponentially accord¬
ing to the first-order rate equation.6 Improved
gastrotolerability of drugs can be obtained by
microencapsulation while good bioavailability is
maintained.7 To prove the tolerability of the mi¬
croencapsulated product, one study of gastroin¬
testinal bleeding was done with Cr-labeled red
blood cells in 20 subjects treated for 3 months
with microencapsulated KC1 in the amount of
3 g daily. The daily blood loss in the feces of 20
subjects after administration of microencapsu¬
lated KC1 was practically nil, mean values rang¬
ing from 0.432 to 0.596 ml in any 24-hour pe¬
FIG. 13-36. In vitro release patterns of amphetamine sul¬ riod, as opposed to 0.1 to 2.2 ml blood loss with
fate pellets pan coated with various amounts of a fat-wax
raw KC1. In a study by McMahon et al., healthy
coating. A, 17% coating; B, 15% coating; C, 13% coating;
D, 11% coating; E, 9% coating; F, 7% coating; G, selected male volunteers who had had no previous evi¬
blend of uncoated pellets and coated pellets. (From the data dence of gastrointestinal disease were examined
of Rosen et al5 Courtesy Am. Pharmaceut. Assoc.) by endoscopy after ingestion of microencapsu-

418 • The Theory and Practice of Industrial Pharmacy

lated KC1 and wax matrix KC1 tablets.8 The re¬ Table 13-8. Microencapsulation Processes and
sults of the study indicated that microcapsules Their Applicabilities
had minimal endoscopically discernible lesions
when compared with wax matrix tablets. Microencapsulation Applicable Core Approximate
Process Material Particle Size (pm)

Air suspension Solids 35-5000*

Equipment and Processing Coacervation-phase Solids & liquids 2-5000*
The equipment required to conduct microen¬ separation
capsulation varies from complex machines de¬ Multiorifice Solids & liquids 1-5000*
signed specifically for microencapsulation to centrifugal
rather simple processing equipment common to Ban coating Solids 600-5000*
many laboratories. The variation of microen¬ Solvent evaporation Solids & liquids 5-5000*
capsulation equipment is evidenced by the de¬ Spray drying and Solids & liquids 600
scriptions included in the following methodol¬ congealing
ogy section. *The 5000-/xm size is not a particle limitation. The methods are
Microcapsules as bulk materials, in either dry also applicable to macrocoating, i.e., particles greater than
powder or dispersed form, can be processed into 5000-ptm in size.
final product applications using common equip¬
ment such as V-blenders, tablet machines, indicated in the drawing. The design of the
granulators, homogenizers, kneaders, hard- chamber and its operating parameters effect a
gelatin capsule filling machines, or coating recirculating flow of the particles through the
equipment if deposition onto a substrate is de¬ coating zone portion of the chamber, where a
sired. The specific processing equipment em¬ coating material, usually a polymer solution, is
ployed depends on the final product form de¬ spray-applied to the moving particles. During
sired and on the microcapsule properties. All
processing and formulation operations must be
conducted with continual caution to avoid possi¬
ble adverse effects (rupture, attrition, or dissolu¬
tion) upon the thin microcapsule coating.

Methodology
Microencapsulation methods that have been
or are being adapted to pharmaceutical use in¬
clude air suspension, coacervation-phase sepa¬
ration, spray drying and congealing, pan coating,
and solvent evaporation techniques. Methods
not currently applicable to pharmaceutical prep¬
arations are vacuum deposition and polymeriza¬
tion techniques.
The physical nature of the core materials and
the particle size ranges applicable to each proc¬
ess are given in Table 13-8.

Air Suspension
Microencapsulation by air suspension tech¬
niques is generally ascribed to the inventions of
Professor Dale E. Wurster during his tenure at
the University of Wisconsin.906 Basically, the
Wurster process consists of the dispersing of
solid, particulate core materials in a supporting
air stream and the spray-coating of the air-
FIG. 13-37. Schematic drawings of Wurster Air Suspen¬
suspended particles. Figure 13-37 depicts a type
sion Apparatus: A, control panel; B, coating chamber; C,
of the Wurster air suspension encapsulation particles being treated; D, process airflow; E, air distribu¬
unit. Within the coating chamber, particles are tion plate; F, nozzle for applying film coatings. (Courtesy
suspended on an upward moving air stream as of Wisconsin Alumni Research Foundation.)

capsules• 419
each pass through the coating zone, the core eration of the particles to some larger size is nor¬
material receives an increment of coating mate¬ mally achieved.17
rial. The cyclic process is repeated, perhaps sev¬
eral hundred times during processing, depend¬
ing on the purpose of microencapsulation, the Coacervation-Phase Separation
coating thickness desired, or whether the core Microencapsulation by coacervation-phase
material particles axe thoroughly encapsulated. separation is generally attributed to The Na¬
The supporting air stream also serves to dry the tional Cash Register (NCR) Corporation* and
product while it is being encapsulated. Drying the patents of B. K. Green et al.19-28 The general
rates are directly related to the volume tempera¬ outline of the processes consists of three steps
ture of the supporting air stream.17 carried out under continuous agitation: (1) for¬
Processing variables that receive considera¬ mation of three immiscible chemical phases; (2)
tion for efficient, effective encapsulation by air deposition of the coating; and (3) rigidization of
suspension techniques include the following: the coating (Fig. 13-38).
Step 1 of the process is the formation of three
1. Density, surface area, melting point, solubil¬ immiscible chemical phases: a liquid manufac¬
ity, friability, volatility, crystallinity, and turing vehicle phase, a core material phase, and
flowability of the core material. a coating material phase. To form the three
phases, the core material is dispersed in a solu¬
2. Coating material concentration (or melting tion of the coating polymer, the solvent for the
point if not a solution). polymer being the liquid manufacturing vehicle
3. Coating material application rate. phase. The coating material phase, an immisci¬
ble polymer in a liquid state, is formed by utiliz¬
4. Volume of air required to support and fluidize ing one of the methods of phase separation-
the core material. coacervation, that is, by changing the tempera¬
5. Amount of coating material required. ture of the polymer solution; or by adding a salt,
nonsolvent, or incompatible polymer to the poly¬
6. Inlet and outlet operating temperatures. mer solution; or by inducing a polymer-polymer
interaction. These general modes of effecting
The air suspension process offers a wide vari¬ liquid-liquid phase separation are discussed in
ety of coating material candidates for microen¬ more detail later in this chapter.
capsulation. The process has the capability of Step 2 of the process consists of depositing the
applying coatings in the form of solvent solu¬ liquid polymer coating upon the core material.
tions, aqueous solutions, emulsions, disper¬ This is accomplished by controlled, physical
sions, or hot melts in equipment ranging in ca¬ mixing of the coating material (while liquid) and
pacities from one pound to 990 pounds.17 A the core material in the manufacturing vehicle.
partial listing of the coating materials is listed in Deposition of the liquid polymer coating around
Table 13-7. The coating material selection ap¬ the core material occurs if the polymer is ad¬
pears to be limited only in that the coating must sorbed at the interface formed between the core
form a cohesive bond with the core material.18 material and the liquid vehicle phase, and this
The process generally is considered to be appli¬ adsorption phenomenon is a prerequisite to ef¬
cable only to the encapsulation of solid core ma¬ fective coating. The continued deposition of the
terials as indicated in Table 13-8. Indirectly, coating material is promoted by a reduction in
however, liquids can be encapsulated by the the total free interfacial energy of the system,
process at relatively low active levels by coating brought about by the decrease of the coating
solid sorbents that have been pretreated with material surface area during coalescence of the
liquid sorbates. In regard to particle size, the air liquid polymer droplets.
suspension technique is applicable to both Step 3 of the process involves rigidizing the
microencapsulation and macroencapsulation coating, usually by thermal, cross-linking, or
coating processes. The practical particle size desolvation techniques, to form a self-sustaining
range for microencapsulation, however, is con¬ microcapsule.
sidered to be in excess of 74 microns. Under ide¬ Because of the latitude in the material sys-
alized conditions, particles as small as 37 mi¬
crons can be effectively encapsulated as single
entities. Core materials comprised of micron or *The NCR Corporation’s diversified microencapsulation
submicron particles can be effectively encapsu¬ patents and technology are now owned by Eurand Amer¬
lated by air suspension techniques, but agglom¬ ica Inc.

420 • The Theory and Practice of Industrial Pharmacy

 tfJaxZ^

Step 1. Core and Liquid Coating in Manufacturing Step 2. Deposition of Liquid Coating Material
Vehicle

m
M
ryvSL

Step 3. Completed Capsules in Manufacturing Vehicle

FIG. 13-38. Photomicrographs showing coating formation during phase-separation/'coacervation process. A, Step 1. Core
and liquid coating manufacturing vehicle. B, Step 2. Deposition of liquid coating material. C, Step 3. Completed manufac¬
turing vehicle. x300 magnification. (From Bakan.28)
terns associated with the utilization of this gen¬ lose, a water-insoluble polymer, is applied to a
eral scheme of accomplishing microencapsula¬ water-soluble core material, N-acetyl p-amino-
tion, a representative example to illustrate each phenol, by utilizing the temperature-solubility
method is given here. characteristics of the polymer in the hydrocar¬
Temperature Change. Figure 13-39 illus¬ bon solvent cyclohexane. The etherified cellu-
trates a general temperature-composition phase losic, containing a relatively high ethoxyl con¬
diagram for a binary system comprised of a poly¬ tent (high degree of substitution), is insoluble in
mer and a solvent. A system having an overall cyclohexane at room temperature, but is soluble
composition, represented as point X on the ab¬ at elevated temperatures. Consequently, a work¬
scissa, exists as a single-phase, homogeneous ing example involves dispersing ethylcellulose
solution at all points above the phase-boundary in cyclohexane to yield a polymer concentration
or binodal curve, FEG. As the temperature of the of 2% by weight.23 The mixture is heated to the
system is decreased from point A along the ar¬ boiling point to form a homogeneous polymer
rowed line AEB, the phase boundary is crossed solution. The core material, finely divided crys¬
at point E, and the two-phase region is entered. talline N-acetyl p-aminophenol, is dispersed in
Phase separation of the dissolved polymer oc¬ the solution with stirring at a coating-to-core
curs in the form of immiscible liquid droplets, material (dry) ratio of 1:2. Allowing the mixture
and if a core material is present in the system, to cool, with continued stirring, effects phase-
under proper polymer concentration, tempera¬ separation/coacervation of the ethyl-cellulose
ture, and agitation conditions, the liquid poly¬ and microencapsulation of the core material. Al¬
mer droplets coalesce around the dispersed core lowing the mixture to cool further to room tem¬
material particles, thus forming the embryonic perature accomplishes gelation and solidifica¬
microcapsules. The phase-boundary curve indi¬ tion of the coating. The microencapsulated
cates that with decreasing temperature, one product can then be collected from the cyclohex¬
phase becomes polymer-poor (the microen¬ ane by filtration, decantation, or centrifugation
capsulation vehicle phase) and the second phase techniques.
(the coating material phase) becomes polymer- Incompatible Polymer Addition. Liquid
rich. At point B, for instance, the segmented phase separation of a polymeric coating material
tie-line suggests that vehicle phase is essentially and microencapsulation can be accomplished by
pure solvent, point C, whereas the coexisting utilizing the incompatibility of dissimilar poly¬
phase, point D, is a concentrated polymer- mers existing in a common solvent. Microen¬
solvent mixture. In practice, the loss of solvent capsulation using this phenomenon is best
by the polymer-rich phase can constitute gelatin described by considering the process in con¬
of polymer, and hence rigidization or solidifica¬ junction with the general phase diagram shown
tion of the microcapsule polymeric coating. in Figure 13-40. The diagram illustrates a ter¬
The following example illustrates a microen¬ nary system consisting of a solvent, and two pol¬
capsulation procedure that utilizes the phase- ymers, X and Y. If an immiscible core material is
separation/coacervation principle. Ethylcellu- dispersed in a solution of polymer Y (point A in

SOLVENT

FIG. 13-40. General phase diagram of phase-separation!

FIG. 13-39. General phase diagram—coacervation in¬ coacervation induced by the addition of an incompatible
duced thermally. (From Baton.28) polymer. (From Bakan.)

422 • The Theory and Practice of Industrial Pharmacy

Figure 13-40) and polymer X is added to the sys¬ SOLVENT

tem, denoted by the arrowed line, the phase

boundary will be crossed at point E. As the
two-phase region is penetrated with the further
addition of polymer X, liquid polymer, immisci¬
ble droplets form and coalesce to form embry¬
onic microcapsules. The coating of the micro¬
capsules existing at point B, for example,
consists of a concentrated solution of polymer Y
dispersed in a solution comprised principally of
polymer X, as indicated by the segmented tie¬
line and the phase-boundary intercepts C and D.
The polymer that is more strongly adsorbed at
the core material-solvent interface, in this case
polymer Y, becomes the coating material.
NON SOLVENT POLYMER
In practice, solidification of the coating mate¬
rial is accomplished by further penetration into FIG. 13-41. General phase diagram for phase-separation/
the two-phase region, chemical cross-linking, or coacervation induced by the addition of a nonsolvent.
(From Bakan28)
washing the embryonic microcapsules with a
liquid that is a nonsolvent for the coating, poly¬
mer Y, and that is a solvent for polymer X. lose acetate butyrate is prepared, and in it, mi-
The microencapsulation of methylene blue cronized methylscopolamine hydrobromide is
hydrochloride with ethylcellulose by this mode dispersed with stirring. A core-material to coat¬
of phase separation (incompatible polymer addi¬ ing-material ratio (methylscopolamine) hydro¬
tion) is described as follows. Ethylcellulose is bromide to cellulose acetate butyrate) of about
dissolved in toluene to yield a polymer concen¬ 2:1 is used. The resulting mixture is heated to
tration of 2% by weight. Crystalline methylene 55°C, and isopropyl ether, a nonsolvent for the
blue hydrochloride, being essentially insoluble coating polymer, is added slowly to effect phase-
in toluene, is dispersed, with stirring, in the separation/coacervation and microencapsulation
polymer solution at a ratio, for instance, of 4 of the suspended core material. The system is
parts methylene blue hydrochloride to 1 part slowly cooled to room temperature, and the mi¬
ethylcellulose. Phase-separation/coacervation is croencapsulated particles are separated by cen¬
accomplished by slowly adding liquid polybuta¬ trifugation, washed with isopropyl ether, and
diene in sufficient quantity to yield a ratio of 25 dried in vacuo.25
parts polybutadiene to 1 part ethylcellulose.24 Salt Addition. Soluble inorganic salts can be
The polybutadiene, being quite soluble in tolu¬ added to aqueous solutions of certain water-
ene and incompatible with ethylcellulose, ef¬ soluble polymers to cause phase separation (Fig.
fects the demixing of the ethylcellulose from the 13-42). The following example of an oil-soluble
polybutadiene toluene solution, and subsequent
microencapsulation of the dispersed core mate¬
WATER
rial results. The ethylcellulose coating is solidi¬
fied by adding a nonsolvent for the coating poly¬
mer, ethylcellulose, such as hexane. Also, the
poly butadiene, being soluble in hexane, is
washed from themixture by decantation and by
additional hexane wash cycles. The resultant
product, crystalline methylene blue hydrochlo¬
ride coated with ethylcellulose, is collected by
standard filtration and drying techniques.
Nonsolvent Addition. A liquid that is a
nonsolvent for a given polymer can be added to a
solution of the polymer to induce phase separa¬
tion, as indicated by the general phase diagram
given in Figure 13-41. The resulting immiscible,
liquid polymer can be utilized to effect microen¬ 100% 100%
capsulation of an immiscible core material as il¬ SALT POLYMER
lustrated in the following example. A 5%, weight FIG. 13-42. General phase diagram for phase-separation/
to volume, methyl ethyl ketone solution of cellu- coacervation induced by salt addition. (From Bakan.28)

capsules • 423
vitamin microencapsulation induced by adding oppositely charged polyelectrolytes occurs, in¬
sodium sulfate to a gelatin solution illustrates ducing phase separation within the phase¬
the concept.26 An oil-soluble vitamin is dissolved boundary curve ABA. The segmented tie-lines
in com oil and is emulsified to the desired drop indicate that a system, having an overall compo¬
size in a 10% solution of high-quality pigskin sition within the two-phase region (point C for
gelatin having an isoelectric point at about pH example), consists of two phases, one being
8.9. Twenty parts oil to 100 parts water, by polymer poor, point A, and one containing the
weight, are used for the preparation of the oil/ hydrated, liquid complex, Pe+ and Pe“, point B.
water emulsion. The emulsification process is As in the case of the previously described
conducted at 50°C, well above the gelation tem¬ phase-separation/coacervation phenomena, mi¬
perature of the gelatin. With the temperature of croencapsulation can be accomplished by
the emulsion maintained at 50°C, phase-separa- polymer-polymer interaction. Gelatin and gum
tion/coacervation is induced by slowly adding a arable are typical polyelectrolytes that can be
20% solution of sodium sulfate. The salt solution caused to interact. Gelatin, at pH conditions
is added in a ratio of 10 parts emulsion to 4 parts below its isoelectric point, possesses a net posi¬
salt solution. The addition of the salt solution to tive charge, whereas the acidic gum arabic is
the continuously stirred emulsion effects the negatively charged. Under the proper tempera¬
microencapsulation of the oil droplets with a ture, pH, and concentrations, the two polymers
uniform coating of gelatin. The resultant protein can interact through their opposite electrical
coating is rigidized by transferring the mixture charges, forming a complex that exhibits phase-
into a sodium sulfate solution that is 7% by separation/coacervation. The following method
weight and is maintained at 19°C, with contin¬ for microencapsulating the water-immiscible
ued agitation. The gelatin salt solution com¬ liquid, methyl salicylate, is an example of this
prises a volume approximately ten times that of process.27 Aqueous solutions of gum arabic and
the microencapsulation mixture volume. The pigskin gelatin (isoelectric point 8.9) are pre¬
microencapsulated product is collected by filtra¬ pared, each being 2% by weight in concentra¬
tion, washed with water, chilled below the gela¬ tion. The homogeneous polymer solutions are
tion temperature of the gelatin (to remove the mixed together in equal amounts, diluted to
salt), and voided of water by standard drying about twice their volume with water, adjusted to
techniques such as spray drying. pH 4.5, and warmed to 40 to 45°C. The oppo¬
Polymer-Polymer Interaction. The inter¬ sitely charged macromolecules interact at these
action of oppositely charged polyelectrolytes can conditions and undergo phase-separation/
result in the formation of a complex having such coacervation. While maintaining the warm tem¬
reduced solubility that phase separation occurs. perature conditions, the liquid core material,
Figure 13-43 illustrates the phase diagram for a methyl salicylate, is added at a weight ratio of,
ternary system comprised of two dissimilarly for instance, 25 parts methyl salicylate to one
charged polyelectrolytes and the solvent, water. part gelatin-gum arabic (dry). The core material
In the dilute solution region, interaction of the is emulsified by stirring to yield the desired drop
size. The mixture is then slowly cooled to 25°C,
with continued stirring, over a period of about
100% WATER one hour. During the cooling cycle, phase-sepa¬
ration/coacervation is further enhanced, result¬
ing in the microencapsulation of the core mate¬
rial with the gelatin-gum arabic complex. The
coating is rigidized for drying purposes by cool¬
ing the mixture to about 10°C.
Owing to the fact that core materials are mi¬
croencapsulated while being dispersed in some
liquid manufacturing vehicle, subsequent dry¬
ing operations may be required. Typical drying
methods such as spray, freeze, fluid bed, sol¬
vent, and tray drying techniques are amenable
to the microencapsulated products. The phase-
separation/coacervation processes are conducted
as batch operations using common production
equipment in the manner illustrated in Figure
FIG. 13-43. Phase diagram for phase-separation/coacer- 13-44. A wide variety of liquids, solids, or sus¬
vation by polymer interaction. (From Bakan.28) pensions can be microencapsulated in various

424 • The Theory and Practice of Industrial Pharmacy

 JACKETED COATING CORE MATERIAL 5.COAT1NG MATERIAL

FIG. 13-45. Sectional diagram of multiorifice-centrifugal

microencapsulation apparatus. (From Mattson.30 Cour¬
tesy Conover-Most Publications, Inc.)
CONCENTRATION EQUIPMENT DRYING EQUIPMENT
(OPTIONAL) (OPTIONAL)

•FILTER •FLUIDIZED BED

•EXTRACTOR - ^ •TRAY
the system. The coating material, 6, under cen¬
•CENTRIFUGE •SPRAY trifugal force imparted by the cylinder rotation,
•FREEZE
flows outward along the side of the immediate
FIG. 13-44. Flow diagram of a typical phase-separation/ groove into the countersunk portion and forms a
coacervation process. (From Bakan.28) film across the orifice. A counter rotating disc, 7,
mounted within the cylinder, atomizes or dis¬
perses the core material fed through the cen¬
trally located inlet, 8. The rotating disc flings the
sizes (see Table 13-8) having a variety of coat¬ particulate core material (liquid) droplets or
ings (see Table 13-7). Microcapsules are being solid particles) toward the orifices. The core
manufactured in vessels up to 2000 gallons in material arrives at the orifices and encounters
capacity, at a multimillion pound per annum the coating material membrane. The impact and
rate. centrifugal force, generated by the rotating cyl¬
inder, hurls the core material through the envel¬
oping coating membrane, 9, which is immedi¬
Multiorifice-Centrifugal Process ately regenerated by the continually overflowing
The Southwest Research Institute (SWRI) coating material.
has developed a mechanical process for produc¬ The embryonic microcapsules, upon leaving
ing microcapsules that utilizes centrifugal forces the orifices, are hardened, congealed, or voided
to hurl.a core material particle through an envel¬ of coating solution by a variety of means. For
oping microencapsulation membrane, thereby example, the microcapsules can be flung into a
effecting mechanical microencapsulation.29 The heated, countercurrent air stream to harden or
apparatus, illustrated cross-sectionally in Figure congeal coatings containing residual solvent.
13-45, depicts a rotating cylinder, 1, a major and Also, the microcapsules can be forced into a ro¬
essential portion of the device. Located within tating hardening or congealing bath. The coat¬
the cylinder are three circumferential grooves, ing material, if a melt, can be hurled into a cool
2, 3, and 4. Countersunk in the intermediate liquid (nonsolvent for the coating material) de¬
groove, 3, are a plurality of orifices spaces closely creasing the temperature below the melting
and circumferentially around the cylinder. The point of the coating. Also, the hardening bath
upper and lower grooves, also located circumfer¬ can contain a coating nonsolvent that is capable
entially around the cylinder, carry the coating of extracting the coating solution solvent. The
material in molten or solution form, via tubes, 5, rotating hardening bath not only provides a coat¬
to the respective grooves. The ridges of the coat¬ ing desolvation or congealing function, but
ing material grooves, 2 and 4, serve as a weir serves as a means of removing the microcap¬
over which the coating material overflows when sules from their impact points, thus reducing
the volume of the upper and lower grooves is agglomeration tendencies. It also provides a
exceeded by the volume of material pumped into means of accumulating the coated product. The

CAPSULES • 425
hardening liquid, after removing the microen¬ dry, and the excess talc is removed by vacuum.
capsulated product to where it can be collected, The product is then screened through a 12-
can be recycled to the hardening bath for subse¬ mesh screen and 20.0 kg of coated product is
quent reuse. collected. One quarter of the batch is set aside,
Processing variables include the rotational and the remainder is coated with a wax-fat coat¬
speed of the cylinder, the flow rate of the core ing solution consisting of 6300 g of glyceryl
and coating materials, the concentration and monostearate, 700 g of white beeswax, and
viscosity of the coating material, and the viscos¬ 2100 ml of carbon tetrachloride, maintained at
ity and surface tension of the core material.30 70°C. The wax-fat solution, 425 ml is applied to
The multiorifice-centrifugal process is capable the rotating pellets and subsequently dried with
of microencapsulating liquids and solids (if the air. The coating operation is repeated until a
solids are dispersed in a liquid) of varied size 10% coating weight is achieved, whereupon one
ranges, with diverse coating materials (see Ta¬ third of the batch is removed.
bles 13-7 and 13-8). The encapsulated product The remaining product is again coated with
can be supplied as a slurry in the hardening the wax-fat solution as described previously.
media or as a dry powder. Production rates of 50 Subsequently, one half of the material is re¬
to 75 pounds per hour have been achieved with moved and the remainder is again coated to
the process. yield an additional coating of about 10% by
weight. The four groups of pellets are then thor¬
oughly mixed to yield the sustained-release form
Pan Coating of the sympathomimetic.
The macroencapsulation of relatively large
particles by pan methods has become wide¬
spread in the pharmaceutical industry, and the Spray Drying and Spray
topic is covered in depth in Chapter 12 of this
text. With respect to microencapsulation, solid Congealing
particles greater than 600 microns in size are Spray-drying and spray-congealing methods
generally considered essential for effective coat¬ have been used for many years as microen¬
ing, and the process has been extensively em¬ capsulation techniques. Because of certain simi¬
ployed for the preparation of controlled-release larities of the two processes, they are discussed
beads (see Chap. 14). Medicaments are usually together.
coated onto various spherical substrates such as Spray-drying and spray-congealing processes
nonpareil sugar seeds, and then coated with pro¬ are similar in that both involve dispersing the
tective layers of various polymers. core material in a liquefied coating substance
, In practice, the coating is applied as a solu¬ and spraying or introducing the core-coating
tion, or as an atomized spray, to the desired solid mixture into some environmental condition,
core material in the coating pan. Usually, to whereby relatively rapid solidification (and for¬
remove the coating solvent, warm air is passed mation) of the coating is effected. The principal
over the coated materials as the coatings are difference between the two methods, for the
being applied in the coating pans. In some cases, purpose of this discussion, is the means by
final solvent removal is accomplished in a drying which coating solidification is accomplished.
oven. Coating,solidification in the case of spray drying
Blythe describes a method of preparing sus¬ is effected by rapid evaporation of a solvent in
tained-release pellets in which nonpareil seeds which the coating material is dissolved. Coating
are coated initially with dextroamphetamine sul¬ solidification in spray congealing methods, how¬
fate, and then with a release-rate retarding ever, is accomplished by thermally congealing a
wax-fat coating.31 Nonpareil seeds (sugar pel¬ molten coating material or by solidifying a dis¬
lets), 15.5 kg and 12 to 40 mesh in size, are solved coating by introducing the coating-core
placed in a rotating, 36-inch coating pan. USP material mixture into a nonsolvent. Removal of
syrup, 240 ml, is slowly poured onto the pellets the nonsolvent or solvent from the coated prod¬
to wet them evenly. An 80/20 mixture (750 g) of uct is then accomplished by sorption, extraction,
dextroamphetamine and calcium dihydrate are or evaporation techniques.
sprinkled onto the wetted nonpareil seeds. The In practice, microencapsulation by spray dry¬
pellets were dried with warm air. This coating ing is conducted by dispersing a core material in
operation is repeated three times. The fifth coat¬ a coating solution, in which the coating sub¬
ing, talc, is accomplished by wetting the product stance is dissolved and in which the core mate¬
with 240 ml of syrup followed by dusting 600 g rial is insoluble, and then by atomizing the mix¬
of talc on the seeds. The pellets are rolled until ture into an air stream. The air, usually heated,

426 • The Theory and Practice of Industrial Pharmacy

supplies the latent heat of vaporization required The microcapsule coating is dissolved in a vola¬
to remove the solvent from the coating material, tile solvent, which is immiscible with the liquid
thus forming the microencapsulated product. manufacturing vehicle phase. A core material to
The equipment components of a standard spray be microencapsulated is dissolved or dispersed
dryer include an air heater, atomizer, main in the coating polymer solution. With agitation,
spray chamber, blower or fan, cyclone and prod¬ the core coating material mixture is dispersed in
uct collector, as described in detail in Chapter 3. the liquid manufacturing vehicle phase to obtain
Process control variables include feed material the appropriate size microcapsule. The mixture
properties such as viscosity, uniformity, and is then heated (if necessary) to evaporate the
concentration of core and coating material, feed solvent for the polymer. In the case in which the
rate, method of atomization, and the drying rate, core material is dispersed in the polymer solu¬
which is normally controlled by the inlet and tion, polymer shrinks around the core. In the
oudet temperatures and the air stream solvent case in which the core material is dissolved in
concentration. The process produces microcap¬ the coating polymer solution, a matrix-type mi¬
sules approaching a spherical structure in the crocapsule is formed. Once all the solvent for the
size range of 5 to 600 microns (Table 13-8). polymer is evaporated, the liquid vehicle tem¬
Characteristically, spray drying yields products perature is reduced to ambient temperature (if
of low bulk density, owing to the porous nature required) with continued agitation. At this stage,
of the coated particles. Low active contents are the microcapsules can be used in suspension
normally required to provide the necessary pro¬ form, coated on to substrates or isolated as pow¬
tection desired. For instance, the adequate re¬ ders.
tention of volatile, liquid core materials is diffi¬ Process variables would include, but not be
cult to achieve without maintaining low active limited to, methods of forming dispersions,
content levels, perhaps below 20%. evaporation rate of the solvent for the coating
Many coating materials (see Table 13-7) can polymer, temperature cycles, and agitation
be applied to liquid and solid core materials by rates. Important factors that must be considered
spray drying coating solutions containing the when preparing microcapsules by solvent evapo¬
dispersed core material. The process is com¬ ration techniques include choice of vehicle
monly employed in the microencapsulation of phase and solvent for the polymer coating, as
liquid flavors yielding dry, free-flowing powders these choices greatly influence microcapsule
for use in foods and pharmaceuticals. properties as well as the choice of solvent recov¬
Microencapsulation by spray congealing can ery techniques.
be accomplished with spray drying equipment The solvent evaporation technique to produce
when the protective coating is applied as a melt. microcapsules is applicable to a wide variety of
General process variables and conditions are liquid and solid core materials. The core materi¬
quite similar to those already described, except als may be either water-soluble or water-insolu¬
that the core material is dispersed in a coating ble materials. A variety of film-forming polymers
material melt rather than a coating solution. can be used as coatings as exemplified in
Coating solidification (and microencapsulation) Table 13-7.
is accomplished by spraying the hot mixture into
a cool air stream. Waxes, fatty acids and alco¬
hols, polymers and sugars, which are solids at
Polymerization
room temperature but meltable at reasonable A relatively new microencapsulation method
temperatures, are applicable to spray-congealing utilizes polymerization techniques to form pro¬
techniques. Typically, the particle size of spray- tective microcapsule coatings in situ. The meth¬
congealed products can be accurately controlled ods involve the reaction of monomeric units lo¬
when spray drying equipment is used,32 and has cated at the interface existing between a core
been found to be a function of the feed rate, the material substance and a continuous phase in
atomizing wheel velocity, dispersion of feed ma¬ which the core material is dispersed. The con¬
terial viscosity, and other variables. tinuous or core material supporting phase is
usually a liquid or gas, and therefore the polym¬
erization reaction occurs at a liquid-liquid,
Solvent Evaporation liquid-gas, solid-liquid, or solid-gas interface.
This technique has been used by companies The polymerization method most applicable,
including The NCR Company, Gavaert Photo- perhaps, to pharmaceutical or medical use is
Production NV, and Fuji Photo Film Co., Ltd. to that developed by Chang37'41 in his research at
produce microcapsules.33’36 The processes are McGill University. Chang has been able to ac¬
carried out in a liquid manufacturing vehicle. complish permselective membrane properties

CAPSULES• 427
for microcapsules having coatings of nylon 4. The National Cash Register Company. Unpublished
formed by interfacial polymerization, or collo¬ data. Dayton, OH.
5. Rosen, E., Ellison, T., Tannenbaum, P., et al.: J.
dion formed by phase-separation/coacervation
Pharm. Sci., 56:365, 1967.
techniques. The membranes, typically about 6. Wiegand, R.G., and Taylor, J.D.: Drug Standards,
200 angstroms thick, have an equivalent aque¬ 27.T65, 1959.
ous pore radius of about 16 angstroms. The mi¬ 7. Clanchi, M.: Eurand Studies on Some Advantages of
crocapsules have been shown to be permselec¬ Drug Microencapsulation. Third International Sym¬
tive in that protein and enzyme core materials, posium on Microencapsulation, Tokyo, Japan, 1976.
8. McMahon, F., et al.: Lancet, November 13, 1982, p.
for instance, do not transfer out of the microcap¬
1059.
sule, whereas smaller molecules such as en¬ 9. Wurster, D.E.: U.S. Patent 2,648,609 (1953).
zyme substrates and resultant reaction products 10. Wurster, D.E.: U.S. Patent 2,799,241 (1957).
can permeate the membrane.41 11. Wurster, D.E.: U.S. Patent 3,089,824 (1963).
Chang’s interfacial polymerization method for 12. Wurster, D.E., and Lindlof, J.A.: U.S. Patent
forming polyamide (nylon) membranes involves 3,117,027 (1964).
13. Wurster, D.E., and Lindlof, J.A.: U.S. Patent
the reaction occurring at the liquid-liquid inter¬
3,196,827 (1965).
face existing between an aqueous solution of an 14. Wurster, D.E., Battista, J.V., and Lindlof, J.A.: U.S.
aliphatic diamine and a water-immiscible or¬ Patent 3,207,824 (1965).
ganic solution of a dicarboxylic acid halide. The 15. Wurster, D.E., and Lindlof, J.A.: U.S. Patent
polymerization reaction depends on the fact that 3,241,520 (1966).
acid halides, such as sebacoyl chloride, are 16. Wurster, D.E.: U.S. Patent 3,253,944 (1966).
nearly water-insoluble, and diamines, such as 17. Hinkes, T.M.: The Wurster Process for Encapsula¬
tion. Presented at Microencapsulation Course, Cen¬
hexanediamine, have an appreciable partition ter for Professional Advancement, Somerville, New
coefficient toward the water-immiscible organic Jersey, September 1972.
phase. Hence, the hexanediamine diffuses to 18. Harvard Business School: Report on Microencapsula¬
the organic sebacoyl chloride phase, and the tion. Management Reports, 38 Commington Street,
polycondensation reaction occurs forming the Boston, 1963.
19. Green, B.K.: U.S. Patent 2,712,507 (1955).
polyamide. Because the chemical reaction rate
20. Green, B.K., and Schleicher, L.: U.S. Patent
exceeds the diffusion rate of the diamine into 2,730,456 (1956).
the nonaqueous phase, the polyamide is depos¬ 21. Green, B.K.: U.S. Patent 2,800,457 (1957).
ited almost entirely at the interface existing be¬ 22. Miller, R.E., and Anderson, J.L.: U.S. Patent
tween the two solutions.40 3,155,590 (1964).
Using this phenomenon, Chang prepares mi¬ 23. Miller, R.E., Fanger, G.O., and McNiff, R.G.: Union
of So. Africa Patent 4211-66 (1967).
crocapsules containing protein solutions by in¬
24. The National Cash Register Co.: Gr. Br. Patent
corporating the protein in the aqueous diamine 907,284 (1963).
phase. Chang has demonstrated the permselec¬ 25. Heistand, E.N., Wagner, J.G., and Knoechel, E.L.:
tivity of microcapsules containing the enzyme, U.S. Patent 3,242,051 (1966).
urease, by their ability to convert blood urea to 26. Green, B.K.: U.S. Patent Re 24,899 (1960).
ammonia, the enzyme remaining within the 27. Brynko, C., Bakan, J.A., Miller, R.E., and Scarpelli,
microcapsules when incorporated within an ex¬ J.A.: U.S. Patent 3,341,466 (1967).
28. Bakan, J.A.: Microencapsulation of Foods and Re¬
tracorporeal shunt system. Numerous groups
lated Products. Food Technology, 7:34, 1973.
are utilizing polymerization techniques to ac¬ 29. Somerville, G.R., Jr.: U.S. Patent 3,015,128 (1962).
complish microencapsulation. Examples are the 30. Mattson, H.W.: Int. Sci. Technol., 40:66, 1965.
National Lead Corporation, Union Carbide Cor¬ 31. Blythe, R.H.: U.S. Patent 2,738,303 (1956).
poration, Pennwalt Corporation, Eurand Amer¬ 32. Scott, M.W., Robinson, M.J., Pauls, V.F., and Lantz,
ica Inc., Appleton Papers Inc., and Moore Busi¬ R.S.: J. Pharm. Sci., 53:670, 1964.
33. Herbig, J.A., and Hanny, J.F.: U.S. Patent 3,732,172
ness Forms, Inc. The processes are not
(1973).
discussed in this chapter, however, nor is 34. Vrancken. M.N.. and Claeys, D.S.: U.S. Patent
microencapsulation that is effected by electro¬ 3,523,906 (1970).
static and vacuum deposition techniques.42-59 35. Matsukana, H.: U.S. Patent 3,660,304 (1972).
36. Yoshida, N.H.: U.S. Patent 3,657,144 (1972).
References 37. Chang, T.M.S.: Science, 146:524, 1964.
38. Chang, T.M.S., and Macintosh, F.C.: Pharmacologist,
1. Goieone, M., et al.: Current Therapeutic Research, 6:198, 1964.
31:3, 1982. 39. Chang, T.M.S.: Ph.D. Thesis, McGill University,
2. Herbig, J.A.: Encyclopedia of Polymer Science and Montreal, Canada, 1965.
Technology. Vol. 8. John Wiley and Sons, New York, 40. Chang, T.M.S., Macintosh, F.C., and Mason, S.G.:
1968. Canad. J. Physiol. Pharmacol., 44:415, 1966.
3. Bakan, J.A., and Sloan, F.D.: Drug and Cosmetic 41. Chang, T.M.S.: Trans Am. Soc. Artif. Int. Organs,
Ind., March 1972. 12:13. 1966.

428 • The' Theory and Practice of Industrial Pharmacy

42. Brynko, C.: U.S. Patent 2,969,330 (1961). Gutcho, M.: Microcapsules and Other Capsules—
43. Brynko, C., and Scarpelli, J.A.: U.S. Patent 2,969,331 Advances Since 1975. Noyes Data Corporation, Ridge
(1961). Park, NJ, 1979.
44. Orsino, J.A., Herman, D.F., and Brancato, J.J.: U.S. Gutcho, M.: Microcapsules and Microencapsulation
Patent 3,121,698 (1964). Techniques. Noyes Data Corporation, Ridge Park, NJ,
45. Orsino, J.A., and Mandel, C.E.: U.S. Patent 1976.
3,121,658 (1964). Gutcho, M.: Capsule Technology and Microencapsula¬
46. Herman, D.F., and Dunlap, I.R.: TAPPI, 48:418, tion. Noyes Data Corporation, Ridge Park, NJ, 1972.
1965. Journal of Controlled Release. Elsevier Science Publish¬
47. Gorham, W.F., and Chappaqua, W.: U.S. Patent ers, The Netherlands, began issuing 1984.
3,330,332 (1967). Journal of Microencapsulation. Taylor and Francis Ltd.,
48. Chem. Week, February 27, 1965, p. 59. London, England, began issuing 1984.
49. Vandegaer, J.E., and Meier, F.G.: U.S. Patent Kondo, T.: Microencapsulation. Techno Inc., Tokyo,
3,464,926 (1969). Japan, 1979.
50. Vandegaer, J.E., and Meier, F.G.: U.S. Patent Kydonieus, A. (ed.): Controlled Release Technologies:
3,355,882 (1971). Methods, Theory and Applications. Vols. I and II.-CRC
51. Vandegaer, J.E.: U.S. Patent 3,577,515 (1971). Press, Boca Raton, FL, 1980.
52. Moore Business Forms, Inc.: Gt. B. Patent 1,046,409 Lim, F. (ed.): Biomedical Applications of Microencapsula¬
(1966). tion. CRC Press, Boca Raton, FL, 1983.
53. Langer, G., and Yamate, G.: U.S. Patent 3,294,704 Luzzi, L.A.: J. Pharm. Sci., 59:1367, 1970.
(1966). Merory, S.: Food Flavorings, Composition, Manufacture
54. Berger, B.B., Miller, C.D., Langer, W., and Langer, and Use. Avi Publishing, Westport, CT, 1960.
G.: U.S. Patent 3,208,951 (1965). Nixon, J.R. (ed.): Microencapsulation—Drugs and Phar¬
55. Baer, C.W., and Steeves, R.W.: U.S. Patent 2,846,971 maceutical Sciences. Vol. 3. Marcel Dekker, New York,
(1958). 1976.
56. Chem. Eng. News, June 26, 1961. Roseman, T., and Mansdorf, Z. (eds.): Controlled Release
57. Kiritani, M„ et al.: U.S. Patent 3,981,821 (1976). Delivery Systems. Marcel Dekker, New York, 1983.
58. Foris, P.L., et al.: U.S. Patent 4,001,140 (1977). Sirine, G.: Drug and Cosmetic Ind., September 1969.
59. Speiser, P„ et al.: U.S. Patent 4,021,364 (1977). Sparks, R.E., Salemme, R.M., Meier, P.M., et al.: Trans.
Am. Soc. Artif. Int. Organs, 14:353, 1969.
Sprowls, J.B., Jr.(ed ): Prescription Pharmacy. 2nd Ed.
General References J.B. Lippincott, Philadelphia, 1970.
Swintosky, J.V.: Ind. J. of Pharm., 25:360. 1963.
Bungenberg de Jong, H.G., and Kruyt, H.R.(eds.): Colloid Vandegaer, J.E. (ed.): Microencapsulation—Processes
Science. Vol. II. Elsevier Publishing Company, Amster¬ and Applications. Plenum Press, New York, 1974.
dam, 1949.
Chang, T.M.S.: Artificial Cells. Charles C Thomas,
Springfield, IL, 1972.
Chang, T.M.S. (ed.): Microencapsulation and Artificial Acknowledgment
Cells. Humana Press, New York, 1984.
The author would like to express his sincere
Deasy, P.: Microencapsulation and Related Drug Proc¬
esses. Marcel Dekker, New York, 1984. appreciation to J. L. Anderson, Appleton Papers,
Eurand Lectures to International Symposia, Eurand In- Inc., for his historical contribution to the prepa¬
temation. Viale Monza, Milano, Italy, 1977. ration of this chapter.

CAPSULES• 429
 14

Sustained Release
Dosage Forms
NICHOLAS G. LORDI

With many drugs, the basic goal of therapy is to been formulated for oral, injectable, and topical
achieve a steady-state blood or tissue level that is use, and include inserts for placement in body
therapeutically effective and nontoxic for an ex¬ cavities as well.1
tended period ot time, t he design of proper dosr The pharmaceutical industry provides a vari¬
ageYSgimens is an important element in accom¬ ety of dosage forms and dosage levels of particu¬
plishing this goal. A basic objective in dosage lar drugs, thus enabling the physician to control
form design is to optimize the delivery of medi¬ the onset and duration of drug therapy by alter¬
cation so as to achieve a measure of control of ing the dose and/or mode of administration. In
the therapeutic effect in the face of uncertain some instances, control of drug therapy can be
fluctuations in the in vivo environment in achieved by taking advantage of beneficial drug
which drug release takes place. This is usually interactions that affect drug, disposition and
accomplished by maximizing drug availability, elimination, e.g., traction of probenicid, which
i.e., by attempting to attain a maximum rate and inhibits the excretion of penicillin, thus prolong¬
extent of drug absorption; however, control of ing its blood level. Mixtures of drugs might be
drug action through formulation also implies utilized to potentiate, synergize, or antagonize
controlling bioavailability to reduce drug absorp¬ given drug actions. Alternately, drug mixtures
tion rates. In this chapter, approaches to the for¬ might be formulated in which the rate and/or
mulation of drug delivery systems, based on the extent of drug absorption is modified. Sustained
deliberate control of drug availability, are consid¬ release dosage form design embodies this ap¬
ered with emphasis on peroral dosage forms. proach to the control of drug action, i.e., through
a process of either drug modification or dosage
form modification, the absorption process, and
The Sustained Release Concept subsequently drug action, can be controlled.
Sustained release, sustained action, prolonged Physicians can achieve several desirable ther¬
action, controlled release, extended action, apeutic advantages by prescribing sustained re¬
timed release, depot, and repository dosage lease forms. Since the frequency of drug admin-
forms are terms used to identify drug delivery istration is reduced, patient compliance can be
systems that are designed to achieve a prolonged improved, and drug administration can be made
therapeutic effect by continuously releasing more convenieht~as well. I ticTblood level oscilla¬
medication over an extended period of time after tion characteristic of multiple dosing of conven¬
administration of a single dose'. In the case of tional dosage forms is reduced, because a more
injectable dosage forms, this period may vary even blood lever is maintained. A less obvious
from days to months. In the caSe of orally ad¬ advantage, implicit in the design of sustained
ministered forms, however, this period is meas¬ release form's, is that the total anrotmt of drug
ured in hours and critically depends on the resi¬ administered can be reduced, thus maximizing
dence time of the dosage form in the Availability with a minimum dose. In addition,
gastrointestinal (GI) tract. The term “-controlled better control of drug absorption can be attained,
release” has become associated-with those sys¬ since the high blood level peaks that may be ob¬
tems fromwhich therapeuiie-agents may be au¬ served after administration of a dose of a high-
tomatically delivered at predefined rapes over a availability drug can be reduced by formulation
long period of "time. Products ot tnis type Pave in an extended action form. The safety margin of

430
~=fogh-potency drugs can be increased, and the didates for sustained release formulation. For
incidence ot both local and systemic adverse some drugs in this group, however, a properly
sidg'gffects can be reduced in sensitive patients. designed sustained release formulation may be
"uveraH, administration of sustained release advantageous. Because single doses capable of
forms enables increased reliability of therapy.2 producing equally prolonged effects often yield
In evaluating drugs as candidates for sus¬ significant concentration peaks immediately
tained release formulation, the disadvantages of after each dosing interval, control of drug release
such formulations that must be considered in¬ may be indicated if toxicity or local gastric irrita¬
clude the followingJ^jl'f Administration of sus¬ tion is a hazard. Drugs with narrow require¬
tained release medication does not permit the ments for absorption (e.g., drugs dependent on
prompt termination of therapy. Immediate position in the GI tract for optimum absorption)
changes in drug need during therapy, such as are also poor candidates for oral sustained re¬
might be encountered if significant adverse ef¬ lease formulation, since absorption must occur
fects are noted, cannot be accommodated. throughout the length of the gut. Very insoluble
CS^The physician has less flexibility in adjust¬ drugs whose availability is controlled by dissolu¬
ing dosage regimens. This is fixed by the dosage tion (e.g., griseofulvin) may not benefit from for¬
form design. (9) Sustained release forms are mulation in sustained release forms since the
designed for the normal population, i.e., on the amount of drug available for absorption is lim¬
basis of average drug biologic half-lives. Conse¬ ited by the poor solubility of the compound.
quently, disease states that alter drug disposi¬ Before proceeding with the design of a sus¬
tion, significant patient variation, and so forth tained release form of an appropriate drug, the
are not accommodated, i^4) Economic factors formulator should have an understanding of the
must also be assessed, since more costly proc¬ pharmacokinetics of the candidate, should be
esses and equipment are involved in manufac¬ assured that pharmacologic effect can be corre¬
turing many sustained release forms. lated with drug blood levels, and should be
Not all drugs are suitable candidates for for¬ knowledgeable about the therapeutic dosage
mulation as prolonged action medication. Table range, including the minimum effective and
14-1 lists specific drug characteristics that maximum safe doses.
would preclude formulation in ]
release forms. Drugs with long hiolonic half-lives
(e.g., digoxin—^14' hours) arejnherently-leng- Theory ^
acting_and thus are viewed as questionable can-

Design
Table 14-1. Characteristics of Drugs Unsuita¬ To establish a procedure for designing sus¬
ble for Peroral Sustained Release Forms tained release dosage forms, it is useful to exam¬
ine the properties of drug blood-level-time pro¬
Characteristics Drugs
files characteristic of multiple dosing therapy of
Not effectively absorbed in Riboflavin, ferrous salts immediate release forms. Figure 14-1 shows
the lower intestine. typical profiles observed after administration of
equal doses of a drug using different dosage
Absorbed and excreted rap¬ Penicillin G, furosemide schedules: every 8 hours (curve A), every 3
idly; short biologic half-
hours (curve B), and every 2 hours (curve C). As
lives (<1 hr).
the dosage interval is shortened, thenumber of
Long biologic half-lives Diazepam, phenytoin doses required to attain as teach-state" drug level
(> 12 hr). increasesTTheUmpfitude of the drug level oscil¬
lations diminishes, and the steady state average
Large doses required Sulfonamides
blood level is increased. As a first approximation,
(>1 g)-
the optimum dosage interval can be taken to be
Cumulative action and Phenobarbital, digitoxin equal to the biologic half-life, in this case, 3
undesirable side effects; hours. Curve D represents a profile in which
drugs with low therapeutic the first or loading dose is made twice that of
indices. all subsequent doses administered, i.e., the
Precise dosage titrated to Anticoagulants, cardiac maintenance doses. This dosing regimen allows
individual is required. glycosides the relation between the loading (Di) and main-,
tenance (Dm) doses to be determined as follows:
No clear advantage for sus¬ Griseofulvin
tained release formulation.
Di = Dm(l - exp(-0.693r/tj))

SUSTAINED RELEASE DOSAGE FORMS • 431

FIG. 14-1. Multiple patterns of dosage that characterize nonsustained peroral administration of a drug with a biologic
half-life of 3 hr and a half-life for absorption of 20 min. Dosage intervals are: A. 8 hr: B. 3 hr: C, 2 hr; and D, 3 hr (loading
dose is twice the maintenance dose). E, Constant rate intravenous infusion.

where r is the dosing interval and t* is the bio¬ quately approximated by a one-body-compart¬
logic half-life. If t4 = r, Di = 2Dm. Selection of ment model. That is, drug distribution is suffi¬
the proper dose and dosage interval is a prereq¬ ciently rapid so that a steady state is
uisite to obtaining a drug level pattern that will immediately attained between the central and
remain in the therapeutic range. peripheral compartments, i.e., the blood-tissue
Elimination of drug level oscillations can be transfer rate constants, k]2 and k2i, are large.
achieved by administration of drug through con¬ Under the foregoing circumstances, the drug
stant-rate intravenous infusion. Curve E in Fig¬ kinetics can be characterized by three parame¬
ure 14-1 represents an example whereby the in¬ ters: the^ elimination rate constant fkel orJrio-
fusion rate was chosen to achieve the same
average drug level as a 3-hour dosage interval constant (ka), and the apparent distribution vol¬
for the specific case illustrated. The objective in ume fVdi. which defines the apparent body
formulating a sustained release dosage form is to space in which drug is distributed. A large Vd
be able to provide a similar blood level pattern value (e.g., 100 L) means that drug is exten¬
for up to 12 hours after oral administration of the sively distributed into extravascular space: a
drug. small Vd value (e.g., 10 L) means that drug is
To design an efficacious sustained release largely confined to the plasma. It is best inter¬
dosage form, one must have a thorough knowl¬ preted as a proportionality factor which when
edge of the pharmacokinetics of the drug chosen multiplied by the blood level gives the total
for this formulation. Figure 14-2 shows a gen¬ amount of drug in the body. For the two-body-
eral pharmacokinetic model of an ideal sus¬ compartment representation of drug kinetics, Vc
tained release dosage form/. For the purposes of is the volume of the central compartment, in¬
this discussion, measurements of drug blood cluding both blood and any body water in which
level are assumed to correlate with therapeutic drug is rapidly perfused.
effect and drug kinetics are assumed to be ade¬ A diagrammatic representation of a dosage

432 • The Theory and Practice of Industrial Pharmacy

FIG. 14-2. A general pharmacokinetic model of an ideal peroral sustained release dosage form.

form, which identifies the specific parameters drug is released for absorption by zero-order and
that must be taken into account in optimizing first-order processes with and without loading
sustained release dosage form designs, is shown doses. In the former case, designs based on both
in Figure 14-2 at the absorption site. These are immediate and delayed release of maintenance
the loading or immediately available portion of dose have been described. The following general
the dose (Di), the maintenance or slowly avail¬ assumptions have been made in developing
able portion of the dose (Dm), the time (Tm) at these designs: (1) Drug disposition can be de¬
which release of maintenance dose begins (i.e., scribed by a one-compartment open model.
the delay time between release of Di and Dm), (2) Absorption is first-order and complete.
and the specific rate of release (kr) of the main¬ (3) Release of drug from the dosage form, not
tenance dose. absorption, is rate-determining, i.e., the effect of
Figure 14-3 shows the form of the body drug- variation in absorption rate is minimized (ka >
level time profile that characterizes an ideal per¬ ke).
oral sustained release dosage form after a single
administration. Tp is the peak time, and h is the
total time after administration in which the drug Zero-Order Release
is effectively absorbed. Cp is the average drug
level to be maintained constantly for a period of
Approximation
time equal to (h - Tp) hours; it is also the peak The profile shown in Figure 14-3 can most
blood level observed after administration of a nearly be approximated by a design consisting of
loading dose. The portion of the area under the a loading dose and a zero-order release mainte¬
blood level curve contributed by the loading and nance dose, as described by Robinson and Erik-
maintenance doses is indicated on the diagram. sen.3 If a zero-order release characteristic can be
To obtain a constant drug level, the rate of drug implemented in a practical formulation, the re¬
absorption must be made equal to its rate of lease process becomes independent of the mag¬
elimination. Consequently, drug must be pro¬ nitude of the maintenance dose and does not
vided by the dosage form at a rate such that the change during the effective maintenance pe¬
drug concentration becomes constant at the ab¬ riod. Table 14-2 fists the expressions that dan be
sorption site. used to estimate the design parameters for an
Detailed theoretic treatments of a number of optimized zero-order model, for both simultane¬
sustained release dosage form designs have ous and delayed release of maintenance dose.
been reported. These include systems in which Their application is illustrated using procaina-

SUSTAINED RELEASE DOSAGE FORMS • 433

mide, an important antiarrhythmic agent, as an level ratio >2 at the steady state. Sustained re¬
example. lease formulations have been shown to have
Table 14-3 lists the pharmacokinetic parame¬ advantages as an alternate dosage form. A com¬
ters characterizing the disposition of procaina¬ parison is made between estimates based on
mide, which is described by a two-body- three cases: (1) the one-compartment model as¬
compartment open model, in an average patient sumption with delayed release of maintenance
based on data reported by Manion et al. for 11 dose, (2) the actual two-compartment fit of pro¬
subjects.4 Conventional formulations are admin¬ cainamide pharmacokinetic data with delayed
istered every 3 hours for maintenance of ther¬ release of maintenance dose, and (3) the two-
apy, resulting in a maximum-to-minimum blood compartment model with simultaneous release

Table 14-2. Expressions Useful for Estimation of Design Parameters for Zero-Order Sustained
Release Dosage Form Models

Parameter Equation

Maximum body drug content Am = CpVd Eq. (1)

to be maintained

Zero-order rate constant kr0 = keAm Eq. (2)

Peak time Tp = (2.3/(ka - ke))log(ka/ke) Eq. (3)

Bioavailability factor F = (AUC)oral/(AUC)iv Eq. (4)

Fraction of dose (Di) at Eq. (5)

peak (F = 1)

Maintenance dose Dm = kr0(h - Tm)/F Eq. (6)

Loading dose (Tm = Tp) Di = Am/fF Eq. (7)

Loading dose (Tm = 0) Di = (Di - kr0Tp) Eq. (8)

434 • The Theory and Practice of Industrial Pharmacy

Table 14-3. Pharmacokinetic Parameters for Vd, is used to calculate Am for the two-compart-
Procainamide in an Average Subject (Weight: ment model, i.e., Am = CpVc. For example:
75 kg)
Case 1: kr0 = 0.21 x 1 x 205
Parameter Value Parameter Value = 43 mg/hr
P 0.21 hr ki2 3.15 hr Cases 2 and 3: kr0 = 0.97 x 1 x 59
h 3.4 hr ^21 1.4 hr = 57 mg/hr
ke 0.97 hr Vc 59 L
ka 2.0 hr Vd 205 L
2\ Estimation of Tm. Release of maintenance
F 0.83 Tp 0.5 hr
doseTs'set at the peak, time for the loading dose
From Manion, C.-V., et al., J. Pharm. Sci., 66:981, 1977. Re¬ (cases 1 and 2). Equation (3) is used to calculate
produced with permission of the copyright owner, the American the peak time from known value absorption
Pharmaceutical Association. (2 hr-1) and ehmingtiSn (0.21 hri-1) rate con¬
stants. Since equation (3) applies only to the
one-compartment model, Tm, which is actually
of loading and maintenance doses. In all cases,
0.5 hours, is significantly overestimated. For
the blood level is assumed to be maintained at
example:
1 £ig/ml for 8 hours, i.e., Cp = 1 mg/L, and h -
Tp = 8. Table 14-4 summarizes the results of
„ , ^ ^ 2.3 x log(2/0.21)
the calculation of sustained release design pa¬ Case 1: Tm = Tp (Eq. 3) =-2 -021 ~—
rameters for procainamide, assuming zero-order
release kinetics. The following steps are re¬ = 1.2 hr
quired to estimate the design parameters listed Case 2: Tm = Tp (actual value) = 0.5 hr
in the table. (Equation numbers refer to equa¬
tions in Table 14-9,7) _ Case 3: Tm = 0
l.[ Estimation of kr0) Equation (2) is derived
by considering that at the steady state the rate of 3 .f Estimation of Dm) The maintenance dose
ahsorptrorris^onsfant and equal to the rate of is estimated as the product of release rate and
maintenance time (equation 6), corrected for the
elimination^ that is: Kate Absorption = ka •
Xa = hate Elimination~=~ke_; Xb where Xa is bioavailability factor, F (equation 4), which is
thc arnount of drug at the absorption site, and the fraction of the administered dose absorbed
Xb is the body drug content, which is set equal from a reference nonsustained release dosage
to Vd • Cp, orAm in equation (1), the body drug form. The F-value is estimated as'the ratio of the
area under the plasma level curve_(AUC-value)
content to be maintained constant. If absorption
measured after oral administration to the AUC-
of the loading dose is effectively complete,
kaXa = kr0. For case 1 in Table 14-4, ke = 0.21 value observed after intravenous administration
of the same dose of drug. Infhe example, F < 1,
(the beta disposition constant), since the bio¬
logic half-life is estimated from thebermirial part since procainamide is- subject to the first-pass
ofrihe~hioodTevel curve if a one-compartment effect, in which a small portion of the absorbed
modelis usecTto approximate blood level data. dose is metabolized in the liver. Dm is also a
ForxasesTTancTS, kfT= 0797. The apparent vol- function of the loading dose and an inverse
umeof the central compartment, Vc, rather than function of the biological half-life, i.e., Dm =
0.693f(h - Tm) Di/tj, a relation obtained by
combining equations (2), (6), and (7). Practi¬
Table 14-4. Estimated Sustained Release Design cally, h is not likely to exceed 10 to 12 hours,
Parameters for Procainamide (Cp = 1 gg/ml, depending on the residence time in the small
h =^TrfT= 8 hours) intestine. For drugs that are not efficiently ab¬
sorbed in the stomach, such as procainamide,
Parameter Case 1 Case 2 Case 3 the gastric emptying rate is an uncertain varia¬
ble that contributes to Tm. For example:
Am (mg)- 205 59 59
kr0 (mg/hr) 43 57 57
Tm 1.2 0.5 0 Case 1: Dm = 43 x 8/0.83 = 414 mg
Dm (mg) 414 549 549
Cases 2 and 3: Dm = 57 x 8/0.83 = 549 mg
f 0.768 0.274 0.274
Di (mg) 322 259 (Di) 224
Dm/Di 1.28 2.12 2.45
Significant increases in dose size are required
Dm + Di (mg) 736 808 773
for drugs with short biologic half-lives, e.g., Dm

SUSTAINED RELEASE DOSAGE FORMS • 435

is doubled if the biologic half-life is halved. For listed in Table 14-4. Curve A is the profile ob¬
case 1, Dm would be 228 mg for t4 = 6 hr, served after administration of the loading dose
456 mg for tj = 3 hr, and 685 mg for = 2 hr. calculated for case 2. Calculations based on the
4. Estimation of Di. The loading dose is that assumption of a one-compartment model (curve
portion of the total dose that is initially released B) fail to approximate the desired profile ade¬
as a bolus and is therefore immediately available quately. The procedure suggested for estimation
for absorption. It results in a peak blood level of kr0, however, based on the actual two-
equal to the desired level to be maintained. compartment model that fits procainamide data,
Equation (7) allows estimation of Di if Dm is gives a reasonable approximation of the opti¬
delayed (cases 1 and 2). If release of Dm is not mum profile (curve C). A formulation designed
delayed (case 3), the loading dose calculated to release loading and maintenance doses simul¬
using equation (7) is adjusted for the quantity of taneously (case 3) results in a profile (curve D)
drug provided by the zero-order release process that does not significantly differ from case 2.
in time Tm as shown by equation (8). For exam¬ The total dose required to maintain a blood level
ple: of 1 jag/ml for 8 to 10 hours is about the maxi¬
mum (<1 g) that can be formulated in a reason¬
ably sized solid peroral dosage form. The usual
Case 1: Di = 205/(0.768 x 0.83) = 327 mg
minimum therapeutic level required for procain¬
Case 2: Di = 59/(0.274 x 0.83) = 259 mg amide is 3 to 4 /xg/ml. Multiple units of a sus¬
tained release procainamide would have to be
Case 3: Di = (259 - 57 x 0.5) = 224 mg
administered at each dosing interval to attain a
therapeutic level.
Figure 14-4 shows the simulated blood level Computer simulation provides a valuable tool
profiles that result from administration of theo¬ for evaluating the performance of sustained re¬
retic sustained release dosage forms of procaina¬ lease dosage form designs. Curve E in Figure
mide to the average subject for the three cases 14-4 demonstrates another application of simu-

2—patient differs from average.

436 • The Theory and Practice of Industrial Pharmacy

lation, that is, to examine the performance of the lists the parameters calculated for a drug fitted
dosage form in a patient in which the disposition by a one-body-compartment model, and Figure
of the drug (procainamide in the example) dif¬ 14-5 shows the resulting profiles for each exam¬
fers significantly from the average. In this sub¬ ple considered. Doses fisted in Table 14-6 are
ject, the pharmacokinetic parameters were as expressed as fractions of loading dose, using the
follows: ka = 1.2, ke = 0.47, k12 = 0.8, k2i = calculation for a zero-order model (case 1, Table
0.77, Vc = 101, and F = 0.7. Lower blood levels 14-4) as a reference.
are observed initially, and higher blood levels are Method 1. Simultaneous, release of Dm
observed at the end of the maintenance period, and Di. The crossing time, Ti, is the time at
since the absorption rate was lower and the bio¬ which the blood level profiles produced by ad¬
logic half-life higher (approximately 4 hours) ministration of separate loading and mainte¬
than average in this patient. Overall, the differ¬ nance doses intersect. The closest approxima¬
ence in response of this patient to the dosage tion to the ideal profile is obtained if the crossing
form is not significant. point is made at least equal to the desired main¬
tenance period (h - Tp). Equation (9) shown in
\ Table 14-5, is an approximation of equation (11)
where ke > kr]. The maintenance dose is esti¬
First-Order Release mated from the initial release rate, i.e.,
Approximation krjDm = keAm = kr0. The loading dose is esti¬
mated by correcting the immediate release dose
The rate of release of drug from the mainte¬
required to achieve the maintenance level for
nance portion of the dosage form should be zero-
the quantity of drug delivered by the mainte¬
order if the amount of drug at the absorption site
nance dose in the time Tp. For example:
is to remain constant. Most currently marketed
sustained release formulations, however, do not
Ti = 9.2 - 1.2 = 8 hr
release drug at a constant rate, and conse¬
quently do not maintain the relative constant kri = 0.23exp(-0.23 x8) = 0.055 hr
activity implied by Figure 14-3. Observed blood
Dm = 0.173/0.055 = 3.1
levels decrease over dme until the next dose is
administered. In many instances, the rate of Di = (0.75/0.75 x 1) - 0.173 x 1.2 = 0.8
appearance of drug at the absorption site can be
approximated by an exponential or first-order Method 2. Delayed release of Dm: Tm =
process in which the rate of drug release is a Tp. If Dm is large and kr is made small, mainte¬
function only of the amount of drug remaining nance dose may be released as a pseudo-zero-
in the dosage form. Table 14-5 lists the expres¬ order process. As a first approximation, kr] may
sions that can be used to estimate the design be estimated as the reciprocal of the mainte¬
parameters for optimized first-order release nance time. Dm is then calculated as in method
models. Three different designs are considered: 1. Better approximation of a zero-order response
Dm not delayed. Dm delayed where Tm = Tp, can be obtained if Dm is. increased and krj is
and Dm delayed where Tm > Tp. Table 14-6 reduced to maintain the product lay DM con-

Table 14-5. Expressions Useful for Estimation of Design Parameters for First-Order Sustained
Release Dosage Form Models

Parameter Method 1 Method 2 Method 3

Tm 0 Tp (Eq. 3) 4.6/ka (Eq. 10)

Ti (h -Tp) — (h - Tp)/2

kr. ke(exp(-keTi)) l/(h - Tp)

(Eq. 9) <*■»>
Dm kro/kr] kro/kr] Dm - exp(kr](2Ti Tm) (Eq. 12)
KTi

. Dika
Ai “ (ka _ ke) exP( ke(Tl + Tm)) (Eq- 13)

Di CpVd/fF - kr0Tp CpVd/fF CpVd/fF

SUSTAINED RELEASE DOSAGE FORMS • 437

FIG. 14-5. Simulated blood level profiles observed after administration of a theoretic sustained release dosage form to an
average patient based on different first-order release models. Blood level is plotted as the fraction of dose absorbed (CpVdJ
FDi).

stant. For example: which 99% of the loading dose has been ab¬
sorbed is selected using equation (10) in Table
Tm = Tp = 1.2 hr 14-5. The release rate constant is iteratively cal¬
culated from equation (11) such that a peak is
krj = l/(9.2- 1.2) = 0.125 hr
obtained from the maintenance dose at the mid¬
Dm = 0.173/0.125 = 1.4 point of the maintenance time. The amount of
drug required to produce a second peak at this
Di = 0.75/0.75 x 1 = 1
time is the maintenance dose, calculated from
equations (12, 13). For example:
Since krjDm = 0.173, then kt! should be re¬
duced to 0.86 if Dm is increased to 2.0, to main¬
tain this product constant. Tm = 4.6/2.0 = 2.3 hr
Method 3. Delayed release of Dm: Tm > Tp.
Ti = (9.2 - 1.2)/2 = 4 hr
Increasing the delay time, Tm, allows the use of
faster release rates. A period equal to the time at 4 = 2.3 x log(kra/0.23)/(kr! - 0.23)

Table 14-6. Estimated Design Parameters for a First-Order Sustained Release Model*

Parameter Zero-Order Method 1 Method 2 Method 3

Tm hr 1.2 0 1.2 2.3

Ti hr — 8 — 4
krx hr (kr0 = 0.173) 0.055 0.125 0.27
Dm/Di 1.4 3.1 1.4 1.45
Di 1.0 0.8 1.0 1.0
(Di + Dm)/Di 2.4 3.9 2.4 2.45
' Drug Characteristics: One-Compartment Model

t$ = 3 hr ka = 2hr ke = 0.23 hr f = 0.75

Tp = 1.2 hr h = 9.2 hr F= 1 CpVd = 0.75

438 • The Theory and Practice of Industrial Pharmacy

 (Solve this expression iteratively by finding cally determined dosage regimen can be used as
the value of kr , that satisfies the equality, in this a basis for estimation of Dm-values. One may
case, lay = 0.27.) assume that Dm equals the sum of the mainte¬
nance doses ordinarily administered in the de¬
Di = 0.75/0.75 x 1 = 1 sired maintenance time. For example, for a drug
administered 4 times a day, Di is the single dose,
Ai = (1 x 2)exp(—0.23(4 + 2.3))/(2.0 - and Dm the sum of two doses for a maintenance
0.23) = 0.267 period of 12 hours. As a rule of thumb, the total
Am = Wke = 0.173/0.23 = 0.74 drug dose can be reduced from 5 to 10%.

Dm = (0.23/0.27X0.74 - 0.267)exp(0.27(2 x
4 - 2.3)) =1.45
Multiple Dosing
Methods 1 and 2 have the disadvantage that Like conventional dosage forms, peroral sus¬
large maintenance doses are required, resulting tained release forms are administered as multi¬
in a significant loss of drug available for absorp¬ ple dosing regimens in which the objective is to
tion. In the examples plotted in Figure 14-5, maintain the required average drug level for the
50% of the dose calculated using method 1 and duration of therapy with a minimal fluctuation
30% of the dose calculated using method 2 were between doses. If the dosing interval is made
not available after 10 hours. Method 1 repre¬ equal to (or less than) the total anticipated drug
sents a design that is least efficient in terms of release time (Fig. 14-6, curve A), accumulation
the dose required to achieve the design objec¬ results from formulations designed with loading
tive. Drugs characterized by large loading doses doses. Significant blood level peaks may be ob¬
and small biologic half-fives could not be practi¬ served with the zero-order release model; how¬
cally formulated in these designs. In spite of the ever, minimal fluctuation between administered
fluctuation observed in the profile characteriz¬ doses can be obtained if the dosing interval is set
ing method 3, a reasonably average level is equal to (h + t4), as shown by curve B (Fig. 14-
maintained with a minimum maintenance dose. 6). Increasing the dosing interval further while
Furthermore, only 15% of the dose remains un¬ diminishing the peak also deepens the trough in
released after 10 hours. The maximum dose, the drug level profile, defeating one of the objec¬
which usually should be formulated in a sus¬ tives of the dosage form design. Even with the
tained release dosage form, should not exceed zero-order model, multiple dosing therapy can
the total dose administered by conventional result in non-ideal drug level profiles.
forms during the maintenance period. If the In sustained release therapy, only the dosing
total dose is released all at once, it should not interval is adjustable. If two units are initially
result in a blood level exceeding the maximum administered followed by single-unit subsequent
safe level. doses, as is common in therapy with nonsus-
Optimization of sustained release dosage form tained forms, a slow fall in overall drug level oc¬
design requires minimization of the total dose curs after several doses to the average level de¬
delivered and maximization of the duration of termined by the dosage form design. Welling has
drug release. In the case of the zero-order model, described several strategies for attaining approx¬
adjustment of the maintenance dose is a func¬ imations of the ideal profile in the multiple dos¬
tion only of the duration time. Designs based on ing of different sustained release designs based
simultaneous release of Dm and Di require the on both cumulative and noncumulative ap¬
minimum total dose (e.g., case 3, Table 14-4). proaches.5
Optimum first-order designs are those in which Alternately, administration of formulations
Dm is delayed beyond the peak obtained from designed without loading doses can result in
the loading dose (e.g., method 3, Fig. 14-5). minimal fluctuation during long term therapy.
From a practical point of view, the procedures In Figure 14-6, curve C shows the result of this
summarized here provide a starting point for type of multiple dosing regimen where a zero-
implementation. The use of mean values for order based design consisting only of the slow
parameters and the inherent variation in the release maintenance dose is administered at in¬
population using the dosage form often lead to tervals of h hours. If absorption is consistent,
larger variations than the errors resulting from profiles obtained are equivalent to those result¬
the approximate nature of these calculations. ing from administration of drug by constant rate
Where therapeutic effect cannot be correlated infusion (curve E, Fig. 14-1), with one dosing
with measured body drug content, or where interval required to attain near-steady-state drug
such measurements cannot be obtained, a clini¬ levels. Accumulation does not take place unless

SUSTAINED RELEASE DOSAGE FORMS • 439

FIG. 14-6. Multiple patterns of dosage of sustained release dosage forms where ka = 2 hr, ke - 0.23 hr, (t = 3 hr), F = 1,
and H - 8 hr. Dosage intervals are: A, 8 hr; B, 12 hr; and C, 8 hr with no loading dose.

the dosing interval is made less than the effec¬ modified may be formulated as liquid suspen¬
tive maintenance time. sions, capsules, or tablets. Loading doses of
unmodified drug may also be incorporated in
formulations that are ordinarily formulated to
Implementation of Designs release both unmodified and modified drugs
without significant delay.
Approaches Based on Drug Figure 14-7 identifies the mechanisms in¬
volved in controlling the release of drug from
Modification complexes, adsorbates, and prodrugs. In the
Two general sets of methods have been devel¬ case of drug complexes, the effective release rate
oped for implementation of practical sustained is a function of two processes: the rate of disso¬
release dosage form designs: methods based on lution of the solid complex into the biologic
modification of the physical and/or chemical fluids and the rate of dissociation or breakdown
properties of the drug and methods based on of the complex in solution. In general, the disso¬
modification of the drug release rate characteris¬ lution step may be described by the following
tics of the dosage that affect bioavailability. The expression:
physicochemical properties of a drug may be al¬
tered through complex formation, drug-adsorb¬ Rate Dissolution = ks(Solubility)(Surface Area)
ate preparation, or prodrug synthesis. These
techniques are possible only with drug moieties where ks is the dissolution rate constant, a func¬
containing appropriate functional groups (e.g., tion of the hydrodynamic state as well as factors
acidic or basic). The principal advantage of this influencing the diffusion process (e.g., viscos¬
approach to sustained release is that it is inde¬ ity).
pendent of the dosage form design. Drugs so The formulator has the option of altering sur-

440 • The Theory and Practice of Industrial Pharmacy

 DRUG COMPLEX
Dissolution Dissociation Absorption

¥
DC, solid DC .solution D

DRUG ADSORBATE
Desorption Absorption
*■

AD, solid D

PRO DRUG
Dissolution Absorption Metabolism Elimination
*
PD .solid -«— =:~‘PD .solution — —►PD , plasma-► D
FIG. 14-7. Mechanisms of sustained release based cm drug modification.

face area through particle size control and/or sol¬ hand, if the rate of dissociation is greater than
ubility of the drug complex through selection of the rate of dissolution, the dissolution of the
the complexing agent. While both processes are complex is rate-determining. Particle size of the
dependent on the pH and composition of the complex should be adjusted to establish the
gastric and intestinal fluids, the dissociation most appropriate rate of release. With sufficient
step is critically so, since its rate may be pH- excess solid phase, a zero-order release may also
dependent, may be determined by the ionic be approximated. The complex may be viewed
composition of the fluid, and may be affected by in this instance as simply a means of reducing
the natural digestive processes including enzy¬ the solubility of the drug in order to reduce its
matic and bile salt action. The formulator should availability.
select the appropriate complex for preparation Equation (14) describes the rate (R) at which
with knowledge of the specific in vivo processes drug is made available through dissolution
involved in the control of drug release from the under conditions of diminishing surface:
complex. For example, tannate complexes of
bases are hydrolyzed in both acidic and basic
4.85DCs W»
media, the dissociation of the complex being R= ks'Wi (14)
more rapid at the gastric pH. Drug release from
hpi
cationic ion-exchange resin complexes depends
on sodium ion concentration in GI fluids, and where D is the diffusion coefficient, h is the
although a stearate salt of a weak base resists the thickness of the diffusion layer, Cs is the solubil¬
action of gastric fluid, natural digestive proc¬ ity, p is the density, and W is the weight of un¬
esses in the intestine act to dissociate the com¬ dissolved solid. This expression has been de¬
plex. rived assuming that the simple diffusion-layer
If the rate of dissolution is greater than the model applies, that the particles are spherical in
rate of dissociation, a zero-order release pattern form, and that a near sink condition is main¬
might be realized, because the concentration of tained with respect to dissolved complex. Conse¬
complex is maintained at its saturation point if quently, the rate of drug availability, expressed
the solubility of the complex is sufficiently low as the rate of decrease in mass of undissolved
so that excess solid complex is present during complex, diminishes during the effective main¬
most of the effective maintenance time. In this tenance period if the surface area decreases as
case, high specific surface material should be drug is dissolved and absorbed. The amount of
prepared to promote dissolution. On the other drug available at any time can be calculated

SUSTAINED RELEASE DOSAGE FORMS • 441

from the integrated form of equation (14) (the Since the extended release form of the drug,
cube-root law): whether complex, prodrug, or solid dispersion,
when formulated as a liquid suspension, is in
Wi = (Wo* - ks't) (15) contact with a fluid medium, an equilibrium is
established in the formulation with respect to
If ks' = 3 mgi/hr and the maintenance dose is “free” drug and “bound” drug. The chemical sta¬
900 mg, then 324 mg of drug would be available bility of these systems with respect to the con¬
after 4 hours, and only 36 mg would be available version of “bound” to “free” drug, in addition to
after 8 hours of dissolution. physical stability problems characteristic of sus¬
Drug adsorbates represent a special case of pensions, adds an additional dimension to their
complex formation in which the product is es¬ overall formulation. The development of injecta¬
sentially insoluble. Drug availability is deter¬ ble depot forms as suspensions of phvsicochemi-
mined only by the rate of dissociation (desorp¬ cally modified drugs has been proven to be an
tion), and therefore, access of the adsorbent effective means of achieving controlled release
surface to water as well as the effective surface in antibiotic therapy.
area of the adsorbate.
Prodrugs are therapeutically inactive drug
derivatives that regenerate the parent drug by Approaches Based On Dosage
enzymatic or nonenzymatic hydrolysis. Figure
14-7 shows the scheme that identifies the poten¬ Form Modification
tial processes for achieving sustained action. Most peroral sustained release products have
The solubility, specific absorption rate, and/or been formulated as encapsulations or tablets.
elimination rate constant of an effective prodrug Formulations based on modification of the phy¬
should be significantly lower than that of the sicochemical properties of these dosage forms
parent compound. Kwan has described the phar¬ can be classed into three product types: encap¬
macokinetics of a prodrug in which the sus¬ sulated slow release beads (or granules),
tained blood level is determined by the meta¬ tabletted mixed or slow release granulations,
bolic rate, i.e., by formation of the active moiety and slow release (core) tablets. Fabrication of
after absorption.6 If the solubility of a drug has tablets allows for direct incorporation of loading
been significantly reduced by the formation of doses, by preparation of either multilayered or
prodrug, and if breakdown of the prodrug takes press-coated tablets. One layer or the outer coat
place at the absorption site, then availability is of the tablet is prepared from a potentially rapid
limited by dissolution rate, and the same argu¬ disintegrating granulation, leaving the less
ments as in the case of an insoluble drug com¬ quickly disintegrating layer or core, which con¬
plex apply. Examples of drugs from which tains the maintenance dose. Systems prepared
prodrugs designed for prolonged action have as tabletted mixed released granulations may or
been synthesized include isoproterenol, isonia- may not be designed to disintegrate quickly,
zid, and penicillin.7 simulating the administration of an encapsu¬
Approaches based on drug modification are lated form in the latter case.
sensitive to in vivo conditions. An important ob¬ Encapsulated sustained release dosage forms
jective of sustained release formulation is to have two specific advantages over core tablet
minimize the effect of in vivo variables on drug designs. (1) Undisintegrated tablets may remain
release. An alternate approach, which has been in the stomach for extended periods of time, ex¬
advanced by Banker, involves preparation of cessively delaying absorption of the mainte¬
drug dispersions through “molecular scale drug nance dose. Disintegration of the capsule shell
entrapment” in suitable carrier materials that in the gastric fluid releases particles that can
act to retard release.8 Compositions of this type pass unimpeded through the pyloric valve.
can be prepared by induced flocculation of a (2) There is statistical assurance of drug release
polymer latex (e.g., acrylic copolymers). Control with encapsulated forms, since release of drug
of drug release is accomplished by varying the by a significant fraction of the granules is highly
nature of the carrier material, the loading dose of probable. If a core tablet fails to release drug, all
drug, and particle size of the product (i.e., sur¬ of the maintenance dose is lost.
face area). These systems follow a scheme simi¬ Two general principles are involved in retard¬
lar to that suggested for drug adsorbates. They ing drug release from most practical sustained
also have the advantage of allowing formulation release formulations involving dosage form
of different dosage forms and may, with appro¬ modification. These are the embedded matrix
priate selection of the carrier, be less influenced and the barrier principle, which are schematic¬
by in vivo variables. ally shown in Figures 14-8 and 14-9. In the

442 • The Theory and Practice of Industrial Pharmacy

 MATRIX . EXTRACTING MEDIA

FIG. 14-8. Embedded matrix concept as a mechanism of controlled release in sustained release dosage form design.
Network model (a): drug is insoluble in the retardant material. Dispersion model (b): drug is soluble in the retardant
material. Diffusion profile (c) characterizes drug release from a matrix system.

former case, drug is dispersed (embedded) in a permeation of the matrix by water, leaching (ex¬
matrix of retardant material, which may be en¬ traction or diffusion) of drug from the matrix,
capsulated in particulate form or compressed and erosion of matrix material. Alternately, drug
into tablets. Release is controlled by a combina¬ may dissolve in the matrix material and be re¬
tion of several physical processes. These include leased by diffusion through the matrix material
or partitioned between the matrix and extracting
fluid. Matrices may be prepared from insoluble
or erodable materials (e.g., silicone polymers or
lipids).
Higuchi has provided the theoretic basis for
defining drug release from inert matrices.9 The
equation describing drug release from the planar
surface of an insoluble matrix is:

Q = [(DeCs/r)(2A - eCs)t]» (16)

where Q is the amount of drug released per unit

surface after time t, D is the diffusion coefficient
of the drug in the elution medium, r is the tortu¬
osity of the matrix, e is the porosity of the ma¬
trix, Cs is the solubility of the drug in the elution
FIG. 14-9. Barrier-mediated models of sustained release
medium, and A is the initial loading dose of drug
dosage form designs. A, Drug diffusion through the barrier.
B. Permeation of barrier by elution media followed by drug in the matrix. This expression was derived as¬
diffusion. C, Erosion of barrier, releasing drug. D, Rupture suming a linear diffusion gradient as dia¬
of barrier as a result of permeation of elution media. grammed in Figure 14-8c. Drug release is trig-

SUSTAINED RELEASE DOSAGE FORMS • 443

gered by penetration of eluting media into the adjustment by manipulation of the parameters
matrix, dissolving drug, thereby creating chan¬ defined by equations (16), (17), and (18). The
nels through which diffusion takes place (Fig. release characteristics of a base formulation can
14-8b). The depletion zone gradually extends be defined by the slopes of plots of cumulative
into the core of the matrix. A high tortuosity drug released versus tj. The effect of formulation
means that the effective average diffusion path modifications such as change in drug loading
is large. The porosity term takes into account the can then be predicted.
space available for drug dissolution; an in¬ Figure 14-10 shows the forms of different
creased porosity results in increased drug re¬ drug-release profiles from different dosage form
lease. Both porosity and tortuosity are functions planar models, including zero-order (curve A),
of the amount of dispersed drug, the physico¬ first-order (curve B), and square root of time
chemical properties of the matrix, and the dis¬ (curve C). Profiles have been adjusted to show
persion characteristics of the drug in the matrix. 50% release at the same time. Analysis of in
If the drug is freely soluble in the elution me¬ vitro release data of many different sustained
dium, i.e., Cs»A, such that the dissolution rate release formulations has demonstrated a pseu-
is rapid, then equation (17), which describes the do-first-order release characteristic, if the log
release of drug from a solution entrapped in an percentage of unreleased drug was plotted
insoluble matrix, applies: against time.12. The observed apparent first-
order rate constants, however, could not be in¬
Q = 2A(DtAnr)4 (17) terpreted in terms of the fundamental properties
of the dosage form as in the case for systems
Release rate is directly proportional to the characterized by curve C. Curve D represents a
amount of dispersed drug, A; it is proportional to situation in which erosion is superimposed on
At for insoluble drugs if 2A = Cs. These expres¬ matrix-controlled release. In the planar case,
sions predict that plots of Q versus t* be linear. erosion should be zero-order, a function of the
The theory has been extended to defining product of the drug concentration in the matrix
matrix-controlled release from spherical pellets and the effective dissolution rate of the retard¬
as well as from cylindric and biconvex compacts. ant. Release due to erosion is, in general, more
In Chien’s description of the application of a rapid than matrix-controlled release. This has
general expression for the case of a drug dis¬ been demonstrated with dispersions of chlor¬
persed in a matrix in which the drug dissolves pheniramine maleate in methylcellulose matri¬
(Fig. 14-8a), both matrix and partition control ces.13
are possible.10 The drug has low solubility in the The barrier concept of controlled release im¬
elution media, partition control dominates, and plies that a layer of retardant material is imposed
the release is zero-order, that is: between the drug and the elution medium.14 ,
Drug release results from diffusion of drug
Q = KDCst/h (18) through the barrier, permeation of the barrier by
moisture, and/or erosion of the barrier. In addi¬
where K is the partition coefficient (K = Cs/Cp), tion to barrier composition and physicochemical
Cp is the solubility in the matrix phase, and h is properties, thickness and integrity of the barrier
the thickness of the hydrodynamic diffusion are important variables in controlling drug re¬
layer. A modified form of equation (16) applies lease. Figure 14-9 summarizes the more signifi¬
in the former case (diffusion takes place in the cant models of barrier-mediated release. Figure
matrix phase), in which the drug has a high sol¬ 14-11 shows the form of the drug-release pro¬
ubility in the elution media. files characteristic of these models.
These expressions have been successfully For case A, the barrier is impermeable to the
applied to interpreting drug release from insolu¬ elution medium; drug is present in the reservoir
ble polymer matrices as well as from such poten¬ as a solution or suspension. At the steady state,
tially erodable materials as wax-lipid composi¬ the release rate into a sink is:
tions and hydrophilic polymers. With the latter,
hydration of the polymer forms a gel, which con¬ R = SDmCsm/l (19)
trols the initial stages of drug release. The varia¬
bles affecting drug release, which have been where S is the surface area, Dm is the diffusion
studied using these models, have included the coefficient of drug in the membrane, 1 is the
nature of retardant, drug solubility, effect of thickness of the membrane barrier, and Csm is
added diluents, drug loading, drug mixtures, the solubility of drug in the membrane, assum¬
and drug-matrix interaction.11 The rate of drug ing constant activity of drug in the reservoir. For
release from embedded matrices is capable of the membrane-encapsulated solution, release is

444 • The Theory and Practice of Industrial Pharmacy

FIG. 14-10. Drug-release profiles characteristic of different dosage form models representing embedded matrix systems.
A, Zero-order model. B, First-order model. C, Diffusion model. D, Diffusion model with erosion.

LAG
TIME

FIG. 14-11. Drug-release profiles characteristic of barrier-mediated models. A, B, Membrane-controlled diffusion.

SUSTAINED RELEASE DOSAGE FORMS • 445

first-order. If membrane diffusion is slower than testing. Second, in vitro testing is necessary to
dissolution, release is zero-order for membrane- ensure batch-to-batch uniformity in the produc¬
encapsulated suspensions. Two forms of release tion of a proven dosage form. Different methods
profiles may be observed: a burst effect if the are usually required by these two distinctly dif¬
membrane is saturated with drug (Fig. 14-11, ferent testing situations. Although attempts to
curve A), and a time lag if drug has not pene¬ correlate in vitro release profiles with clinical
trated the membrane (Fig. 14-11, curve B). performance are useful once sufficient clinical
Drug release approximates first-order kinetics testing has been completed, in-vitro/in-vivo cor¬
during the depletion phase. This principle has relation must not be assumed. In vitro studies
been successfully applied in the development of are not sufficient to establish the efficacy of a
ophthalmic, intravaginal, and transdermal con¬ new preparation.
trolled release devices. Tests developed for the purpose of quality con¬
For case B (Fig. 14-9), in which the barrier is trol are generally limited to USP dissolution test¬
permeable to the elution media, a time lag is in¬ ing methods, using either the rotating basket
volved since drug is not released until moisture (apparatus 1), the paddle (apparatus 2), or the
has penetrated the barrier, dissolving drug in modified disintegration testing apparatus (appa¬
the reservoir. Additional mechanisms might in¬ ratus 3). In many instances in which USP test
volve timed erosion of the barrier (case C) or procedures are followed, upper and lower limits
rupture of the barrier after sufficient moisture are specified for drug release in simulated gas¬
has permeated the membrane (case D). tric and/or intestinal fluid. Measurements are
The pharmaceutical formulator can select made at specified time intervals appropriate to
from a variety of potential sustained release dos¬ the specific product. Complete release profiles
age form designs.15 Those based on drug modifi¬ are not measured unless automated techniques
cation are limited to drugs with appropriate are used. At present, there are no specific USP
structural characteristics. In principle, dosage specifications for sustained release dosage
form designs may be applied to all drug types; forms. Procedures are determined by nature of
however, the selection of a particular dosage the dosage form (e.g., tablet or capsule), the
form may be limited by the specific drug proper¬ principle utilized to control drug release (e.g.,
ties (e.g., solubility, dissociation constant, stabil¬ disintegrating or nondisintegrating), and the
ity, etc.), the manufacturing technology avail¬ maintenance period.
able, and the methodology needed to establish During formulation development, testing
the validity of the design. For example, water- methods should be designed to provide answers
insoluble drugs may not be suited to designs to the following questions.
based on the embedded matrix principle using 1. Does the product “dump” maintenance
insoluble matrices, but may be suited to barrier dose before the maintenance period is complete?
controlled release, which is applicable to a wide Sustained release products are subject to either
variety of drug characteristics. Prior to begin¬ of twojnodes of failure: Insufficient dose is re-
ning the development of a practical formulation, leasedTor :qq much drug is made available too
the formulator must have established an in vitro quickly.
testing methodology to serve as an aid to formu¬ 2. What fraction of the dose remains unavail¬
lation, and have a clear view of the requirements able^ Tje7T^vfilLScfionI^I[rnqt_be released in
for in vivo testing of drug availability from sus¬ the projected time of transit in the GI tract?
tained release products. 3. What is the effect of physiologic variables
on drug release? For example, jjelavecTgastric
emptying, interaction between drug and GI con¬
Product Evaluation and Testing stituents, ciaappsitiorLand volume offGI fluids,
and variation in intensity of agitation should be
In Vitro Measurement of Drug considered.
4. Is the loading dose (if present) released
Availability immediately? Is release of the maintenance dose
It is not possible to simulate in a single in vitro delayed/ If so, is the delay time within the de¬
test system the range of variables that affect sired range?
drug release during the passage of sustained re¬ 5. What is the unit-to-unit variation? How
lease medication through the GI tract. Properly predictable is the release profile?
designed in vitro tests for drug release serve two 6. What is the sensitivity of the drug release
important functions, however. First, data from profile to process variables?
such tests are required as a guide to formulation 7. What is. the stability of the formulation
during the development stage, prior to clinical with respect to its drug release profile?

446 • The Theory and Practice of Industrial Pharmacy

 8. In short, does the observed release profile hours, depending on the design specifications of
fit expectations? the dosage form. If formulations contain retard¬
TfreTnethods used to measure drug release ants whose function depends on the action of
profiles should have the following characteris¬ normal constituents of the GI fluids (e.g., bile
tics. The analytic technique should be auto¬ salts, pancreatin, and pepsin), then the appro¬
mated so that the complete drug release profile priate materials must be included in the simu¬
can be directly recorded. Allowance should be lated release media. Apparatus of the Sartorius
made for changing the release media from simu¬ type would be advantageous in these circum¬
lated gastric to simulated intestinal fluid at vari¬ stances if the analytic procedure for the drug
able programmed time intervals, to establish the would be adversely affected by the presence of
effect of retention of the dosage form in gastric these substances. Otherwise, the simulated
fluid as well as to approximate more closely the fluids consisting of pH 1.2 and 7.2 buffers, as
pH shifts that the dosage form is likely to en¬ well as intermediate pH-values, which represent
counter in vivo. In addition, the hydrodynamic the transition between gastric and intestinal pH,
state in the dissolution vessel should be control¬ would suffice at 37°. For insoluble dosage forms,
lable and capable of variation. The apparatus flow rates should be set at the practical maxi¬
should be calibrated using a nondisintegrating mum to minimize diffusion in the hydrody¬
dissolution standard (e.g., salicylic acid com¬ namic layer at the dosage form interface as a
pacts). significant factor affecting release. For disin¬
Besides the USP dissolution testing appara¬ tegrating or erodable units, measurements
tus, testing equipment used for in vitro testing should be obtained at several rates of fluid flow
of sustained action formulations have included to establish the effect of this variable, so that
the rotating bottle, stationary basket/rotating fil¬ conditions can then be established to generate a
ter, Sartorius absorption and solubility simula¬ release profile encompassing the length of time
tor, and column-type flow-through assembly. the dosage form is designed to release drug in
The rotating bottle method was developed for vivo. Encapsulated products should be removed
evaluation of sustained release formulations.16 from the capsule shell for testing.
Samples are tested in 90-ml bottles containing Figure 14-12 shows the observed release pro¬
60 ml of fluid, which are rotated end over end in file of an encapsulated slow release bead form of
a 37° bath at 40 rpm. The method is not adapta¬ papaverine hydrochloride, measured in a flow-
ble to automated analysis, however, or to easy
manipulation of the dissolution media. The Sar¬
torius device includes an artificial lipid mem¬
brane, which separates the “dissolution” cham¬
ber from a simulated plasma compartment in
which drug concentrations are measured. Alter¬
nately, a dialysis type membrane may be used.
Systems of this type are advantageous in meas¬
uring release profiles of disintegrating dosage
units, and suspension, granular, and powdered
material, if the permeability of the membrane is
properly defined. The column flow-through ap¬
paratus possesses similar advantages since drug
release is confined to a relatively small chamber
by highly permeable membrane filters. This
apparatus is flexible, well-defined, and meets all
the necessary requirements for measurement of
drug release profiles from sustained release dos¬
age forms. It can also be adapted to measure¬
ments under near sink conditions if the release
medium is passed only once through the disso¬
lution chamber, directly measuring the rate of
release. Alternately, the dissolution fluid might
be recirculated continuously from the reservoir,
allowing measurement of the cumulative release
profile. The composition of the release media as
well as the flow rate can readily be altered. FIG. 14-12. In vitro release profile of a papaverine hydro¬
The time of testing may vary from 6 to 12 chloride sustained release capsule.

SUSTAINED RELEASE DOSAGE FORMS • 447

through apparatus at three pH-values.17 No sig¬ In Vivo Measurement of Drug
nificant effect of flow rate was observed for this
product. The profiles show that the amount of Availability
drug released depends on the length of time the Validation of sustained release product de¬
formulation is in contact with gastric fluid, and signs can be achieved only by in vivo testing.
more significandy, on the length of time it is The basic objective is to establish the bioequiva¬
exposed to media of pH 4 to 5, i.e., the transition lence of the product for which a controlled re¬
between gastric and intestinal pH. In effect, re¬ lease claim is to be made with conventional dos¬
lease is controlled by the dissolution characteris¬ age forms of the formulated drug.18 Since no
tics of the drug and apparently not by the dosage unnecessary human testing should be done, ani¬
form design. Papaverine has maximum solubil¬ mal models, such as dogs, should be used ini¬
ity at pH 4.5. These data demonstrate the impor¬ tially during the product development stage to
tance of measuring release profiles from dosage tune the formulation to the desired specifica¬
units exposed to a variety of conditions in a sin¬ tions. It is necessary to verify that dumping or
gle test. insufficient drug availability are not observed in
As with all pharmaecutici dosage forms, sta¬ vivo. Tests in both animal and subsequent
bility testing is an important aspect of the devel¬ human trials should include periodic blood level
opment stage. The same standards that apply to determinations, comparison of urinary excretion
conventional dosage forms with respect to active patterns, serial radiophotographs (in humans) to
ingredient stability and dosage form integrity follow the course of the dosage form in the GI
should be used. The stability testing program tract, and sequential observations of pharmaco¬
includes storage of the formulation under both logic activity. In some instances (e.g., with insol¬
normal (shelf) and exaggerated temperatures so uble core tablets), egested dosage forms should
that appropriate extrapolations for long-term sta¬ be recovered and assayed for drug content. If
bility can be made. The stability of the release drug level cannot be measured in biologic fluids,
profile in addition to that of the active ingredient then the pharmacologic effect must be observed
must be assessed. as a function of time, or clinical trials must be
Most sustained release formulations are com¬ designed, to establish the effectiveness of the
plex. They may be formulated with ingredients drug product.
that often present special problems regarding The FDA has promulgated the general bioa¬
their physical stability upon storage. Further¬ vailability and bioequivalence requirements for
more, accelerated stability testing may induce drug products.19 These are made to ensure that
changes in some systems (e.g., polymorphic or the new drug product meets its controlled re¬
amorphous to crystalline transitions); these lease claims, that no dose dumping occurs, that
changes would not be observed under normal performance is consistent between individual
shelf storage conditions. In addition, observed dosage units, and that steady-state drug levels
release profiles measured after storage at ele¬ obtained with the product are equivalent to cur¬
vated temperatures reflect loss of drug due to rently marketed products with approved new
degradation. Consequently, predictions of long¬ drug applications (NDAs). Reference materials
term release profile stability based on acceler¬ can include the pure drug substance in solution
ated tests could lead to erroneous conclusions. or suspension as well as conventional dosage
The stability testing program for a sustained re¬ forms administered according to their usual
lease product cannot be outlined specifically. It dosage schedules or according to the dosage
depends on the dosage form and its composition. schedule of the controlled release product.
There are many advantages to treating re¬ Bioavailability studies are ordinarily single-dose
lease-profile data kinetically by using equations comparisons of tested drug products in normal
(16), (17), and (18), or equation (19), or a first- adults in a fasting state. A crossover design in
order approximation, to obtain a rate constant. which all subjects receive both the product and
Confidence limits for the kinetic parameters can reference material on different days is preferred.
be calculated, allowing establishment of limits Guidelines for clinical testing have been pub¬
for the percentage of released drug under lim¬ lished for multiple-dose steady-state studies as
ited testing conditions established for purposes well as for single-dose studies, Correlation of
of quality control. Comparison of results ob¬ pharmacologic activity or clinical evidence of
tained with the same product using different therapeutic effectiveness with bioavailability
testing methods as well as comparisons between may be necessary to validate the clinical signifi¬
multiple runs, different lots, samples in stability, cance of controlled release claims.
and different products can be made more read¬ Figure 14-13 shows one example of the type of
ily./' data required in an in vivo study designed to

448 • The Theory and Practice of Industrial Pharmacy

 ample, encapsulated forms showed less peaking
during multiple dosing, and therefore, better
control of blood level within the desired limits.21
Attempts to correlate in vivo performance
with in vitro availability tests generally 'fiSve
been based on “single-point” measurements.
For example, AUC-values, peak blood levefsy or
peak times might be correlated with the time
required for 50% of drug to be released in vitro.
The best that can be expected from this ap¬
proach is a rank-order correlation. Significant
bioavailability difference between formulations
might be masked by improper in vitro methods,
or drug release studies might indicate a greater
difference than is actually seen in vivo.
TIME (HOURS!
Two general approaches to interrelating in
vivo and in vitro measurements of drug release
FIG. 14-13. In vivo validation of a sustained release tab¬
have been suggested. In one approach, an in
let of phendimetrazine tartrate. A, 105-mg sustained re¬
lease tablet. B, 35-mg nonsustained release tablet. C, 105- vitro release profile is transformed into a pre¬
mg nonsustained release tablet. D, 35-mg nonsustained dicted in vivo response. A weighting function
release tablet administered q4h for three doses. characterizing a reference product is deter¬
mined between the release profile and the aver¬
age in vivo response, which is measured in a
demonstrate the validity of a sustained release panel of human subjects by the mathematical
product design.20 Comparison is made between operation of deconvolution. The in vivo re¬
blood level profiles observed after administration sponse, predicted in vitro, of the dosage form
of a single unit of the sustained release product undergoing testing is obtained by convolution of
(curve A), a conventional tablet form containing the observed release profile and the weighting
the usual single dose of active ingredient (curve function. The method has been successfully
B), the total dose in the sustained release form applied to prediction of plasma levels of warfarin
as a tablet (curve C), and the total dose adminis¬ and acetazolamide from tablet dissolution data.
tered as three divided doses at the recom¬ The technique is computationally complex, but
mended dosing interval (curve D). Samples maximizes the amount of information derived
should be taken over a period of 24 hours or from in vitro dissolution testing.22 Alternately, a
three half-lives of the active ingredient at suffi¬ reference blood level profile is used as the input
cient frequency to permit reasonable estimation to a feedback-controlled dissolution testing ap¬
of peak concentrations. Pharmacokinetic model- paratus, which is subsequently forced to yield a
independent methods are best employed to release profile close to the standard by dynami¬
quantitate the data. The data represented in Fig¬ cally changing release media and flow rates.
ure 14-13 show the equivalence between admin¬ The conditions established using the reference
istration of the sustained release form and that product are used for testing other formulations.
of three divided doses of drug. Equivalence is Application of these techniques to sustained re¬
demonstrated by comparison of measured blood lease products requires a similar formulation as
levels and the AUC-values (area under blood the reference.
level curve). In the second approach, the apparent in vivo
While single-dose studies are usually suffi¬ drug release profile is computed from smoothed
cient to establish the validity of sustained re¬ blood level or urinary excretion data.23 This
lease dosage form designs, multiple-dose studies technique requires knowledge of the pharmaco¬
are required to establish the optimum dosing kinetic model of the drug. The in vivo data are
regimen. They are also required when differ¬ used as input to a computer simulation of the
ences may exist in the rate but not the extent of pharmacokinetic model; the output represents
absorption, when there is excessive subject-to- the amount of drug released at the absorption
subject variation, or when the observed blood site as a function of time. Beckett, in applying
levels after a single dose are too low to be meas¬ this method to a sustained release form of phen¬
ured accurately, A sufficient number of doses dimetrazine, found that measured in vitro re¬
must be administered to attain steady-state lease rates were significantly faster than com¬
blood levels. According to an extensive study of puted in vivo release rates.23
sustained release theophylline products, for ex¬ In vivo testing involves a number of simplify-

SUSTAINED RELEASE DOSAGE FORMS • 449

ing assumptions regarding the uniformity of the keted. Salts of cationic or anionic exchange res¬
absorption process and the suitability of using ins are insoluble complexes in which drug re¬
average data points to represent the population. lease results from exchange of “bound” drug
Since the formulator has no control over physio¬ ions by ions normally present in GI fluids (Na+,
logic variables, it is essential that clinical studies H+, Cl-, OH-). Resins used are special grades
be based on sufficiently large cross-sections of of styrene/divinyl benzene copolymers that con¬
the population to provide meaningful results. tain appropriately substituted acidic groups (car¬
Both in vivo and in vitro testing methods play a boxylic or sulfonic for cation exchangers) or
major part in validating the effectiveness of sus¬ basic groups (quaternary ammonium for anion
tained release formulations. exchangers) on the styrene moiety of the resin.
Ion-active sites are distributed uniformly
throughout the resin structure. Variables relat¬
ing to the resin are the degree of cross-linking,
Practical Formulation
which determines the permeability of the resin,
its swelling potential, and the access of the ex¬
Drug Complexes change sites to the drug ion; the effective pKa of
The principal advantage of preparing drug the exchanging group, which determines the ex¬
derivatives for sustained release is that such change affinity; and the resin particle size,
materials can be formulated into diverse dosage which controls accessibility to exchange ions.
forms. This approach has proven effective in the Drug-resin salts, for example, may be pre¬
development of injectable depot forms, in which pared by percolation or equilibrium of the resin
release profiles are not subject to the variability in acid form with a concentrated solution of drug
characteristic of the gastrointestinal tract. Sensi¬ hydrochloride salt. The resin is washed with ion-
tivity to in vivo variables is a definite disadvan¬ free water and partially dried. The resulting
tage of perorally administered forms: in vivo product can be encapsulated, tabletted, or sus¬
studies may not consistently support sustained pended in ion-free vehicles. The following equa¬
release claims. tions represent the preparation and exchange
If an alcoholic solution of a basic drug and reaction affecting drug release in vivo:
tannic acid are mixed in a 5:1 drug: tannic acid
ratio at reduced temperature, tannate complexes RESIN - S03Na + DRUGHC1
containing one amine per digallyl moiety are
precipitated. These complexes are split by hy¬ = NaCl + RESIN - S03.DRUGH
drolysis in gastric and intestinal fluid. Ampheta¬ RESIN - S03.DRUGH + NaCl
mine and antihistamine tannates were once
marketed in both tablet and suspension forms =-- DRUGHC1 + RESIN - S03Na
with sustained release claims. Breakdown of the
tannate complex depended on pH, being some¬ A strong acid resin must be used to minimize
what faster in gastric than intestinal fluid, as exchange of drug by hydrogen ion, to avoid ex¬
well as on the low solubility of the complex. cessive drug release in the gastric fluid. The
Other complex acids used to prepare relatively percentage of cross-linking is the most impor¬
insoluble and degradable complexes of basic tant variable affecting release profiles. Resins
drugs have included polygalacturonic acid, al- with minimum cross-linking show maximum
ginic acid, and arabogalactone sulfate. Products swelling when converted from free acid to salt
obtained by interaction of montmorillonite clays forms. Subsequent contact with acid can cause
(e.g., bentonite) with cationic drugs or amine shrinkage and reduction of pore volume at the
salts and certain nonionic drugs have also been resin periphery, thus entrapping large ions.
investigated.24 Both cation exchange and strong However, more drug is available for release at
chemisorption contribute to the interaction. The higher pH-values. Increased cross-linking de¬
release profiles can be varied by altering the creases resin porosity, not only reducing drug
drug:clay ratio. A 1:20 complex of ampheta¬ availability but also limiting access of exchange
mine, for example, is reported to release drug groups to drug ions during preparation. Particle
effectively in intestinal fluid, with little release size control becomes important when pore and
in gastric fluid. Since the clays are anionic, ef¬ molecular size are important. Similar observa¬
fective adsorbates cannot be prepared from ani¬ tions apply to drug resinates, which are prepared
onic drugs. by reaction of sodium salts of acidic drugs with
Ion-exchange resin complexes, which potenti¬ resin chlorides.
ally can be prepared from both acidic and basic The amount of drug that can be incorporated
drugs, have been more widely studied and mar¬ in these systems is limited to a maximum of 200

450 • The Theory and Practice of Industrial Pharmacy

to 300 mg, since larger doses require too much smooth rather than discontinuous release pro¬
resin. Release profiles characteristic of resin file. Variables that can be manipulated to alter
complexes are sensitive to variation of in vivo the release pattern include the amount of drug
ion concentrations. Coating of the resin beads per pellet, the composition and thickness of the
with appropriate polymers, which act as a diffu¬ coating, and the number of peEets included in
sion barrier to both exchange ions and ex¬ each group. Regulation of coating and mainte¬
changed drug and water, provides a controllable nance of the proper mix of beads during encap¬
rate-limiting factor that minimizes the effect of sulation present specific production difficulties.
in vivo variables.25 In one process, the resin par¬ In the case of high-miEigram potency formu¬
ticles are pretreated with polyethylene glycol to lations, individual crystals of drug or peEetized
provide a base for a subsequent coating of ethyl- drug may be coated by pan or fluidized-bed proc¬
cellulose plasticized with a refined vegetable oil. esses with a retardant barrier. Combinations of
Release profiles can be controEed by appropriate waxes, fatty acids, alcohols, and esters can be
mixing of both coated and uncoated drug-resin applied using fluidized-bed technology. Such
complexes. The complexes can be formulated in enteric materials as ceEulose acetate phthalate
encapsulated or suspension forms. Different and formalized gelatin, as weE as Epid composi¬
drugs might be readily combined as coated resin tions, have been used to control release by ero¬
forms with independently controEed release sion. Microencapsulation by spray-drying or
characteristics in the same product. coacervation has also been used to prepare sus¬
tained release encapsulations.26
Many encapsulation formulations that imple¬
Encapsulated Slow Release ment barrier controEed release have been de¬
signed to produce granules with uniform rather
Granules than mixed release characteristics, thus ehmi-
The first significant marketed sustained- nating some of the production complexities as¬
release dosage forms were encapsulated mixed sociated with the manufacture of mixed release
slow release beads, to which was applied the bar¬ peEets. One group of products consists of peEets
rier principle of controlling drug release, based coated with a hydrolyzed sytrene maleic acid
on model D (Fig. 14-9). For low-miEigram po¬ copolymer, which produces a pH-sensitive bar¬
tency formulations, nonpareil seeds (20/25- rier. Formulations of methylpredriisolone have
mesh sugar-starch granules) are initiaEy coated been described as releasing 5% drug in 2 hours
with an adhesive followed by powdered drug, at pH 1.2, and 90 to 100% drug in 4 hours at pH
and the peEets are dried. This step is repeated 7.5. Delayed release ascorbic acid consisting of
until the desired amount of drug has been ap¬ ascorbic acid crystals encapsulated in partiaEy
plied. The resultant granules are subsequently hydrogenated cottonseed oE has been marketed
coated with a mixture of solid hydroxylated Ep- for the food industry. Typical formulations con¬
ids such as hydrogenated castor oE or glyceryl tain up to 50% Epid. Pseudo-latexes of ethylcel-
trihydroxystearate mixed with modified ceEu- lulose modified by the addition of dibutyl seba-
loses. The thickness of the barrier was regulated cate and plasticized by triethyl citrate have been
by the number of applied coatings to obtain the shown to produce effective retardant barriers
desired release characteristic. The original for¬ whose permeabEity can be altered by varying the
mulations utilized glyceryl monostearate bees¬ additive concentration. A near zero-order release
wax compositions, which tended to be physicaEy is claimed with a coating containing 24% seba-
unstable, showing altered release patterns on cate.27
aging. A unique appEcation of the barrier concept
A unit of this type contains hundreds of color- involves the preparation of granules described
coated peEets divided into 3 to 4 groups, which as microdialysis ceEs (model B, Fig. 14-9). Drug-
differ in the thickness of the time-delay coating. containing peEets might be coated with ethylcel-
A typical mix consists of uncoated peEets provid¬ lulose, a water-insoluble and pH-insensitive
ing the loading dose and peEets designed to re¬ polymer, modified by the addition of suspended
lease drug at 2 or 3 hours, 4 or 6 hours, and 6 or sodium chloride particles or other water-soluble
9 hours. The key factor controlling drug release materials (e.g., polyethylene glycol). Leaching
is moisture permeation of the barrier, which the salt from the film results in a dialytic mem¬
depends on coating thickness. Absorption of brane formed in situ. This allows permeation of
moisture by the core and subsequent swelling water, dissolution of drug, and diffusion of drug
rupture the coating, releasing drug. Some peEets through the essentiaEy intact membrane. These
within each group release drug at intervals over¬ microdialysis ceEs have been apphed to produce
lapping other peEet groups, resulting in a a sustained release form of nitroglycerin, which

SUSTAINED RELEASE DOSAGE FORMS' 45]

is claimed to be independent of the composition duce sustained release beads. With the latter,
of the GI fluids; however, release of acidic or curing agents are required, and the reaction is
basic drugs from this system is generally pH- carried out in a silicone oil phase in which the
dependent. Pellet cores containing propoxy¬ curing agent and the drug dispersed in the liq¬
phene in a buffer system are claimed to produce uid resin are insoluble. Drug release from such
a pH-independent drug release if formulated as systems is controlled by both matrix diffusion
microdialysis cells.28 Drug may also be microen¬ and partitioning as defined by equation (19).
capsulated in ethylcellulose using a thermally
induced phase separation technique in which
polyisobutylene is used to control particle size
and release rate.29 Tabletted Slow Release
Alternately, placebo pellets may be coated
with polyethylene glycol modified ethylcellulose,
Granulations
shellac, or cellulose acetate phthalate containing Compression of timed-release granulations
suspended drug, which is leached from the coat¬ into tablets is an alternate to encapsulation.
ing as it is eroded by the action of intestinal Such tablets should be designed to disintegrate
fluid. This approach combines both barrier and in the stomach so as to simulate the administra¬
embedded matrix models of drug release. Re¬ tion of a capsule form having the advantages
lease profiles conform to patterns C or D in Fig¬ associated with sustained release encapsula¬
ure 14-10, depending on the relative importance tions, while retaining the advantages of the tab¬
of erosion.30 let dosage form. Three examples, each utilizing
The embedded matrix principle has also been a different process, illustrate this type of formu¬
applied to prepare sustained release encapsula¬ lation. The first is a tabletted mixed release
tions. Medicaments are dispersed in molten granulation in which binders with different re¬
lipid materials to form a slurry, which may be tardant properties are used to prepare three dif¬
spray-congealed, or after solidification, granu¬ ferent granulations, which are color coded for
lated. Preferred retardant materials include hy¬ identification, blended, and tabletted. The first
drogenated oils, glyceryl stearates, fatty alcohols, is a conventional nonsustained release granula¬
and microcrystalline wax. The addition of 2 to tion prepared using gelatin as a binder; the sec¬
10% wicking agents, i.e., finely divided powders ond uses vinyl acetate, and the third uses shel¬
of methylcellulose, alginic acid, or car- lac, as binders. Drug release is controlled by
boxymethylcellulose, is claimed to produce a erosion of the granulation in intestinal fluid—
greater uniformity of drug release, which more the vinyl acetate granulation disintegrates at a
nearly approximates a zero-order process in in faster rate than the shellac granulation.
vitro testing. These agents promote the permea¬ The second example is illustrated by a sus¬
tion of moisture into the matrix, facilitating its tained release aspirin formulation based on the
erosion. Time-delay matrix materials may con¬ microdialysis cell principle. Aspirin crystals are
stitute 45 to 75% by weight of the formulation. microencapsulated in a retardant barrier and are
Spray-congealing is advantageous since spheri¬ compressed to form a tablet that rapidily disinte¬
cal pellets varying in size from 250 to 2000 mi¬ grates into sustained release granules. The bar¬
crons can be obtained. Sustained release is rier approach is particularly advantageous for
achieved in part by the random mix of different formulation of high-milligram-potency drugs
particle sizes and random dispersal of drug in such as aspirin, since only a relatively small
the matrix.31 amount of retardant is required in the formula¬
Suspension or emulsion polymerization has tion. The third example is represented by a sus¬
been used to produce resin beads containing tained release form of theophylline, which is
drug for sustained release. For example, methyl claimed to release drug zero-order for a 12-hour
methacrylate monomer containing drug and dosing interval. The tablet is formulated as a
methacrylic acid, a water soluble monomer that matrix of loading dose of theophylline contain¬
is added to contribute a swelling characteristic to ing theophylline pellets encapsulated in a semi-
the final product, are dispersed in an aqueous permeable coating. Disintegration of the matrix
solution containing appropriate suspending and in the stomach releases the extended action pel¬
deflocculating'agents. Benzoyl peroxide is added lets. The loading dose granulation should have
to catalyze the polymerization. The resulting physical characteristics, e.g., size, similar to the
product consists of uniformly sized beads that maintenance dose pellets to ensure homogene¬
can be encapsulated.32 Vinyl acetate and epoxy ous mixing of the two granulations during com¬
resins have also been used successfully to pro¬ pression.

452 • The Theory and Practice of Industrial Pharmacy

Matrix Tablets these formulations is liquid penetration into the
One of the least complicated approaches to matrix unless channeling (wetting) agents are
the manufacture of sustained release dosage included to promote permeation of the polymer
forms involves the direct compression of blends matrix by water, which allows drug dissolution
of drug, retardant material, and additives to form and diffusion from the channels created in the
a tablet in which drug is embedded in a matrix matrix. Formulations should be designed so that
core of the retardant. Alternately, retardant-drug pore diffusion becomes rate-controlling, release
blends may be granulated prior to compression. is defined by equation (16) or (17), and the re¬
Table 14-7 identifies examples of the three lease profile is represented by curve C (Fig. 14-
classes of retardant material used to formulate 10). Drug bioavailability, which is critically de¬
matrix tablets, each class demonstrating a differ¬ pendent on the drug:polymer ratio, may be
ent approach to the matrix concept. The first modified by inclusion of diluents such as lactose
class consists of retardants that form insoluble in place of polymer in low-milligram-potency
or “skeleton” matrices; the second class repre¬ formulations. 3
sents water-insoluble materials that are potenti¬ Egested tablets contain unreleased drug in the
ally erodable; and the third class consists of poly¬ core. In one study of polyvinyl chloride matrix
mers that form hydrophilic matrices. Loading tablets containing prednisolone disodium phos¬
doses are best included as the second layer of a phate, egested tablets contained 72% of the
two-layer tablet or in a coating applied to the maintenance doSe for matrices containing 87%
matrix core. plastic and 2% drug, and 28% drug for matrices
Insoluble, inert polymers such as polyethyl¬ containing 84% plastic and 3% drug.34 These
ene, polyvinyl chloride, and acrylate copolymers forms of matrix tablets are not useful for high-
have been used as the basis for many marketed milligram-potency formulations in which the
formulations. Tablets prepared from these mate¬ polymer content would be insufficient to form a
rials are designed to be egested intact and not matrix, or for highly water-insoluble drugs in
break apart in the GI tract. Tablets may be di¬ which dissolution in the matrix would become
rectly compressed from mixtures of drug and rate-limiting. Release of water-soluble drugs,
ground polymer; however, if ethyl cellulose is however, should be unaffected by the amount of
used as the matrix former, a wet granulation liquid, pH-value, enzyme content, and other
procedure using ethanol can be employed. The physical properties of digestive fluids, unless
rate-limiting step in controlling release from the drug is in a salt form that precipitates within

Table 14-7. Materials Used as Retardants in Matrix Tablet Formulations

Matrix Characteristics Material

Insoluble, inert Polyethylene

Polyvinyl chloride
Methyl acrylate-methacrylate copolymer
Ethylcellulose

Insoluble, erodable Camauba wax

Stearyl alcohol
Stearic acid
Polyethylene glycol
Castor wax
Polyethylene glycol monostearate
Triglycerides

Hydrophilic Methylcellulose (400 cps, 4000 cps)

Hydroxyethylcellulose
Hydroxypropylmethylcellulose
(60 HG, 90 HG, 25 cps, 4000 cps, 15,000 cps)
Sodium carboxymethylcellulose
Carboxypolymethylene
Galactomannose
Sodium alginate

SUSTAINED RELEASE DOSAGE FORMS - 453

the matrix pores on dissolution when penetrated prepare sustained release theophylline tablets.
by acid or basic media. The wax:glycol ratio could be adjusted to vary
Waxes, lipids, and related materials form ma¬ the release characteristics.
trices that control release through both pore dif¬ A novel approach to the development of a lipid
fusion and erosion (curve D, Fig. 14-10). Re¬ matrix utilizes pancreatic lipase and calcium
lease characteristics are therefore more carbonate as additives, with triglycerides as re¬
sensitive to digestive fluid composition than to tardants. The lipase is activated on contact with
the totally insoluble polymer matrix. Total re¬ moisture and thus promotes erosion indepen¬
lease of drug from wax-lipid matrices is not pos¬ dent of intestinal fluid composition. The release
sible, since a certain fraction of the dose is profile is controlled by the calcium carbonate,
coated with impermeable wax films. Release is since calcium ions function as a lipase accelera¬
more effectively controlled by the addition of tor.36 In another technique, drug is mass-
surfactants or wicking agents in the form of hy¬ blended with stearyl alcohol at a temperature
drophilic polymers, which promote water pene¬ above its glass transition (approximately 60°C),
tration and subsequent matrix erosion. and the mass is cooled and granulated with an
Camauba wax in combination with stearyl alcoholic solution of zein. This formulation is
alcohol or stearic acid has been utilized as a re¬ claimed to produce tablets with stable release
tardant base for many sustained release matrix characteristics. Since natural waxes and lipids
formulations. Mixtures of (1:1) hydrogenated are complex mixtures, and a fusion process is
castor oil and propylene glycol monostearate and usually required for processing, hardening with
of camauba wax and stearyl alcohol or stearic decrease in effective drug release on aging may
acid have been extensively studied as retardants be observed, owing to polymorphic and amor¬
for both water-soluble and water-insoluble com¬ phous to crystalline transitions.
pounds. Materials with melting points that are The third group of matrix formers represents
too low or materials that are too soft cannot be nondigestible materials that form gels in situ.
readily processed to form tablets with good phys¬ Drug release is controlled by penetration of
ical stability. Such retardants as camauba wax water through a gel layer produced by hydration
or hydrogenated castor oil provide the necessary of the polymer and diffusion of drug through the
physical characteristics to form an easily com¬ swollen, hydrated matrix, in addition to erosion
pressible stable matrix. If used singly, these of the gelled layer (curve D, Fig. 14-10). The ex¬
materials excessively delay drug release. tent to which diffusion or erosion controls re¬
Three methods may be used to disperse drug lease depends on the polymer selected for the
and additive in the retardant base. A solvent formulation as well as on the drug:polymer
evaporation technique can be used, in which a ratio. Low-molecular-weight methylcelluloses
solution or dispersion of drug and additive is in¬ release drug largely by attrition, since a signifi¬
corporated into the molten wax phase. The sol¬ cant intact hydrated layer ir r‘_ maintained.
vent is removed by evaporation. Dry blends of Anionic polymers such as carboxymethyl cellu¬
ingredients may be slugged and granulated. A lose and carpolene can interact with cationic
more uniform dispersion, however, can be pre¬ drugs and show increased dissolution in intesti¬
pared by the fusion technique, in which drug nal fluid. Carboxypolymethylene does not hy¬
and additive are blended into the molten wax drate in gastric fluid. The best matrix former in
matrix at temperatures slightly above the melt¬ this group is hydroxymethylcellulose 90 HG
ing point (approximately 90° C for camauba 15,000 cps, an inert polymer that does not ad¬
wax). The molten material may be spray- versely interact with either acidic or basic drugs,
congealed, solidified and milled, solidified and and that on contact with water slowly forms a gel
flaked, or poured on a cold rotating drum to form that is more resistant to attrition. Release rates
sheets, which are then milled and screened to can be adjusted for low-milligram-potency for¬
form a granulation. mulations by replacing polymer with lactose.
In the absence of additives, drug release is High drug:polymer ratios result in formulations
prolonged and nonlinear. Apparent zero-order from which drug release is controlled by attri¬
release can be obtained by addition of additives tion.37
such as polyvinyl pyrrolidone or polyoxyethylene The process used to prepare formulations for
lauryl ethers. In a study by Dahkuri et al., 10 to compression depends on the polymer and
20% hydrophilic polymer effectively controlled drug:polymer ratio. With high drug:polymer
release from camauba-wax/stearyl-alcohol ma¬ ratios, a wet granulation process is required.
trices of tripelennamine hydrochloride.35 Matri¬ Low-milligram-potency formulations may be
ces prepared from camauba-wax/polyethylene- direcdy compressed or granulated using alcohol
glycol compositions have also been used to if the polymer is not in a form amenable to direct

454 • The Theory and Practice of Industrial Pharmacy

compression. Formulations of this type are de¬ A. OSMOTIC PUMP
signed to release 100% of drug in vivo, unlike DELIVERY ORIFICE
the other matrix forms, which may be partially
egested and consequently must be formulated to
contain drug in excess of that required to attain
the desired therapeutic effect.
Pseudo-latex forms of the normally water- ^''SEMI-PERMEABLE
insoluble enteric polymers, such as cellulose MEMBRANE
acetate phthalate and acrylic resin, can be used
as granulating agents for high-milligram-
potency drugs. Erodable matrix tablets can be
prepared from these granulations. This ap¬
proach has been tested with theophylline.38

Controlled Release Technology

Controlled release dosage forms are designed
to release drug in vivo according to predictable
rates that can be verified by in vitro measure¬ C. MICROSEAL DELIVERY SYSTEM
ments. Of the many approaches to formulation o ' o -BARRIER
of sustained-release medication described in O °
this chapter, those fabricated as insoluble matrix o O
tablets come closest to realization of this objec¬ ° °o
o O
tive, since release of water-soluble drug from
o o O
this form should be independent of in vivo varia¬ Oj o
bles. Controlled release technology implies a
quantitative understanding of the physicochem¬
/
DISPERSED LIQUID
ical mechanism of drug availability to the extent FIG. 14-14. Controlled release dosage forms. A, Cross-
that the dosage form release rate can be speci¬ section of osmotic pump. B, Release rate profile character¬
fied. Potential developments and new ap¬ istic of osmotic pump. C, Micro-seal drug-delivery system.
proaches to oral controlled release drug delivery
include hydrodynamic pressure controlled sys¬
tems, intragastric floating tablets, transmucosal increases to its maximum value, drug release is
tablets, and microporous membrane coated tab¬ zero-order, as shown in Figure 14-14B, until all
lets.39 solid material is dissolved. Thereafter, the deliv¬
One example of a dosage form design that il¬ ery rate decreases parabolicaJly to zero.
lustrates the application of controlled release The diameter of the orifice must be smaller
technology to pharmaceutical formulation is the than a maximum size to minimize drug delivery
orally administered elementary osmotic pump by diffusion through the orifice, and larger than
shown in Figure 14-14A. This device is fabri¬ a minimum size to minimize the hydrostatic
cated from a tablet that contains water-soluble pressure in the system, which acts in opposition
osmotically active drug, or that is blended with to the osmotic pressure. For devices containing
an osmotically active diluent, by coating the tab¬ potassium chloride, orifices can range from 75 to
let with a cellulose triacetate barrier, which 275 pm in diameter. The device can be used as
functions as a semipermeable membrane.40 A a drug delivery system for any water-soluble
laser is used to form a precision orifice in the drug and can be designed to deliver significant
barrier. Since the barrier is permeable only to fractions of the total dose at zero-order rates
water, initial penetration of water dissolves the unaffected by in vivo conditions. Since ions do
outer part of the core, resulting in the develop¬ not diffuse into the device, release of acidic and
ment of an osmotic pressure difference across basic drugs is independent of gastrointestinal
the membrane. The system imbibes water at a pH.
rate proportional to the water permeability and A design that provides zero-order release of
effective surface area of the membrane and to potassium chloride consists of the soluble tablet
the osmotic gradient of the core formulation. core coated with a microporous membrane,
The device delivers a volume of saturated solu¬ which controls the diffusion rate. The mem¬
tion equal to the volume of water uptake through brane is produced in situ by leaching out sucrose
the membrane. After an initial lag time (approxi¬ that has been suspended in a polyvinyl chloride
mately 1 hour) during which the delivery rate membrane.41

SUSTAINED RELEASE DOSAGE FORMS • 455

 Another example of the application of con¬ 10. Chien, Y.W., and Lambert, H.J.: J. Pharm. Sci.,
trolled release technology to dosage form design 63:515, 1974.
11. Desai, J., et al.: j. Pharm. Sci., 55:1224, 1966.
consists of a polymer matrix in which a drug 12. Wagner, J.C.: Drug Standards, 27:178, 1959.
containing solution is dispersed in the form of 13. Lapidus, H., and Lordi, N.G.: J. Pharm. Sci., 57:129,
microcells (Fig. 14-14C).42 The barrier permea¬ 1968.
bility and drug solubility in the dispersed solu¬ 14. Baker, R.W., and Lonsdale, H.K.: Controlled release:
tion are variables that can be adjusted to provide Mechanisms and rates. In Advances in Experimental
Medicine and Biology. Vol. 47. Edited by A.C. Tan-
predictable drug release rates. This device can
quarv and R.E. Lacey. New York, Plenum Press,
be used to provide controlled drug release by 1974.
topical, subdermal, intravaginal, and intrauter¬ 15. Williams, A.: Sustained Release Pharmaceuticals.
ine administration.43 Park Ridge, NJ, Noyes Development Corp., 1969.
Most pharmaceutical formulations, including 16. Krueger, E.O., and Vliet, E.B.: J. Pharm. Sci., 51:181,
sustained release dosage forms, have been de¬ 1962.
veloped through a process of “guided empiri¬ 17. Timko, R.J., and Lordi, N.G.: J. Pharm. Sci., 67:496,
1978.
cism,” which merges the application of funda¬
18. Lazarus, J., and Cooper, J.: J. Pharm. Sci., 50:715,
mental principles with elements of trial and 1961.
error. The future of sustained release formula¬ 19. Federal Register, 40:26164, 1975.
tion would seem to lie in the development of 20. Hadler, A.J.: J. Clin. Pharmacol.. 8:113, 1968.
novel drug delivery systems, such as the osmotic 21. Upton, R.A., et al.: J. Pharmacokinet. Biopharm.,
pump. Ideally, all pharmaceutical dosage forms 8:131, 1980.
22. Smolen, V.F., Ball, L., and Scheffler, M.: Pharm.
should be controlled release formulations—with
Tech., 3:88, 1979.
rate specified and bioavailability assured by the 23. Beckett, A.H., Staniforth, D.H., and Raisi, A.: Drug
drug delivery design. The distinction between a Dev. and Ind. Pharm., 6:121, 1980.
sustained release and an immediate release dos¬ 24. McGinity, J.W., and Lach, J.L.: J. Pharm. Sci., 66:63,
age form is one of degree, i.e., whether the drug 1977.
release rate is specified to be near-instantaneous 25. Raghunathan, Y., et al.: J. Pharm. Sci., 70:379, 1981.
26. Harris, M.S.: J. Pharm. Sci., 70:391. 1981.
or some finite value.
27. Banker, G.S.. and Peck, G.E.: Pharm. Tech.. 5:55,
1981.
28. Bechgaard. H., and Baggesen, S.: J. Pharm. Sci..
69:1327, 1980.
29. Kawashima, Y., et al.: Drug Dev. and Ind. Pharm.,
References 10:467, 1984.
1. Ballard, B.E.: An overview of prolonged action drug 30. Chandrasekaran, S.K., and Hillman, R.: J. Pharm.
dosage forms. In Sustained and Controlled Release Sci., 69:1311, 1980.
Drug Delivery Systems. Edited by J.R. Robinson. 31. Lantz, R.J., and Robinson, M.J.: U.S. Patent
New York, Marcel Dekker, 1978. 3,146,167 (1964).
2. Urquhart, Controlled-Release Pharmaceuticals. 32. Khanna, S.C., and Jecklin, T.: J. Pharm. Sci., 59:614,
Washington, DC, American Pharmaceutical Associa¬ 1970.
tion, 1981. 33. Salomon, J.L., and Doelker, E.: Pharm. Acta Helv.,
3. Robinson, J.R., and Eriksen, S.P.: J. Pharm. Sci., 55:174, 1980.
55:1254, 1966. 34. D’Arcy, P.F., et al.: j. Pharm. Sci., 60:1028, 1971.
4. Manion, C.V., et al.: J. Pharm. Sci., 66:981, 1977. 35. Dahkuri, A., Butler, L.D., and DeLuca, PP J.
5. Welling, P.G., and Dobrinska, M.R.: Multiple dosing Pharm. Sci., 67:357, 1978.
of sustained release systems. In Sustained and Con¬ 36. Javaid, K.A., Fincher, J.H., and Hartman, C.W'.: J.
trolled Release Drug Delivery Systems. Edited by J.R. Pharm. Sci., 60.1709, 1971.
Robinson, New York, Marcel Dekker, 1978. 37. Salomon, J.L., and Doelker, E.: Pharm. Acta Helv.,
6. Kwan, K.C.: Pharmacokinetic considerations in the 55:189, 1980.
design of controlled and sustained release drug deliv¬ 38. McGinity, J.W., Cameron, C.G., and Cuff, G.W.:
ery systems. In Sustained and Controlled Release Drug Dev. and Ind. Pharm., 9:57, 1983.
Drug Delivery Systems. Edited by J.R. Robinson. 39. Chien, Y.W.: Drug Dev. and Ind. Pharm., 9:1291,
New York, Marcel Dekker, 1978. 1983.
7. Sinkula, A.A.: Methods to achieve sustained drug de¬ 40. Theeuwes, F.: J. Pharm. Sci., 64:1987, 1975.
livery—The chemical approach. In Sustained and 41. Kallstramd, G., and Ekman, B.: J. Pharm. Sci.,
Controlled Release Drug Delivery Systems. Edited by 72:772, 1983.
J.R. Robinson. New York, Marcel Dekker, 1978. 42. Chien, Y.W.. Rozek, L.F., and Lambert, H.J.: J.
8. Banker, G.S., and Larson, A.B.: J. Pharm. Sci., Pharm. Sci., 67:214, 1978.
65:838, 1976. 43. Chien, Y.W.: Novel Drug Delivery Systems. New
9. Higuchi, T.: J. Pharm. Sci., 52:1145, 1963. York, Marcel Dekker, 1982.

456 • The Theory and Practice of Industrial Pharmacy

 15

Liquids
J. C. BOYLAN

The oral use of liquid pharmaceuticals has gen¬ application of the scientific method still plays a
erally been justified on the basis of ease of ad¬ distressingly minor role. Thus, the successful
ministration to those individuals who have diffi¬ formulation of liquids, as well as other dosage
culty swallowing solid dosage forms. A more forms, requires a blend of scientific acuity and
positive argument can be made for the use of pharmaceutical “art.”
homogeneous liquids (systems in which the
drug or drugs are in solution). With rare excep¬
tions, a drug must be in solution in order to be
absorbed. A drug administered in solution is Solubility
immediately available for absorption, and in Whether or not a substance dissolves in a
most cases, is more rapidly and efficiently ab¬ given system and the extent to which it dis¬
sorbed than the same amount of drug adminis¬ solves depend largely on the nature and inten¬
tered in a tablet or capsule. sity of the forces present in the solute, the
The formulation of solutions presents many solvent, and the resultant solute-solvent interac¬
technical problems to the industrial pharmacist. tion. The nature of these interaction energies
Some drugs are inherently unstable; this prop¬ and the interplay of electronic and steric factors
erty is magnified when the drug is in solution. in determining the solubility of substances in
Special techniques are required to solubilize various classes of solvents has been clearly pre¬
poorly soluble drugs. The final preparation must sented by Martin et al.1
satisfy the requirements of pharmaceutical ele¬ The equilibrium solubility of the drug of inter¬
gance with regard to taste, appearance, and vis¬ est should be determined in a solvent that is
cosity. This chapter discusses those factors par¬ similar to the one intended for use in the final
ticularly important in the formulation and product. This can readily be done by placing an
manufacture of solutions. The various dosage excess of drug (the drug should be finely pow¬
forms that fall under this general classification dered to minimize the time required to attain
are treated as a group. No attempt is made to equilibrium) in a vial along with the solvent.
treat each dosage form individually. Whenever The tightly closed vial is then agitated at con¬
possible, however, specific examples are given stant temperature, and the amount of drug in
to illustrate the application of the principles dis¬ solution is determined periodically by assay of a
cussed. filtered sample of the supemate. Equilibrium is
not achieved until at least two successive sam¬
plings give the same result.
Formulation Considerations Solubility studies are generally conducted at
To solve the formulation problems encoun¬ fixed temperatures, preferably at temperatures
tered With pharmaceutical liquids, an interest¬ somewhat higher than room temperature (e.g.,
ing dichotomy of investigative skills is required. 30°C), so that constant conditions can be main¬
On the one hand, solubility and stability factors tained regardless of normal laboratory tempera¬
can be approached with the precision long asso¬ ture variations. During the normal distribution
ciated with the exact sciences; on the other process, however, it is possible and even likely
hand, flavoring and other organoleptic charac¬ that the product will be exposed to a wide range
teristics remain subjective factors for which the of temperature conditions. For this reason, in-

457
formation relative to the influence of tempera¬ amount of drug in solution?” a modified form of
ture on solubility should be generated. As a rule, equation (4) is frequently useful:
a solution should be designed in which the solu¬
bility of the solute is not exceeded even at tem¬ KsKa
peratures as low as 4°C.
ST - Ks =
[H+]
(6)
The approach used when the required con¬
centration of drug exceeds the aforementioned or
solubility criteria depends on the chemical na¬
ture of the drug and the type of product desired. KsKa
[H+] (7)
pH. A large number of modem chemothera¬ ST - Ks
peutic agents are either weak acids or weak
bases. The solubility of these agents can be For example: What must the pH of an aqueous
markedly influenced by the pH of their environ¬ formulation be to maintain in solution 10 mg/ml
ment. Through application of the law of mass of a weakly acidic drug, molecular weight
action, the solubility of weakly acidic or basic (MW) = 200, K = 1 x 10-5, Ks = 0.001 M/L?
drugs can be predicted, as a function of pH, with
a considerable degree of accuracy. Consider, for
The desired molar (M.)
v MW /
concentration of
example, the reactions involved in the dissolu¬ 0.010 x 1000
tion of a weakly acidic drug, DH: drug = 0.05M.
200

DH (solid) *=± DH (solution) (1) _ (i x icr3)(i x nr5) = 1 x io~8

' l 1H 1 ~ 0.05 - 0.001 0.049
where DH (solution) is equal to the solubility of
[H+] = 2.04 x 10~7
the undissociated acid in moles per liter and is a
constant generally referred to as Ks. pH = 7 - log 2.04 = 7 - 0.31
The undissociated acid is also in equilibrium
pH = 6.69
with its dissociation products:
An equation that is useful for poorly soluble,
DH (solution) ^D' + H*
weakly basic drugs can be similarly derived:
[D-][H+]
Ka = (2) DOH (solid) ?=± DOH (solution)
[DH]
Ks = DOH (solution)
[D-] = Ka[DH! (3)
[H+] and DOH (solution) is equal to the solubility of
the undissociated base in moles/liter.
The total amount of drug in solution is the The dissociation of the weak base can be writ¬
sum of the ionized form [D-] and the un-ionized ten as:
form [DH]. The equation for total solubility, Sx,
therefore can be written as: DOH (solution) <=^ D+ + OH'
[D+][OH-j
ST = [DH] + [D“] Kb = (8)
DOH (solution) '
= [DHT+KaJpj- (4) Kb[DOH (solution)]
D+ (9)
OH-
since DH has previously been defined as equal
to Ks: The total solubility of the base, ST, is the sum
of the ionized form [D+] and the un-ionized form
[DOH]:
ST = Ks + Ks-jjprj- = Ks(l + (5)
ST = [DOH] + [D+]
This equation is a most useful one for deter¬
_ m0TTl
— [DOH] +, KbtD0H]
QH_ 00)
mining the total solubility of a weak acid at a
specific hydrogen ion concentration. Since the
question most frequently asked is “What must KbKs
the pH of the formulation be to maintain X
Sx — Ks +
OH-
(ID

458 • The Theory and Practice of Industrial Pharmacy

Since: 1.0

Kw = [H+][0H-]
Kw
[0H-]
H"

then:

KbKs KsKb
Sy Ks + Ks + [H+] (12)
Kw Kw
H+

Rewriting to solve for [H+]:

ST Ks KsKb
(13)
[H+] [H+] Kw

or:

[H+1 = IfeKb (St " Ks) <14>

In practice, these equations hold reasonably

FIG. 15-1. Effect of alcohol concentration on the solubil¬
well; however, there are limitations that the ity (Ks) of un-kmized sulfatkiazole. (From Higucki, T.,
reader should be aware of: Gupta, M., and Busse, L.W.: J. Am. Pharm. Assoc., Sci. Ed.,
42:157, 1953.)
1. The values for the solubility constant Ks
and the dissociation constants Ka or Kb that are
reported in the literature (or determined in
preformulation studies) are usually for the drug
in distilled water. These values may be consider¬
ably different in a pharmaceutical dosage form
such as an elixir, which contains a high percent¬
age of solids and cosolvents. In general, cosol¬
vents such as alcohol or glycerin have the effect
of increasing Ks and decreasing the dissociation
constant, as shown in Figures 15-1 and 15-2.2
2. The equations assume little or no interac¬
tions between the solute and itself or between
the solute and other formulation components. At
low concentrations of solute (below several per¬
cent), this assumption is generally valid.

In selecting the pH environment for adequate

solubility, several other factors should be consid¬
ered. The pH that satisfies the solubility require¬
ment must rot conflict with other product re¬
quirements, such as stability and physiologic
compatibility. In addition, if pH is critical to
maintaining drug solubility, the system must be
adequately buffered. The selection of a buffer
must be consistent with the following criteria:
FIG. 15-2 .Effect of alcohol concentration on the dissocia¬
tion constant (Ka) of sulfatkiazole. (From Higuchi, T,
1. The buffer must have adequate capacity in Gupta, M., and Busse, L.W.: ]. Am. Pharm. Assoc., Sci. Ed.,
the desired pH range. 42:157, 1953.)

LIQUIDS - 459
2. The buffer must be biologically safe for the as cosolvency, and the solvents used in combina¬
intended use. tion to increase the solubility of the solute are
known as cosolvents. The mechanism responsi¬
3. The buffer should have little or no deleterious
ble for solubility enhancement through cosol-
effect on the stability of the final product.
vency is not clearly understood. It has been pro¬
4. The buffer should permit acceptable flavor¬ posed that a cosolvent system works by reducing
ing and coloring of the product. the interfacial tension between the predomi¬
nately aqueous solutions and the hydrophobic
The first three points have been discussed by solute.6 Recent work supports the theory that
Windheuser3; the last needs no further elabora¬ amides adsorb to the solute at the interface with
tion. Figure 15-3 is a graphic representation of a water, thereby diminishing the hydrophobic sur¬
number of pharmaceutically useful buffer sys¬ face or solute/water interfacial tension.7 As a
tems and their effective buffer ranges. In gen¬ result, the soluble hydrophilic portion of the
eral, a buffer system has adequate capacity amide cosolvent remains oriented toward the
within one pH unit of its pK. As an example of aqueous phase. Some workers have looked upon
research in this area, Wang and Paruta have re¬ the phenomenon as a result of the independent
cently studied the effect of aqueous buffer sys¬ solubility of the solute in each cosolvent. This is
tems and temperature on the solubility of com¬ obviously a gross oversimplification, since the
monly used barbiturates.4,5 Basic information of solubility of a substance in a blend of solvents is
this type is valuable to the formulator of liquid usually not equal to the value predicted on the
products. basis of its solubility in the pure solvents. For
For many drugs, a pH adjustment does not example, undissociated phenobarbital has a sol¬
provide an appropriate means for effecting solu¬ ubility of approximately 1.2 g/L in water and
tion. In the case of very weak acids or bases, the 13 g/L in ethyl alcohol. The ratio of solvents, as
required pH may be unacceptable in terms of well as pH, can alter solubility (Fig. 15-4).
physiologic considerations or owing to the effect Ethanol, sorbitol, glycerin, propylene glycol,
of pH extremes on the stability of formulation
adjuvants (such as sugars and flavors) or of the
drug itself. The solubility of nonelectrolytes will,
for all practical purposes, be unaffected by hy¬
drogen ion concentration. In these cases, if solu¬
tion is to be achieved, it must be done by the use
of cosolvents, solubilization, complex phenom¬
ena, or in special circumstances, chemical modi¬
fication of the drug to a more soluble derivative.
Cosolvency. Weak electrolytes and nonpolar
molecules frequently have poor water solubility.
Their solubility usually can be increased by the
addition of a water-miscible solvent in which the
drug has good solubility. This process is known

EFFECTIVE WftNGES OF PHARMACEUTICAL BUFFERS j

-I- NH4CI I
OlETHANOLAMINE-I-
--4-‘TRIETHANOLAMINE
-1-BORIC
-1-CARBONIC -H—
■-1- PHOSPHORIC -1— PHOSPHORIC -
-1-1- GLUTAMIC -1-
-1-1-SUCCINIC
-1-1-MALIC
-1-1-TARTARIC
-1-1-GLUTARIC
-1-1-1—— ACONITIC
-1-1-1-CITRIC
-1——ACETIC
-1-BENZOIC
-1-LACTIC
-1-GLYCERIC
-1-GLUCONIC
_I_1_J_I_I_I_I_I_I_1_1_1_
0 t 2 3 4 5 G Z 9 9 fO II 12
pH
FIG. 15-4. Interdependence of pH and alcohol concentra¬
FIG. 15-3. Commonly used pharmaceutical buffers and tion on the solubility of phenobarbital. (From Lin, K.S.,
their effective buffer ranges. (From Windheuser, ].: Bull. Anschel, J., and Swartz, C.J.: Bull. Parenteral Drug Assoc.,
Parenteral Drug Assoc., 17:1, 1963.) 25:44, 1971.)

460 • The Theory and Practice of Industrial Pharmacy

and several members of the polyethylene glycol to the solubility parameter approach is the ther¬
polymer series represent the limited number of modynamic values that must be known to solve
cosolvents that are both useful and generally the Hildebrand-Scott equation for solubility:
acceptable in the formulation of aqueous liquids.
Spiegel and Noseworthy, in their review of non- . v _ AHmF /' Tm - T
aqueous solvents used in parenteral products, l0gX2 4575 V TmT
cited a number of solvents that might also be
useful in oral liquids.® These include glycerol ACp / Tm - T \
dimethylketal, glycerol formal, glycofurol, + 4575V T /
dimethylacetamide, N-(/3-hydroxy ethyl j-lac ta¬ _ J(Cp_logTm
rn ide, ethyl lactate, ethyl carbonate, and 1,3-
1.987 K T
butylene glycol. It should be emphasized, how¬
ever, that with the possible exception of dimeth¬
ylacetamide, all of these solvents are unproven -4^f<5l-S^2 (15)
with respect to their acceptability for systemic
use. Dimethylacetamide has been used as a where:
cosolvent in parenteral products, but its use in
oral liquids is seriously limited, owing to the dif¬ X2 mole fraction solubility at temper¬
ficulty of masking its objectionable odor and ature T
taste. Thus, the spectrum of solvents from AHmF heat of fusion of the solute at its melt¬
which one may make a selection is extremely ing point Tm
narrow. Nevertheless, the frequency of their use ACp Cp1 - Cps where Cp1 and Cps are the
is high, as can readily be seen by reviewing the molal heat capacities of the liquid and
formulas for a variety of official and proprietary solid forms
oral liquids.
V2 molar volume of the solute
Cosolvents are employed not only to effect sol¬
Si solubility
ubility of the drug, but also to improve the solu¬ / AEV\1/Z
parameter
bility of volatile constituents used to impart a or
of the solvent V V /
desirable flavor and odor to the product.
Much of the early data on the solubility of So solubility AH - RT\1/2
pharmaceutical solutes in mixed solvents have parameter
been reported as a function of solvent composi¬ of the solute
tion; no attempt has been made to explain the 4>i volume fraction of the solvent
data. In recent years, much more emphasis has
been placed on cultivating a basic understand¬ Assuming that the solubility parameter values
ing of this phenomenon, with the objective of were known for all pharmaceutically useful sol¬
developing a mathematical approach to inter¬ vents, the thermodynamic data for each solute of
preting and predicting solubility behavior. Hil¬ interest would still have to be determined.
debrand and Scott have developed an equation Martin and co-workers attempted to use this
that yields a thermodynamic measure of the theory in their study concerning the solubility of
cohesive forces that exist within a homogeneous benzoic acid in mixed solvent systems.11,12 The
substance.9,10 This number is often referred to solubility of benzoic acid was found to be in gen¬
as Hildebrand’s solubility parameter. eral agreement with the values predicted by the
There are several serious limitations to the Hildebrand equation, particularly when the sol¬
practical application of the solubility parameter ubility parameter of the mixed solvent was ap¬
concept to pharmaceutical systems. Tbs ap¬ proximately equal to the solubility parameter of
proach is restricted to what Hildebrand terms benzoic acid. The same general conclusions
“regular solutions.” A regular solution has been were reached when the solubility of a series of
defined as one in which there are no interac¬ p-hydroxybenzoic acid esters were studied, and
tions between the various solvents present and the experimental data were compared with the
between the solute and the solvents. All mole¬ value predicted by the solubility parameter ap¬
cules are randomly distributed and oriented in proach. Other authors have extended solubility
the system. In thermodynamic language, this studies with benzoic acid to other binary and ter¬
may be stated as “a solution involving no en¬ nary solvent systems.13
tropy change when a small amount of one of its Dielectric Constant. A more practical, al¬
components is transferred to it from an ideal so¬ though admittedly less rigorous, approach to the
lution of the same composition, the total volume solubility problem may be found in what has
remaining unchanged.’’10 An additional liability come to be known as the “dielectric require-

LIQUIDS * 461
ment” for solubility.14-18 According to this the¬ tions, they tend to orient at the air-liquid
ory, every solute shows a maximum solubility, in interface. As additional surfactant is added, the
any given solvent system, at one or more specific interface becomes fully occupied, and the excess
dielectric constants.* molecules are forced into the bulk of the liquid.
The absolute solubility of a solute may vary At still higher concentrations, the molecules of
considerably in two different solvents of the surfactant in the bulk of the liquid begin to form
same dielectric constant, but the solubility pro¬ oriented aggregates or micelles; this change in
file, as a function of dielectric constant, appears orientation occurs rather abruptly, and the con¬
to be similar for a solute in a wide variety of sol¬ centration of surfactant at which it occurs is
vent systems. known as the critical micelle concentration
Solubility profiles as a function of dielectric (CMC). Solubilization is thought to occur by vir¬
constants have been reported for numerous tue of the solute dissolving in or being adsorbed
pharmaceuticals in a variety of liquid solvent onto the micelle. Thus, the ability of surfactant
systems. Examples of substances studied in¬ solutions to dissolve or solubilize water-insolu¬
clude barbiturates, parabens, xanthine deriva¬ ble materials starts at the critical micelle con¬
tives, antipyrine, and aminopyrine.19-26 centration and increases with the concentration
The dielectric constants of most pharmaceuti¬ of the micelles.
cal solvents are known;27,28 values for a number Solubilizing agents have been used in phar¬
of binary and tertiary blends have been re¬ maceutical systems for many years. As early as
ported,18 and if not reported, can be readily esti¬ 1868, it was reported that cholesterol was mark¬
mated. Molal boiling point and dielectric con¬ edly more soluble in aqueous soap solutions
stant equations may be used to estimate than in pure water.
solubility of pure solvents and miscible solvent In recent years, the application of solubiliza¬
blends.29 The use of each varies, depending tion phenomena to pharmaceutical systems has
upon the literature values and/or laboratory greatly increased. Table 15-1 shows the type of
equipment available. To determine the dielectric solubilizing agents most frequently used in
requirement of the substance of interest, pharmaceutical systems and the types of drugs
dioxane-water blends having known dielectric for which these agents have been effective. The
constants are used, and the dielectric con¬ acceptability of these surfactants for oral use
stants) at which maximum solubility is attained should be determined on an individual basis.
is noted. Pharmaceutical formulations of compa¬ It is readily apparent from this tabulation that
rable dielectric constant(s) can then be pre¬ a wide variety of substances can be solubilized.
pared, and the most appropriate system can be McBain has stated, “Any material can be solubi¬
selected on the basis of the solubility require¬ lized in any solvent by proper choice of solubiliz¬
ments, stability, and organoleptic characteris¬ ing agent.”38 This may well be true, but the
tics. questions that must be asked and answered are:
Solubilization. Solubilization has been de¬ To what extent can the substance be solubi¬
fined by McBain as the spontaneous passage of lized? How is the proper solubilizing agent se¬
poorly water-soluble solute molecules into an lected? What effect will the solubilizing agent
aqueous solution of a soap or a detergent, in have on the stability, efficacy, and physical char¬
which a thermodynamically stable solution is acteristics of the product?
formed.30 The mechanism for this phenomenon It has generally been observed that lyophilic
has been studied quite extensively and involves surface active agents with hydrophilic-lipophilic
the property of surface-active agents to form col¬ balance (HLB) values higher than 15 are the
loidal aggregates known as micelles. When sur¬ best solubilizing agents. Final selection of solu¬
factants are added to a liquid at low concentra- bilizing agents should be based on phase solubil¬
ity studies in a manner similar to that employed
by Guttman et al. in their studies concerning the
*The dielectric constant is the property of a solvent relat¬
solubilization of prednisolone, methyl predni¬
ing to the amount of energy required to separate two op¬
positely charged bodies in the solvent as compared with solone, and fluorometholone with Triton WR-
the energy required to separate the same two oppositely 1339.39 They determined the equilibrium solu¬
charged bodies in a vacuum. By definition, the dielectric bility of the steroids at 25°C as a function of
constant of a vacuum is unity. The dielectric constant of surfactant concentration. Figure 15-5 is a plot
water at 25°C is 78.5; thus, it takes 78.5 times more en¬ showing the apparent solubility of steroid as a
ergy to separate two oppositely charged bodies in a vac¬
uum than in water. This property is closely related to the
function of Triton WR-1339. A similar plot could
polarity of solvents, and it is therefore not surprising that be constructed in which the solubility of a spe¬
a solute shows a preference for solvent systems having a cific substance is determined as a function of
specific dielectric constant. surfactant concentration, and several surfac-

462 • The Theory and Practice of Industrial Pharmacy

Table 15-1. Solubilizing Agents Used in Pharmaceutical Systems

Solubilizer Solubilizate Reference

Polyoxyethylene Acetomenaph tone 31

sorbitan
Fatty acid esters 21 - Acetoxypregnenolone 31
(Tween® series)
Barbital 32
Caffeine 32
Benzocaine 32
Chloramphenicol 31
Chloroform 31
Chlorotrianisene 31
Cortisone acetate 31
Cyclocoumarol 31
Desoxycorticosterone acetate 31
Dicoumarol 31
Dienestrol 31
Diethylstilbestrol 31
Digi toxin 31
Volatile oils 33
Essential oils 31
Estrone 31
Ethylbiscoumacetate 31
Hexestrol 31
Menthol 32
Methyltestosterone 31
Phenobarbital 32
Progesterone 31
Reserpine 34,35
Salicyclic acid 32
Testosterone 31
Vitamin A (alcohol and esters) 31
Vitamin D 31
Vitamin E (alcohol and esters) 31
Vitamin K 31

Polyoxyethylene Essential oils 36

monoalkyl ethers
(BRU® and MYRJ® Volatile oils 36
series)
Benzocaine 31
Benzoic acid derivatives 31
Chloroxylenol 31
Iodine 31

Sucrose monoesters Vitamin A (alcohol and esters) 31

Vitamin D 31
Vitamin E (alcohol and esters) 31

Lanolin esters Essential oils 37

and ethers
Volatile oils 37
Hexachlorophene 37
Vitamin A palmitate 37

®Registered trademarks of I.C.I. United States, Inc.

liquids - 463
 complex, can be readily observed and quanti¬
tated by one or more of numerous published
techniques.1 One of the more widely used meth¬
ods, and one that is highly germane to this dis¬
cussion, is the solubility analysis technique.
Every substance has a specific, reproducible
equilibrium solubility in a given solvent at a
given temperature. Any deviation from this in¬
herent solubility must be due to the formation of
a new species in solution.* In the case of weakly
acidic and basic compounds, the total solubility
is equal to the inherent solubility of the undisso¬
ciated compound plus the concentration of the
dissociated species. Similarly, when complex
formation occurs, the total solubility is equal to
the inherent solubility of the uncomplexed drug
plus the concentration of drug complex in solu¬
tion. Consider the interaction between a drug,
D, and a complexing agent, C:

xD + yC *=± DxCy (16)

where x and y denote the stoichiometry of the

FIG. 15-5. The effect of varying concentrations of Triton interaction. For simplicity, only the case in
WR-1339 in water on the solubility of some anti-inflam¬ which one species of complex is formed is con¬
matory steroids. (From Guttmah, D.E., Hamlin, W.E., sidered here; it is possible for several species of
Shell, J.W., and Wagner, J.G.: J. Pharm. Sci., 50:305, 1961.
complexes to coexist.
The total solubility of drug in this case is:
tants of interest are included in the study. The
appropriate surfactant can then be selected on ST = [D] + X[DxCy] (17)
the basis of its efficiency as a solubilizer and its
effect on other product characteristics. where:
The major producers of surface active agents
have carried out extensive studies on the physi¬ [D] = the solubility of uncomplexed drug
ologic effects of products that they recommend = Ks
for pharmaceutical use. Although the agents
X[DxCy] = concentration of drug in complexed
are, in themselves, generally free of toxicity,
form
their use must be tempered with a full under¬
standing of the secondary effects that they may
By use of the solubility analysis technique, the
produce. While nontoxic surfactants have been
stoichiometry of this interaction, as well as its
shown to improve the stability of vitamin A,40,41
equilibrium constant, can be determined. This
other surfactants have been shown to have a del¬
is carried out by placing excessive quantities of
eterious effect on formulation components such
the drug, together with solutions containing var¬
as dyes.42 Addition of surface active agents to
ious concentrations of complexing agent, in
drug systems has in some instances enhanced
gastrointestinal absorption and pharmacologic
activity, and in other cases inhibited the same.
'Apparent solubility can be influenced by the size and
Of comparable importance is the effect that sur¬ shape of solute particles when the particles are in the
factants can have on formulation adjuvants. The micron size range. The observed solubility increased with
activity of several preservatives, for example, decreasing particle size in accordance with the equation:
has been found to be significandy decreased in
the presence of a number of surface active ! A = _2
agents. So 2.303RTr
Complexation. Organic compounds in solu¬
where S is the observed solubility. So the inherent equi¬
tion generally tend to associate with each other
librium solubility, y the surface tension of the particles, v
to some extent. Frequently, this association is the molar volume, R is the gas constant (8.314 x 107
too weak to be detected by standard techniques. ergs/deg mole), T is the temperature absolute, and r is the
In other cases, the intermolecular association, or radius of the particles.

464 • The Theory and Practice of Industrial Pharmacy

well-closed containers. The containers are agi¬ of drug added to the system (DT) less the
tated at a constant temperature until equilib¬ amount of drug in solution at point A(R). The
rium is achieved. Aliquot samples of the super¬ amount of complexing agent entering into the
natant liquid are then removed and assayed for reaction over the plateau region can be read di¬
total concentration of drug. A typical solubility rectly from the abscissa and is equal to b - a.
analysis profile is shown in Figure 15-6. Therefore, the stoichiometry is given by:
The increase in solubility of drug from points
S to A is due to complex formation. At point A, Dt — R
the solution is saturated with respect to both the b - a
drug and the complex. The composition of the
solution does nqt vary from point A to B because _moles of drug in complex_
as drug in solution interacts with complexing moles of complexing agent in complex
agent, it is replaced from the excess present in (18)
the system and the additional complex-formed
precipitates, since the solution is already satu¬ If the ratio of drug to complexing agent is
rated with respect to this component. At point B, found to be 1, then the complexing reaction may
all of the excess drug has been consumed, and be written as:
the further addition of complexing agent results
in a depletion of the uncomplexed drug in solu¬ D + C: DC
tion. If no higher complexes were formed, the
curve would approach a value equal to the solu¬ and the stability constant is:
bility of the complex (R - S). The increase in
this case indicates the formation of one or more K [DC] (19)
secondary complexes. [D][C]
The stoichiometry of the interaction can be
determined as follows. where:
The excess drug remaining in the system at
point A is entirely converted to complex at point [DC] = total drug in solution at point A less the
B. The amount of drug entering into the com¬ solubility of the uncomplexed drug (S)
plex over this range is equal to the total amount
[D] = solubility of the uncomplexed drug (S)
[C] = the concentration of complexing agent
added to the system at point A (a) less
the amount of complexing agent in the
drug complex [DC]

The extent to which the solubility of the drug

can be increased in the foregoing example is
limited by the solubility of the complex (Fig. 15-
6). In other cases, the limitation may be imposed
by the solubility of the complexing agent. To the
pharmaceutical investigator, however, the major
concerns are how much drug can be put into
solution by a specific complexing agent and how
the resultant complex affects the safety, stabil¬
ity, and therapeutic efficacy of the product.
The formulator must also be aware of poten¬
tial detrimental interaction between ingredients.
An example of such interaction is the complexa-
tion of nonionic surfactants, such as polysorbate
80, with parabens resulting in the inactivation of
the preservatives. Certain polyols have been
shown to inhibit this complexation. thus main¬
taining paraben antimicrobial activity. Unfortu¬
MOLAR CONCENTRATION OF COMPLEXING AGENT(C) nately, a commonly used polyol, sorbitol, does
FIG. 15-6. Phase diagram showing the effect of varying not inhibit these complexation reactions, proba¬
concentrations of complexing agent on the apparent solu¬ bly because it is too polar to partition into the
bility of drug. surfactant micelle (Fig. 15-7). 0

LIQUIDS- 465
 tive necessary to produce modest increases in
solubility.
The practical application of complexation and
hydrotrophy is quite limited with respect to solu¬
bility enhancement in pharmaceutical liquids.
Many agents have been studied that associate
with a variety of drug substances. The degree of
association, however, and the extent to which
the solubility can be increased are generally not
adequate for practical use in formulation re¬
search. These deficiencies are further compli¬
cated by the fact that many of the known com-
plexing agents are either physiologically active
substances (i.e., the xanthines) or are of un¬
known biologic character.
Wolfson and Banker have reported significant
increases of barbiturate solubilities as a result of
complexation with poly-N-vinyl-5-methyl-2-
oxazolidone.45 Polyvinylpyrrolidone participates
in complex formation with a variety of organic
and inorganic pharmaceuticals, the most dra¬
matic of which is the well known PVP-iodine
FIG. 15-7. Influence of sorbitol on the binding of methyl-
paraben to 10% (w/v) polysorbate 80 to 30°. Key: O, meth-
complex. The principle of hydrotrophy has been
ylparaben alone; and •, methylparaben plus sorbitol effectively applied in the solubilization of adre-
(1:1). (From Blanchard, ]., Fink, W.T., and Duffy, J.P.: nochrome monosemicarbazone with sodium sa¬
}. Pkarm. Scz., 66:981, 1977. Reproduced with permission licylate (Adrenosem ampuls and oral liquid,
of the copyright owner, the American Pharmaceutical As¬ Massengill).
sociation.) Chemical Modification of the Drug.
Many poorly soluble drugs can be chemically
modified to water-soluble derivatives. This ap¬
Hydrotrophy. The term hydrotrophy has proach has been highly successful in the case of
been used to designate the increase in solubility corticosteroids. The solubility of betamethasone
in water of various substances due to the pres¬ alcohol in water, for example, is 5.8 mg/100 ml
ence of large amounts of additives.43,44 The at 25°C. The solubility of its 21 disodium phos¬
mechanism by which this effect occurs is not phate ester is greater than 10 g/100 ml, an in¬
clear. Some workers have speculated that crease in solubility greater than 1500-fold. In
hydrotrophy is simply another type of solubiliza¬ general, however, this approach has severe prac¬
tion, with the solute dissolved in oriented clus¬ tical limitations. New derivatives must be sub¬
ters of the hydrotrophic agent. Hydrotrophic so¬ jected to essentially the same testing protocol as
lutions do not show colloidal properties, the parent compound, including biologic activity
however. Others feel that this phenomenon is studies, acute and chronic toxicity, pharmaceu¬
more closely related to complexadon involving a tical evaluation, and clinical testing. An under¬
weak interaction between the hydrotrophic taking of this magnitude can be justified only if
agent and the solute. Still others reason that the no other reasonable approach is available.
phenomenon must be due to a change in solvent
character because of the large amount of addi¬
tive needed to bring about the increase in solu¬
bility. Preservation
The influence on large concentrations of so¬ In recent years, adequate preservation of liq¬
dium benzoate on the solubility of caffeine is a uid products has increased in importance. Re¬
classic example of this phenomenon applied to a ports of clinical complications arising from mi¬
pharmaceutical system. Other examples include crobial contamination of oral and topical
the solubilization of benzoic acid with sodium products have originated in several European
benzoate, and of theophylline with sodium ace¬ countries and the United States. Numerous
tate and sodium glycinate. Except for these ex¬ product recalls and tightened regulatory and
amples, little use has been made of hydrotrophy compendia limits have re-emphasized the need
in pharmaceutical systems, probably due to the for the formulator to carefully and thoroughly
large amount (in the range of 20 to 50%) of addi¬ consider all aspects of the preservative system

466 • The Theory and Practice of Industrial Pharmacy

chosen for a particular formula.46,47 In addition Table 15-2. Some Pharmaceutically Useful Pre¬
to presenting a health hazard to the user, micro¬ servatives
bial growth can cause marked effects on product
stability. Usual
Numerous sources of contamination exist. Concentration
Class (%)
Including among these are raw materials, pro¬
cessing containers and equipment, the manu¬
Acidic
facturing environment, operators, packaging Phenol 0.2-0.5
materials, and the user. Chlorocresol 0.05-0.1
Manufacturing techniques to minimize mi¬ O-phenyl phenol 0.005-0.01
crobial contamination are presented under the Alkyl esters of parahydroxybenzoic acid 0.001-0.2
heading “Manufacturing Considerations.” The Benzoic acid and its salts 0.1-0.3
remainder of this section deals with preservative Boric acid and its salts 0.5-1.0
systems for liquid products. Sorbic acid and its salts 0.05-0.2
An ideal preservative can be qualitatively de¬
fined as one that meets the following three crite¬ Neutral
ria: Chlorbutanol 0.5
Benzyl alcohol 1.0
1. It must be effective against a broad spectrum /3-phenylethyl alcohol 0.2-1.0
of microorganisms.
Mercurial
2. It must be physically, chemically, and micro- Thimerosal 0.001-0.1
biologically stable for the lifetime of the prod¬ Phenylmercuric acetate and nitrate 0.002-0.005
uct. Nitromersol 0.001-0.1

3. It must be nontoxic, nonsensitizing, ade¬

Quaternary Ammonium Compounds
quately soluble, compatible with other formu¬
Benzalkonium chloride 0.004-0.02
lation components, and acceptable with re¬ 0.01-0.02
Cetylpyridinium chloride
spect to taste and odor at the concentrations
used.

No single preservative exists that satisfies all achieve the desired antimicrobial effect. Methyl
of these requirements for all formulations. The and propyl parahydroxybenzoic acid, for exam¬
selection of a preservative system must be made ple, are often used together in a ratio of 10 to 1,
on an individual basis, using published informa¬ respectively. The use of more than one ester
tion and “in house” microbiologic studies for makes possible a higher total preservative con¬
guidance. Frequently, a combination of two or centration, owing to the independent solubilities
more preservatives are needed to achieve the of each, and according to some researchers,
desired antimicrobial effect. serves to potentiate the antimicrobial effect. The
The antimicrobial agents that have been used solubilities of a series of parabens have been
as preservatives can be classified into four major studied at four temperatures. The solubilities
groupings: acidic, neutral, mercurial, and qua¬ were expressed in terms of ideal, actual, and
ternary ammonium compounds. Table 15-2 lists excess free energies.48
some representative members of these group¬ The remaining three classes of preservatives
ings and the concentration ranges at which they have been widely used in ophthalmic, nasal, and
have been used. parenteral products, but have been little used in
The phenols are probably the oldest and best oral liquids. The neutral preservatives are all
known pharmaceutical preservatives, but are lit¬ volatile alcohols, and their volatility introduces
tle used in oral pharmaceuticals, owing to their odor problems as well as concern for preserva¬
characteristic odor and instability when exposed tive loss on aging. The mercurials and quater¬
to oxygen. The more useful members of the se¬ nary ammonium compounds are excellent pre¬
ries, for this application, are the parahydroxy- servatives. They are, however, subject to a
benzoic acid esters, and the salts of benzoic and variety of incompatibilities, with mercurials
sorbic acid. They are adequately soluble in aque¬ being readily reduced to free mercury and the
ous systems and have been demonstrated to pos¬ quaternary compounds being inactivated by a
sess both antifungal and antibacterial proper¬ variety of anionic substances. The incompatibili¬
ties. ties common to these and other preservatives
Frequently, a combination of two or more es¬ are discussed by Lachman.49
ters of parahydroxybenzoic acid are used to Syrups containing approximately 85% sugar

LIQUIDS - 467
resist bacterial growth by virtue of their exos- Chemical analysis for the antimicrobial con¬
motic effect on microorganisms. Syrups that stituent frequently provides a helpful guide but
contain less than 85% sucrose, but a sufficient can be misleading. Molecular interactions in¬
concentration of polyol (such as sorbitol, glyc¬ volving preservatives and commonly used phar¬
erin, propylene glycol, or polyethylene glycol) to maceutical adjuvants, such as surfactants and
have an exosmotic effect on microorganisms, cellulose derivatives, have been observed. For
similarly resist bacterial growth. It is possible, example, it has been shown that Tween 80 inter¬
however, for surface dilution to take place in a acts to a significant extent with the methyl and
closed container as a result of solvent evapora¬ propyl esters of parahydroxybenzoic acid, and
tion followed by condensation, with the conden¬ that the preservative-surfactant complex is es¬
sate flowing back onto the liquid surface. The sentially devoid of antibacterial activity.49
resulting diluted surface layer makes an excel¬ Chemical analysis for the parahydroxybenzoate
lent medium for bacterial and fungal growth. esters would not differentiate between the un¬
These products, therefore, should be designed bound substance (microbiologically active) and
so that even after dilution, they do not support the bound substance (microbiologically inac¬
microbial growth. This can be done either by tive).
incorporating a sufficient concentration of pre¬
servative, so that a diluted sample of the product
resists microorganism growth, or by including
approximately 5 to 10% ethanol in the formula¬ Subjective Product
tion. The vapor pressure of ethanol is greater
Characteristics
than that of water and normally vaporizes to the
surface of the liquid and the cap area, prevent¬ Many product qualities, such as taste and ap¬
ing, or at least minimizing, the potential for pearance, cannot be quantitatively measured.
microorganism growth as a result of surface di¬ These characteristics are often referred to under
lution. the heading of “pharmaceutical elegance.” The
An effectively designed preservative system word elegance has, however, a superficial con¬
must retain its antimicrobial activity for the notation, which is not justified. The value of a
shelf-life of the product. To ensure compliance pharmaceutical product is measured by both its
with this precept, the preservative characteris¬ medical significance and its commercial suc¬
tics of the product in its final form (including cess. A satisfactory performance on either of
formulation and package) must be studied as a these ratings can only be achieved with a prod¬
function of age. The best method of demonstrat¬ uct that is convenient to use and receives pa¬
ing preservative characteristics is by microbio¬ tient acceptance.
logic evaluation.
To determine whether a specific organism is
hazardous, one must consider the nature of the
product and its dose, the state of health of the Sweetening Agents
user, and clinical reports on the frequency and Sweetening agents generally constitute a
severity of infections caused by the microorgan¬ major portion of the solids content in those dos¬
ism. age forms requiring them. Sucrose has had a
The FDA distinguishes between organisms long history of use. It is soluble in aqueous
that are “always objectionable” and “usually ob¬ media (solutions containing approximately 85%
jectionable.” The former designation is based on sucrose can be prepared); it is available in highly
only two factors—pathogenicity of the organism purified form at reasonable cost, and it is chemi¬
and site of use. The latter designation is based cally and physically stable in the pH range of 4.0
on an additional determinant, the state of health to 8.0. It is frequently used in conjunction with
of the user. The official compendia are continu¬ sorbitol, glycerin, and other polyols, which are
ally reevaluating their standards based on the said to reduce the tendency of sucrose to crystal¬
latest FDA data and guidelines. lize. One of the manifestations of sucrose crys¬
Specific organisms generally recognized as tallization is cap-locking, which occurs when the
undesirable in oral liquids include Salmonella product crystallizes on the threads of the bottle
species, Escherichia coli, Enterobacter species, cap and interferes with cap removal. This phe¬
Pseudomonas species (commonly P. aerugin¬ nomenon has been studied, and several vehicles
osa), proteolytic species of Clostridium, and containing sucrose, glucose, sorbitol, and glyc¬
Candida albicans. Some liquid pharmaceuticals erin have been reported as acceptable in terms
(i.e., ophthalmic solutions) must be processed of product characteristics and resistance to cap¬
aseptically and rendered sterile. locking.50

468 • The Theory and Practice of Industrial Pharmacy

 Liquid glucose is an extremely viscid sub¬
stance that imparts both body and sweetness to
liquid formulations. It is prepared by the partial
hydrolysis of starch with strong acid, and con¬
tains, as its main component, dextrose with
smaller amounts of dextrins and maltose. In a
manner similar to that of honey and molasses,
but to a lesser degree, this agent imparts a char¬
acteristic odor and flavor to the formulations in
which it is used. Although liquid glucose is not a
pure chemical entity, its method of manufacture
can be well controlled, and batch-to-batch varia¬
bility is usually not a significant problem. The
same is not true for such materials as honey and
molasses. The quality of these substances var¬
ies, depending on the source from which they
are obtained, and if the source is held constant,
depending on the time of year they are produced
and on other natural factors over which there is TEMPERATURE °C

little or no control. The use of these and other

FIG. 15-8. Effect of pH and temperature on aspartame
naturally occurring materials should be predi¬
solubility in water. (Reprinted with permission from
cated on a rigorous quality control regimen, Beck, C.I.: Application potential for aspartame in low calo¬
which gives maximum assurance of product rie and dietetic foods. In Low Calorie and Special Dietary
uniformity. Foods. Edited by B.K. Dwivedi. CRC Press, 1978, p. 68.
Saccharin is used to supplement sugars and Copyright CRC Press, Inc., Boca Raton, FL.)
polyols as sweeteners. It is approximately 250 to
500 times as sweet as sugar, but it can have a
bitter aftertaste if not properly used in the for¬
mula.
Numerous countries have approved a new
synthetic sweetener, aspartame, for use as a
food and/or drug ingredient. Aspartame is the
methyl ester of aspartic acid and phenylalanine.

o ch2—ch—nh—c—ch—nh2

COOCH3
Aspartame
II
CH2—COOH

It is approximately 200 times sweeter than su¬

crose and has none of the aftertaste of saccharin.
Aspartame’s aqueous solubility is quite adequate
for formulation purposes (Fig. 15-8.) Although it
is very stable as a dry powder, its stability in
aqueous solutions is quite pH- and temperature-
dependent. Aspartame’s greatest stability is be¬
tween pH 3.4 and 5.0 and at refrigerated tem¬
peratures (see Fig. 15-9 and Table 15-3).51
Sweetness enhancement by aspartame is syn¬
ergistic with saccharin, sucrose, glucose, and
cyclamate. In addition, its taste properties have FIG. 15-9. Effect of pH and time on aspartame stability
been improved using sodium barcarbonate, glu¬ in aqueous buffer systems at 40°C. (Reprinted with per¬
mission from Beck, C.I.: Application potential for
conate salts, and lactose.31 For further informa¬
aspartame in low calorie and dietetic foods. In Low Calorie
tion, the pharmaceutical formulator should con¬ and Special Dietary Foods. Edited by B.K. Dwivedi. CRC
sult the excellent review on the food uses of Press, 1978, p. 68. Copyright CRC Press, Inc., Boca
aspartame by Beck.51 Raton, FL.)

liquids - 469
Table 15-3. Effect of Storage Temperature on Flavors
Aspartame Stability in Aqueous Solutions at pH
Flavoring can be divided into two major cate¬
4.0
gories: selection and evaluation. Much has been
Calculated time for written on both phases of pharmaceutical flavor¬
Temperature 20% decomposition ing, but selection remains a totally empiric activ¬
storage (°C) (days) ity.
The four basic taste sensations are salty, bit¬
10 387 ter, sweet, and sour. Some generalizations con¬
20 134 cerning the selection of flavors to mask specific
30 51 types of taste have been suggested by
40 22
Janovsky,52 and by Wesley.53 (See Table 15-4.)
55 5
A combination of flavoring agents is usually
68 2
required to mask these taste sensations effec¬
80 1
0.15
tively. Menthol, chloroform, and various salts
90
frequently are used as flavor adjuncts. Menthol
Reprinted with permission from Beck, C.I.: Application po¬ and chloroform are sometimes referred to as de¬
tential for aspartame in low calorie and dietetic foods. In Low sensitizing agents. They impart a flavor and odor
Calorie and Special Dietary Foods: Edited by B.K. Dwivedi. CRC
of their own to the product and have a mild an¬
Press, 1978. Copyright CRC Press, Inc., Boca Raton, FL.
esthetic effect on the sensory receptor organs
associated with taste. Monosodium glutamate
has been widely used in the food industry, and
to a lesser extent, in pharmaceuticals, for its re¬
Viscosity Control ported ability to enhance natural flavors. A care¬
fully selected panel reported this substance to be
It is sometimes desirable to increase the vis¬
effective in reducing the metallic taste of iron-
cosity of a liquid, either to serve as an adjunct
containing liquids, as well as the bitterness and
for palatability or to improve pourability. This
aftertaste of a variety of other pharmaceutical
can be achieved by increasing the sugar concen¬
preparations.54 It cannot be used in pediatric
tration or by incorporating viscosity-controlling
products, however.
agents such as polyvinylpyrrolidone or various
Chemburkar and Joslin have reported that the
cellulosic derivatives (e.g., methylcellulose or
partitioning of parabens into flavoring oils from
sodium caxboxymethylcellulose). These com¬
aqueous systems depends on the concentration
pounds form solutions in water that are stable
of the flavoring oil, the nature and concentration
over a wide pH range. Methylcellulose and car-
of the additives, and pH.55
boxymethylcellulose are available in a number
Wesley’s Pharmaceutical Flavor Guide con¬
of different viscosity grades. Carboxymethylcel-
tains suggestions for flavoring over 51 types of
lulose may be used in solutions containing high
pharmaceutical preparations. 3 It and many
concentrations of alcohol (up to 50%) without
similar reports provide some guidance for the
precipitating. It is precipitated, however, as an
formulation chemist, but the final selection
insoluble salt of a number of multivalent metal
ions such as Al+++, Fe+++, and Ca++. Methyl¬
cellulose polymers do not form insoluble salts
with metal ions, but can be salted out of solution Table 15-4. Flavor Selection
when the concentration of electrolytes or other Taste
dissolved materials exceed certain limits. These Sensation Recommended Flavor
limits may vary from about 2 to 40%, depending
on the electrolyte and the type of methylcellu¬ Salt Butterscotch, maple, apricot, peach,
lose involved. vanilla, wintergreen mint
Viscosity-inducing polymers should be used
with a degree of caution. They are known to Bitter Wild cherry, walnut, chocolate, mint
form molecular complexes with a variety of or¬ combinations, passion fruit, mint spice,
anise
ganic and inorganic compounds, and in so
doing, influence the activity of these com¬
Sweet Fruit and berry, vanilla
pounds. It is conceivable that highly viscid sys¬
tems that resist dilution by gastrointestinal
Sour Citrus flavors, licorice, root beer,
fluids might impede drug release and absorp¬
raspberry
tion.

470 • The Theory and Practice of Industrial Pharmacy

must result from a trial and error approach. In¬ when large volumes of liquid are involved. A dis¬
herent in this approach is what is referred to as cussion of clarification and filtration procedures
taste fatigue. Repeated samplings of strong tast¬ can be found in Chapter 7. It is in order at this
ing substances soon result in decreased flavor point, however, to mention some of the effects
acuity, and therefore, impaired ability to evalu¬ that this process can have on the product. The
ate flavor properly. Preliminary flavoring should filter pads most frequently used for oral liquids
be carried out on diluted samples. This is done were formerly composed either entirely of asbes¬
by preparing flavored vehicles and adding incre¬ tos or of mixtures of asbestos and cellulose. With
ments of the medicament or other formulation the finding that asbestos fibers can cause can¬
components responsible for the taste problem. cer,58,59 liquids are now filtered, whenever pos¬
The concentration at which the taste of the me¬ sible, through membrane filters. A number of
dicament is perceptible is referred to as the min¬ manufacturers make available membrane filters
imum threshold level. The vehicles that are most in a variety of materials and pore sizes. Com¬
effective in masking low levels of drug are candi¬ bined with filter aids and prefilters, they can be
dates for full-strength flavor evaluation. used to filter most pharmaceutical liquids.
Flavor evaluation techniques have progressed Studies should be carried out before and after
to a much greater extent than flavor selection. filtration to determine the extent, if any, to
Taste panels can be useful in selecting one of which actives, preservatives, flavors, colorants,
several candidate formulations. This subject, as and other important product components are
well as other flavor considerations, has been adsorbed. Production conditions should be sim¬
surveyed in an excellent book assembled by Ar¬ ulated as closely as possible, and particular at¬
thur D. Little, Inc.56 tention given to filtration rate and liquid-to-filter
surface area ratio.
Adsorption observed in the filtration of small
batches in which the ratio of adsorptive surface
Appearance to liquid volume is large may be misleading.
The overall appearance of liquid products de¬ Under production conditions, when the ratio of
pends primarily on their color and clarity. Color adsorptive surface to liquid volume is small, this
selection is usually made to be consistent with effect may be insignificant. If adsorption is a sig¬
flavor, i.e., green or blue for mint, red for berry. nificant problem and a nonadsorptive filter can¬
The types of colorants available for pharmaceuti¬ not be found, a satisfactory filtration process
cal use, their relative stabilities, and areas of may require the use of an appropriate over¬
application have been reviewed by Swartz and charge or preequilibration of the filter medium
Cooper.57 with the formulating component(s) being ad¬
The dyes (and the maximum amounts) per¬ sorbed.
mitted for use in pharmaceuticals vary from A much less common problem is that of ex¬
country to country. Each regulatory agency also traction of materials from the filter pad. This is
revises its approved list from time to time. Be¬ only of concern insofar as the extracted material
fore formulating a product that may be marketed may affect the physical and chemical stability of
in several countries, it would be wise to check the product. (Pharmaceutically acceptable filter
the current status of each dye. Suppliers of the pads and aids contain no biologically active com¬
dyes are usually excellent sources of information ponents). For this reason, stability studies must
on this subject. be carried out on product made by the same
A purification step invariably is required to process as the one to be used for ultimate pro¬
achieve maximum clarity. Particulate matter duction.
may be introduced through lint and fibers from
the solvent or trace quantities of insoluble con¬
taminants in one or more of the, formulation
components. It is quite common, for example, Stability
for alcoholic solutions of natural flavors to pre¬ Chemical Stability. Techniques for predict¬
cipitate pectins and resins on addition to the ing chemical stability of homogeneous drug sys¬
bulk aqueous solution. The removal of this and tems are well defined.60 Chemical instability of a
other particulate matter is referred to as “polish¬ drug invariably is magnified in solution, as op¬
ing,” and technically may be accomplished in posed to solid or suspension systems. This liabil¬
several ways: (1) by settling and subsequent ity, however, is to a large extent offset by the
decantation, (2) by centrifugation, and (3) by fil¬ rapid and accurate stability predictions, which
tration. Filtration is the only practical method are possible with homogeneous systems but are

LIQUIDS - 471
 extremely risky with heterogeneous dosage flavors and perfumes, but has rarely been suc¬
forms. cessfully applied to a finished pharmaceutical
Studies involving evaluation of stability in liq¬ product.
uid drug systems include the effect of amino An integral part of any stability study should
acids on the stability of aspirin in propylene gly¬ include consideration of the package and the ef¬
col solutions,61 and a systematic study of the fect the package may have on the contents as
autoxidation of polysorbates.62 well as the effect the contents may have on the
Physical Stability. A physically stable oral package. For this reason, stability studies that
liquid retains its viscosity, color, clarity, taste, are intended to support a New Drug Application
and odor throughout its shelf-life. All of these and/or marketing of a drug must be carried out
characteristics can and should be evaluated sub¬ on the package intended for ultimate use. A
jectively, and objectively if possible, during the well-designed stability protocol should call for a
course of stability assessment. A freshly made thorough evaluation of both the package and its
sample should serve as a reference standard for contents at various conditions of storage, includ¬
subjective evaluations. ing exposure to both natural and artifical light of
Objective measurements should be made known amounts.
when such tests are practical. Color can readily It is important to store the final product in the
be measured spectrophotometrically, and the same container in which it was marketed until
absorbance at the appropriate wave length of its expiration date. Flavors and colors often
aged samples can be compared with the initial change with time, owing to adsorption by plastic
value to determine the extent of color change. containers or closures, or evaporation of the sol¬
Clarity is best determined by shining a focused vent, with a resultant concentrating of the prod¬
beam of light through the solution. Undissolved uct or chemical breakdown. One example of
particles scatter the light, and under these con¬ chemical breakdown is oxidative breakdown
ditions, the solution appears hazy. Light-scatter¬ induced by repeated opening of a pint or gallon
ing equipment is available to give a quantitative container to dispense prescriptions. This results
measure of turbidity. In general, however, this in a new source of oxygen being introduced and
type of measurement is not necessary in the a larger headspace with each dispensing.
evaluation of oral liquids. In most cases, a liquid Most oral liquids are packaged in either amber
that becomes noticeably turbid with age is unac¬ or flint glass containers with plastic or metal
ceptable. A quantitative measure of the turbidity caps. Fortunately, glass is generally inert to
is of little importance except as a tool in deter¬ aqueous solutions in the pH range appropriate
mining factors that influence the rate at which for oral liquids. The same is not necessarily true
the liquid becomes turbid. for the cap and liner. Plastic caps may undergo
Taste and odor continue to be subjectively stress cracking on contact with some liquids,
evaluated by the formulation chemist. This is whereas under some conditions, corrosion may
done either by the pharmaceutical investigator, be a problem with metal caps. In both cases, it is
or preferably, by a panel of unbiased, taste-sensi¬ important to select a liner that on the basis of
tive individuals. Coded aged samples are sub¬ actual testing, is compatible with the package
mitted to each panel member along with a simi¬ contents.
larly coded reference sample. The odor and taste The integrity of the seal between a cap and
of the reference sample should be known to be container depends on the geometry of the cap
intact. Product that has been stored in the refrig¬ and container, the materials used in their con¬
erator frequently is used as the reference sam¬ struction, the composition of the cap liner, and
ple. Each panel member is asked to taste and the tightness with which the cap is applied.
compare the coded samples. If most of the panel Torque is a measure of the circular force, meas¬
members cannot detect a difference between ured in inch-pounds, appbed in closing or open¬
samples, obviously the organoleptic character of ing a container. The application and removal
the aged sample has not significantly changed. torque should be considered an integral part of
Some time should be allowed to pass between any pharmaceutical development project involv¬
the preparation of a flavored sample and taste ing a threaded package and is of particular im¬
testing. Aging for about two weeks to one month portance with respect to liquid formulations. An
is recommended to permit flavor blending. inadequate cap seal may result in excessive loss
Some attempts have been made, mainly by of volatile components or leakage of product
the perfume and flavor industry, to characterize from the container. Extreme tightening may
products by vapor phase chromatography. This deform or break closures and make the cap ex¬
approach has proven useful with respect to pure cessively difficult to remove. Product prepared

472 • The Theory and Practice of Industrial Pharmacy

for stability evaluation should be capped with facturing. Additional processing may be neces¬
essentially the same torque as anticipated for sary to obtain a desirable property, such as
use in production. particle size or freedom from microorganisms.
The optimum application torque for closures With regard to microbial contamination of raw
and containers varies, depending on the mate¬ materials, it is usually much easier to begin with
rial used in their manufacture. The proper appli¬ low counts in the raw materials than to try to
cation torque should be determined experimen¬ reduce these counts substantially during pro¬
tally by the use of containers and closures of the cessing.
same size, neck finish, and composition as those Aside from the active ingredient, water is usu¬
intended for use in the final product. The rec¬ ally the most important constituent in a liquid
ommended application torque is generally a product. It should meet the USP requirements
compromise between the torque providing maxi¬ for purified water. It may be obtained by distilla¬
mum product protection and the torque that al¬ tion or ion-exchange treatment. In recent years,
lows for convenient cap removal. manufacturers have devoted considerable effort
to upgrading the microbial purity of the water
supply used in oral liquids. Techniques em¬
ployed include reverse osmosis purification, ul¬
Manufacturing Considerations traviolet sterilization, membrane filtration, and
The basic principles involved in the prepara¬ constant circulation in piping systems that have
tion of homogeneous liquids are the same re¬ no “dead ends” where microorganisms can
gardless of the quantity of material involved. thrive. In general, the most difficult microbes to
The solubility of the solute and intramolecular remove from a purified water system are the
and intermolecular interactions in the final solu¬ pseudomonads. Figure 15-10 shows a purified
tion at equilibrium are independent of the water system designed to minimize microbial
manner in which the solution is made. This growth.
assumes, of course, that the method of com¬ Many of the ideas incorporated in Figure
pounding does not affect the final composition of 15-10 have been taken from experience gained
the system, as would be the case if a volatile in preparing and storing pyrogen-free water for
component were charged to a heated solution. injection and adapted to the manufacture of
The rate at which equilibrium is achieved, how¬ high-quality de-ionized water for use with liquid
ever, is highly dependent on the details of the pharmaceutical products.
compounding procedure and the equipment The ion-exchange resins used in the water
used. system are important to the successful mainte¬
The reader is directed to an article by Carsten- nance of low bacteria counts. An example of an
sen and Mehta for a discussion of several factors appropriate mixed resin bed would be Amber-
involved in scaling-up solution dosage forms for gard XE-352 and Amberlite IR-120. Ambergard
manufacturing.63 Areas covered include heat¬ XE-352 is a large-pore, macroreticular, Type 1
ing, agitation, and clarification. Basic equations quaternary ammonium anion-exchange resin. It
and example calculations are provided in the is effective for a wide range of flow rates and for
article. many different bacterial strains.65 Amberlite IR-
Liquid processing lends itself to computer- 120 is a strongly acidic, cation-exchange resin
controlled automation. A few pharmaceutical that balances the chemical equilibrium of the
firms have already instituted automated or semi- water.
automated processes for several large-selling liq¬ The use of ultraviolet sterilization of water has
uid products. Yelvigi has written a good basic been discussed in some detail in the litera¬
review of this developing area of technology.64 ture.66,67 Two factors should be emphasized at
this point: (1) The flow rate of the water should
not exceed the capability of the sterilizing unit,
and (2) even if sterility is achieved, a filter
Raw Materials should still be used downstream to remove the
The raw materials used in manufacturing liq¬ dead microorganisms and particulate matter.
uids should conform to well thought out specifi¬ Although the first point seems self-evident, it is
cations. These specifications should assure violated surprisingly often—compromising the
identity, purity, uniformity, and freedom from effectiveness of the entire system.
excessive microbial contamination. Incoming A number of in-line filtration units are com¬
raw materials should be impounded and thor¬ mercially available. These filters are discussed
oughly tested before they are released for manu¬ in Chapter 7.

LIQUIDS - 473
FIG. 15-10. Schematic drawing of a deionized water system for the manufacture of liquid pharmaceutical products.

Equipment the compounding of the bulk liquid, they have a

built-in agitation system.
In the most general terms, the type of equip¬ Water condensate that forms on the lid of mix¬
ment used in the manufacture of oral solutions ing tanks and similar processing equipment dur¬
consists of mixing tanks equipped with a means ing heating and chilling steps may provide a
of agitation, measuring devices for large and source of microbial contamination that is often
small amounts of solids and liquids, and a filtra¬ overlooked.
tion system for the final polishing and/or sterili¬ The liquid is then clarified by cycling through
zation of the solution. In addition, most produc¬ a filtration system, and the polished solution is
tion facilities are equipped with systems for bulk stored in an adjacent tank until released by the
material handling, such as tote bins and tote bin quality control department. The liquid may then
discharging equipment. be transported to the filling line, either manually
FitzSimon has written a valuable and practical by filling into portable transport tanks or by
discussion on the design of piping, valves, mix¬ pumping (or gravity flow) through a suitable liq¬
ers, pumps, and controls to produce high-quality uid delivery conduit.
liquid products.68 The distance the product travels between the
All equipment must be thoroughly cleaned holding tank and the filling fine should be held
and sanitized (sterilized if possible) before use. to a minimum to reduce the chance of microbial
Appropriate disinfectants include dilute solu¬ contamination. All lines should be easy to disas¬
tions of hydrogen peroxide, phenol derivatives, semble, clean, and sanitize.
and peracetic acid. Equipment and lines can be A major source of microbial contamination is
sterilized by such methods as alcohol, boiling often the processing operators. Head covering
water, autoclaving, steam, or dry heat. should be worn at all times. Gloves and face
Tanks are usually constructed of polished masks should be worn as necessary.
stainless steel and are usually jacketed to allow An ongoing education program is recom¬
for heating or cooling of the contents. They can mended to maintain operator interest and con¬
be obtained in a number of different sizes, and cern for good work habits.
are completely covered and equipped with see- In additions, the use of portable laminar flow
through charging ports and illumination for easy units can be an aid in certain operations (such
observation of the contents. If tanks are used for as the addition of ingredients to a tank).

474 • The Theory and Practice of Industrial Pharmacy

Compounding Procedure the alcohol, and this alcohol solution is charged
to the batch (step 6). As previously mentioned,
Dilute solutions, prepared from rapidly dis¬ the equilibrium solubility of all solutes is the
solving materials, are simply prepared by charg¬ same regardless of the manner in which they are
ing the solute to the solvent and agitating until charged. The rate at which solution is achieved,
the solution is homogeneous. When more con¬ however, can be markedly influenced by the
centrated solutions are being made, or when the compounding procedure. In this case, predis¬
solute is slowly dissolving, it may be advanta¬ solving the menthol and flavor in alcohol, in
geous to employ heat. The syrup formula and which both solutes are highly soluble, and then
manufacturing method presented in Table 15-5 charging the resultant alcoholic solution to the
illustrate some of the steps involved in com¬ main part of the batch effect rapid approach to
pounding a complex liquid formulation. equilibrium conditions.
The rationale for most of the steps cited in this Solutes present in small concentrations, par¬
procedure is obvious. Several steps, however, ticularly dyes and other intensely colored mate¬
warrant some discussion. Step 1 calls for the rials, should be predissolved prior to mixing with
metering of a specific amount of purified water the main portion of the batch, as is indicated in
into the compounding tank. The precise quan¬ step 8. This is done to ensure complete solution
tity of water in this case is not critical, but in of the substance before the batch is further proc¬
spite of this, a confirmatory volumetric check is essed. If the solutes were charged directly to the
desirable, to protect against the consequences of bulk mixing tank, it would be extremely difficult
a malfunctioning metering device. The purified to determine the presence of a small amount of
water is heated in step 2 primarily to facilitate undissolved material at the bottom of the tank.
the solution of sucrose, the other solutes being As a rule, complete solution should usually be
rapidly soluble even in cold water. In step 5, the confirmed at every stage in the manufacture of a
menthol and flavor are dissolved in an aliquot of homogeneous liquid.

Table 15-5. Syrup Formula and Manufacturing Method

Per batch
Formula Per ml (5000 L)

Drug 2.00 mg. 10.0 kg.

Sodium benzoate USP 1.00 mg. 5.0 kg.
Menthol, USP 0.10 mg. 0.5 kg.
Alcohol, USP 0.05 ml. (40.8 mg.) 250.0 filers (204.0 kg.)
Flavor 0.005 ml. (4.5 mg.) 25.0 liters (22.5 kg.)
Dye FD&C Yellow No. 6 0.10 mg. 0.5 kg.
Glycerin 0.05 ml. (62.45 mg.) 250.0 liters (312.250 kg.)
Sorbitol solution, USP 0.10 ml. (128.5 mg) 500.0 liters (642.5 kg.)
Standard granulated sugar 550.00 mg. 2750.0 kg.
Purified water, USP q.s. to 1.0 ml. 5000 liters

Compounding Instructions:
1. Charge 2000 L of purified water through the water meter 7. Charge the balance of the specified amount of alcohol to the
into the compounding tank. Check the volume against the outage batch. Agitate until homogeneous.
chart. Heat to approximately 50°C. 8. Charge 10 L of purified water to a clean stainless steel con¬
2. To the water in the compounding tank, charge the following tainer. Add to the water and dissolve the specified amount of
materials in the amounts specified in the batch sheet. Dissolve FD&C Yellow No. 6.
each one, with agitation, before adding the next: (a) drug, 9. Charge the dye solution to the batch in the compounding
(b) sodium benzoate, (c) standard granulated sugar. Agitate the tank, and agitate until homogeneous.
contents of the compounding tank until homogeneous, and then 10. Add to the compounding tank sufficient purified water to
cool to 30°C. bring the batch volume to 5000 L.
3. Charge the specified amount of glycerin to the compounding 11. Weigh out 2.5 kg of filter aid, and charge it to the contents
tank. Agitate until the .batch is homogeneous. of the compounding tank. Agitate for 10 min. The batch is now
4. Charge the specified amount of sorbitol solution to the com¬ ready to filter.
pounding tank. Agitate until the batch is homogeneous. 12. Cycle the batch through the filter and back to the com¬
5. Measure 20 L of alcohol into a suitable stainless steel con¬ pounding tank until the filtrate is clear. At this point, the filtrate
tainer. Add and dissolve the specified charge of menthol. Add and may be discharged and collected in the designated holding tank.
dissolve the specified charge of flavor. 13. Sample the batch, and submit for testing in accordance
6. Charge the alcoholic solution of menthol and flavor to the with standard procedure.
batch in the compounding tank. Agitate until homogeneous.

liquids* 475
 Step 11 calls for the addition of a specified ton, causing uncontrollable dripping from the
amount of filter aid to the contents of the com¬ Ming spout and associated fill inaccuracies.
pounding tank. The amount and type of filter aid These problems can be controlled to a large ex¬
must be determined during the development of tent by proper engineering of the filling ma¬
the product. The amount used does not usually chine. An inherent problem with volumetric fill¬
exceed 0.5 g/L. ing, however, is encountered when containers
In the laboratory, liquids are usually meas¬ are used that are not dimensionally uniform. In
ured by volume. When large quantities of liquid this case, even though the M amount is accu¬
materials are handled, however, it is frequently rate, the M height varies inversely with the con¬
more convenient and accurate to use gravimet¬ tainer capacity, i.e., an oversized package ap¬
ric means of measurement. For this reason, all pears to have a slack M, whereas an undersized
liquid components of the cited formula are ex¬ package appears to have an excessive M.
pressed in units of both volume and weight. Constant-level filling uses the container as the
means for controlling the M of each unit. The
M amount is varied by adjusting the height to
Packaging which the container is filled. Any dimensional
The specific method used for filling a pharma¬ variations in the containers result in comparable
ceutical liquid varies greatly depending on the variations in the net M per unit. The oldest form
characteristics of the liquid (e.g., viscosity, sur¬ of a constant-level Mer involves the use of a si¬
face tension, foam-producing qualities, and phon; however, this method of filling is usually
compatibility with the materials used in the con¬ slow and is rarely used when high production
struction of the filling machine), the type of rates are required. The high-speed, automated,
package into which the liquid is placed, and the constant-level filling machines in use today are
required production output. Three basic filling generally based on the siphon principle, with the
methods—gravimetric, volumetric, and con¬ major modification being the induced pressure
stant level—are used for most liquid filling oper¬ differential between the liquid discharge nozzle
ations, The latter two methods are used most and the constant-level .overflow system. The
frequently in the Ming of pharmaceutical liq¬ most widely used methods can be broadly classi¬
uids. Filling containers to a given weight (gravi¬ fied into three categories: vacuum filling,
metric filling) is generally limited to large con¬ gravity-vacuum filling, and pressure-vacuum
tainers or to highly viscous products. The filling.
process does not readily lend itself to high¬ The principle of vacuum filling is illustrated
speed, automatic equipment. in Figure 15-11. To M by vacuum, a seal must
Volumetric filling is usually accomplished by be made between the filling head and the con¬
positive displacement piston action.* Each M- tainer. A vacuum is then developed within the
ing station is equipped with a measuring piston container, which causes the liquid to flow from
and cylinder. The M accuracy is controlled by the bulk liquid tank to the container. The liquid
the close tolerances to which the pistons and level rises until it reaches the vacuum tube,
cylinders are manufactured. The M amount is which is positioned at the desired constant level.
measured by the stroke of the piston, which on Excess liquid is drawn through the vacuum tube
all machines can be varied to a limited degree. and can be recycled to the bulk liquid tank. In
Major changes in fill amount usually necessitate gravity-vacuum filling, the bulk liquid tanks are
changing the piston and cylinder assembly. This a level above the filling stem, so that the driving
type of device is capable of accuracy to within force for liquid flow results from both the nega¬
fractions of a milliliter. There are, however, sev¬ tive pressure in the container and the force of
eral significant problems associated with volume gravity. Similarly, in pressure-vacuum filling, a
filling. Highly viscous liquids may cause the pis¬ positive pressure is applied to the bulk liquid,
tons to seize, resulting in either loss of M accu¬ which in combination with the vacuum devel¬
racy or fine breakdown. On the opposite side of oped in the container, results in a pressure dif¬
the spectrum, thin liquids may flow past the pis- ferential that allows for rapid filling of even
highly viscous liquids. The latter two methods
require some valve mechanism that is respon¬
’Volumetric filling can also be accomplished by the sive to the presence of the container, to open
pumping of a liquid at a constant pressure through an
and subsequently close a valve device in the M-
orifice of constant size for a predetermined period of time.
The volume can be varied by increasing or decreasing the ing stem assembly. Vacuum filters do not re¬
pressure and by varying the time between opening and quire such a mechanism, since a pressure dif¬
closing the filling nozzle. ferential to promote liquid flow can only be

476 • The Theory and Practice of Industrial Pharmacy

 References

1. Martin, A.N., Swarbrick, J., and Cammarata, A.:

Physical Pharmacy. 2nd Ed. Lea & Febiger, Philadel¬
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Sci., 52:1149, 1963.
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some with high-speed automatic equipment, is Paruta, A.N.: J. Pharm. Sci., 53:463, 1964.
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air or other gases that participate in the forma¬ 20. Paruta, A.N., and Irani, S.A.: J. Pharm. Sci., 55:1055,
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All of these methods introduce considerable J. Pharm. Sci., 55:1144, 1966.
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55:1208, 1966.
be preferable to formulate the product with care¬
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A microbial survey should be performed on all 26. Breon, T.L., Mauger, J.W., Osborne, G.E., et al.:
packaging materials that come into contact with Drug. Dev. Comm., 2:521, 1976.
27. The Handbook of Chemistry and Physics. 45th Ed.
the product to ensure that microbial contamina¬
The Chemical Rubber Co., Cleveland. OH, 1964,
tion is not introduced at this point. Attention p. 30.
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operations. For example, on small-volume or¬ Constants of Pure Liquids. N.B.S. Circ. 514, US.
ders in which bottle closures or tips for plastic Govt. Printing Office, Washington, DC, 1951.
squeeze-spray containers are often placed on the 29. Breon, T.L., Mauger. J.W., and Paruta, A.N.: Drug
Dev. and Ind. Pharm., 6:87, 1980.
product by hand, this procedure can be a source
30. McBain, J.W.: Advances in Colloid Science. Vol. 1.
of microbial contamination from the hands of Interscience, New York, 1942.
operators unless gloves are used that are pre¬ 31. Swarbrick, J.: J. Pharm. Sci., 54:1229, 1965.
sterilized and periodically disinfected during 32. Kuettel, D.: Pharm. ZentralhaUe, 102:116, 1963
use. (through Chem. Abstracts).

LIQUIDS • 477
33. MonteBovi, A.J., Halpem, A., and Mazzola, P.: J. Am. 51. Beck, C.I.: Application potential for aspartame in low
Pharm. Assoc., Pract. Ed., 15:162, 1954. calorie and dietetic foods. In Low Calorie and Special
34. Hamed. H.S., and Owen, B.B.: The Physical Chemis¬ Dietary Foods. Edited by B.K. Dwivedi. CRC Press,
try of Electrolyte Solutions. 3rd Ed. Reinhold, New W. Palm Beach, FL, 1978, p. 68.
York, 1958, p. 161. 52. Janovsky, H.L.: Drug and Cosmetic Industry, 86:335,
35. Leyden, A.F., Pomerantz, E., and Bouchard, E.G.: 1960.
J. Am. Pharm. Assoc., Sci. Ed., 45:773, 1956. 53. Wesley, F.: Pharmaceutical Flavor Guide. Fritzsche
36. Bulletin, Atlas Chemical Industries Inc., Wil¬ Brothers Inc., New York, 1957.
mington, DE. 54. Caul, J.F., and Rockwood, E.L.: J. Am. Pharm. Assoc.,
37. Conrad, L.I., Kalmen, M., and Maso, H.F.: Drug and Sci. Ed., 42:682, 1953.
Cosmetic Industry, 83.160, 1958. 55. Chemburkar, P.G., and Joslin, R.S.: J. Pharm. Sci.,
38. McBain, M.E.L., and Hutchinson, E.: Solubilization. 64:414, 1975.
Academic Press, New York, 1965. 56. Flavor Research and Food Acceptance. Arthur D. Lit¬
39. Guttman, D.E., Hamlin. W.E., Shell, J.W., and Wag¬ tle Inc., Reinhold, New York, 1958.
ner, J.G.: J. Pharm. Sci., 50:305, 1961. 57. Swartz, C.J., and Cooper, J.: J. Pharm. Sci., 51:89,
40. Kern, C.J., and Antoshkiw, T.: Ind. Eng. Chem., 1962.
42:709, 1950. 58. Selikoff, I.J., Chung, J., and Hammond, E.C.:
41. Coles, C.L.J., and Thomas, D.F.W.: J. Pharm. Phar¬ J.A.M.A., 188:22, 1964.
macol., 4:898, 1952. 59. Selikoff, I.J., Hammond, E.C., and Chung, J.:
42. Scott, M.J., Goudie, A.J., and Huetteman, A.J.: J. Am. J.A.M.A., 204:106, 1968.
Pharm. Assoc., Sci. Ed., 49:467, 1960. 60. Garrett, E.R.: Kinetics and mechanisms in stability of
43. Neuberg, C., et al.: Biochem. Z., 76:107, 1916. drugs. In Advances in Pharmaceutical Sciences.
44. Neuberg, C., et al.: Biochem. Z., 229:467, 1930. Vol. 2. Academic Press, New York, 1967.
45. Wolfson, B.B., and Banker, G.S.: J. Pharm. Sci., 61. Narang, P.K., and Lim, J.K.: J. Pharm. Sci., 68:645,
54:195, 1965. 1979.
46. McGregor Scott, H.: Manuf. Chem. Aerosol News, 62. Donbrow, M., Azaz, E., and Pillersdorf, A.: J. Pharm.
1972. Sci., 67.T676, 1978.
47. Bruch, C.W.: Drug and Cosmetic Industry, 110:32, 63. Carstensen, J.T., and Mehta, A.: Pharm. Tech., 6:64,
1972. 1982
48. Alexander, K.S., LaPrada, B., Mauger, J.W., and 64. Yelvigi, M.: Pharm. Tech., 8:47, 1984.
Paruta, A.N.: J. Pharm. Sci., 67:624, 1978. 65. Scruton, S.H.: Pharm. Tech., 4:39, 1980.
49. Lachman, L.: Bull. Parenteral Drug Assoc., 22:127, 66. Ellner, G.G., and Ellner, S.: Drug and Cosmetic In¬
1968. dustry, 104:54, 1969.
50. Ward, D.R., Lathrop, L.B., and Lynch, M.J.: Drug 67. Olson, S.W.: Amer. Perfumer. Cosmetic, 85:97,1970.
and Cosmetic Industry, 99:48, 1966. 68. FitzSimon, R.: Drug Dev. Commun., 2:1, 1976.

478 • The Theory and Practice of Industrial Pharmacy

 16

Pharmaceutical Suspensions
NAGIN K. PATEL, LLOYD KENNON,* and R. SAUL LEVINSON

Suspensions form an important class of pharma¬ boiling-point elevation, and osmotic-pressure

ceutical dosage forms. These disperse systems phenomena.
present many formulation, stability, manufac¬ Suspensions are heterogeneous systems con¬
turing, and packaging challenges. The primary sisting of two phases. The continuous or external
objective of this chapter is not to develop a for¬ phase is generally a liquid or semisolid, and the
mulary, but rather to put forth some of the basic dispersed or internal phase is made up of partic¬
theoretic and practical considerations that apply ulate matter that is essentially insoluble in, but
to suspension systems, and to relate these prin¬ dispersed throughout, the continuous phase; the
ciples to formulation methods, evaluation proce¬ insoluble matter may be intended for physiologic
dures, and manufacturing techniques. The absorption or for Internal or external coating
reader is assumed to have at least some knowl¬ functions. The dispersed phase may consist of
edge of basic pharmaceutical technology. discrete particles, or it may be a network of parti¬
For the most part, only aqueous suspensions cles resulting from particle-particle interactions.
are discussed, and little attention is paid to oils Almost all suspension systems separate on
or aerosol propellants as suspension vehicles. standing. The formulator’s main concern, there¬
Also, this discussion is limited to suspensions fore, is not necessarily to try to eliminate separa¬
with particles having diameters greater than tion, but rather to decrease the rate of the set¬
0.2 micron, approximately the lower limit of res¬ tling and to permit easy resuspendability of any
olution of optical microscopes; for purposes of settled particulate matter. A satisfactory suspen¬
comparison, a human hair has a diameter of sion must remain sufficiently homogeneous for
about 75 microns (0.003 in.). Systems with par- at least the period of time necessary to remove
ticles smaller than 0.1 to 0.2 micron are gener¬ and administer the required dose after shaking
ally-considered to be colloidal, and they exhibit its container. Traditionally, certain kinds of
properties that lie between those of true molecu¬ pharmaceutical suspensions have been given
lar solutions and suspensions of visible particles. separate designations, such as mucilages, mag¬
Thus, although suspended particles do not ex¬ mas, gels, and sometimes aerosols; also included
hibit all the properties of colloids, such as the would be dry powders to which a vehicle is
so-called colhgative properties, they do have added at the time of dispensing.
heightened surface properties, that is, whatever
surface properties exist are magnified because
of the increased surface area. In actual experi¬
Theoretic Considerations
ence, this additional action expresses itself as an A knowledge of the theoretic considerations
enhanced power of adsorption. The colligative pertaining to suspension technology should ulti¬
properties just noted depend on the number of mately help the formulator to select the ingredi¬
^particles” (molecules, ions, aggregates! rather ents that are most appropriate for the suspen¬
than on their nature. Tfieyare possessed by true sion and to use the available mixing and milling
solutions and by many colloidal solutions and equipment to the best advantage. Some under¬
are manifested as freezing-point depression, standing of wetting, particle interaction, elec¬
trokinetics, aggregation, and sedimentation con¬
cepts facilitates the making of good formulatory
‘Deceased p^'t^ decisions.

-i
- * 0- f*
479
 A frequently encountered difficulty that is a the hydrophobic surface-, with the polar moiety
factor of prime importance in suspension formu¬ of the'surfactant being then directed toward die
lation concerns the wetting of the solid phase by aaueous~phase. Other materials that can beused
the suspension medium. By definition, a sus¬ To~ai3_d5spersion of hydrophobic solids are, hy-
pension is essentially an incompatible system, Pdrophilic polymers such as sodium car-
but to exist at all, it requires some degree of boxymethylcellulose and certain water-insoluble
compatibility, and good wetting of the sus- (§) hydrophilic materials such as bentonite, alu-
pended material is important in achieving this minum-magnesium silicates, and colloidal sil¬
end. ica, either alone or in combination. These mate¬
When a strong affinity exists between a liquid rials also exert viscosity-building effects,
and a solid, the liquid easily forms a film over depending on the specific type and concentra¬
the surface of the solid. When this affinity is tion used. These hydrophilic agents may, if used
nonexistent or weak, however, the liquid has at too high a concentration, cause an undesira¬
difficulty displacing the air or other substances ble gelling instead of just the desired degree of
surrounding the solid, and there exists an angle viscosity or thixotropy: the latter term refers to
of contact between the liquid and the solid. This the formation of a gel-like structure that is easily
contact angle, 6, results from an equilibrium broken and becomes fluid upon agitation.
involving three interfacial tensions, specifically, RHeologically) the liquid is said to have a yield
those acting at the interfaces between the liquid value. Incidentally, Carless and Ocran reported
and vapor phases, at the solid and liquid phases, that in pharmaceutical suspensions, the yield
and at the solid and vapor phases. These ten¬ value of a vehicle having the density of water
sions are caused by unbalanced intermolecular must be about 0.3 dyne cm-2 to support solid
forces in the various phases similar to the famil¬ particles having a diameter of 0.2 micron and a
iar analogous phenomenon of the convex “skin’’ density of 1.5.
formation over the surface of a glass of water Various screening techniques have been de¬
filled to the .hnrn. The contact angle concept is vised to facilitate the comparison of possible al¬
important because it affords a method of consid¬ ternatives during the selection of a wetting
ering degrees'of w'cttalVililv arid ~indicaFe.s that agent. Some examples follow. Hiestand,2 in an
surface properties are important. An involved excellent review of suspensions, suggested the
mathematicaTtreatment of wetting is possible, use of a narrow lyophobic trough, one end of
but needed data usually are not available to which holds the powder while a solution of the
make any equations useful. It is easier for the wetting agent is placed in the other end. The
formulator simply to try a few surfactants to find relative rates of penetration of different agents
a good wetting agent. can then be directly observed, the better agents
Certain solids are readily wet by liquid media showing the faster rates. Another technique in¬
whereas others are not. In aqueous suspension volved measuring the relative ability of solutions
terminology, solids are said to be either hydro* of different wetting agents to carry powder
philic (iyophilic or solvent-loving, rarely lyo¬ through a gauze as the solutions are dropped
tropic) or hydrophobic (lyophobic). Hydrophilic, onto the gauze supporting the powder. Obvi¬
substances are easily wet by water or other polar) ously, the better wetters are able to function
liquids; they may also greatly increase the vis¬ more effectively as vehicles and carry more pow¬
cosity of water suspensions. Hydrophobic sub¬ der through the gauze than the poorer wetters.
stances repel water but can usually be wetted by With respect to determining wettability, it is
nonpolar liquids; they usually do not alter the interesting to note that there have also been de¬
viscosity of aqueous dispersions. Hydrophilic veloped methods of comparing the wetting of
solids usually can be incorporated into suspen¬ powders by nonaqueous liquid vehicles; such
sions without the use of a wetting agent, but wetting can be enhanced by certain lanolin de¬
hydrophobic materials are extremely difficult to rivatives. Obviously, lanolin derivatives, of
disperse and frequently float on the surface of which many lipophilic and hydrophilic types are
the fluid owing to poor wetting of the particles or available, find their major use in topically ap¬
the presence of tiny air pockets. plied preparations. Two techniques developed by
A frequently helpful pharmaceutical tech¬ the paint industry that could be applied pharma¬
nique for modifying the wetting characteristics ceutically involve determining the so-called wet
of powders involves the use of surfactants and flow points. The wet point measuresTthe
(sometimes with shearing) to decrease the soHffi amount of vehicle needed to just wet all of the
liquid interfacial tension. The mechanism of powder. Reduction of the wet point by an addi-

480 • The Theory and Practice of Industrial Pharmacy

tive indicates initial surface wetting by that be achieved by coating the powder with the ad¬
agent in that powder-vehicle combination. The ditive in alcohol, which is then evaporated from
flow point measures the amount of vehicle the slurry. When lanolin derivatives are used
needed to produce pourability. The extent to with powders such as talc, titanium dioxide, or
which the flow point of a powder-vehicle system ferric oxide, values for the flow and wet points
is reduced by a surface active agent measures are in the same general range as previously
the degree to which the agent deaggregates the mentioned, although somewhat lower values
system, i.e., inhibits the buildup of a network¬ tend to be observed.
like structure by the solid phase. A low wet point
coupled with a low flow point (and a smalldif-
ference between the two) indicatesgood deag¬ Particle Interactions and
gregation or dispersion.
The wet point method involves incorporating Behavior
the additive in the powder by rubbing the mix¬ The terms lyophobic (hydrophobic) and lyo-
ture on a glass plate with a spatula. The vehicle philic (hydrophilic) were mentioned in the pre¬
is then added drop-wise and worked thoroughly vious section. These terms are sometimes con¬
through the mass after each addition. The end¬ sidered synonymous with nonwetting and
point is reached when just enough vehicle has wetting, respectively. The primary behavioral
been incorporated to form a coherent mass that difference between these two classes of materi¬
does not break or separate. Good reproducibility als is their sensitivity to the presence of electro¬
in the determination of the endpoint can be ob¬ lytes. Lyophobic materials in suspension are
tained. The sharpness of the endpoint values sensitive to the addition of salts, whereas lyo-
depends on the powder, vehicle, and additive philic materials are not. A lyophilic material,
employed. The wet point is expressed as mil¬ such as a gum, is readily wet by water, although
liliters per 100 grams and may, for example, in this instance, large amounts of electrolyte
have values of 15 to 45 with a 10% additive con¬ may affect the solution by salting out effects. As
centration. The better the wetting agent, the distinct from lyophobic materials, dilution with
lower is the wet point value. the vehicle reverses the precipitation of lyophilic
The flow point is also measured by mixing the solids. However, one may not observe aggrega¬
additive with the powder, but in a beaker rather tion, the desired form of matrix formation dur¬
than on a plate. The vehicle is added and incor¬ ing sedimentation, in the case of the lyophobic
porated by thorough mixing. The endpoint is particle. The stability of lyophobic colloids is also
reached when just enough vehicle has been reduced by lowering the repulsive potential of
added to permit the mixture to flow from the the electrochemical double layer or by decreas¬
spatula in a uniform stream. The flow point may ing the degree of hydration.
be expressed as milliliters per 100 grams. The In addition to the repulsion between particles
sharpness of the endpoint varies, as in the wet resulting from the diffuse double layer, the ionic
point determination, depending on the powder, strength and the valence and size of the ions on
vehicle, and additive. The flow point may have the surface and in the double layer influence
values at a 10% additive level in the range of both the total charge (range: 0 to 50 millivolts)
50 to 250, with the better wetting agents produc¬ and the thickness of the double layer; these fac¬
ing the lower values. tors also influence hydration. Some of these
Testing an additive at only one concentration overall interrelationships are illustrated in Fig¬
may not present an accurate evaluation of its ef¬ ure 16-1. Note that increasing the concentration
fectiveness as a dispersant because dramatic of ions in the solution decreases the thickness of
decreases in the flow or wet points may be the diffuse double layer by “swamping,” and
caused by concentration changes of only a small therefore aggregation is encouraged. Specific
percentage. It is wise to investigate several addi¬ adsorption of an ion by the system also neutral¬
tive concentrations before drawing conclusions izes the surface charge of the particle and allows
relating to the utility of any particular agent. aggregation. The concentration of electrolyte
A similar technique could be applied to aque¬ needed to effect optimal aggregation depends on
ous systems. In this analogous method, water is the balance and type of interacting ion; addition
added to a mixture of the material to be wetted of electrolyte past this point may result in a re¬
and the various additives to be evaluated. Some versal of charge, which in turn would cause
test method modifications may be required to deaggregation and ultimate caking of the sys¬
ensure that the powder and additive are mixed tem. These ion effects, can be systematized by
well, that is, in both tests, the additive and pow¬ referring to the Schulze-Hardy rule.
der must be in intimate contact. This may best The Schulze-Hardy rule states that the va-

PHARMACEUTICAL SUSPENSIONS • 481

 -Wotw

+Water
Polarized water
Nermt potential

Zeta potential

Lyaphilk tyophobic

Charge Discharge

- Water

+Water Precipitated panicta

FIG. 16-1. Stability of colloidal particles in aqueous suspension depends on hydration and electrostatic charge; these
depend on the chemical composition and structure of the substrate at the liquid-solid interface. (From Industrial and
Engineering Chemistry, 54:39, J962. Reprinted by permission of the American Chemical Society.)

lence of the ions having a charge opposite to that rule applies to hydrophilic particles in a manner
of the hydrophobic particle appears to determine somewhat analogous to the Schulze-Hardy rule,
the effectiveness of the electrolyte in aggregat¬ and takes into account not only the charge but
ing the particles. The aggregating value or effi¬ also the ionic size and hydration capability. In
ciency therefore increases with the valence of order of decreasing aggregating ability, the mon¬
the ions. Divalent ions are ten times as effective ovalent cation and anion progressions are re¬
as monovalent; trivalent are one thousand times spectively Cs+, Rb+, NH4+, K+, Na+, Li+, and
as effective as monovalent. It is important to F+. I03-, H2P(V, BiOa“, Cl", CI(V, Br-,
remember that this rule is valid only for systems NO3-, CIO4-, I", CNS".
in which there is no chemical interaction be¬ Although there have been several attempts in
tween the aggregating electrolyte and the ions of the literature to clarify the imprecise terminol¬
the double layer of the particle surface. Note ogy used to describe aggregation phenomena,
also, incidentally, that aggregating forces are of the problem of definition is formidable.3,4 The
sufficient magnitude to overwhelm the electro¬ terms used in colloid science and pharmaceuti¬
static repulsion between particles having net cal science do not coincide, and to make matters
charges of the same sign. With respect to actual worse, individual workers tend to use the terms
electrolyte concentrations used, satisfactory ag¬ “flocculation,” “coagulation,” and “aggregation”
gregation has been found to occur at the follow¬ interchangeably. Regardless of the mechanism
ing approximate ion concentrations: 25 to 150 of aggregation, it is convenient to classify the
mmol/L for monovalent ions, 0.5 to 2.0 mmol/L end result of the aggregation of suspension par¬
for divalent ions, and 0.01 to 0.1 mmol/L for tri¬ ticulates on the basis of the morphologic charac¬
valent ions. The influence of valence and con¬ teristics of the aggregate.
centration on the aggregation of a lyophobic Note first the open network aggregate, or floc-
particle suspension can be determined experi¬ cule. This aggregate is characterized by a fi¬
mentally by either measuring the change in zeta brous, fluffy, open network of aggregated parti¬
potential or by observing the degree of aggrega¬ cles,4 as illustrated by Figure 16-2. The
tion in terms of some measurable parameter structure is quite rigid; hence, these aggregates
such as sediment height. settle quickly to form a high sediment height
Although it is not pharmaceutically useful to a and are easily redispersible because the particles
great extent, the Hofmeister or lyotropic series constituting individual aggregates are suffi-

482 • The Theory and Practice of Industrial Pharmacy

 o o o
o
O O o o
FIG. 16-4. An artist’s conception of dispersed suspension
form.

pared with the closed and open aggregate types),

attains the lowest possible sediment height, and
owing to the closeness of the particle surfaces
FIG. 16-2. An artist’s conception of open-network suspen¬
sion aggregate. upon sedimentation, possesses a high potential
for caking, because of the ease of formation of
extensive crystal bridging, which is mentioned
ciently far apart from one another to preclude later in this chapter. Obviously, a pharmaceuti¬
caking. cal suspension must be redispersible on only
Note second the closed aggregate, or coagule. mild agitation to ensure dosage uniformity.
This aggregate is characterized by a tight pack¬ The tendency of particles to aggregate de¬
ing produced by surface film bonding,4 as shown pends on the forces of attraction and repulsion
by Figure 16-3. These aggregates settle slowly to between them. If the repulsion is of sufficient
low sediment heights that approach the sedi¬ strength, the particles remain dispersed; if not,
ment density of a dispersed particulate system, they aggregate. The attractive forces between
which is discussed in the following paragraph. particles is thought to be due to London or van
Characteristically, sediments composed of der Waals forces. The van der Waals forces of
closed aggregates are not easily redispersed. The intermolecular attraction were named after a
affinity of surface films to each other is responsi¬ scientist who used certain constants in the gas
ble for the tenacity of the aggregate not only equation he formulated as a correction to the
within an individual aggregate, but also to sur¬ ideal gas law. The forces are due to combina¬
rounding aggregates. Upon sedimentation, the tions of ionic, dipole, and induced dipole intera¬
aggregates tend to form a single large “film- tomic and intermolecular phenomena effected
bonded” aggregate, which is difficult, if not im¬ through dipole moments; the London forces ter¬
possible, to redisperse. The surface films that minology emphasizes the induced, dipole—as¬
lead to coagule formation are often surfactants, pects. For example, in a suspension of clay parti¬
gases, immiscible liquids, and in the case of cles, as an increasing amount of sodium chloride
nonaqueous suspensions, water. is added, the repulsive forces decrease. As in¬
In addition to the two aggregation types just creasing amounts continue to be added, the re¬
discussed, one should be cognizant of the deag- pulsive forces can no longer counteract the van
gregated or dispersed form. In this suspension der Waals attraction, and the system aggregates.
type, the individual particles are dispersed as Sedimentation and aggregation rates are prop¬
discrete entities,4 as illustrated by Figure 16-4. erties of suspension systems governed by parti¬
This suspension type sediments slowly (as com- cle size, particle-particle interactions, densities
of the particles and the medium, and the viscos¬
ity of the continuous phase. Subsidence is a
term often used to describe the settling of an
aggregated system and refers to the settling rate
or descending of the boundary between the sedi¬
ment and the clear supernatant above it. In
polydispersed systems (i.e., those having many
different particle sizes present), this measure¬
ment is of little value because the boundary is
not well defined. In this case, the large particles
settle downward more rapidly than the smaller
FIG. 16-3. An artists’s conception of closed suspension particles, whereas in concentrated aggregated
aggregate. suspensions, the larger particles exhibit hin-

PHARMACEUTICAL SUSPENSIONS • 483

dered settling, and the smallest setde more rap¬ type tend to cake easily, owing to the compact
idly. In aggregated suspensions, the particles axe sedimentation that occurs when these suspen¬
linked together into floes, which initially settle sions settle. Since suspensions are saturated so¬
according to the size of the floe and porosity of lutions of the particulate substance, small
the aggregated mass. Later, the rate is governed changes in temperature that occur during shelf
by compaction and rearrangement processes. A storage lead to unexpectedly rapid caking via
clear supernatant is formed on settling, since crystal bridging, much in the same way that
even the smallest particles are entrapped in the crystal growth yields can be optimized by alter¬
mesh-like network of the floe. Intermediate nately warming and cooling a mother crystalliza¬
states are possible in which all particles are not tion liquor. This process, known as Ostwald rip¬
associated with floes. ening, is unavoidable in pharmaceutical
As experimental examples, it is noted that suspensions of the dispersed type. Caking via
Jones, Matthews, and Rhodes studied the stabil¬ crystal bridging can be minimized by utilizing
ity of sulfaguanidine suspensions as they were the open network aggregate (floccule) suspen¬
affected by electrolyte (aluminum chloride), sion type, as the particles cannot sediment to a
type and concentration of surfactant (cetyltri- close proximity because of the rigidity of the
methylammonium bromide, polysorbate 80), aggregate. From a practical point of view, since
and nature of vehicle (water with various fully aggregated suspensions are often un¬
amounts of glycerol).5 They achieved optimum sightly, partial aggregation is often a desired ob¬
stability by balancing the adjuvants to obtain a jective, as it leads resistance to caking and im¬
controlled aggregation. Also of interest, Carless parts esthetic qualities to a suspension
and Ocran related, in hectorite dispersions, for formulation.
example, particle shape, particle interaction Caking can also occur by extensive closed ag¬
mediated by added electrolytes, and some rheo¬ gregate (coagule) formation, although the mech¬
logic properties.6 As reported in a patent, Storz,7 anism of nonredispersibility is different in that
doing research on intramuscular injectables crystal bridging is not involved. A sedimented,
containing steroidal and other water-insoluble highly coagulated suspension tends to form
medicaments, found that a pharmaceutically large coagules as the surface films present on
elegant, readily redispersible, stable, well- coagulated particles cause the “filmed” particles
preserved, moderately aggregated suspension to cling to each other. Although crystal growth
would form in an aqueous vehicle having as may not occur upon sedimentation because of
additives a nonionic polyether surfactant (up to the presence of the surface films, the end result
1% of, for example, polysorbate 80, PEGs, or of a film-bonded sediment that cannot be redis¬
polyoxyethylenepolyoxypropylene block poly¬ persed is often observed for coagulated suspen¬
mers) and normal preservative concentrations of sions.
benzyl alcohol (0.5 to 1.5%) and the parabens
(0.1 to 0.3%).
To determine whether a suspension is aggre¬
Sedimentation Rates
gated, a differential manometer can be used to
compare the pressure of a suspension near its With regard to actual settling rates, the well-
bottom and top in a container. This device has known Stokes relation describes the sedimenta¬
been described by Tingstad.8 An aggregated sus¬ tion velocity of a particle in suspension:
pension shows the same pressure at both points,
as it exerts little or no pressure on the liquid be¬ 2 r2(di - d2)g = D2(d] - d2)g
cause the particles essentially support each 9rj I817
other. A deaggregated suspension, however,
exerts more pressure near its bottom. where v = velocity of the sedimentation in cm/
Caking is defined as the formation of a sec; r = particle radius and D = particle diame¬
nonredispersible sediment within a suspension ter in cm; di and d2 = density of the particle and
system. The major causes of caking are crystal the liquid, respectively, in g/ml; g=
bridging and closed aggregate (coagule) forma¬ gravitational constant = 980.7 cm sec-2; and
tion. 77 = the viscosity of the medium in poises, i.e.,

In crystal bridging, particle surface crystal g cm-1 sec-1 in cgs units. Note, incidentally,
growth occurs on two or more particles simulta¬ that water at 20° has a viscosity of approximately
neously and results in the steady formation of one centipoise (0.01 poise). The student should
crystal-finked particles, ultimately leading to the be aware of the fact that assumptions were
formation of a highly linked sediment akin to needed to facilitate the derivation of this rela¬
concrete or plaster. Suspensions of the dispersed tionship. Pharmaceutical systems containing

484 • The Theory and Practice of Industrial Pharmacy

less than 2 g of solids per 100 ml generally fol¬ paragraph.) Fluid flow through packed beds had
low the Stokes equation. Obviously, if the two been previously treated mathematically by
densities involved are such that a negative ve¬ Kozeny. Starting with the Kozeny equation,
locity results, this is the rate of flotation or Higuchi developed an equation that somewhat
creaming. resembles the Stokes equation with respect to
To illustrate by example a Stokes Law calcula¬ the parameters needed to solve it. Specifically,
tion, one could find the settling rate of a particle one needs all the factors in Stokes’ Law except
having a radius of 4 microns and a specific grav¬ the particle radius, and in addition, one needs
ity of 4 in a medium with a viscosity of 100 cps an empiric constant, the volume fraction of the
and a specific gravity of 1.2. Using the Stokes phases (which is a measure of the porosity of the
equation (after changing the radius and viscos¬ “bed”), and the specific surface area of the parti¬
ity to the proper units), a velocity of approxi¬ cles, i.e., the area in cm2/g.
mately 1 x 10~4 cm/sec is found. This means Such an equation does not take into account
that this suspension packaged in a 10-cm high the size or size distribution of the particles (an
bottle would settle in 105 sec or in a little over advantage over Stokes), and it is of some validity
one day. Similar “ideal calculations” make it where it can be used, i.e., in more concentrated
clear that pharmaceutical suspensions are des¬ systems in which the suspended phase forms a
tined to settle, even though one can slow the sort of bed or where the aggregated structure is
process, well within the shelf-life times of phar¬ relatively firm. The equation has not been sub¬
maceutical products. As the equation indicates, jected to a great deal of experimental verifica¬
the parameter most powerful in changing the tion, but sample calculations show that the
velocity of the settling is the particle diameter or Stokes relationship (which does not take into
radius, as it is a squared term; as technologists, account explicitly the concentration of the inter¬
the formulators are most able to control this and nal phase) gives too fast a rate of settling as op¬
the viscosity of the medium. posed to actual observations made on more con¬
Although the Stokes equation has been pre¬ centrated suspensions. The newer equation
sented in the pharmaceutical literature for many shows that the rate of settling decreases rapidly
years, a reader of Stokes’ original publications with the concentration of solid phase. Pharma¬
will discover, as a point of historical interest, ceutically speaking, the extension of this con¬
that pharmaceutical suspensions were not an cept corroborates the observation that pastes do
object of his studies. George Gabriel Stokes, a not settle in the usual sense, although small
professor of mathematics at the University of quantities of liquid components may separate.
Cambridge more than a century ago, wrote pa¬ The new equation neglects, as does Stokes’ Law,
pers on hydrostatics that dealt with the motion the contribution made to suspension stability by
of fluids around spheres and with the motions of the various particle interactions. In summary, it
pendulums in fluids. is interesting to observe that suspensions are
To handle more concentrated pharmaceutical complex systems from a theoretic standpoint.
suspensions (i.e., those containing more than Regarding sedimentation and factors affecting
10 g of solid per 100 ml) requires the develop¬ it, it should be remembered that as the solids
ment of equations that go beyond the Stokes der¬ content is increased, viscosity also is increased.
ivation. Obviously, the mathematics becomes Hence, study of the viscosity characteristics of
even more complex if one tries to handle the vehicle alone may not always produce valid
heterodispersed particles (i.e., not all particles observations. Also, the discussions of particle
are the same size), and in addition, irregularly charges, aggregation, zeta potential, and sedi¬
shaped particles. One can, however, bring basic mentation rates dealt with aqueous systems.
physical and chemical thinking to the kinetic The vehicles used for pharmaceutical suspen¬
settling and creaming problems; although exact sions are usually aqueous, but may be oleagi¬
and completely useful equations may not be de¬ nous. Examples of oleaginous vehicles include
veloped, some conceptual value is gained. peanut, sesame, cottonseed, com, safflower, and
T. Higuchi,9 among others, has approached castor oils and also fluorocarbon aerosol propel¬
this problem of the hindered settling of relatively lants. Particle-particle and particle-liquid inter¬
concentrated suspensions and has obtained an action vary greatly depending on the vehicle.
equation with somewhat fewer limitations. By Since the electrical potential between two
recasting the problem, he considered the set¬ charges is inversely proportional to the dielectric
tling phenomenon to be equivalent to the move¬ constant of the medium between them, the dis¬
ment of an external liquid phase through a bed tribution of ions in the double layer also depends
of internal phase. (Note the similarity to the on the dielectric constant of the vehicle. In low
studies of Stokes mentioned in the second last dielectric liquids such as oils, the double layer is

PHARMACEUTICAL SUSPENSIONS • 485

many times thicker than in aqueous systems Crystal Structure Factors
with high dielectric constants. It is therefore
much more difficult to produce an aggregated A question of fundamental importance arises
particle structure in a low dielectric medium. when formulations are prepared by either dis¬
persion or precipitation techniques. It concerns
the effect, if any, that the method of preparing
the particles has on their initial or subsequent
physical stability in the suspension. Effects on
Crystal Habit the properties of the crystals are more often pro¬
Crystal habit may be defined as the outward duced when the precipitation procedure is used
appearance of an agglomeration of crystals. Al¬ to create the particles. Closely allied in impor¬
though seemingly trivial, crystal habit can be of tance to the way the particles are prepared are
great importance in suspension redispersibility, the nature of the vehicle used and its effect on
sedimentation, physical stability, and appear¬ suspension properties. Smith, Buehler, and Rob¬
ance. For example, sulfisoxazole can be pro¬ inson, during development of a sustained action
duced in a single geometric crystal form having suspension of an insoluble derivative of dextro¬
relatively similar sizes, but an agglomerate of methorphan, noted that dramatic differences in
the crystals can have physical properties vastly physical behavior and stability were encoun¬
different from those of single crystals. Small tered when the derivative was coated by differ¬
clumps of sulfisoxazole crystals may exhibit lit¬ ent methods and crystallized from different sol¬
tle tendency to disperse because of the tenacity vent systems.10
of the clump. These clumps may exhibit re¬ The factors controlling crystal characteristics
tarded dissolution and thus retarded bioavaila¬ involve basically either the production of a
bility rates due to the inability of a dissolution change in crystal habit (physical shape such as
fluid to penetrate to the interior crystal compo¬ needle, plate, prism) or the production of no
nents of the clump. change in crystal habit. When there is no
A mental picture of the effect of crystal habit change in the crystal habit, the following factors
can be gained by considering sucrose in all of its may still be considered: drug decomposition
commercial forms. Rock candy, lump sugar, leading to salting in or out, pH changes with
granulated sugar, and powdered confectioner’s changes in the particle size distribution, and the
sugar are all crystalline sucrose having identical effect of change in temperature. When there is a
crystalline geometry. Each of these forms of su¬ change in crystal habit, solvation and poly¬
crose, however, possesses distinctly different morphism (presence of one or more crystalline
dissolution rates in water. The effect is directly and/or amorphous forms) are of importance. It is
attributable to the crystal habit. Much in the also notable that the rate of physiologic absorp¬
same way, crystalline drugs destined for suspen¬ tion can be greatly altered, depending on which
sion formulation can exhibit different physical crystalline or amorphous forms are adminis¬
properties due to the influence of different crys¬ tered.
tal habits. Drug breakdown may occur because the prod¬
Traditionally, crystal habit was classified on ucts of decomposition cause a shift in pH, which
the basis of the geometry of the agglomerate in turn, could have a marked effect on solubility.
(needle, prism, plate, etc.), but in reality, most A salting in effect also may exert an autocatalytic
crystal habit morphology is of a nondescript effect on the rate of drug decomposition. These
form. The relatively strong, rigid crystalline effects are particularly apparent when the chem¬
structure that exists within a crystal is not re¬ ical stability of suspensions is studied at ele¬
sponsible for the agglomeration of crystals. vated temperatures: This is a good reason for
Rather, weak van der Waals interactions occur¬ viewing data obtained from high temperature
ring at crystal surfaces hold the agglomerate of storage studies with caution because these con¬
crystals in form. Mostly, this occurs as non- ditions may contribute to the manifestation of
geometrically classifiable clumps. greater chemical instability than may occur at
For reasons delineated previously, it is impor¬ room temperature.
tant for the pharmaceutical formulator to specify The effect of cyclic temperature changes, as
the desired crystal habit for component crystal¬ mentioned in the discussion of caking, is impor¬
line ingredients in pharmaceutical formulations tant in measuring suspension stability from a
and to specify quality control procedures so that physical as well as chemical standpoint. The
possible changes in crystal habit, which may temperature effects depend on the magnitude of
adversely affect a finished pharmaceutical prep¬ the change in temperature over a given period of
aration, may be adequately tracked. time, the time interval, the effect of temperature

486 • The Theory and Practice of industrial Pharmacy

on the solubility of the suspended drug, and on stable polymorph may be rapid or slow. When
recrystallization phenomena. With respect to this rate of conversion is very slow, it may be
the latter point, it is known that at each crystal feasible to use the metastable form commer¬
contact point there exists a thin layer of super¬ cially. On the other hand, if it occurs within
saturated solution that facilitates crystal growth. days, as for example in the case of cocoa butter,
The type of inherent crystal form may be nee¬ the metastable form may not interfere with the
dles, plates, cubes, rods, or prisms, and produc¬ material when used in a marketed product. Con¬
tion of these is determined by the factors that versions of intermediate speed, i.e., those that
govern the rate of crystal growth. The rate of occur gradually over a period of one to several
cooling, the extent and degree of agitation, and months, could be troublesome.
the size and number of nuclei are all elements
that affect the degree of supersaturation of the
solution in contact with the crystal. Other im¬ Suspension Formation
portant factors include pH, solvent effects, and
perhaps most important, the impurities present.
The formation of distinct new crystalline entities Precipitation Methods
during storage due to solvation and polymorph¬ Three precipitation methods are discussed in
ism is also a possibility. An originally anhydrous this section: organic solvent precipitation, pre¬
drug in suspension may rapidly or slowly form a cipitation effected by changing the pH of the
hydrate. medium, and double decomposition.
Experimentally, Varney investigated the fac¬ Water-insoluble drugs can be precipitated by
tors controlling the sensitivity of crystalline sus¬ dissolving them in water-miscible organic sok.
pensions to temperature fluctuations.11 He vents and then adding the organic phase to dis-
showed that crystal growth increases with an tiifed water under standard conditions. Exam¬
increase in particle solubility; thus, excipients ples of organic solvents used include ethanol,
that increase the particle solubility should be methanol, propylene glycol, and polyethylene
kept to a minimum. Also demonstrated was the glycol. Several important considerations are in¬
fact that in a dilute suspension, growth in¬ volved when this method is used. Perhaps the
creases with stirring (as compared to a quiescent most important factor next to particle size con¬
formulation), since the mean free diffusion path trol is that the “correct” polymorphic form or
of the solute molecules is reduced. Similarly, if hydrate of the crystal he obtained. For example,
sedimentation occurs—even if the sediment is different forms are obtained when prednisolone
easily redispersed—the local increase in particle is precipitated from aqueous methanol as op¬
concentration increases particle growth. posed to aqueous acetone. The methanolic pre¬
Polymorphism as applied to crystals specifi¬ cipitate forms a sesquihydrate when dried,
cally refers to the different crystal structures the whereas the acetone precipitate forms a meta¬
same chemical compound may have. These var¬ stable, anhydrous, crystalline product; only the
ious forms may exhibit different solubilities, former is easily suspended in water. Besides the
melting points, and x-ray diffraction patterns. influence of the solvent on crystal characteris¬
The storage temperature, the solvent chosen for tics, the following additional factors may need to
crystallization, and the rate of cooling are impor¬ be considered: possible preparation under sterile
tant factors in determining which polymorph is conditions, inherent solvent entrapment and
obtained, and at what speed it is obtained. All subsequent toxicity, the volume ratios of the
organic substances appear to exist in several pol¬ organic to the aqueous phase, rate and method
ymorphic forms. In fact, experts have remarked of addition of one phase to the other, tempera¬
that the number of forms found and character¬ ture control (cooling rate and drying conditions),
ized is directly proportional to the time and method of drying the precipitate (forced air, vac¬
money spent looking for them. It is usually eco¬ uum, or freeze drying), and finally, the washing
nomically prohibitive to prepare a large number of the precipitate. Sometimes,'the need for a
of polymorphic forms and then proceed to test ■ narrow particle size range for parenteral or inha¬
them to find the most stable ones. Quite exten¬ lation therapy is indicated. With respect to the
sive studies have been done on cortisone, how¬ latter point, the particles should be in the 1- to
ever; of the four polymorphic forms of cortisone 5-micron range. If they are too small, they are
acetate known, only one is stable in aqueous exhaled; if too large, they are not able to get to
media. Another example that may be cited is and be absorbed from the lung area. The com¬
prednisolone; of the prednisolone polymorphs, bined use of sterile precipitation, drying,
only one is stable in aqueous media. micronization, ethylene oxide sterilization, and
The rate of conversion of a metastable to a sterile resuspension may be necessary. Where

PHARMACEUTICAL SUSPENSIONS • 487

 pertinent, sterilant residues should not be over¬ rate of nucleation are greatest at the beginning
looked (e.g., ethylene glycol from ethylene oxide of the process, so that crystals formed initially
gas sterilization procedures). become the largest because they are exposed to
The method of changing the pH of the me¬ the supersaturated solution for the longest pe¬
dium is perhaps more readily accomplished and riod of time. It appears, therefore, that when less
does not present the same difficulties associated concentrated solutions are used, the particle size
with organic solvent precipitation. The tech¬ distribution is broader than when more concen¬
nique, however, is only applicable to those drugs trated solutions are used.
in which solubility is dependent on the pH Making suspensions by double decomposition
value. For example, estradiol suspensions can involves only simple chemistry, although some
be prepared by changing the pH of its aqueous of the aforementioned physical factors also come
solution; estradiol is readily soluble in such al¬ into play. The reader is referred to standard
kali as potassium or sodium hydroxide solutions. pharmacy texts to review the preparation of
If a concentrated solution of estradiol is thus White Lotion (NF XIII), that is, forming zinc
prepared and added to a weakly acidic solution “polysulfide” by mixing zinc sulfate and sulfu-
of hydrochloric, citric, or acetic acids, under rated potash solutions.
proper conditions of agitation, the estradiol is
precipitated in a fine state of subdivision. The
type of crystal or polymorphic form depends on Dispersion Methods
such factors as the concentrations of acid and When the dispersion method is utilized for
base and the degree and type of fluid shear im¬ suspension preparation, the vehicle must be for¬
parted to the system. mulated so that the solid phase is easily wetted
Insulin suspensions also may be prepared by a and dispersed. The use of surfactants is desira¬
pH change method. Insulin has an isoelectric ble to ensure uniform wetting of hydrophobic
point of approximately pH 5. When it is mixed solids. The use of suspending agents, such as
with a basic protein, such as protamine, it is the synthetic polymeric polyelectrolytes, natural
readily precipitated when the pH is between the gums, or clay, may be indicated, depending on
isoelectric points of the two components, i.e., the specific application. The actual method of
pH 6.9 to 7.3. Protamine zinc insulin (PZI) con¬ dispersing the solid is one of the more important
tains an excessive quantity of zinc to retard ab¬ considerations because particle size, reduction
sorption. According to the British Pharmaco¬ may or may not result from the dispersion proc¬
poeia of 1958, a phosphate buffer is added to ess. If particle-size reduction occurs, the parti¬
each individual vial containing the acidified so¬ cles obtained may have different solubilities if a
lution of insulin, protamine, and zinc, so that metastable state is involved, and this may lead to
the pH is between 6.9 and 7.3; the preparation is transient supersaturation of the system. A num¬
compounded in the final container by mixing ber of dispersion methods axe used to prepare
the PZI and the buffer in the filling operation. suspension products. For present purposes,
Adrenocorticotropin (ACTH) zinc suspensions there is no need to describe and discuss the
are prepared in a similar manner. The precipi¬ comminuting and shearing equipment commer¬
tate formed in the process is zinc hydroxide or cially available because information on such
zinc phosphate, on which the ACTH is ad¬ equipment is easily obtained. The reader need
sorbed; this combination results in a long acting only recall that much of what has been and will
preparation when administered. The addition of be discussed with respect to basic suspension
phosphate salts and organic phosphate to pre¬ technology applies regardless of how the sus¬
pare an even longer acting ACTH preparation is pension is made.
also possible.
When either the change in pH or the organic
solvent precipitation method is used to prepare a Formulation of Suspensions
suspension, a degree of supersaturation is As the discussion thus far implies, many fac¬
brought about suddenly in the batch process to tors must be considered in the course of devel¬
give rise to crystal nucleation and growth, after oping a suspension dosage form. The basic con¬
which the initial supersaturation subsides. cern involves the fact that suspensions settle,
Thus, the degree of supersaturation changes and it is necessary to redistribute them before
throughout the process, and neither the rate of using or dispensing them as products. A desira¬
nucleation nor the rate of crystal growth is con¬ ble suspension should be easily redispersed by
stant; therefore, the particle size distribution is shaking, should remain suspended long enough
variable. The degree of supersaturation and the to withdraw an accurate dose, and should have

488 • The Theory and Practice of Industrial Pharmacy

the desired flow properties. In the early phases must be careful, especially with the nonionic
of formulation, a decision must be made as to surfactants, not to use too high a concentration
the general type of suspension system desired. of the agent. Over the critical micelle concentra¬
As noted, aggregated systems usually exhibit a tion, intact micelles are adsorbed to particle sur¬
minimum of serious separation, depending on faces, providing a continuous film for coagule
the solids content and the degree of aggregation formation, as discussed previously.
that has taken place. At times, an aggregated Suspension systems intended for oral, paren¬
system may appear to be coarse because of the teral, ophthalmic, or topical use may not appear
aggregates formed. On the other hand, in a dis¬ elegant because they usually exhibit poor drain¬
persed system, the particles are well distributed age in vials or bottles due to the clusters of parti¬
and settle singly but more slowly than an aggre¬ cles. These properties may be improved by the
gated system. The particles, however, have a addition of protective colloids. Protective colloids
tendency to fonn a sediment or cake that is diffi¬ differ from surfactants in that they do not reduce
cult to redisperse. interfacial tension. Their solutions differ in vis¬
cosity and are used in higher concentrations
than are surfactants. Protective colloids also dif¬
Aggregated (Open Network fer from other agents in that their effect is due
Aggregate) Systems not only to their ability to increase the zeta po¬
tential, but also to their formation of a mechani¬
Before aggregating the suspension particles in
cal barrier or sheath around the' particles. .An
the open network aggregate, it is important to
example of this approach is-the use of silica gel,
ensure that the particles are well dispersed in
a form of precipitated silicic acid. It is used in
the aqueous phase or other vehicle. A proper
concentrations up to 10% and may be gelled
surfactant in appropriate concentration im¬
with surfactants; it is primarily limited to topical
proves the dispersion by reducing the interfacial
preparations. Another example involves the use
tension. For example, if surfactants with nega¬
of aluminum hydroxide gel as a vehicle; com¬
tive charges are adsorbed on the particles, this
mercially, this approach was employed in a tri¬
prevents or minimizes aggregation in the pres¬
ple sulfonamide suspension. When this type of
ence of positive ions because of the mutual re¬
vehicle is used, it is important to consider the
pulsion of like charges. Examples of such agents
alkalinity present and its possible effect on the
include sodium lauryl sulfate and sodium dioctyl
active ingredient. Hence, the use of a nonreac¬
sulfosuccinate.
tive type of gelling agent may be advantageous.
The concentration of added electrolyte neces¬
sary to produce the aggregated state corresponds
to the quantification expressed in the Schulze- Dispersed Systems
Hardy rule previously discussed. In some cases
As previously discussed in the section “Parti¬
in which incompatibility factors are absent, very
cle Interactions and Behavior,” the individual
small amounts of aluminum chloride or potas¬
particles in dispersed systems are generally dis¬
sium biphosphate may act as aggregating
persed with the aid of an agent to lower the in-
agents. In practice, a nonionic surfactant is usu¬
terfacial tension. To maintain this state, how¬
ally used to aid the dispersion of the insoluble
ever, a viscosity-imparting suspending agent is
phase. Polyoxyethylene ethers of mixed partial
usually required as an adjunct. These agents
fatty acid esters of sorbitol anhydrides
retard settling and agglomeration of the particles
(Tweens),* the same compounds without the
by functioning as an energy barrier, which mini¬
hydrophilic oxyethylene groups (Spans),’ higher
mizes interparticle attraction and ultimate ag¬
molecular weight polyethylene glycols (Car-
gregation. The general choice of suspending
bowaxes),* and molecular combinations of
agents includes protective colloids, viscosity-
polyoxyethylene and polyoxypropylene (Pluron-
inducing agents, surfactants, and dispersing
ics),* are frequently used in this manner. One
agents. Combinations of various types of sus¬
pending agents may be used to achieve the de¬
sired rheologic properties. It is particularly with
‘Tween and Span are trademarks of ICI United dispersed suspension systems that the following
States Inc., Concord Pike and New Murphy Road, Wil¬ factors involved in Stokes’ Law become impor¬
mington, DE 19897. Carbowax is a trademark of the
Union Carbide Corporation, Chemicals and Plastics,
tant: the particle size, the density of the vehicle
270 Park Avenue, New York, NY 10017. Pluronic is a and of the particle, and the viscosity of the me¬
trademark of BASF Wyandotte Corporation, 1609 Biddle dium. Some of the suspending agents used to a
Avenue, Wyandotte, MI 48192. large extent in formulation include modified cel-

PHARMACEUTICAL SUSPENSIONS • 489

lulose polymers, proteins such as gelatin, and Clays can be formulated in systems in which the
totally synthetic polymers. Of the modified cel¬ pH is between 6 and 11, but they are most stable
lulose polymers, sodium carboxymethylcellulose between pH 9 and 11. Alkaline buffers usually
(CMC),* methylcellulose (Methocel),* and are included to maintain the pH. All dispersions
hydroxypropylmethylcellulose (Methocel, HG)* of the clays are drastically affected by electro¬
are widely used in oral, topical, and parenteral lytes in accordance with the Schulze-Hardy rule;
dosage forms. Sodium carboxymethylcellulose is ethanol also affects these agents by dehydrating
an anionic polymer, whereas methylcellulose the colloid, thereby reducing the viscosity. Clay
and hydroxypropylmethylcellulose are nonionic. suspensions and gels are excellent media for
Sodium carboxymethylcellulose is used in con¬ mold and bacterial growth, and should therefore
centrations of up to 0.5% in injectable prepara¬ be adequately preserved with nonionic antimi¬
tions. In oral dosage forms, they are frequently crobial preservatives. The paraben esters and
used in higher concentrations because of the benzoates are useful, but cationic “quaternary”
higher solids content of the systems. Sodium preservatives are ineffective. Heat and aging
carboxymethylcellulose does have some disad¬ usually increase the viscosity of clay mixtures,
vantages: it is incompatible with a number of but this may become less significant in the more
electrolytes and quaternary ammonium com¬ concentrated systems.
pounds, and it forms complexes with certain As noted, another Stokes’ Law factor that is
surfactants. Methylcellulose and hydroxypropyl¬ especially important in deaggregated systems is
methylcellulose gel on heating and are affected the density of the medium. There are several
by electrolytes. One of the more useful of the ways to approach density adjustment when fea¬
totally synthetic polymers is polyacrylic acid sible. The addition to die system of nonionic
(Carbopol);* it is used mostly in external lotion substances such as sorbitol, polyvinylpyrroli¬
and gel preparations. After being uniformly dis¬ done, glycerine, sugar, or one of the polyethyl¬
persed in water, it is neutralized with an organic ene glycols (or combinations of these) may be
amine such as triethanolamine or with inor¬ helpful. In addition to the change in the density
ganic alkali to achieve the desired viscosity in a of the medium, a considerable effect on the vis¬
range from pH 6 to 10. The material is ex¬ cosity also may be achieved, owing to the viscos¬
tremely sensitive to electrolytes, but is suited for ity-building effects created by hydrogen bonding
use equally in aqueous and nonaqueous sys¬ of the water molecules and the glycols. When
tems. These polymeric agents function primarily suspensions of higher solids content are pre¬
as protective colloids and alter the viscosity of pared, as in toothpastes, for example, the use of
the medium. a combination of a clay and a gum such as so¬
As a group, the clays (essentially hydrated alu¬ dium carboxymethylcellulose may be desirable.
minum and/or magnesium silicates) are also
quite useful in suspension formulating. They
hydrate further in water to a high degree to form
colloidal dispersions having high viscosities.
The manner in which the members of the group Rheologic Considerations
are prepared, however, has a profound effect on The rheologic characteristics of a pharmaceu¬
the final product. The clay should always be tical suspension can be of great importance as
added to the water with high shear to effect uni¬ the determining factor in the optimization of the
form dispersion and maximum hydration. The physical stability of the suspension system. In
pH of aqueous clay dispersions is somewhat al¬ particular, a suspension that possesses highly
kaline, in the range of pH 8.5 to 9.5; therefore, developed thixotropy is most desirable. Such a
they also possess some acid neutralizing capac¬ suspension, properly formulated, can prevent
ity. The viscosity of aqueous dispersions of these sedimentation, aggregation, and caking by vir¬
agents varies, depending on the type and tue of a high yield-value/viscosity at rest, while
amount of solids dispersed. In general 5 to 10% sharp agitation reduces the viscosity to permit
concentrations of the clay form firm opaque gels. pouring and thus dispensing of the product. The
high viscosity can reform rapidly when the sus¬
pension is again at rest, virtually eliminating the
*CMC is a trademark of Hercules Inc., 910 Market Street, possibility of the physical instabilities previously
Hercules Tower, Wilmington, DE 19899. Methocel is a discussed. The bentonite clays and some poly¬
trademark of the Dow Chemical Company, Abbott Road,
meric resins tend to form well-developed aque¬
Midland, MI 48640.
‘Carbopol is a trademark of the B. F. Goodrich Chemical ous thixotropic media.
Company, 6100 Oak Tree Boulevard, Cleveland, OH The pharmaceutical formulator would be well
44131. advised to expend efforts to avoid certain rheo-

490 • The Theory and Practice of Industrial Pharmacy

 logic characteristics in a pharmaceutical product and combinations of penicillin and dihydrostrep¬
under development. In particular, the following tomycin. It is also used in preparations with
rheologic characteristics are most undesirable high solids content, in which formulation modi¬
because of their poor physical stability: pseudo¬ fications cannot measurably improve the drain¬
plastic (in which there is no yield value), age of the preparation.
dilatant, and rheopexic (in which viscosity in¬ There has been a trend to package suspension
creases with shear force). systems for oral and topical administration in
polyethylene or other plastic containers. Many
factors must be considered when a suspension is
Formulation Adjuvants evaluated in-such a container. These factors in¬
Certain aspects of suspension formulation clude loss of flavor and perfume, preservative
pertain to both aggregate and dispersed suspen¬ adsorption, and leaching into the product of sub¬
sion systems and are therefore discussed to¬ stances from the container. Before evaluative
gether. Suspension adjuvants must be consid¬ procedures are discussed per se, it must be
ered. These agents include the preservative, stressed that after the initial stability observa¬
color, perfume, and flavor; they may materially tions are completed, the determination of the
^affect the characteristics of the suspension sys¬ stability of the suspension in the final package is
tem. In general, most colors are used in small an important step of the product development
quantities and are usually compatible; flavors procedure.
and perfumes are similarly used and are also
usually compatible with the vehicle. To illustrate
that one must be on guard against adjuvant in¬
teraction, it is noted that Bean and Dempsey Preparative Techniques
showed that the adsorptive power of kaolin sus¬ The actual preparation of suspensions in¬
pensions can reduce the activity of some pre¬ volves choosing the ingredients (utilizing princi¬
servatives.12 Kaolin hurt the quaternary benzal- ples already discussed) and determining the
konium chloride (BAK), but not the nonionic type of manufacturing equipment to be used.
and less surface-active m-cresol. Similarly, it Needless to say, each suspension is a separate
was shown that procaine penicillin adsorbed the case and absolute generalization is not possible.
quaternary and that the supernatants of the BAK If the suspension is made by a dispersion
systems had less activity than the suspensions; process, it is best to achieve pulverization of the
thus, the adsorbent acted as a reservoir. solid by a micronization technique. This in¬
Perhaps the final “adjuvant” one should con¬ volves subjecting the particles to a turbulent air
sider is the package. Usually, initial laboratory chamber in which they collide with each other
screening employs conventional graduates or and fracture. Particles under 5 microns are
readily available bottles. When final packaging readily obtained. Although it is not widely used
is considered, it should be noted that various for this purpose, spray-drying also can be con¬
types of glass are available. The types vary with sidered a method of comminution to produce a
respect to their ability to resist water attack, the finely divided solid phase.
degree of attack being related to the amount of If the suspension is made by controlled crys¬
alkali released from the glass. The USP should tallization, a supersaturated solution should be
be consulted for further details, as it describes formed and then quickly cooled with rapid stir¬
both the tests and standards that should be met ring. This causes the formation of many nuclei
by containers to be used for packaging paren¬ and hence many crystals; it is just the opposite
teral and nonparenteral (oral or topical) prod¬ of letting crystals grow large.
ucts. One point of terminology may be noted: At some time during suspension formation, it
“flint” refers to clear, colorless, brilliant glass. is likely that shearing will be desired. This ho¬
Originally, it contained lead and was also called mogenization can be accomplished by the con¬
“lead” or “crystal” glass; today in commerce, ventional stator-rotor colloid mills. Ultrasonic
nonlead, highly color-free, soda-lime-silica equipment also can be used to effect high inten¬
glasses, the most common general-purpose sity mixing, but usually, this technique is not
transparent glasses, are also called flint. Paren¬ applied commercially. Of interest, however, is
teral multiple-dose vials may be “flint” (color¬ the work of Sheikh, Price, and Gerraughty, who
less) or amber, and may be silicone-coated to studied the effect of ultrasound on polyethylene
improve drainage of the suspensions. (Silicone spheres in aqueous suspension.15 The ultra¬
coating also minimizes the leaching of alkali sound reduced the sphere size only when sur¬
from the glass.) This technique of silicone coat¬ factants were added, especially those having
ing is used widely for suspensions of steroids high HLBs. When such agents were used as

PHARMACEUTICAL SUSPENSIONS *491

additives, the particles were readily dispersed treated lightly even though it does not deal with
and hence completely surrounded by liquid. absolute standards.
Since ultrasound waves and cavitation shock
waves are transmitted to the particles through
the liquid medium, a poor suspension would not
be as susceptible to size reduction as a better Sedimentation Volume
dispersed one. Excessive sheaiing (or high tem¬ Since redispersibility is one of the major con¬
peratures) may irreversibly damage polymeric siderations in assessing the acceptability of a
materials such as gums, so that viscosity loss is suspension, and since the sediment formed
suffered. Instead of trying to hydrate gums and should be easily dispersed by moderate shaking
clays by massive shearing, it is often better, to yield a homogeneous system, measurement of
when possible, to give the material the neces¬ the sedimentation volume and its ease of
sary time to hydrate under conditions of mild redispersion form two of the most common basic
shearing. An alternate procedure is to mix with, evaluative procedures.
or preferably spray the gum with, a chlorinated The concept of sedimentation volume is sim¬
hydrocarbon, acetone, or alcohol solution of a ple. In short, it considers the ratio of the ulti¬
wetting agent (e.g., sodium dioctyl sulfosucci- mate height (Hu) of the sediment to the initial
nate). About 0.4% (based on the gum weight) of height (Hc) of the total suspension as the sus¬
the wetting agent should be added to the gum. pension settles in a cylinder under standard con¬
This technique can produce a marked beneficial ditions. The larger this fraction, the better is the
effect, as wetting of the gum and hence hydra¬ suspendability.
tion is greatly accelerated. Methods utilizing the sedimentation volume
A final comment is that processing studies in obtained in a cylinder offer a practical approach
a pilot plant are needed because it is axiomatic to the determination of the physical stability of
that the scale-up operation from laboratory suspension systems. Particularly good is the fact
batches to production lots brings with it many that the system remains undisturbed. Specifi¬
troubles and unexpected results. cally, it is worth knowing how to use the Hu and
H0 concepts. The formulator should obtain the
Hu/H0 ratios and plot them as ordinates with
Evaluation of Suspension time as the abscissae. Note that although the
conventional Hu is called the “ultimate” height
Stability of the sediment, ultimate really means the
Since stability testing is discussed elsewhere height at any particular time. The plot just de¬
in the pharmaceutical literature, the only em¬ scribed will at time zero start at 1.0, with the
phasis here is on the most pertinent aspects of curve then being either horizontal or gradually
suspension stability. Techniques for the evalua¬ sloping downward to the right as time goes on.
tion of heterogeneous systems generally are One can compare different formulations and
coniplex and are far from being completely satis¬ choose the best by observing the lines, the better
factory. Some test methods are so drastic that formulations obviously producing lines that are
the stability information is obtained during an more horizontal and/or less steep. Another tech¬
evaluation that destroys the system being evalu¬ nique that utilizes essentially the same parame¬
ated. Some methods are somewhat empiric in ters may be used to evaluate highly concentrated
nature, i.e., the exact basis on which they oper¬ suspensions, which might be difficult to com¬
ate cannot be explicitly defined mathematically. pare because there would be only minimum
All test procedures suffer some limitations, and supernatant liquid. The technique involves di¬
the results, therefore, must be cautiously evalu¬ luting the suspension with additional vehicle,
ated and interpreted. As the methodology in¬ i.e., with the total formula with all ingredients
volved in the pertinent stability studies is often except the insoluble phase. As an example, one
somewhat complicated, this section of the chap¬ could dilute 50 ml of a suspension to a volume
ter is more fully referenced so that further de¬ of 100, 150, or 200 ml. The Hu reading then be¬
tails can be obtained if desired. The purpose comes the volume of sediment in the diluted
here is to point out explicitly one method, and sample, and H0 equals the original volume of the
then indicate only the general nature of some of sample before dilution. The Hu/H0 ratio may in
the other approaches taken. Use of evaluation this case be greater than 1. Regardless, the ratio
techniques permits the formulator to screen the is again plotted against time, and comparisons
initial preparations made and also to compare between formulas are made as before.
One additional concept should also be consid¬
the improved formulations to competitive com¬
ered by the formulator. In ail the compansons
mercial products. The latter point should not be

492 • The Theory and Practice of Industrial Pharmacy

just mentioned, the screening technique results methods can also be used to help determine the
only in a relative ranking; this indicates which settling behavior and the arrangement of the
preparations are the better ones. It is also useful, vehicle and particle structural features for pur¬
however, to consider the possibility of making an poses of comparison.
absolute evaluation; this may be done as follows. The majority of rheologic investigations of
The degree of settling can be related to the suspension systems have been done at high
amount of sediment that would be produced in shear rates and on systems that must be made
the ultimate dispersed state. To obtain the com¬ uniform before evaluation. For present pur¬
pletely dispersed suspension form, which repre¬ poses, the importance of using low shear rates
sents the least void space for the solid phase and and undisturbed samples cannot be overempha¬
hence the smallest sedimentation volume, elec¬ sized. The prime reason for this is the fact that
trolytes that promote settling may be added or the structure achieved on storage is what should
the preparation may be centrifuged. The Hu/H0 be evaluated. A practical rheologic method in¬
ratio observed is then the lowest figure obtaina¬ volves the use of the Brookfield viscometer
ble. This figure serves as a base line and gives mounted on a helipath stand. The T-bar spindle
some idea of the degree of aggregation obtained is made to descend slowly into the suspension,
because ratios higher than this minimum repre¬ and the dial reading on the viscometer is then a
sent the existence of the desired aggregated measure of the resistance the spindle meets at
state. In reference to the plots discussed, it is various levels in a sediment. In this technique,
clear that data that produce a fine that quickly the T-bar is continually changing position and
drops toward this reference point do not repre¬ measures undisturbed samples as it advances
sent a good suspension, as any aggregation if down into the suspension. This technique also
there is any at all, is too temporary and infirm. indicates in which level of the suspension the
Another use for Hu/H0 data is possible, and structure is greater, owing to particle agglomera¬
particularly pertinent are the various relation¬ tion, because the T-bar descends as it rotates,
ships of Ward and Kammermeyer.14 In essence, and the bar is continually entering new and es¬
these workers attempted to quantitate settling sentially undisturbed material. Data obtained on
further using Hu and H0 values. It is known that samples variously aged and stored indicate
the ultimate height of the solid phase after set¬ whether undesired changes are taking place.
tling depends on the concentration of solids and Thus, using the T-bar spindle and the helipath,
the particle size. These workers found that if H0 the dial reading can be plotted against the num¬
and Hu readings (taken on a series of different ber of turns of the spindle. This measurement is
concentrations of the same solids having a par¬ made on undisturbed samples of different ages.
ticular average particle size range) are measured The results indicate how the particles are set¬
in a certain vehicle, the resulting data form a tling with time. In a screening study, the better
straight line plot if the logarithm of the weight suspensions show a lesser rate of increase of dial
percentage of solids is plotted against the ratio reading with spindle turns, i.e., the curve is hor¬
Hu/H0. One can then predict Hu for any given izontal for a longer period
solids concentration by multiplying H0 by the A method combining the use of both rheologic
“relative concentration factor,” i.e., by Hu/H0. and sedimentation parameters is illustrated by
As noted, the evaluation of redispersibility is the work of Foemzler, Martin, and Banker,
also important. To help quantitate this parame¬ who studied the effect of thixotropy on stability.
ter to some extent, a mechanical shaking device Although this method does not observe the sys¬
may be used. It simulates human arm motion tem under equilibrium conditions and is subject
during the shaking process and can give repro¬ to some challenge, the authors attempted to pre¬
ducible results when used under controlled con¬ dict physical stability by a rheologic evaluation
ditions. It should be remembered, however, that of thixotropy. Incidentally, Wood used these
the test conditions are not the same as those workers’ data to develop additional correla¬
encountered under actual use, and further test¬ tions.16 It is important to note that the use of
ing should be considered. Nevertheless, the test most viscometers and centrifuges in stability
results are useful and provide guidance during studies is not ideal for aggregated systems be¬
screening procedures. cause their use destroys the structure formed.
Wood, Catacalos, and Lieberman studied
aging magnesium aluminum silicate suspen¬
sions and uncovered interesting, logarithmic,
Rheologic Methods atypical kinetic relationships involving the time
In addition to techniques involving sedimen¬ and temperature of storage and shear rate and
tation and redispersibility factors, rheologic shear stress.17 It would not be useful to discuss

PHARMACEUTICAL SUSPENSIONS • 493

this further in detail, but for practical purposes, the physiologic availability and thus the thera¬
it is noted that work such as this illustrates that peutic effect of the active ingredients may be
clay and gum hydration is not attained instanta¬ influenced by such changes. Particle size distri¬
neously, but is part of the aging process and butions are sometimes determined by micro¬
hence is not necessarily completed even by the scopic means. This method of necessity requires
stress a formulation undergoes in a manufactur¬ dilute suspensions that are counted with the aid
ing procedure, of an ocular grid. In some instances, photomi¬
Although the previously mentioned Brookfield crographs may be taken for permanent records.
instrument sees wide industrial application, This method is quite tedious, especially when
many types of viscometers are available. It is large numbers of samples are to be evaluated.
worth noting that various types of rheologic It is worth noting that certain suspension
equipment, together with their applications, components, e.g., the preservative or the protec¬
have been discussed and reviewed in the book tive colloid, may have a profound effect on the
by Van Wazer, Lyons, Kim, and Colwell.18 physical performance of the suspension under
freeze-thaw conditions. When a low solids con¬
tent steroid injectable preparation containing
Electrokinetic Techniques sodium carboxymethylcellulose (CMC)’ and
In a discussion of the physicochemical princi¬ benzyl alcohol, and one containing CMC,* meth-
ples involved in suspensions, Martin noted the ylparaben, and propylparaben, were subjected to
applicability of an electrophoretic method that freezing and thawing, the former suspension
employed a microelectrophoresis apparatus.19 caked badly, while the latter was unaffected.
Such instrumentation permitted measurement Protective colloids may thus be adversely af¬
of the rhigratiflJgLvelocity of the particles with fected by freezing, thawing, or elevated tempera¬
respect to the surface electric charge or the fa¬ tures; for example, gelatin is sensitive to low
temperatures whereas methylcellulose is ad¬
miliar zeta potential; the latter has units of vis¬
cosity times electrophoretic mobility, or more versely affected by higher temperatures. Al¬
familiarly, volts. Stanko and DeKay also evalu¬ though freeze-thaw cycle studies are useful
ated suspensions by electrokinetic methods and guides, the best stability information is still ob¬
showed that the zeta potential changes upon the tained from studies conducted at room tempera¬
addition of additives and is related to stability.20 ture.
Haines and Martin studied some of the formula¬
tion factors that influence the stability of sus¬ Reviews
pensions.21 They correlated the zeta potential to
visually observed caking; zeta potential was Stability testing methods pertaining to the
again determined by microscopic electrophore¬ suspension product form have been reviewed by
sis. It was found that certain zeta potentials pro¬ Kennon.26 Additionally, Matthews and Rhodes
duced more stable suspensions because aggre¬ reviewed and interpreted suspension stability,
gation was controlled and optimized. Nash has coagulation, and aggregation processes on the
also published an excellent review of this sub¬ basis of a comparison of the forces of electro¬
ject.22'23 static repulsion and of van der Waals attrac¬
tion.27,28 Somewhat similarly. Ho, Toguchi, and
Higuchi made a comparison of theoretic equa¬
tions involving electrostatic repulsion.29 Also
Particle Size Changes pertinent here is the review by Hiestand of the
The freeze-thaw cycling technique is particu¬ physical properties of coarse suspensions, par¬
larly applicable to stressing suspensions for sta¬ ticularly as it helped to clarify the mechanisms
bility testing purposes. This treatment promotes of the control of floe structure.30 Although
particle growth and may indicate the probable measurement problems still exist, it appears
future state of affairs after long storage at room that a study of the potential structural changes
temperature. Thus, it is of prime importance to in floe may be more useful in predicting shelf
be alert for changes in absolute particle size, par¬ life than are sedimentation-caking studies. Ex¬
ticle size distribution, and crystal habit. With perimentally, Carstensen and Su studied the
respect to the latter point, Carless et al. investi¬ sedimentation kinetics of aggregated suspen-
gated the various crystal forms of cortisone ace¬
tate and also noted the acceleration of sulfathi-
azole crystal growth in suspensions that *As noted previously, CMC is a trademark of Her¬
underwent temperature cycling. 4,25 Obviously, cules Inc.

494 • The Theory and Practice of Industrial Pharmacy

sions to derive equations that were consistent cortisone acetate and the wetting principle as
with both experimental data and with theory.31 follows.33
Also, Matthews and Rhodes used a Coulter
counter and digital computer to evaluate the sta¬
bility of aggregating monodisperse polystyrene Percentage
systems,'2 and in another study, Matthews Ingredients in Formula
used microelectrophoresis (to measure zeta
potential) along with other standard stability Cortisone acetate, USP microfine 2.5
tests to monitor the stability of various griseoful- Polysorbate 80,* USP (wetting agent) 0.4
Carboxymethylcellulose sodium, USP
vin suspensions.28
(suspending agent) 0.5
Sodium chloride, USP (for isotonicity) 0.9
Illustrative Examples Benzyl alcohol, NF (preservative) 0.9
Water for injection, USP, q.s. to make 100.0
This section presents certain formulas that
demonstrate some of the principles discussed in “Marketed as Tween 80 by ICI Americas, Inc., Wilmington, DE
this chapter. Additives exert a great influence 19899.
on the stability and the drug bioavailability of
formulations. The whole area of suspension On the industrial scale, all the ingredients
product development is a study of the perform¬ except cortisone acetate can be dissolved in
ance characteristics of adjuvants. Skill in find¬ water for injection using suitable mixing equip¬
ing and matching the everlasting marriage be¬ ment. Cortisone acetate can now be dispersed in
tween the suspending characteristics and the solution. The entire dispersion may be
desired drug bioavailability determines the de¬ passed through a colloid mill (e.g., Gaulin type
gree of excellence represented in the final prod¬ with an aseptic provision).*
uct. It is also the purpose of this section to The principles of aggregation and wetting may
discuss biopharmaceutical aspects of the sus¬ also be observed by making the preparations la¬
pending agents in contemporary suspensions. beled A through F in the table below.
Illustrative formulations are discussed here in Comparison of preparations A and B demon¬
these categories: (a) suspensions with wetting strates the value of a wetting agent. It is easy to
and aggregating agents; (b) suspensions with disperse sulfamerazine in B, but it setdes on
low solids content; (c) suspensions with high standing and forms a cake because of its deag-
solids content; (d) antacids; (e) biopharmaceuti¬ gregated nature. In C, the inclusion of the cati-
cal considerations.
Suspensions With Wetting and Aggregat¬
ing Agents. A patent by Macek describes a ‘Gaulin high-energy homogenizer, marketed by Gaulin
noncaking aqueous parenteral suspension of Corporation, Everett, MA 02149.

Percentage
in Preparations

Ingredients A B c D E F

Sulfamerazine, USP 2.0 2.0 2.0 2.0 2.0 2.0

Docusate sodium,* USP — 0.2 0.2 0.15 0.2 —

Aluminum chloride
hexahydrate/ USP — — 0.1 0.1 — 0.25
Carboxymethylcellulose
sodium (7MP),* USP — — — 0.02 — 0.15
Potassium biphosphate, NF — — — — 0.1 —
Purified water, USP
q.s. to make 100 100 100 100 100 100

“Add as 0.2% solution.

fAdd as 1% solution.
*Add as 0.1% solution.

PHARMACEUTICAL SUSPENSIONS • 495

onic aluminum (which should be added last) components to a solution of the preservative(s).
yields an aggregated suspension. Although the The latter should be prepared using about 80%
aggregates settle rapidly, they form a high- of the final total volume. This solution is then
volume sediment that does not cake and is easily added to the portion containing the active ingre¬
redispersed. dient, and sufficient purified water is added to
Preparation D is similar to C except that it bring it to the final volume. Note that the pre¬
contains carboxymethyleellulose, which acts as servatives are added in a slightly excess amount
a protective colloid and a viscosity builder. to compensate for their binding to polysor-
Therefore, this aggregated suspension does not bate 80. This binding has been shown to inacti¬
cake on standing and settles more slowly than C. vate the preservative in direct proportion to the
From a physical stability point of view, D is the amount bound.34,35
best suspension in this series. Suspension E The following observations are made with re¬
cakes on standing because the anionic biphos¬ spect to Table 16-1:
phate does not cause aggregation as was evident
in C, in which the cationic aluminum acted as
an aggregating agent. Preparation F illustrates a A—No dispersion or very little wetting of
gross incompatibility of a negatively charged cel¬ solid; this may depend on the recrystalli¬
lulose derivative with the positively charged alu¬ zation solvent (acetone versus dimethyl-
minum ions. form amide).
For additional examples illustrating the phe¬ B— Good dispersion, rapid settling, caking.
nomena of aggregation and wetting in aerosol C—Good dispersion, rapid settling, severe
dispersion systems, the reader is referred to caking, poor redispersibility, deaggrega¬
Chapter 20, “Pharmaceutical Aerosols.” tion.
Suspensions With Low Solids Content. D—Good dispersion, rapid settling, slight ag¬
Table 16-1 illustrates the components that are gregation.
required to prepare a model parenteral suspen¬ E—Good dispersion, slow settling, moderate
sion. This route of administration limits the for- aggregation.
mulator to a rather narrow range of additives. F— Good dispersion, slow settling, fine aggre¬
The samples are best prepared by making a con¬ gation.
centrate of the dispersant in a volume equal G—Good dispersion, slow settling, aggrega¬
to 10% of the final volume, thoroughly mixing in tion.
the active ingredient with the help of a colloid H—-Good dispersion, slow settling, coarse
mill or other device, and adding the remaining aggregation.

Table 16-1. Low Solids Content Suspensions

Concentration in mg/ml

Sample A B c D E F G H

Steroid* 25 25 25 25 25 25 25 25
Polysorbate 80* — 1.0 1.0 1.0 1.0 1.0 1.0 1.0
(dispersant)
—
Sodium citrate — — — 10.0 — — —
(buffer)
Sodium chloride 9.0 9.0 9.0 — 9.0 9.0 9.0 9.0
(for isotonicity)
Benzyl alcohol — — 9.0 9.0 9.0 — 9.0 —
(preservative)
Chlorobutanol — — — — 5.0 5.0 — —
(preservative)
Methylparaben — — — — — — 1.8 1.8
(preservative)
Propylparaben 0.2 0.2
(preservative)
Purified water q.s. to make 1.00 ml

‘Cortisone acetate or prednisolone acetate.

fTween 60 or Tween 40 could also be used. These are trademarks of ICI Americas, Inc., Wilmington, DE 19899.

496 • The Theory and Practice of Industrial Pharmacy

 It is important to note that protective colloids, cult to redisperse; samples C, D, F, and G are
such as polyethylene glycol 4000, car- easily redispersed. If samples are stored for
boxymethylcellulose sodium, and methylcellu- longer periods of time at room temperature,
lose all modify these characteristics. Sorbitol or samples A to D show color formation, while E to
dextrose can be included to adjust density. G do not show color formation (or show it only
Suspensions With High Solids Content. slightly), owing to the antioxidant effect. Since
Table 16-2 illustrates a different set of sample the product is normally refrigerated during stor¬
preparations. Again, it should be recognized that age, the antioxidant is an added safeguard
additives often markedly affect the properties of against deterioration. A good test of the influ¬
the formulation. ence of preservatives on the products involves
The samples are best prepared as follows. The drawing 5 ml of the preparations into a hypoder¬
lecithin is added to the penicillin G, then the mic syringe fitted with a 22-gauge needle, and
remaining vehicle containing the other compo¬ trying to eject the contents of the syringe.
nents is added. The product is first passed Samples A, B, and E are difficult to eject,
through a 40-mesh screen, then through a col¬ whereas the aggregated samples C, D, F, and G,
loid mill, so that the procaine penicillin G is uni¬ because of their structure, are more easily emp¬
formly coated with the lecithin. The products tied, and as indicated before, are generally
must be placed in silicone-treated vials or cylin¬ redispersible.
ders for proper study because of the poor drain¬ Antacid Suspensions. Antacids constitute a
age from the walls of containers that are not so single class of drugs available in both suspen¬
treated. sion and tablet forms; consumers prefer the sus¬
The samples exhibit characteristics that are pension form. This is due to in vivo effective¬
not as readily distinguishable as those seen with ness of a well-formulated antacid suspension
the low solids content suspensions. Phase sepa¬ superior to that of its tablet counterpart. (De¬
ration is not the primary criterion for evaluating tailed discussion is in the next section.) There¬
the physical performance of the product as it is fore, antacid formulations merit special treat¬
with the low solids suspensions. ment.
The following is observed if the products are Aqueous aluminum hydroxide (but not mag¬
shaken after standing for about one week at nesium hydroxide) antacid suspensions tend to
room temperature. Samples A, B, and E are diffi¬ thicken or gel during their shelf-life. This gelling

Table 16-2. High Solids Content Suspensions

Concentration: in mg/ml

Sample A B C D E F G

Penicillin G procaine,* 200,000t 200,000 200,000 200,000 200,000 200,000 200,000

USP
Procaine hydrochloride, 20.0 -20.0 20.0 20.0 20.0 20.0 20.0
USP
Sodium citrate, USP 20.0 20.0 20.0 20.0 20.0 20.0 20.0
(buffer)
Lecithin (protective) 2.0 2.0 2.0 2.0 2.0 2.0 2.0
colloid)
Sodium formaldehyde 2.5 2.5 2.5
sulfoxylate, USP
(antioxidant)
Benzyl alcohol, NF — 5.0 — — 5.0 —
(preservative)
Butylparaben, NF —
— 0.15 — — 0.15
(preservative)
Methylparaben/propyl- 1.0/0.1 1.0/0.1
paraben, NF
(preservatives)
Purified water q.s. to make 1 :0 ml

*Micronized, sterile.
+Based on 1000 units/mg.

PHARMACEUTICAL SUSPENSIONS • 497

accelerates during storage under warm condi¬ col, glycerin, or polyethylene glycol 400 in place
tions (30 to 40°C). Dramatic thickening is ob¬ of sorbitol or mannitol does not prevent gelling.
served in the case of high-potency antacids con¬ Aluminum hydroxide has a constipating ef¬
taining large amounts of aluminum hydroxide fect. Therefore, it is normally combined with the
gel. A patent by Alford teaches how to circum¬ laxative effect of magnesium hydroxide in com¬
vent this problem by the addition of a hexitol mercial antacid formulations, as shown in the
(sorbitol or mannitol) in concentrations from table at the top of page 499. These formulas can
0.5 to 7%, depending on the concentration of be manufactured by dissolving the methylpara¬
aluminum hydroxide in the suspension.36 This ben, propylparaben, saccharin, and peppermint
gelling can also be prevented by the addition of oil in alcohol and then transferring the mixture,
0.1 to 0.5% potassium or sodium citrate, the with agitation, to a vessel containing nearly
former of which is preferred because of con¬ one third of the volume of purified water in
sumer demand for low-sodium antacids, particu¬ which either the potassium citrate or the sorbitol
larly with those of higher potency. The gel¬ solution has been dissolved. The aluminum hy¬
preventing action of the citrate ions may be droxide gel, AHLT-LW, is added along with the
analogous to the mechanism of action of mono¬ magnesium hydroxide paste, and the mixture is
basic potassium phosphate on the positively agitated with a high-speed disperser. Alter¬
charged bismuth subnitrate suspension.37 Alu¬ nately, the entire product can be passed through
minum hydroxide particles have an excess of a colloid mill. The final volume is made up with
positive charge because of surrounding purified water. A neutral gum-type suspending
Al3+ ions. With the addition of potassium citrate agent may be included to reduce the separation.
to the aluminum hydroxide gel-type antacids, The taste of an antacid must be considered for
the apparent zeta potential may be decreased to consumer acceptance. Potassium citrate or sor¬
a point at which the system exhibits a maximum bitol solution are included to prevent gelling;
aggregation with a resultant thinning effect. however, potassium citrate has its own unpleas¬
The following formula demonstrates a hexitol ant taste, while the sorbitol has a cool sweet
stabilized antacid system. taste that is pleasant. The parabens at the con¬
centrations given previously impart a numbing
aftertaste to the tongue, especially in the pres¬
ence of the peppermint flavor. The paraben con¬
Percentage centrations may be reduced to some extent pro¬
Ingredients in Formula
vided the following factors are considered. The
Aluminum hydroxide gel, 36.000 pH of the antacid product is around 8, and the
AHLT-LW* pKa of the parabens is approximately 8.38 Thus,
Sorbitol, NF, or mannitol, LISP 7.000 50% of the parabens are in the inactive ionized
Methylparaben, NF 0.200 form. The concentrations can be somewhat re¬
Propylparaben, NF 0.020 duced, however. This can be accomplished by
Saccharin, NF 0.050 either including an oxidizing-type preservative
Peppermint oil, NF 0.005 with a decomposing half-life of about two weeks
Alcohol, USP 1.000 or by pasteurizing the final bottled product.
Purified water, USP q.s. to make 100.000 Biopharmaceutical Considerations. On a
theoretic basis, one would expect the drug bioa¬
‘Supplied by Chattem Chemicals Division, Chattem Inc.,
vailability from a suspension to be equal or
1715 West 38th Street, Chattanooga, TN 37409.
somewhat better than that from a tablet during
the first hour after administration of the dosage
The formula can be prepared by dissolving the form. This is because the tablet must invariably
methylparaben, propylparaben, saccharin, and undergo disintegration before drug dissolution
peppermint oil in the alcohol and transferring can occur. The suspension, on the other hand,
the solution, with agitation, to a vessel contain¬ already contains discrete drug particles. Data
ing nearly one half of the volume of purified showing that the suspension drug dosage form
water with agitation. The aluminum hydroxide is either equally or more bioavailable during the
gel, AHLT-LW, is added and then dispersed first hour after administration have been docu¬
using'a high-speed propeller or other high-speed mented in the literature.39,40
disperser. To demonstrate the effect of sorbitol In suspension, the drug is present in the form
or mannitol, the preparation should be made of solid particles, which must disperse in the
with and without it. Each product is then stored gastrointestinal media and dissolve in them.
in bottles at ambient temperature and at 40°C. The rate of drug dissolution, and potentially the
The addition of sucrose, dextrose, propylene gly¬ drug bioavailability, can be affected by such

498 • The. Theory and Practice of Industrial Pharmacy

 Percentage
Ingredients in Formula

A B

Aluminum hydroxide gel, AHLT-LW* 23.330 28.750

Magnesium hydroxide (Hydro-magma)" paste 13.110 16.400
Sorbitol solution, (70%) USP — 10.000
Potassium citrate, USP 0.600 —

Methylparaben, NF 0.200 0.200

Propylparaben, NF 0.020 0.020
Saccharin, NF 0.100 0.050
Peppermint oil, NF (or other flavor) 0.005 0.005
Alcohol, USP 1.000 1.000
Purified water, USP q.s. to make 100.000 100.000

“Supplied by Chattem Chemicals Division, Chattem Inc., 1715 West 38th Street, Chattanooga, TN 37409.
rHydro-magma is a trademark of Merck & Co. Inc., 126 East Lincoln Avenue, Rahway, NJ 07065.

physical factors as dispersibility, particle size magnesia oral suspension.43 Using the in vitro
and shape, and polymorphism. method, which is claimed to simulate the mild
Considering the hydrodynamic conditions agitation in the stomach, they showed that there
generated by the mild agitation of the gastroin¬ were significant differences in the neutraliza¬
testinal musculature, one would expect the sus¬ tion capacity of various commercial antacid sus¬
pending agents to influence the efficacy of sus¬ pensions. One product in particular failed to dis¬
pensions with poor dispersion characteristics in perse through the reaction medium, which can
the gastric milieu. Antacid suspensions are the he attributed to the nature, of the suspending
case in point. This class of products also demon¬ agent in this product. Similarly, Fordtran and
strates that the suspension dosage form is far co-authors,41 and Drake and Hollander,42 have
better than the tablet in terms of in vivo effi¬ shown the varying neutralization capacity of
cacy.41,42 Using their peristaltic assembly, Sim¬ numerous commercial antacid suspensions, as
mons and co-authors demonstrated an excellent illustrated in Table 16-3.
correlation between the in vitro and in vivo neu¬ In addition to the suspending agent, the na¬
tralization capacity of a commercial alumina and ture of the raw material and the manufacturing

Table 16-3. In Vitro Neutralization Capacity of Several Commercial Antacids

Neutralization
Product Capacity Antacid Content (mg/ml)*
(Manufacturer) (mEq/miy Aluminum hydroxide Magnesium hydroxide

Maalox TC" (Rorer) 4.2 120 60

Mylanta II** (Stuart) 4.14 80 80
Delcid" (Merrell-Dow) 4.1 120 133
Gelusil II* (Parke-Davis) 3.0 80 80
Aludrox** (Wyeth) 2.81 61.4 20.6
Maalox** (Rorer) 2.58 45.4 40
Di-Gel** (Plough) 2.45 56.2 17.4
Mylanta** (Stuart) 2.38 40 40
Silain-GeP* (Robins) 2.31 56.4 56.4
Maalox Plus" (Rorer) 2.3 45.4 40
Gelusil" (Parke-Davis) 2.2 40 40
Amphogel** (Wyeth) 1.93 64 —
Kolantyl Gel** (Merrell-Dow) 1.69 15 15

*A mEq of antacid is defined as the mEq of HC1 that is required to maintain the antacid suspension at pH 3 in vitro for a specific time.
**pH 3 maintained for 2 hours.42
fpH 3 maintained for 1 hour.43
"Estimated from Facts and Comparisons, J.B. Uppincott Co., Philadelphia, 1984.

PHARMACEUTICAL SUSPENSIONS • 499

 process (milling and homogenization) exert a crystals of drug suspended in water, sesame oil,
significant effect on the neutralization capacity and peanut oil gave delayed drug absorption
of antacid suspensions. For example, aluminum with prolonged blood levels; however, when 2%
hydroxide gel, AHLT-LW (Chattem Chemicals aluminum monostearate was included as a gel¬
Division, Chattem Inc.), showed superior neu¬ ling agent in sesame and peanut oils, the mi-
tralization capacity in comparison with other cronized drug form exhibited a more prolonged
similar raw materials when tested under mild blood level in rabbits. This effect was further
agitative conditions.43 Because of its fluid na¬ confirmed by a study in humans. It might have
ture, this raw material is also pumpable during been due to the incipient depot formation
large-scale production of the antacid suspen¬ brought about by the gelling agent. Frederick
sion. The milhng operation reduces the size of proposed that it was a result of the marked ce¬
the suspended antacid particles, thereby making menting action of the fine particles.46
them more reactive with the gastric acid under An important factor affecting drug absorption
mild agitation. The aforementioned factors may from an intramuscular parenteral suspension is
account for the observed differences in the neu¬ that of body movement (stirring) at the injection
tralization capacity of various commercial antac¬ site. Thus, Robinson administered an intramus¬
ids in Table 16-3, and of those reported else¬ cular injection of procaine penicillin G suspen¬
where.43 sion in which small drug particles were sus¬
Howard and associates illustrate a dissolution pended in peanut oil with 2% aluminum
profile of a prednisolone acetate ophthalmic sus¬ monostearate.47 She showed that active ambula¬
pension that is relatively inferior, owing to the tory patients had serum penicillin levels that
presence of hydroxypropyl methylcellulose in a were initially higher than those of sedentary pa¬
commercial and also an experimental formula¬ tients. She believes this was due to increased
tion as compared with formulations not having massage of the injection site, which released
this suspending agent.44 penicillin into the bloodstream earlier. Other
The remainder of the chapter deals with the workers have confirmed that the degree of body
physicochemical factors, influence of excipi¬ movement influences the onset and duration of
ents, and the drug absorption effects due to body benzathine penicillin G depot preparation.48
movements, as they relate to bioavailability of As stated in the previous discussions and as
parenteral suspensions. demonstrated in this section, the desired form of
During preparation of a physically stable and sedimentation is a state of controlled aggrega¬
therapeutically effective parenteral suspension, tion. Complete aggregation may produce a for¬
the foimulator should consider the effects of mulation with too coarse an appearance, but just
possible changes in the crystal form (polymorph¬ the right degree provides a truly elegant final
ism) and adjuvants on the absorption process. product. In terms of bioavailability, a suspension
There exists a very thin layer of saturated drug should be easily dispersed upon shaking, allow¬
solution around the suspended crystal. Depend¬ ing for removal of a precise drug dose during
ing on the conditions, e.g., shelf temperature administration. The suspending agent should
cycles and crystallization properties of the drug permit free and easy drug dispersion in the gas¬
from a particular vehicle, there may be a growth tric (or other body) medium under mild agita¬
in the crystal. This change may be accompanied tional conditions.
by a change in crystal habit (external shape),
which thereby causes the formation of one or
more polymorphic or solvate forms of the drug. References
This often results in a change in the particle size 1. Caxless, J.E., and Ocran, J.: J. Pharm. Pharmacol.,
distribution of the parenteral formulation. 24:717, 1972.
Macek’s work demonstrates how one crystal 2. Hiestand, E.N.: J. Pharm. Sci., 53:1, 1964.
form of cortisone acetate in an aqueous paren¬ 3. Ecanow, B., Levinson, R.S., and Takrur, H.: Am. Cos¬
metics, Perfumer., 84:30, 1969.
teral suspension underwent conversion to a 4. Ecanow, B., Gold, B:, and Ecanow, C.: Am. Cosmet¬
stable form when allowed to stand undisturbed ics, Perfumer., 84:27, 1969.
for some time at room temperature.33 It was ac¬ 5. Jones, R.D.C., Matthews, B.A., and Rhodes, C.T.:
companied, however, by crystal growth and cak¬ J. Pharm. Sci., 59:518,.1970.
ing, which made the product unacceptable. 6. Carless, J.E., and Ocran, J.: J. Pharm. Pharmacol.,
The influence of particle size, vehicle, and 24:637 1972.
7. Storz, G.K.: U.S. Patent No. 3,733,408 (1973).
- additive on the absorption profile of intramuscu¬ 8. Tingstad, J.E:: J. Pharm. Sci., 53:955, 1964.
lar procaine penicillin G suspensions is dis¬ 9. Higuchi, T.: J. Pharm. Sci., 47:657, 1958.
cussed in the extensive work of Buckwalter and 10. Smith, W.E., Buehler’ J.D., and Robinson, M.J.:
Dickinson.45 Their study showed that larger J. Pharm. Sci., 59:776, 1970.

500 • The Theory and., Practice of Industrial Pharmacy

11. Vamey, G.t J. Pharm. Pharmacol., 19 (Suppl.):19S, 30. Hiestand, E.N.: J. Pharm. Sci., 61:268, 1972.
1967.' 31. Carstensen, J.T., and Su, K.S.E.: J. Pharm. Sci.,
12. Bean, H.S., and Dempsey, G.: J. Pharm. Pharmacol., 59:666, 671, 1970.
23:699, 1971. 32. Matthews, B.A., and Rhodes, C.T.: J. Pharm. Sci.,
13. Sheikh, M.A., Price, J.C., and Gerraughty, R.J.: 57:557, 569, 1968.
J. Pharm. Sci., 55:1048, 1966. 33. Macek, T.J.: U.S. Patent No. 2,671,750 (1954).
14. Ward, H.T., and Kammermever, K.: Ind. Eng, Chem., 34. Patel, N.K., and Kostenbauder, H.B.: J. Am. Pharm.
32:622, 1940. Assoc., Sci. Ed., 47:289, 1958.
15. Fo'emzler, E.C., Martin, A.N., and Banker, G.S.: 35. Patel, N.K.: Can. J. Pharm. Sci., 2:77, 1967.
J. Am. Pharm. Assoc., Sci. Ed., 49:249, 1960. 36. Alford, C.E.: U.S. Patent No, 2,999,790 (1961).
16. Wood, J.H.: Am. Perfumer, 76:37, 1961. 37. Martin, A., Swarbrick, J., and Cammarata, A.: Physi¬
17. Wood, J.H., Catacalos, G., and Lieberman, S.V.: cal Pharmacy. 3rd Ed. Lea &. Febiger, Philadelphia,
J. Pharm. Sci.,-52:354, 1963. 1983, p. 549.
18. Van Wazer, J.R., Lyons, J.W., Kim, K.Y., and Col¬ 38. Patel, N.K.: Ph.D. Dissertation. University of Mary¬
well, R.E.: Viscosity and Flow Measurement—A Lab¬ land, College Park, MD, 1962.
oratory Handbook of Rheology. Interscience, New 39. Bates, T.R., Lambert, D.A., and Johns, W.H.:
York, 1963. J. Pharm. Sci., 58:1468, 1969.
19. Martin, A.M.: J. Pharm. Sci., 50:513, 1961. 40. Meyer, M.C., Straughn, A.B., Ramachander, G.,
20. Stanko, G.L., and DeKay, H.G.: J. Pharm. Sci., et al.: J. Pharm. Sci., 67:1659, 1978.
47:104, 1958. 41. Fordtran, J.R., Morawski, S.G., and Richardson, C.T.:
21. Haines, B.A., Jr., and Martin, A.N.: J. Pharm. Sci., N. Engl. J. Med., 288:923, 1973.
50:753, 756, 1961. 42. Drake, D., and Hollander, D.: Ann. Intemat. Med.,
22. Nash, R.A.: Drug & Cosmetic Ind., 97:843, 1965. 94:215, 1981.
23. Nash, R.A.: Drug 8t Cosmetic Ind., 98:39, 1966. 43. Simmons, D.L., Patel, N.K., Chenier, M., et al.: Drug
24. Carless, J.E., Moustafa, M.A., and Rapson, H.D.C.: Dev. Ind. Pharm., 7:621, 1981.
J. Pharm. Pharmacol., 28 (Supply. 1908, 1966. 44. Howard, S.A., Mauger, J.W., and Phusanti, L.:
25. Carless, J.E., and Foster, A.A.: J. Pharm. Pharmacol., J. Pharm. Sci., 66:557, 1977.
18:697, 1966. 45. Buckwalter, F.J., and Dickinson, H.L.: J. Am. Pharm.
26. Kennon, L.: J. Soc. Cosmetic Chemists, 17:313,1966. Assoc., Sci. Ed., 47:661, 1958.
27. Matthews, B.A., and Rhodes, C.T.: J. Pharm. Sci., 46. Frederick, K.J.: J. Pharm. Sci., 50:531, 1961.
59:521, 1360, 1970. 47. Robinson, J.M.: J. Michigan State Med. Soc., 48:337,
28. Matthews, B.A.: J. Pharm. Sci., 62:172, 1973. 1949.
29. Ho, N.F.H., Toguchi, H., and Higuchi, W.I.: 48. Lukash, W.M., and Fraser, P.F.: Am. J. Med. Sci.,
J. Pharm. Sci., 62:851, 1973. 246:429, 1963.

PHARMACEUTICAL SUSPENSIONS • 501

 17

Emulsions
MARTIN M. RIEGER

This chapter is divided into three parts. The first approximately 74% of the total volume of an
part deals with emulsions in a nonmathemati- emulsion. It is evident, however, that the inter¬
cal, descriptive way. The second part covers the nal phase can exceed 74% if the spherical parti¬
equipment and the chemical arid physical condi¬ cles are not monodisperse (as in most emul¬
tions for the preparation of emulsions. The last sions). A further increase in the ratio of
portion of the chapter is devoted to a discussion intemahextemal phase can result if the internal
of the physical and chemical characteristics and phase is assumed to consist of polyhedra rather
stability of emulsions. than spheres.1
An emulsifier functions and is operationally
defined as a stabilizer of the droplet form (glob¬
Overview ules) of the internal phase. On the basis of their
A precise definition of the term emulsion de¬ structure, emulsifiers (wetting agents or surfac¬
pends on the observer’s point of view. The phys¬ tants) may be described as molecules compris¬
ical chemist defines an emulsion as a thermody¬ ing both hydrophilic (oleophobic) and hydropho¬
namically unstable mixture of two essentially bic (oleophilic) portions. For this reason, this
immiscible liquids. For the product develop¬ group of compounds is frequently called amphi¬
ment technologist, it is more useful to regard an philic (i.e., water- and oil-loving).
emulsion as an intimate mixture of two immisci¬ It is almost universally accepted that the term
ble liquids that exhibits an acceptable shelf life emulsion should be liiriited to liquid-in-liquid
near room temperature. Other definitions exist, systems. Emulsions are normally formed by
but the two given here suffice for the purpose of “mixing” two immiscible liquids. If necessary,
this chapter. the two phases are heated to ensure that they
are liquids during emulsification. The most
common types of pharmaceutical or cosmetic
Practical Definitions emulsions include water as one of the phases
When two immiscible liquids are mechani¬ and an oil or lipid as the other. If the oil droplets
cally agitated, both phases initially tend to form are dispersed in a continuous aqueous phase,
droplets. When the agitation is stopped, the the emulsion is termed oil-in-water (o/w); if the
droplets quickly coalesce, and the two liquids oil is the continuous phase, the emulsion is of
separate. The lifetime of the droplets is materi¬ the water-in-oil type (w/o). It has been observed
ally increased if an emulsifier is added to the two that o/w emulsions occasionally change into w/o
immiscible liquids. Usually, only one phase per¬ emulsions and vice versa. This change of emul¬
sists in droplet form for a prolonged period of sion type is called inversion.
time. This phase is called the internal (disperse Since approximately 1978, two additional
or discontinuous) phase, and it is surrounded by types of emulsions, classified as multiple emul¬
an external (continuous) phase. An assembly of sions, received the attention of surface chemists.
close-packed monodisperse* spherical droplets It is entirely feasible to prepare a multiple emul¬
as the internal phase can occupy no more than sion with die characteristics of oil-in-water-in¬
oil (o/w/o) or of water-in-oil-in-water (w/o/w)
emulsions. Such emulsions also can invert;
*AU particles have the same size. however, during inversion they usually form

502
“simple” emulsions. Thus, a w/o/w emulsion important reason why emulsions are popular
normally yields an o/w emulsion.2 oral and topical dosage forms. Many medicinal
The particle size of the disperse phase deter¬ agents have an objectionable taste or texture,
mines the appearance of an emulsion. The ra¬ and can be made more palatable for oral admin¬
dius of the emulsified droplets in an opaque, istration when formulated into emulsions. As a
usually white, emulsion ranges from 0.25 to result, mineral oil-based laxatives, oil-soluble
10 microns. It is fairly well established that vitamins, and high-fat nutritive preparations are
dispersed particles having a diameter of less commonly administered as o/w emulsions. The
than V4 the wave length of visible light, i.e., less utility of orally administered emulsions resides
than approximately 120 nm, do not refract light in their efficacy, i.e., absorption or bioavailability
and therefore appear transparent to the eye. Dis¬ of the drug. It has been demonstrated that some
persions of a liquid to such small particle sizes drugs are more readily absorbed when they are
yield microemulsions or micellar emulsions. administered orally in the form of emulsions.3 It
Often, these terms are erroneously used inter¬ has even been reported that noimally unabsorb-
changeably because such emulsions appear able macromolecules, such as insulin and hepa¬
transparent to the human eye in daylight. In a rin, are absorbed when they are incorporated
microemulsion, disperse globules having a ra¬ into emulsions.
dius below the range of 10 to 75 nm are present. Patient acceptance is also important in topi¬
The production of a transparent dispersion of cally applied emulsions. Emulsions possess a
an oil by micellization* does not result in the for¬ certain degree of elegance and are easily washed
mation of droplets, but in the inclusion of the off whenever desired. In addition, the formula-
lipid into micelles, which may, but need not, tor can control the viscosity, appearance, and
possess spherical shapes. In terms of size, mi¬ degree of greasiness of cosmetic or dermatologic
celles have dimensions ranging from about 5 to emulsions.
20 nm. To the practicing technologist, transpar¬ With regard to emulsion type, o/w emulsions
ent emulsions, solubilized oils, micellar emul¬ are most useful as water-washable drug bases
sions, and microemulsions are one and the same and for general cosmetic purposes. W/o emul¬
because they appear clear. However, solubiliza¬ sions are employed more widely for the treat¬
tion in any form represents an entirely different ment of dry' skin and emollient applications. The
phenomenon, from that of emulsification. utility of topical emulsions depends on their
ability to “penetrate.” This much abused term
has entirely different meanings to the layman
Applications and Utility and to the technologist. To the former, rapid
Emulsions are sometimes difficult to prepare “penetration” is desirable and refers to the dis¬
and require special processing techniques. To appearance of the product or of oiliness from the
warrant this type of effort and to exist as useful skin during inunction. It is generally believed
dosage forms, emulsions must possess desirable that this process of penetration into the skin is
attributes and cause a minimum of associated facilitated if the emulsion is thixotropic, i.e., if it
problems. The “mixing” of immiscible liquids becomes less viscous during shearing. To the
for various purposes has been met by the emul¬ technologist, penetration of the vehicle is of sec¬
sification process for centuries. Today, emul¬ ondary importance; instead, rapid and efficient
sions continue to have a variety of cosmetic and penetration of the drug moiety to the site that
pharmaceutical applications.. The latter may be needs to be treated is desired.4
further classified by route of administration, i.e., Emulsions have been used for the intrave¬
topical, oral, or parenteral. In principle, cosmetic nous administration of lipid nutrients, which is
applications and topical pharmaceutical applica¬ facilitated by emulsification and probably would
tions are similar and together form one of the be impossible unless the lipid were in the form
most important groups of emulsions. of an emulsion. Such emulsions of the o/w type
Patient acceptance undoubtedly is the most require the most rigorous control of the emulsi¬
fying agent and/or particle size (normally less
than 100 nm).
“Micelles are the result of self structuring of surface ac¬ Some other pharmaceutical and clinical appli¬
tive materials in order to reach a state of minimum en¬ cations of emulsions include the following. Radi¬
ergy. For example, sodium stearate, in a clear aqueous opaque emulsions have been used as diagnostic
solution at a concentration above the critical micelle con¬
agents in x-ray examinations. W/o emulsions
centration (CMC), forms structures with the nonpolar
ends of several molecules in contact with each other (hy¬ have been employed to disperse water-soluble
drophobic bonding) and with the polar ends exposed to antigenic materials in mineral oil for intramus¬
the surrounding water. cular depot injection. The presence of emulsifi-

EMULSIONS • 503
ers in injectable drugs that are relatively insolu¬ Droplet Stabilization. Two conceptual al¬
ble in water (or serum) may help lower the ternatives exist for creating opaque, i.e., milky-
tendency of the drug to crystallize and cause appearing, emulsions. Such dispersions can be
thrombophlebitis. Finally, emulsification of formed and stabilized by lowering the interfacial
perfluorinated hydrocarbons is required to make tension and/or by preventing the coalescing of
them useful as oxygen carriers in blood replace¬ droplets. According to classic emulsion theory,
ments. surface active agents are capable of performing
Emulsions also possess an important cost ad¬ both objectives: They reduce interfacial tension,
vantage over single-phase preparations. Most and they act as barriers to droplet coalescence
lipids and solvents for lipids that are intended since they are adsorbed at the interface, or more
for application to or into the human body are rel¬ precisely, on the surface of the suspended drop¬
atively cosdy. As a result, dilution with a safe lets. Emulsifying agents assist in the formation
and inexpensive diluent, such as water, is of emulsions by three mechanisms:
highly desirable from an economic point of view
as long as efficacy or performance is not im¬ 1. Reduction of interfacial tension—thermo¬
paired. dynamic stabilization.
2. Formation of a rigid interfacial film—
mechanical barrier to coalescence.
Descriptive Theory of
3. Formation of an electrical double layer—
Emulsification electrical barrier to approach of particles.
The fundamental principles of surface chem¬
istry and of emulsification are included in Chap¬ Interfacial Tension. Even though reduc¬
ter 5. Therefore only a few concepts of practical tion of interfacial tension lowers the interfacial
importance need be discussed here to make the free energy produced on dispersion, it is the role
formulation steps better understood. When oil of emulsifying agents as interfacial barriers that
and water are mixed and agitated, droplets of is most important. This can be seen clearly
varying sizes are produced. A tension exists at when one considers that many polymers and-
the interface because the two immiscible phases finely divided solids, not efficient in reducing^
tend to have different attractive forces for a mol¬ interfacial tension, form excellent interfacial
ecule at the interface. A molecule of phase A is barriers, act to prevent coalescence, and are use¬
attracted into phase A and repelled by phase B. ful as emulsifying agents.
In general, the greater the degree of immis- Interfacial Film. The formation of films by
cibility, the greater is the interfacial tension. For an emulsifier on the surface of water or oil drop¬
example, liquid hydrocarbons, such as those lets has been studied in great detail. The con¬
found in mineral oil, exhibit an interfacial ten¬ cept of an oriented (monomolecular) film of the
sion against water of approximately 50 dynes/ emulsifier on the surface of the internal phase of
cm, whereas a more polar vegetable oil, such as an emulsion is of fundamental importance to an
olive oil, exhibits a value of 23 dynes/cm. The understanding of most theories of emulsifica¬
interfacial tension at a liquid interface is defined tion.5 Scheme 1 in Figure 17-1 illustrates how
as the work required to create 1 cm2 of new in¬ emulsifiers are believed to surround the droplets
terface. of the internal phase.
A fine dispersion of oil and water necessitates It is reasonable to expect an amphiphilic
a large area of interfacial contact, and its produc¬ molecule to align itself at a water-oil interface
tion requires an amount of work equal to the in the most energetically favorable position—
product of interfacial tension and the area oleophilic portion in the oil phase and hydro¬
change. Thermodynamically speaking, this work philic portion in the aqueous phase. It is also
is the interfacial free energy imparted to the sys¬ well established that the surface-active agents
tem. A high interfacial free energy favors a re¬ tend to concentrate at interfaces and that emul¬
duction of interfacial area, first by causing drop¬ sifiers are adsorbed at oil-water interfaces as
lets to assume a spherical shape (minimum monomolecular films. If the concentration of the
surface area for a given volume) and then by emulsifier is high enough, it forms a rigid film
causing them to coalesce (with a resultant de¬ between the immiscible phases, which acts as a
crease in the number of droplets). This is the mechanical bar to both adhesion and coales¬
reason for including the words “thermodynami¬ cence of the emulsion droplets. Measurements
cally unstable” in the classic definition of of the area occupied by a single molecule of sur¬
opaque emulsions. face-active agent at the interface of emulsion

504 • The Theory and Practice of Industrial Pharmacy

 o/w emulsions stabilized by mixtures of sodium
cetyl sulfate and cholesterol, which were known
from other experiments to form rigid and tightly
packed films, were extremely stable (scheme 1,
Fig. 17-1). When oleyl alcohol was substituted
for cholesterol, however, the steric effect of a
double bond (which produces a kink in the car¬
bon chain) resulted in the formation of a poor
interfacial complex, and emulsion stability was
proportionately low (scheme 2, Fig. 17-1). On
the other hand, if this last system was changed
somewhat by using sodium oleate and cetyl alco¬
hol, it was possible to obtain a rather poor emul¬
sion, but one that was more stable than that of
the previous case (scheme 3, Fig. 17-1). Thus, a
tightly packed emulsifier film contributes to the
stability of the emulsion. This steric argument
by Schulman and Cockbain has been used to
explain the well-known fact that mixed emulsifi¬
ers are often more effective than single emulsifi¬
ers. The ability of the mixture of emulsifiers to
pack more tightly contributes to the strength of
the film, and hence, to the stability of the emul¬
sion. Most emulsifiers probably form fairly
dense gel structures at the interface and pro¬
duce a stable interfacial film.
Recent studies have helped to clarify further
the nature of these interfacial films. Stable
emulsions are now believed to comprise liquid
crystalline layers on the interface of emulsified
droplets with the continuous phase.7'9 In their
pioneering studies, Friberg and co-workers were
able to show by optical (polarized fight) and elec¬
tron microscopy and low-angle x-ray diffrac-
tometry that mixed emulsifiers can interact with
water to form three-dimensional association
structures. The classic concept of emulsions as
two-phase systems with a monomolecular layer
of emulsifier at the interface must be revised.
Emulsions should instead be viewed as three-
\
/ component systems comprising oil, water, and
lamellar liquid crystals, the latter consisting of
consecutive layers of water-emulsifier-oil-water
FIG. 17-1. Schematic representation of the relationship
between mixed film formation, mechanical strength, and (Fig. 17-2).
the stability of emulsions. (From Schulman and Cock- Interlamellar layers representing the internal
bain.6) 1, © Cetyl sulfate Na; • cholesterol; closely packed and external phases of an emulsion have re¬
condensed complex; excellent emulsion. 2, © Cetyl sulfate cently been identified by freeze fracture microg¬
Na; • oleyl alcohol; no closely packed condensed complex; raphy of o/w creams.19 In addition, it has re¬
poor emulsion. 3, O Cetyl alcohol; © sodium oleate; fairly
cently been learned that emulsion droplets can
closely packed monolayer; negligible complex formation:
rather poor emulsion. be surrounded by liquid crystals of a closed la¬
mellar type in appropriately prepared emul¬
sions.11
droplets have shown that in stable emulsions, This field of emulsion science is currently
the molecules of surface-active agents are in fact undergoing active investigation by scientists
closely packed and form a tough interfacial film. throughout the world. Efforts have been made to
This concept is illustrated by the classic study measure the mechanical properties of associa¬
of Schulman and Cockbain.6 They found that tion structures by studying interfacial shear vis-

EMULSIONS • 505
 double layer, which may arise from electrically
QcfiQQQjOCoPfioPQGPS QnfrOt charged groups oriented on the surface of emul¬
88nWHn%xv>/ffii¥n5.Bog
sified globules (Chap. 5). To simplify, let us con¬
EwM^F'ER sider the case of an o/w emulsion stabilized by a
sodium soap. Not only are the molecules of this
EMULSIFIER surfactant concentrated in the interface, but
OIL because of their polar nature, they are oriented
EMULSIFIER as well (Fig. 17-3). The hydrocarbon tail is dis¬
solved in the oil droplet, while the ionic heads
WATER are facing the continuous aqueous phase. As a
EMULSIFIER result, the surface of the droplet is studded with
W*T ssir
wsmm charged groups, in this case negatively charged
carboxylate groups. This produces a surface
FIG. 17-2. A lamellar liquid crystal consists of consecu¬ charge on the droplet, while cations of opposite
tive layers of water - emulsifier - oil - emulsifier - water. sign are oriented near the surface, producing
(From Friberg.9) what is known as the (diffuse) double layer of
charge (Chap. 5).
cosity.12 These investigations are expected to The potential produced by the double layer
lead to a fuller understanding of the complex creates a repulsive effect between the oil drop¬
droplet-droplet interactions that lead to coales¬ lets and thus hinders coalescence. Although the
cence and emulsion instability. There is little repulsive electrical potential at the emulsion in¬
doubt that nonionic emulsifiers, proteins, and terface can be calculated, it cannot be measured
macromolecular gums stabilize emulsions by directly for comparison with theory. The related
forming interfacial films. quantity, however, zeta potential, can be deter¬
Electrical Repulsion. It has just been de¬ mined. The zeta potential for a surfactant-stabi¬
scribed how interfacial films or lamellar liquid lized emulsion compares favorably with the cal¬
crystals significandy alter the rates of coales¬ culated double-layer potential. In addition, the
cence of droplets by acting as barriers. In addi¬ change in zeta potential parallels rather satisfac¬
tion, the same or similar film can produce repul¬ torily the change in double-layer potential as
sive electrical forces between approaching electrolyte is added. These and related data on
droplets. Such repulsion is due to an electrical the magnitude of the potential at the interface

©
© 0

© ©
WATER
PHASE
©
©
© ©
©
FIG. 17-3. Idealized representation of the electrical double layer at an oil-water interface.

506 • The Theory and Practice of Industrial Pharmacy

can be used to calculate the total repulsion be¬ tion is nearly impossible, and only a few general¬
tween oil droplets as a function of the distance ized and somewhat empiric rules can be given.
between them. 1. If the amphiphile is essentially water-
Droplet Interaction. A plot of the total re¬ soluble (e.g., potassium soap or polyoxyethylene
pulsive potential between two charged droplets alkyl ether with more than 5 ethylene oxide
as a function of the interparticle distance has units), it will usually favor o/w emulsification; if
been shown in Figure 5-20. This potential in¬ the surfactant is primarily soluble in the lipid
cludes not only the repulsive electrical potential, portion (calcium soap, polyoxyethylene alkyl
but also a series of other interactions, known as ether with less than 5 ethylene oxide units), it
van der Waals forces or London interactions. may yield w/o emulsions if the other conditions
The repulsive potential at large distances is are favorable.
small and then rises sharply as the distance be¬ 2. The polar portions of emulsifier molecules
tween the droplets decreases. To the left of the are generally better barriers to coalescence than
peak, the repulsive force drops rapidly to zero, their hydrocarbon counterparts. It is, therefore,
and this corresponds, of course, to coalescence possible to make o/w emulsions with relatively
of emulsion droplets. The barrier to coalescence high internal phase volumes. On the other
is high (many multiples of kT, the translational hand, w/o emulsions (in which the barrier is of
energy) and probably cannot be overcome by two hydrocarbon nature) are limited in this regard
approaching droplets. If, as is now believed, liq¬ and invert easily if the amount of water present
uid crystal phases surround the emulsified drop¬ is significant. For example, a water-mineral oil-
lets, and if these phases adhere tenaciously, sorbitan monooleate system, ordinarily expected
their presence can be expected to cause a to favor w/o emulsion formation because of the
change in the van der Waals potential. The dis¬ lack of ethylene oxide units, does so only if the
tance at which this change occurs depends not amount of water present constitutes less than
only on the droplet radius but also on the sur¬ 40% by volume. At higher amounts of water,
rounding liquid crystalline phase, and the com¬ only o/w emulsions form.
pressibility and rheology of this assembly. 3. Even at 20% and 30% water, w/o emul¬
Another important point is that the curve has sions form only if the water is added to the oil
two minima, and the minimum at a separation with mixing. The addition of both phases to¬
of approximately 5 to 15 nm is responsible for gether, followed by mixing, favors o/w emulsions
the initial adhesion of emulsion particles. When at all concentrations above 10% water.
the droplets fall into this secondary minimum of 4. Finally, the type of emulsion formed is in¬
the potential energy curve, they flocculate. The fluenced to some extent by the viscosity of each
smallness of this minimum explains why emul¬ phase. An increase in the viscosity of a phase
sion flocculation is a reversible process. It is be¬ aids in making that phase the external phase.
lieved that flocculated droplets may remain in Despite these complications, one can expect a
this minimum for a fairly long time, but that predominandy water-soluble emulsifier to form
some rearrangements of the surface active com¬ o/w emulsions, whereas the reverse is true of
pound occurs at the interface. This modifies the primarily oil-soluble surfactants. Occasionally, it
potential picture and allows coalescence to take is desirable to determine the type of emulsion
place. formed. Methods for. this purpose are shown in
Emulsion Type. Only o/w and w/o emul¬ Table 17-1.
sions have achieved commercial and practical Microemulsions. Operationally, micro¬
importance. To understand the various factors emulsions may be defined as dispersions of in¬
that determine whether an o/w or a w/o emul¬ soluble liquids in a second liquid that appear
sion will be produced, one must again think in clear and homogeneous to the naked eye.
terms of two critical features: (1) droplet forma¬ Microemulsions are frequently called solubilized
tion and (2) formation of an interfacial barrier. systems because on a macroscopic basis they
The phase volume ratio, i.e., the relative amount seem to behave as true solutions. Careful exami¬
of oil and water, determines the relative number nation of these complex systems has shown that
of droplets formed initially and hence the proba¬ clear emulsions can exist in several differentia¬
bility of collision; the greater the number of ble forms. Microemulsions should not be con¬
droplets, the greater is the chance for collision. fused, however, with solutions formed by cosol-
Thus, normally, the phase present in greater vency, e.g., the clear system consisting of water,
amount becomes the external phase. benzene, and ethanol.
To predict the type of emulsion formed under Blending of a small amount of oil with water
a given set of conditions, the interaction of vari¬ results in a two-phase system because “water
ous parameters must be estimated. This estima¬ and oil do not mix.” If the same small amount of

EMULSIONS • 507
Table 17-1. Methods for the Determination of Emulsion Type*
Test Observation Comments

Dilution test Emulsion can be diluted only with Useful for liquid emulsions
external phase. only.

Dye test Water-soluble solid dye tints only o/w May fail if ionic emulsifiers
emulsions and reverse. Microscopic are present.
observation usually helpful.
CoCl2/fllter paper Filter paper impregnated with CoCl2 and May fail if emulsion is
dried (blue) changes to pink when o/w unstable or breaks in
emulsion is added. presence of electrolyte.

Fluorescence Since oils fluoresce under UV light, o/w Not always applicable.
emulsions exhibit dot pattern, w/o
emulsions fluoresce throughout.

Conductivity Electric current is conducted by o/w Fails in nonionic o/w

emulsions, owing to presence of ionic emulsions.
species in water.

'For details, consult Becher,13 p. 413.

oil is added to an aqueous solution of a suitable and for stabilizing them in the external phase.
surfactant in the micellar state, the oil may pref¬ The complete process must be designed in such
erentially dissolve in the interior of the micelle a way that these two steps are carried out before
because of its hydrophobic character. This type the internal phase can coalesce. Usually, the
of micellar microemulsion, which was observed breakup of the internal phase (by physical
by McBain many years ago, has also been called means) is fairly rapid; however, it is believed
an o/w micellar solution. Similarly, w/o solubili¬ that the stabilization step and the rate of coales¬
zation—especially that by anonionic surfactant— cence are time- and temperature-dependent. It
has recendy been attributed to the existence of is therefore a requirement in the design of any
swollen micelles. In these systems, sometimes emulsification process that the variable physical
called reverse micellar solutions, water mole¬ and chemical parameters are selected and con¬
cules are found in the polar central portion of a trolled to favor emulsion formation.
surfactant micelle, the nonpolar portion of
which is in contact with the continuous lipid
phase. A third type of microemulsion (usually of Physical Parameters
the w/o type) is formed by ionic surfactants (e.g.,
sodium stearate) in the presence of cosur¬ The application of energy in the form of heat,
factants (e.g., pentanol or dioxyethylene dodecyl mechanical agitation, ultrasonic vibration, or
ether) with hydrocarbons (e.g., hexadecane) and electricity is required to reduce the internal
water. phase into small droplets. The amount of work
In general, microemulsions or solubilized sys¬ input depends on the length of time during
tems are believed to be thermodynamically which energy is supplied; thus, timing (schedul¬
stable. Transparent or clear emulsions in which ing of work input) becomes another important
a water-insoluble oil or drug is “dissolved” in an physical parameter.
aqueous surfactant system play an important Heat. Vaporization is an effective way of
role in drug administration. In addition, a wide breaking almost all the bonds between the mole¬
variety of clear proprietary and toiletry products cules of a liquid. It is possible, therefore, to pre¬
are in fact clear emulsions of all types of oils and pare emulsions by passing the vapor of a liquid
lipids in water. into an external phase that contains suitable
emulsifying agents. This process of emulsifica¬
tion, called the condensation method, is rela¬
Formation of Emulsions tively slow, is limited to the preparation of dilute
The spontaneous formation of an emulsion is emulsions of materials having a relatively low
a relatively rare occurrence. Instead, emulsion vapor pressure, and is therefore primarily of the¬
preparation by the commonly employed disper¬ oretical importance.
sion method requires a sequence of processes The more practical emulsification by disper¬
for breaking up the internal phase into droplets sion is affected by heat—or better, changes in

508 • The Theory and Practice of Industrial Pharmacy

temperature—in a number of ways. The interac¬ and the size of emulsified oil droplets begins to
tions are complex, and it is almost impossible to increase. A continued rise in the temperature
predict whether a raise in temperature will favor causes separation into an oil phase, a surfactant
emulsification or coalescence. An increase in phase, and water. It is near this temperature
temperature decreases interfacial tension as that the now water-insoluble surfactant begins
well as viscosity. One would therefore predict— to form a w/o emulsion containing both water-
and this is usually true—that emulsification is swollen micelles and emulsified water droplets
favored by an increase in temperature. At the in a continuous oil phase.
same time, however, an increase in temperature Timing. Timing, just like variation in tem¬
raises the kinetic energy of droplets and thereby perature, exerts a profound and complex influ¬
facilitates their coalescence. This type of insta¬ ence on the process of emulsification. During
bility is normally observed when emulsions are the initial period of agitation required for emul¬
stored at elevated temperatures for long periods sification, droplets are formed; however, as agi¬
of time. Changes in temperature alter the distri¬ tation continues, the chance for collision be¬
bution coefficients of emulsifiers between the tween droplets becomes more frequent, and
two phases and cause emulsifier migration. The coalescence can occur. It is generally advisable,
distribution of the emulsifier as a function of therefore, to avoid excessive periods of agitation
temperature cannot be correlated directly with during and after the formation of an emulsion.
either emulsion formation or stability, since On the other hand, it is impossible to specify the
changes in surface tension and viscosity occur time required for agitation, and the optimum
simultaneously. period necessary for emulsification is usually
Phase Inversion Temperature. The most determined empirically.
important influence that temperature has on an The criticality of the interaction between agi¬
emulsion is probably inversion. Almost 50 years tation and timing was demonstrated more than
ago it was observed that w/o emulsions of ben¬ 50 years ago by Briggs. In the most obvious
zene in water that were stabilized with sodium manner of preparing an emulsion, two immisci¬
stearate invert to o/w emulsions upon heating ble liquids are mixed in a suitable container in
and reform w/o emulsions upon cooling. The the presence of an emulsifier and are then
temperature at which the inversion occurs de¬ shaken until the emulsion has formed. Briggs
pends on emulsifier concentration and is called showed that the best way of forming an emul¬
phase inversion temperature (PIT). This type of sion by this technique is to use intermittent
inversion can occur during the formation of shaking. He found that he could emulsify 60%
emulsions, since they are generally prepared at by volume of benzene in 1% aqueous sodium
relatively high temperatures and are then al¬ oleate by mechanically shaking 750 times dur¬
lowed to cool to room temperature. Emulsions ing a period of four to five minutes. The same
formed by a phase inversion technique are gen¬ mixture, however, could be completely emulsi¬
erally considered quite stable and are believed to fied with merely five hand shakes in about two
contain a finely dispersed internal phase. The minutes, if the emulsion was allowed to rest for
PIT is generally considered to be the tempera¬ 20 to 30 seconds after each shake. The reasons
ture at which the hydrophilic and the lipophilic for the observed time-dependent droplet sta¬
properties of the emulsifier are in balance and is bilization may be distribution of the emulsi¬
therefore also called the HLB temperature: fier between the phases, slow formation of the
Shinoda’s description of the processes at or (double-layer) film on the surface of the benzene
near the PIT is almost universally accepted droplets, or interruption of droplet formation by
today.14 An o/w emulsion stabilized by a noni¬ continuous shaking.
onic polyoxyethylene-derived surfactant con¬ Timing or scheduling also affects the speed
tains oil-swollen micelles of the surfactant as with which the two immiscible liquids are
well as emulsified oil. When the temperature is blended. In the case of an o/w emulsion, for ex¬
raised, the water-solubility of the surfactant de¬ ample, the rate at which the oil phase is added to
creases*; as a result, the micelles are broken, the aqueous phase can materially affect particle
size and ultimate stability of the finished emul¬
sion. Finally, there is a relationship between
‘The water solubility of ether-type surfactants depends temperature and timing, i.e., the cooling/heating
on the formation of hydrogen bonds between water and cycle. It is routine to prepare emulsions at ele¬
the O-atoms of the ether. The surfactant’s solubility de¬
vated temperatures. The cooling rate of the ini¬
creases when H-bonds are broken by heat and/or the pres¬
ence of electrolytes. The cloud point, i.e., the temperature tially formed emulsion also has a profound influ¬
at which the solution of an emulsifier becomes cloudy, is ence on the ultimate characteristics of the
an important analytic criterion for nonionic amphiphiles. emulsion. Unfortunately, it is impossible to pre-

EMULSIONS • 509
diet whether a slow or a rapid cooling cycle is Various types of equipment are available to
desirable for a given emulsion. effect droplet breakup and emulsification either
Low-Energy Emulsification. The classic in the laboratory or in production. Regardless of
process of emulsification just described requires size and minor variations, such equipment can
considerable expenditure of energy during both be divided into four broad categories: (1) me¬
the heating and cooling cycles of emulsion for¬ chanical stirrers, (2) homogenizers, (3) ultra-
mation. The principle of low energy emulsifica¬ sonifiers, and (4) colloid mills.
tion has been formalized by Lin in recent years, During the formulation of an emulsion, the
although some of his suggestions may have been mechanical requirements of preparation, and
previously used by other practitioners.15,16 In particularly the problems associated with scale-
low-energy emulsification, all of the internal up to production-size equipment, must be con¬
phase, but only a portion of the external phase, sidered. The most important factor involved in
is heated. After emulsification of the heated por¬ the preparation of an emulsion is the degree of
tions, the remainder of the external phase is shear and turbulence required to produce a
added to the emulsion concentrate, or the pre¬ given dispersion of liquid droplets. The amount
formed concentrate is blended into the continu¬ of agitation required depends on the total vol¬
ous phase. In those emulsions in which a phase ume of liquid to be mixed, the viscosity of the
inversion temperature exists, the emulsion con¬ system, and the interfacial tension at the oil-
centrate is preferably prepared above the PIT, water interface. The latter two factors are deter¬
which results in emulsions having extremely mined by the emulsion type, the phase ratio, and
small droplet size. As in the case of the classic the type and concentration of emulsifiers. For
emulsification technique, the temperature for this reason, no single method of dispersion can
the preparation of the emulsion concentrate is be used for all emulsions, and conversion from
critical. It is important to effect in situ neutrali¬ one method to another is difficult.
zation of acidic emulsifying components during Mechanical Stirrers. An emulsion may be
the emulsion step. By careful control of the vari¬ stirred by means of various impellers mounted
ables (emulsification temperature, mixing in¬ on shafts, which are placed directly into the sys¬
tensity, the amount of the external phase em¬ tem to be emulsified. Simple top-entering pro¬
ployed during emulsification, and the method of peller mixers are adequate for routine develop¬
blending), it is reportedly possible to produce ment work in the laboratory and for production
emulsions with smaller and more uniform parti¬ purposes, if the viscosity of the emulsion is low.
cle size than those resulting from the conven¬ If more vigorous agitation is required, or if the
tional process. preparation has moderate viscosity, turbine type
mixers are employed both in the laboratory and
in production. Other mixers, provided with pad¬
dle blades, counter rotating blades, or planetary
Mechanical Equipment for action blades, are available for special require¬
ments. The degree of agitation is controlled by
Emulsification the speed of impeller rotation, but the patterns
Almost all methods used for breaking up the of liquid flow and the resultant efficiency of mix¬
internal phase into droplets depend on “brute ing are controlled by the type of impeller, its po¬
force” and require some sort of agitation. When sition in the container, the presence of baffles,
a liquid jet of one liquid is introduced under and the general shape of the container (Chaps. 5
pressure into a second liquid, the initially and 15). Despite the variation in flow behavior
cylindric jet stream is broken up into droplets. and the efficient mixing that can be produced,
The factors that enter into the breakup of a liq¬ the use of stirrers for the formation of emulsions
uid jet include the diameter of the nozzle, the is often limited when vigorous agitation of vis¬
speed with which the liquid is injected, the den¬ cous systems is required, when extremely fine
sity and the viscosity of the injected liquid, and droplets are needed, or when foaming at high
of course, the interfacial tension between the shear rates must be avoided.
two liquids. A similar breakup into droplets oc¬ Homogenizers. In a homogenizer, the dis¬
curs when a liquid is allowed to flow into a sec¬ persion of two liquids is achieved by forcing
ond liquid that is agitated vigorously. Once the their mixture through a small inlet orifice at
initial breakup into droplets has occurred, the high pressures. A homogenizer generally con¬
droplets continue to be subject to additional sists of a pump that raises the pressure of the
forces due to turbulence, which cause deforma¬ dispersion to a range of 500 to 5,000 psi and an
tion of the droplet and further breakdown into orifice through which this fluid impinges upon
smaller droplets.11 the homogenizing valve held in place on the

510 •The Theory and Practice of Industrial Pharmacy

valve seat by a strong spring (Fig, 17-4). As the use of a homogenizer is warranted whenever a
pressure builds up, the spring is compressed, reasonably monodisperse emulsion of low parti¬
and some of the dispersion escapes between the cle size (1 nm) is required. Another useful piece
valve and the valve seat. At this point, the en¬ of equipment, which combines mixing with
ergy that has been stored in the liquid as pres¬ some homogenizing action, is the rotor-stator
sure is released instantaneously and subjects homogenizer described in Chapter 23.
the product to intense turbulence and hydraulic Ultrasonifiers. The use of ultrasonic energy
shear. to produce pharmaceutical emulsions has been
Homogenizers can also be built with more demonstrated, and many laboratory-size models
than one emulsifier stage, and it is possible are available. These transduced piezoelectric
to recycle the emulsion and pass it through devices have limited output and are relatively
the homogenizer more than one time. expensive. They are useful for the laboratory
Homogenizers of varying designs are useful for preparation of fluid emulsions of moderate vis¬
handling either liquids or pastes, since the rate cosity and extremely low particle size. Commer¬
of throughput is litde affected by viscosity. It cial equipment is based on the principle of the
must be remembered, however, that homogeni¬ Pohlman liquid whistle shown in Figure 17-5.
zation raises the temperature of the emulsion, The dispersion is forced through an orifice at
and subsequent cooling may be required. The modest pressures and is allowed to impinge
upon a blade. The pressures required range from
approximately 150 to 350 psi and cause the
blade to vibrate rapidly to produce an ultrasonic
note. When the system reaches a steady state, a
cavitational field is generated at the leading edge
of the blade, and pressure fluctuations of ap¬
proximately 60 tons psi can be achieved in com¬
mercial equipment.
Colloid Mills. Homogenizers and ultrasonic
equipment depend on sudden changes in pres¬
sure to effect the dispersion of liquids. By con¬
trast, colloid mills operate on the principle of
high shear, which is normally generated be¬
tween the rotor and the stator of the mill
(Chap. 23). Colloid mills are used primarily for
the comminution of solids and for the dispersion
of suspensions containing poorly wetted solids
but are also useful for the preparation of rela¬
tively viscous emulsions.
Spontaneous Emulsification. Spontane¬
ous emulsification occurs when an emulsion is
formed without the application of any external

FIG. 17-5. Principle of Pohlman whistle. A, Nodally sup¬

ported blade. B, Edge-mounted blade. (From Gopal, E.S.R.:
Principles of emulsion formation. In Emulsion Science.
Edited by P. Sherman. Academic Press, London, 1968, p.
FIG. 17-4. Schematic representation of a homogenizer.17 47.)

EMULSIONS • 511
 agitation. Emulsifiable concentrates and micro¬ Chemical Parameters
emulsions are typical examples. The former are
blends of the internal phase with emulsifiers, It is difficult to designate a general approach
which “bloom” when they are added to the ex¬ or a set of rules for selecting the components and
ternal phase. Microemulsions commonly form their amounts to yield a desired emulsion. The
spontaneously, but not all spontaneous emul¬ ingredients of any pharmaceutical or cosmetic
sions are transparent. The phenomenon of spon¬ emulsion must conform to various require¬
taneous emulsification is observable when a ments. There are situations in which certain
drop of oil is placed on an aqueous solution of an oils, emulsifiers, and other ingredients must be
emulsifier, in which case the interface becomes avoided or used exclusively. Usually, however,
extremely unstable and results in the formation, ingredient selection is made on the basis of the
of fine droplets. Spontaneous emulsification evi¬ experience and personal tastes of the formulator
dently is not practiced commercially. and by trial and error.
Production Aspects. In routine production, Formulators are cautioned to establish the
it is customary to prepare emulsions by a batch safety and regulatory acceptance of emulsion
process using kettles, agitators, and related ingredients for a particular application.
equipment. However, it is possible to design Chemical Stability. Chemical inertness is
combinations of equipment that permit continu¬ an absolute and almost obvious requirement for
ous manufacturing of emulsions. The selection emulsion ingredients. For example, it would be
of commercial equipment for the production of futile to utilize a soap as an emulsifier in a sys¬
emulsions is based in part on the production tem having a final pH of less than 5. Similarly,
capacity and the power requirements for various one would not use an easily hydrolyzed ester in
types of apparatus. Propeller-type agitators and an emulsion that is either acidic or alkaline.
turbine impellers require the least amount of Some lipids are subject to chemical changes due
energy and are capable of handling large quanti¬ to oxidation (rancidity); in general it is simpler
ties of product. Their greatest utility is for the to avoid their use than to depend on antioxi¬
slow mixing of emulsions that have been pre¬ dants to ensure their stability. It is important,
pared by the melting of waxes followed by slow therefore, that the chemical nature of all emul¬
cooling. The power requirements for homog¬ sion constituents be understood before a selec¬
enizes are much higher than those for simple tion for a given preparation is made.
agitators; nevertheless, their output is slower. Unfortunately, predictions of hydrolytic stabil¬
The least efficient type of mixer is the colloid ity made by classic chemical or pharmaceutical
mill, which has the highest power requirements procedures may on occasion be unreliable, as a
and the slowest production rate of any commer¬ result of micellar catalysis. This type of catalysis
cially useful equipment. can be observed whenever the reactive species is
Foaming during Agitation. During the agi¬ present on or near the micellar surface. Under
tation or transfer of an emulsion, foam may be these conditions, hydrolytic (and substitution)
formed. Foaming occurs because the water- reactions can be accelerated. The decomposition
soluble surfactant required for emulsification of drugs via micellar catalysis has not been stud¬
generally also reduces the surface tension at the ied extensively, but the hydrolysis of alkyl sul¬
air-water interface. To minimize foaming, emul¬ fates is a simple and particularly important ex¬
sification may be carried out in closed systems ample of micellar catalysis. The hydrolysis of
(with a minimum of free air space) and/or under dodecyl sulfates has been shown to depend not
vacuum. In addition, mechanical stirring, par¬ only on the pH of the medium, but also on the
ticularly during the cooling of a freshly prepared presence of a variety of electrolytes and on the
emulsion, can be regulated to cause air to rise to concentration of the surfactant; in addition, it is
the top. If these precautions should fail to elimi¬ subject to micellar catalysis.-18’19
nate or reduce foaming, it is .sometimes neces¬ Safety. Safety and toxicologic clearance of
sary to add*foam depressants’ (antifoams); how¬ components of pharmaceutical and cosmetic
ever, their use-should -be avoided, if at all emulsions are absolute requirements. It is es¬
possible, since they represent a chemical source sential, therefore, for the formulator to depend
of incompatibility. Sometimes the use of ethyl heavily on toxicologic information from suppli¬
alcohol accelerates the coalescence of foam on ers or in the scientific literature, as well as on
the surface of emulsions. On the other hand, the regulatory activities by governmental agencies.
most effective defoamers are long-chain alcohols Despite these almost obvious limitations, the
and commercially available silicone derivatives, formulator has an enormous choice of emulsion
both of which are generally believed to spread ingredients, which differ in their cost and their
over the air-water interface as insoluble films. ability to yield the desired product.

512 • The Theory and Practice of Industrial Pharmacy

 Choice of the Lipid Phase. The materials Phase Ratio. The ratio of the internal phase
making up the oil portion of an emulsion and to the external phase is frequently determined
their relative amounts are determined primarily by the solubility of the active ingredient, which
by the ultimate use of the product. For pharma¬ must be present at a pharmacologically effective
ceutical and cosmetic products, the oil phase, level. If this is not the primary consideration, the
unless it is the active ingredient, may include a phase ratio is normally determined by the de¬
wide variety of lipids of natural or synthetic ori¬ sired consistency. As a rule of thumb, it can be
gin. The consistency of these lipids may range assumed that fluid emulsions result from low
from mobile liquids to fairly hard solids. Some of levels of the internal phase, whereas heavier
the lipids useful for pharmaceutical or cosmetic emulsions are the result of higher percentages of
emulsions are listed in Table 17-2. the internal phase. Also, a high internal phase
A drug in an emulsion type of dosage form dis¬ ratio normally requires a high level of emulsify¬
tributes itself between the oil phase and the ing agent; this point affects the decision con¬
aqueous phase in accordance with its oil/water cerning the phase ratio.
partition coefficient. The drug’s absorption by Choice of Emulsifying Agents. It is cus¬
the gastrointestinal tract or the skin can be ex¬ tomary to differentiate three broad classes of
pected to depend on its solubility in the oil emulsifying agents: the surfactants, the hydro¬
phase, and this is an important pharmacokinetic philic colloids, and the finely divided solids. Al¬
observation (Chap. 9). In principle, the less solu¬ though hydrophilic colloids and finely divided
ble an active ingredient is in. the nonvolatile por¬ solids can be used as the only emulsifier, their
tion of the vehicle, the more readily it penetrates greatest utility is in the form of auxiliary emulsi¬
into and through a barrier. On the other hand, a fiers; accordingly, they are discussed under this
finite solubility of the active ingredient in the heading.
vehicle is necessary to ensure its presence in a A particular class of emulsifier is selected pri¬
fine state of subdivision. It is generally accepted marily on the basis of required “shelf-life” stabil¬
that the release of a medicinal agent from a dos¬ ity, the type of emulsion desired, and emulsifier
age form is a function of the solubilities of the cost.
agent in the base and in the body membrane. Choice of Surfactant. The number of sur¬
The key point is that the drug must not be so factants available for the formation of emulsions
soluble preferentially in the base that it prevents is so huge that even a cursory description is im¬
penetration or transfer. possible. Only a general classification can be
A final consideration in the selection of a lipid given here (Table 17-3). Important and useful
component for a topical preparation is its “feel.” sources for background material are the trade lit¬
Emulsions normally leave a residue of the oily erature and the publications that originate from
components on the skin after the water has commercial suppliers.
evaporated. Therefore, the tactile characteristics Emulsion technologists have for many years
of the combined oil phase are of great impor¬ selected emulsifiers from an intuitive knowl¬
tance in determining consumer acceptance of edge of their hydrophilic, lipophilic behavior and
an emulsion. of the type of emulsion produced with a given

Table 17-2. Ingredients for Oil Phase of Emulsions

Class Identity Consistency

Hydrocarbon Mineral oils Fluids of varying viscosity

Hydrocarbon Petrolatum Semisolid
Hydrocarbon Polyethylene waxes Solids
Hydrocarbon Microcrystalline waxes Solids
Ester Vegetable oils Fluids of varying viscosity
Ester Animal fats Fluids or solids
Ester Lanolin Semisolid
Ester Synthetics (e.g., i-propylmyristate) Fluids
Alcohols Long-chain (natural & synthetic) Fluids or solids
Fatty acids Long-chain (natural & synthetic) Fluids or solids
Ethers Polyoxypropylenes Fluids of varying viscosity
Silicones Substituted Fluids of varying viscosity
Mixed Plant waxes (e.g., Candelilla) Solid
Mixed Animal waxes (e.g., Bees) Solid

EMULSIONS • 513
Table 17-3. Classification of Surfactants for Pharmaceutical Emulsions
Typical Representatives* Utility

Anionic Group
Carboxylic acids Soap T
Lactylates TO
Polypeptide condensates T
Sulfuric acid esters Sulfated monoglycerides TO
Alkyl sulfates TO
Alkyl and alkyl-aryl sulfonates Dodecylbenzene sulfonates T
Phosphoric acid esters Trioleyl phosphate T
Substituted alkyl amides Sarcosinates TO
Taurates T
Hemiesters Sulfosuccinates TO

Cationic Group
Amines Alkoxyalkylamines T
Quaternaries Benzalkonium chloride TO

Amphoteric Group
Ammonium carboxylates N -alkylaminoacids TO
Ammonium phosphates Lecithin TOP

Nonionic Group
Polyalkoxyethers Polyoxyethylene alkyl/aryl ethers T
Polyoxyethylene polyoxypropylene TOP
block polymers
Polyalkoxyesters Polyoxyethylene fatty acid esters TO
Polyoxyethylene sorbitan TO
acid esters
Polyalkoxy amides T
Fatty acid esters of polyhydric alcohols Sorbitan esters TO
Glyceryl esters TO
Sucrose esters TO
Fatty alcohols Lauryl alcohol T

* Illustrative examples only.

T = some representatives useful in topicals.
O = some representatives useful in oral preparations or ingested drugs.
P = some representatives useful in parenterals.

lipid or aqueous phase. This approach is most puted as long as the structural formula of the
readily illustrated with nonionic surfactants, but surfactant is known. The HLB value of individ¬
the principles involved can be extrapolated to ual emulsifiers or their combinations is of little
any type of emulsifier or combination of emulsi¬ value unless some specific information, is also
fiers. For example, a number of emulsions with available for determining the HLB value re¬
surfactants of different polarities can be pre¬ quired for the formation of a particular type of
pared using polyoxyethylene derivatives having emulsion. Despite some pitfalls, the HLB sys¬
the same nonpolar group but varying numbers tem continues to be used by formulators for the
of ethylene oxide units, and can be evaluated on selection of emulsifiers or emulsifier blends. It is
their appearance and stability. It is apparent that appropriate, therefore, to describe the practical
the choice of specific emulsifiers by this application of this approach in some detail.
method, although practical, is empiric and tedi¬ Griffin defined the HLB value of a surfactant
ous. as the mol % of the hydrophilic group divided by
To systematize the hydrophilic/lipophilic ap¬ 5. A completely hydrophilic molecule (without
proach to emulsifier selection, Griffin in 1947 any nonpolar poup) has an HLB value of 20.
developed the (still somewhat empiric) system The simple arithmetic determination of the HLB
of the Hydrophilic-Lipophilic Balance (HLB) of value is applicable only to polyoxyethylene
surfactants. The HLB value of an emulsifier can ethers; as a result, the HLB for many other ma¬
be determined experimentally or can be com¬ terials must be estimated by laborious experi-

514 • The Theory and Practice of Industrial Pharmacy

mental methods. A useful means of finding the oretic concepts of surface chemistry,13,22 espe¬
HLB of an unknown emulsifier is'that proposed cially the solubility parameter.23
by Davies, which permits calculation of the HLB The HLB required for emulsifying a particular
value by algebraically adding the values as¬ oil in water can be determined by trial and error,
signed to a particular atomic grouping within i.e., by preparing appropriate emulsions with
the molecule of the emulsifier.20 Only a few emulsifiers having a range of HLB values and
HLB values are listed in Table 17-4, but a more then determining that HLB value that yields the
comprehensive listing has been compiled by “best emulsion.” Although the numbers have
Fox."1 In general, molecules that are oil-soluble been derived empirically, they are useful start¬
or oil-dispersible have low HLB values; those ing points for the preparation of a variety of
that are water-soluble have high HLB values. emulsions. A list of required HLB values for lip¬
This simplified classification of HLB values by ids that are of interest in pharmaceutical prepa¬
dispersibility in water is included in Table 17-4. rations is shown in Table 17-5. The knowledge
Efforts have been made to provide a theoretic of the required HLB permits selection of an
basis for the HLB values of surfactants. As a re¬ emulsifier or a combination of emulsifiers that
sult, it has been possible to establish correlations will produce the required HLB.
between the practical term HLB and several the¬ Occasionally, it will be found that a single

Table 17-4. HLB Values of Selected Emulsifiers

Chemical Designation HLB Water Dispersibility

Ethylene glycol distearate 1.5 '

Sorbitan tristearate 2.1
| No dispersion
Propylene glycol monostearate 3.4
Sorbitan sesquioleate 3.7 .

Glyceryl monostearate, non-self-emulsifying 3.8 '

Propylene glycol monolaurate 4.5
Sorbitan monostearate 4.7 Poor dispersion
Diethylene glycol monostearate 4.7
Glyceryl monostearate, self-emulsifying 5.5 .

Diethylene glycol monolaurate 6.1 '

Sorbitan monopalmitate 6.7
Sucrose dioleate 7.1 Milky dispersion (not stable)
Polyethylene glycol (200) monooleate 8.0
Sorbitan monolaurate 8.6 J
Polyoxyethylene (4) lauryl ether 9.5 1
Polyoxyethylene (4) sorbitan monostearate 9.6 Milky dispersion (stable)
Polyoxyethylene (6) cetyl ether 10.3 J
Polyoxyethylene (20) sorbitan tristearate 10.5
Polyoxyethylene glycol (400) monooleate 11.4
Translucent to clear dispersion
Polyoxyethylene glycol (400) monostearate 11.6
Polyoxyethylene (9) nonyl phenol 13.0

Polyethylene glycol (400) monolaurate 13.1

Polyoxyethylene (4) sorbitan monolaurate 13.3
Polyoxyethylene (20) sorbitan monooleate 15.0
Polyoxyethylene (20) oleyl ether 15.4
Polyoxyethylene (20) sorbitan monopalmitate 15.6
Polyoxyethylene (20) cetyl ether 15.7 Clear solution
Polyoxyethylene (40) stearate 16.9
Sodium oleate 18.0
Polyoxyethylene (100) stearate 18.8
Potassium oleate 20.0
Sodium lauryl sulfate Approx. 40

EMULSIONS • 515
Table 17-5. HLB Values Required by Commonly Used Lipids
O/W Emulsion W/O Emulsion
(Fluid) (Fluid)

Cetyl alcohol 15 —

Stearyl alcohol 14 —

Stearic acid 15 —

Lanolin, anhydrous 10 8
Mineral oil, light and heavy 12 —

Cottonseed oil 10 5
Petrolatum 12 5
Beeswax 12 4
Paraffin wax 11 4

emulsifier can yield the desired type of emulsion the HLB concept that the HLB value is critical,
at the desired viscosity. More often, however, but this is not always the case. There is no as¬
especially in the case of o/w emulsions, stable surance that a stable emulsion prepared from
emulsions can be prepared readily by utilizing a one chemical class of emulsifiers at a particular
combination of a lipophilic and a hydrophilic HLB can be duplicated by another class of emul¬
surfactant. Such combinations appear to pro¬ sifiers exhibiting the same HLB. Thus, marked
duce mixed interfacial phases of high surface differences in emulsion type, viscosity, and time
coverage as well as of sufficient viscosity to pre¬ for phase separation were noted when poly¬
vent creaming and promote stability (see “Spe¬ oxyethylene ether derivatives were compared to
cific Formulation Considerations; Consist¬ polyoxyethylene ester-type surfactants having
ency”). HLB values of combinations may be the same HLB and concentration. Additional
determined by taking weighted averages of the complications arise from the observations that
individual surfactant HLB values. For example, the HLB required for a particular emulsion to
Table 17-5 indicates that a w/o emulsion of lano¬ some extent depends on the phase ratio and the
lin requires an HLB of about 8. Thus, a 68:32 salt content.
mixture of sorbitan monostearate (HLB 4.7) and Several improvements on the classical HLB
polyoxyethylene (20) sorbitan monooleate (HLB system for the selection of emulsifiers have been
15.0) could be used to yield an emulsifier exhib¬ proposed. The phenol index, developed by
iting an average HLB value of about 8.0.* In Marszall, makes it possible to determine the “ef¬
fact, almost any HLB can be obtained by appro¬ fective” HLB of nonionics as a function of their
priate blending of emulsifiers, with the addi¬ concentration and in the presence of additives
tional advantage, in most cases, of greater such as alcohols and glycols.25 Shinoda has
efficiency at lower concentrations. However, pointed out that the HLB-temperature (or PIT)
optimal emulsion stability and desirable rheo¬ can be determined easily on a series of test
logic characteristics cannot be achieved by ran¬ emulsions of varying HLB.26 For optimal stabil¬
dom blending of emulsifiers. Shinoda and ity of an o/w emulsion, this temperature should
co-workers point out that the blending of two be 25 to 70°C higher than the proposed storage
emulsifiers of very high and very low HLB to temperature of the emulsion. The selection of
achieve an intermediate HLB can result in an the emulsifier system best suited for an emul¬
unstable emulsion unless an emulsifier of me¬ sion thus becomes relatively easy. The PIT can
dium HLB is included.24 Therefore, a 65:35 be particularly critical for the high-temperature
blend of sorbitan tristearate and polyoxyethylene stability and appearance of clear emulsions.
(100) stearate, which has an HLB of about 8, It is generally believed that more hydrophilic
could be expected to be inferior for the indicated emulsifiers favor o/w emulsions, whereas more
emulsification to the blend of sorbitan monoste¬ nonpolar surfactants favor w/o emulsions. Grif¬
arate and polyoxyethylene (20) monooleate. fin originally proposed that emulsifiers with
Emulsion specialists generally agree that the HLB values ranging from 3.5 to 6.0 should be
HLB system is useful and that it may be used used for w/o emulsions, but Ford and Furmidge
judiciously and with caution. It is a dictum of showed that correlation between emulsion type
and HLB is far from perfect.2' Stable mineral
oil-in-water emulsions have been obtained with
*0.68 x 4.7 + 0.32 x 15.0 = 8.0 a combination of nonionic ethers having an HLB

516 •The Theory and Practice of Industrial Pharmacy

value as low as 1.9. HLB may be one considera¬ mixture of which the least amount is required
tion in the preparation of a stable emulsion; an¬ for optimal stability of an emulsion. Often, this
other is the solubility of the emulsifier’s lipid goal can be achieved by determining the amount
chain in the oil phase. of water that can be solubilized in a given oil-
A final complication arises from the observa¬ plus- surfactant(s) mixture under carefully con¬
tion that a hydrophilic surfactant placed into one trolled temperature and stirring conditions.30
of the phases of an emulsion prior to emulsifica¬ For this purpose, 10 g of the lipid/surfactant
tion migrates to the other phase after or during mixture is weighed into a 68-ml capacity square
emulsification until equilibrium is estab¬ glass vial. After equilibration at a temperature at
lished.28 The rate of surfactant migration is be¬ which this (not always homogeneous) system is
lieved to depend on the presence of a second fluid, water is added in 0.10-ml increments. The
(hydrophobic) surfactant, which retards the es¬ mixture is shaken and allowed to stand at the
tablishment of this equilibrium and influences equilibration temperature until all air bubbles
emulsion formation and stability. In a recent have escaped. The addition of water (in 0.10-ml
report, Lin and co-workers point out that the sig¬ increments) is continued until the system re¬
nificance of surfactant location before emulsion mains permanently turbid. If the initial lipid/
might be related to phase inversion.29 Their surfactant mixture is not clear, it will usually
studies and those of Shinoda26 show that an become clear upon addition of water and then
emulsion prepared by a process involving phase become cloudy again upon continued addition of
inversion exhibits smaller particle sizes and pos¬ water. This second cloudpoint is the end of the
sesses improved emulsion stability. titration. As a rule, the most stable o/w emulsion
The practical importance of emulsification with the finest particle size results at that sur¬
temperature on emulsion stability has been factant/oil ratio that can tolerate the largest
known to formulators for many years. As a rule, quantity of water and still remain clear.
maximum particle size reduction occurs at or Most of our current knowledge of the selection
near the PIT. At that temperature, surfactants of emulsifiers is based on the HLB concept and
that are normally water-soluble may actually is applied to the commonly used nonionic sur¬
become soluble in the oil phase. As the emulsion factants. Recently, the optimization of the stabil¬
cools, emulsifiers migrate, e.g., by changing ity of a parenteral, ultrasonically emulsified nu¬
their location from the internal to the external trient oil preparation stabilized with various
phase of the emulsions. How this alters emul¬ phospholipids and a nonionic has also been ex¬
sion formation, particle size, and stability has plained on the basis of HLB.31 A somewhat dif¬
not been rigorously studied; however, some of ferent interpretation of the emulsifying efficacy
Lin’s data in Table 17-6 illustrate these points.29 of phospholipids, which does not involve HLB,
In this simple system of one single emulsifier at was offered by Rydhag.32 She reported that the
HLB 9.9, complete placement of the surfactant best soya bean oil in water emulsions can be ob¬
into the oil phase seems most advantageous re¬ tained with mixed (commercial) phospholipids
gardless of the temperature. However, the emul¬ containing the largest amounts of negatively
sification will be successful regardless of the lo¬ charged phospholipids (i.e., phosphatidyl inosi¬
cation of the emulsifier as long as the tol, phosphatidic acid, and phosphatidyl serine).
temperature exceeds the PIT during emulsifica¬ Pure phosphatidyl choline (or its combination
tion. with phosphatidyl ethanolamine) yields the least
This discussion of the selection of emulsifiers stable emulsion. These findings are best ex¬
would be incomplete without a brief examina¬ plained by the phase-forming ability of these
tion of how one can determine that surfactant emulsifiers as postulated by Friberg. ~9

Table 17-6. Effect of Surfactant Lotion and Emulsification Temperature on Droplet Size

Average Droplet Size (fim) at Emulsification Temp.

Percentage of Emulsifier in Oil Phase* 30°C 40°C 5 0°C 60°C

0 15.0 13.0 11.0

40 13.0 10.0 9.0 0.2
80 2.0 2.0 1.5
100 1.5 1.5 0.9 0.2

“The emulsion consists of 30% mineral oil, 5% polyoxyethylene (5) oleyl ether, and 65% water. The emulsifier was added to one or both
phases before emulsification at the indicated temperatures.

emulsions *517
 Choice of Auxiliary Emulsifiers. Solids. sions or for suspending solids, such as pigments,
Finely divided solids have been shown to be in makeup preparations. A large variety of natu¬
good emulsifiers, especially in combination with ral and synthetic clays is available, and the se¬
surfactants and/or macromolecules that increase lection of a useful clay is occasionally difficult.
viscosity. Included are polar inorganic solids, The most commonly used clays, bentonites, are
such as heavy metal hydroxides, certain derived from montmorillonite, a typical smectite
nonswelling clays, and pigments. Even nonpolar clay. These swell in the presence of water but
solids, e.g., carbon or glvceryltristearate, can be raise the viscosity of aqueous media only at pH 6
used. Polar solids tend to be wetted by water to a or higher. Clays derived from the amphibole
greater extent than by the oil phase, whereas the group, such as attapulgite, thicken not by swell¬
reverse is true for nonpolar solids. In the ab¬ ing but primarily because of particle anisotropy,
sence of surfactants, w/o emulsions are favored which interferes with formation of a compact
by the presence of nonpolar solids, presumably sediment.
because the wetting by oil facilitates the coales¬ The naturally occurring gums and synthetic
cence of oil droplets during the initial steps of hydrophilic polymers listed in Table 17-7 are
emulsification. An analogous interpretation may useful as emulsifiers and as emulsion stabiliz¬
be given for the tendency of polar solids to favor ers. Most natural hydrocolloids are polysaccha¬
water as the external phase. rides, and their chemistry is extremely complex.
In the presence of wetting agents, i.e., when These gums exhibit some type of incompatibility
such solids are used as auxiliary emulsifiers, or instability depending on the presence of vari¬
their behavior is controlled by the so-called ous cations, on pH, or on a second hydrophilic
Young equation, which was given in Chapter 5, polymer. Some of the most useful synthetic hy¬
equation (18). For example, barium sulfate in drocolloids are ethers derived from cellulose.
the presence of sodium laurate (at pH 12) favors Among the completely synthetic group of poly¬
o/w emulsions, whereas barium sulfate coated mers, the carboxyl vinyl polymers deserve spe¬
with sodium dodecyl sulfate favors w/o emul¬ cial mention: Their outstanding characteristic is
sions. In view of the limited utility of such solids their ability to impart a yield value to aqueous
as primary emulsifiers, or even as auxiliary systems.’ These materials are also included in
emulsifiers, they are not of major interest to the Table 17-7.
formulator. The water-sensitive hydrocolloids generally
Hydrophilic Colloids. Polymers that are favor o/w emulsions because they form excellent
water-sensitive (swellable or soluble) have some hydrophilic barriers. Their use is warranted
utility as primary emulsifiers; however, their whenever it is desired to increase the viscosity of
major use is as auxiliary emulsifiers and as an emulsion without a corresponding increase
thickening agents. Natural and synthetic clays
of the smectite or amphibole groups are com¬ ‘A system is said to possess a yield value if a minimum
monly used for building the viscosity of emul¬ shear is required before the m exhibits any flow.

Table 17-7. Organic Hydrocolloids Useful in Emulsion Technology

Source Name Comment

Tree exudate Gum Arabic (Acacia) Essentially neutral polysaccharide

Gum Ghatti Essentially neutral polysaccharide
Karaya Essentially neutral polysaccharide
Tragacanth Essentially neutral polysaccharide
Sea weeds Agar, Carrageenan Sulfated polysaccharide
Alginates Acidic polysaccharide
Seed extracts Locust bean Essentially neutral polysaccharide
Guar Essentially neutral polysaccharide
Quince seed Essentially neutral polysaccharide
Synthetic Xanthan gum Essentially neutral polysaccharide
(fermentation)
Cellulose Methyl-, hydroxyethyl-hydroxypropyl-ether Neutral polysaccharide
Carboxymethyl-ether Anionic polysaccharide
Collagen Gelatin Amphoteric protein
Synthetic Polyoxethylene polymer Neutral
Carboxyvinyl polymer (cross-linked) Anionic

518 •The Theory and Practice of Industrial Pharmacy

in the lipid portion of the emulsion. Proteins, as 1. There is a linear relationship between
a group, are effective not only as primary emul¬ emulsion viscosity and the viscosity of the con¬
sifiers but also as auxiliary emulsifiers. They are tinuous phase: (The use of gums and clays for
particularly useful in oral dosage forms. The the¬ o/w emulsions has already been noted.) In the
oretical basis for effectiveness, i.e., amphilic case of w/o emulsions, the addition of polyvalent
characteristics, and the practical application of metal soaps or the use of high melting waxes
proteins as emulsifiers have been reviewed by and resins in the oil phase can be used to in¬
Cante and co-workers.33 crease viscosity. Emulsion viscosity is not very
Multiple emulsions of the w/o/w type are nor¬ sensitive to viscosity changes of the internal
mally prepared by first forming a w/o emulsion phase.
with the aid of a low HLB emulsifier. This w/o 2. The greater the volume of the internal
emulsion is then slowly incorporated into an phase, the greater is the apparent viscosity.
aqueous phase that contains an emulsifier of a 3. To control emulsion viscosity, three inter¬
significantly higher HLB, i.e., approximately 12 acting effects must be balanced by the formula-
to 14. tor: (1) The viscosity of o/w and w/o emulsions
Specific Formulation Considerations. can be increased by reducing the particle size of
Consistency. Once the desired emulsion and the dispersed phase, (2) emulsion stability is
emulsifiers have been chosen, a consistency improved by a reduction in particle size, and
that provides the desired stability and yet has (3) flocculation, or clumping, which tends to
the appropriate flow characteristics must be at¬ structure the internal phase, can be a stabilizing
tained. It has already been mentioned that the effect, but it increases viscosity.
viscosity of an emulsion can be altered by ma¬ 4. As a rule, the viscosity of emulsions in¬
nipulating the composition of the lipid phase, by creases upon aging.
variations in the phase ratio and the surfactants Clear Emulsions. In general, the considera¬
and by the addition of gums. It is well known tions applicable to opaque emulsions are also
that the creaming of fluid emulsions depends on pertinent to the preparation of clear emulsions.
their rheologic character as well as on the sur¬ The amount of internal phase in clear emulsions
face characteristics of the interfacial film. The or in solubilized systems is generally lower than
use of gums, clays, and synthetic polymers in that in opaque emulsions. Most emulsion tech¬
the continuous phase of emulsions is a powerful nologists have found that an increase in the sur¬
tool for enhancing an emulsion’s stability. As factant concentration(s) reduces the opacity of
was pointed out in Chapter 16, the sedimenta¬ all types of emulsions, and if carried further, can
tion or creaming rate of suspended spherical result in solubilization.
particles is inversely proportional to the viscosity Cosmetic and pharmaceutical microemul¬
in accordance with Stake’s law. When all other sions usually do not employ the cosolvents
variables are held constant, an increase in vis¬ required for the more classic microemul¬
cosity generally minimizes creaming, rising, or sions of theoretic interest. Instead, modem com¬
sedimentation. mercial solubilized systems are frequently based
Since emulsions should flow or spread, and on nonionic emulsifiers, which results in the
since higher viscosity favors stability, thixotropy formation of micellar solutions. If the
in an emulsion is desirable.* In the case of emul¬ solubilizate is a drug, the drug available for ab¬
sions that also contain suspended solids, the sorption through the skin may not equal the
presence of a yield value assures at least reason¬ total amount of drug in the product. That portion
able stability. of the drug that is incorporated into the interior
It is routinely observed that the building up of of micelles may not be available for absorption
viscosity in a freshly prepared emulsion requires unless the micelles exhibit instability. The ac¬
some time. It is recommended, therefore, that a tual location of the drug is described by a micel¬
newly formulated emulsion be allowed to rest lar distribution coefficient defined as:
undisturbed for 24 to 48 hours before it is deter¬
mined whether its rheologic properties corre¬
spond to those that are required.
The viscosity of emulsions responds to
changes in composition in accordance with the where Sm is the solubility of the active ingredi¬
following generalizations.34-37 ent in the micellar phase and Sw is its solubility
in water.38 The value for Km is established by
’Shear thinning refers to the phenomenon in which the classic solubility determinations. The value for
viscosity of a preparation is reduced by agitation but in¬ Sm, e.g., in the case of dexamethasone, in¬
creases after agitation has been stopped. creases linearly with increasing concentrations

EMULSIONS* 519
of a nonionic surfactant, such as polyoxyeth¬ of impure raw materials or from poor sanitation
ylene (20) stearyl alcohol.39 Comparable results during preparation. Alternately, contamination
are obtained by equilibrium (or differential) dial¬ may be the result of invasion by an opportunistic
ysis through membranes that are impermeable microorganism. Finally, the consumer may ac¬
to surfactant micelles but permeable to the free tually inoculate the product during use. It is
steroid, which also yields a slightly different dis¬ commonly believed that a preservative or a sys¬
tribution coefficient, K'm. In the case under dis¬ tem of preservatives can protect the emulsion
cussion, Km is large (=400) and almost identi¬ against all of these possibilities. The formulation
cal to K'm. of a self-sterilizing emulsion is exceedingly diffi¬
During the processing of solubilizates, these cult without the use of potent antimicrobial
“clear” emulsions are frequently opaque at high agents, most of which have been or are in the
temperatures (in view of the PIT). Clearing of process of being- reviewed by governmental reg¬
the emulsion occurs as the preparation cools, ulatory agencies. Prevention of contamination is
and solubilized systems (in the absence of cosol- recommended, and certain cardinal rules must
vents) usually remain clear to temperatures be observed. The most important one is the use
close to the freezing point of one of the major of uncontaminated raw materials, including the
components. In the case of nonionic o/w water. A second precaution is meticulous house¬
solubilizates, it is sometimes helpful to include a keeping and careful cleaning of equipment (with
small amount of a surfactant with a high HLB live steam). Once a microbiologically uncontam¬
(e.g., alkyl sulfate) to raise the PIT if it is too inated product has been prepared, a relatively
close to the expected storage temperature. mild antimicrobial agent suffices to protect the
Whenever it is desirable to “dissolve” a small product against chance contamination by micro¬
amount of a flavor or fragrance in an essentially organisms. It is also desirable that the preserva¬
aqueous system, the formulator should be tive system be effective against invasion by a
guided by some important practical rules: variety of pathogenic organisms and be adequate
1. Surfactants in the HLB range of 15 to 18 are to protect the product during use by the con¬
ideal solubilizing agents for this purpose (see sumer.
Tables 15-1 and 17-4). 2. It sometimes helps to As is true of most ingredients of a formulation,
add a small amount of a surfactant with an HLB the preservative system must first meet the gen¬
in the range of 8 to 12. 3. As a rule, 3 to 5 times eral criteria of low toxicity, stability to heat and
as much surfactant as oil is required to effect storage, chemical compatibility, reasonable cost,
solubilization. 4. The oil should always be and acceptable taste, odor, and color. Efficacy
blended with the surfactant before addition to against a variety of organisms is required since
the (wanned) aqueous phase. This is particu¬ fungi, yeasts, and bacteria are common contami¬
larly important for the oil-soluble vitamins. nants. The more important groups of preserva¬
5. The incorporation of a flavor or fragrance into tives and some popular examples used in emul¬
solubilizing systems generally reduces the orga¬ sions are shown in Table 17-8. The activity of
noleptic impact of the oil, since as described the antimicrobial agents listed in the table varies
above, part of it is entrapped into micelles. To widely and depends on the microorganism in¬
enhance flavor or fragrance intensity, it is some¬ volved.
times necessary to use a cosolvent, such as etha¬ The concentration of preservative required in
nol. an emulsion depends to a large extent on its abil¬
Choice of an Antimicrobial Preservative. ity to interact with microorganisms. Since mi¬
Emulsions often contain a number of ingredi¬ croorganisms can reside in the water or the lipid
ents, such as carbohydrates, proteins, sterols, phase or both, the preservative, regardless of its
and phosphatides, all of which readily support, water-oil partition coefficient, should be avail¬
the growth of a variety of microorganisms. Even able at an effective level in both phases. It is
in the absence of any of the aforementioned nat¬ almost inconceivable that a single preservative
ural ingredients, the mere presence of a mixture could distribute itself at effective concentrations
of lipid and water in intimate contact frequently between the phases, regardless of their composi¬
allows microorganisms to establish themselves. tions. It is therefore customary to include a pre¬
As a result, the inclusion of a preservative is a servative that is soluble in the water phase and
necessary part of the formulation process. Sev¬ one that is primarily soluble in the oil phase.
eral points must be kept in mind in selecting The esters of p-hydroxybenzoic acid are particu¬
a preservative. Microbial contamination may larly good examples because the methyl ester is
occur during the development or production of water-soluble, whereas the propyl and higher
an emulsion or during its use. Frequently, the esters exhibit almost no water solubility. The
microbial contamination can arise from the use distribution of a preservative between the lipid

520 • The Theory and Practice of Industrial Pharmacy

Table 17-8. Some Typical Preservatives Used in Pharmaceutical and Cosmetic Emulsions

Type Example Characteristics & Utility

Acids and acid

derivatives Benzoic acid j
Sorbic acid and salts I
Propionic acid and salts [ Antifungal agent
Dehydroacetic acid j
Alcohols Chlorobutanol Eye preparations
Phenoxy-2-ethanol Synergist
Aldehydes Formaldehyde 1
Glutaraldehyde j Broad spectrum
Formaldehyde donors Hexamethylenetetramine
Mono- (and di-) methyloldimethyl
hydantoin
Phenolics Phenol
Cresol
Chlorothymol
o-Phenylphenol
p-Chlorometaxylenol
Methyl p-hydroxybenzoate
Propyl p-hydroxybenzoate
Benzyl p-hydroxybenzoate Broad spectrum
Butyl p-hydroxybenzoate
Quaternaries Chlorhexidine and salts
Benzethonium chloride
Benzalkonium chloride
Cetyltrimethyl ammonium bromide
Cetylpyridinium chloride
Mercurials Phenylmercuric acetate
Sodium ethylmercurithiosalicylate
Miscellaneous 6-Acetoxy-2, 4-dimethyl-m-dioxane
2, 4, 4'Trichloro-2'-hydroxy-
diphenylether Primarily against gram positive bacteria
(l-(3-Chloroallyl)-3,5,7-triazo-
1 -azoniaadamantane
chloride Broad spectrum and synergist
Imidizolidinyl urea compound Synergist
Bromo-2-nitropropanediol-1,3
5-Bromo-5-nitrol-l ,3-dioxane
2-Thiopyridine N-oxide (and salts) Broad spectrum
2-Methyl-4-isothiazolin-3-one and
5-chloro derivative

This tabulation is not complete and may include antimicrobial agents, use of which is prohibited in some countries. Formulators must
consult pertinent regulations and toxicity studies.

and the aqueous phase of emulsions can be de¬ available to exert antimicrobial activity. It is ap¬
termined by procedures commonly employed for parent that the phenolic preservatives are espe¬
evaluating distribution coefficients.40,41 cially susceptible to interaction with compounds
Complex problems arise whenever the pre¬ containing polyoxyethylene groups.
servative interacts with one of the emulsion in¬ A basic mathematical model for understand¬
gredients. Such interactions may inactivate the ing the relationship between preservative con¬
preservative. The interaction with emulsion in¬ centration and microbiological activity was de¬
gredients of various alkyl hydroxybenzoates (the veloped by Garrett. This basic concept was
most widely used preservatives in emulsions) confirmed by Kazmi and Mitchell41 with the aid
has been studied for many years and is illus¬ of a dialysis method and by Shimamoto and co-
trated by the data in Table 17-9.42,43 As a rule, workers^4 with the aid of an ultrafiltration tech¬
the so-called bound preservatives are not readily nique. The current interpretation of preserva-

EMULSIONS • 521
Table 17-9. Interaction of Parabens with Emulsion Ingredients

Methyl-p-hydroxy Propyl-p-hydroxy
benzoate benzoate

Macromolecular free bound free bound

Compounds (%) (%) (%) (%)

Gelatin 92 8 89 11
Methyl cellulose 91 9 87 13
Polyethyleneglycol 4000 84 16 81 19
Polyvinylpyrrolidone 78 22 64 36
Polyoxyethylene monostearate 55 45 16 84
Polyoxyethylene sorbitan monolaurate 43 57 14 86
Polyoxyethylene sorbitan monooleate 43 57 10 90

tive inactivation by surfactants rests on the con¬ Although much has been written on the sub¬
cept that part of the preservative is unavailable ject of preservation and on the utility of a partic¬
for activity by virtue of incorporation into surfac¬ ular preservative or preservative combination,
tant micelles or other relatively stable surfactant the selection of a preservative for actual use in a
phases.45 This concept is no different from the specific emulsion is somewhat empiric. Formu-
rationale proposed for the unavailability of a sol¬ lators are cautioned not to depend on chemically
ubilized drug, which was briefly described before. determined availability of preservatives to estab¬
To compensate for the loss of preservative by lish the microbiologic cleanliness of a product.
interactions, an amount equal to the complexed Instead, rigorous microbiologic examination of
material may be added. It has also been found the final composition is required to determine
that the addition of various alcohols seems to whether an emulsion is properly preserved.46,4'
activate p-hydroxybenzoate esters in the pres¬ Choice of Antioxidant. Many organic com¬
ence of nonionics; propylene glycol appears to be pounds are subject to autoxidation upon expo¬
especially useful. sure to air, and emulsified lipids are particularly
Several other factors can alter the ability of sensitive to attack. Many drugs commonly incor¬
preservatives to protect a product against micro¬ porated into emulsions are subject to autoxida¬
bial contamination. The pH is known to exert a tion and resulting decomposition.
major influence on the ability of acidic or pheno¬ Upon autoxidation, unsaturated oils, such as
lic preservatives to interfere with microbial vegetable oils, give rise to rancidity with resul¬
growth. These agents are almost completely in¬ tant unpleasant odor, appearance, and taste. On
activated by converting them into anions.42,43 the other hand, mineral oil and related saturated
Other factors include the phase ratio, the degree hydrocarbons are subject to oxidative degrada¬
of aeration during preparation, and especially tion only under rare circumstances.
the presence of flavors and perfumes, some of Autoxidation is a free radical chain oxidation
which have antimicrobial properties. Combina¬ reaction. It can be inhibited, therefore, by the
tions of preservatives are often used, since they absence of oxygen, by a free radical chain
have been shown to increase the effectiveness of breaker, or by a reducing agent. Materials that
preservative action, either by an enhancement are useful as antioxidants by one or more of
of the spectrum of activity or by some synergistic these three mechanisms are listed in Table
behavior. 17-10. The choice of a particular antioxidant

Table 17-10. List of Antioxidants

Gallic acid L-Tocopherol

Propyl gallate Butylated hydroxytoluene
Ascorbic acid Butylated hydroxyanisol
Ascorbyl palmitate 4-HydroxymethyI-2,6-di-£ert-butylphenol
Sulfites

Although incomplete, this listing includes materials, use of which may

be restricted by governmental regulations.

522 • The Theory and Practice of Industrial Pharmacy

depends on its safety, acceptability for a particu¬ fiers are commonly added to the lipid phase,
lar use, and its efficacy. Antioxidants are com¬ whereas the water-soluble emulsifiers are dis¬
monly used at concentrations ranging from solved in the aqueous phase. Occasionally, it
0.001 to 0.1%. may prove advantageous to include even the
Butylated hydroxyanisole (BHA), butylated water-soluble emulsifier in the oil phase. In the
hydroxytoluene (BHT), L-tocopherol, and the preparation of w/o emulsions, it is almost always
alkyl gallates are particularly popular in pharma¬ necessary to add the water phase slowly to the
ceuticals and cosmetics. BHT and BHA have a oil/emulsifier blend.
pronounced odor and should be used at low con¬ To avoid losses, volatile flavors or perfumes
centrations. Alkyl gallates have a bitter taste, are preferably added at the lowest temperature
whereas L-tocopherol is well suited for edible or at which incorporation into the emulsion is pos¬
oral preparations, such as those containing vita¬ sible (usually 55 to 45°C).
min A. Almost all antioxidants are subject to dis¬ If a gum is employed, it should be completely
coloration in the presence of light, trace metals, hydrated or dissolved in the aqueous phase be¬
and alkaline solutions. Combinations of two or fore the emulsification step. If a heat-sensitive
more antioxidants have been shown to produce gum is used, it may be necessary to incorporate
synergistic effects. In some cases, compounds the gum solution after the emulsion has been
completely devoid of antioxidant activity by formed. The use of two different organic gums
themselves enhance the effectiveness of certain can cause incompatibility. It is also noted that
antioxidants. For example, alkyl gallates, BHT, anionic and cationic emulsifiers in about equi¬
and BHA are much more effective in the pres¬ molar quantities rarely yield satisfactory emul¬
ence of citric, tartaric, or phosphoric acids. A re¬ sions.
lated way of enhancing the activity of phenolic Not unexpectedly, emulsions designed for
antioxidants involves the use of a small amount parenteral administration can be prepared with
of a sequestrant for heavy metal, calcium, and only a limited number of emulsifiers (see Table
magnesium ions. 17-3). Since the use of conventional preserva¬
Additional Recommendations. In the lab¬ tives is contraindicated, such preparations re¬
oratory development of emulsions, it is common quire sterilization at high temperature but must
practice to prepare an oil phase containing all still yield acceptable emulsions after this
the oil-soluble ingredients and to heat it at about heating/cooling cycle. It is recommended, there¬
5 to 10°C above the melting point of the highest fore, that parenteral emulsions, especially those
melting ingredient. The aqueous phase is nor¬ designed for intravenous injection, be homoge¬
mally heated to the same temperature, and then nized until a satisfactory particle size is
the two phases are mixed. A laboratory beaker achieved.
containing a hot emulsion cools fairly rapidly to Whenever an emulsion is formed at elevated
room temperature, but a production tank filled temperatures, the loss of water due to evapora¬
with hundreds of gallons of hot material cools tion must be made up. This is done best by ad¬
more slowly unless external means of cooling justing to “final weight” with water when the
are employed. This is one reason that the simple emulsion reaches about 35°C.
transfer of a laboratory process to production Practical Examples. A few selected formu¬
requires extensive studies of the cooling and agi¬ lations that have been published in the literature
tation schedule. It is also advisable to utilize are presented below.* They have not been pre¬
jacketed equipment for the large-scale prepara¬ pared by the author nor have they been screened
tion of emulsions, so that the heating and cool¬ for stability or safety. They are cited here merely
ing cycles can be carefully controlled. to illustrate the utility of various emulsifiers and
In the preparation of anionic or cationic o/w to indicate some practical means for forming
emulsions, it is customary to add the oil phase to various emulsions. Only the first one is dis¬
the water phase, although some technologists cussed in detail.
prefer the inversion technique, i.e., addition of
the water phase to the oil phase. In the case of 1. Oral Emulsion (o/w)
nonionic emulsions, which exhibit a PIT, the (A) Cottonseed oil, winterized 460.0 g
inversion technique is not required since tem¬ Sulfadiazine 200.0 g
perature alone can be used to control this stage Sorbitan monostearate 84.0 g
of emulsification. If soap is used as the emulsi¬
fier, it is usually prepared in situ by combining
the alkali with the water phase and the fatty acid
with the oil phase. Similarly, oil-soluble emulsi¬ ‘Some additional emulsions are discussed in Chapter 1C.

EMULSIONS • 523
(B) Polyoxyethylene (20) sorbitan 2. Medicated Ointment
monostearate 36.0 g Base (w/o)
Sodium benzoate 2.0 g
% wt/wt
Sweetener qs
Water, potable 1000.0 g (A) Mineral oil, U.S.P.
(125/135 Saybolt units at 100°F) 25.0
(C) Flavor oil qs
Microcrystalline wax
Procedure: (M.P. 170-180°F) 10.0
1. Heat (A) to 50°C and pass through colloid mill. Cetyl alcohol 5.0
2. Add (A) at 50°C to (B) at 65°C and stir while cooling Mixed lanolin alcohols
to 45°C. (high in cholesterol)* 10.0
3. Add (C) and continue to stir until room tempera¬ Sorbitan sesquioleate 3.0
ture is reached. Propyl p-hydroxybenzoate 0.1
Discussion and Critique. Sulfadiazine is essen¬ (B) Glycerine 3.0
tially water-insoluble. A suspension or emulsion is Methyl p-hydroxybenzoate 0.1
required to yield a fluid oral dosage form. To maintain Deionized water 43.8
sulfadiazine in suspension, the viscosity of the final (C) Medicament qs.
product must be reasonably high. This could be
achieved by the use of gums or by developing an ''Rita Chern. Corp.
emulsion high in internal phase. The choice of a cot¬ Procedure:
tonseed oil o/w emulsion is probably arbitrary except 1. Heat (A) and (B) separately to 75°C.
for the fact that o/w preparations are quite palatable. 2. Add (B) to (A) and stir while cooling to 45°C.
Table 17-4 shows that an HLB of about 10 is re¬ 3. Add (C), mix, and package.
quired to yield a fluid emulsion of cottonseed oil. Al¬
though a single emulsifier, such as polyoxyethylene Discussion and Critique. This emulsion illus¬
(4) sorbitan monostearate (HLB 9.6), might be satis¬ trates a conventional approach (the addition of solid
factory, the use of mixed emulsifiers is generally pre¬ oil-soluble components) for increasing the viscosity of
ferred. In view of their “safety” and availability, a the external phase in a w/o emulsion. Lanolin and its
blend of sorbitan monostearate (HLB 4.7) and derivatives are generally useful for formulating w/o
polyoxyethylene (20) sorbitan monostearate (HLB emulsions and may assist in effecting dissolution of
14.9) seems promising. The ratio required to yield an the medicament. The addition of preservatives to both
HLB of 10.0 is computed from a x 4.7 + b x 14.9 = phases is noteworthy.
10, where a and b are the weight fraction of each of
the two emulsifiers and where a + b = 1. It is found 3. Emollient Cream (o/w)
that a blend of 48% of the lipophilic and 52% of the % wt/wt
hydrophilic emulsifier yields the desired HLB. In fact,
Acetylated lanolin* 2.00
the formula calls for 70% of the hydrophobic emulsi¬
Stearic acid 2.00
fier, equivalent to an HLB of the blend of 8.2. This
Petrolatum 4.00
must be attributed to the presence of the sulfadiazine
Lanolin absorption base’ 6.00
and the need for a high viscosity emulsion. The ratio
Glyceryl monostearate, pure 12.00
of emulsifiers: oil (about 1:4) is high and again points
Propyl p-hydroxybenzoate 0.15
toward an unpredictable effect of the sulfadiazine.
To develop a smooth product, it is necessary to re¬ Water 62.90
duce the particle size of the sulfadiazine. For this pur¬ Glycerol 10.00
pose, the blend of the drug, the oil, and the oleophilic Sodium lauryl sulfate 0.50
emulsifier is warmed slightly and passed through a Methyl p-hydroxybenzoate 0.15
colloid mill. The emulsion itself is formed by adding Perfume 0.30
the drug suspension to the aqueous phase, but in con¬
“Amerchol Division, C.P.C. International
trast to usual emulsion technique, the two phases are
blended at different temperatures. Presumably, heat¬ Procedure:
ing of the drug suspension to 65°C would materially 1. Heat (A) and (B) separately to 75°C.
lower its viscosity and cause excessive settling of the 2. Add (A) to (B) and stir until temperature reaches
drug particles unless specialized stirring equipment 45°C.
were employed. 3. Add perfume and continue to stir gently until room
The addition of the flavoring oils at a lower tempera¬ temperature is reached.
ture prevents loss due to volatility. The following addi¬
tional points are pertinent: Since sulfadiazine has a Discussion and Critique. This cosmetic prepara¬
broad antimicrobial spectium, the absence of a pre¬ tion illustrates the use of relatively high concentra¬
servative in the oil phase is not surprising. Neverthe¬ tions of glyceryl monostearate to create a viscous o/w
less, the emulsion should be protected against molds emulsion. Lanolin absorption bases are blends of lano¬
and fungi; the use of sodium benzoate for this purpose lin (and its derivatives) with hydrocarbons and a small
is of doubtful merit. The absence of an antioxidant in amount of emulsifier. They are normally employed in
this emulsion suggests the presence of additives in the formulation of w/o emulsions. Evidently, the
the cottonseed oil. method of emulsification and the use of the extremely

524 • The Theory and Practice of Industrial Pharmacy

hydrophilic sodium lauryl sulfate permit formation of 200 monopalmitate, purified* 1.2
an o/w emulsion. Particularly striking is the use of free Tartaric acid ester
stearic acid as a means of bodying the lipid portion of of cotton seed fatty acid mono
this cream. The preparation's viscosity would be re¬ glyceride, purified* 0.3
duced significantly if the stearic acid were neutral¬ (B) Polyoxyethylene-poly
ized, e.g. with triethanolamine.. oxypropylene block polymer* 0.3
Isotonic glucose solution 83.2
4. Makeup Cream (o/w)
% wt/wt Procedure:
1. Blend and heat (A) and (B) separately to 45°C.
(A) Magnesium aluminum
2. Circulate (B) in a two-stage homogenizer at 3000
silicate* 2.60 psi
Sodium carboxymethyl 3. Add (A) to (B) at 40 to 45°C and raise pressure to
celluloset 0.40 4000 psi
Water, distilled 42.40 4. Continue homogenization until the emulsion has
(B) Dispersing agent* 0.30 been cycled five times.
Propylene glycol 5.00 5. Package and autoclave at 121°C for 17 min.
Water, distilled 12.30
*For details consult Singleton, W. S., et al.: J. Am. Oil Chem. Soc..
(C) Talc 18.50 39:260, 1961.
Kaolin 1.30
Titanium dioxide 3.70 Discussion and Critique. This emulsion is un¬
Iron oxides 1.50 usual since it could be expected to show signs of hy¬
(D) Isopropyl myristate 5.00 drolysis of the lipid and a drop in pH upon storage.
Stearyl alcohol 2.00 Better stability could be achieved through use of a sys¬
Lanolin absorption tem of Pluronic F68 and L-a-phosphatidyl choline as
base* 2.00 described by Guay and Bissailon31:
Sorbitan monolaurate 0.75
Polyoxyethylene (20)
Soybean oil 10.0%
sorbitan monolaurate 2.25
Dextrose 4.0%
Preservative q.s.
Emulsifier (blend of L-a-phosphatidyl
Perfume q.s.
choline and Pluronic F-68 at
*R. T. Vanderbilt Co. HLB 10) 3.0%
^Hercules, Inc. Water q.s. 100.0%
:Amerchol Div., C.P.C. International The aqueous phase (at 95°C) was added to the oil
Procedure: phase (also at 95°C), and the blend was mechanically
1. Blend solids of (A) and add to water at 80°C; stir stirred for 45 min. Two hundred grams of this mixture
until smooth. was then sonicated in a 400 ml beaker—using a
2. Micropulverize (C) and add to (B); pass through model W140D (20 kHz) sonifier (Branson Sonic
colloid mill to yield smooth paste. Power Co.)—in an ice bath at 16 kHz for 12 min. The
3. Add (B) + (C) to (A) and heat to 60 to 65°C. emulsion was then autoclaved at 121°C and 15 psi for
4. Heat (D) to 70°C and add to (A) + (B) + (C) blend; 15 min. The resulting product exhibits good pH stabil¬
stir until temperature reaches 45°C; add perfume ity and resistance to creaming and coalescence during
and mix until cool. centrifugation.

Discussion and Critique. This composition illus¬ 6. High Internal Phase Emulsion (w/o)
trates the use of an organic gum and an inorganic clay
to achieve viscosity and a yield point in order to re¬ % wt/wt
duce settling of heavy pigments. The need for a pig¬ (A) Glyceryl monoisostearate 2.5
ment dispersing agent (a complex alkyl-aryl sulfonate) Isoparaffin (Ci0-C12) 5.0
can generally be avoided by blending the m cropul- Mineral oil (light) 5.0
verized pigments (C) with the warm oil phase (D) and Microcrystalline wax 0.3
passing this blend through a colloid mill. The mixture Acetylated lanolin 1.0
of (C) + (D) can then be added to the aqueous phase Propyl p-hydroxybenzoate 0.1
containing the gums, humectants, and a trace of sur¬ (B) Monosodium glutamate 3.0
factant (about 0.1% sodium lauryl sulfate). Methyl p-hydroxybenzoate 0.2
Water 82.7
5. Fat Emulsions for Perfume 0.2
Parenteral Nutrition (o/w)
Procedure:
wt/vol 1. Heat (A) and (B) separately to about 60°C.
(A) Cottonseed oil, 2. Add the aqueous phase to the oil phase and homog¬
winterized 15.0 enize.
Polyethylene glycol 3. Add perfume at about 40 to 45°C.

emulsions • 525
 Discussion and Critique. This low viscosity skin sizes of particles of the dispersed phase per unit
cream illustrates the concept that exceptionally high volume of weight of the continuous phase. The
internal phase ratio products can exhibit reasonable total interfacial energy must be invariant with
stability. Glyceryl monoisostearate probably has an time to conform to this definition.”48
HLB of about 3.5 to 4.0 and is a good w/o emulsifier.
Thermodynamic stability of emulsions differs
The key to the stability of this preparation is the use of
from stability as defined by the formulator or the
an amino acid salt as an emulsion stabilizer. The prac¬
tical feasibility of this approach is documented in Eu¬ consumer on' the basis of entirely subjective
ropean Patent #0,009,404 of 4/2/80, but no theoretic judgments. Acceptable stability in a pharmaceu¬
basis for this concept has been provided. tical dosage form does not require thermody¬
namic stability. If an emulsion creams up (rises)
7. Mouthwash or creams down (sediments), it may still be
1. Cetylpyridinium chloride 1.00 g pharmaceutically acceptable as long as it can be
2. Citric acid, USP l.oo g reconstituted by a modest amount of shaking.
3. Sweetener (sodium saccharin) 0.40 g Similar considerations apply to cosmetic emul¬
4. Flavor oils (peppermint, sions; however, in the latter, creaming is usually
eucalyptus, and clove oils) 1.50 ml unacceptable because any unsightly separation
5. Polyoxyethylene (20) sorbitan makes the product cosmetically inelegant. It is
monostearate 3.00 g important, therefore, to remember that the
6. Alcohol, USP 100.00 ml
standard of stability depends to a large extent on
7. Sorbitol solution (70%) 200.00 g
the observer, since subjective observations or
8. Water, potable q.s. 1000.00 ml
opinions by themselves do not suffice to define
Procedure: such a parameter as acceptable stability. Stabil¬
1. Dissolve components 1, 2, and 3-in a sufficient ity should be defined in the sense given to it by
amount of the water and add component 6. Garrett, i.e., on a purely objective basis. Shelf
2. Mix components 4 and 5 and add blend slowly to
life is a useful term to describe the subjective
the hydroalcoholic solution while stirring.
3. Add the remaining ingredients (7 and 8).
evaluation of stability.
A product’s shelf life may be directly related to
.Discussion and Critique. The level of surfactant its “kinetic” stability. Kinetic stability means
in this preparation is surprisingly low, as is the level of that the physicochemical properties of an emul¬
alcohol. It would appear that the level of sorbitol sion do not change appreciably during a reason¬
(14%) in this product contributes to the solubilization ably long period of time. On the other hand,
efficacy of this mouthwash. Cetylpyridinium chloride, “thermodynamic” stability of the type commonly
which is included primarily as an antimicrobial agent, postulated for solubilized systems or
also contributes to the solubilizing power of the sys¬
microemulsions is generally temperature-
tem. This product illustrates the use of alcohol in the
presence of a solubilizer to increase flavor impact (see
dependent. Thus, after the temperature of a sol¬
under previous section “Clear Emulsions.”). ubilized product has been disturbed, it will even¬
tually return to its original (and in this particu¬
lar case clear or transparent) state when the
Properties and Stability of temperature is returned to “normal.” Thermody¬
namics does not and cannot predict how quickly
Emulsions the original (clear) state is restored.
Becher has indicated that the physical proper¬ Symptoms of Instability. As soon as an
ties of atn emulsion and its stability cannot be emulsion has been prepared, time- and tempera¬
considered separately.13 Accordingly, this sec¬ ture-dependent processes occur to effect its sep¬
tion is concerned with the more important phys¬ aration. During storage, an emulsion’s instabil¬
ical properties of emulsions, their changes ity is evidenced by creaming, reversible
under external influences, and their relation¬ aggregation (flocculation), and/or irreversible
ship to emulsion stability. aggregation (coalescence).
Creaming. Under the influence of gravity,
suspended particles or droplets tend to rise or
Emulsion Stability sediment depending on the differences in spe¬
It has already been noted that on purely ther¬ cific gravities between the phases. If creaming
modynamic grounds, emulsions are physically takes place without any aggregation, the emul¬
unstable. A reduction of the interfacial area by sion can be reconstituted by shaking or mixing.
coalescence reduces the system’s energy, and The Stokes equation (see Chap. 16 under “Sedi¬
this process is thermodynamically favored. For mentation Rates) is most useful in gaining an
this reason, Garrett defined a stable emulsion as understanding of the process of creaming, even
one that “would maintain the same number of though Stokes made a number of unrealistic as-

526 • The Theory and Practice of Industrial Pharmacy

 sumptions: The equation is based on spherical tration of dissolved substances, especially elec¬
particles that have essentially the same size and trolytes and ionic emulsifiers. For example, a
are separated by a distance that makes the 2% hexadecane-in-water emulsion stabilized
movement of one particle independent of that of with 0.09% Aerosol O.T., a negatively charged
another. In fact, creaming involves the move¬ surfactant, remains deaggregated in the form of
ment of a number of heterodisperse droplets, single droplets, presumably as a result of repul¬
and their movements interfere with each other sion between negatively charged oil droplets. An
and may cause droplet deformation. If floccula¬ increase of the ionic strength with electrolytes or
tion takes place, the criterion of sphericity is an increase of the emulsifier concentration
lost, and complex corrections for these varia¬ tends to promote flocculation. Although electro¬
tions must be made before Stokes’ law can be lytes are commonly used for demulsification, a
applied quantitatively to the behavior of emul¬ modest level of electrolyte is frequently helpful
sions. in stabilizing emulsions. A typical example is the
Despite its defects, Stokes’ equation is qualita¬ observation by Void and Groot that sodium chlo¬
tively applicable to emulsions. It shows that the ride reduces oil separation in a Nujol/water
rate of creaming is a function of the square of emulsion exposed to ultracentrifugation.49
the radius of the droplet. Thus, larger particles A high internal phase volume, i.e., tight pack¬
cream much more rapidly than smaller particles. ing of the dispersed phase, tends to promote
It is also apparent that the formation of larger flocculation. However, gum acacia can produce
aggregates by coalescence and/or by flocculation a flocculated o/w emulsion with as little as
will accelerate creaming. The reverse is also 0.002% of orange oil. Thus, it is1 probably safe to
true, i.e., the smaller the particle size of an say that most practical o/w and w/o emulsion
emulsion, the less likely it is to cream. Stokes’ systems exist in a flocculated state.
equation predicts that no creaming is possible if Flocculation, emulsion viscosity, and shear
the specific gravities of the two phases are equal. thinning may be closely related. The viscosity of
Adjusting the specific gravity of the dispersed an emulsion depends to a large extent on floccu¬
phase is frequently a practical means of achiev¬ lation, which restricts the movement of particles
ing improved emulsion stability. Finally, Stokes’ and can produce a fairly rigid network. Agitation
law shows that the rate of creaming is inversely of an emulsion breaks the particle-particle inter¬
proportional to the viscosity; this is the reason actions with a resulting drop of viscosity, i.e.,
for the well known fact that increased viscosity shear thinning.
of the external phase is associated with im¬ Coalescence. Coalescence is a growth proc¬
proved shelf life.34-37 ess during which the emulsified particles join to
Flocculation. Emulsion flocculation in form larger particles. Any evidence for the for¬
terms of energetics has been mentioned in this mation of larger droplets by merger of smaller
chapter, and the importance of controlled floccu¬ droplets suggests that the emulsion will eventu¬
lation for suspensions of solids in a liquid me¬ ally separate completely. The major factor which
dium is discussed in Chapter 5. prevents coalescence in flocculated and unfloc¬
Flocculation of the dispersed phase may take culated emulsions is the mechanical strength of
place before, during, or after creaming. It is best the interfacial barrier. This is particularly true in
described as reversible aggregation of droplets of o/w systems containing nonionic surfactants
the internal phase in the form of three-dimen¬ and in w/o emulsion-systems in which electrical
sional clusters. Flocculation is influenced by the effects are negligible. Thus, it is widely recog¬
charges on the surface of the emulsified glob¬ nized that good shelf life and absence of coales¬
ules. In the absence of a protective (mechanical) cence can be achieved by the formation of a
barrier at the interface, e.g., if an insufficient thick interfacial film from macromolecules or
amount of emulsifier is present, emulsion drop¬ from particulate solids.50 This is the reason a
lets aggregate and coalesce rapidly. Flocculation variety of natural gums and proteins are so use¬
of emulsion droplets can occur only when the ful as auxiliary emulsifiers when used at low lev¬
mechanical or electrical barrier is sufficient to els, but can even be used as primary emulsifiers
prevent droplet coalescence. In other words, at higher concentrations.
flocculation differs from coalescence primarily
by the fact that the interfacial film and the indi¬
vidual droplets remain intact. The reversibility Assessment of Emulsion
of this type of aggregation depends on the
strength of the interaction between particles, as Shelf Life
determined by the chemical nature of the emul¬ The final acceptance of an emulsion depends
sifier, the phase volume ratio, and the concen¬ on stability, appearance, and functionality of the

EMULSIONS • 527
packaged product. The most obvious problems actions. It is important, therefore, for the formu¬
facing the formulator are (1) What is acceptable lator to realize that exposure to unrealistically
emulsion shelf'life? and (2) What are the predic¬ high temperatures may produce meaningless
tive indicators of shelf life? The formulator re¬ results. It is clearly established that many emul¬
quires unequivocal and quantitative answers to sions may be perfectly stable at 40 or 45°C, but
these questions. cannot tolerate temperatures in excess of 55 or
As is true with most dosage forms, the con¬ 60° even for a few hours. The varied effects of
tainer used for packaging an emulsion may be temperature changes on emulsion parameters
expected to be a source of incompatibility. Possi¬ have been discussed before: viscosity, partition¬
ble problems include interaction of ingredients ing of emulsifiers, inversion at the phase inver¬
with the container, extraction of material from sion temperature, and crystallization of certain
the container, and loss of water and volatile in¬ lipids. In view of these problems, shelf life can¬
gredients through the container or the closure. not be predicted by studying emulsions at tem¬
For this reason, whatever the nature of the con¬ peratures in excess of 50°C even for relatively
tainer, final evaluation of the product must be short periods of time, unless there is some rea¬
conducted in the container that will be used son to believe that the preparation will be ex¬
commercially. posed to such a high temperature in normal
No quick and sensitive methods for determin¬ handling, such as in sterilization of parenteral
ing potential instability in an emulsion are avail¬ emulsions.
able to the formulator. Instead, he is forced to A particularly useful means of evaluating
wait for interminable periods at ambient condi¬ shelf life is cycling between two temperatures.
tions before signs of poor shelf life become Again, extremes should be avoided, and cycling
clearly apparent in an emulsion. To speed up his should be conducted between 4 and 45°C. This
stability program, the formulator commonly type of cycling approaches realistic shelf condi¬
places the emulsion under some sort of stress. tions, but places the emulsion under enough
Alternately, he may seek a test or parameter that stress to alter various emulsion parameters.
is more sensitive for the detection of instability The normal effect of aging an emulsion at ele¬
than mere macroscopic observations. Both ap¬ vated temperature is acceleration of the rate of
proaches may be faulty. The first one may elimi¬ coalescence or creaming, and this is usually cou¬
nate many good emulsions because excessive pled with changes in viscosity. Most emulsions
artificial stress has been applied. An accelerated become thinner at elevated temperature and
aging test should speed up only the processes thicken when allowed to come to room tempera¬
involved in instability under “normal” storage ture. This thickening can be excessive if the
conditions. If the stress is excessive, abnormal emulsion is not agitated during the cooling
processes may come into play. The second one cycle; sometimes, the low viscosity can be “fro¬
may eliminate only those emulsions that are ex¬ zen” into the emulsion if it is chilled rapidly. In
tremely poor unless the parameter correlates view of these variations, tin. io.mulator must
well with shelf life. It is therefore essential to evaluate each emulsion separately and on the
use sound judgment and great care in setting up basis of his own personal experience. Freezing
a meaningful stability program for a given emul¬ can damage an emulsion more than heating,
sion. since the solubility of emulsifiers, both in the
Stress Conditions. Stress conditions nor¬ lipid and aqueous phases, is more sensitive to
mally employed for evaluating the stability of freezing than to modest warming. In addition,
emulsions include (1) aging and temperature, the formation of ice crystals develops pressure
(2) centrifugation, and (3) agitation. that can deform the spherical shape of emulsion
Aging and Temperature. It is routine to droplets.
determine the shelf life of all types of prepara¬ Centrifugation. It is commonly accepted
tions by storing them for varying periods of time that shelf life under normal storage conditions
at temperatures that are higher than those nor¬ can be predicted rapidly by observing the sepa¬
mally encountered. The Arrhenius equation, ration of the dispersed phase due to either
which predicts that a 10°C increase in the tem¬ creaming or coalescence when the emulsion is
perature doubles the rate of most chemical reac¬ exposed to centrifugation. Stokes’ law shows
tions, is not applicable to emulsions. The Arrhe¬ that creaming is a function of gravity, and an
nius equation is based on the concept that the increase in gravity therefore accelerates separa¬
same chemical reactions take place at all tem¬ tion. Becher indicates that centrifugation at
peratures albeit at different rates. It is generally 3750 rpm in a 10-cm radius centrifuge for a pe¬
recognized that in the case of emulsions, riod of 5 hours is equivalent to the effect of grav¬
changes in temperature bring into play new re¬ ity for about one year.13 The modest speed sug-

528 • The Theory and Practice of Industrial Pharmacy

gested by Becher is probably reasonable. On the byproducts.52 The instability of nonionic esters
other hand, ultracentrifugation at extremely leading to hydrolytic degradation may result in
high speeds (approximately 25,000 rpm or changes in the dielectric constant of the emul¬
more) can be expected to cause effects that sion. This phenomenon parallels observations of
are not observed during normal aging of an physical instability and has been attributed to
emulsion. Ultracentrifugation of emulsions the formation of stearic acid from, for example,
creates three layers: a top layer of coagulated polysorbate 80.53
oil, an intermediate layer of uncoagulated emul¬ Physical Parameters. The most useful pa¬
sion, and an essentially pure aqueous layer. rameters commonly measured to assess the ef¬
Rapid formation of a clear oily layer is the first fect of stress conditions on emulsions include
clue to “abnormal” phenomena taking (1) phase separation, (2) viscosity, (3) electro¬
place during ultracentrifugation. Groot and phoretic properties, and (4) particle size analysis
Void showed how the rate of oil forma¬ and particle count.
tion in a Nujol: water: sodium dodecyl sulfate Phase Separation. The rate and extent of
(50:50:0.2%) emulsion depends on the rate of phase separation after aging of an emulsion may
centrifugation.51 Separation was extremely be observed visually or by measuring the volume
rapid at 56,000 rpm, somewhat slower at about of separated phase. It is important to differenti¬
40,000 rpm, and no oil was separated after 2i ate between creaming and coalescence, since
hours of centrifugation at approximately the means of correcting these defects are differ¬
11,000 rpm. These findings suggest that the ent.*
force of ultracentrifugation does not cause oil Relatively little quantitative information is
separation until it is high enough to break or available concerning oil separation in practical
rupture the absorbed layer of emulsifier that systems in the absence of centrifugation. A
surrounds each droplet. It is concluded that cen¬ study of mineral oil-water emulsions stabilized
trifugation, if used judiciously, is an extremely with either polyoxyethylene sorbitan monooleate
useful tool for evaluating and predicting shelf or sodium lauryl sulfate showed that the amount
life of emulsions. of coalescence observed at room temperature
Agitation. It is a paradigm of emulsion sci¬ depends on the concentration of emulsifier.54 At
ence that the droplets in an emulsion exhibit low levels, i.e., below 0.1%, visible coalescence
Brownian movement. In fact, it is believed that of the oil phase occurs after only one month’s
no coalescence of droplets takes place unless storage. When the concentration of emulsifier is
droplets impinge upon each other owing to their raised to 2 or 5%, the amount of visible coales¬
Brownian movement. Simple mechanical agita¬ cence is negligible even after two years’ storage.
tion can contribute to the energy with which two Two additional points are noteworthy: The two
droplets impinge upon each other. It is rarely emulsifiers perform similarly, and coalescence
appreciated how useful the evaluation of an can be observed quite early.
emulsion by agitation at or near room tempera¬ A particularly simple means of determining
ture can be. It was already noted that excessive phase separation due to creaming or coalescence
shaking of an emulsion or excessive homogeni¬ is apparently so trivial that it has evidently not
zation may interfere with the formation of an been described in the literature. It involves
emulsion. As a corollary, agitation can also break withdrawing small specimens of the emulsion
emulsions. A typical case, well known to all, is from the top and the bottom of the preparation
the manufacture of butter from milk. Some clear after some period of storage and comparing the
microemulsions become cloudy upon short agi¬ composition of the two samples by appropriate
tation in a blender due to coalescence of parti¬ analysis of water content, oil content, or any
cles. Similarly, conventional emulsions may de¬ suitable constituent.
teriorate from gentle rocking on a reciprocating Viscosity. Although the viscosity of an emul¬
shaker. This is related in part to impingement of sion is an essential performance criterion, its
droplets and in part to reduction of viscosity of a use for shelf life studies is not concerned with
normally thixotropic system. the absolute values of viscosity, but with
Chemical Parameters. The need for chem¬ changes in viscosity during aging. The number
ical stability of the components of emulsions has of instruments available for the determination of
already been noted. A typical problem encoun¬ consistency/viscosity is overwhelming.55 Since
tered in the presence of polyethylene glycols or
derivatives of polyethylene glycol is their pro¬
’Creaming can usually be controlled by an increase in
pensity toward autoxidation. This phenomenon viscosity or by addition of an emulsifier having high solu¬
can cause formation of undesirable odors, of bility in the external phase; coalescence generally re¬
acidic components, and of all types of oxidative quires examination of alternate systems of emulsifiers.

emulsions • 529
emulsions are generally non-Newtonian and visibly apparent, utilizes the Helipath attach¬
since the instrument should have universal util¬ ment of the Brookfield viscometer.* As a result
ity, it is best to avoid capillary and falling sphere of emulsion separation, the descending rotating
viscometers. Viscometers of the cone-plate type spindle meets varying resistance at different lev¬
are particularly useful for emulsions, but instru¬ els and registers fluctuations in viscosity. For
ments utilizing coaxial cylinders are the easiest example, Lotion A in Figure 17-7 contains solids
to use. In the case of fairly viscous materials, the suspended in an emulsion, and the high viscos¬
use of a penetrometer is often helpful in detect¬ ity near the top is due to nonwetted solid and
ing changes of viscosity with age. creamed emulsion; the high viscosity at lower
As a rule, globules in freshly prepared w/o levels is due to sedimented particles. The addi¬
emulsions flocculate quite rapidly. Conse¬ tion of polyoxyethylene sorbitan monooleate and
quently, the viscosity drops quickly and contin¬ methylcellulose (Lotion B) yields a much more
ues to drop for some time (5 to 15 days at room uniform viscosity pattern after eight weeks’ stor¬
temperature), and then remains relatively con¬ age.
stant.56 O/w emulsions behave quite differently. The collection of such data is certainly useful;
In this case, globule flocculation causes an im¬ however, it is apparent from these two examples
mediate increase in viscosity. After this initial that it is impossible to predict long-term viscos¬
change, almost all emulsions show changes in ity behavior from data collected during the first
consistency with time, which follow a linear re¬ few weeks of storage after an emulsion has been
lationship when plotted on a log-log scale. 57 The prepared. According to Sherman, the best way of
complete absence of a slope (no change in vis¬ using viscosity determinations for the prediction
cosity with age) is believed to be ideal, although of shelf life is to relate them to changes in parti¬
most acceptable systems exhibit modest in¬ cle size.34-3' As a rule, a decrease in viscosity
creases of viscosity between 0.04 and 400 days with age reflects an increase of particle size due
(Fig. 17-6). Other emulsions exhibit much more to coalescence and is indicative of poor shelf life.
drastic and sudden nonlinear increases in vis¬
cosity after two or three months’ aging; such
behavior is frequently followed by a drop in vis¬ ‘The Brookfield viscometer determines the resistance
encountered by a rotating spindle or cylinder immersed in
cosity, which is probably associated with phase
a viscous material. The Helipath attachment slowly low¬
separation. ers the rotating spindle into the medium so that the re¬
A practical approach for the detection of sistance measured is always that of previously undis¬
creaming or sedimentation, before it becomes turbed test substance.

Elapsed Time (Days)

FIG. 17-6. Simplified aging curves of emulsions. Ideal shelf life (A), typical shelf life (B), and questionable shelf life (C).
(After Wood and Catacalos.57)

530 • The Theory and Practice of Industrial Pharmacy

 about 15 to 50 pA. Measurements are made on
emulsions stored for short periods of time at
room temperature or 37°C. Reportedly, the con¬
ductivity depends on the degree of dispersion.
O/w preparations with fine particles exhibit low
resistance; if the resistance increases, it is a sign
of oil droplet aggregation and instability. A fine
emulsion of water in a w/o product does not con¬
duct current until droplet coagulation, i.e., insta¬
bility occurs.
Particle Size Number Analysis. Changes
of the average particle size or of the size distribu¬
tion of droplets are important parameters for
evaluating emulsions. Particle size analysis may
be carried out by a number of methods, each
giving a somewhat different average for
heterodisperse systems.60 For example, micro¬
scopic measurements of the apparent diameter
FIG. 17-7. Use of the Helipath in the evaluation of cream¬ give an average value dependent on the number
ing and sedimentation. Lotion B is the same as A except of particles of each size.29 On the other hand,
that 0.1 % polysorbate 80 and 0.25% methyl cellulose have some electronic counting devices measure parti¬
been added. (From unpublished results from the Upjohn
cle volume, and since the volume of a sphere is
Co., Kalamazoo, ML)
'7rd3/6, they give greater weight to larger particles
when volume is converted to diameter. Such
Viscosity measurements should be carried out counting devices, e.g., the Coulter counter, also
in undisturbed containers to avoid changes due require that the emulsion be diluted, sometimes
to previous stresses. To avoid artefacts, replicate with a conducting electrolyte. The changes
samples should be prepared in advance, or spe¬ caused by these steps as well as changes caused
cial studies must be carried out to determine the by sampling, even for a microscopic assessment
time necessary for a disturbed emulsion to re¬ of particle size, often make the counted sample
cover its original viscosity. It must always be no longer representative of the bulk emulsion.
remembered that the act of measuring the vis¬ Light scattering and related reflectance rela¬
cosity disturbs the system. Also, the viscosity of tionships have been used for particle size deter¬
emulsions at several different shear rates must minations. Thus, the change of reflectance at
be determined to obtain a clear picture of the wave length at which the colored internal phase
rheologic behavior of an emulsion. Measure¬ partially absorbs the incident light has been
ments at low shear rates frequently reflect as¬ found to be inversely proportional to a power of
pects of flocculation. High shear rates overcome the particle diameter (see Chap. 26).
the attractive forces between particles and can The utility of particle size for predicting or in¬
result in a precipitous loss of viscosity. terpreting emulsion shelf life is somewhat
Electrophoretic Properties. The zeta po¬ doubtful. Two studies utilizing fairly stable
tential of emulsions can be measured with the emulsions have shown that the initial increase
aid of the moving boundary method or, more in particle size is rather rapid, but is followed by
quickly and directly, by observing the movement a much slower change.34,61 Almost no change in
of particles under the influence of electric cur¬ particle size has been noted, even in the case of
rent. The zeta potential is especially useful for emulsions that show appreciable coalescence
assessing flocculation since electrical charges on due to a low level of emulsifier.62 One would
particles influence the rate of flocculation.58 If expect that particle size, the number of particles,
the instability is due to coalescence, the deter¬ the droplet surface area, or the droplet volume
mination of the surface charges of particles may should vary linearly with time. Hill and Knight
not be relevant for the prediction of shelf life. claim good correlation with experimental data by
The measurement of electrical conductivity plotting the total surface area of all droplets (2)
has been claimed to be a powerful tool for the in accordance with the following equation: 1/
evaluation of emulsion stability shortly after 2 = at + b, where a and b are constants and t
preparation.59 The electrical conductivity of o/w equals time.62
or w/o emulsions is determined with the aid of Practical Recommendations for Shelf
Pt electrodes (diameter 0.4 mm; distance 4 mm) Life Predictions. The preceding discussion
microamperometrically to produce a current of has pointed out that surprisingly little evidence

EMULSIONS *531
exists to suggest that instability under stress can 5. Harkins, W. D.. The Physical Chemistry of Surface
be related to normal shelf life. It is most impor¬ Films. Reinhold, New York, 1954.
6. Schulman, J. J., and Cockbain, E. G.: Trans. Faraday
tant, therefore, to set up a realistic stability pro¬ Soc., 36:651, 1940.
gram to assess the shelf life of emulsions. 7. Friberg, S.: J. Coll. Interf. Sci., 37:291, 1971,
A typical test program for an “acceptable” 8. Friberg, S., and Jansson, P. O.: J. Coll. Interf. Sci.,
emulsion (in the temperate zone) might estab¬ 55:614, 1976.
lish the following: The emulsion should be 9. Friberg, S.: J. Soc. Cosmetic Chemists, 30:309,1979.
10. Junginger, H.: Pharm. Weekblad, 6:141, 1984.
stable with no visible signs of separation for at
11. Suzuki, T., et al.: J. Disp. Sci. Technol., 5:119, 1984.
least 60 to 90 days at 45 or 50°C, 5 to 6 months at
12. Orecchioni, A. M., et al.: Int. J. Cosmetic Sci., 6:131,
37°C, and 12 to 18 months at room temperature. 1984.
Similarly, there should be no visible signs of sep¬ 13. Becher, P.: Emulsions Theory and Practice. 2nd Ed.
aration after one month’s storage at 4°C and Reinhold, New York, 1965.
preferably after two or three freeze-thaw cycles 14. Shinoda, K., and Kunieda, H.: Phase properties of
between -20 and +25°C. An emulsion should emulsions: PIT and HLB. In Encyclopedia of Emul¬
sion Technology. Vol. I. Edited by P. Becher. Marcel
survive at least six or eight heating/cooling cy¬
Dekker, New York, 1983, p. 337.
cles between refrigerator temperature and 45°C 15. Lin, T. J., et al.: J. Soc. Cosmetic Chemists, 29:745,
with storage at each temperature of no less than 1978.
48 hours. A stable emulsion should show no se¬ 16. Lin, T. J., et al.: Low energy emulsification. In Sur¬
rious deterioration by centrifuging at 2,000 to factants in Cosmetics. Edited by M. M. Rieger. Mar¬
3,000 rpm at room temperature. The emulsion cel Dekker, New York, 1985, p. 87.
17. Griffin, W. C.: Emulsions in Kirk Othmer Encyclope¬
should not be adversely affected by agitation for dia of Chemical Technology. Vol. 8. 3rd Ed. Wiley
24 to 48 hours on a reciprocating shaker (ap¬ Interscience, New York, 1979, p. 922.
proximately 60 cycles per minute at room tem¬ 18. Garnett, C. J., et al.: J. Chem. Soc., 79:953, 1983.
perature and at 45°C). Iff. Garnett, C. J., et al.. Faraday Trans. 1, 965, 1983.
During the testing period just described, the 20. Davies, J. T.: Proc. 2nd Int. Congress Surface Activ¬
samples stored at various conditions should be ity, London, 1:426, 1957.
21. Fox, C.: Cosmetic emulsions. In Emulsions and
observed critically for separation, and in addi¬
Emulsion Technology, Part II. Edited by K. J. Lissant.
tion, monitored at reasonable time intervals for Marcel Dekker, New York, 1974, p. 701.
the following characteristics: 22. Becher, P.: J. Soc. Cosmetic Chemists, 11:325, 1960.
23. Schott, H.: J. Pharm. Sci., 73:790, 1984.
Change in electrical conductivity 24. Shinoda, K., et al.: J. Dispersion Sci. Technol., 1:1,
1980.
Change in light reflection 25. Marszall, L.: Cosmetics Toiletries, 93:53, 1978.
Change in viscosity 26. Shinoda, K., and Saito. H.: J. Coll. Interf. Sci., 30:258,
1969.
Change in particle size 27. Ford, R. E., and Furmidge, C. G. L.: J. Coll. Interf.
Change in chemical composition Sci., 22:331, 1966.
28. Lin, T. J., and Lambrechts, J. C.: J. Soc. Cosmetic
Chemists, 20:627, 1969.
In addition to these physical measurements, a 29. Lin, T. J., et al.: J. Soc. Cosmetic Chemists, 26:121,
shelf life program for emulsions should include 1975.
testing of the emulsion for microbiologic con¬ 30. Lin, T. J.: J. Soc. Cosmetic Chemists, 30:167, 1979.
tamination at appropriate intervals. It should be 31. Guay, F., and Bisaillon, S.: Drug Develop. Ind.
remembered that the distribution of emulsifiers Pharm., 5:107, 1979.
32. Rydhag, L.: Fette Seifen Anstrichm., 81:168, 1979.
in a freshly prepared emulsion is different from 33. Cante, C. J., et al.: J. Am. Oil Chem. Soc., 56:71A,
distribution of one that has been aged for several 1979.
months at 45°C. As a result, an emulsion’s re¬ 34. Rogers, J, A.: Cosmetics Toiletries, 93:49, 1978.
sistance to microbial contamination may be af¬ 35. Sherman, P. J.: J. Phys. Chem., 67:2531, 1964.
fected by redistribution or micellization of the 36. Sherman, P. J.: J. Pharm. Pharmacol., 18:589, 1966.
preservative. 37. Lissant, K. J.: Basic theory. In Emulsions and Emul¬
sion Technology. Part I. Edited by K. J. Lissant. Mar¬
cel Dekker, New York, 1974, p. 1.
38. Humphrey, K. J., and Rhodes, C. T.: J. Pharm. Sci.,
57:79, 1968.
References 39. Moes-Henschel, V., and Jaminet, F.: Intemat. J. Cos¬
1. Lissant, K. J.: J. Soc. Cosmetic Chemists, 21:141, metic Sci., 2:193, 1980.
1970. 40. Garrett, E. R.: J. Pharm. Pharmacol., 18:589, 1966.
2. Frenkel, M., et al.: J. Coll. Interf. Sci., 94:174, 1983. 41. Kazmi, S. J. A., and Mitchell, A. G.: J. Pharm. Sci.,
3. Carrigan, P. J., and Bates, T. R.: J. Pharm. Sci., 60:1422, 1971.
62:1476, 1973. 42. Nowak, G. A.: Soap, Perfumery & Cosmetics, 36:914,
4. Idson, B.: Drug Metab. Rev., 14:207, 1983. 1963.

532 • The Theory and Practice of Industrial Pharmacy

43. Pisano, F. D., and Kostenbauder. H. B.: J. Am. Lissant, K.: Emulsions and Emulsion Technology. Marcel
Pharm. Assoc., Sci. Ed., 48:310, 1959. Dekker, New York, 1974.
44. Shimamoto, T., et al.: Chem. Pharm. Bull., 21:316, Rosen, M. J.: Surfactants and Interfacial Phenomena.
1973. John Wiley and Sons, New York, 1978.
45. Rieger, M. M.: Cosmetics Toiletries, 96:39, 1981. Sherman, P.: Emulsion Science. Academic Press, Lon¬
46. Moore, K. E.: J. Appl. Bacteriol., 44:S29, 1978. don, 1968.
47. Davis, J. G.: Soap Perfumery Cosmetics, 53:133, Sherman, P.: Rheology of Emulsions. Academic Press,
1980. London, 1968.
48. Garrett, E. R.: J. Pharm. Sci., 54:1557, 1965. Sherman, P.: Industrial Rheology. Academic Press, Lon¬
49. Void, R. D., and Groot, R. C.: J. Soc. Cosmetic Chem¬ don, 1970.
ists, 14:233, 1963. Shinoda, K.: Principles of Solution and Solubility. Marcel
50. Ottewill, R. H.: J. Coll. Interf. Sci., 38:357, 1977. Dekker, New York, 1978.
51. Groot, R. C., and Void, R. D.: Proc. 4th Int. Congress
Surface Activity, 11:1233, 1967. Recommended Reading
52. Rieger, M. M., Cosmetics Toiletries, 90:12, 1975. Becher, P: J. Disp. Sci. Technol., 5:81, 1984. (Update on
53. Reddy, R. B., and Dorle, A. K., Cosmetics Toiletries, HLB)
99:67, 1984. Bomfriend, R.: Cosmetics Toiletries, 93:61, 1978. (Pro¬
54. Rowe, E. L.: J. Pharm. Sci., 54:260, 1965. cessing)
55. Sherman, P.: Rheology of Emulsions. Academic Florence, A. T., and Rogers, J. A.: J. Pharm. Pharmacol.,
Press, London, 1968. 23:153, 233, 1971. (Emulsion stabilization)
56. Sherman, P.: Industrial Rheology. Academic Press, Freese, E., and Levin, B.C.: Action mechanisms of pre¬
London, 1970. servatives and antiseptics. In Developments in Indus¬
57. Wood, J. H., and Catacalos, G.: J. Soc. Cosmetic trial Microbiology. Vol. 19. Edited by L. S. Underkofler.
Chemists, 14:147, 1963. American Institute Biological Sciences, Washington,
58. Sherman, P.: Soap, Perfumery & Cosmetics, 44:693, DC, 1978, p. 207 (Preservation)
Groves, M. J., and Freshwater, D.C.: J. Pharm. Sci.,
1971.
59. Mrukot, M., and Schmidt, M.: Parfumerie Kosmetik, 57:1273, 1968. (Particle size)
Mulley, B. A.: Medicinal emulsions. In Emulsions and
57:337, 1976.
Emulsion Technology. Part I. Edited by K. J. Lissant.
60. Groves, M. J., and Freshwater, D. C.: J. Pharm. Sci.,
Marcel Dekker, New York. 1974, p. 291. (Pharmaceuti¬
57:1273, 1968.
cal emulsions)
61. Rehfeld, S. J.: J. Coll. Interf. Sci., 24:358, 1967.
Quack, J. M.: Cosmetics Toiletries, 91:21, 1976. (Emul¬
62. Hill, R. A. W., and Knight, J. T.: Trans. Faraday Soc.,
sion stability)
61:170, 1965.
Reynolds, J. A.: Interactions between proteins and amphi-
philes. In Lipid-Protein Interaction. Vol. 2. Edited by
P. C. Jost and O. H. Griffith. John Wiley and Sons, New
General References York, 1982, p. 193. (Amphilic/protein interactions in
Books vitro and in vivo)
Adamson, A. W.; Physical Chemistry of Surfaces. 3rd Ed. Rieger, M. M.: Cosmetics Toiletries, 97, VIII:27, 1982.
Interscience, New York, 1976. (Prediction of stability)
Becher, P.: Emulsions Theory and Practice. 2nd Ed. Rieger, M. M.: Cosmetics Toiletries, 97, X:49, 1982. (Sol¬
Reinhold, New York, 1965. ubilization)
Becher, P.: Encyclopedia of Emulsion Technology. Vol. I. Takamura, A., et al.: J. Pharm. Sci., 73:676, 1984. (In
Marcel Dekker, New York, 1983. vitro drug release methodology)

emulsions • 533
 18

Semisolids
BERNARD IDSON and JACK LAZARUS*

Pharmaceutical semisolid preparations include ued levigation until the solids are uniformly dis¬
ointments, pastes, cream emulsions, gels, and persed in the vehicle.
rigid foams. Their common property is the abil¬ Creams are semisolid emulsion systems with
ity to cling to the surface of application for rea¬ opaque appearances, as contrasted with translu¬
sonable duration before they are washed or worn cent ointments. Their consistency and rheologic
off. This adhesion is due to their plastic rheo¬ character depend on whether the emulsion is a
logic behavior, which allows the semisolids to water-in-oil or oil-in-water type and on the na¬
retain their shape and cling as a film until acted ture of the solids in the internal phase. The sub¬
upon by an outside force, in which case they de¬ ject of emulsions is treated in Chapter 17.
form and flow.1 Gels are semisolid systems in which a liquid
Ointments, in general, are composed of fluid phase is constrained within a three-dimensional
hydrocarbons meshed in a matrix of higher¬ polymeric matrix (consisting of natural or syn¬
melting solid hydrocarbons. While most oint¬ thetic gums) in which a high degree of physical
ments are based on mineral oil and petrolatum, (or sometimes chemical) cross-linking has been
there are alternative types. Polyethylene can be introduced. The polymers used to prepare phar¬
incorporated into mineral oil to yield a plastic maceutical gels include the natural gums traga-
matrix (e.g., Plastibase, manufactured by canth, pectin, carrageen, agar, and alginic acid
Squibb). Mixtures of polyethylene glycols can and such synthetic and semisynthetic materials
yield products of ointment consistency that are as methylcellulose, hydroxyethylcellulose, car-
water-soluble. Most ointments are prepared by boxvmethylcellulose, and the Carbopols, which
melting the components together. Drugs or are synthetic vinyl polymers with ionizable car¬
other components are added in the fluidized boxyl groups. Gels are prepared by either a fu¬
state. If the solids are insoluble and to be sus¬ sion process or a special procedure necessitated
pended, the system is put through a milling by the gelling characteristics of the gellant.
process (a colloid mill, homogenizer, or ultra¬ The bulk of these semisolid preparations are
sonic mixer) so that the solids are fully dis¬ applied to the skin, where they usually serve as
persed. vehicles for topically applied drugs, as emol¬
Pastes are basically ointments into which a lients, or as protective or occlusive dressings. A
high percentage of insoluble solids has been lesser portion of topical semisolid dosage forms
added. They are valuable as protective barriers are applied to mucous membranes, such as rec¬
on the skin, such as for treating diaper rash or tal tissue, buccal tissue, vaginal mucosa, ure¬
protecting the face and Ups from the sun. Pastes thral membrane, external ear lining, nasal mu¬
are usually prepared by incorporating a solid di¬ cosa, and cornea. The mucous membranes
rectly into a congealed system by levigation with permit more ready access to the systemic circu¬
a portion of the base to form a paste-like mass. lation, whereas normal skin is relatively impene¬
The remainder of the base is added with contin- trable. The emphasis of this chapter is on the
skin and on dermatologicals, but the general
concepts and rationale apply to all semisolid top¬
* Deceased. ical therapy.

534
 three tissue layers: the epidermis, the dermis,
and the subcutaneous fat layer. Figure 18-1 rep¬
The skin is a large multilayered organ that in resents an idealized section of the skin, showing
the average adult weighs about eight pounds, the glands, hair follicles, nerves, blood vessels,
excluding fat. It covers a surface exceeding and other skin accessories. The outermost layer
20,000 cm2 and has varied functions and prop¬ is the stratum comeum, or homy layer, which
erties. The skin serves as a barrier against physi¬ consists of compacted, dead, keratinized cells in
cal and chemical attack. Some materials, such stratified layers with a density of 1.55. Because
as nickel ions, mustard gas, and the oleoresins of the dense nature of the stratum comeum, val¬
from Rhus toxicodendron, commonly known as ues of diffusion coefficients in this tissue are a
poison ivy, can penetrate the barrier, but most thousand or more times smaller than in any
substances cannot. The skin acts as a thermo¬ other skin tissue, which results in higher resist¬
stat in maintaining body temperature, shields ance and general impenetrability.2
the body from invasion by micro-organisms, pro¬ The stratum comeum is the rate-limiting bar¬
tects against ultraviolet rays, and plays a role in rier that restricts the inward and outward move¬
the regulation of blood pressure. ment of chemical substances. Structurally, the
Anatomically, the skin has many histologic stratum comeum is a heterogeneous tissue com¬
layers, but in general, it is described in terms of posed of flattened keratinized cells, the outer

FIG. 18-1. Stratified organization of the skin. (From Pillsbury, D. M.: A Manual of Dermatology. W. B. Saunders, Phila¬
delphia, 1971).

SEMISOLIDS • 535
layers of which are less densely packed than salt solution. The apocrine glands are found in
those adjacent to the underlying granular layer. the axillae (armpits), in anogenital regions, and
The stratum comeum exhibits regional differ¬ around nipples. They are coiled tubular glands
ences in thickness over the body. It is as thick as about ten times larger than eccrine glands and
several hundred micrometers on the palms of extend entirely through the dermis and well into
the hand and soles of the feet in an adult, but the subcutaneous layer.11
over most of the body it is about 10 fim thick
when dry, increasing to about 40 to 50 /am when
fully hydrated.3
Percutaneous Absorption
There is limited knowledge of the chemical The usual object of dermatologic drug therapy
composition of the barrier. The main cellular is to produce a desired therapeutic action at spe¬
components are the proteins, lipid, and water, cific sites on the epidermal tissue. While certain
combined into an ordered structure. The ap¬ topical drugs such as emollients, antimicrobials,
proximate composition in the dry state is 75 to and deodorants act primarily on the surface of
85% protein, 15 to 20% lipid, and 15% water. the skin, the target area for most dermatologic
Although the surface lipids offer little resistance disorders lies in the viable epidermis or upper
to the passage of compounds, studies of the re¬ dermis. This requires diffusive penetration of
moval of lipids from the cutaneous surface indi¬ the skin or percutaneous absorption.
cate that they participate in epidermal water
function.4-10 Barrier function is restored when
the extracted lipids are returned to the skin, Routes of Penetration
which suggests variations in biologic membrane When a drug system is applied topically, the
permeability, depending largely on the specific drug diffuses out of its vehicle onto the surface
nature or distribution of the lipid contained in tissues of the skin. There are three potential por¬
the cell membrane. tals of entry: through the follicular region,
Beneath the stratum comeum are the meta- through the sweat ducts, or through the unbro¬
bolically active layers of the epidermis. The ken stratum comeum between these append¬
basal or germinal layer lies right above the der¬ ages. There is little convincing evidence that
mis. Epidermal cells start their mitotic journey eccrine sweat glands play any significant role in
upward to the surface; the cells flatten and cutaneous permeability. Material may enter the
shrink as they slowly die from lack of oxygen ducts, and even the glands, but there appears to
and nutrition. be no penetration from these areas to the der¬
The next distinctive histologic layer shown in mis.
Figure 18-1 is the dermis, or corium, which is For substances absorbed by the transepider-
approximately one eighth of an inch thick and mal route, penetration is fairly rapid, although
constitutes the main mass of the skin. The der¬ slower than intestinal tract absorption, and is
mis essentially consists of about 80% of protein almost always accompanied by some degree of
in a matrix of mucopolysaccharide “ground sub¬ pilosebaceous penetration as well. For sub¬
stance.”11 stances that are absorbed through both path¬
Contained and supported within the dermis ways, the transepidermal route is the principal
are numerous blood vessels, lymphatics, and portal of entry because of the total, relatively
nerves, as well as the epidermal appendages small, absorbing surface offered by the piloseba¬
such as the hair follicles, sebaceous glands, and ceous units. The epidermis presents a surface
sweat glands. Hair follicles are distributed over area 100 to 1000 times greater than the other
the entire skin surface with the exception of the routes of absorption. The appendages, sweat
soles of the feet, the palms of the hand, the red glands, and hair follicles are scattered through¬
portion of the lips, and select portions of the sex out the skin in varying numbers, but are com¬
organs. Each hair follicle is associated with one paratively sparse; their total cross-sectional area
or more sebaceous glands, which are outgrowths is probably between 0.1 and 1.0% of the skin
of epithelial cells. The fractional area of the skin area.
surface occupied by the hair follicles has been The particular route a substance may take
estimated to be roughly 1/1000 of the total sur¬ and the relative importance of one in contrast
face.12 The sweat glands are divided into the with the other, depend almost entirely on the
eccrine and apocrine types. They are widely dis¬ physicochemical properties of the drug and the
tributed over the surfaces of the body. The ec¬ condition of the skin. Under the appropriate
crine glands are particularly concentrated in the conditions, each of the contending routes of per¬
palms and soles. The principal function of the meability may change and be the overwhelm¬
glands is for heat control, as they secrete a dilute ingly dominant one. In particular, the transient

536 • The Theory and Practice of Industrial Pharmacy

diffusion that occurs shortly after the> applica¬ quantity per unit area per unit time. Radioactive
tion of a substance to the surface of the skin is agents have not taken over completely. Many
shown to be potentially far greater through the chemical agents penetrate in sufficient concen¬
appendages than through the matrix of the stra¬ tration to be determined by one or the other
tum comeum. After steady-state diffusion has techniques of physical or chemical analysis.
been established, the dominant diffusion mode More recently, model systems have been used
is probably no longer intra-appendageal, but oc¬ that do not use membranes. Solvents such as
curs through the matrix of the stratum cor- alcohol-water have been utilized as models cho¬
neum. Flux through shunts is difficult to mea¬ sen to have negligible solubility in the phase
sure experimentally, except possibly through representing the skin, but in which the drug is
hair. The recognition of transient diffusion, oc¬ fairly soluble.13-17 A receptor phase or “sink” is
curring primarily via follicles and ducts, and used to receive the penetrant. Chloroform and
steady-state diffusion, occurring primarily isopropyl myristate have served as sinks. Since
through the intact stratum comeum, results in a they are immiscible with the alcohol-water, it is
considerably more self-consistent and orderly not necessary to introduce an artificial mem¬
treatment of the process of percutaneous absorp¬ brane to separate these sinks from the vehicles.
tion. The important factors influencing the release
Once a substance passes through the stratum into the receptor phase are the solubility in the
comeum, there is apparendy no significant fur¬ vehicle and the partition coefficient of the drug
ther hindrance to penetration of the remaining between the vehicle and the receptor phase.
epidermal layers and corium; there is then a Optimal release is obtained from vehicles con¬
ready entry into the circulation via the capillar¬ taining the minimum concentration of solvent
ies. The concentration gradient essentially ends required for complete solubilization of the
in the dermal layer at the beginning of the circu¬ drug.13
lation. The systemic circulation acts as a reser¬ In Vivo Technique. The major in vivo
voir or “sink” for the dmg. Once in the general methods are histologic techniques, use of trac¬
circulation, the dmg is diluted and distributed ers, analysis of body tissues and fluids, and elici¬
rapidly with litde systemic buildup.1 tation of a biologic response. Tissue changes in
Diffusion through the homy layer is a passive skin following the application of various sub¬
process. There is little evidence to support spe¬ stances to the cutaneous surface can yield infor¬
cialized active transport systems for cells of the mation about the specific tissue affected, so that
stratum comeum. The passive process is af¬ not only absorption, per se, is revealed, but also
fected only by the substance being absorbed, by the route of penetration. The method is limited
the medium in which the substance is disper¬ to dyes and to a small number of other sub¬
sed, and by ambient conditions. On the other stances that yield perceivable colored end prod¬
hand, percutaneous absorption is a more compli¬ ucts with specific chemical reactions. Following
cated process, of which epidermal diffusion is the movements of penetrants through dyes, flu¬
the first phase, and clearance from the dermis orescence and radioactive labeling represent the
the second. The latter depends on effective most widespread tracer methods. The studies
blood flow, interstitial fluid movement, lymphat¬ are always combined with other techniques
ics, and perhaps other factors that combine with such as histologic or chemical analysis of tissues
dermal constituents.5 or fluids. While radioactive methods give infor¬
mation on the amount of the compound that
moves across the skin, they yield little or no in¬
Study Methods formation on the route of penetration or on the
In Vitro Technique. The principal in vitro localization of the penetrant within the structure
technique for studying skin penetration involves of the skin.
use of some variety of a diffusion cell in which Urine analysis is by fax the most frequently
animal or human skin is fastened to a holder and used method. Although the urinary method is
the passage of compounds from the epidermal extremely valuable, caution is indicated since
surface to a fluid bath is measured. The simplic¬ the recovered agent will not necessarily by the
ity of methods and equipment ranges from just original material or the amount needed to pene¬
stretching human skin over the mouth of a fun¬ trate the skin. Some of the applied agent may
nel to using special glass chambers. The pene¬ have gone elsewhere than into the urine; some
tration rates can be quantitated, particularly by may have been metabolized and therefore may
radioactive measurements. The area of spread of be no longer detectable. A steady state between
radioactive agent on the surface is detected with absorption and excretion needs to be reached
autoradiographs, allowing expression in terms of before measurements can be accepted. The use

SEMISOLIDS • 537
of topical agents that elicit a physiologic reaction little correlation between the size and the pene¬
when they reach the dermis makes it possible to tration rate. Materials of higher molecular
demonstrate not only penetration, but also the weight also show variable penetration. Very
time required for a reaction to occur. The large molecules, such as proteins and polysac¬
method is intriguing because it is simple and charides, go through poorly, if at all.19, 0
has practical applications. For example, re¬ Vehicles and Skin Penetration. The effi¬
sponses such as sweat secretion, vasoconstric¬ ciency of various types of vehicles in aiding pen¬
tion, vasodilation, pigmentation, and vascular etration can be reasonably predicted by the way
permeability can be recorded with reasonable in which the vehicle alters the activity of water
accuracy by visual observation. in the stratum comeum and influences the
Various methods have been used for studying stratum comeum/vehicle partition coefficient.
in vitro and in vivo percutaneous absorption. Greases and oils are the most occlusive vehicles
There are three variables in all the methods: and induce the greatest hydration through sweat
application of the medicament, apparatus, and accumulation at the skin-vehicle interface. This
measurement of the medicament. The combina¬ is accentuated if the skin is covered with occlu¬
tions of these variables lead to numerous meth¬ sive bandages or plastic. Emulsions of the water-
ods, and comparisons between investigations is in-oil type are somewhat less occlusive than
difficult.18 greases. Substances in the vehicle, such as
Factors in Skin Penetration. The factors humectants, which have a high affinity for
that influence skin penetration are essentially water, may under certain circumstances dehy¬
the same as those for gastrointestinal absorp¬ drate the stratum comeum and decrease pene¬
tion, with the rate of diffusion depending pri¬ tration. Similarly, powders increase the surface
marily on the physicochemical properties of the area and increase the rate of evaporation of
drug and only secondarily on the vehicle, pH, water, and so decrease the extent of hydration.
and concentration. Differing physiologic varia¬ Conversely, vehicles may also affect penetration
bles involve the condition of the skin, i.e., by their ability to reduce loss of water vapor on
whether it is intact or injured, the skin age, the the skin surface. Paraffin bases suppress trans-
area of skin treated, the thickness of the skin epidermal water diffusion, whereas a number of
barrier phase, the species variation, and the skin other standard vehicles cause a lesser degree of
moisture content. transepidermal water loss suppression.
The principal physicochemical factor in skin The role of vehicles on skin penetration is
penetration is the hydration state of the stratum often confusing and contradictory, since the
comeum, which affects the rate of passage of all emphasis has generally been placed on the com¬
substances that penetrate the skin. Hydration patibility, stability, and appearance of the prod¬
results from water diffusing from underlying uct. Only in recent years has attention been
epidermal layers or from perspiration that accu¬ given to the influence of components in the ve¬
mulates after application of an occlusive vehicle hicle on the movement of the drug through the
or covering on the surface. Under occlusive con¬ skin. The release of a substance is favored by the
ditions, the stratum comeum is changed from a selection of vehicles that have a low affinity for
tissue that normally contains little water (5 to the penetrant or in which the drug is least solu¬
15%) to one that contains as much as 50% ble. This is consistent with the view that the rate
water. The clinical importance of hydration can of release is governed by the vehicle-to-receptox
be found in the use of occlusive plastic film in phase (stratum comeum) partition coefficient.
steroid therapy. Here, the prevention of water For a given concentration of drug in certain ve¬
loss from the stratum comeum and the subse¬ hicles, the activity coefficient of the drug at that
quent increased water concentration in this skin concentration may vary by as much as 1000-fold
layer apparently enhances the penetration of the from one vehicle to the other. The thermody¬
steroid. The temperature of the skin and the namic activity of the drug in the vehicle is the
concentration of drug play significant roles, but product of the concentration of the drug and the
they are secondary to that of hydration. activity coefficient of the drug in the vehicle.
The solubility of a drug determines the con¬ Solutes held firmly by the vehicle, such as those
centration presented to the absorption site, and occurring when the drug forms a soluble com¬
the water/lipid partition coefficient influences plex with the vehicle, exhibit low activity coeffi¬
the rate of transport. An inverse relationship cients: hence, the rate of release from such
appears to exist between the absorption rate and drug-vehicle combinations is slow. Solutes held
the molecular weight. Small molecules pene¬ “loosely” by the vehicle (with less affinity of the
trate more rapidly than large molecules, but vehicle for the drug or solute) exhibit high activ¬
within a narrow range of molecular size, there is ity coefficients; therefore, the rate of release

538 • The Theory and Practice of Industrial Pharmacy

from such drug-vehicle combinations is fast. The Federal Food and Drug Administration
Varied materials require individual formulation (FDA) approves chemical substances and states
based on solubility characteristics, and the for¬ the maximum concentration that is considered
mulation may also need modification for differ¬ to be safe for use in a particular food or cosmetic.
ent concentrations of the agent to obtain maxi¬ The information is published in the “Federal
mal release rates. Register,” and a compilation of all such sub¬
Materials have been experimentally studied in stances is available.21 All raw materials should
attempts to increase the rate of absorption of be checked against this list if there is any doubt
topically applied drugs. These agents are often regarding the current status of a particular sub¬
called “accelerants.” They appear to swell the stance; however, each new pharmaceutical dos¬
stratum comeum and leach out essential struc¬ age form must receive individual approval. The
tural material, thus reducing the diffusional re¬ supplier of a chemical substance usually indi¬
sistance and increasing the permeability. The cates in his brochure, or upon request, the safety
most effective is dimethylsulfoxide (DMSO) fol¬ tests that have been performed and whether
lowed by dimethylformamide (DMF), dimethyl- appr val from the FDA has been received for its
acetamide (DMA), urea, propylene glycol, and use in a particular form. The tests should be
surface-active agents. DMSO, DMF, and DMA thorough and well designed; they should include
are all strongly hygroscopic and it is likely that human patch tests, eye irritation studies, deter¬
the presence of these substances in the stratum mination of minimum lethal dose on at least two
comeum increases the hydration of the tissue animal species, and chronic toxicity studies.
and therefore its permeability. These agents are Names of suppliers of various raw materials
currently restricted to experimental use. Sur¬ for semisolids, manufacturing equipment, and
face-active agents appear to increase the perme¬ other pertinent information can be obtained
ability of the skin to water by altering the physi¬ from trade and scientific journals. Consultation
cal state of water in the skin in such a way as to with representatives of suppliers frequently re¬
permit greater freedom to the passage of charged duces the development time required for a new
hydrophilic substances. When penetration oc¬ pharmaceutical semisolid, but independent crit¬
curs, anionics penetrate best, followed by ical judgment is needed.
cationics and nonionic surfactants. Among ani¬ The suppliers of raw materials such as emol¬
onic substances, the laurate ion is reported to lients, emulsifiers, fats, oils, waxes, cellulose
have the greatest penetration and the greatest derivatives, humectants, lanolin derivatives,
effect on the penetration of other solutes. Soaps and water absorption bases have detailed knowl¬
of different fatty acids have this property in vary¬ edge of their specific products. Many of the sup¬
ing degrees, with penetration more significant pliers have well-equipped laboratories in which
for salts of fatty acids having a carbon length of workers are constantly developing new uses for
10 or less. The penetration of fatty acid soaps their materials in the pharmaceutical, cosmetic,
varies inversely with pH. At higher pH (approxi¬ toiletries, and chemical specialties fields. The
mately 11), the action of the anionic surfactant formulator must be cautious, however, in ac¬
appears to be attenuated or overshadowed by the cepting a supplier’s claims about the utility of a
influence of the more alkaline pH itself. raw material. It is necessary to ascertain the bio¬
logic properties as well as the significant physi¬
cal and chemical parameters of the substance
Raw Materials and its stability on storage at different tempera¬
More raw materials are available for use on tures.
the skin than for oral use, and in turn, more are It is a fundamental concept in formulating
available for oral use than for parenteral use. any dosage form that chemical and physical in¬
The difference in the number of materials avail¬ compatibilities that affect the therapeutic effi¬
able for each route of administration is due to cacy of a drug must be avoided. In advance of
the type of absorption barrier and physicochemi¬ any formulation, the physicochemical properties
cal environment surrounding the absorption of the drug must be evaluated. The stability of
sites. Substances such as isopropyl myristate the active substance under alkaline or acidic
and butyl stearate may be used topically without conditions can be established from its pH pro¬
toxic effects, yet these esters may not be used file. The sensitivity of the drug to oxidation and
orally, because hydrolysis of the esters by diges¬ reduction, moisture, and light, and its solubility
tive enzymes yields poorly tolerated alcohols. in various materials, indicate the type of base
The absence of comparable hydrolytic enzymes most suitable for the stability of the drug and for
on the skin surface makes these compounds sat¬ its absorption. Compatibility with the container
isfactory for dermatologic medication. is of equal importance, and it is necessary to

SEMISOLIDS • 539
conduct stability studies of the product in the they are less tacky and greasy. An excellent re¬
finished container. view of the chemistry and the properties of pet¬
Perfumes generally are not included in the rolatum and mineral oil has been published.22
semisolid formulations because in the past
many dermatologists have objected to their use
for the treatment of a skin condition in view of Hydrocarbon Waxes
the danger of sensitization. Many manufactur¬ Hydrocarbon waxes frequendy are employed
ers of fragrances have run toxicity, sensitization, in the manufacture of creams and ointments to
and irritation tests on the various perfume mate¬ increase the viscosity of mineral oil in order to
rials and can supply fragrances that have suc¬ prevent its separation from an ointment. Ozoke¬
cessfully passed critical testing in animals. How¬ rite is a mined wax with a melting point range of
ever, such animal tests do not obviate the need 65 to 75°C and consists of a mixture of saturated
for testing on humans. hydrocarbons ranging in carbon content from
The industrial pharmacist who develops the C35 to Css. Paraffin wax is obtained from petro¬
dosage form must be aware of the chemical com¬ leum and is available in a variety of melting
position of the materials at his disposal and their points ranging from 35 to 75°C. Another wax
physical properties, so that he can set or have that is often used is ceresin, which is a mixture
specifications set for the raw materials. Broad of ozokerite and paraffin wax. Its melting point
specification limits may lower the cost of a raw varies, depending on the paraffin wax content.
material, but represent false economy if the Ozokerite and ceresin possess the property of
quality of the product is affected. New raw mate¬ retaining oils within a matrix-like structure
rials suitable for use in semisolids are continu¬ without the sweating or oozing of the oils.
ally being introduced. Flynn has published an Synthetic waxes have been developed from
excellent compilation of these materials that in¬ vegetable oils and naturally occurring waxes by
cludes their functions in formulations.1 a process of hydrogenation and catalytic splitting
that involves long Ci8-C36 hydrocarbon chains.
Like all true waxes, the synthetic waxes exhibit
thermoplastic, crystalline properties and are not
Hydrocarbons pure chemical compounds but complex mix¬
Except for water, petrolatum and mineral oil tures of mainly long chain saturated aliphatic
are perhaps the most widely used substances in chemical entities. The synthetic waxes are
semisolids. Petrolatum is a complex mixture of chemically closely related to the naturally occur¬
semisolid hydrocarbons, containing aliphatic, ring waxes in that they contain long chain wax
cyclic, saturated, unsaturated, branched, and fatty acids, but are not considered to be direct
unbranched substances in varying proportions. replacements for them. However, they may be
Although extensively used for more than 85 used in conjunction with or can replace the nat¬
years, petrolatum still has broad physical and ural waxes in some formulations to achieve cer¬
chemical specifications in the USP. Wide den¬ tain desired properties. Synchrowaxes,* the
sity and melting point ranges, as well as varia¬ brand name of a series of such waxes, have
tion in chemical composition, are permitted in unique gelling characteristics that may be used
the official compendia throughout the world. in formulating synthetic petrolatums with occlu¬
Petrolatum is available in the form of a short sive properties to help moisturize the skin with¬
or long “fiber.” The type of fiber possessed by the out the inelegant properties of natural petrola¬
petrolatum is usually determined by dipping the tum.
index finger into the petrolatum sample and
then withdrawing it slowly. The long fiber type
tends to form a transparent continuous film or Oleaginous Substances
thread joining the finger and the sample. The Vegetable oils such as peanut oil, almond oil,
short fiber variety ruptures easily and does not sesame oil, and olive oil are mono-, di-, and tri¬
exhibit this film. The long fiber petrolatum is glycerides of mixtures of unsaturated and satu¬
preferred for an occlusive dressing because of rated fatty acids. Trace metal contaminants in
the continuous film it forms over the surface of the oils may catalyze oxidation reactions that
the skin. can be prevented by the addition of antioxidants,
Mineral oil is obtained from petroleum, as is such as butylated hydroxyanisole, butylated
petrolatum, by collection of a particular vis¬
cosity-controlled fraction. It is produced in many
viscosity and specific gravity ranges. The lower *Synchrowaxes are available from Croda, Inc., New York,
viscosity oils are preferred for semisolids, since NY.

540 • The Theory and Practice of Industrial Pharmacy

hydroxy toluene or propyl-gallate, and by the tion of stearic acid crystals. Creams formed with
addition of metal chelating agents such as salts sodium stearate are much firmer in consistency.
of ethylenediamine tetraacetic acid. Stearyl alcohol and cetyl alcohol (palmityl al¬
Antioxidants may produce problems of drug cohol) are used in creams as auxiliary emulsifi¬
compatibility or dermal sensitivity in some pa¬ ers and emollients. In sufficient quantity, stearyl
tients. The exact chemical composition of a par¬ alcohol produces a firm cream that may be soft¬
ticular vegetable oil varies from lot to lot because ened with cetyl alcohol.
of its natural origins. Its composition depends on For a description of waxes of animals, insect,
the climatic conditions, the soil, the amount of and vegetable origin such as lanolin, beeswax,
rainfall during the growth of the vegetable crop, camauba wax, candelila wax, silicones,
and the storage conditions of the harvested crop branched chain compounds, isopropylesters,
and the oil. polyols, cellulose ethers, and other raw materials
The trend toward the isolation and synthesis suitable for creams and ointments, the reader is
of pure chemical entities present in the vegeta¬ advised to check sources such as the CTFA Cos¬
ble oils is evident in the literature and supplier’s metic Ingredient Dictionary,23 as well as suppli¬
catalogs. Perhaps when these chemically pure ers’ catalogs.
substances are available in quantity, the influ¬ A list of the various raw materials and their
ence of a homologous series of compounds, ei¬ functions has recently been published.1 Another
ther individually or in combination, on the qual¬ fisting of cosmetic raw materials appeared in the
ity of an emulsion and the release of a drug from FD&C Reports (“The Rose Sheet”)24 which was
such a base can be more rigidly controlled. reproduced from the Japan Cosmetic Ingredient
Dictionary of 148 government-approved raw
materials. The dictionary is the result of a collab¬
Fatty Acids and Alcohols orative effort between the Cosmetic, Toiletry and
The commercially available fatty acids are Fragrance Association (CTFA), the U.S. Com¬
really mixtures of related fatty acids. Stearic and merce Department, the Japanese Government,
palmitic acids are present in the greatest propor¬ and the Japan Cosmetic Industry Association
tion in triple pressed stearic acid along with (JCIA). The second supplement to the dictionary
varying quantities of other fatty acids. Various fists 173 raw materials and is reproduced in a
fixed ratios of stearic/palmitic acids can be ob¬ later issue of the same trade periodical.24 The
tained from the suppliers. A slight change in the dictionary will eventually fist approximately
ratio of the saturated fatty acids changes the 2,000 to 3,000 raw materials. According to the
structure and size of the fatty acid crystal, the CTFA, inclusion of the raw materials in the dic¬
x-ray diffraction pattern, and the solubility. For tionary is based on “(1) chemical (not brand
this reason, stearic acid of rigidly controlled pu¬ name), (2) whether the substance is free from
rity is used in many topical preparations. patent and/or ‘technical know-how problems,’
Similar variations in chemical structure exist (3) whether it is free of safety problems, and (4)
in almost all materials of natural origin, in poly¬ a specified alkyl group.” The interest and pur¬
meric substances having a long chain length, pose of CTFA is “to eliminate testing, certifica¬
and in combinations of polymers with fatty acids tion, and standards activities that act as barriers
or alcohols. The number of moles of ethylene to trade with Japan.”
oxide, for example, in a polyethylene reaction
product such as ROCH2CH2[OC2H4]nOH
merely represents an average rather than an Emulsifiers
exact amount. Rigid purchasing and quality con¬ The water-soluble soaps were among the first
trol specifications must be established for such emulsifiers used for semisolid oil-in-water emul¬
materials if variations in the quality and consist¬ sions. The viscosity of the cream or ointment
ency of semisolid emulsions are to be avoided. prevents coalescence of the emulsified phases
Stearic acid is used in water-removable and helps to stabilize the emulsion. The addition
creams as an emulsifier to develop a certain con¬ of fatty polar substances, such as cetyl alcohol
sistency in the cream and to give a matt effect on and glyceryl monostearate, tends to stabilize the
the skin. When a stearate soap is used as an semisofid oil-in-water emulsion. The interfacial
emulsifier, enough potassium hydroxide or tri¬ film formed around the dispersed phase globules
ethanolamine usually is added to react with in such a system is generally solid, thereby mak¬
about 8 to 20% of the stearic acid. The unre¬ ing the emulsified preparation more rigid. Poly¬
acted fatty acid increases the consistency of the valent ions, such as magnesium, calcium, and
cream. These creams are soft and develop a aluminum, tend to stabilize water-in-oil emul¬
sheen or luster upon aging, owing to the forma¬ sions by cross-linking with the polar groups of

semisolids • 541
the fatty materials. Nearly all semisolid creams Formula #2
and emulsified ointments require more than one %(w/u>)
emulsifier. The combination of a surface active
agent with an oil-soluble auxiliary emulsifier is A Magnesium aluminum silicate (MAS)* 2.0
referred to as a mixed emulsifier system. Trieth¬ Purified water 37.0
anolamine stearate soap combined with cetyl
B Mineral oil, light 20.0
alcohol is an example of an oil-in-water mixed
Petrolatum 9.0
emulsifier; beeswax and divalent calcium ions Isopropyl myristate 5.0
or small quantities of a water-soluble surface Lantrol (lanolin oil)f 3.0
active agent exemplify mixed emulsifiers for a 70% sorbitol solution 20.0
water-in-oil emulsion. Maximum stability of an Arlacel 186 (glyceryl oleate and propylene
emulsion occurs when a complex interfacial film glycol)! 1.0
is formed. Such a film forms when an oil-soluble Polysorbate 80 1.0
substance is added and reacts at the interface Preservative q.s.
with the water-soluble surfactant. Soft water-in-
•Available from Veegum, R.T. Vanderbilt Co., Norwalk, CT.
oil cream bases can be made with calcium ions
tAvailable from Emery Industries, Cincinnati, OH.
as an auxiliary emulsifier. The bases can be (Available from ICI Americas, Inc., Wilmington, DE.
made firmer by decreasing the mineral oil con¬ Procedure: Add the MAS to the water slowly, agitating continu¬
tent. Formula #1 is used to make a soft water- ally until smooth. Heat A to 70 to 75°C. Heat B with stirring to 70
in-oil cream base employing divalent calcium to 75°C. Add A to B, and mix until cooled.
ions in the form of water-soluble saccharated
lime. The soap-type emulsion may be unstable in
the presence of acidic substances. Cationic or
nonionic emulsifiers are preferable for drugs
requiring an acid pH. Quaternary ammonium
Formula #1 compounds like cetyl trimethyl ammonium
% chloride help to stabilize these emulsions in
combination with such fatty alcohols as cetyl
A Mineral oil, 65 to 75 viscosity 30.00 alcohol.
Lantrol* 3.00 The nonionic emulsifiers are employed for
Microcrystalline waxt 2.00 both oil-in-water and water-in-oil emulsified
Acidlan 20* 4.00 pharmaceutical semisolids because they are
Propylparaben 0.20 compatible with many drug substances. The-
B Borax 0.20 nonionic emulsifiers are versatile and may be
Methylparaben 0.20 used with strongly acidic salts or with strong
Water 49.75 electrolytes.

C Saccharated lime 0.65

Purified water 10.00 Formula #3
Tripelennamine Hydrochloride Cream*
"Available from Emery Industries, Cincinnati, OH.
tShould have a melting point of 75 to 79”C and should be tested %(wfw)
for safety on animal and human skin, since petroleum residues
may be present in the wax. Oil Phase
Procedure: Heat parts A, B, C separately to 78°C. Add B to A. Cetyl alcohol 5.0
After the emulsion has formed, add C. Cool and pass through a Glyceryl monostearate 15.0
homogenizes Sorbitan monooleate 0.3
Polysorbate 80, USP 0.3

Aqueous Phase
The clay, magnesium aluminum silicate, has
Tripelennamine HC1 2.0
been used as a thickener, suspending agent, and
Methylcellulose 100 cps 1.0
oil-in-water emulsion stabilizer because of the Purified water, q.s. ad 100.0
colloidal structure of its aqueous dispersions. It Preservative q.s.
also contributes to the stability of water-in-oil
emulsions when used with suitable emulsifiers, * Available from ICI Americas, Inc., Wilmington, DE.
Procedure: Disperse the methylcellulose in hot water in which
probably owing to its thickening action on the
the preservative has been dissolved, and then chill at 6°C until
internal phase whereby it inhibits coalescence. dissolved. Heat the oil phase to 70°C. Heat the methylcellulose
The magnesium aluminum silicate may migrate solution to 72°C, and add to the oil phase, stirring continuously.
to the interfacial area, resulting in a stronger Add the tripelennamine HC1 at 35°C, and stir continuously until
film.25 dissolved.

542 • The Theory and Practice of Industrial Pharmacy

 Recently, a series of emulsifiers have been To achieve adequate stability in creams in
marketed that contain chemically bonded lactic which the oil content exceeds 10%, the supplier
acid with fatty acids. These acyl lactylates are recommends the use of a co-emulsifier to
claimed to be mild and nonirritating to the skin achieve adequate stability. The HLB system
and eyes,* to produce an emollient feel to the should be utilized to calculate the ratio between
skin, and to serve as oil-in-water or water-in-oil the two emulsifiers for the lipid(s) being used.
emulsifiers. The sodium salts are suggested for Several ratios should be checked to either side of
use in oil-in-water. The particular fatty acid lac- the calculated HLB value to optimize the emul¬
tylate that is selected should be based on the sion.
desired application of the final product as well as
on the most compatible fatty acid derivative.
Some of the available lactylates and the calcu¬ Formula #5
lated HLB values are as follows: Antipersrpirant Cream
%(wfw)

Types of A Oil Phase

Fatty Acid Calculated HLB Mineral oil 23.0
Calcium stearoyl-2-lactylate 3.2
1. Stearic 6.5 PEG 400 dioleate 0.8
2. Stearic/Palmitic 8.3
3. Lauric/Myristic 14.4 B Aqueous Phase
4. Capric/Lauric 11.3 Glycerine 3.0
5. Isostearic 5.9 Sodium lactate (60%) 10.0
Purified water 20.0

Items 3 and 4 are foamers. Item 4 shows good C Aluminum chlorohydrate (50%) 40.0
bacteriostatic properties, owing to the presence
Procedure: Heat A, B, and C to 70°C in separate vessels. Add B
of the moderately short chain capric acid. to C immediately before adding to A. Mix with moderate agitation
An example of an oil-in-water cream utilizing while cooling.
one of the emulsifiers that can serve as a vehicle
for a compatible active substance follows: The Promulgens* are a series of nonionic
emulsifiers composed of a mixture of fatty alco¬
Formula #4 hols and their ethoxylates. Two types, D and G,
%(w/w) are available and are described in the boxed area
below.
A Oil Phase The two types differ in melting point and in
Cetearyl alcohol 5.0 consistency of the emulsions that they form.
Silicone oil, 200 fluid 1.0
According to the supplier, the emulsions formed
Isopropyl myristate 2.0
with type D are usually thicker in consistency.
Sodium stearoyl-2-lactylate 2.0
Since there are no ester linkages, these emulsifi¬
B Aqueous Phase ers are not subject to hydrolysis. In addition,
Propylene glycol 5.0 they are compatible with anionic surfactants of
Sodium citrate 0.2 the sodium lauryl sulfate type or with cationics
Preservative q.s. such as quaternary ammonium compounds.
Purified water, q.s. ad 100 Type D tends to form creams, and type G tends
Procedure: Mix A and heat to 65°C. Combine B and heat to
to form liquid emulsions. It is suggested that
70°C. Add B to A with suitable agitation. Mix with moderate agita¬ they be used in combination to achieve a desired
tion while cooling. viscosity level.

Promulgen D Promulgen G

CTFA adopted name— Cetearyl alcohol and Ceteareth-20 Stearyl alcohol and Ceteareth-20
Chemical description— Cetearyl alcohol and ethoxylated Stearyl alcohol and ethoxylated
cetearyl alcohol cetearyl alcohol

Melting point— 47 to 55°C 55 to 63°C

‘Available from Patco Products, Kansas City, MO. ‘Available from Amerchol Corporation, Edison, NJ.

semisolids • 543
Polyols is vitally important. Following its incorporation
into the semisolid, the maintenance of the se¬
Glycerine, propylene glycol, sorbitol 70%, and
lected polymorphic form in the semisolid is of
the lower molecular weight polyethylene glycols equal concern. The components of the vehicle
are used as humectants in creams. The choice of
and the method of preparation of the semisolid
a humectant is based not only on its rate of mois¬
dosage form affect the stability of the polymor¬
ture exchange, but also on its effect on the tex¬
phic form.
ture and viscosity of the preparation. These ma¬
terials prevent the cream from drying out and
prevent the formation of a crust when the cream
is packaged in a jar. They also improve the con¬ Types of Vehicles
sistency and rub-out qualities of the cream The vehicle used for a pharmaceutical differs
when it is applied to the skin, permitting the from that used for a cosmetic because with a
ere am to be spread without rolling. Increasing cosmetic, penetration into the skin is not de¬
the humectant content tends to cause tackiness. sired. Penetration or protection is desired in a
Sorbitol 70% is more hygroscopic than glycer¬ pharmaceutical semisolid, and its cosmetic ef¬
ine and is used at a lower concentration, usually fect or appearance on the skin is less important.
3% as compared to 10% for glycerine. Propylene A well-formulated pharmaceutical semisolid
glycol and the polyethylene glycols occasionally should be both therapeutically effective and cos¬
are used in combination with glycerine, since metically appealing, with the major effort in the
their ability to absorb moisture is less than that
medical direction.
of glycerine. The therapeutic preparations included in the
semisolids classification are products intended
for application to the skin, scalp, and certain
Insoluble Powders body orifices. These preparations include oph¬
Insoluble drugs must be uniformly dispersed thalmic ointments, nasal jellies, gels, and sterile
throughout the vehicle to ensure homogeneity lubricants for surgical use. In this chapter, how¬
of the product. The solid must be impalpable to ever, attention is given to those dosage forms
the touch; otherwise, grittiness results. Particles that are used in the prevention or treatment of
less than 74 microns in size, equivalent to the skin disease.
mesh openings in a 200-mesh sieve in the U.S. The solubility and stability of the drug in the
Standard Sieve series, are impalpable to most base, as well as the nature of the skin lesion,
people. Milling to a finely divided state provides determine the choice of the semisolid vehicle.
more surface area for contact with the dermal The United States Pharmacopeia (USP) XX
site and increases the rate of dissolution of recognizes four classes of semisolids under the
poorly soluble substances. general classification of ointments: hydrocarbon
Some powders do not disperse uniformly, but bases, absorption bases, (anhydrous form and
tend to aggregate in the base, whereas others emulsion form), water-removable bases, and
present no difficulties even though the particle water-soluble bases.27
size is the same. The difference may be due to
the electrically charged surface condition of the
particles after milling. Aggregation of particles
becomes a problem for those that are 5 microns Hydrocarbon Bases
or smaller in size. For particles below 0.5 mi¬ Petrolatum and white ointment, which is pet¬
crons in size, the dispersion problems increase rolatum with 5% beeswax, are typical of this
exponentially. Different powdered substances class of lipophilic vehicles. The most commonly
show similar problems of aggregation in the sub¬ used raw material in ointment vehicles is petro¬
micron size. latum because of its consistency, its bland and
Many drug substances used in topical prepa¬ neutral characteristics, and its ability to spread
rations (e.g., prednisolone; fluorocortisone ace¬ easily on the skin. These bases are difficult to
tate) exist in several polymorphic states. Com¬ wash off the skin and may be used as occlusive
pounds that exist in different crystalline forms coverings to inhibit the normal evaporation of
at room temperature possess varying amounts of moisture from the skin. A thin film of petrola¬
free energy or thermodynamic activity. The tum produces a sensation of warmth on the skin
physiologic activity and availability of a drug because the insensible moisture does not evapo¬
substance often are directly related to its ther¬ rate. Very little water can be incorporated into
modynamic activity26 and the choice of the these greasy bases without the addition of other
proper crystalline form for use in the semisolid substances.

544 • The Theory and. Practice of Industrial Pharmacy

Absorption Bases water-in-oil emulsions. A typical example of a
The absorption bases are formed by the addi¬ lanolin absorption base follows:
tion of substances miscible with hydrocarbons
and possessing polar groupings, such as the sul¬
fate, sulfonate, carboxyl, hydroxyl, or an ether Formula #7
Lanolin Absorption Base
linkage. Lanolin, lanolin isolates, cholesterol,
%
lanosterol and other sterols, acetylated sterols, or
partial esters of polyhydric alcohols (e.g., sorbi- Lanolin alcohols 10
tan monos terate or monooleate) may be added to Lanolin 25
make the hydrocarbon bases hydrophilic. Such Mineral oil, low viscosity 30
hydrophilic mixtures have been known as “ab¬ Purified water 35
sorption bases,” although the term “absorption”
is a misnomer. The bases do not absorb water on
contact, but with sufficient agitation, they do Mineral oil is added to reduce the tackiness of
absorb aqueous solutions and can be considered the base. Nonionic water-in-oil emulsifiers,
water-in-oil emulsions. (The notations o/w for such as glyceryl monostearate, cholesterol, cetyl
oil-in-water and w/o for water-iii-oil are conven¬ alcohol, and the sorbitan fatty acid derivatives,
ient abbreviations for the respective emulsion may be added for improved stability and water¬
types.) absorbing capacity. These vehicles have “emol¬
The absorption bases are of two types: the lient” properties and deposit an oily film upon
anhydrous form and the emulsion form. Anhy¬ the skin. Examples of water-in-oil emulsion ve¬
drous lanolin and hydrophilic petrolatum are hicles that utilize the absorption base principle
examples of anhydrous vehicles that absorb are given in Formulas #8 and #9.
water to form water-in-oil emulsions.

Formulas #8* #9f

Formula #6 % %
Hydrophilic Petrolatum (USP XX)
Oil Phase
3
Lanolin, anhydrous USP 3.1 15.0
Cholesterol 30.0 Petrolatum, white, USP 25.0 —
Stearyl alcohol 30.0 Mineral oil, heavy 25.0 8.0
White wax 80.0 Beeswax (white wax, USP) 10.0 7.0
White petrolatum 860.0 Sorbitan sesquioleate 1.0
1000.0 Propylparaben 0.05 0.05
Amerchol CAB — 20.0

Aqueous Phase
The maximum amount of water that can be Sodium borate, USP 0.7 —
added to 100 g of such a base at a given tempera¬ Polyethylene glycol 1500 — 5
ture is known as the water number. To deter¬ Methylparaben 0.15 0.15
mine the water number, the base is stirred con¬ Purified water 35.0 49.8
tinuously as the water is being added. Distilled
•Available from Hans Schott, Temple University, Philadelphia,
or deionized water should be used. The end
PA.
point is reached when no more water can be “ab¬ tAvailable from Amerchol, a Unit of CPC International, Inc.,
sorbed” into the base, as evidenced by droplets Edison, NJ.
of water remaining in the container. Procedure: Heat the oil phase to 70°C, and add the aqueous
In a study involving the separate addition of a solution at 72°C to the oil phase, stirring continuously.
series of surfactants to a semisolid base, it was
found that the water-absorbing capacity of the Cold cream base, which reportedly dates back
base increased as the HLB number (hydrophilic- to Galen, was the forerunner of these water-in-
lipophilic number) of the surfactant decreased28 oil emulsion vehicles.
(see Table 18-1). The cold cream type of emulsion frequently
Hydrous lanolin was the prototype or forerun¬ utilizes a borax-beeswax combination as the
ner of the absorption bases because of its ability emulsifier, with mineral oil or a vegetable oil as
to absorb water. Various absorption bases were the continuous phase. A protective oil film re¬
developed as various lanolin isolates and deriva¬ mains on the skin following the evaporation of
tives became commercially available. Many of the water. The slow evaporation of water gives
these lanolin fractions aid in the formation of the skin a cooling effect.

SEMISOLIDS • 545
Table 18-1. Determination of Water Numbers Using 10-g Samples

Surfactant HLB Grams Water Absorbed Water Number

Sample 1 Sample 2

(Control: White petrolatum) 0.40 0.40 4.0

Sorbitan monolaurate 8.6 5.21 5.41 53.1
Sorbitan monopalmitate 6.7 8.20 8.52 83.6
Sorbitan monostearate 4.7 10.59 10.17 103.8
Sorbitan monooleate 4.3 24.75 25.25 250.0
Sorbitan sesquioleate 3.7 29.84 31.04 304.4
Sorbitan trioleate 1.8 41.95 40.31 411.3

From Mendes, R.W., et al.: Drug Cosm. Ind., 95:34, 1964.

Semisolid water-in-oil emulsions of the borax- Hydrophilic ointment is an example of a

beeswax type frequently exhibit poor long-term water-in-oil absorption base type vehicle that
physical stability. The development and large- does not have any lanolin or its derivatives in the
scale commercial manufacture of water-in-oil formula.
emulsifiers have made it possible to prepare
stable semisolids that are oily to the touch. Also,
relatively nongreasy water-in-oil emulsions may
be prepared by a judicious combination of raw
materials.
Synthetic substances are replacing natural Formula #11
raw materials as the latter become restricted in Hydrophilic Ointment (USP XX)
availability. As an example, the supplies of natu¬ %
ral beeswax have declined with the steady price
rises that result from both supply and inflation. Methylparaben 0.25
A number of synthetic beeswaxes have appeared Propylparaben 0.15
with properties quite similar to the natural. Syn¬ Sodium lauryl sulfate 10.00
Propylene glycol 120.00
thetic spermaceti types have replaced the natu¬
Stearyl alcohol 250.00
ral grade since the latter was banned as a result
White petrolatum 250.00
of endangering the whale. Formula #10 illus¬
Purified water 370.00
trates the use of synthetic beeswax in a rela¬
tively nongreasy cold cream.

Formula #10
Cold Cream29 This ointment can be used as a vehicle for
% many drug substances, but is not a cosmetically
elegant preparation. The high petrolatum con¬
A Purified water 34.60 tent leaves an unctuous residue upon the skin
Borax 1.00 that may be uncomfortable. Modification of the
Methylparaben 0.25
formulation by reducing the petrolatum content,
B Light mineral oil 50.00 and the addition of other emollients such as
Synthetic beeswax cetyl alcohol, hexadecyl alcohol, and fatty acid
flakes 13.00 esters (isopropyl myristate or palmitate), can add
Glyceryl monostearate, pure 1.00 cosmetic appeal to the preparation. The effect of
Propylparaben 0.15 such modifications on the activity of a drug sub¬
Procedure: Dissolve the methylparaben and borax in water at
stance incorporated in the base must be deter¬
75 to 80°C. Dissolve the propylparaben in a well-mixed mixture of mined.
phase B heated to 75 to 80°C. Add phase A to phase B while Formulas #12 and #13 represent different
stirring rapidly. types of hydrophilic ointment bases.

546 • The Theory and Practice of Industrial Pharmacy

 ishing cream bases in which different types of
Formula #22
emulsifiers are used are given in Table 18-2.
Hydrophilic Ointment Base*
Removal of these creams from skin or clothing
%
is facilitated by the oil-in-water emulsifiers they
Oil Phase contain. Creams may be applied to moist skin
Amerchol CAB* 50.0 lesions, since the oil-in-water vehicle tends to
Cetyl alcohol 2.0 absorb any serous discharge. The water remova¬
Stearyl alcohol 2.0 ble bases form a semipermeable film on the site
of application following the evaporation of water.
Aqueous Phase
The semisolid water-in-oil emulsions, however,
Sodium lauryl sulfate 2.0
Water 34.0
tend to form a hydrophobic layer on the skin.
Methyl gluceth-20 10.0
Semisolid emulsions are intimate, relatively
Preservative q.s. stable mixtures or dispersions of a hydrophilic
phase with a lipophilic phase. The phase that is
* Available from Amerchol, a Unit of CPC International, Inc., dispersed in the form of fine microscopic glob¬
Edison, NJ.
ules is referred to as the discontinuous or inter¬
Procedure: Add the water phase at 80°C to the oil phase at 80°C.
Cool while mixing to just above congealing temperature.
nal phase; the other is the continuous or exter¬
Variations: For greater firmness, increase ratio of stearyl to cetyl nal phase. The vanishing cream type vehicles
alcohol. are representative of the oil-in-water emulsions,
whereas the absorption bases are generally
water-in-oil emulsions.

Formula #13
Hydrophilic Ointment Base*
Water-Soluble Bases
%
Water-soluble vehicles are prepared from
Oil Phase mixtures of high- and low-molecular-weight
Acetylated lanolin* 5.0 polyethylene glycols, which have the general
Mineral oil 70 vis. 5.0 formula: HOCH2[CH2OCH2]nCH2OH. The
Amerchol L-500* 10.0 low-molecular-weight glycols in this category
Amerchol CAB' 15.0 are liquids; those with a moderately higher mo¬
Microcrystalline wax, 195°C 5.0 lecular weight are somewhat unctuous; and the
Cetyl alcohol 5.0 higher molecular weight polyethylene glycols
Brij 521 6.0 are solids. Suitable combinations of high- and
Brij 581 4.0 low-molecular-weight polyethylene glycols yield
products having an ointment-like consistency,
Aqueous Phase
which soften or melt when applied to the skin.
Water 40,0
No water is required for their preparation. They
Methyl Gluceth-20 5.0
are water-soluble because of the presence of
Preservative q.s.
many polar groups and ether linkages.
‘Available from Amerchol, a Unit of CPC International, Inc., If the polyethylene glycol ointment has a high
Edison, NJ. percentage of crystalline material, the softening
fAvailable from ICI Americas, Inc., Wilmington, DE.
and melting of the ointment rubbed onto the
Procedure: Add the water phase at 80°C to the oil phase at 80°C.
Cool while mixing to just above congealing temperature.
skin will not be as gradual as with petrolatum,
since the crystalline material melts sharply with
an increase in temperature. The polyethylene
glycol ointments are much less occlusive than in
water-in-oil emulsions of the absorption base
Water-Removable Bases type; they mix with skin exudates and are read¬
The water-removable bases are oil-in-water ily washed from the skin. The polyethylene gly¬
emulsions and are referred to as “creams.” The col vehicles are softened by the addition of
vanishing cream bases fall into this category. water, owing to solution of the glycols. The USP
The vanishing creams are so termed because states that 5% of the polyethylene glycol 4000
upon application and rubbing into the skin, may be replaced with an equal amount of stearyl
there is little or no visible evidence of their alcohol when 6 to 25% of aqueous solution is to
former presence. Formulas for some typical van¬ be added to the vehicle.

SEMISOLIDS • 547
 The “water-soluble” bases are also known as
Formula #19
greaseless ointment bases. The compatibility of
%
these bases with drug substances and their re¬
lease rate must be evaluated for each class of Carbomer 940 0.75
drugs. Purified water 34.25
Solulan 98* 3.00
S.D. alcohol #40 50.00
Diisopropanolamine, 10% in water 12.00
Pastes, Gels, and Jellies ‘Available from Amerchol, a unit of CPC International, Inc.,
Pastes are dispersions of high concentrations Edison, NJ.
Procedure: Prepare a Carbomer slurry in water with gentle agi¬
of insoluble powdered substances (20 to 50%) in
tation, and add mixture of SDA #40 and Solulan mixture, mixing
a fatty or aqueous base. The fatty bases are less until no particles are visible. Neutralize carefully with
greasy as well as stiffer in consistency than oint¬ diisopropanolamine solution to avoid incorporating air.
ments because of the large amount of powdered For greater firmness, increase the concentration of the Carbo¬
material present. These pastes adhere well to mer and diisopropanolamine.
the skin and are of benefit in the treatment of
chronic or lichenified lesions. Zinc gelatin paste,
USP XX, for example, is used when a protective Gels are also formed with celluloses such as
film on the skin is desired following the evapora¬ hydroxypropylcellulose and hydroxypropyl-
tion of water. Pastes provide a protective layer, methylcellulose. A popular over-the-counter
and when covered with suitable dressings, pre¬ benzoyl peroxide gel contains 6% polyoxy¬
vent excoriation of the patient’s skin by scratch¬ ethylene lauryl ether, 40% ethyl alcohol, colloidal
ing. magnesium aluminum silicate, hydroxypropyl-
Jellies are water-soluble bases prepared from methylcellulose, citric acid, and purified water.
natural gums such as tragacanth, pectin, algi¬
nates, and boroglycerin, or from synthetic deriv¬
atives of natural substances such as methylcel- Ophthalmic Ointments
lulose and sodium carboxymethylcellulose. Semisolid ophthalmic vehicles frequently con¬
Gels are usually clear transparent semisolids
tain soft petrolatum, a bland absorption base, or
containing the solubilized active substance. Car-
a water-soluble base. The water-soluble base
bomer 940 swells when dispersed in water in the
may be prepared with polyethylene glycols or
presence of such alkaline substances as trietha¬
with a water-soluble gum. Mineral oil is fre¬
nolamine or diisopropanolamine to form a semi¬
quently added to petrolatum to lower its fusion
solid.
point, but its addition introduces a problem of
separation upon storage. Such oil separation
may be prevented by the addition of small quan¬
tities of natural waxes such as ozokerite, ceresin,
Formula #18 or microcrystalline wax. The amount of wax
% added should not appreciably raise the melting
A Carbomer 940* 0.5
point of the base.
Water 42.5 All materials used in the ophthalmic ointment
Sorbitol 70% solution 2.0 should be impalpable to avoid eye discomfort
and possible irritation. Ophthalmic ointments,
B Ameroxol OE 20t 10.0 especially when used on injured eyes, should be
Solulan 981 3.0
sterile.
Polyvinylpyrrolidone (PVP) K-30 1.0 Numerous variations of the aforementioned
Triethanolamine 1.0
basic vehicles are possible because of the availa¬
S.D. alcohol #40 40.0
bility of new raw materials, which permit the
’Available from B.F. Goodrich Company, Cleveland, OH. pharmacist to vary his formulation to obtain the
tAvailable from Amerchol, a unit of CPC International, Inc., desired therapeutic effect and to make a semi¬
Edison, NJ. solid that is both convenient and comfortable for
Procedure: Phase A—Disperse Carbomer 940 thoroughly in
the patient to apply. A minimal number of mate¬
water with good stirring. Add sorbitol solution. Phase B—Add the
Ameroxol OE 20 to the alcohol, warm to 35°C, and stir until uni¬
rials should be used in a semisolid dosage form,
form. Add Solulan 98, PVP, and triethanolamine consecutively, since fewer constituents reduce inventory, de¬
mixing after each addition. Add phase B to phase A with gentle crease the possibility of chemical interference
mechanical mixing until gel forms. with the analytic procedure, and decrease the

548 • The Theory and. Practice of Industrial Pharmacy

Table 18-2. Formulas for Vanishing Cream Bases

#14 #15 #16 #17

Anionic Stearate Anionic Nonionic Cationic
Emulsifier Emulsifier Emulsifier Emulsifier
% % % %
By Weight By Weight By Weight By Weight30

Stearic acid 13.0 7.0 14.0

Stearyl alcohol 1.0 5.0
Cetyl alcohol 1.0 2.0 1.0
Glyceryl monostearate 10.0
Isopropyl palmitate 1.0
Lanolin 2.0
Methylparaben 0.10 0.10 0.10 0.1
Propylparaben 0.05 0.05 0.05
Sorbitan monostearate 2.0
Glycerin 10.0 10.0 15.0
Sorbitol solution [70%] 3.0
Potassium hydroxide 0.90
Sodium lauryl sulfate 1.0
Polysorbate 60 1.5
Stearyl colamino formyl methyl 1.5
pyridinium chloride
Purified water, q.s. ad 100 100 100 100

danger of allergic reactions in unusually sensi¬ Preservation from Microbial

tive patients.
Many formulas for creams and ointments can
Spoilage
be found in the scientific literature, formularies, Chemical preservatives for semisolids must be
and catalogs of chemical suppliers of emulsifiers carefully evaluated for their stability with regard
and other raw materials. These formulas should to the other components of the formulation as
only serve as a guide for developmental work, well as to the container. Plastic containers may
because many of them have not been checked absorb the preservative and thereby decrease
for stability, ease of application, or ability to re¬ the quantity available for inhibiting or destroy¬
lease the drug to the absorption site. The re¬ ing the microorganisms responsible for spoilage.
quirements of the drug should determine what Some preservatives may sting or irritate the
materials are used. Only by subsequent experi¬ mucous tissues of the eye or nasal passages.
mentation can the typical problems regarding Methylparabens and propylparabens tend to be
consistency, application, and stability be over¬ more irritating when applied in the nose than
come. quaternary ammonium compounds (e.g. benzal-
In the past, many pharmaceutical semisolids konium chloride) or the phenylmercuric salts.
used to treat skin disease lacked the elegance Boric acid may be used in the ophthalmic prepa¬
and aesthetic appeal of the better cosmetics and rations, but is omitted from products to be used
toiletries. However, the availability of a host of in the nose because of possible toxic effects if
new and safe raw materials suitable for use as absorbed in large quantities.
dermatologic semisolids has made it possible for The preservatives are added to semisolids to
the patient to apply to his skin a preparation that prevent contamination, deterioration, and spoil¬
is therapeutically effective and cosmetically ac¬ age by bacteria and fungi, since many of the
ceptable. For cosmetic appeal, the semisolid components in these preparations serve as sub¬
should be easy to apply and feel comfortable on strates for these microorganisms. Several terms
the skin. It should not feel clammy, excessively are used to describe microbial organisms associ¬
moist, or too dry. When a protective film is ated with pharmaceutical and cosmetic prod¬
formed or deposited on the skin, the film should ucts: “harmful,” “objectionable,” and “opportun¬
not be tacky or excessively adhesive. All these istic.”
properties may be summed up under the expres¬ The USP XX uses the term “harmful” to refer
sion “pharmaceutical elegance.” to microbial organisms or their toxins that are

SEMISOLIDS • 549
responsible for human disease or infection. Ex¬ value for the minimum preservative concentra¬
amples of organisms that must not be present in tion required for a formulation, but to ensure
a product are given, namely, Salmonella species, quality, the product must be tested for its ability
Escherichia coli, certain species of Pseudomo¬ to withstand accidental and deliberate microbial
OC
nas, including P. aeruginosa, and Staphylococ¬ contamination.
cus aureus. An “objectionable” organism can Preservative efficacy in a formulation is deter¬
cause disease, or its presence may interrupt the mined by the addition of pure or mixed cultures
function of the drug or lead to the deterioration of microbial organisms to the finished prepara¬
of the product. Organisms are defined as “oppor¬ tion. The number of microorganisms initially
tunistic” pathogens if they produce disease or present in the inoculated material is determined
infection under special environmental situa¬ by plating aliquots of suitable dilutions. Table
tions, as in the newborn or the debilitated per¬ 18-3 gives the USP XX procedure and the inves¬
son. Included in the latter group are the aged, tigational FDA procedure for topicals, including
those undergoing extensive surgical or acciden¬ the organisms used, the levels of inoculum,
tal trauma, and the compromised host, defined sampling periods, and the measure of effective¬
as those who are on antibiotic, anticancer, or ness. Various neutralizers for the preservative
immunosuppressive therapy. The newborn has are added to the culture media to recover a max¬
increased susceptibility to gram-negative infec¬ imum number of organisms. A TAT broth con¬
tions, while the other individuals have various sisting of tryptone (2%), azolectin (0.5%), and
forms of immunologic deficiency, which in¬ polysorbate 20 (4%) has been found to be a suit¬
crease the susceptibility to infections. Recog¬ able medium for topical products. Azolectin is a
nized opportunistic pathogens are “objectiona¬ neutralizing agent for quaternary ammonium
ble.”31 The following objectionable organisms compounds and polysorbate 20 inactivates para-
should not be present in a pharmaceutical or bens. The samples should be tested at intervals
cosmetic product: P. putida, P. multivorans, P. for both slow-growing and rapidly proliferating
maltophilia, Proteus mirabilis, Serratia marces- organisms.
cens, Klebsiella sp., Acinetobacter anitratus The USP XX has procedures for determining
(Bacterium anitratum), and Candida sp.32 the microbial content of raw materials and fin¬
The success or failure of a preservative in pro¬ ished products. Suitable limits on the number
tecting a formulation against microbial spoilage
depends upon many factors. The interaction of
the preservative with surfactants, active sub¬ Table 18-3. Preservative Efficacy (High-Level
stances, other components of the vehicle, sorp¬ Inocula Challenge) Tests
tion by polymeric packaging materials, and
product storage temperature may change the A. USP XX Procedure
concentration of the unbound or free preserva¬ 1. Organisms used: C. albicans, A. niger, E. coli, S.
tive in the aqueous phase. aureus, P. aeruginosa.
Perfumes, high concentrations of glycerine, 2. Inoculum: 0.1ml/20 ml; 100,000 to 1,000,000 cells/
and electrolytes make the environment less fa¬ ml.
vorable to microbial growth, thus enhancing the 3. Sampling at 7, 14,21, and 28 days following inocu¬
effectiveness of the preservatives. Preservative lation.
action appears to depend on the concentration of 4. Effectiveness: vegetative cells not more than of
the free preservative in the aqueous phase. Sur¬ 0.1% of initial concentrations by 14th day; concen¬
tration of viable yeasts and molds at or below initial
factant solubilized preservative may be bound
concentration after 14 days; concentration of each
within the micelles and there inactivated, or on
test organism remains at or below these levels after
the contrary, the micelles may act as reservoirs
28 days.
of preservative in an actively preserved system.
The minimum inhibitory concentration of B. Investigational FDA Procedure for Topicals
preservative necessary to prevent microbial 1. Organisms used: same as USP XXplus P. putida, P.
spoilage may be estimated by (1) the use of ex¬ multivorans, Klebsiella sp., S. marcescens.
perimentally determined physicochemical pa¬ 2. Inoculum: 0.2 ml/20 ml; .0.8-1.2 x 106 cells/ml.
rameters such as the oil/water partition coeffi¬ 3. Sampling: weekly observations.
cient, concentration of surfactant, the number of 4. Effectiveness: vegetative cells <0.01% survival by
28 days; C. albicans <1% survival; A. niger <10%
independent binding sites on the surfactant, oil/
survival.
water phase ratio, and concentration of free pre¬
5. Re-inoculate: vegetative cells: 1-2 x 105 cells/ml;
servative in the aqueous phase;33 (2) an ultra-
0.1% survival in 28 days.
centrifuge technique;34 and (3) direct dialysis.33
These techniques provide an approximate Modified from Bruch: Drug and Cosm. Ind., 110:32, 1972.

550 • The Theory and Practice of Industrial Pharmacy

and types of microorganisms have not been offi¬ that contain high levels of microorganisms must
cially specified, however. All materials must be be treated before use to remove these contami¬
free of the harmful microorganisms listed in the nants. The greatest source of contamination in
USP XX. Manufacturers have set up their own nasal jellies, for example, axe the natural gums,
microbiologic specifications suitable to their raw- but treatment of the thickener with ethylene
materials and finished products. A typical man¬ oxide vapor destroys the bacterial and fungal
ufacturer’s microbiologic specification may read contaminants. Tests for ethylene oxide residues
as follows: (1) The material must be free of via¬ should be made before using the material. The
ble organisms restricted by the USP XX. (2) The amount of allowable ethylene oxide residues
total aerobic count must not be more than 5000 have not been established. The residues are eth¬
microorganisms per gram; (3) not more than ylene oxide (ETO), ethylene chlorohydrin
100 molds per gram; (4) not more than 100 (ETC), and the various monomeric forms of eth¬
yeasts per gram; and (5) not more than 90 coli- ylene glycol (ETG). Bruch has stated: “Recent
forms per gram. studies have shown the LD50 (Gm./Kg.) by dif¬
Microbiologic quality guidelines have been ferent routes for different animal species to ap¬
established by The Cosmetic, Toiletry and Fra¬ proximate the following: ETC > ETO > ETG
grance Association, Inc.36 These have been (least toxic). Acute topical irritation studies
grouped according to product type: show on Gm./Kg. basis that the activity is
ETO > ETC > ETG.”
1. Baby products—not more than (nmt) 500 The FDA has proposed the following:38
microorganisms per gram or milliliter- “Each drug product of a type listed in this para¬
2. Products used about the eye—nmt 500 mi¬ graph for which ethylene oxide is used as a ster-
croorganisms per gram or milliliter; ilant in the manufacture of the finished product,
its components, or its market container shall
3. Oral products—nmt 1000 microorganisms not, when tested as packaged in its market con¬
per gram or milliliter; tainer, exceed the following residue levels . . .
4. All other products—nmt 1000 microorgan¬ (See Table 18-4.)
isms per gram or milliliter. The manufacturer cannot depend on the pre¬
servative or a type of sterilizing process, such as
There is a further specification that the products radiation sterilization or a liquid chemical steril-
must be free from microorganisms recognized ant, to eliminate organisms introduced during
“as harmful to the user as determined by stan¬ the manufacturing process or by contaminated
dard plate count procedures.”36 raw materials. Though the microbiologic quality
Limits on the maximal microbial content of of a product may be high as a result of the sterili¬
potable and purified water are stated in the zation process, endotoxins may be present as a
United States Public Health Service regula¬ result of lysing of the bacterial cells. Some endo¬
tions.37 The test is made for the presence of the toxins have been shown to be allergens. These
coliform group of bacteria, since experience has substances should be absent from semisolids
shown that this group is a significant indicator just as sterile products should be free of pyro¬
of pollution. The membrane filter technique, as gens. Methods for detection of endotoxins are
well as the fermentation tube method, is used being investigated.39
for detecting and estimating the number of coli¬ A manufacturer can lessen the microbial haz¬
form bacteria present. ards in his products by following the Good Man¬
Raw materials of botanical or animal origin ufacturing Practices (GMPs) recommended by

Table 18-4. Residue Limits of Ethylene Oxide and Derivatives (Parts per million)

Drug product Ethylene oxide Ethylene chlorohydrin Ethylene glycol

Ophthalmics (for topical use) 10 20 60

Injectables (including veterinary
intramammary infusions) 10 10 20
Intrauterine device
(containing a drug) 5 10 10
Surgical scrub sponges
(containing a drug) 25 250 500
Hard gelatin capsule shells 35 10 35

From Federal Register, 43(122), June 23, 1978, part 221, p. 27482.

SEMISOLIDS • 551
the FDA.40 These procedures do not spell out preservative can be overcome by an excess of
the specific details that a manufacturer should the same preservative, by the substitution of a
follow to avoid contamination with microbial or noncomplexing preservative, or by the substitu¬
foreign matter in pharmaceutical products. An tion of a noncomplexing emulsifier system.
interesting sanitary guideline was developed The antibacterial or bacteriostatic activity of
with the food industry in mind, but it is applica¬ the preservative depends also on its partition
ble to any industry in which sanitary procedures coefficient. The preservative may partition be¬
must be followed. The Sanitary Design Princi¬ tween the oil and the aqueous phase, and if the
ples are in the form of a checklist covering many preservative is more soluble in one phase than
details, such as the construction of the manufac¬ another, an additional quantity of the preserva¬
turing plant, processing and packaging equip¬ tive must be added so that both phases are pro¬
ment, floors, walls and ceilings, plant services, tected from microbial spoilage. Hence, methyl¬
and the relative ease of cleaning both equipment paraben and propylparaben are frequently used
and the environment.41 in semisolids because of their better solubility in
If the bacterial count in the finished product aqueous and oil phases, respectively.
is high despite precautions taken to prevent con¬ Many of the preservative studies reported in
tamination in the raw materials, including the the literature are performed in simple aqueous
water supply, then the pipelines, filling equip¬ systems. It is comforting to know that the pre¬
ment, and containers must be checked for servatives appear to be more effective in the fin¬
sources of contamination or interference with ished formulations than indicated in the com¬
the activity of the preservatives. For example, plexation studies. The interactions occurring in
some filling equipment may still contain some of a complex emulsion system in a semisolid ap¬
the semisolid after rinsing or flushing of the parently do not apply.40 However, in view of the
equipment during the cleaning operation. In fact that interaction of preservatives with macro-
such cases, complete disassembly and thorough molecules does occur, the finished formulation
cleaning are mandatory. should be tested microbiologically for^preserva-
The container may contribute to contamina¬ tive adequacy.
tion by harboring bacterial spores, or by sorption The p-hydroxybenzoate esters axe used in
or chemical interaction with the preservative, combination with one another because of their
which thereby lowers its concentration in the synergistic action. In general, they are employed
preparation. Plastic containers, rubber seals, at a concentration level approaching their maxi¬
and closures have been shown to react with mum solubility in water. The solubilities of some
some preservatives.42 Reduced preservative commonly used preservatives are given in Table
concentration also can occur through chemical 18-6. The propyl or butyl ester is usually dis¬
complexation with the surfactant or gum as solved in the fat phase and should be increased
shown in Table 18-5. for vehicles with a high fat content. Satisfactory
In the presence of 5% polysorbate 80, 80% of protection of the emulsion against microbial
the total methylparaben present in the aqueous growth may possibly be attained with sorbic
phase is inactive.44 Such inactivation also oc¬ acid, in which the p-hydroxybenzoate esters
curs with benzalkonium chloride, benzoic acid, prove to be ineffective.45
cetylpyridinium chloride, dehydroacetic acid, The paraben esters of p-hydroxybenzoic acid
and sorbic acid. The partial inactivation of the are still popular as preservatives because their
toxicity is low, they are odorless, they do not dis¬
color, and they are nonirritating to the skin. On
the negative side, the parabens have a low solu-
Table 18-5. Degree of Binding of p-Hydroxy-
hility in water and are less effective against
benzoate Esters by Various Macromolecuies
gram-negative bacteria than molds and yeasts.
Macromolecule Unbound Unbound Combining the parabens with phenoxy-
2% wh> Methylparaben % Propylparaben % ethanol,47 or with imidazolidinyl urea (Germall
II),48 improves their activity against bacteria,
Gelatin 92 89 yeast, and molds. The supplier* claims that the
Methylcellulose 91 87 combination system retains activity against
Carbowax 4000 84 81 yeast and mold even when paraben activity has
PVP 78 64 been diminished by interaction with nonionics
Myij 52 55 16
or other substances in the formulation, or has
Tween 20 43 14
Tween 80 43 10

From Barkley, E. L.: Am. Perf. Aromat., 73:33, 1959. *Sutton Laboratories, Inc., Chatham, NJ

552 • The Theory and Practice of Industrial Pharmacy

Table 18-6. Solubilities of Some Preservatives in g/100 ml Solvent at 25°C

Mineral Propylene
Water Oil Glycol

Bithional 0.0004 1.0 0.5

Butyl-p hydroxybenzoate 0.02 s 110
p-Chloro-m-xylenol 0.0025 SS 1.5*
Dehydroacetic acid 0.10 0.01 1.7
Ethyl paraben 0.075
Methyl-p-hydroxy benzoate 0.25 0.03 22
Propyl-p-hydroxybenzoate 0.06 26
Sorbic acid 0.2 5.5

S = soluble; SS = slightly soluble; * = in glycerin. These descriptive terms are approximate solubilities as defined in USP XX.

migrated into the oil phase. Germall II is used in uated for their effectiveness in the product, and
concentrations of 0.1 to 0.5% alone or in combi¬ their effect on the physicochemical stability of
nation with the parabens. It should be added to the product. As with all new dermatologicals
the product below 60°C. under development, patch testing must be con¬
The solid parabens may be difficult to incorpo¬ ducted to eliminate any possibility of skin irrita¬
rate into some formulations because of their low tion or sensitivity with the products containing
water solubility. A 50% by weight oil-in-water these substances.
emulsion (Liqua Par*) has been marketed. The Rapid determination of preservative efficacy
oil phase is a mixture of p-hydroxybenzoic acid in semisolids can be done in 48 hours for bacte¬
esters: n-butyl, isobutyl and isopropyl. The aque¬ ria and 7 days for molds.49 The method utilizes
ous portion contains water with emulsion stabi¬ the so-called D-value, or decimal reduction time,
lizers. The solubility of the active ingredients in which is calculated from a plot of the log number
water at 25°C is 0.06 g/100 g and is freely misci¬ of surviving organisms per gram against time of
ble with propylene glycol. The preservative inoculation of the product with specific orga¬
should be added to the aqueous phase at a tem¬ nisms. The D-value is a numerical value of rate
perature not exceeding 70 to 75°C and stirred of destruction of a particular organism in a spe¬
until thoroughly dissolved before the prepara¬ cific product. Since it is a quantitative expres¬
tion of the emulsion. Paraben hydrolysis may sion, it can be used to compare the rate of inacti¬
occur if the temperatures exceed 80°C. The sup¬ vation of different organisms in one or more
plier recommends the use of a concentration products. The D-value permits the calculation of
ranging from 0.05 to 0.3% active ingredient. the time required for the complete destruction of
Another preservative that is available is any size population of organisms.
Dowicil 2001, which is described as a broad- The method consists of inoculating the prod¬
spectrum antimicrobial effective against bacte¬ uct with known amounts of the test organisms.
ria, yeast, and molds at concentrations of 0.02 to The products are then sampled periodically to
0.3% weight. It is not inactivated by nonionic, record the population of each test organism, and
anionic, or cationic formulation ingredients. The the log of the surviving organisms at each sam¬
substance is extremely soluble in water but is ple time is plotted. The slope of the line is deter¬
virtually insoluble in oils and organic solvents. mined by linear regression, and the negative
Chemically, it is the cis isomer l-(3-chloroallyl)- reciprocal of the slope represents the D-value.
3,5,7-triaza-l-azoniaadamantane chloride. The The time predicted for complete destruction of
preservative should not be heated above 50°C the test organism in a product is calculated by
and is unstable in solution below pH 4 and above linear estimate of the x-intercept. Figure 18-2
pH 10. Discoloring of this material may occur, shows the effect of different concentrations of
but can be prevented by the addition of sodium parabens on the death rate of Staphylococcus
sulfite. Strong oxidizing or reducing agents aureus in a cream.
should be avoided since these may adversely af¬ The D-values for the control, the cream with
fect the antimicrobial efficacy. the lower, and the cream with the higher con¬
Newer preservatives are being marketed, but centrations of parabens were 18, 4, and 0.6 hr,
all of these substances must be thoroughly eval- respectively. The times predicted for the com¬
plete destruction of S. aureus in these samples
"Mallinckrodt, Inc., St. Louis, MO. were 63, 19, and 3 hr for the control, low-
tDow Chemical, U.S.A., Midland, MI. paraben-content cream, and high-paraben-

SEMISOUDS • 553
 Antioxidants
Antioxidants are added to semisolids when¬
ever oxidative deterioration is anticipated. The
antioxidant system is determined by the com¬
ponents of the formulation, and the selection
depends on several factors, such as toxicity,
irritancy, potency,-compatibility, odor, discolora¬
tion, solubility, and stability. Often, two antioxi¬
dants are used, since the combination is often
synergistic. Listed in Table 18-8 are some physi¬
cal and chemical properties of antioxidants in
common use. Acids such as citric, maleic, phos¬
phoric, or tartaric may be added to the combina¬
tion to chelate trace quantities of metals.

Industrial Processing
Pilot plant or small-scale production equip¬
ment is essential in developing a manufacturing
procedure for a production-size batch. The prep¬
aration of many batches, ranging in size from
2.5 to 25.0 or more kilograms, for product evalu¬
ation and clinical testing provides opportunity to
observe, correct, or improve the effects of minor
but important variations in the manufacturing
technique or formula. Mixing and stirring opera¬
tions are critical in the preparation of emulsions,
FIG. 18-2. Survivor curves showing the effects of different and in the laboratory these operations can be
concentrations ofparabens on the rate of death of Staphy¬ carefully controlled in 0.5- or 1.0-kg-batches of
lococcus aureus in a cream. Symbols: •—•, cream with no
finished product.
parabens (control): ■—■, cream with 0.12% methyl- and
0.08% propyl-paraben; and A—A, cream with 0.2% The electrically operated propeller-type mixer
methyl- and 0.1% propyl-paraben. (From Orth, D. S.: can be manually adjusted and positioned in the
J. Soc. Cosm. Chem., 30:321, 1979.) laboratory mixing vessel to achieve maximum
turbulence. The angle of entry of the propeller
shaft and the depth of the propeller can be easily
varied in the laboratory to prevent aeration. A
metal spatula can be held or positioned in the
beaker during mixing to serve as a baffle to in¬
content cream, respectively. The time required crease turbulence without entrainment of air.
for the complete destruction of a specific organ¬ Similar maneuverability and control of the mix¬
ism of known population in a particular product ing action is more limited with larger stationary
may be predicted from the D-value. If the mean equipment used for the manufacture of semisol¬
D-value for S. aureus in a product is 2.5 hr, the ids. High-speed agitation may introduce air into
time for 106 S. aureus per milliliter to be totally the product, and slow mixing may not form a
inactivated is given by the product of the log satisfactory emulsion.
number of the organisms per milliliter multi¬ Such problems occur in large-scale manufac¬
plied by the D-value, or 6 x 2.5 hr = 15 hr. ture, but would not be apparent in small 1- or
Table 18-7 shows the composition of the vehi¬ 2-kg batches for which a beaker and a laboratory
cles of several corticosteroid creams. It is de¬ mixer are used. Small-scale equipment similar
signed to show how currently marketed semisol¬ to the production models can approximate pro¬
ids utilize the principles described in the duction conditions. It may not be possible to pre¬
previous sections, namely, the different physio¬ dict the exact mixing time and rotational speed
logically innocuous fatty materials used in the of the agitator, but the overall processing charac¬
fat phase, the emulsifier systems, and the teristics can be ascertained if identical mixers
humectants, preservatives, antioxidants, and are used.
chelating agents. Aeration of the semisolid should be avoided,

554 • The Theory and Practice of Industrial Pharmacy

 since it may lead to emulsion instability and var¬ substance is dissolved in the melted fats and
iation in density within a batch, resulting in waxes, or in one of the components of the vehi¬
weight variation of the ointment or cream in its cle, and then mixed with the base. The melted
container. Entrainment of air can occur during mass must be mixed while cooling because the
the mixing, homogenizing, or milling stage, dur¬ fatty alcohols, fatty acids, and waxes do not form
ing the transfer of the product to storage and/or true solutions with petrolatum and mineral oil,
filling equipment, and during the filling or pack¬ but crystallize from the melt as the temperature
aging operation. falls.
Aeration may be prevented at the primary Manufacture of Emulsions. Time, temper¬
emulsion step if one phase is introduced into the ature, and mechanical work are the three varia¬
other in such a manner that splashing and bles in the manufacture of emulsified semisol¬
streaming are avoided. The incoming liquid ids. The three factors are interrelated and must
should enter the mixing ketde below the surface be carefully controlled if the same high-quality
of the other liquid, Vortexing and splashing are batches are to be manufactured repeatedly.
overcome by careful adjustment of the mixing Equipment is available for automatically con¬
conditions and liquid flow pattern. trolling many aspects of emulsion manufacture,
Completely enclosed kettles are available for such as the complete control of the temperature
the manufacture of semisolids, which tend to in the jacket and regulation of the mixing time
aerate excessively. The sealed vessels can be and rate of agitation: If the volume warrants the
operated under vacuum; mixing and emulsifica¬ cost, the entire operation can be automated. The
tion can then be performed without entrainment kettles must be thoroughly cleaned before re-use
of air. Loss of moisture and volatile substances because the presence of small quantities of for¬
may present problems, however, because of the eign contaminants or the residue from a previ¬
vacuum. ous batch may have an adverse effect on the sta¬
A closed system prevents aeration of the prod¬ bility and quality of the emulsion.
uct during homogenization or milling, and when
the material is transferred to the storage tanks,
vessels, or hoppers of the filling machines. Preparation of Oil and Aqueous
When an auger device or a wormdrive is used in
the hopper to deliver the material to the tube or Phases
jar at the filling outlet, the hopper must be kept The components of the oil or fat mixture are
full of product, or the rotation of the auger will placed into a stainless steel steam-jacketed ket¬
drive air into the semisolid. de, melted, and mixed.
Rheologic Changes. Homogenization fre¬ Some of the solid components (e.g., stearic
quently increases the consistency of a semisolid acid, cetyl alcohol) are available in many differ¬
emulsion because it increases the number of ent forms: cakes, flakes, or powder. The flakes
emulsified particles. It can also have the oppo¬ are preferable because of the convenience of
site effect, that of decreasing the viscosity of the handling. The powder may have occasional fine
product owing to an electrolyte effect. Some metal contaminants from the pulverizing equip¬
products retain their viscosity if they are not ment. Petrolatum is inconvenient to handle un¬
homogenized. Consistency also is affected by less it is melted and transferred by pumping or
the number of passes through the homogenizer, pouring from its drum. Transfer of large quanti¬
the pressures used for homogenization with the ties of petrolatum is expedited by heating the
valve-type homogenizer, or the clearance be¬ petrolatum in the steel drum in which it is re¬
tween the rotor and stator if a colloid mill is ceived from the supplier by means of immersion
used. heaters, or by placing the drums in a hot room
Some commercial creams are sensitive to agi¬ (60 to 62°C) until the petrolatum is fluid. The
tation and stress. The continuous rotation of an liquefied petrolatum can then be transferred to
auger in the hopper of the filling machine may the mixing kettle by metering pump through
cause a cream to liquefy. Such creams may be metal-reinforced inert plastic hoses and insu¬
made more resistant to agitation by a formula lated pipes. The oil phase is then strained
change; however, the soft and easy spreading through several layers of cheese cloth to remove
properties of the cream on the skin may then be any foreign matter. Alternatively, the petrolatum
lost. The replacement of the auger by another, can be passed through a filter medium, particu¬
gentler feeding device is of value. larly for an ophthalmic preparation. The oil
Fusion Method. Anhydrous ointments are phase is transferred by gravity or pump to the
manufactured by the fusion process. The active emulsion mixing kettle whose walls have been

SEMISOLIDS • 555
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Table 18-8. Commercial Antioxidants
Common name BHA BHT propyl gallate
Chemical name (Butylated hydroxyanisole) (Butylated hydroxytoluene)
3-t-butyl-4-hydroxyanisole 3,5-di-5-butyl-4-hydroxytoluene alkyl gallate
2-t-butyI-4-methoxyphenol 2,6-di-t-butyl-4-methylphenol
Melting point 55°-60°C 70°C 150°C
Solubility at 25°
in % [approx.]
Propylene glycol 70 insoluble 55
Peanut oil 40 30 0.5

Modified from Rosenwald, R.H.: Am. Perf. Cos., 78:41, 1963.

heated to the temperature of the oil phase to pre¬ disperse or aqueous phase in an oil-in-water
vent some of its higher-melting components emulsion is added slowly to the inner phase with
from congealing. The components of the aque¬ agitation. The initial low concentration of water
ous phase are dissolved in the purified water in relation to the concentration of oil results in
and filtered. A soluble drug may be added to the the formation of a water-in-oil emulsion. The
aqueous phase at this time, provided the high viscosity of the emulsion continues to increase
temperature does not degrade the active sub¬ as more water is added, and the volume of the oil
stance or the emulsion is not adversely affected; phase also increases up to a point of its maxi¬
otherwise, the soluble drug may be added in so¬ mum expansion. Beyond this point, the viscosity
lution after the emulsion has formed and has decreases, and emulsion inversion is said to
cooled. occur. The phases reverse themselves, and the
Mixing of Phases. The phases are usually inner phase is finely dispersed.
mixed at a temperature of 70 to 72°C, because at Batch sizes are on a weight basis, which is
this temperature intimate mixing of the liquid independent of variations in temperature and
phases can occur. The phase mixing tempera¬ density. To measure the weight in a kettle, load
ture can be lowered a few degrees if the melting cells are placed onto the bases of the manufac¬
point of the fat phase is low enough to prevent turing kettle. The kettle exerts a pressure on the
the premature crystallization or congealing of its cell, which is transmitted by means of a hydrau¬
components. Decreasing the temperature at lic force exerted by a layer of oil seated on a dia¬
which the phases are mixed decreases the cool¬ phragm and can be read on a dial or recorded.
ing time, which is a significant factor when the Figure 18-3 is a schematic presentation of a load
batch size is large. The properties of some emul¬ cell. Figure 18-4 is a photograph of a manufac¬
sions (borax-beeswax type) depend on the tem¬ turing kettle resting on a load cell.
perature at which the phases are mixed. The ini¬ Cooling the Semisolid Emulsion. Follow¬
tial mixing temperature must be raised above 70 ing the addition of the phases, the rate of cooling
to 72°C, because intimate mixing of the compo¬ is generally slow to allow for adequate mixing
nents at monolayer levels cannot occur, since while the emulsion is still liquid. The tempera¬
the emulsion that forms immediately has a high ture of the cooling medium in the kettle jacket
viscosity. The phases can be mixed in one of should be decreased gradually and at a rate con¬
three ways: (1) simultaneous blending of the sistent with the mixing of the emulsion and
phases, (2) addition of the discontinuous phase scraping of the kettle walls to prevent formation
to the continuous phase, and (3) addition of the of congealed masses of the ointment or cream,
continuous phase to the discontinuous phase. especially when the semisolid contains a large
The simultaneous blending of the phases re¬ percentage of high-melting substances. Figure
quires the use of a proportioning pump and a 18-5 is a photograph of a manufacturing kettle
continuous mixer. This method of emulsifica¬ showing agitator and sweep blades. Aeration
tion is satisfactory for continuous or large-batch may occur if the semisolid thickens considerably
operation. The second method may be used for upon cooling, and steps should be taken to pre¬
emulsion systems that have a low volume of dis¬ vent this. If perfume is to be added to an oil-in-
persed phase. The third process is preferred for water emulsion, it is best done while the mix¬
many emulsion systems, since the emulsions ture is at a temperature of 43 to 45°C to avoid
undergo an inversion of the emulsion type dur¬ chilling the emulsion and to facilitate dissolu¬
ing the addition of the continuous phase, which tion of the perfume oil in the still incompletely
results in a finer dispersed phase globule. The congealed oil phase. The perfume may be added

558 • The Theory and Practice of Industrial Pharmacy

 prior to removing the semisolid from the kettle
for homogenization and/or storage. Figure 18-6
shows a Gifford-Wood homomixer after it has
been withdrawn from a kettle used for dispers¬
ing solids. The cooling of the semisolid stored in
a large covered vessel is not uniform, since cool¬
ing is more rapid at the surface or the walls of
the container. Hence, variation in physical prop¬
erties of the semisolid may occur, such as differ¬
ences in the size of the fat and wax crystals and
the dispersed globules.
Adjustment of the final water content of a
water-in-oil emulsion is not easy once the emul¬
sion has been formed. Several batch runs help to
determine the amount of water lost on heating
in the particular process, and this lost water
FIG. 18-3. Schematic diagram of a cross-section of a hy¬
should be added to the required amount at the
draulic load cell. The hydraulic load cell is a frictionless
piston and cylinder assembly u/ith a fixed acting'area. It is start of manufacture. The oil film surrounding
specifically designed for the conversion of force or weight each emulsified water droplet in a water-in-oil
into a proportional hydraulic pressure. This pressure may emulsion tends to retard evaporation, so that
be connected to a dial indicator, a recorder, a controller, or water loss is not excessive following this type of
transducers. (Courtesy of the A. H. Emery Company, blew emulsification.
Canaan, CT.)

near room temperature to a water-in-oil emul¬ Low-Energy Emulsification

sion, since dissolution of the perfume oils is to The high cost of energy has prompted re-
occur in the outer phase of the system. evaluation of manufacturing procedures in an
The drug is added in solution form, if not al¬ attempt to limit the amount of thermal and me¬
ready incorporated, or as crystals, provided it is chanical energy expended in the production of
soluble in the external phase. An insoluble pow¬ emulsions. It has been shown that the use of a
der should be dispersed in the continuous phase minimum amount of the emulsion phase in the

FIG. 18-4. Photograph of a load cell set under one of the legs of a manufacturing kettle. (Permission ofCiba-Geigy Corp.)

semisolids • 559
FIG. 18-5. Stainless steel jacketed mixing kettle equipped with a slow-speed. anchor-type sweep blade agitator which
takes the material from the side wall and swirls it around the secondary, bur type mixer. The bar-type mixer rotates at a
higher speed and directs the flow of material downward for thorough agitation. (Permission of Ciba-Gcigy Corp.)

emulsification stage can result in a considerable dilution stage. The savings in energy could be
reduction in energy requirements and process¬ considerable.
ing time without compromising the quality of' The quality, stability, rheologic properties,
the product. The major cost saving is achieved and the particle size distribution of the internal
by heating both the oil phase and a portion of phase of the finished product prepared by this
water or external phase to the required tempera¬ process depend on several variables. These in¬
ture to form a concentrated emulsion. The bal¬ clude the temperature required for forming the
ance of the aqueous phase is added at room tem¬ concentrated emulsion, the ratio of the external
perature during the cooling state. Thus, the phase to the internal phase forming the concen¬
energy used to heat the aqueous phase and the trated emulsion, the phase inversion tempera¬
mechanical energy of mixing during the cooling ture, the type and intensity of mixing, and the
stage are reduced. rate of addition of the external phase.50,51
Figure 18-7 illustrates the usual method of Homogenization. The creams or ointments
emulsion manufacture. The internal phase of an that require further treatment are then trans¬
oil-in-water emulsion usually consists of fats, ferred or pumped to the proper homogenizer, the
waxes, preservative, and perhaps an emulsifier. selection of which is governed by the degree and
The external phase contains the water-soluble rate of shear stress required. The choices in¬
substances. Both are heated to a high tempera¬ clude a low-shear gear pump, a roller mill, a col¬
ture and then mixed to form an emulsion. The loid mill, a valve-type homogenizer, and a suita¬
emulsion is then cooled. The low-energy ble sonic homogenizer. Uniform dispersion of an
method, illustrated in Figure 18-8, shows that a insoluble drug in a semisolid, as well as reduc¬
major portion of the aqueous phase, which may tion of the size of the fatty aggregates can be
be as much as 70%, can be added at the cool attained by the passage of the warm (30 to 40°C)

560 • The Theory and Practice of Industrial Pharmacy

ointment or cream through a homogenizer or has been packaged. These preliminary quality
mill.
control tests are time-consuming and delay the
Storage of Semisolids. Unless rapid in- packaging process; however, it is less costly to
process methods of analysis are developed, it is wait for the assay and to store the material until
the usual practice to store the semisolid until the it can be scheduled for filling than to package
specified quality control tests have been com¬
and then perhaps be compelled to empty the
pleted before packaging into appropriate con¬ containers to recover the material, should the
tainers: tubes, jars, or single-dose packets. A
semisolid fail to meet the established specifica¬
product is considered to be “in-process” until it tions for the product. Some semisolids have a

SEMISOLIDS • 561
 operation, or pumped to the filling equipment. It
must be able to resist the shear stress developed
in the transfer of the product, as well as that due
to the mechanical action of the filling equip¬
ment.
Once a formal manufacturing procedure has
been established, there should be no deviation
from it. If a change is necessary, however, the
problem should be carefully re-evaluated, first in
the research and development laboratory and
then at the pilot plant and manufacturing level.
Although the design and the evaluation of
semisolids usually does not include the equip¬
ment cleaning operation following the manufac¬
ture and filling of the product, it is mandatory
that the cleaning operation be thorough to avoid
FIG. 18-7. Conventional emulsion processing. (Modified any contamination between batches. Cleaning
from Lin, T.J.: J. Soc. Cosm. Chem., 29:745, 1978.) of large-scale equipment is facilitated and labor
costs and downtime of equipment can be re¬
tendency to “set up” or exhibit an increase of duced through the use of high-pressure (up to
viscosity on storage, and such products cannot 1000 psi), low-volume pump systems now avail¬
be stored for any length of time. The industrial able. The cutting force of high-pressure hot
pharmacist must be aware of the delays caused water that may contain detergent can be applied
by quality control requirements and packaging like a knife edge to clean difficult-to-reach tight
schedules, so that he can develop formulations spots inside kettles and tanks and a variety of
that tolerate storage in bulk without undergoing manufacturing and processing equipment, elim¬
marked changes in consistency which might inating old-fashioned manual scrubbing.
cause filling problems. The active substance in Homogenizers, pumps, and filling equipment
the cream or ointment may react with the stor¬ that have areas wherein pockets of water or
age container unless a highly resistant #316, product may accumulate and that are ordinarily
stainless steel, is used for bulk storage. Evapora¬ inacessible must be completely disassembled,
tion of water from a cream must be retarded; this cleaned, sanitized, and dried before reassembly.
can be effectively accomplished by placing non¬ Ball valves and sanitary (Ladish) type or sanitary
reactive plastic sheeting in direct contact with threaded piping should be used throughout. The
the cream, as well as covering the storage con¬ packing material used as lubricant for the shafts
tainer with a tight-fitting stainless steel lid. of mixers should also be replaced during the
Transfer of Material For Packaging. The cleanup process if there is any possibility that
semisolid may be gravity fed, if it is a two-level they may harbor microorganisms. The manufac-

EXTERNAL EXTERNAL
INTERNAL PHASE PHASE
PHASE PART (1) PART (2)

CONCENTRATED FINISHED
■>
EMULSION EMULSION

FIG. 18-8. Low-energy emulsion processing. (Modified from Lin, T.J.: J. Soc. Cosm. Chem., 29:745, 1978).

562 • The Theory and Practice of Industrial Pharmacy

turing and packaging equipment should be sani¬ 22. Franks, A.J.: Soap, Perf. and Cosm., 37:221, 319,
tized following thorough cleaning with deter¬ 1964.
23. CTFA Cosmetic Ingredient Dictionary. 2nd Ed. The
gents. They should be flushed with chlorinated Cosmetic, Toiletry and Fragrance Association, Inc.,
water, formalin, or other suitable sterilant fol¬ Washington, DC.
lowed by a bacteria-ffee water rinse. Water and 24. The Rose Sheet. FDC Reports. Washington, DC,
swab samples should be taken to verify micro¬ 2(37), Sept. 14, 1981, p. 8.
bial elimination. 25. Ciullo, P.A.: Drug and Cosm. Ind., 126:50, 1980.
26. Shefter, E., and Higuchi, T.: J. Pharm. Sci., 52:781,
1963.
27. United States Pharmacopoeia XX, Mack Publishing
Co., Easton, PA, 1980.
28. Mendes, R.W., Morris, R.N., and Brown, E.T.: Drug
Cosm. Ind., 95:34, 1964.
References 29. Abrutyn, E.: Drug and Cosm. Ind., 126:46, 1980.
1. Flynn, G.L.: Percutaneous absorption. In Modem 30. Strianse, S.J.: Hand creams and lotions. In Cosmet¬
Pharmaceutics. Edited by G.S. Banker and C.T. ics: Science and Technology. Edited by E. Sagarin.
Rhodes. Marcel Dekker, New York, 1979. Interscience, New York, 1957.
2. Scheuplein, R.J., and Blank, I.H.: Physiol. Rev., 31. Bruch, C.W.: Drug and Cosm. Ind., Ill:51, 1972.
51:762, 1971. 32. Bruch, C.W.: Drug and Cosm. Ind., 110:32, 1972.
3. Scheuplein, R.J.: J. Invest. Derm., 46.334, 1965. 33. Kazmi, S.J.A., and Mitchell, A.G.: J. Pharm. and
4. Blank, I.H.: J. Invest. Derm., 18:433, 1952. Pharmacol., J6:533, 1964.
5. Blank, I.H., Gould, E., and Theobald, A.B.: J. Invest. 34. Garrett, E.R.: J. Pharm. and Pharmacol., 18:589,
Derm., 42:363, 1964. 1966.
6. Wurster, D.E., and Kramer, S.F.: J. Pharm. Sci., 35. Kazmi, S.J.A., and Mitchell, A.G.: Soap, Perf. and
50:288, 1961. Cosmetics., 45:549, 1972.
7. Winsor, T., and Burch, G.E.: Arch. Intern. Med., 36. Microbiological Limit Guidelines for Cosmetics and
74:428, 1944. Toiletries. Revised Aug. 18, 1972. The Cosmetic, Toi¬
8. Onken, H.D., and Moyer, C.A.: Arch. Derm., 87:584, letry and Fragrance Association, Inc., Washington,
1963. DC.
9. Stoughton, R.B.: Arch. Derm., 91:657, 1965. 37. Standard Methods for the Examination of Waste and
10. Sweeney, T.M., and Downing, D.T.: J. Invest. Derm., Waste Water. 13th Ed. American Public Health Asso¬
55:135, 1970. ciation, New York, 1971.
11. Woodboume, R.T.: Essentials of Human Anatomy, 38. Federal Register, 43(122), June 23.1978, part 221. p.
Oxford University Press, New York, 1965. 27482.
12. Scheuplein, R.J.: j. Invest Derm., 48:79, 1967. 39. Evans, J.R., GUden, M.M., and Bruch, C.W.: J. Soc.
13. Schutz, E.: Arch. Exp. Path. Pharmacol., 232:237, Cosm. Chem., 23:549, 1972.
1957. 40. Federal Register, 36:601, 1971.
14. Poulsen. B.J., Young, E., Coquilla, V., and Katz, M.: J. 41. Baur, F.J. (ed.): Sanitary design principles. Food Pro¬
Pharm. Sci., 57:928, 1968. cessing, January 1973.
15. Coldman, M.F., Poulsen, B.J., and Higuchi, T: j. 42. Marcus, E., Kim, H.K., and Autian, J.: J. Am. Pharm.
Pharm. Sci., 58.T098, 1969. Assoc., Sci. Ed., 48:457, 1958.
16. Busse, M.J., Hunt, P., Lees, K.A., et al.: Brit. J. 43. Barkley, E.L.: Am Perf. Aromat., 73:33, 1959.
Derm., 81:103, Suppl. 4, 1969. 44. Patel, N.K., and Kostenbauder, H.B.: J. Am. Pharm.
17. Poulsen, B.: Brit. J. Derm., 82:49, Suppl. 6, 1970. Assoc., Sci. Ed., 47:289, 1958.
18. Nugent, F.J., and Wood, J.A.: Canad. J. Pharm. Sci., 45. Blaug, S.M., and Ahsan, S.S.: J. Pharm. Sci., 50:441,
15:1, 1980. 1961.
19. Tregear, R.T.: The permeability of the skin to mole¬ 46. Charles, R.D., and Carter, P.J.: J. Soc. Cosm. Chem.,
cules of widely differing properties: In Progress in the 10:383, 1959.
Biological Sciences in Relation to Dermatology-2. 47. Boehm, E.E., and Maddox, D.N.: Amer. Perf. and
Edited by A. Rook. University Press, Cambridge, Cosm., 85:31, 1970.
1964, p. 275. 48. Berke, P.A., and Rosen, W.E.: J. Soc. Cosm. Chem.,
20. Tregear, R.T.: Physical Functions of the Skin. Aca¬ 32:37, 1980.
demic Press, New York, 1966. 49. Orth, D.S.: J. Soc. Cosm. Chem., 30:321, 1979.
•21. Food and Color Additives Directory. Hazelton Labora¬ 50. Lin, T.J.: J. Soc. Cosm. Chem., 29:117, 1978.
tories, Inc., Falls Church, VA. 51. Lin, T.J.: J. Soc. Cosm. Chem., 29:745, 1978.

semisolids • 563
 19

Suppositories
LARRY J. COBEN and HERBERT A. LIEBERMAN

A suppository is a medicated solid dosage form dose is given for all but very potent drugs. The
generally intended for use in the rectum, vagina, range in dose can be attributed to the availability
and to a lesser extent, the urethra. Rectal and of the drug from the particular suppository base
urethral suppositories usually employ vehicles used. The correct dose for any drug dependson
that melt or soften at body temperature, whereas the rate of release of the drug from the supposi¬
vaginal suppositories, sometimes called pes¬ tory. As a consequence, the suppository base and
saries, are also made as compressed tablets that the amount of drug must be considered concom¬
disintegrate in the body fluids. itantly. Since the vehicle can change the rate of
Oleum Theobromae was first recommended to drug absorption, the amount of drug to be given
American pharmacists by A. B. Taylor in 1852, in suppository form depends on the vehicle and
and it soon grew in popularity as the suppository the chemical and physical form of the drug
base of choice. Glycerinated gelatin mixtures did given.
not appear as suppository vehicles until about Rectal suppositories for adults weigh about
1875. In 1913, Bruno Solomon published a criti¬ 2 g and axe usually tapered to resemble a tor¬
cal study of suppository bases, in which he clas¬ pedo shape. Children’s suppositories weigh
sified them into three broad types: (1) cocoa but¬ about 1 g and have a corresponding reduction in
ter, (2) fat and wax combinations with cocoa size. Vaginal suppositories weigh about 3 to
butter, and (3) glycerinated gelatin bases. 5.0 g and usually axe molded in the globular or
In the 1930s, several unwanted side effects oviform shape, or compressed on a tablet press
and disadvantages inherent to oral therapy fo¬ into modified conical shapes. Urethral supposi¬
cused attention, principally in Europe, on the tories, sometimes called bougies, axe pencil¬
rectal route for administering drugs. Industrial shaped and pointed at one extremity. Urethral
concerns, principally in Germany and France, suppositories intended for males weigh about
synthesized special hpid excipients, which were 4 g each and are 100 to 150 mm long; for fe¬
designed to replace cocoa butter. Water-soluble males, they are 2 g each and usually 60 to
polyethylene glycol type bases were introduced 75 mm in length. Figure 19-1 illustrates a repre¬
as an improvement on glycerinated gelatin and sentative sampling of several commercially
lipid type suppository bases. available suppositories.
For the combined prescription and over-the-
counter market, suppositories represent about
1% of all medications dispensed in the United Therapeutic Uses
States. The suppository is a far more popular Drugs may be administered in suppository
medication in Europe and South America than form for either local or systemic effects. Such
in the United States. action depends on the nature of the drug, its
concentration, and the rate of absorption. Emol¬
lients, astringents, antibacterial agents, hor¬
Dose Characteristics mones, steroids, and local anesthetics are dis¬
Opinion is mixed concerning the amount of pensed in suppository form for treating local
drug that should be given rectally as compared conditions of either the vagina, rectum, or ure¬
with the oral dose. In general, for rectal adminis¬ thra.
tration, one-half to two or more times the oral Many articles have been published recently

564
FIG. 19-1. Types and shapes of suppositories.

on the use of prostaglandin-containing vaginal the digestive juices, or their therapeutic activity
suppositories for interruption of early preg¬ is modified by the liver after absorption. After a
nancy. drug is absorbed from the small intestine, the
Rectal suppositories are primarily intended for drug is carried by the hepatic portal vein to the
the treatment of constipation and hemorrhoids. liver. The liver modifies many drugs chemically
Suppositories are also administered rectally for and thereby often reduces their systemic effec¬
systemic action. A wide variety of drugs are tiveness. On the other hand, a major portion of
employed, e.g., analgesics, antispasmodics, sed¬ the same drugs can be absorbed from the ano¬
atives, tranquilizers, and antibacterial agents. rectal area and still retain therapeutic values.
Rectal suppositories are also utilized for sys¬ The lower hemorrhoidal veins surrounding the
temic actions in conditions where oral medica¬ colon and rectum enter into the inferior vena
tion would not be retained or absorbed properly, cava and thus bypass the liver. The upper hem¬
such as during severe nausea and vomiting or in orrhoidal vein does connect with the portal veins
paralytic ileus. leading to the liver. More than half (50 to 70%)
of rectally administered drugs were reported
absorbed directly into the general circulation.1
Factors Affecting Drug
The lymphatic circulation helps also in absorb¬
Absorption from Rectal ing a rectally administered drug and in diverting
Suppositories the absorbed drug from the liver.2
The pH of the rectal mucosa plays a signifi¬
cant rate-controlling role in drug absorption.
Physiologic Factors Schanker reported that the rat colon has a pH of
A number of drugs cannot be administered approximately 6.8, a pH slightly more acidic
orally, because either the drugs are affected by than previously believed.3 Rectal fluids have vir-

SUPPOSITORIES • 565
tually no buffer capacity, and as a consequence, nous wall is covered with a relatively continuous
the dissolving drugs determine the pH existing mucous blanket, which can act as a mechanical
in the anorectal area. Schanker states that barrier for the free passage of drug through the
weaker acids and bases are more readily ab¬ pore space where absorption occurs.
sorbed than the stronger, highly ionized ones. Drugs absorbed from the small and large in¬
These findings suggest that the barrier separat¬ testines would most likely be absorbed from the
ing the colonic lumen from the blood is prefer¬ anorectal area. The similarity in the patterns of
entially permeable to the un-ionized forms of drug absorption from the small and large intes¬
drugs. Thus, the absorption of a drug would be tines makes it unlikely that a drug that has
enhanced most likely by a change in the pH of passed through the small intestine would be sig-
the rectal mucosa that would increase the pro¬ nificandy absorbed from the colon.5 Conversely,
portion of un-ionized drug. The effect of intra¬ a drug that can be absorbed from the colon most
luminal pH on the absorption of several acidic likely would have been completely absorbed in
and basic drugs is shown in Table 19-1. the' small intestine before reaching the colon.
As shown in Table 19-1, absorption of acidic It should be recognized that although average
drugs was markedly increased when the pH of body temperature is 37°C, patient temperatures
the surrounding fluids was lowered. The absorp¬ may vary from 36 to 38°C, owing to daily and
tion of salicylic acid rose from 12% at a pH of monthly cycles. The suppository formulator
approximately 7 to 42% at pH 4. In contrast, must bear in mind the lower limit as a “worst
with a basic drug like quinine, which becomes case.”
more ionized at the lower pH values, absorption
was decreased from 20% at pH 7 to 9% at pH 4.
Phenol is a weak acid and is almost completely Physicochemical Characteristics
un-ionized at both pH 7 and pH 4. Conse¬
quently, there was litde change in absorption of the Drug
when the pH was lowered. The sequence of events leading to drug ab¬
Riegelman and Crowell have demonstrated sorption from the anorectal area can be
that one of the rate-limiting steps in drugs ab¬ diagramatically represented as follows:
sorption is the diffusion of the drug to the site on
the rectal mucosa at which absorption occurs. Drug in vehicle-* Drug in colon fluids
This diffusivity is influenced not only by the na¬ -* Absorption through the rectal mucosa
ture of the medicament, such as the presence of
surfactant or the water-lipoidal solubility of the In order for the drug to be available for absorp¬
drug, but also by the physiologic state of the tion, it must be released from the suppository
colon, that is, the amount and chemical nature and distributed by the surrounding fluids to
of the fluids and solids present. sites of absorption. By dissolving in the fluids,
The state of the anorectal membrane also there is wide contact of the drug with the lumen
plays a role in drug absorption.4 This membra- walls, thereby increasing drug contact with a
large number of absorption sites. If the drug has
a lipid-water coefficient favoring fat solubility,
Table 19-1. Effect of Intraluminal pH on Ab¬ the drug is released slowly from its suppository
sorption from the Rat Colon excipient. Allawala and Riegelman report that a
drug that is very soluble in cocoa butter and
pH of the Perfusion
present in low concentration does not escape to
Solution
the surrounding aqueous solution as readily as
Drug pKa 6.8-7.2* 3.6-4.0f the drug that is slightly soluble in the cocoa but¬
ter vehicle and present at levels at or close to
Acid % Absorbed % Absorbed saturation.6 Thus, water-soluble, oil-insoluble
Salicylic 3.0 12 42 ±3 salts are preferred in fat-base suppositories. For
Benzoic 4.2 19 50 ±7
water-soluble suppository type bases, from
Phenol 9.9 36 37 ± 1
which the drug is released as the vehicle dis¬
Base solves, the water-soluble type salt is the one of
Aniline 4.6 44 32 ±5 choice for quicker drug absorption. For example,
Quinine 8.4 20 9 ± 1 to increase the absorption rate from supposito¬
ries, ephedrine sulfate and quinine hydrochlo¬
“The solution, which entered the colon with a pH of 7.2 and left
with a pH of 6.8, is a weakly buffered saline solution. ride, as well as sodium barbital and sodium sa¬
tThis highly buffered solution entered the colon with a pH licylate, are preferred to their corresponding
of 3.6 and left with a pH of 4.0. bases and acids.

566 • The Theory and Practice of Industrial Pharmacy

 The rate-limiting step in drug absorption from nium compounds and sulfonic acid derivatives
suppositories is the partitioning of the dissolved are poorly absorbed. Un-ionized substances that
drug from the melted base and not the rate of are lipid-insoluble also are poorly absorbed.3
solution of the drug in the body fluids. Riegel- The relation between the degree of ionization
man and Crowell have shown that the rate at and the rate of absorption of drugs is illustrated
which the drug diffuses to the surface of the in Table 19-1. Weak acids with a pKa below 4.3
suppository, the particle size of the suspended and weak bases with a pKa below 8.5 are usually
drug, and the presence of surface-active agents readily absorbed.3 Highly ionized compounds
are factors that affect drug release from supposi¬ are poorly absorbed. Acids having pKa values
tories.4 Solution of the drugs in solid polyethyl¬ below 3.0 and pKa values for bases above 10.0
ene glycol and oleaginous bases resulted in pro¬ (quaternary ammonium salts) indicate negligi¬
longed absorption times, because the drug is ble absorption rates. This relation suggests that
slowly eluted into the surrounding fluids. As the anorectal and colonic mucosae are selec¬
would be expected, the larger the particle size, tively permeable to the uncharged drug mole¬
the slower the rate of solution, and as a conse¬ cule, whereas the ionized drugs penetrate the
quence, the drug absorption rate is decreased mucosa poorly or negligibly. Thus, drug absorp¬
with an increase in drug particle size. Surfac¬ tion can be increased by the use of buffer solu¬
tants can both increase and decrease drug ab¬ tions or salts that convert the pH of the anorectal
sorption rate. For instance, in the case of sodium area to a value that increases the concentration
iodide, absorption is accelerated in the presence of un-ionized drug.
of surfactants and appears to be proportional to In summary, absorption of drugs from the
the relative surface tension lowering of the vehi¬ anorectal area is affected by such physiologic
cle. In addition, Riegelman and Crowell state factors as colonic contents, circulation, pH, lack
that the acceleration of sodium iodide absorption of buffering capacity, physiologic state, and the
might also be attributed to the mucus-peptizing mucous blanket on the lumen wall. The physico¬
action of the vehicle.4 The rectal membrane is chemical characteristics of drugs affecting ab¬
covered by a continuous mucous blanket, which sorption are the lipid/water partition coefficient
may be more readily washed away by colonic and the degree of ionization. When the amount
fluids that have reduced surface tension. The of drug in the rectal fluids is above the rate¬
cleansing action caused by the surfactant- determining level, marked increases in drug
containing vehicle may make additional pore concentration play no role in altering established
spaces available for drug absorption, thus facili¬ drug absorption rates. Drug concentration is re¬
tating drug movement across the rectal mem¬ lated, however, to release rates from suppository
brane barrier. In the case of phenol-type drugs, bases. The presence of surfactant may or may
absorption rate is decreased in the presence of not aid absorption, depending on concentration
surfactant, probably because of the formation of and possible interaction with the drug. Drug
a drug-surfactant complex. particle size is directly related to absorption rate.
Schanker showed that the absorption of sev¬
eral acid and base compounds in solution, as in a
retention enema, was not affected over a 10-fold Physicochemical Characteristics
range of concentration. In the case of the reten¬
tion enema, the absolute amount of drug ab¬ of the Base and Adjuvants
sorbed was directly proportional to the initial sat¬ Various properties of the suppository base can
uration concentration present and not to any affect drug absorption. Heinmann et al. reported
excess beyond this amount. If the luminal con¬ that with use of sodium phenobarbital, the ab¬
centration of drug is above a particular amount, sorption rate is faster from fatty bases having a
which varies with the drug, the rate of absorp¬ lower melting range than from those with higher
tion does not change with further increases in melting ranges.7 It was also shown that absorp¬
drug. Thus, colonic absorption of drugs is a mat¬ tion rate increases along with hydroxyl values.
ter of simple diffusion across the colonic mem¬ Pasich et al.,8 using polyethylene glycol bases,
brane. In suppositories, however, concentration showed a decrease in absorption time with in¬
does play a role in determining the rate of re¬ crease in the molecular mass of the polyethylene
lease of the drug from suppository bases. glycols (PEGs) used.
Once the drug is released from the supposi¬ Since fatty bases may harden for several
tory base and reaches the site of absorption on months after molding, this rise in melting range
the lumen wall, the lipid-soluble undissociated certainly would affect absorption (see “Exam¬
drug is the most readily absorbed form. Com¬ ples of Typical Stability Problems,” presented
pletely ionized drugs like quaternary ammo¬ later in this chapter).

SUPPOSITORIES • 567
 Adjuvants in the formula can affect drug ab¬
sorption through changes in the rheologic prop¬
erties of the base at body temperature, or by af¬
fecting the dissolution of the drug in the media
of the dosage form.
In emulsion type bases, it was shown that the
amount of water-soluble drug released increased
with the water content of the base, and that the
rate of drug released could be prolonged by the
addition of an aqueous polymer.9
Addition of hydrophobic colloidal silicon oxide
to fat base suppositories dramatically changed
the rheologic behavior of the mass.10
Salicylates were found to improve the rectal
absorption of water-soluble antibiotics in lipo¬
philic bases.11
Drug release from cylindric hydrogels of hy-
droxyethyl methacrylate decreased as increasing
percentages of the cross-linking agent ethylene
glycol dimethacrylate were used.12 (See “Un¬
usual Types of Suppositories,” in this chapter.)
FIG. 19-2. Plasma concentration of theophylline follow¬
ing single dose of theophylline mcmoethanolamine
(gamma per 100 ml). (From Rudolfo et al.13)
Blood Levels From Different
Dosage Forms
The literature is replete with conflicting infor¬ sorption of sodium iodide is slower by the rectal
mation concerning the effectiveness of drugs route than by the oral route, but varies consider¬
administered in suppository form. The informa¬ ably from one individual to another. Shichiri
tion is difficult to correlate because of different et al. reported increased intestinal absorption of
or inadequate methods for determining blood insulin from a suppository.15 Copsidas and
levels, the nature of the drug and the supposi¬ Ward-McQuaid found pentazocine suppositories
tory base, as well as the inability of many pa¬ equal in relief of moderate pain to pethidine in¬
tients to retain the suppository. In some studies, jections and saw less side effects with the sup¬
blood levels from suppositories were obtained, pository.16 Turrell, Marino, and Nerb report the
and in some of these studies, these blood levels same dosage requirement for sulfanilamide in
were considered therapeutically effective. glycerinated gelatin suppositories as in tablets.17
Rudolfo et al. reported on blood levels result¬ Higher concentrations of the sulfonamide are
ing from the oral, rectal, and intravenous ad¬ found in the blood following its administration
ministration of theophylline derivatives (Fig. by enema than by suppository. Thus, in some
19-2).13 Rectal retention enemas and intrave¬ cases, the suppository does yield effective thera¬
nous injections showed that these two routes are peutic blood levels, although the enema yields
similarly effective if allowance is made for the faster and higher concentrations of drug in the
approximately 30-min delay required for drug blood. To maintain the therapeutic effectiveness
absorption from the rectum. of a drug in a suppository requires, therefore, a
The fact that the rectum or colon is a depend¬ wise choice of both the drug salt and the suppos¬
able site for drug absorption seems well estab¬ itory base.
lished, but not all investigators agree that the
suppository dosage form yields therapeutically
adequate blood levels. Several investigators re¬ Types of Suppository Bases
port adequate absorption of drug from supposito¬ A variety of substances have been used as
ries. Enesco and co-workers made a comparative suppository bases throughout the history of
study on the absorption time of six drugs, medicine. Their uses and applications were
namely sodium salicylate, chloral hydrate, meth¬ prompted by availability rather than scientific
ylene blue, atropine, morphine, and sodium io¬ knowledge. More exacting requirements and
dide.14 The first five drugs are absorbed rectally specifications were applied, however, to this
more quickly and at therapeutically more effec¬ area of pharmaceutical dosage form in the past
tive levels than with oral administration. Ab- decades. The use of chemical and physical

568 • The Theory and Practice of Industrial Pharmacy

measurements has provided the yardsticks with
which to set standards for suppository7 bases, as
well as for the finished suppositories, and some
of these parameters are included with the bases
given in Table 19-2.
Specifications for suppository bases usually
include any number of the following.
1. Origin and Chemical Composition. A
brief description of the composition of the base
reveals the source of origin (i.e., either entirely
natural or synthetic, or modified natural prod-
uets)-and chemical makeup (i.e., compound, or
a well-defined or poorly elucidated mixture).
Physical or chemical incompatibilities of the
bas^ with the other constituents may be pre¬
dicted if the exact formula composition is
known, including preservatives, antioxidants,
and emulsifiers.
2. Melting Range. Since fatty suppository
bases are complex mixtures of triglycerides and
therefore do not have sharp melting points, their
melting characteristics are expressed as a range
indicating the temperature at which the fat
starts to melt and the temperature at which it is
completely melted. Although the “melting
range” is usually determined by the USP
FIG. 19-3. Typical solid-fat indices.
method, manufacturers of bases occasionally
use different methods for determining melting
characteristics, such as “Wiley melting point,” the milligrams of KOH that would neutralize the
“capillary melting point,” “softening point,” “in¬ acetic acid used to acetylate 1 g of fat.
cipient melting (or thaw) point,” and others.]S 5. Solidification Point. This value allows
3. Solid-Fat Index (SFI). From this graph prediction of the time required for solidifying the
of the percentage of solids versus temperature, base when it is chilled in the mold. If the inter¬
one can deteimine the solidification and melting val between the melting range and solidification
ranges of fatty bases as well as the molding char¬ point is 10°C or more, the time required for so¬
acter, surface feel, and hardness of the bases lidification may have to be shortened by aug¬
(see Fig. 19-3). menting refrigeration to produce a more effi¬
A base with a sharp drop in solids over a short cient manufacturing procedure.
temperature span proves brittle if molded too 6. Saponification Value. The number of
quickly. This type of base requires a reduced dif¬ milligrams of potassium hydroxide required to
ferential between mold temperature and mass neutralize the free acids and saponify the esters
temperature for trouble-free molding. Supposi¬ contained in 1 g of a fat is an indication of the
tory hardness can be determined by the solids type (mono-, di-, or tri-) glyceride, as well as the
content at room temperature. Since skin tem¬ amount of glyceride present.
perature is about 32°C, one can predict a product 7. Iodine Value. This value expresses the
that would be dry to touch from a solids content number of grams of iodine that reacts with
over 30% at that temperature. 100 g of fat or other unsaturated material. The
Since SFI is determined by dilatometry, possibility of decomposition by moisture, acids,
which necessitates melting the base to carry out and oxygen (which leads to rancidity in fats) in¬
measurements, this set of data is reflective only creases with high iodine values.
of the base immediately after molding and not of 8. Water Number. The amount of water, in
an equilibrium or hardened state. (See “Exam¬ grams, that can be incorporated in 100 g of fat is
ples of Typical Stability Problems,” in this chap¬ expressed by this value. The “water number”
ter.) can be increased by the addition of surface ac¬
4. Hydroxyl Value. This is a measure of tive agents, monoglycerides, and other emulsifi¬
unesterified positions on glyceride molecules ers.
and reflects the monoglyceride and diglyceride 9. Acid Value. The number of milligrams of
content of a fatty base. The number represents potassium hydroxide required to neutralize the

SUPPOSITORIES • 569
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570 • The Theory and Practice of Industrial Pharmacy

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574 • The Theory and Practice of Industrial Pharmacy

free acid in 1 g of substance is expressed by this heating, isomerize to an undesirable lowered
value. Low “acid values” or complete absence of melting point.
acid are important for good suppository bases. Cocoa butter is primarily a triglyceride, with
Free acids complicate formulation work, be¬ the predominant glyceride chains being oleopal-
cause they react with other ingredients and can mitostearin and oleodistearin. It is a yellowish-
also cause irritation when in contact with mu¬ white, solid, brittle fat, which smells and tastes
cous membranes. like chocolate. Its melting point lies between
30°C and 35°C (86°F to 95°F), its iodine value is
between 34 and 38, and its acid value is no
The Ideal Suppository Base higher than 4. Because cocoa butter can easily
melt and become rancid, it must be stored in a
The ideal suppository base may be described
cool, dry place and be protected from light.
as follows. (1) Having reached equilibrium crys¬
Cocoa butter exhibits marked polymorphism
tallinity, the majority of components melt at rec¬
(the property of existing in different crystalline
tal temperature 36°C but bases with higher
forms), a phenomenon probably attributable to
melting ranges may be employed for eutectic
the high proportion of unsaturated triglycerides.
mixtures, addition of oils, balsams, and supposi¬
Each of the different forms of cocoa butter has
tories intended for use in tropical climates.
different melting points, as well as different
(2) The base is completely nontoxic and nonirri¬
drug release rates. When cocoa butter is heated
tating to sensitive and inflamed tissues. (3) It is
above its melting temperature (about 36°C) and
compatible with a broad variety of drugs. (4) It
chilled to its solidification point (below 15°C),
has no metastable forms. (5) It shrinks suffi¬
immediately after returning to room tempera¬
ciently on cooling to release itself from the mold
ture this cocoa butter has a melting point of
without the need for mold lubricants. (6) It is
about 24°C, approximately 12° below its original
nonsensitizing. (7) It has wetting and emulsify¬
state. A knowledge of these polymorphic states is
ing properties. (8) The “water number” is high,
essential for an understanding of how uniform
i.e., a high percentage of water can be incorpo¬
drug release patterns can be obtained from sup¬
rated in it. (9) It is stable on storage, i.e., does
pository bases consisting primarily of cocoa but¬
not change color, odor, or drug release pattern.
ter.
(10) It can be manufactured by molding by ei¬
Cocoa butter is thought to be capable of exist¬
ther hand, machine, compression, or extrusion.
ing in four crystalline states:
If the base is fatty, it has the following addi¬
tional requirements: (11) “acid value” is
1. The a form, melting at 24°C, is obtained by
below 0.2; (12) “saponification value” ranges suddenly cooling melted cocoa butter to 0°C.
from 200 to 245; (13) “iodine value” is less
2. The 0' form crystallizes out of the liquefied
than 7; (14) the interval between “melting cocoa butter with stirring at 18 to 23°C. Its melt¬
point” and “solidification point” is small or the
ing point lies between 28 and 31°C.
SFI curve is sharp.
3. The p' form changes slowly into the
A suppository base containing all of these stable p form, which melts between 34 and
properties has not been found. Indeed, some of 35°C. This change is accompanied by a volume
the properties are mutually exclusive and are
contraction.
not ideal in all situations. Often, the addition of
4. The y form, melting at 18°C, is obtained by
drugs changes the desirable characteristics of pouring a cool (20°C) cocoa butter, before it so¬
the base. Judicious formulation requires the use lidifies, into a container, which is cooled at deep¬
of the physical values described, for they help in freeze temperature.
the choice of the base for the drug.
The formation of the various forms of cocoa
butter depends on the degree of heating, on the
Cocoa Butter (Theobroma Oil) cooling process, and on conditions during this
Cocoa butter is the most widely used supposi¬ process. At temperatures below 36°C, negligible
tory base; it is often used in compounding pre¬ amounts of the unstable forms are obtained, but
scriptions when no base is specified. It satisfies prolonged heat above that critical temperature
many of the requirements for an ideal base, causes the formation of the unstable crystals
since it is innocuous, bland, and nonreactive, with resulting lowered melting points. The re¬
and melts at body temperature. Cocoa butter has conversion to the stable p form takes one to four
several disadvantages, however. It can become days, depending on the storage temperature—
rancid, melt in warm weather, liquefy when in¬ the higher the temperature, the faster the
corporated with certain drugs, and with over¬ change.

SUPPOSITORIES • 575
 The formation of the unstable forms can be is imperative to eliminate broad variations in
avoided by various methods. (1) If the mass is color and consistency between batches.
not completely melted, the remaining crystals
prevent the formation of the unstable form.
(2) Small amounts of stable crystals added to the
Cocoa Butter Substitutes
melted cocoa butter accelerate the change from The mechanization of suppository manufac¬
the unstable to the stable form; this process is ture, as well as the disadvantages inherent to
called “seeding.” (3) The solidified melt is tem¬ cocoa butter, have prompted a search for suita¬
pered at temperatures between 28 and 32°C for ble substitutes. The satisfactory ones maintain
hours or days, causing a comparatively quick the many desirable properties of cocoa butter,
change from the unstable to the stable form. and attempts are made to eliminate the objec¬
All of these properties of cocoa butter may tionable ones.
cause considerable difficulties in the manufac¬
turing process. As a general rule, the minimal
use of heating in the process of melting the fats Typical Treatment of Vegetable
is recommended. Prolonged heating must be Oils to Produce Suppository
avoided as much as possible. There are several
additional disadvantageous characteristics in¬ Bases
herent to cocoa butter as a suppository base. Fat-type suppository bases are produced from
Low contractility during solidification causes a variety of materials, either synthetic or natural
the suppositories to adhere to molds and neces¬ in origin. For example, such vegetable oils as
sitates the use of mold release agents or lubri¬ coconut or palm kernel oil are modified by ester¬
cants. ification, hydrogenation, and fractionation at dif¬
The solidification point of cocoa butter lies ferent melting ranges to obtain the desired prod¬
about 12 to 13° below its melting point. This uct.
property can be utilized in working with cocoa An inexpensive method involves hydrogenat¬
butter in suppository formulations, in which the ing com oil to reduce unsaturation and so in¬
mass can be kept in a fluid state at compara¬ crease the percentage of solid triglycerides at
tively low temperatures. Constant agitation room temperature. The triglycerides with lower
maintains cocoa butter liquid at temperatures melting points are then removed by solvent ex¬
below its solidification point. traction or by pressing. Manufacturers of fats
Cocoa butter does not contain emulsifiers and and oils refer to this type of product as a “hard
therefore does not take up large quantities of butter.”
water (maximum 20 to 30 g of water to 100 g of A common method of producing fats intended
cocoa butter). The addition of emulsifiers such for use as suppository bases involves interester¬
as Tween 61 (5 to 10%) increases the water ab¬ ification. In this process, coconut oil, palm ker¬
sorption considerably. Emulsifiers also help to nel oil, and/or palm oil (allrV*™-;"' for their high
keep insoluble substances suspended in the fat. content of lauric acid moieties) are refined to
Suspension stability is further obtained by the remove free fatty acids, deodorized to remove
addition of materials (aluminum monostearate, volatiles, hydrogenated as described previously,
silica) that give melted fats thixotropic proper¬ and then interesterified. This final step, cata¬
ties. There is always the possibility that the sup¬ lyzed by sodium methoxide, more equally dis¬
positories containing these additives will harden tributes the fatty acid moieties among the
on storage. Therefore, prolonged, careful stabil¬ glycerin molecules, creating more common tri¬
ity observations are recommended. glycerides, and therefore a more narrow melting
Such drugs as volatile oils, creosote, phenol, range.
and chloral hydrate lower the melting point of A third method utilizes re-esterification. First,
cocoa butter to a considerable extent. To correct the oil is split into fatty acids and glycerin by
this condition, wax and spermaceti were com¬ treatment with high-pressure steam. The glyc¬
monly used. Now special bases with high melt¬ erin is removed from the mixture, and the re¬
ing ranges are available for this purpose. Exam¬ maining free fatty acids consist of C6-C18 chain
ples of these bases can be found in Table 19-2. length compounds, namely caproic, caprylic,
The quality of cocoa butter varies with the ori¬ capric, lauric, myristic, palmitic, oleic, and ste¬
gin and treatment. Thus, it is quite possible to aric acids. Caproic, caprylic, and capric acids are
obtain different physical characteristics with removed by fractional vacuum distillation, be¬
two cocoa butters from different sources, al¬ cause they are readily rancidified and also may
though both are within all specifications of the cause irritation of mucous membranes. The
USP. The selection of a reliable source of supply remaining fatty acids, consisting mainly of Iau-

576 • The Theory and Practice of Industrial Pharmacy

ric acid, are hydrogenated to harden the mixture with gentle stirring, in the heated glycerin, after
and lower its iodine value. The catalyst used in which the purified water is added and mixed,
the hydrogenation process is removed, and then and the hot mixture is immediately poured into
the fatty acid mixture is re-esterified with an a suitable mold.
excess of glycerin to form a mixture of triglycer¬ In addition to the above official preparation,
ides, diglycerides, and monoglycerides. The USP XX also provided an unofficial formula for
manufacturer controls the re-esterification to glycerated gelatin suppositories:
build into the base the desired characteristics,
e.g., melting range, good mold release, smooth¬
Drug and purified water 10 g
ness, and viscosity. In the final steps, the base is
Gelatin 20 g
deodorized and purified by filtration. Glycerin 70 g
The solid-fat indices of bases produced by
these methods are illustrated in Figure 19-3.
Index A represents a typical hard butter. In¬ This formula is most often used in vaginal
dices B and C represent interesterified and re- suppositories, where local application of antimi¬
esterified products respectively. crobial agents is intended. The suppository dis¬
solves slowly to prolong the activity of the drug.
Because glycerin is hygroscopic, these supposi¬
Typical Suppository Bases tories are packaged in materials that protect
A number of suppository bases are available them from environmental moisture.
commercially, manufactured for specific pur¬ Glycerinated gelatin suppositories do not melt
poses. These bases are listed and described at body temperature, but rather dissolve in the
in 19-2. secretions of the body cavity in which they are
Certain characteristics are usually considered inserted. Solution time is regulated by the pro¬
in the selection of a suppository base: (1) a nar¬ portion of gelatin/glycerin/water used, the na¬
row interval between the melting and the solidi¬ ture of the gelatin used, and the chemical reac¬
fication points (e.g., melting point 34°C, solidifi¬ tion of the drug with gelatin.
cation point 32°C), which is useful in Glycerinated gelatin suppositories support
prescription pharmacy and in certain small- mold or bacterial growth, and as a consequence,
scale hospital and industrial formulations; they are stored in a cool place and often contain
(2) high melting ranges (37 to 41°C) for incorpo¬ agents that inhibit microbial growth.
rating drugs that lower melting points of bases—-
camphor, chloral hydrate, menthol, phenol, thy¬
mol, and several types of volatile oils—or for
formulating suppositories for use in tropical cli¬
The Polyethylene Glycols
mates; (3) low melting ranges (30 to 34°C) when The various polyethylene glycol polymers
the substances added to the suppository base or are marketed in the United States as Carbo-
large amounts of total solids increase the viscos¬ wax and Polyglycols and are suggested for use
ity of the melted suppository; (4) low acid values as suppository bases. Long-chain polymers
(below 3) and iodine values (below 7) which are of ethylene oxide have the general formula
essential characteristics for suppository bases HOCH2(CH2OCH2)xCH2OH and exist as liquids
intended for long shelf-life. when their average molecular weight ranges
from 200 to 600, and as wax-like solids when
their molecular weights are above 1000. Their
water solubility, hygroscopicity, and vapor pres¬
Hydrophilic Suppository Bases
sure decrease with increasing average molecular
weights. The wide range of melting points and
Glycerin Suppositories solubilities makes possible the formulation of
USP XX described the following formula for suppositories with various degrees of heat stabil¬
glycerin suppositories for use as a cathartic: ity and with different dissolution rates. They do
not hydrolyze or deteriorate, are physiologically
Glycerin 91 g inert, and do not support mold growth.
Sodium stearate 9 g Several combinations of polyethylene glycols
Purified water 5 g have been prepared for suppository bases having
To make approximately 100 g different physical characteristics. Examples of
these formulas can be illustrated by a few sug¬
The glycerin is heated in a suitable container to gested in the work of Collins, Hohmann, and
about 120°C. The sodium stearate is dissolved, Zopf.19

SUPPOSITORIES • 577
 Base 1 prepared suitably by hand rolling. Polyethylene
Polyethylene glycol 1000 96% glycol suppositories do not require a mold lubri¬
Polyethylene glycol 4000 4% cant and are easier to prepare than cocoa butter
suppositories.15
This base is low-melting and may require refrig¬ Disintegration times of polyethylene glycol
eration during the summer months. It is useful type suppository bases, measured in vitro by de¬
when rapid disintegration is desired. termining the rate of solution in water at body
temperature, do not coincide with the human
Base 2 in vivo results, measured by x-ray study of
suppositories containing barium sulfate. See
Polyethylene glycol 1000 75%
Table 19-3 for comparative results.19 Thus, clin¬
Polyethylene glycol 4000 25%
ical results seem the best criterion for choosing
the desired polyethylene glycol base, and in vitro
This base, more heat stable than Base 1, may be
test methods should be used for controlling
stored at higher temperatures than the previous
product uniformity of different production lots.
one. It is useful when a slow release of active
Reports of many workers on adverse reactions
ingredients is preferred.
of these polymers indicated little difference in
Bases 1 and 2, which do not contain water, are
sensitivity to individual bases, but a diminished
usually dipped in water before insertion, so that
reaction with the 6000 polymer. In one study,
possible irritation to mucous membranes may be
the problem of safety, sensitization, and chemi¬
eliminated. This irritation, or “sting,” is caused
cal inertness was attributed to impurities and
when the water is drawn from the mucosa. Most
not to the base itself.22
patients do not feel discomfort from the use of
these suppositories. Cheymol, Buffet, and
Lechat suggested the addition of 10% water to Water-Dispersible Bases
facilitate solution of the suppository after inser¬
tion.20 Several nonionic surface active materials,
closely related chemically to the polyethylene
The polyethylene glycol suppositories can be
glycols, have been developed as suppository ve¬
prepared by both molding and cold compression
hicles. Many of these bases can be used for
methods. A mixture of 6% hexanetriol-1,2,6
formulating both water-soluble and oil-soluble
with polyethylene glycol 1540, and 12% of the
drugs. The water-dispersible bases offer the ad¬
polyethylene oxide polymer 4000 are especially
ditional advantages of storage and handling at
suitable bases for the cold compression tech¬
elevated temperatures, with claims of broad
nique.3,21 The drug is incorporated by dissolving
drug compatibility, nonsupport of microbial
or dispersing in the molten base. Special precau¬
growth, nontoxicity, and nonsensitivity.
tions are necessary in preparing a molded sup¬
The surfactants most commonly used in sup¬
pository with the polyethylene glycol bases. The
mold must be dry because of the solubility of the pository formulations are the polyoxyethylene
base in water. The melted mass must be allowed sorbitan fatty acid esters (Tween’'), the
to cool almost to the congealing point before polyoxyethylene stearates (Myij*), and the sorbi-
pouring, or the resultant suppository will be fis¬ Ean-fatty acid esters (Span* and ArlaceP). These
sured owing to the crystallization and contrac¬ surface active 'agents may be used alone,
tion of the polymer. Such suppositories may be blended, or used in combination with other sup-
easily fractured in packaging or handling. The
polyethylene glycol base suppositories cannot be * Atlas Chemical Industries, Inc., Wilmington, DE.

TABLE 19-3. Comparison of In Vivo Solution Time to Th Vitro-Disintegration Time of Three

Suppository Bases

Solution Disintegration
Base Time Time

Polyethylene glycol 1000 13 min 15 min

Cocoa butter 3 min 3 min
A base made of:
Polyethylene glycol 1540—94%
Hexanetriol 1,2,6—6% 18 min 40 min

From Collins, A. P., Hohmann, J. R., and Zopf, L. E.: American Professional Pharmacist, 23:231, 1957.

578 • The Theory and Practice of Industrial Pharmacy

 pository vehicle materials to yield a wide range as carbon-dioxide-releasing laxative supposito¬
of melting points and consistencies. ries.31 These effervescent base tablets require a
Caution must be exercised in the use of sur¬ small amount of water for rapid disintegration.
factants with drugs. There are reports indicating This compressed rectal suppository is dipped in
increased rate of drug absorption,23-26 and other or sprayed with a thin coating of water-soluble
reports showing interaction of these surface ac¬ polyethylene glycol to add an external film for
tive agents with drugs and a consequent de¬ protection of the core and for aid in insertion
crease in therapeutic activity.4,6,23'27 Each for¬ into the rectum.
mulation must be tested in vivo to evaluate its Compressed tablets weighing about 3 g are
medicinal effectiveness, as well as its safety. used as vaginal suppositories. Fat base vaginal
Gross and Becker recommend a water- suppositories are sometimes rejected because of
dispersible, high-melting-point (50°C) supposi¬ the discomfort resulting from the seepage ob¬
tory base consisting of polyoxyethylene 30 stea¬ tained from suppositories with a water-insoluble
rate (Myij 51), water, white wax, and dioctyl base. The moisture level of the vagina is suffi¬
sodium sulfosuccinate (Aerosol OT*) 28 The use cient to allow ready dissolution of a tablet if it is
of the Aerosol OT in the formula is claimed to formulated to require minimum water for disin¬
lend synergism to the surfactant and thus aid in tegration.
the rapid disintegration of the suppository. The The compressed tablet for vaginal use is usu¬
drugs studied were phenobarbital, quinine hy¬ ally almond-shaped fo ease insertion and to pro¬
drochloride, tannic acid, and chloramphenicol. vide maximum surface area, which facilitates
Whitworth and Larocca studied, by in vivo tablet disintegration and hastens dispersion of
and in vitro methods, nineteen different formu¬ the drug on the vaginal wall. A typical vaginal
las for suppository bases.24 These suppositories tablet contains active ingredients, with lactose
contained hydrogenated cottonseed oil as the and/or anhydrous dextrose as excipients, and
main constituent and varying amounts of sur¬ boric and/or phosphoric acid(s) for adjusting the
factant to increase the release of a dye, which acidity of the vagina to approximately pH 5.
was intended to represent a drug. Judging from Vaginal suppositories are usually used for top¬
the rate of release of dye, the bases containing ical therapy, as in the treatment of vaginitis, or
35 to 40% of the emulsifying agents studied as a spermatocide. They also can be used for in¬
(combinations of Tweens, Tweens and Spans, troducing drugs with systemic effects.
and Tweens and Arlacel) gave best release.
Ward reports on several polyoxyethylene sor-
bitan derivatives (Tweens), which are designed Unusual Types of Suppositories
to melt at body temperature into liquids that dis¬ There is a patent that describes a layered sup¬
perse readily in the body fluids.29 A 2.5 g sup¬ pository comprising an outer shell that has a
pository consisting of Tween 61 (60%) and melting point of 37 to 38°C and a core that has a
Tween 60 (40%), and one of Tween 61 (90%) melting point of 34 to 35°C and that is contained
and glyceryl laurate (10%), melted at 37.5°C in within and completely surrounded by the
about 16 min. The combination of Tween 61 shell.32 Each layer contains different drugs. The
(85%) and glyceryl laurate (15%) melted in layering also may be accomplished by multi¬
about 12 min. layering the suppository in the horizontal plane.
Another type of water-dispersible suppository This is accomplished by partially filling the
vehicle reported is based on the use of water- mold, allowing the mass to congeal, and pouring
soluble cellulose derivatives,'sufch as methylcel- additional layers on those previously solidified.
lulose and sodium carboxymethflcellulose.30 Multilayered suppositories serve the dual pur¬
pose of separating incompatible drugs in differ¬
ent layers and providing different melting char¬
Compressed Tablet Suppositories acteristics for controlling the rate of drug
Rectal suppositories usually are not com¬ absorption.
pressed as tablets, because the amount of liquid Coatings have been applied to suppositories to
in the rectal cavity is inadequate for tablet disin¬ protect them from fast disintegration, to act as
tegration. Effervescent base tablets, which con¬ lubricants, and to prevent coalescing of adjacent
tain dried sodium biphosphate, sodium bicar¬ suppositories during storage. Polyethylene gly¬
bonate, and to further aid disintegration, starch col, cetyl alcohol, or a patented polyvinyl alcohol
or finely divided cellulose, have been described and Tween coating is applied for these purposes
by dipping the suppository in the coating solu¬
‘American Cyanamid and Chemical Coip., New York, tion until the desired coating thickness is ob¬
NY. tained.33

SUPPOSITORIES • 579
 r

Soft gelatin capsules of varying shapes, filled making suppositories in this manner are de¬
with either liquid or solid mixtures of the drug, scribed in basic pharmacy texts.
have been made for rectal and vaginal use. The cold compression method is simple and
Gstimer described a novel procedure for mak¬ results in a more elegant appearance than does
ing suppositories.34 Solutions of either gelatin, hand molding. It avoids the possibilities of sedi¬
alginates, cellulose derivatives, polyvinylpyrroli¬ mentation of the insoluble solids in the supposi¬
done, or silicates mixed with the desired active tory base, but is too slow for large-scale produc¬
ingredients are poured into the appropriately tion. One of the major disadvantages in the use
shaped molds and lyophilized. The resultant of the cold compression technique for molding
suppositories are nonmelting, but readily dis¬ fat type base suppositories is air entrapment.
solve in body fluids. This unavoidable inclusion of air makes close
Rectal administration of a cylindrical hydrogel weight control impossible and also favors the
for 12-hour periods after it has been soaked in possible oxidation of both the base and active
an aqueous drug solution, followed by with¬ ingredients.
drawal and replacement by a second soaked cy¬
lindrical hydrogel, was described by DeLeede,
DeBoer, and Breimar.35 Use of an osmotic deliv¬ Pour Molding
ery system was also detailed.36 The most commonly used method for produc¬
ing suppositories on both a small and a large
scale is the molding process. First, the base ma¬
Manufacture of Suppositories terial is melted, preferably on a water or steam
Four methods are used in preparing supposi¬ bath to avoid local overheating, and then the ac¬
tories, namely molding by hand, compression, tive ingredients are either emulsified or sus¬
pour molding, and compression on a regular tab¬ pended in it. Finally, the mass is poured into
let press. cooled metal molds, which are usually chrome-
or nickel-plated.

Hand Molding
The simplest and oldest method of preparing a Automatic Molding Machine
suppository is by hand, i.e., by rolling the well-
The molding operations (pouring, cooling, and
blended suppository base containing the active removal) can be performed by machine. All fill¬
ingredients into the desired shape. The base is
ing, ejecting, and mold-cleaning operations are
first grated and then kneaded with the active fully automated. The output of a typical rotary
ingredients by use of a mortar and pestle, until
machine ranges from 3500 to 6000 suppositories
the resultant mass is plastic and thoroughly an hour.
blended. The active ingredients are usually
In the rotary molding machine, as illustrated
finely powdered, or dissolved in water, or some¬
in Figure 19-4, chrome-plated brass molds are
times mixed with a small amount of wool fat to
installed radially in the cooling turntable. First,
help incorporation with the suppository base.
the prepared mass is fed into a filling hopper
The mass is then rolled into a cylindric rod of
where it is continuously mixed and maintained
desired length and diameter, or into vaginal balls
at constant temperature. The suppository mold
of the intended weight. Starch or talcum powder
is lubricated by brushing or spraying and then
on the rolling surface and hands prevent the
filled to a slight excess. After the mass solidifies,
mass from adhering. The rod is cut into por¬
the excess material is scraped off and collected
tions, and then one end is pointed. This method
for re-use. All pumping and scraping units are
is practical and economical for the manufacture
heated electrically at controlled temperatures.
of small numbers of suppositories.
The cooling cycle is adjusted, as required by the
individual suppository mass, by adjusting the
speed of the rotary cooling turntable. The solidi¬
Compression Molding fied suppositories are moved to the ejecting sta¬
A more uniform and pharmaceutically elegant tion, where the mold is opened and the supposi¬
suppository can be made by compressing the tories are pushed out by steel rods. The mold is
cold-grated mass into a desired shape. A hand- closed, and then moved on to the spraying sta¬
turned wheel pushes a piston against the sup¬ tion for lubrication and a repeat of the cycle.
pository' mass contained in a cylinder, so that the Temperatures and output speeds are regu¬
mass is extruded into molds (usually three). lated to create optimal conditions for continu¬
Hand-operated instruments and procedures for ous, automatic production. Molds must be kept

580 • The Theory and Practice of Industrial Pharmacy

 carried on - a track through a cooling tunnel,
where scrape-off and ejection occur.

Packaging of Molded
Suppositories
Suppositories must be packaged so that each
suppository is overwrapped, or they must be
placed in a container in such a manner that they
do not touch each other. Staining, breakage, or
deformation by melting caused by jostling or
adhesion can result from poorly wrapped and
packaged suppositories.
Suppositories in direct contact with one an¬
other are marred by fusion resulting from
changes in ambient temperature. Partially
melted suppositories stain the outer package
unless they are overwrapped or are packaged
with some other barrier that prevents contact
with the outer container. Suppositories usually
are foiled in tin or aluminum; paper and plastic
strips are also used.
Overwrapping of suppositories is done by
hand or machine. Hand packaging is slow and
yields a nonuniform and generally inelegant
preparation. Modem packaging machines over¬
come these difficulties. They are capable of
wrapping uniformly about 8000 .suppositories
per hour. In one type of machine, the chill-
hardened suppositories are placed in a notched
turntable and then fed to the packaging station,
where the foil is unwound from a roll, cut to size,
and finally rolled around each suppository. In
other machines, the suppositories are enclosed
in cellophane or heat-sealing aluminum foils.
Plastic may be thermoformed into two package
halves, with the suppository placed mechani¬
cally in one half and the second half sealed on
afterward. The heat sealer makes contact with
FIG. 19-4. A and B, Rotary suppository molding ma¬
chine: 1, feeding device and filling hopper; 2, rotating cool¬
the plastic strips only momentarily and at a suf¬
ing turntable; 3, suppository ejection station; 4, scraping ficient distance, so that the suppository is not
device; 5, refrigerant inlet and outlet. (Crespi, Milano, affected by the heat.
Italy.) Many suppositories are not individually
wrapped. In such cases, they are placed into
cardboard boxes or plastic containers that have
clean to prevent any deposition of mass from in¬ been molded to provide compartments for six to
terfering with their proper closure. Incomplete 12 suppositories.
closure of the molds results in overweight sup¬ The individually wrapped suppositories are
positories with mold marks. Air jets blow loose usually packaged in slide, folding, or set-up
particles out of the molds and thus help to mini¬ boxes. Occasionally, hygroscopicity or volatility
mize machine downtime for cleaning. of ingredients necessitates packaging the sup¬
On the straight-line machine, molds are ar¬ positories in glass or plastic containers. In the
ranged for increased productivity, that is, up to case of glycerinated gelatin suppositories, a well-
about 10,000 suppositories per hour. The sealed package is required. Changes in weight of
straight-line machine carries out the same steps suppositories depend on the types of packaging
as the rotary model. The individual molds are materials used.3'

SUPPOSITORIES '581
In-Package Molding ease of molding and release in the manufactur¬
ing equipment are simultaneously studied. After
A significant advance in suppository manu¬
these parameters are established, toxicity (irri¬
facturing was the development of automated
tancy) and drug availability are measured in ani¬
methods for molding suppositories directly in
mals before the medication is ready for human
their wrapping material. This is currently ac¬
clinical trials.
complished with either plastic or aluminum foil.
Machines utilizing plastic either thermoform
the mold and fill the mold in sequence, or simply Suppositories for Systemic Effect
fill the mass into previously thermoformed
A selection of possibly desirable suppository
molds. Machines using aluminum foil/
bases should be made, e.g., by choosing from
polypropylene/lacquer laminates emboss two
those suggested in Table 19-2. Availability and
parallel strips of foil so that when they are sealed
cost of the suppository bases must be considered
together, molds are formed.
before the formulation work is begun. Which¬
In both plastic and aluminum approaches, the
ever base is used, the drug should be homoge¬
tops of the molds are left open for the entrance of
neously dispersible in it, but releasable at the
filling nozzles. After the mass has been injected,
desired rate to the aqueous body fluids sur¬
usually by means of small, variable-throw piston
rounding the suppository. Therefore, the solubil¬
pumps, the tops are sealed. The strips are then
ity of the active ingredient(s) in water or other
passed in an upright position through a cooling
solvents should be known. If the drug favors
station. Using these techniques, one machine
water, a fatty base with low water number may
can make 12,000 to 20,000 suppositories per
be preferred. On the other hand, if the drug is
hour. The advantages of in-package molding
highly fat-soluble, a water-type- base, perhaps
include high production rates, no generation of
with the addition of a surfactant to enhance sol¬
scrapings, no bulk handling or storage of un¬
ubility, may be the preferred choice.
wrapped suppositories, and maintenance of
The theoretically desirable suppository formu¬
strict temperature controls. The disadvantages
lations are molded in the laboratory and stored at
are dependence on the shape of the formed mold
room temperature (25 ± 3°C) for at least
and seal completeness for the shape of the sup¬
48 hours before undergoing in vitro testing for
pository and depression formation in the rear of
release rate, to be described in the section “Test¬
the suppository since no scraping takes place.
ing of Suppositories.” To enhance the homoge¬
Disposable molds have the additional advan¬
neity of drug in the desired base, either a suita¬
tage of being suited for suppositories intended
ble solvent is used or the drug is finely
for tropical climates. If the mass should melt at
comminuted before incorporation. A drug that is
the high storage temperatures, the mold still re¬
soluble in a minimal quantity of water, or in an¬
tains it in its proper shape, so that upon cooling
other liquid miscible with the base, can be dis¬
it can be dispensed without distortion.
solved and the solution added to the molten
base. If the drug is to be incorporated directly
An Approach to Formulating into the base, it should be finely ground so that
100% can be passed through a 100-mesh USP
Suppositories screen. Fragility, brittleness, and ease of han¬
The first considerations of the formulator are: dling the suppository formulations on produc
tion equipment are some of the screening tests
1. Is the medication intended for local or sys¬ performed before the time-consuming and costly
temic use? animal and human tests begin.
The fluid content in the rectum is small.
2. Is the site of application rectal, vaginal, or
Therefore, in vitro findings of release rates, in
urethral?
which comparatively large amounts of water are
3. Is the desired effect to be quick, or slow and generally used, can be regarded only as a general
prolonged? guideline for formulation and after the formula
is in production, as a quality control procedure.
Preliminary suppository bases to be studied In many cases, there is reasonable correlation of
are first evaluated by measuring drug availabil¬ in vitro to in vivo release rates (see Table 19-3),
ity from the suppository in water at 36 to 37°C. but this is not necessarily so. In vivo clinical
Stability of both active ingredients and base con¬ findings in man are the ultimate criteria for
taining drug(s) at 4°C and room temperature is choosing a desired formulation, and the supposi¬
the next consideration. To reduce the number of tory formulation so chosen yields the in vitro re¬
suppository bases chosen for stability studies, lease rate pattern that is to be used as the de-

582 • The Theory and Practice of Industrial Pharmacy

sired standard. The clinical findings may be Tests in animals must show no irritancy if the
based on blood levels of the drug and/or desired suppository is to be used in man. The stability
clinical effects in man. Thus, since the supposi¬ testing program is as described above for sup¬
tory formula is not chosen until the desired clin¬ positories intended for systemic use, the stabil¬
ical effects in man are determined, screening of ity testing program is as described previously.
several prototype formulas by laboratory tests is
the practiced procedure. Chemical and physical
stability, consistency of in vitro drug release pat¬ Specific Problems in
terns within theoretically desired ranges, and Formulating Suppositories
animal toxicity are some characteristics studied
before suppository formulas are chosen for
Water in Suppositories
human clinical trials.
Once several likely candidates are chosen for Use of water as a solvent for incorporating
intense human clinical studies, at least two for¬ substances in suppository bases should be
mulations, each containing different batches of avoided for the following reasons.
acceptable-quality ingredients, are placed on
prolonged stability tests. The parameters tested 1. Water accelerates the oxidation of fats.
are described in the section “Specific Problems 2. If the water evaporates, the dissolved sub¬
in Formulating Suppositories.” The supposito¬ stances crystallize out.
ries are stored at room temperature (25 ± 3°C) 3. Unless the water is present at a level sig¬
and at 4°C. They are tested at regular intervals nificantly higher than that required for dissolv¬
(1- ,3-, and 6-month and 1- and 2-year periods) ing the drug, the water has little value in facili¬
for changes in appearance, melting and soften¬ tating drug absorption. Absorption from
ing range, drug stability, base stability, and in water-containing suppositories is enhanced only
vitro drug release pattern. The minimum age of if an oil-in-water emulsion exists with more than
the samples to be used in clinical trials should be 50% of the water in the external phase.38
determined by the stability of the melting range 4. Reactions between ingredients contained
of the formula, since nearly all shift upward ini¬ in suppositories are more likely to occur in the
tially, but the time required to reach equilibrium presence of water. Sometimes, anhydrous chem¬
varies. icals are used to avoid this possibility.
5. The incorporation of water or other sub¬
stances that might be contaminated with bacte¬
Suppositories for Local Effect rial or fungal growth necessitates the addition of
Drugs intended for local action are generally bacteriostatic agents such as the parabens.
nonabsorbable, e.g., drugs for hemorrhoids, local
anesthetics, and antiseptics. The bases used for
these drugs are virtually nonabsorbable, slow in
Hygroscopicity
melting, and slow in drug release, as contrasted Glycerinated gelatin suppositories lose mois¬
with suppository bases intended for systemic ture by evaporation in dry climates and absorb
drugs. Local effects are generally delivered moisture under conditions of high humidity.
within a half hour and last at least 4 hours. Polyethylene glycol bases are also hygroscopic.
The base chosen is one intended for local The rate of moisture change in polyethylene gly¬
action; several such bases are depicted in col bases depends not only on humidity and
Table 19-2. The drug must be homogeneously temperature, burialso on the chain length of the
distributed in the suppository base. This is ac¬ molecule. As the*molecular weight of these eth¬
complished as described previously for incorpo¬ ylene oxide polymers increases, the hygroscopi¬
rating the drug in a systemic base. The supposi¬ city decreases, with a significant drop for the
tory is tested 48 hours after molding by 4000 and the 6000 series.
immersion in a 36 or 37°C water bath. (See the
section “Testing of Suppositories.”) The desired
base should release an adequate amount of drug Incompatibilities
within a half hour, and completely melt with re¬ Polyethylene glycol bases were found to be
lease of all drug between 4 and 6 hours. A sup¬ incompatible with silver salts, tannic acid, ami-
pository that does not melt within the 6-hour nopyrine, quinine, ichthammol, aspirin, benzo-
test period would probably not completely re¬ caine, iodochlorhydroxyquin, and sulfonamides.
lease its drug, cause discomfort to the patient, Many chemicals have a tendency to crystallize
and be expelled by the patient before it is fully out of polyethylene glycol, e.g., sodium barbital,
utilized. salicylic acid, and camphor. Higher concentra-

SUPPOSITORIES • 583
tions of salicylic acid soften polyethylene glycol and mold should be as small as possible. Addi¬
to an ointment-like consistency, and aspirin tion of a small amount of Tween 80, Tween 85,
complexes with it. Penicillin G, although stable fatty acid monoglycerides, castor oil, glycerin, or
in cocoa butter and other fatty bases, was found propylene glycol imparts plasticity to a fat and
to decompose in polyethylene glycol bases. Fatty renders it less brittle.
bases with significant hydroxyl values may react
with acidic ingredients.
Density
To calculate the amount of drug per supposi¬
Viscosity tory, the density of the base must be known. The
The viscosity of the melted suppository mass volume of the mold cavity is fixed, and therefore,
is important in the manufacture of the supposi¬ the weight of the individual suppository depends
tory and to its behavior in the rectum after melt¬ on the density of the mass. Knowledge of the
ing. Melted cocoa butter and some of its substi¬ suppository weight can be obtained from a given
tutes have low viscosities, whereas the mold and density of the chosen base; the active
glycerinated gelatin and polyethylene glycol type ingredients can then be added to the bulk base
base have viscosities considerably higher than in such an amount that the exact quantity of
cocoa butter. In the manufacture of supposito¬ drug is present in each molded suppository. If
ries made with low-viscosity bases, extra care volume contraction occurs in the mold during
must be exercised to avoid the sedimentation of cooling, additional compensation must be made
suspended particles. Poor technique can lead to to obtain the proper suppository weight. Thus,
nonuniform suppositories, particularly in the density alone cannot be the sole criterion for cal¬
distribution of active ingredients. To prevent culating suppository weight per fixed volume
segregation of particles suspended in molten mold. When volume contraction occurs, the
bases, the well-mixed mass should be handled at suppository weight is determined empirically by
the lowest temperature necessary to maintain small batch runs.
fluidity, constantly stirred without entrapping
air, and quickly solidified in the mold.
The following approaches may be taken to
Volume Contraction
overcome the problems caused by use of low vis¬ This phenomenon occurs in many melted
cosity bases. suppository bases after cooling in the mold. The
results are manifested in the following two ways.
1. Use a base with a more narrow melting
range that is closer to body temperature. 1. Good mold release. This is caused by the
2. The inclusion of approximately 2% alumi¬ mass pulling away from the sides of the mold.
num monostearate not only increases the viscos¬ This contraction facilitates the removal of the
ity of the fat base considerably, but also aids in suppositories from the mold, eliminating the
maintaining a homogeneous suspension of in¬ need for mold release agents.
soluble materials. Cetyl, stearyl, or myristyl alco¬ 2. Contraction hole formation at the open end
hols or stearic acid are added to improve the con¬ of the mold. This undesirable feature results in
sistency of suppositories. lowered suppository weight and imperfect ap¬
pearance of the suppository. The contraction
can be eliminated by pouring a mass slightly
Brittleness above its congealing temperature into a mold
warmed to about the same temperature. In vol¬
Suppositories made from cocoa butter are ume production using standard molds, where
quite elastic and do not fracture readily. Syn¬
adequate control of temperature may not be fea¬
thetic fat bases with a high degree of hydrogena¬
sible, the mold is overfilled so that the excess
tion and high stearate contents, and therefore a
mass containing the contraction hole can be
higher solids content at room temperature, are
scraped off.
usually more brittle. Fracturing of the supposi¬
tory made with such bases is often induced by
rapid chilling (shock cooling) of the melted Lubricants or Mold Release
bases in an extremely cold mold. Brittle supposi¬
tories are troublesome not only in manufactur¬ Agents
ing, but also in the subsequent handling, wrap¬ Cocoa butter adheres to suppository molds
ping, and use. To overcome this difficulty, the because of its low volume contraction. These
temperature differential between melted base suppositories are difficult to remove from the

584 • The Theory and Practice of Industrial Pharmacy

 molds, and various mold lubricants or release mass; (2) the volume of the mold cavity; (3) the
agents must be used to overcome this difficulty. specific gravity of the base; (4) the volume varia¬
Mineral oil, an aqueous solution of sodium lau- tion between molds—good machining of the
ryl sulfate, various silicones, alcohol, and tinc¬ molds should keep the volume of each cavity
ture of green soap are examples of agents em¬ within 2% of a desired value; (5) weight varia¬
ployed for this purpose. They are applied by tions between suppositories due to the inconsist¬
wiping, brushing, or spraying. The release of encies in the manufacturing process, e.g., in¬
suppositories from damaged molds was im¬ complete closing of molds, uneven scrapings.
proved by coating the cavities with polytetra- Regardless of the reason for the variation in
iluoroethylene (Teflon).37 weight, it should be within ±5%.
The German and Russian Pharamcopeias
state individual weight variations of rectal sup¬
Dosage Replacement Factor positories at ±5% of the average weight. The
Pharmacopeia Nordica allows ±10% of the aver¬
The amount of base that is replaced by active
age weight for 90% of the suppositories, but
ingredients in the suppository formulation can
these deviations must not exceed ±20%.
be calculated. The replacement factor, f, is de¬
rived from the following equation:

lOO(E-G) Rancidity and Antioxidants

(G)(X) Many investigators confuse the acidity of fats
with rancidity. The presence of free fatty acids
where: E = weight of pure base suppositories in either small or large quantities is no indica¬
G = weight of suppositories with X% tion of rancidity, or that such a product may nec¬
active ingredient essarily become rancid.
Rancidity results from the autoxidation and
Most commonly used drugs are tabulated by re¬ subsequent decomposition of unsaturated fats
placement factor, using cocoa butter arbitrarily into low- and medium-molecular-weight (C.3-
assigned the value 1 as the standard base: Cn) saturated and unsaturated aldehydes, ke¬
tones, and acids, which have strong, unpleasant
Boric acid 0.67 odors. The lower the content of unsaturated
Phenobarbital 0.81 fatty acid constituents in a suppository base, the
Mild silver protein 0.61 greater is its resistance to developing rancidity.
Balsam Peru 0.83 Since this reaction begins with the formation of
Bismuth subgallate 0.37 hydroperoxides, a measure of autoxidation in
Bismuth subnitrate 0.33 progress is the peroxide value. This peroxide or
Camphor 1.49 active oxygen value is a measure of the iodine
White or yellow wax 1.0 liberated from an acidified solution of potassium
Spermaceti 1.0 iodide by the so-called ‘‘peroxide oxygen” of the
Chloral hydrate 0.67 fats.
Quinine hydrochloride 0.83
Examples of effective antioxidants are
Digitalis leaves, powdered 0.61
phenols, such as m- or p-diphenols; a-naphthol;
Ichthammol 0.91
quinones, such as hydroquinone or /3-naph-
Castor oil 1.0
thoquinone; tocopherols, particularly the (3 and
Phenol 0.9
Procaine hydrochloride 0.8
a forms; gossypol present in cottonseed oil;
Resorcin 0.71 sesamol present in sesame oil; propyl gallate and
Salol 0.71 gallic acid; tannins and tannic acid; ascorbic
" Sulfanilamide 0.6 acid and its esters; butylhydroxyanisole (BHA);
Sulfathiazole 0.62 and butylhydroxytoluene (BHT).
Theophylline sodium acetate 0.6
Zinc oxide 0.15-0.25
Testing of Suppositories
Others can be found in the literature.39,40 The literature is well documented with test
methods to assure that each manufactured lot of
suppositories consistently meets the standards
Weight and Volume Control established during the manufacture of early ex¬
The amount of active ingredient in each sup¬ perimental lots.41-44 Finished suppositories axe
pository depends on (1) its concentration in the routinely inspected for appearance, and after

SUPPOSITORIES • 585
being sliced lengthwise, for uniformity of the
mix. They are assayed for active ingredients to
ensure that they individually conform to labeled
content. Melting range tests are performed to
check the physical and absoiption characteris¬
tics of each manufactured batch. Fragility tests
are carried out to ascertain that the supposito¬
ries can be packaged and shipped with minimal
breakage.

Melting Range Test

This test is also called the macromelting range
test and is a measure of the time it takes for the
entire suppository to melt when immersed in a
constant-temperature (37°C) water bath. In con¬
trast, the micromelting range test is the melting
range measured in capillary' tubes for the fat
base only. The apparatus commonly used for
measuring the melting range of the entire sup¬
pository is a USP Tablet Disintegration Appara¬
tus. The suppository is completely immersed in FIG. 19-5. Apparatus for measuring the liquefaction time
the constant water bath, and the time for the of rectal suppositories; the dimensions are in millimeters.
entire suppository to melt or disperse in the sur¬ The thermometer scale is divided into tenths of a degree
rounding water is measured. and a scale ranging from 32 to 45° is adequate. (From Set-
nikar, I., and Fantelli, S.: J. Pharrn. Sci., 51:566, 1962.)
The in vitro drug release pattern is measured
by using the same melting range apparatus. If
th,e volume of the water surrounding the sup¬
the tube open. Water at 37°C is circulated
pository is known, then by measuring aliquots of
through the condenser at such a rate that the
the water for drug content at various intervals
lower half of the cellophane tube collapses and
within the melting period, a time-versus-drug
the upper half gapes. The hydrostatic pressure
content curve (in vitro drug release pattern) can
of the water in the apparatus is approximately
be plotted.
zero when the tube starts to collapse. When the
water temperature is stabilized at 37°C, the sup¬
Liquefaction or Softening Time pository is dropped into it so that it sits at the
level shown in Figure 19-5, and the time is
Tests of Rectal Suppositories measured for the suppository to melt completely
A modification of a method developed by in the tube.44
Krowczynski is another useful test of finished
suppositories.45,46 It consists of a U-tube par¬
tially submersed in a constant-temperature Breaking Test
water bath. A constriction on one side holds the Brittleness of suppositories is a problem for
suppository in place in the tube. A glass rod is which various solutions have already been de¬
placed on top of the suppository, and the time for scribed. The breaking test is designed as a
the rod to pass through to the constriction is re¬ method for measuring the fragility or brittleness
corded as the “softening time.” This can be car¬ of suppositories. The apparatus used for the test
ried out at various temperatures from 35.5 to consists of a double-wall chamber in which the
37°C, as a quality control check and can also be test suppository is placed (Fig. 19-6). Water at
studied as a measure of physical stability over 37°C is pumped through the double walls of the
time. A water bath with both cooling and heating chamber, and the suppository, contained in the
elements should be used to assure control dry inner chamber, supports a disc to which a
within 0.1°C. rod is attached. T he other end of the rod consists
The “softening test” measures the liquefac¬ of another disc to which weights are applied.
tion time of rectal suppositories in an apparatus The test is conducted by placing 600 g on the
that simulates in vivo conditions (Fig. 19-5). A platform. At 1 -min intervals, 200-g weights are
dialysis membrane, i.e., a cellophane tube, is added, and the weight at which the suppository
tied to both ends of a condenser with each end of collapses is the breaking point, or the force that

586 • The Theory and Practice of Industrial Pharmacy

 Storage
Suppositories should be protected from heat,
preferably by storing in the refrigerator. Polyeth¬
ylene glycol suppositories and suppositories en¬
closed in a solid shell are less prone to distortion
at temperatures slightly above body tempera¬
ture. Glycerinated gelatin suppositories should
be protected from heat, moisture, and dry air by
packaging in well-sealed containers and storing
in a cool place.

Examples of Typical Stability

Problems
The suppository, including active ingredients
and the base, must be chemically and physically
stable at refrigerator temperatures as well as at
room temperature storage conditions for at least
two years. Storage stability studies are normally
conducted at 4°C and at room temperature
(25 ± 3°C).
Cocoa butter suppositories in storage some¬
FIG. 19-6. Breaking test apparatus: 1, double-wall cham¬ times “bloom,” i.e., form a white powdery de¬
ber: 2, test suppository; 3, constant temperature water posit on the surface. This is unsightly and usu¬
bath and pump; 4, rod; 5, disc for weights; 6, 200-g
ally can be avoided if the suppositories are
weights.
wrapped in foil, and stored at uniform cool or
refrigerator temperatures.
Fat base suppositories have been shown to
harden for a period of time after manufacture.54
determines the fragility or britdeness character¬ This upward shift in melting range is due to
istics of the suppository. Differently shaped sup¬ slow crystallization to the more stable polymor¬
positories have different breaking points. The phic forms of the base. Depending on the initial
desired breaking point of each of these variously melting range and the formula of the supposi¬
shaped suppositories is established as the level tory, this phenomenon may affect the melting of
that withstands the break forces caused by vari¬ the suppository and subsequent drug absorption
ous types of handling, i.e., production, packag¬ rates. The softening time test and differential
ing, shipping, and patient in-use handling. scanning calorimetry can be used as stability-
indicating test methods to predict problems of
this sort. Storage immediately after manufacture
at an elevated temperature below the melting
Dissolution Testing range speeds up the aging process. Since the
Testing for the rate of in vitro release of drug hardening phenomenon is a finite process, this
substances from suppositories has always posed tempering approach can minimize further
a difficult problem, owing to melting, deforma¬ changes in melting range, which may be worth
tion, and dispersion in the dissolution medium. the addition to manufacturing cycle time.
Early testing was carried out by simple place¬ The suppository overwrap foil also can cause
ment in a beaker containing a medium.4' problems in time. For example, if the supposi¬
In an effort to control the variation in mass/ tory contains an acid, the foil wrapping may be
medium interface, various means have been attacked and develop pinholes.
employed, including a wire mesh basket,48 or a Stability studies of suppositories intended for
membrane,49 to separate the sample chamber tropical climates must be conducted in the final
from the reservoir. Samples sealed in dialysis package at temperatures at which the supposito¬
tubing or natural membranes have also been ries will eventually be kept. High-melting bases,
studied.50 Flow cell apparati have been used, water-soluble bases, and special polyethylene
holding the sample in place with cotton,51 wire shell packages 'must be considered. Labeling
screening,02 and most recently with glass should emphasize storage in a cool place Efforts
beads.53 should be made in formulating suppositories for

SUPPC S1TORIES • 587

the tropics to maintain the physical and chemi¬ 21. Triols. Technical Information Sheet No. 779, Carbide
cal stability of these suppositories in their final and Carbon Chemicals Company, New York, NY.
22. Manz, E.: Siiddeut, Apoth. Ztg., 90:320, 1950.
package, even when they are stored at tempera¬ 23. Eckert, V., and Muhlemann, H.: Pharmaeeutica Acta
tures as high as 50°C (122°F). Helvetiae, 33:649, 1958.
Storage studies also should include antici¬ 24. Whitworth, C.W., and Larocca, J.P.: J. Am. Pharm.
pated problems resulting from shipment. To test Assoc., Sci. Ed., 48:353, 1959.
the effects of handling the product in the field, 25. Tardos, L., Efio, I., Magda, K., and Jobbagyi, L.: Acta
Pharm. Hung., 29:22, 1959.
suppositories often are shipped by the desired
26. Tardos, L., Weisman, L.J., and EEo, I.: Pharmazie,
transport facilities to several areas in the coun¬ 14:526, 1960.
try, and then tested physically, and occasionally 27. Hennig, W.: fiber die Rektale Resorption von
chemically, for stability. Cool conditions for Medicamenten. Zurich, Juris Verlag, 1959.
shipment often are required. 28. Gross, H.M., and Becker, C.H.: J. Am. Pharm. Assoc.,
Sci. Ed., 42:498, 1953.
29. Ward, W.C.: J. Am. Pharm. Assoc., Sci. Ed., 39:265,
1950.
30. Davies, R.E.M.: Pharm. J. 165:347, 1950.
31. U.S. Patent 3,121,663.
32. U.S. Patent 3,122,475.
References 33. U.S. Patent 2,477,292.
1. Bucher, K.: Helv. Physiol, et Pharmacol. Acta, 6:821, 34. Gstimer, F.: Mitt. Deutsch. Pharm. Ges., 39:21,
1948. 1969.
2. Fabre, M.R., and Regnier, M.: Ann. Pharm. Franc., 35. De Leede, L.G.J., De Boer, A.G., and Breimer, D.D.:
9:318, 1951. Rate-con trolled rectal drug delivery with a hydrogel
3. Schanker, L.S.: J. Pharmacol. Exptl. Therap., preparation: 11. Drug release in vivo. An experimen¬
126:283, 1959. tal study in healthy volunteers. In Rate-ControUed
4. Riegelman, S., and Crowell, W.J.: J. Am. Pharm. and Site-Specific Rectal Drug Delivery. Edited by
Assoc., Sci. Ed., 47:115, 123, 127, 1958. De Leede, L.G.J., Gravenhage, Drukkerij J.H. Pas¬
5. Schanker, L.S., Shore, P.A., and Brodie, B.B.: mans B.V., 1983, p. 101.
J. Pharm. Expd. Therap., 120:528, 1957. 36. De Leede, L.G.J., et al.: J. Pharmacokin. Biopharm.,
6. Allawala, N.A., and Riegelman, S.: J. Am. Pharm. 10:525, 1982.
Assoc., Sci. Ed., 42:267, 1953. 37. Puffer, H.W., and Barnett, P.A.: j. Pharm. Sci.,
7. Helmann, G., Neuwald, F., and Gladtke, E.: Arzneim. 5.9:848, 1970.
Forsch., 28:1023, 1978. 38. Giacomini, G., and MasciteUi, E.: Sommistraoe del
8. Pasich, J., Galoch, B., and Kustra, K.: Pharmazie, Farmaci per Via rettale. Gitti Ed., Milano, 1954.
34:413, 1979. 39. Biichi, J.: Pharm. Act. Helvet., 20:403, 1943.
9. Noro, S., Komatsu, Y., and Uesugi, T.: Chem. Pharm. 40. V. Czetsch-Lindenwald, H.. Suppositorien. Editio
Bull., 30:2912, 1982. Cantor. Aulendorf, Germany, 1958.
10. Tukker, J.J., Van Vught, W., and DeBlaey, C.J.: Acta 41. Muhlemann, H.. and Neuenschwander, R.H.:
Pharm. Tech., 29:187, 1983. Pharm. Act. Helvet., 31:303, 1956.
11. Nishihata, T., et al.: Int. J. Pharmaceutics, 21:239, 42. Biichi, J., and Oesch, P.: Pharm. Act. Helvet., 19:363,
1984. 1944.
12. De Leede, L.G.J., De Boer, A.G., Portzgen, E., and 43. Del Pozo, A., and Cemeli, J.: Galenica Acta, 6:193,
Breimer, D.D.: Rate-controlled rectal drug delivery 1953.
with a hydrogel preparation: I. Drug release in vitro. 44. Setnlkar. 1., and FanteUi, S.: J. Pharm. Sci., 51:566,
In Rate-Controlled and Site-Specific Rectal Drug De¬ 1962.
livery. Edited by De Leede, L.G.J., Gravenhage, 45. Coben, L.J.: Drug Dev. and Ind. Pharm., 3:523, 1977.
Drukkerij J.H. Pasmans B.V., 1983, p. 89. 46. Krowczynski, L.: Diss. Pharm., 13:269, 1959.
13. Rudolfo, A.S., et al.: Am. J. Med. Sci., 237:585, 1959. 47. Gross, H.M., and Becker, C.H.: J. Am. Pharm. Assoc.,
14. Enesco, J., Branisteanu, D., and Dangeaunu, J.: Bull. Sci. Ed„ 42:96, 1953.
Acad. Med. Roumanie, 4:1, 1939. 48. Parrott, E.L.: J. Pharm. Sci., 64:878, 1975.
15. Shichiri, M., Yamasaki, Y., Kawamori, R., et al.: 49. Krowczynski, L.: Acta Pol. Pharm., 19:127, 1962.
]. Pharmacol., 30:806, 1978. 50. Ayres, J.W.. Lorskulsint, D., Lock, A., et al.: J. Pharm.
16. Copsidas, E., and Ward-McQuaid, J.: J. Int. Med. Sci., 65:832,1976.
Res., 7:592, 1979. 51. Baichwal, M.R., and Lohit, T.V.: J. Pharm. Pharma¬
17. TurreE, R., Marino, A.W.M., and Nerb, L.: Ann. col., 22:427, 1970.
Surg., 112:417, 1940. 52. Puffer, H.W., and Crowell, W.J.: J. Pharm. Sci.,
18. Bailey, C.R.: J. Chem. Soc., 123:2579, 1923. 62:242, 1973.
19. Collins, A.P., Hohmann, J.R., and Zopf, L.E.: Am. 53. Roseman, T.J., Derr, G.R., Nelson, K.G., et al.:
Profess. Pharmacist, 23:231, 1957. J. Pharm. Sci., 70:646, 1981,
20. Cheymol, Buffet, and Lechat, P.: Ann. Pharm. 54. Coben. L.J., and Lordi, N.G.: J. Pharm. Sci., 69:955,
•Franc., 5:59, 1947. 1980.

588 • The Theory and Practice of Industrial Pharmacy

 20
Pharmaceutical Aerosols
JOHN J. SCIARRA and ANTHONY J. CUTIE

The packaging of therapeutically active ingredi¬ spray, stream, quick-breaking foam, or stable
ents in a pressurized system is not new to the foam.
pharmaceutical industry. According to present Irritation produced by the mechanical ap¬
day usage, an aerosol or pressurized package is plication of topical medication is reduced or
defined as “a system that depends on the power eliminated.
of a compressed or liquefied gas to expel the con¬ Other advantages are ease and convenience of
tents from the container." it is in light of this application and application of medication in a
definition that the terms aerosol, pressure pack¬ thin layer.
age, pressurized package, and other similar
terms are used in this chapter.
Although pressurized packages existed during Components of Aerosol Package
the early 1900s, it was not until 1942, when the
An aerosol product consists of the following
first aerosol insecticide was developed by Good-
component parts-. (1) propellant, (2) container,
hue and Sullivan of the United States Depart¬
(3) valve and actuator, and (4) product concen¬
ment of Agriculture,1 that the aerosol industry
trate.
was begun. The principles of aerosol technology
were applied to the development of pharmaceu¬
tical aerosols in the early 1950s. These aerosol
products were intended for topical administra¬ Prope Hants
tion for the treatment of bums, minor cuts and The propellant is responsible for developing
bruises, infections, and various dermatologic the proper pressure within the container, and it
conditions. Aerosol products intended for local expels the productwheiTthe valve is openedand
activity in the respiratory tract appeared in aids in theatomization or foam production of the
1955, when epinephrine was made available in a ■product. Various' types oFpropellants are uti¬
pressurized package. Based on their acceptabil¬ lized. While the fluorinated hydrocarbons such
ity to both patient and physician, and their wide¬ as trichloromonofluoromethane (propellant 11),
spread use, pharmaceutical aerosols represent a dichlorodifluoromethane (propellant 12), and »
significant dosage form and should be consid¬ dichlorotetrafluoroethane (propellant 114) find
ered along with other dosage forms, such as tab¬ widespread use in most aerosols for oral and in¬
lets, capsules, solutions, etc. halation use, topical pharmaceutical aerosols
An examination of the aerosol dosage foim utilize hydrocarbons (propane, butane, and iso-
reveals the following specific advantages over butane) and compressecTgases such as nitrogen,
other dosage forms: carbon dioxide, and nitrous oxide. The physico¬
Y_l>Adose can be removed without contamina¬ chemical properties of the propellants have been
tion of remaining material. Stability is enhanced reviewed in other publications.2-4 Listed in
for those substances adversely affected by oxy¬ Table 20-1 are the commonly used propellants
gen and/or moisture. When sterility is an impor¬ together with several of their physicochemical
tant factor, it can be maintained while a dose is properties. Those properties of particular inter¬
being dispensed. est to the industrial pharmacist have been in¬
2. The medication can be delivered directly to cluded. Blends of various fluorocarbon propel-
the affected area in a desired form, such as iants^are generally used for pharmaceutical
Table 20-1. Physicochemical Properties of Fluorocarbon and Hydrocarbon Propellants5

Vapor Liquid
Pressure Boiling Density
(psia) Point (g/ml)

Numerical
Chemical Name Designation 7 0°F 130°F °F °C 7 0°F

Trichloromonofluoromethane 11 13.4 39.0 74.7 23.7 1.49

Dichlorodifluoromethane 12 84.9 196.0 -21.6 -29.8 1.33
Dichlorotetrafluoroe thane 114 27:6 63.5 38.4 3.6 1.47
Difluoroethane 152a 76.4 191.0 -11.2 -24.0 0.91
Butane A-17 31.6 82.0 31.1 -0.6 0.58
Isobutane A-31 45.8 111.0 10.9 -11.8 0.56
Propane A-108 122.8 270.7 -43.7 -44.6 0.50

aerosols and are indicated in Table 20-2. Ey however, their purity varies, and the blending is
varying the proportion of each component, any done on the basis of the desired final pressure
desired vapor pressure can be achieved within and not on the percentage of each component
the limits of the vapor pressure of the individual present. The pressure of each individual compo¬
propellants. nent varies somewhat, depending on the degree
As with the fluorocarbons, a range of pres¬ of purity. Table 20-3 illustrates some of the com¬
sures can be obtained by mixing the various monly used blends that are commercially avail¬
hydrocarbons in varying proportions. Since the able. *
hydrocarbons are naturally occurring products, The vapor pressure of a mixture of propellants

Table 20-2. Blends of Fluorocarbon Propellants for Pharmaceutical Aerosols

Vapor Pressure Density

Propellant (psig) (g/ml)
Blend* Composition 7 0°F 70°F

50:50 37.4 1.412

60:40 44.1 1.396
70:30 56.1 1.368
40:60 39.8 1.412
12/114 45:55 42.8 1.405
12/114 55:45 48.4 1.390

'It is generally understood that the designation “propellant 12/114 (70:30)” indicates a composition of 70% by weight of propellant 12
and 30% by weight of propellant 114.

Table 20-3. Vapor Pressure of Hydrocarbons6

Pressure Composition (mol %)

(psig)
Designation* 70°F n = Butane Propane lsobutane Other

A-108 108 ± 4 traces 99 1 traces of ethane

A-70 70 ± 2 1 51 48
A-52 52 ± 2 2 28 70
A-46 46 ± 2 2 20 78
A-40 40 ± 2 2 12 86
A-31 31 ± 2 3 1 96
A-24 24 ± 2 49.2 0.6 50 0.1 each neopentane
and isopentane
A-17 17 ± 2 98 traces 2 traces of isopentane

'Designations used by Phillips Chemical Company, Bartlesville, OK.

590 * The Theory and Practice of Industrial Pharmacy

can be calculated according to Dalton’s law, weighty 30
moles12 = 0.2481
which states that the total pressure in any svs- MW12 120.93
terrils equal to the sum of tfielndividiiql nr par¬
tial pressures of the various components. Ra- 0.2481 moles of propellant 12
otflt's law, which regards lowering of the vapor
pressure of a liquid by the addition of another From Roault’s law:
substance, states that the depression of the
vapor pressure of a solvent upon the addition of nn
Pn = PllO
a solute (something added to the solvent! is pro¬ n„ -r n,2
portional to the moleffaction of solute molecules
0.5095
in ~the~sattrfion. tjivetTideal behavior, the vapor Pn =- 13.4 = 9.01 psia
pressure of a mixture consisting of two individ¬ 0.5095 + 0.2481
ual propellants is equal to the sum of the mole 9.01 psia* partial pressure of propellant 11
fraction of each component present multiplied
by the vapor pressure of each pure propellant at U 12
Pl2 = Pl2°
the desired temperature. This relationship can ni2 + n„
be shown mathematically:
0.2481
Pl2 = - 84.9 = 27.80 psia
0.2481 + 0.5095
Pa = ~ TT PaO = NApAo (1)
na + nb 27.80 psia partial pressure of propellant 12-
where: pa = partial vapor pressure of propel¬
Vapor pressure of propellant 12/11 (30:70) then
lant A equals 27.80 + 9.01, or 36.81 psia. Gauge pres¬
pAo = vapor pressure of pure propellant
sure is obtained from:
A
na = moles of propellant A | psia - 14.7 =-psig |
nb = moles of propellant B
Na = mole fraction of component A
or: 36.81 - 14.7 = 22.11 psig
To calculate the partial vapor pressure of propel¬
A difference is noted in comparing the calcu¬
lant B:
lated value for the vapor pressure with the ex¬
perimental value shown in Table 20-2. The dif¬
Pb = „ ■-* Pb° = NBpBo (2) ference is due to deviation from ideal behavior.
nb + na Flanner studied the effect of various polar and
semipolar solvents and prepared vapor pressure
The total vapor pressure of the system is then
curves.7 A curve typical of this deviation is
obtained from:
shown in Figure 20-1.
(3) Figure 20-2 shows the range of pressures
P = Pa + Pb
available using various fluorinated hydrocar¬
where P is the total vapor pressure of the sys¬ bons, while Figure 20-3 illustrates these ranges
tem. for hydrocarbons. Graphs that relate vapor pres¬
When one component is present in relatively sure to temperature are available, and these
low concentration, ideal behavior is approached. graphs can be utilized to determine the vapor
For practical purposes, however, the calculated pressure at the appropriate temperature.5
pressure is sufficiently accurate for most deter¬
minations. The application of Raoult’s law for
calculation of vapor pressure can best be illus¬
Containers
trated by the following example.
Calculate the vapor pressure at 70°F of a pro¬ Various materials as indicated in the following
pellant blend consisting of propellant 12/11 outline have been used for the manufacture of
(30:70) (see Table 20-2). aerosol containers, which must withstand pres¬
sures as high as 140 to 18*0 psig at 130°F.
Moles of each substance:

weight] i 70 ‘The abbreviation psia is for pounds per square inch ab¬
moles n = 0.5095
MW„ 137.38 solute, which can be converted to pounds per square inch
gauge (psig) by subtracting atmospheric pressure (14.7)
0.5095 moles of propellant 11 from psia.

PHARMACEUTICAL AEROSOLS • 591

 Tinplate Containers. The tinplated Steel
container consists of a sheet of steel plate that
hasTbeen electroplated on both sides with tin.
TneTHIcRheis of the tin coating is described in
terms of its weight, for example, #25, #50. and
#100. The size of the container is indicated by a
standard system, which is a measure of the di¬
ameter and height of the container. A container
said to be 202 x 214 is 2Vie inches in diameter
and 214/ig inches in height.8-13
Brief discussion of the procedure used in the •
manufacture of tinplated containers might be
advantageous for a better appreciation of the
quality control aspects, tinplated st££Ljs_ob-
tained in thin sheets, and when required, it is
coated with an organic material. These sheets
are lithographed at this point. After the sheet is
cut into sizes to make a body, a top, and aJaot-
toreg each piece is' fapricated into the desired
shape.Tbe body ig~~shaped into a cylinder.and
seamed via a flanging and soldering-operation.
'fhetop and bottom are attached to the hody. and
a side seam stripe is added to the inside seam-
area when required. The organic coating also
20 40 SO 80 100 can be added to the finished container rather
WEIGHT PROPELLANT
PERCENT
than to the flat sheets. This procedure is slower
FIG. 20-1. Deviation of vapor pressure of nonideal solu¬ and somewhat more expensive, but a more con¬
tions from Roault's law. (Courtesy of Allied Chemical Cor¬ tinuous and durable coating is produced. The
poration, Morristown, NJ.) use of sealing compounds, types of solder, and
organic coatings are discussed in this chapter
under the heading “Formulation of Pharmaceu¬
tical Aerosols.”
A. Metal
A recent development in metal tinplate con¬
1. Tinplated steel
a. Side-seam (three-piece)
tainers is the welded side-seam.14 Welding elim¬
b. Two-piece or drawn inates the soldering operation, saves considera¬
c. Tin-free steel ble manufacturing time, and decreases the
2. Aluminum possibility of product/container interaction. In
a. Two-piece general, two processes are used: the Soudronic
b. One-piece (extruded or drawn) system (American Can Company, Crown Cork
3. Stainless steel and Seal, and the Southern Can Company) and
B. Glass the Conoweld system (Continental Can Com¬
1. Uncoated glass pany). The Soudronic system is based on an
2. Plastic-coated glass electronically controlled resistance welding
method that uses a copper wire as an electrode.
The rounded bodies are welded and then sent to
the conventional line, where the top and bottom
ends are flanged as indicated previously. The
Conoweld system passes the folded body
through two rotating electrode rings. The rest of
the container is manufactured in the usual man¬
ner.
Aluminum Containers. Aluminum is used
to manufacture extruded (seamless) agrasoi
containers. Many existing pharmaceuticals are
packaged in aluminum containers, probably be¬
FIG. 20-2. Range of pressures obtainable at 70° F with cause of the lessened danger of incompatibility
various fluorocarbon propellants. (Courtesy of E.I. duPont due to its seamless nature and greater resistance
de Nemours and Co., Inc., Wilmington, DE.) to corrosion. Aluminum can be rather unpredict-

592 • The Theory and Practice of Industrial Pharmacy

BJLmosgv 3yynos y3d saNncd ' 3«nss3a^ aorfVA

o
o
in

o
in

o
o

o
in
CO

o
o
CO

o
m
N

FIG. 20-3. Vapor pressures of hydrocarbons. (Courtesy of Phillips Chemical Company, Bartlesville, OK.)
o
o
N

U.

Ld
a:
D
O h
O <
tr
Ul
a.
O 2
<D bJ
h
O
ID

O
N

PHARMACEUTICAL AEROSOLS • 593

able, however, in that it is corroded by pure
water and pure ethanolThe combination of eth¬
anol and propellant 11 in an aluminum con¬
tainer has been shown to produce hydrogen,
acetyl chloride, aluminum chloride, propellant
21, and other corrosive products.
Stainless Steel Containers. These con¬
tainers are limited to the smaller sizes, owing to
production problems as well as cost. They are
extremely strong and resistant to most materi¬
als. Stainless steel containers have been used for
inhalation aerosols. In most cases, no internal
organic coating is required.
Glass Containers. Glass aerosol containers
have been used for a large number of aerosol
pharmaceuticals. Glass containexs-are-availahle

coating may be totally adhered (except for the

neck ring) or nonadhered and vented. By adjust¬
ing the formulation and limiting the type and
quantity of propellant, satisfactory aerosol prod¬ © Gasket

ucts can be formulated and packaged in glass

containers. Glass aerosol containers are prefera¬
ble from a compatibility viewpoint, since corro¬ I Spring

sion problems are eliminated The use of glass

also allows for a greater degree of freedom in
cfesign of the container

Valves
The present-day aerosol valve is multifunc¬
tional in that it is capable of being easily opened
and closed, and in addition, is capable of deliver¬
ing the rnntpnt in fmm F'irfhor-
more, especially in the case of pharmaceuticals,
the valve is expected to deliver a given amount
of medication. Valves for pharmaceuticals usu¬
ally do not differ from the valves used for
nonpharmaceutical aerosol products, but the NY.)

requirements for pharmaceuticals are usually

more stringent than for most other products.13
The materials used in the construction of the respectively. These valve assemblies consist of
valve must be approved by the Food and Drug the following parts.
Administration. Pharmaceutical aerosols may be Ferrule or Mounting Cup. The ferrule or
dispensed as a spray, foam, or solid stream, and mounting cup is used to attach tlTtHShn proper
they may or may not require dosage control. The to tEecontainer. For use with containers having
need for several different types of valves be¬ a one-inch opening, the cup is made from tin¬
comes apparent. plate steel, although aluminum also can be used.
Continuous Spray Valves. An aerosol valve Since the underside of the valve cup is exposed
consists of many different parts and is assem¬ to the contents of the container and to the ef¬
bled using high-speed production techniques. fects of oxygen trapped in the head space, a sin¬
The valve manufacturers adhere to relatively gle or double epoxy or vinyl coating can be added
close tolerances during manufacture and assem¬ to increase resistance to corrosion .^Ferrules are
bly of the valve. Various materials are used to used with glass bottles or small aluminum tubes
manufacture the many components of the valve. ahd~are~usiianv made from a~softer metal such as
Figures 20-4 and 20-5 illustrate typical aerosol aluminum or brass. The ferrule is attached to
valve assemblies for use with cans or bottles, the container either by rolling the end under the

594 • The Theory and Practice of Industrial Pharmacy

 compatible with most pharmaceutical formula¬
tions.
Spring. The spring serves to hold the gasket
in place, and when the actuator is depressed and
released, it returns the valve to its closed posi¬
tion. Stainless steel can be used with most aero¬
sols.
Dip Tube. Dip tubes are made from polyeth¬
ylene or polypropylene. Both materials are ac-
ceptabie tor use although the polypropylene tube
is usually more rigid. The inside diameter of the
commonly used dip tube is about 0.120 inch to
0.125 inch, although capillary dip Tubes are
about 0.050 inch, and dip tubes for highly vis¬
cous products may be as large as 0.195 inch^Vis-
cosity and the desired delivery rate play an im-
poftant~~role in the selection of the inner
F fiiameterof the dip tube.
Meternig~VaIves. Metering valves are appli¬
cable to the dispensing n£ potent medication.
These operate on the principle of a chamber
whose size determines the amount of medica¬
FIG. 20-5. Aerosol bottle valve assembly: A, ferrule; B, tion dispensed. This is shown in Figure 20-6.
stem; C, valve seat; D, valvebody, E, mounting gasket; F, Although these have been used to a great extent
dip tube. (Courtesy ofRisdon Manufacturing Co., Nauga¬
tuck, CT.)
for aerosol products, they are limited in both size
and accuracy of dosage. Approximately 50 to
150 mg ± 10% of liquid material can be dis¬
pensed at one time with the use of such valves.

lip of the bottle or by clinching the metal under

the lip.
Valve Body or Housing. The housing is
generally manufactured from Nvlon or Delrin
and contains an opening atlhe poinfof the at-
tachment of the dip tube, which ranges from
about 0.013 inch to 0.080 inch.
The housing may or may not contain another
opening referred to as the “vapor tap.” The vapor
tap allows for the escape of vaporized propellant ,
along with the liquidproduct (see Fig. 20-4A). -
The vapoFtap turther produces a fine particle
size, prevents-valve clogging with products~con- •
taining insoluble materials, allows for the prod-
ucTtcPbe satisfactorily-dispensed with the con¬
tainer in the inverted position reduces, the •
chilling effect of the propellant on the skin, and
in the case of hydrocarbon propellants, allows for
a decrease in flame extension. These vapor tap
opemngs are available in sizes ranging from
about 0.013 inch to 0.080 inch.
Stem. The stem is made from Nylon or Del-
rin, but metals sum’ll as biass <nid~gfalnless steel
can be utilized also. One or more orifices are set
FIG. 20-6. Metering valve for pharmaceutical aerosols: A,
into the stem; they range from one orifice of
mounting ferrule; B, plastic housing; C, capillary dip tube;
about 0.013 inch to 0.030 inch, to three orifices
D, outlet valve seal; E, inlet valve seal; F, two-piece stain¬
of 0.040 inch each. less steel stem; G, stainless steel spring; H. stainless steel
Gasket. JBunaJl—and Neoprene rubber are washer; l, sealing gasket. (Courtesy of Emscm Research,
commonly used for the gasket material and arec Bridgeport, CT.)

PHARMACEUTICAL AEROSOLS • 595

Actuators pass through various openings (of which there
may be one to three on the order of 0.016 inch to
To ensure that the aerosol prodncr is delivered
in the proper and desired form, a specially de¬ 0.040 inch in diameter—see Figure 20-7A).
Where there is a large percentage of propellant
signed button or actuator must be fitted to the
mixture containing a sufficient quantity of alow
valve steuiif' THe Ictuator allows for easy open~
ftoilmg~propellant such as propellant 12 or pro¬
mg and closing of the valve and is an integral
pane, actuators having relatively large orifices
part of almost every aerosol package. It also
can be used. The combination of propellant va¬
serves to aid in producing the required type of
porization and actuator orifice and internal
product discharge.
channels can deliver the spray in the desired
There are many different types of actuators.
particle size range. A spray type actuator can be
Among them are those that produce (1) spray,
used with pharmaceuticals intended for topical
(2) foam, (3) solid stream, and (4) special appli¬
use, such as sprav-on bandages! antiseptics.
cations. "
local anesthetics, and foot preparations. When
Spray Actuators. Figure 20-7 illustrates ac¬
these actuators are used with aerosol products
tuators that are capable of dispersing the stream
containing relatively low amounts of propellants
of product concentrate and propellant into rela¬
(50% or less), the product is dispensed as a
tively small particles by allowing the stream to
stream rather than as a spray, since the propel¬
lant present in the product is not sufficient to
disperse the product fully. For these products, a
mechanical breakup actuator is usually required
(Fig. 20-7B). These actuators are capable of
“mechanically” breaking a stream into fine par¬
ticles by causing the stream to “swirl” through
various channels built into the actuator.
Foam Actuators. These actuators consist of
relatively large orifices ranging from approxi¬
mately 0.070 inch to 0.125 inch and greater
(Fig. 20-8). The orifices allow for passage of the
product into a'relatively Iafge"cHamber, where it
can expand and be dfspensed^through the large
orifice. ~
Solid-Stream Actuators. The dispensing of
such semisolid products as ointments generally
requires these actuators. Relatively large open¬
ings allow for the passage of product through the
valve stem and into the actuator. These are es¬
sentially similar to foam type actuators.
Special Actuators. Many of the pharmaceu¬
tical and medicinal aerosols require a specially
designed actuator to accomplish a specific pur¬
pose. They are designed to deliver the medica¬
tion to the appropriate site of action—throat,
nose, eye, or vaginal tract. Several are shown in
Figure 20-£
Metered-Dose Inhalers. Over the last four
to five years, there has been an increased inter¬
est in modifying metered-dose inhalers (MDIs)
to minimize the number of administration errors
ancTtcT improve the drug delivery of aerosolized
particles'into the nasafpassageways and respira¬
tory airways. Some ot these modifications have
included tfie introduction of tube spacers,
breath actuators, and portable plastic reservoirs
with inhalation aerosols. In the case of intra¬
FIG. 20-7. Actuators for pharmaceutical aerosols. A, In¬
halation spray type. (Courtesy of Riker Laboratories.) B, nasal preparations, new propellant-free metered
Mechanical breakup type. (Courtesy of Risdon Manufac¬ pumps have been introduced to replace the tra¬
turing Co., Naugatuck, CT.) ditional propellant delivery systems.17

596 • The Theory and Practice of Industrial Pharmacy

 During the late 70s and early 80s, there were tive ingredients, or a mixture of active
a number of in vivo and in vitro studies evaluat¬ ingredients, and other necessary agents such as
ing the differences between the con yen ri on a 1 solvents, antioxidants, and surfactants. The pro¬
adaptors and the expanded-chamber adaptors, pellant may be a single propellant or a blend of
referred to as “spacers ” or “tube spacers.”18 At various propellants; it can be compared with
present, many conventional short-stem MDIs other vehicles used in a pharmaceutical formu¬
deliver at best only 10 to i 5% of the dose actu¬ lation. Just as a blend of solvents is used to
ated into the respiratory airways. The balance of achieve desired solubility characteristics, orj/ar-
the dose is either lost to the inner surface of the ious surfactants are mixed to give the proper
adaptor (approximately 10%), or is deposited HLB vaTuelbr an emulsion system, trie propel¬
through inertial impaction in the oropharynx lant is selected to give the desired vapor pres¬
area (80%). The latter leads to swallowing and sure, solubility, and particle size.
possible systemic absorption of the therapeutic Since one must be familiar with the physico¬
agent(s). To reduce this fraction that has been chemical properties of surfactants, solvents, and
lost to The oropharynx and swallnwprl a number suspending agents, it follows that the formulator
of tube spacers of various geometric shapes and of aerosol preparations must be thoroughly fa¬
dimensions were considered, since they should, miliar with propellants and the effect the propel¬
at least in theory, minimize some of the effects lant will have upon the finished product. Propel¬
produced by inertial compaction, which contrib¬ lants can be combined with active ingredients in
utes significantly to this problem. many different ways, producing products with
Tobin et. al., in attempting to further improve varying characteristics. Depending on the type
and simplify the delivery of aerosolized drug of aerosol system utilized, the pharmaceutical
from an MDI, developed a new reservoir aerosol- aerosol may be dispensed as a fine mist, wet
type delivery system (RADS), consisting of a spray, quick-breaking foam, stable foam, semi-
700-ml collapsible plastic bag into which the solid, or solid. The type of system selected de¬
aerosol can be injected.19 This unit is designed pends on many factors, including the following:
to allow patients more time to inhale the medica¬ MTjfphysical, chemical, and pharmacologic prop¬
tion after actuating than did the conventional erties of active ingredients, and'(2(fsite of appli¬
MDI, and it eliminates some of the loss of medi¬ cation.
cation associated with too rapid propulsion or
inhalation of aerosolized drugs. This unit
(InspirEase by Key Pharmaceuticals, Inc.) con¬ Types of Systems20
sists of a collapsible reservoir bag and a special Solution System. A large number of aerosol
mouthpiece that is fitted with a reed that pro¬ products can be formulated in this manner. This
duces a warning sound when patients are inhal¬ system is also referred to as a two-phase system
ing too quickly. and consists of a vapor and liquid phase. Jffiben
A new metered propellant-free intranasai the active ingredients"are soluble in tEe propel¬
pump has recently been introduced to deliver lant, no other solvent is required. Depending on
flunisolide, an effective steroidal agent in the tlieTypg^of^prayTbquiredTthe propellant may
relief of symptoms associated with seasonal .or consist of propellant 12 or A-70 (which produce
perenhiaTThinnus. The pump~permits the ad¬ very fine particles), or a mixture of propellant 12
ministration of a metered dose of steroid without and other propellants as indicated in Tables
utilizing propellants, which by their cooling ef¬ 20-1, 20-2, and 20-3..As other propellants with
fects often cause smarting and irritation to the vapor pressures lower than that of propeDahri2
nasal mucosa. The metered aerosol pump also are addedTcTpropellant 12, ThcTpressure of the
ensures accurate dosage and eliminates many of 'system decreases, resultingTn ihe production of
the administration problems associated with larger particles. A lowering of the vapor pressure
nose drops. The concept of propeLlant-free me¬ also is produced through the addition of less vol¬
tered delivery offers a new dimension to intra¬ atile solvents such as ethyl alcohol, propylene
nasal delivery of potent therapeutic agents. glycol, ethyl acetate, glycerin, and acetone. The
amount of propellant used may vary from 5%
(for foams) to ,95% (Tor inhalation products) of
Formulation of Pharmaceutical the entire formulation. When a spray is pro-
duced with larger particles, a decrease is noted
Aerosols in the number of fine particles, decreasing the
An aerosol formulation consists of two essen¬ danger of inhaling these materials through for¬
tial components: product concentrate and pro¬ mation and subsequent inhalation of airborne
pellant. The product concentrate consists of ac¬ particles. These sprays are also useful for topical

PHARMACEUTICAL AEROSOLS • 597

 Inhalation Liquids, Foams

Inhalation Pharyngeal

Nasal Nasal
FIG. 20-8. Various actuators and applicators for pharmaceuticals. (Courtesy of Peckiney Ugine Kuhlman Development
Inc., Greenwich, CT.)

preparations, since they tend to coat the affected creased, the pressure increases. With the excep¬
area with a film of active ingredients. Depend¬ tion of propellant 12/11 (30:70), the pressure of
ing on the boiling point of the solvent used, the these systems necessitates packaging the con¬
rate of vaporization of the propellant is de¬ tents in a metal container. If the product is to be
creased, thereby increasing any chilling effect packaged in a glass container, a mixture of pro¬
that may be present. This system can best be pellant 12/114 (20:80) or (10:90) can be used.
exemplified by the following general formula¬ Table 20-4 indicates the pressure limitations in
tions: using various aerosol containers.
Aerosols intended for inhalation or for local
Weight activity in the respiratory system in the treat¬
% ment of asthma may be formulated as follows:

Active ingredients to 10-15

Propellant 12/11 (50:50) to 100 Weight
%
Propellant 12/11 (30:70), propellant 12/114
(45:55), or propellant 12/114 (55:45) also can Isoproterenol HC1 0.25
be utilized for oral inhalation aerosols or other Ascorbic acid 0.10
FDA-exempted products such as contraceptive Ethanol 35.75
foams. As the amount of propellant 12 is in¬ Propellant 12 63.90

598 • The Theory and Practice of Industrial Pharmacy

 Nasal Nasal

FIG. 20-8. (Continued) Nasal Auricular

This type of formulation is usually packaged Solvents such as ethanol or

in a 15- to 30-ml stainless steel, aluminum, or propylene glycol up to 10-15
glass container. Since propellant 12 has a rela¬ Distilled wate; 10-15
tively high vapor pressure, the addition of pro¬ Hydrocarbon propellant A-46 55-70
pellant 114 is recommended in order to reduce
the pressure, as illustrated by the following ex¬ Depending on the amount of water present, the
ample:21 final product may belTsolution or a three-phase
system. SolutiorT aerosols produce a fine to
Weight
coarse spray, depending orTtne concentration of
%
the "other ingredients. Hydrocarbon propellant-
A-'/U produces a drier particle, while propellants
Octyl nitrite 0.1
Ethanol 20.0
A-17 and A-31 tend to produce a wetter spray.
Propellant 114 49.2 Hydrocarbon propellants can also be used for
Propellant 12 30.7 products packaged in plastic-coated glass bot¬
tles, provided that the amount of flammable
Hydrocarbons in topical aerosol pharmaceuti¬ hydrocarbon propellant present does not exceed
cal preparations are used as follows: 15% of the total product weight and that the
container has a volumetric capacity not exceed¬
Weight ing 5 fluid ounces. In addition, one of every
% 1000 bottles must be tested to 250~psig without
failure. The manufacturer ofthe aerosol product
Active ingredients up to 10-15 must test one bottle ouf~of^eaHi lotTrPiU.UOO

PHARMACEUTICAL AEROSOLS • 599

Table 20-4. Pressure Limitations of Nonrefilla- golubilize some of the propellant in the water. By
ble Aerosol Containers viitueoFTts surface-tension-lowering properties,
ethanol also aids in the production of small par¬
Maximum ticles.
Pressure Temperature Surfactants have been used to a large extent
Container (psig) °F to produce a~satisfactorv homogeneous disper¬
sion. Surfactants that possess low water solubil-
Tinplated Steel
Low pressure up to 140* 130 TtyaruTTugh solubflity in nonpolar solvents have
2 P from 140 to 160* 130 been found to be the most useful. Long-chain
2 Q from 160 to 180* 130 fatty acid esters of polyhydroxylic compounds
Uncoated glass less than 18t 70 including glycol, glycerol, and sorbitol esters of
Coated glass less than 25t 70 oleic, stearic, palmitic, and lauric acids exem¬
Aluminum up to 180J 130 plify this series. In general, about 0.5 to 2.0% of
Stainless steel up to 180J 130 surfactant is used. The propellant content varies
Plastic less than 25* 70 from about 25 to 60%, but can be as low as 5%,
depending on the nature of the product.
"Department of Transportation (DOT) Regulations. Consult
regulations for definition of 2 P and 2 Q containers.
To achieve the desired fine particle size with
tAerosol containers with a pressure less than 25 psig at 70°F products containing large amounts of water and
and 89 psig at 130°F or a capacity of less than 4 fluid ounces are a low proportion of propellant, a mechanical
not regulated by the DOT. breakup actuator must be used along with a
t Exemptions can be obtained for higher pressures in these con¬ “vapor tap valve.”
tainers.
A recent development that is useful for phar¬
maceutical aerosols is the Aquasol* Valve.22,23
bottles to the hursting-point. and theJamming The new Aquasol system allriws tor the dispens¬
pressure must not he less than 3Qfl psig One ing of Xfine mist or snrav of active ingredient
fullycharged bottle from this lot must be flissoTvecT in water, which is not possible with
dropped to an unyielding surface from a height the usual three-phase system. Since only active
of 4 feet without producing flying glass or a shat¬ ingredient and water are dispensed (propellant
tering effect. Should either of these two bottles is in vapor state and present only in extremely
fail, then 10 additional bottles must be tested for small quantity), there is no chilling effect as oc¬
each failed test. Failure of any of these 10 sam¬ curs with the hydrocarbon propellant.
ples would cause the entire lot to be rejected. The Aquasol system is illustrated in Figures
Finally, one fully charged bottle out of each 20-9 and 20-10. It is designed to dispense pres¬
1000-bottle lot must be heated so that the pres¬ surized products efficiently and economically
sure in the container is equivalent to the equilib¬ using relatively small amounts of hydrocarbon
rium pressure of the contents at 130°F, without propellant; however, it can also function effec¬
evidence of leakage or other defect.* tively using fluorocarbon propellants. This sys¬
Water-Based System. Relatively lame tem, which is essentially a “three-phase” aero¬
amounts of water can bg used to replace alLor sol, permits the use of fairly large quantities of
parirorthenonaqueous~solvents used in aero¬ water in the formulation.
sols. ThescTproducts are generally referred to"as The chief difference between the Aquasol sys¬
“wafer-based” aerosols, and depending on the tem and the “three-phase” system is that the
formulation, are emitted as a spray or foam. To former dispenses a fairly dry spray with very—
produce a spray, the formulation must consist of small particles. This relative drvness and small
a dispersion of active ingredients and other sol¬ particle size are due chiefly to the design of the
vents in an^emulsion” svstemln which theTprcF valve, which dispenses vaporized propellant
ndlant~Is in the external phase. In this way, rather than liquefied propellant. In addition, the
iwflien~the product is dispensed, the propellant vaporized propellant contributes to the nonflam¬
vaporizes and disperses the active ingredients mability of the stream of product as it is dis¬
into minute particles. Since propellant and pensed. For example, a fine, almost dry spray is
water are not miscible, a three-phase aerosol obtained using six parts of water with one part of
forms (propellant phase, water phase, and vapor hydrocarbon propellant. Not only is the resulting
phase;. EtfiahoThas been used as a cosolvent to spray nonflammable, but it actually extin¬
guishes an open flame.
As can be noted from Figure 20-9, the active
'Exemption DOT-E-8008 for 4-oz. aerosol bottles—
Requested and obtained by Wheaton Plasti-Cote Com¬
pany. * Precision Valve Corporation, Yonkers, NY.

600 • The Theory and Practice of Industrial Pharmacy

 VALVE CLOSED

6*s»Er

PBOOUCI

FIG. 20-9. The Aquasol dispenser system—valve closed. (Courtesy of Precision Valve Corporation, Yonfeers, NY.)

ingredient is dissolved or suspended in water or layer may or may not be immiscible. As the
in a mixture of alcohol and water. The hydrocar¬ amount of alcohol increases, the miscibility of
bon propellant floats on top of the aqueous layer these two layers increases. As a pure alcohol sys¬
and exists as both a liquid and a vapor. Depend¬ tem is approached, complete miscibility occurs,
ing on the amount of alcohol present in the at which time a two-phase system that can func¬
aqueous layer, the propellant and water/alcohol tion satisfactorily is produced. Flammability is

PHARMACEUTICAL AEROSOLS *601

 VALVE OPEN PPCVEPT <ja ESP POEUC X

Mix PRIOfl TO SWlRt- CHPMDfS

MQtfMTiNG CUP

FIG. 20-10. The Aquasol dispenser system—valve open. (Courtesy of Precision Valve Corporation, Yonkers, NY.)

increased, however, owing to the large amount while the product is forced into the actuator by
of alcohol present, as well as to the fact that liq¬ the pressure of the propellant. At this point,
uid propellant is now also being dispensed. product and vapor are mixed with violent force,
In the Aquasol system, the vapor phase of the resulting in a uniform, finely dispersed spray.
propellant and the product enter the mixing Depending on the configuration of the valve
chamber of the actuator through separate ducts and actuator, either a fine dry spray or a coarse,
or channels. Moving at tremendous velocity, the wet spray can be obtained. Previous studies
vaporized propellant enters into the actuator have shown that a fine dry spray is obtained

602 • The Theory and Practice of Industrial Pharmacy

when a ratio of about 6 parts of product to 1 part The oleic acid is present as a dispersing agent
of propellant is used. Up to 30 parts of product to for the steroid and is an aid in the prevention or
one part of propellant has also produced a satis¬ reduction of particle growth or agglomeration. In
factory spray, but in this case, a more coarse addition, it serves as a valve lubricant and pre¬
spray results. In the Aquasol system, it is almost vents the metered valve from “sticking” in the
impossible to dispense only the pure propellant open position.
until the package is depleted of the aqueous Particles of certain materials tend to agglom¬
product. erate immediately following suspension or
Suspension or Dispersion Systems. Vari¬ shortly thereafter, owing to solubility, moisture,
ous methods have been used to overcome the or particle size growth. Caking results when the
difficulties encountered that are due to the use aggregates become massive. The degree of ag¬
of a cosolvent. One such system involves.a dis¬ glomeration is accelerated at elevated tempera¬
persion of activeingredients in the propellant nr tures. This phenomenon may range in degree
a mixture of propellants. To decrease the rate of from flocculation, in which the particles are
settling of the dispersed particles, various sur¬ loosely bound, to aggregation, in which the par¬
factants or suspending agents have been added ticles are held together tightly and often fused.
to the systems.^'^ TThese systems have been In severe cases, the particles may adhere to the
developer) primarily Tor use with oral inhalation walls of the container. Agglomeration may result
aerosols. Several examples folluw. in valve clogging, inaccuracy of dosage, and de¬
pending on the nature of the active ingredients,
Weight damage to the liner and possibly to the metal
% container.
The moisture content of both the suspensoid
Epinephrine bitartrate
and the propellant affects the stability of the aer¬
(within 1 to 5 microns) 0.50
osol system and must be below 300 ppm. Higher
Sorbitan trioleate 0.50
moisture levels generally result in particle ag¬
Propellant 114 49.50
glomeration. So that this level is not exceeded,
Propellant 12 49.50
rigid control over the conditions of manufacture
The epinephrine bitartrate has a minimum solu¬ must be exerted, and drying both the suspensoid
bility in the propellant system, but is sufficiently and the propellant prior to manufacture be¬
soluble in the fluids in the lungs to exelt a thera¬ comes necessary. This can be accomplished by
peutic activity. passing the propellant through various desic¬
cants.
Isoproterenol sulfate 33.3 mg Materials suspended in a vehicle in which
Oleyl alcohol 33.3 mg they are partially soluble show signs of particle
Myristyl alcohol 33.4 mg size growth. To decrease this phenomenon, a
Propellant 12 7.0 g chemical derivative of the drug that shows mini¬
Propellant 114 7.0 g mum solubility in the propellant vehicle must be
selected. From a physiological viewpoint, the
The isoproterenol sulfate remains dispersed in
drug must show some solubility in the fluids
the propellant vehicle for a sufficient length of
surrounding the lung tissue. For example, a de¬
time to allow for the dispensing of a suitable
rivative such as epinephrine bitartrate is pre¬
dose. The physical stability of an aerosol disper¬
ferred when preparing a suspension of the drug
sion can be increased by (1) control of moisture
in the propellant system. The hydrochloride or
content, (2) use of derivatives of active ingredi¬
sulfate, however, is preferred when a solution
ents having minimum solubility in propellant
aerosol is being formulated, since they are solu¬
system (the pharmacologic activity must also be
ble in a hydroalcohol solution, which is miscible
considered), (3) reduction of initial particle size
with the propellant.
to less than 5 microns, (4) adjustment of density
The physical stability of a dispersed system
of propellant and/or suspensoid so that they are
depends primarily on the rate of agglomeration
equalized, and (5) use of dispersing agents.
of the suspensoid. This rate is affected by the
A formulation for oral inhalation that contains
initial particle size of the drug, which miist be in
a steroid and is used to alleviate the symptoms of
the range of 1 to 5 microns; the exact size de¬
asthma would include:
pends on the nature of the active ingredient and
Steroid compound 8.4 mg intended use of the product. This particle size
Oleic acid 0.8 mg range is necessary to ensure that the particles
Propellant 11 4.7 g reach the intended site of action. Suspensions
Propellant 12 12.2 g containing materials intended for topical admin-

PHARMACEUTICAL AEROSOLS • 603

istration do not require particles of the same ing irritating ingredients, or when the material
degree of dispersion as the inhalation aerosols, is applied to a limited area.
but for reasons of physical stability, the particles Aqueous Stable Foams. These can be for¬
are seldom over 50 microns in size. The active mulated as follows:
ingredients may be reduced to required particle
sizes through use of suitable grinding equip¬ % w/w
ment. Active ingredients
Consideration must also be given to the den¬ Oil-waxes
95.0-96.5
sity of the suspensoid and the propellant vehicle. o/w Surfactant
By decreasing the difference between these two Water
densities, the rate of settling of the suspensoid Hydrocarbon propellant 3.5-5.0
can be decreased. The density of both the pro¬
pellant and/or suspensoid may be changed by While the total propellant content may be as
the addition of a compound of higher or lower high as 5% in certain cases, it usually is about 8
density, so that the density of the suspensoid to 10% v/v or 3 or 5% w/w. As the amount of
may be made equal to the propellant density. propellant A-70, A-46, etc. increases, a stiffer
Various surfactants and lubricants have been and dryer foam is produced. Lower propellant
investigated in an attempt to control the rate of concentrations yield wetter foams. One, type of
agglomeration. Such agents as isopropyl myris- system producing a stable foam may be illus¬
tate and mineral oil have been added to these trated by the following example:
aerosols to reduce agglomeration and to act as a
lubricant for the particles in passing through the % w/w
valve orifices. They have met with moderate Myristic acid 1.33
success. The addition of surfactants to aerosol Stearic acid 5.33
suspensions has been most successful. These Cetyl alcohol 0.50
surfactants exert their activity by coating each of Lanolin 0.20
the particles in suspension and become oriented Isopropyl myiistate 1.33
Triethanolamine 3.34
at.the solid-liquid interface. Agglomeration is
Glycerin 4.70
reduced, thereby increasing stability by provid¬
Polyvinylpyrrolidone 0.34
ing a physical barrier. According to investiga¬
Water, purified 82.93
tions carried out by Young, Thiel, and Laur-
sen,26 nonionic surfactants were found to be
most effective. Those surfactants having an This can be used in a pharmaceutical aerosol
HLB less than 10, such as sorbitan trioleate, according to the following formula:
could be utilized for aerosol dispersions. Other
agents that were found to be useful are sorbitan % w/w
monolaurate, sorbitan monooleate, and sorbitan Active ingredients 2.0
sesquioleate. These surfactants are effective in a Emulsion base 94.0-95.0
concentration of 0.01 to 1%, depending on the Hydrocarbon propellant A-46 3.0-4.0
concentration of the suspensoid and the in¬
tended use of the product. Several different steroids, antibiotics, and other
Vapor tap valves also have been used with dis¬ agents may be dispensed in this mfirmer. "Both
persion aerosols to decrease the danger of valve hydrocarbons and compressed gas propellants
clogging. The added propellant, escaping as a may be used. Unless an exemption has been
vapor, aids in clearing the valve of solid parti¬ granted by the FDA, fluorocarbons are no longer
cles. used for these products. (Contraceptive foams
Foam Systems. Emulsion and foam aerosols have been exempted.)
consist of active ingredients, aqueous or nona- The techniques used in preparing an aerosol
queous vehicle, surfactant, and propellant, and emulsion are the same as those used for non¬
are dispensed as a stable or quick-breaking aerosol emulsions. Surfactants that showed
foam, depending on the nature of the ingredi¬ some solubility in the propellants were most ef¬
ents and the formulation. The liquefied propel- fective.
lant is emulsified and is generally found in the Nonaqueous Stable Foams. Nonaqueous
internal phase. Nonaerosol emulsions are usu¬ stable foams may be formulated through the use
ally in lotion or viscous liquid form, but aerosol of various glycols such as polyethylene gfvcol.
emulsions are dispensed as.foams, and this can which may be formulated accofdmgTcT the rol-
be advantageous for various applications involv¬ lowing:

604 • The Theory and Practice of Industrial Pharmacy

 % w/w same technology was used to dispense hair col¬
Glycol 91.0-92.5 ors and dyes, but unfortunately, they were sub¬
Emulsifying agent 4.0 ject to some of the same problems, as well as
Hydrocarbon propellant 3.5-5.0 some corrosion problems, and were therefore
unsuccessful. It has been reported that these
The emulsifying agents found most effective systems would be advantageous in dispensing
were from the class of glycol esters, for example, mqdicated foams in which the application of
propylene glycol monostearate. Various medici¬ heat would be desirable. The technology is avail¬
nal agents can be incorporated into this base. able and.is fully discussed in the previous edi¬
Quick-Breaking Foams. In this system, the tion of this book.27
propellant is in the external phase. When dis¬ Intranasal Aerosols, Drug delivery systems
pensed, the product is emitted as a foam, which intended for the deposition of medication into
then collapses into a liquid, t his type of systenT the nasal passageways has long been used as a
is especially applicable to topical medication, most effective means of administering drugs in¬
whichcan be appUedtohmited or to large areas tended to produce either a local or systemic ef¬
without the use of a mechanical force to dis¬ fect. Until recently, the modes of administering
pense the active ingredients. Quick-breaking intranasal preparations have been limited to
aerosol foams may be formulated starting with nasal drops, nonpressurized nasal sprays
the following: (mists), inhalants, and intranasal gels (jellies),
creams, and ointments. A new alternative to
% w/w these traditional intranasal preparations is gain¬
Ethyl alcohol 46.0-66.0
ing rapid popularity—the pressurized metered
Surfactant 0.5-5.0
nasal aerosol.
Water 28.0-42.0
The intranasal aerosol offers numerous ad¬
Hydrocarbon propellant 3.0-15.0
vantages, including the delivery of a measured
dose of dfugTexcellent depth of penetration into
The surfactant can be of the nonionic, ani¬
file nasal passageway with minimal inadvertent
onic, or cationic type. It should be soluble in
penetration into the lungs, reduced droplet or
both alcohol and water. If the proportion of in¬
pmtidgslzerlbwer dosage than comparable sys¬
gredients is varied, foams may be obtained hav¬
temic preparations, maintenance of sterility
ing a wide range in stability.
from dose to dose, greater patient compliance,
A specific formulation for a quick-breaking
decreased mucosal irritability, and greater flexi¬
foam would consist of:
bility in product formulation.
The following aerosol products are available
% w/w
for intranasal administration:
Polawax* 2.0
SDA 40 Anhyd. 61.0
Perfume 1.5 Trade Dosage Active
Menthol 0.1 Name(s) Form .Ingredient Indication
Water, purified 35.4
Decadron Pressurized Dexamethasone Allergic
100.0
Turbinaire* aerosol sodium or inflam¬
suspension phosphate matory
This is pressurized by.mixing 90% concentrate
nasal
and 10% propellant. The pressure should be
conditions.
below 25 psig, and the product can be packaged
in glass aerosol containers using a valve and Beconasef Pressurized Beclomethasone Seasonal
foam actuator. VancenaseJ aerosol dipropionate and
Thermal Foams. These foams were devel¬ suspension perennial
oped several years ago and were used to produce rhinitis.
a warm foam for shaving. They were not readily
accepted by the consumer, however, and were * Merck Sharp & Dohme, West Point, PA.
IGlaxo Inc., Research Triangle Park, NC.
soon discontinued, owing to inconvenience of fSchering Corporation, Kenilworth, NJ.
use, expense, and lack of effectiveness. The

Although the dexamethasone preparation

'Polawax is a nonionic emulsifying wax consisting of ste- (Decadron Turbinaire) was introduced into the
aryl alcohol and ethylene oxide reaction products (Croda, marketplace some 10 to 12 years ago, it was not
Inc., New York, NY.) until the introduction of beclomethasone dipro-

PHARMACEUTICAL AEROSOLS • 605

pionate (Beconase and Vancerase) during the Selection of Components
past two years that these nasal aerosol products
have met with widespread success. This success Propellant. Prior to 1978, fluorinated_hydro-
has been responsible for the increased interest carbons were used almost exclusively as the pro¬
shown by pharmaceutical manufacturers in de¬ pellants for all types of pharmaceutical aerosols.
veloping additional aerosols for administration Their chemical inertness, lack of toxicity, lack of
by the nasal route. flammability and explosiveness, and their safe
The two intranasal aerosols currendy mar¬ record of use made them ideal candidates for
keted in the United States are suspension for¬ use. The publication of the “ozone depletion the¬
mulations. The basic formulation for the intra- ory” in the mid-1970s, however, and the alleged
nasal aerosol suspension is as follows: implication of the fluorocarbons in depleting the
ozone levels in the atmosphere, led to the phas¬
Active ingredients (micronized) up to 1.0% weight ing out and ban of the use of fluorocarbon pro¬
Dispensing agent, additives, pellants in aerosols (with few exceptions) in
solvents, etc. up to 1.0% weight 1978. This ban, promulgated by the Environ¬
Propellant 12/11 (60:40) up to 98.0% weight mental Protection Agency (EPA), Food and Drug
100.0% weight Administration (FDA), and the Consumer Prod¬
ucts Safety Commission, became fully effective
In most cases, the intranasal formulation is in April 1979, when manufacturers could no
almost identical to the comparable inhalation longer ship aerosol products containing fluoro¬
product TeTgT7~Vanceril, Vancenase; Decadron carbons unless the product carried a specific
Respihaler, Decadron Turbinaire). This is not federal exemption.
surprising since the nasal passageways, like the While some propellant manufacturers indi¬
respiratory airways, require a fine uniform dis¬ cated that there were other suitable replace¬
tribution of material to promote therapeutic ac¬ ments for propellants 11, 12, and 114, the only
tivity and minimize irritability. Various attempts ones that have survived the necessary toxicity
have been made to formulate these active in¬ tests (long- and short-range) are fluorocarbons
gredients in a nonaerosol, squeeze-bottle type of 152a, 142B, and 22, which may be of limited
product; however, because of the relatively large value. The other alternatives include hydrocar¬
particle size produced by the squeeze bottle, the bons, compressed gases, and mechanical de¬
product has been found to be quite irritating to vices and pumps. Of these alternatives, how¬
the nasal mucosa, with the particles being rap¬ ever, hydrocarbons were restricted to use with
idly transferred to the back of the mouth, where foams and water-based aerosols, and com¬
they are swallowed or expectorated. pressed gases were of limited value in aqueous
Probably the major difference between the products where lhe propellant and water were
inhalation aerosol product and the intranasal .not miscihla While compressed gases overcame
’aerosol product is the design of the adaptor lhfT the immiscibility of the components, other prob¬
nasal adaptors are considerably shorter and nar¬ lems such as loss of propellant, and to a lesser
rower, minimizing propellant vaporization be¬ degree, dispersion of the spray became appar¬
fore contacting the mucosa. This results in lower ent. Since compressed jasjsystems do not have a
percentages of smaller particles, which is desira¬ chilling effect, they are applicable , to topical
ble because this decreases the number of parti¬ preparations.
cles entering the respiratory airways. With the development of newer valve technol¬
Solution and emulsion tynes of nasal aerosols ogy (the vapor tap and the Aquasol valve), it was
are also regarded as vehicles for the delivery of found that hydrocarbon propellants, such as bu¬
medication through the intranasal passageways, tane, propane, isobutane, and their mixtures,
.but they have proven to be intrinsically more could be safely used not only with aqueous prod¬
complex to formulate. These forms of pressur- ucts, but with solvent-based aerosols as well. At
izecTaefOsoI nasal preparations introduce addi¬ present, hydrocarbons can be used for all types
tional problems, such as vehicle viscosity (cilia of topical aerosols, and their flammability prop¬
effects), irritation Trom additives, and leakage erties (as measured by the flame extension test)
from nasal passageways. Many investigators are can be reduced to within safe limits as allowed
now assessing the biopharmaceutical aspects of by the Department of Transportation (DOT) and
nasal absorption, and in the near future, one can can meet hazard labeling requirements. As a
optimistically expect to see a number of drugs result of this new technology, all nonexempted
administered intranasally for systemic action. 8 topical pharmaceutical aerosols have been satis-

606 • The Theory and Practice of Industrial Pharmacy

factorily reformulated using a hydrocarbon or pure tin or combinations of tin, silver, and other
blend of hydrocarbon as the propellant. metals are used, as well as containers with a
Inhalation aerosols for oral or nasal use have welded side-seam. It is important that specifica¬
been exempted from the FDA ban, and the fluo- tions for containers include these considera¬
rinated hydrocarbons—namely, propellants 19,. tions, and that product stability versus composi¬
12/114, and in somecases 12/11—are still used tion of solder be evaluated. For this reason, the
ContracepSve~foami~are exempted and still uti¬ welded side-seam container is now preferred for
lize fluorocarbons aslhe propellant. Recently the use with pharmaceuticals.
FDA granted an exemption for a topical antibi¬ Chemical Reactions. Special attention
otic aerosol. It should also be indicated that should be given to those products containing
these new products wiF require a new drug ap- alcohol and packaged in aluminum containers.
plicgtion (NDA). Anhydrous ethanol is extremely corrosive to alu¬
The compressed gases—nitrogen, nitrous minum and reacts according to the following
oxide, and carbon dioxide—can be used but are equation:
oflimited value, the pump system Is used for
liquid antiseptics, germicides, and nasal sprays.
Containers. Both glass and metal containers
have been used for pharmaceutical aerosols.
Glass is preferred, but its use is limited, owing to
its brittleness and the danger of breakage should The hydrogen, which is slowly liberated, in¬
the container accidentally be dropped. When the creases the pressure in the container. This in¬
total pressure of the system is below 25 psig and crease in pressure, along with a general dissolv¬
there is not more than15% propellant, glass can ing of some of the aluminum, may result in
be safely used. Pressures up to 33 psig can be rupture of the container. This reaction can be
utilized in conjunction with a glass container reduced or prevented by anodizing the alumi¬
having a doub!g~pIasSc~outer coating. num and adding water to formula. The presence
Most nonaqueous products can be placed into of 2 to 3% water tends to inhibit the reaction.
an unlined tinplated metal container. Depend¬ Nonpolar solvents appear to be relatively safe in
ing on the degree of protection desired, 'A, V2, or aluminum containers. Polar solvents tend to be
1 pound of tin per base box can be used. This corrosive to bare aluminum, but the reaction can
type of container has been found to be satisfac¬ be controlled by the addition of water and/or
tory for many alcohol-based pharmaceuticals, other inhibitors.
e.g., spray-on bandages. Other Containers. Creams and ointments
Products having a low pH and containing may be dispensed from a pressurized container
water utilize organic linings of-epoxy and/or by the use of an aluminum container that has
vinyl resins. Although the vinyl resin forms~a been fitted with a piston and nitrogen or hydro¬
touglfTilm, it is poorly resistant to steam and carbon as the propellant. When the valve is
cannot be used for products that must be heat opened, the pressure against the piston pushes/
sterilized or filled hot (about 200°F). For this the piston, causing the product to be dispensed.
purpose, an epoxy resin can be used since it has The viscosity of the finished product plays sin
a greater degree of heat stability. Both materials important role in the satisfactory dispensing (of
are essentially odorless and flavorless, although the product.
less odor and flavor are found in vinyl as com¬ Many attempts have been made to separate
pared with the epoxy material. A commonly product from the propellant. One such system
used organic coating consists of an undercoat of utilizes an “accordion-pleated” plastic bag as
vinyl and a top coat of epoxy resin. This has shown in Figure 20-11. The product is placed
Hein used to best advantage for those, aqueous inside the bag, and propellant is injected into the
products of low pl L outer container through the rubber-plugged hole
'TTiostr products containing soaps utilize simi¬ located in the bottom of the container.
lar liners, but special attention must be given to Another development in barrier packs uses a
the solder that is used for the “side-seam” of laminated film made into a flexible bag. A perfo¬
some containers. A mixture of 2% tin and 98% rated dip tube is attached to the valve and func¬
lead is used when the pressure is below 40 psig. tions to prevent the bag from collapsing as the
When soaps are involved, lead reacts with the contents are used. This system, termed “Powr
fatty acids present to form insoluble lead salts, Flo” (American Can Company), is useful for dis¬
which cause valve clogging. For this purpose, pensing pnaramceutical ointments and creams.

PHARMACEUTICAL AEROSOLS • 607

 stretches, thereby causing mechanical energy to
squeeze out the contents as the valve is released.
Since this system does not contain a gas, there is
little internal pressure. Two bladders are used,
assembled one inside the other. The outer blad¬
der is usually made from natural rubber latex.
The valve is inserted into the bladder, and this
unit is then fitted into an outer nonpressurized
container. The product is filled through the
valve by means of a piston-type filler, which
forces the product into the bladder.
Valves, Actuators, and Applicators.
Valves are selected on the basis of materials of
construction and size of various orifices. Al-
ffiough it is extremely difficult to indicate the
proper valve for each product, suggested valve
designs for specific applications are available.
Various applicators have been specially de¬
signed for use with aerosol pharmaceuticals.
Inhalation actuators must have all the charac¬
teristics of spray actuators and must allow es¬
cape of propellant vapors so that the vapors are
not inhaled in appreciable amounts by the user.
Throat applicators must be capable of depositing
the medication directly into the throat area.
Elongated tubes having small internal orifices,
FIG. 20-11. Sepro container. (Courtesy of Continental which permit a breakup of the spray, are gener¬
Can Company, Chicago, IL.) ally used. Nasal actuators are designed to fit into
the nose and deliver the product as a fine mist.
Other applicators have been designed for spe¬
The Preval system not only separates the pro¬ cific uses, including vaginal application, oph¬
pellant from the product, but allows the product thalmic application, and others. (See Figs. 20-7
to be dispensed as a spray or powder. This sys¬ and 20-8.)
tem consists of an aluminum cartridge contain¬
ing propellant 12 and an aerosol valve. A dip
tube extends from the propellant chamber to the Stability Testing of
bottom of the container and allows for the flow of
product when the valve is opened. Around the Pharmaceutical Aerosols
top of the valve housing, a vapor tap is placed, One of the most important considerations in
which extends into the propellant chamber. The the formulation of a pharmaceutical aerosol is its
product is added to the container (which need stability. Those aspects directly concerned with
not be a pressure container), and then the valve the components used to prepare the pharmaceu¬
with propellant cartridge is inserted. When the tical aerosol must be fully studied. The effect
specially designed actuator is depressed, propel¬ that the container has upon the product, and
lant vapor escapes from the propellant chamber. conversely, the effect of product upon container,
This creates a “venturi” effect, drawing up some must be considered.
of the product. At this point, mixing of propel¬ The same considerations apply to the valve
lant vapor and product takes place. The vapor¬ components. Even slight changes in the various
ized propellant then aids in carrying the product components of the valve may result in an inop¬
through the actuator, where it is dispersed into erative package. The valve component of the
the desired spray. Varying ratios of propellant to aerosol package has several working parts made
product can be achieved, with results ranging of different materials, such as natural or syn¬
from a fine to a coarse spray (Fig. 20-12). thetic rubber, plastic, and stainless steel. All
A nonaerosol package that is self-evacuating these materials may produce an adverse effect
has been developed by Plant Industries and is on the product and must be fully studied.
known as Selvae. This system utilizes a resilient Since a variety of different materials are used
bladder, which is filled with the product. As the in the make-up of the container, valve, and dip
product is filled into the bladder, the bladder tube, it is difficult to determine whether a reac-

608 • The Theory and Practice of Industrial Pharmacy

 PROPELLANT VAPOR
AND PRODUCT
DISPENSED

FIG. 20-12. Schematic view of Preval. (Courtesy of Precision Valve Corporation, Yonkers, NY.)

tion takes place between the materials and the chromatography curves, color, and odor. These
drug. Many of the components come into inti¬ are then used for comparison during each evalu¬
mate contact with the medicinal agent. To deter¬ ation of the product.
mine whether these reactions do occur, all mate¬ These samples are usually stored on then-
rials must be studied separately and collectively. sides so that the product comes into contact with
Several container coatings as well as valves with both the valve mounting cup and the container.
different subcomponents may be studied so that When three-piece metal cans are used, care
any reaction between the component and the should be taken to ensure that some samples
product may be detected. Samples are prepared have liquid as well as gaseous contact with the
and packaged in glass aerosol containers as con¬ side-seams (soldered or welded).
trols. Container. The contents of the container are
The testing of these aerosols must cover three removed by chilling the contents to a tempera¬
areas: (1) concentrate and propellant, (2) con¬ ture of 0°F or less and opening the container.
tainer, and (3) valve. Evidence of decomposition The container is then examined for signs of cor¬
or deterioration in any of these areas could result rosion. These changes can be detected without
in an ineffective product. A more detailed dis¬ much difficulty, since attack upon tinplate, tin-
cussion of the testing of aerosols can be found free steel, or aluminum is generally visible to the
elsewhere in the literature.29 naked eye and under a microscope. Small pin¬
Concentrate and Propellant. Immediately holes can easily be detected. For those con¬
after preparation, several of the important physi¬ tainers that have internal lacquering, the exami¬
cochemical constants of the product are deter¬ nation must ensure that the lacquer is not
mined. These vary, depending on the nature of softened, dissolved, peeled, or blistered by the
the product, but may well include vapor pres¬ concentrate. Special attention should be paid to
sure, spray rate of valve, pH, density or specific the side-seam and headspace, as there is a
gravity, refractive index, viscosity, total weight, greater danger of attack upon these areas.
assay of active ingredients, infrared, and/or gas When glass is used for the container, an ex~

PHARMACEUTICAL AEROSOLS • 609

animation of the container can be omitted. Plas¬ makes use of a piston arrangement so that a pos¬
tic containers may require special testing to de¬ itive pressure is always maintained. Figure
termine whether leaching or sorption has taken 20-13 illustrates typical laboratory pressure fill¬
place. ing equipment. This equipment cannot be used
Valve. The valve should be examined to en¬ to fill inhalation aerosols fitted with a metered
sure that it is functional and will satisfactorily valve. Pressure filling equipment that fills
dispense the product and be easily closed. This through “pressure-fillable” metered valves is
can readily be determined during the dispensing available.
of the product. The valve cup should be exam¬ Cold Filling Apparatus. Cold filling appara¬
ined for evidence of corrosion. The various valve tus is somewhat simpler than the pressure fill¬
subcomponents should also be examined for evi¬ ing apparatus. All that is needed is an insulated
dence of softening, cracking, elongation, or dis¬ box fitted with copper tubing that has been
tortion. Several of these effects can result in de¬ coiled to increase the area exposed to cooling.
fective valves that will not operate properly. Figure 20-14 illustrates such a unit, which must
Elongation and cracking of the dip tube should be filled with dry ice/acetone prior to use. This
be noted, and if present, corrected. system can be used with metered valves as well
as with nonmetered valves; however, it should
not be used to fill hydrocarbon aerosols since an
Manufacture of Pharmaceutical excessive amount of propellant escaping and
vaporizing may form an explosive mixture at the
Aerosols floor level (or lowest level). Fluorocarbon vapors,
To prepare and package pharmaceutical aero¬ although also heavier than air, do not form ex¬
sols successfully, special knowledge, skills, and plosive or flammable mixtures.
equipment are required. As with other pharma¬ Compressed Gas Filling Apparatus. Com¬
ceutical products, these operations must be car¬ pressed gases can be handled easily in the labo¬
ried out under strict supervision and adherence ratory without the use of elaborate equipment.
to rigid quality controls. Since part of the manu¬
facturing operation (addition of propellant to
concentrate) is carried out during the packaging
operation, the quality control system must be
modified to account for this difference. In addi¬
tion to the equipment used for the compounding
of liquids, suspensions, emulsions, creams, and
ointments, specialized equipment capable of
handling and packaging materials at relatively,
low temperatures (about -40°F) or under high
pressure must-be-available. This equipment is
usually limited to aerosol or pressurized packag¬
ing, and in most instances, cannot’ be iJsed for
other pharmaceutical operations.
Pressure Filling Apparatus. Pressure fill¬
ing apparatus consists of a pressure burette ca¬
pable of metering small volumes of liquefied gas
under pressure into an aerosol container. The
propellant is added through the inlet valve lo¬
cated at the bottom or top of the burette.
Trapped air is allowed to escape through the
upper valve. The desired amount of propellant is
allowed to flow through the aerosol valve into
the container under its own vapor pressure.
When the pressure is equalized between the
burette and the container (this happens with
low-pressure propellants), the propellant stops
flowing. To aid in adding additional propellant, a
hose leading to a cylinder of nitrogen or com¬
pressed air is attached to the upper valve, and FIG. 20-13. Pressure burets for laboratory filling of aero-
the added nitrogen pressure causes the propel¬ sob. (Courtesy of Aerosol Laboratory Equipment Corpora¬
lant to flow. Another pressure filling device tion, Walton, NY.)

610 ‘The Theory and Practice of Industrial Pharmacy

 “Freon"
Cylinder

Stand for holding

“Freon" cylinder
in inverted position

Valve on
cylinder

Tapped and
threaded for
yA" flare fitting

FIG. 20-14. Apparatus for cold filling process. (Courtesy of E. I. duPont de Nemours and Co., Inc., Wilmington, DE.)

Since the compressed gases are under high Large-Scale Equipment

pressure, a pressure-reducing valve is required.
Attached to the delivery gauge is a flexible hose Good pharmaceutical manufacturing practice
capable of withstanding about 1511 pounds per requires that the filling of pharmaceutical aero¬
square inch gauge pressure and fitted with a fill¬ sols be conducted under conditions that ensure
ing head. More elaborate units utilize a flow in¬ freedom from contamination. Only equipment
dicator between the gauge and the flexible hose. used specifically for aerosols is further discussed
To use this equipment for filling aerosols'with in this chapter.
compressed gases, the concentrate is placed in Concentrate Filler. This can range from a
the container, the valve is crimped in place, and single-stage single hopper to a large straight-line
the air is evacuated by means of a vacuum multiple-head filler or a rotary type multiple-
pump. The filling head is inserted into the valve head filler. Production schedules dictate the
opening, the valve is depressed, and the gas is type of filler required. Most of these fillers de¬
allowed to flow into the container. When the liver a constant volume of product and they can
pressure within the container is equal to the de¬ be set to give a complete fill in one or more oper¬
livery pressure, the gas stops flowing. For those ations. Usually, only part of the product is added
products requiring an increased amount of gas, at each stage, assuring a more accurate fill.
or for those in which solubility of the gas in the Valve Placer. The valve can be placed over
product is necessary, carbon dioxide and nitrous the container either manually or automatically.
oxide can be used. To obtain maximum solubil¬ High-speed equipment utilizes the automatic
ity of the gas in the product, the container is valve placer. This orients the valve and places it
shaken manually during and after the filling in position prior to the crimping operation.
operation. Mechanical shakers are also available Purger and Vacuum Crimper. Aerosols are
for this purpose. packaged in both metallic and glass containers,

PHARMACEUTICAL AEROSOLS • 611

each requiring their own style of crimper. Com¬ trol measures during the filling operation to en¬
bination can and bottle cappers can be used for sure that both concentrate and propellant are
most laboratory procedures and operate manu¬ brought together in the proper proportion.
ally or on air pressure (about 80 pounds per The aerosol concentrate is prepared according
square inch). These are capable of producing to generally accepted procedures, and a sample
more than 10 to 12 cans per minute. is tested. Testing at this point can save both time
Most crimpers serve a dual function, that is, to and money should the concentrate prove to be
evacuate the air within the container to about 24 unacceptable. Once the propellant is added and
inches of mercury and then seal the valve in the product is sealed into a container with a
place. Single-head crimpers or multiple-head valve, complete rejects must be discarded, obvi¬
rotary units capable of vacuum crimping up to ously a more costly solution. Early detection pre¬
120 cans per minute are available. These usu¬ vents the loss of the other components. This
ally require both air pressure (90 to 120 pounds would also have made it possible to correct the
per square inch) and vacuum. rejected batch instead of discarding it. In many
Pressure Filler. These units are capable of instances, this can be accomplished by making
adding the propellant either through the valve adjustments to the concentrate prior to aerosol
stem, body, and dip tube, around the outside of filling.
the stem, or under the valve cup before crimp¬ Two methods have been developed for the fill¬
ing. They are either single- or multiple-stage ing of aerosol products. The cold filling method
units arranged in a straight line or as a rotary requires the chilling of all components, includ¬
unit. To speed production, a positive pressure is ing concentrate and propellant, to temperatures
used to force the liquid propellant into the con¬ of -30 or -40°F, whereas the pressure filling
tainer. method is carried out at room temperature uti¬
Evacuation of air from the container, crimp¬ lizing pressure equipment. The type of product
ing the valve, and addition of the propellant can and size of container usually influence the
be achieved in basically one operation through method to be used.
the use of an “under the cap” filler. This unit The cold filling method is restricted to non-
operates as follows. A seal is made by lowering aqueous products and to those products not ad¬
the crimping bell onto the container, air is re¬ versely affected by low temperatures in the
moved by vacuum, and propellant is then me¬ range of -40°F. In this method, product concen¬
tered into the container at room temperature trate is chilled to -40°F and added to the chilled
and high pressure. The crimping collet expands container. The chilled propellant is then added
and crimps the valve into the opening. This unit in one or two stages, depending on the amount.
can be fitted with three to nine filling heads. An alternating method of cold filling is to chill
Leak Test Tank. This consists of a large both concentrate and propellant in a pressure
tank filled with water and containing heating vessel to -40°F and then add their mixture to
units and a magnetized chain so that the cans or the aerosol container. A valve is then crimped in
pucks for glass, aluminum, and plastic con¬ place. The container passes through a heated
tainers are carried through and submerged into water bath in which the contents of the con¬
the water. The length of the tank is such that the tainer are heated to 130°F to test for leaks and
temperature of the product before it emerges strength of container. The container is air-dried,
from the tank is 130°F. spray-tested if necessary, capped, and labeled.
According to DOT regulations, “each com¬ (Containers may be lithographed, and as a con¬
pleted container filled for shipment must have sequence, the latter step is omitted). This filling
been heated until contents reached a minimum method is no longer used to any great extent and
of 130°F, or attained the pressure it would exert has been replaced by the pressure filling proc¬
at this temperature, without evidence of leaking, ess. Metered-dose aerosols can be filled by either
distortion, or other defects.” process.
The pressure filling method, when first devel¬
oped, was generally slower than the cold filling
Manufacturing Procedure method. With the development of newer tech-
In general, the manufacture of aerosol prod¬ - niques, the speed of this method has been
ucts takes place in two stages: manufacture of gready increased to make it comparable in rate
concentrate and addition of propellant. For this of production to the cold filling method. The
reasbn, part of the manufacturing operation concentrate is added to the container at room
takes place during the filling operation, which is temperature, and the valve is crimped in place.
quite different from nonaerosol pharmaceutical The propellant is added through the valve or
products. This necessitates special quality con¬ “under the cap.” Since the valve contains ex-

612 • The Theory and Practice of Industrial Pharmacy

tremely small openings (0.018 inch to 0.030 scrambler, air cleaner, concentrate filler (capa¬
inch), this step is slow and limits production. ble of being chilled), propellant filler (also capa¬
With the development of rotary filling machines ble of being chilled), valve placer, valve crimper,
and newer filling heads, which allow propellant water bath, labeler, coder, and packing table.
to be added around and through the valve stem, The comparable pressure filling line would be
the speed has been increased. For those prod¬ identical in arrangement except that (1) no re¬
ucts adversely affected by the air that may be frigeration for chilling is required; (2) valve
trapped within the container, the air in the placer is located after “concentrate filler,” and a
headspace is evacuated prior to adding the pro¬ purger and vacuum crimper are added; and (3)
pellant. Following the addition of the propellant, this equipment is followed by a pressure filler.
the method becomes similar to the cold filling Where “under-the-cap” filling is used, the
method. purger, vacuum crimper, and pressure filler are
For the most part, the pressure method is also replaced with a single unit.
preferred because some solutions, emulsions,
suspensions, and other preparations cannot be
chilled. Various factors determine the method to Quality Control for
be used. The pressure method is usually pre¬
ferred to the cold method, because there is less Pharmaceutical Aerosols
danger of contamination of the product with Basically, there is no difference between
moisture; high production speeds can be methods used to produce pharmaceutical aero¬
achieved; less propellant is lost; and the method sols and those used to produce nonpharmaceuti-
is not limited, except for certain types of meter¬ cal aerosols, but there are differences in the
ing valves that can only be handled by the cold standards and specifications for their produc¬
filling process or through use of an “under the tion.
cap” filler and valve crimper. Some metered Propellants. Propellants used in medicinal
valves that are pressure-fillable are now avail¬ and pharmaceutical aerosols require special
able. handling', and in many instances, special test
Following the development of the aerosol procedures. All propellants are shipped to the
product, an initial production of about 500 to user with accompanying specification sheets;
1000 units is scheduled. The initial fill is made however, before the propellant is used (in fact,
according to the specifications of the phar¬ before it is even piped into a storage tank), it is
maceutical concern. These units are used for subjected to the same rigid tests necessary for all
additional stability studies, and for the deter¬ other raw materials. A sample is removed and
mination of incompatibilities with various com¬ sent to the laboratory, where its vapor prpggnrp
ponents (containers, valves, gaskets, dip tubes). is determined and compared to specifications.
This run is also used to determine some of the When necessary, the density is also determined,
problems that may become apparent in develop¬ and this is used as a further check. Gas chroma¬
ing the product from the laboratory to full pro¬ tography is used to determine the identity of the
duction. propellant, and~when a Blehd bf propellants is
A larger run of 10,000 to 25,000 units is Tlsed, to'defennineTHecompositionT^ieipurity
scheduled next. At this time, all materials are and acceptability of the propellants is tested by
identical to those utilized for the production run, TmoistureTfralogen. and nonvolatile residue. de-
and the equipment used must be the same as terminations. Depending on the end use of the
the production equipment. These samples can propellants, several of these tests may be more
be used for clinical studies and further testing if important than others. All suppliers of propel¬
necessary. This test run should give the follow¬ lants utilize the aforementioned tests in then-
ing information: (1) suitability of scale-up opera¬ own laboratories, and the tests that are run by
tion, (2) number of rejects to be expected (valve, the user are generally a check on these results,
container, and other components), (3) limita¬ and more important, they ensure that the pro¬
tions of filling process (tolerances for filling, pellants have not become contaminated during
crimping, and other operations), (4) determina¬ shipment. Monographs for propellants 11, 12,
tion of equipment to be used, and (5) check on and 114 are included in USP XX/NF XV (1980);
effectiveness and acceptability of final product. monographs for the hydrocarbons are currently
Should satisfactory results be obtained at this being written.
point, arrangements for full-scale production Valves, Actuators, and Dip Tubes. These
can be made. parts are subjected to both physical and chemi¬
A typical cold filling aerosol line contains the cal inspection. The problem is more complex
following units arranged in the order given: un¬ than with nonaerosol components since a valve

PHARMACEUTICAL AEROSOLS • 613

 is a multicomponent assembly consisting of var¬ Test Solution B
ious parts made to close tolerances. The exami¬
nation at this point must determine whether the % w/w
valves are fit to be used. They are sampled ac¬ Isopropyl myristate 0.10
cording to standard procedures as found in Mili¬ Alcohol USP 49.9
Dichlorodifluoromethanetf J- 25.0
tary Standard Mil-STD-105D.30 One manufac¬
Dichlorotetrafluoroethane | Itf 25.0
turer of aerosols for this purpose actually
assembles valves, using component parts having Specific gravity at 25°C = 1.092
similar tolerances to ensure that parts having
the minimum tolerance do not engage with parts Test Solution C
approaching maximum tolerance.
To provide the means for determining the ac¬ % w/w
ceptance of metered-dose aerosol valves for Isopropyl myristate 0.10
pharmaceutical use, a suitable test method was Trichloromonofluoromethane || 24.9
developed by the Aerosol Specifications Com¬ Dichlorodifluoromethane J2. 50.25
Dichlorotetrafluoroethane jj tj 24.75
mittee, Industrial Pharmaceutical Technology
Section, Academy of Pharmaceutical Sciences. Specific gravity at 25°C = 1.388
The object of this test is to determine the magni¬
tude of the valve delivery and the degree of uni¬ Testing Procedure. A representative sampling of
formity between the individual valves as related the valves from each shipment is made according to exist¬
to the acceptance of any given lot of metered ing methods of sampling. Twenty-five valves are selected
aerosol valves. The test is not designed to deter¬ and placed onto suitable containers, into which has been
mine the suitability or the lack of suitability of placed the specified test solution. Where possible, the
the valves for a specific formulation and/or ap¬ containers may be filled by the pressure process. A
plication. Detailed specifications for metered button-type actuator with a 0.020-inch or larger unre¬
aerosol valves is a matter to be resolved between stricted orifice is attached. This button remains in place
the pharmaceutical manufacturers and the aero¬ throughout the test procedure. The containers are placed
in a suitable atmosphere at a temperature of 25 ± 1°C.
sol valve suppliers.
When the product has attained this temperature, the
The following three test solutions were pro¬
valve should be actuated to the fullest extent for at least 2
posed to rule opt variations in valve delivery
sec following complete dispensing of a single delivery.
brought about by different formulations. These
This procedure is repeated for a total of ten times.
solutions were selected since they represent the The test unit is weighed to the nearest milligram. The
range of propellants and propellant concentra- valve is actuated to the fullest extent for at least 2 sec
05ns mdsTofterTused in pharmaceutical aero¬ following complete dispensing of a single delivery. The
sols: Since~lTmetefed valve delivers ^specific test unit is reweighed, and the difference between it and
volume of liquid with each actuation, it was pro¬ the' previous weight represents the delivery in milligrams.
posed that metered valve delivery be designated The test procedure is repeated for a total of two individual
in terms of valve delivery—volume expressed in deliveries from each of the twejity-five test units. The
microliters. In such a case, the test solutions individual delivery weights in milligrams are divided by
recommended would apply to the control of the specific gravity of the test solution to obtain the valve
valve delivery and uniformity for a great variety delivery per actuation in microliters.
of formulations of different densities. Valve Acceptance. The test procedure applies to
The test solutions may be prepared in bulk two categories of metered aerosol valves having the fol¬
and stored in hermetically sealed containers lowing limits.
with suitable fitments for transferring the test For valves delivering:
solution into the test units. The transfer of the 54 ixL or less, the limits are ±15%.
test solution should be made in such a manner 55 to 200 fTL, the limits are ±10%.
that no change occurs in the proportions of the
1. Of the 50 individual deliveries, if four or more are
ingredients of the test solution.
outside the limits for the specified valve delivery,
the valves are rejected.
2. If three individual deliveries are outside the limits,
Test Solution A
' another twenty-five valves are sampled, and the
test is repeated. The lot is rejected if more than one
% w/w
delivery is outside the specifications.
Isopropyl myristate 0.10
3. If two deliveries from one valve are beyond the lim¬
Dichlorodifluoromethane l> 49.95
its, another twenty-five valves should be taken.
Dichlorotetrafluoroethane (VH 49.95
The lot is accepted if not more than one delivery is
Specific gravity at 25°C = 1.384 outside the specifications.

614 • The Theory and Practice of Industrial Pharmacy

 Containers. Containers are sampled accord¬ impose limitations on the pressure within the
ing to standard sampling procedures and in a container, flash points, flame extension, and
manner similar to valves. Both uncoated and flammability. The provisions of the Hazardous
coated metal containers must be examined for Substances Labeling Act and the Food, Drug
defects in the lining. Several quality control as¬ and Cosmetic Act must be applied. In addition to
pects include specifications for the degree of these federal regulations, many local officials
conductivity of an electric current as a measure impose further restrictions upon aerosols.
of the exposed metal. Glass containers must be Pharmaceutical aerosols can be evaluated by a
examined for flaws. The dimensions of the neck series of physical, chemical, and biologic tests,
and other parts must be checked to determine including:
conformity to specifications. The weight of the
bottle also should be determined. A. Flammability and combustibility
Weight Checking. This is usually accom¬ 1. Flash point
plished by periodically adding to the filling line 2. Flame extension, including flashback
tared empty aerosol containers, which after B. Physicochemical characteristics
being filled with concentrate, are removed and 1. Vapor pressure
then accurately weighed. The same procedure is 2. Density
used to check the weight of the propellant that is 3. Moisture content
being added. When a propellant blend is being 4. Identification of propellant(s)
utilized, checks must be made to ensure a 5. Concentrate-propellant ratio
proper blend of propellants. As a further check, C. Performance
the finished container is weighed to check the 1. Aerosol valve discharge rate
accuracy of the filling operation. 2. Spray pattern
Leak Testing. A means of checking the 3. Dosage with metered valves
crimping of the valve must be available to pre¬ 4. Net contents
vent defective containers due to leakage. For 5. Foam stability
metal containers, this is accomplished by meas¬ 6. Particle size determination
uring the “crimp” dimensions and ensuring that 7. Leakage
D. Biologic Characteristics
they meet specifications.
Final testing of the efficiency of the valve clo¬
sure is accomplished by passing the filled con¬ The flammability and combustibility of aerosol
tainers through the water bath. Periodic checks pharmaceuticals may be determined by the fol¬
are made of the temperature of the water bath, lowing procedures.
and these results are recorded. Flame Projection. This test indicates the
Spray Testing. Many pharmaceutical aero¬ effect of an aerosol formulation on the extension
sols are 100% spray tested. This serves to clear of an open flame. The product is sprayed for
the dip tube of pure propellant (for products about 4 sec into a flame. Depending on the na¬
filled by pressure through the stem, body, and ture of the formulation, the flame is extended,
dip tube), to clear the dip tube of pure concen¬ the exact length being measured with a ruler.
trate (for products filled by pressure under the Flash Point. This is determined by use of
cap or around the stem), and to check for defects the standard Tag Open Cup Apparatus.32 The
in the valve and the spray pattern. For metered 'aerosol product is chilled to a temperature of
valves, it serves to prime the valve so that it is about -25°F and transferred to the test appara¬
ready for use by the consumer. tus. The test liquid is allowed to increase slowly
Several of the basic aspects of a quality control in temperature, and the temperature at which
system have been included in this section. A the vapors ignite is taken as the flash point. Al¬
more detailed discussion is available.31 though the test is still used, the results are of
limited value because the flash point obtained is
usually the flash point of the most flammable
Testing of Pharmaceutical component, which in the case of topical pharma¬
ceuticals is the hydrocarbon propellant.
Aerosols Vapor Pressure. The pressure can be meas¬
Aerosols are “pressurized packages,” and ured simply with a pressure gauge or elaborately
many tests are necessary to ensure proper per¬ through use of~a water bath, test gauges, and
formance of the package and safety during use special equipment. It is important that the pres-
and storage. All aerosol products that are sure variation from container to container be
shipped in interstate commerce are subject to determined, since excessive variation indicates
the regulations of the DOT. These regulations the presence of air in the headspace. A can

PHARMACEUTICAL AEROSOLS '615

 puncturing device is available for accurately method is based on the impingement of the
measuring vapor pressure. Methods are avail¬ spray on a piece of paper that has been treated
able for aerosols packaged in both metal and with a dve-talc mixture. Depending on the na¬
glass containers.32 ture Of the aerosol, an oil-soluble or water-solu¬
Density. The density of an aerosol system ble dye is used. The particles that strike the
may be accurately determined through the use paper cause the dye to go into solution and to be
of a hydrometer or a pycnometer. These meth- absorbed onto the paper. This gives a record of
odsTwhich have been used for the density of the spray, which can then be used for compari¬
nonaerosols, have been modified to accommo¬ son purposes. To control the amount of material
date liquefied gas preparations. A pressure tube coming into contact with the paper, the paper is
is fitted with metal flanges and a Hoke valve, attached to a rotating disk that has an adjustable
which allow for the introduction of liquids tinder slit.
pressure. The hydrometer is placed into the Dosage With Metered Valves. Several
glass pressure tube. Sufficient sample is intro¬ points must be considered: (1) reproducibility of
duced through the valve to cause the hydrome¬ dosage each time the valve is depressed and (2)
ter to rise halfway up the length of the tube. The amount of medication actually received by the
density can be read directly.32 Specific gravity patient. Reproducibility of dosage may be deter¬
can be determined through the use of a high- mined by assay techniques whereby one or two
pressure cylinder of about 500-ml capacity.32 doses are dispensed into a solvent or onto a ma¬
Moisture. Many methods have proven use¬ terial that absorbs the active ingredients. These
ful for this purpose. The Karl Fischer method solutions can then be assayed, and the amount
has been accepted to a great extent32 Gas chro- of active ingredients determined.33 Another
matography has also been used. method that can be used involves accurate
Identification of Propellants. Gas chro¬ weighing of filled container followed by dispens¬
matography and infrared spectrophotometry ing of several doses. The container can then be
“have been used to identify the propellants and reweighed, and the difference in weight divided
also to indicate the proportion of each compo- by the number of doses dispensed gives the av¬
nfent in a blend. erage dose. This must then be repeated and the
Aerosol Valve Discharge Rate. This is de¬ results compared. Determination of the dose
termined by taking an aerosol product of known received by a patient is a rather difficult proce¬
weight and discharging the contents for a given dure, since all of the material dispensed is not
period of time using standard apparatus. By carried to the respiratory tract. An artificial res¬
reweighing the container after the time limit has piratory system has been developed33 and is sat¬
expired, the change in weight per time dis¬ isfactory for this puipose.
pensed is the discharge rate, which can then be Net Contents. Several methods can be used
expressed as grams per second.32 to determine whether sufficient product has
Spray Patterns. A method for comparing been placed into each container. The tared cans
spray patterns obtained from different batches of that have been placed onto the filling line are
material or through the use of different valves is reweighed, and the difference in weight is equal
available32 and is shown in Figure 20-15. The to the net contents. The other method is a de¬
structive method and consists of weighing a full
container and then dispensing the contents. The
contents are then weighed, with provision being
made for the amount retained in the container.
Other modifications consist of opening the con¬
tainer and removing as much of the product as
possible. These tests are not indicated in deter¬
mining the actual net weight of each container
as related to the amount that can actually be dis¬
pensed. The National Bureau of Standards has
issued a method that can be used for foam type,
low-viscosity, high-viscosity, and food aero¬
sols.32 These methods standardize the manner
in which the containers are to be dispensed.
Foam Stability. Various methods have been
suggested for the determination of foam stabil¬
FIG. 20-15. Apparatus for the determination of spray pat¬ ity. The life of a foam can range from a few sec¬
terns. onds (for some quickbreaking foams) to one

616 • The Theory and Practice of Industrial Pharmacy

 V)
hour or more depending on the formulation.
Richman and Shangraw have indicated some of
the factors involved in controlling the stability of
a foam.34 Several methods have been used,
which include a visual evaluation, time for a
given mass to penetrate the foam, time for a
given rod that is inserted into the foam to fall,
and the use of rotational viscometers.34
Particle Size Determination. Many meth¬
ods have been advanced for the measurement of
particle size aerosols.35,36 Among those that
have been used to a great extent are the Cascade
imnactor and “light scatter decay” methods. The
Cascade impactor operates on the principle that
Particle Diameter, microns
in a stream of particles projected through a se¬
ries of nozzles and glass slides at high velocity, FIG. 20-17. Impact efficiency of Cascade impactor
(Model Cl-S-6).
the larger particles become impacted first on the
lower velocity stages, and the smaller particles
pass on and are collected at higher velocity
stages. Figure 20-16 illustrates a unit suitable intensity of a Tyndall beam is measured. They
for the analysis of particles whose diameters noted that the mass median diameter of an epi¬
range from 0.1 to 30 microns. This unit is spe¬ nephrine aerosol ranged from 2.7 to 3.5 microns;
cific for sampling aerosols comprised of particles that 70 to 78% of the particles were less than 5
that might be retained in the respiratory tract. microns, that 88 to 93% were less than 7 mi¬
Figure 20-17 shows the efficiency of this unit for crons, and that 98 to 100% were less than 10
determining particle size. Various modifications microns. Sciarra and Curie developed a method
have been made to improve its efficiency. for the evaluation of different actuators based on
Porush, Thiel, and Young used the light scatter the particle size distribution obtained.38
decay method for determination of particle size Other test methods have been covered by
in epinephrine aerosols.37 As the aerosol setdes Johnsen, Dorland, and Dorland.39 In addition, a
under turbulent conditions, the change in light test procedure for leak testing, delivery rate, and
pressure testing has been included in the USP
XX/NF XV. In several cases, specific test proce¬
dures are indicated in the monographs for the
, .40
aerosol preparation.
Biologic Testing. The final phase involved
in a comprehensive research and development
program for pharmaceutical aerosols must in¬
volve biologic testing. A limited number of these
tests have been used to evaluate the efficiency of
many products, including various antibacterial
agents. These tests are similar to tests per¬
formed on nonaerosol pharmaceuticals. Biologic
testing of aerosol products should include a con¬
sideration of therapeutic efficacy and toxicity.
Therapeutic Activity. Various testing pro¬
cedures are available to determine the therapeu¬
tic activity of aerosols. With the exception of
consideration given to the aerosol feature of the
package, these procedures are similar to existing
tests used for nonaerosols. The dosage of the
product has to be determined for inhalation aer¬
osols, and this must be related to particle size
distribution. Topical preparations are applied to
the test areas in the usual manner, and adsorp¬
tion of therapeutic ingredients can be deter¬
FIG. 20-16. The Cascade impactor for determining the
particle size distribution of aerosols. (Courtesy ofBattelle mined.
Laboratories, Inc., Columbus, OH.) Toxicity. Toxicity testing should include

pharmaceutical aerosols *617

both topical and inhalation effects. Aerosols ap¬ 19. Tobin, M.J., Jenouri, G., Danta, I., et al.: Am. Rev.
Respir. Dis., 126:670, 1982.
plied topically may be irritating to the affected
20. Sciarra, J.J.: Types of aerosol systems. In The Science
area and/or may cause a chilling effect. The de¬ and Technology of Aerosol Packaging. Edited by J.J.
gree of chilling effect depends on the type and Sciarra and L. Stoller. John Wiley and Sons, New
amount of propellant present. There is really no York, 1974, p. 37.
good test available at the present time, although 21. Porush, I., and Maison, G.: U.S. Pat. No. 2,868,691
thermistor probes attached to recording ther¬ (1959).
mometers have been used to indicate the 22. Sciarra, J.J.: Food and Drug Packaging, 37:16, De¬
cember 1, 1977.
change in skin temperature when skin is 23. San Giovanni, M.L.: Aerosol Age, 22:18, July 1977.
sprayed with an aerosol for a given period of 24. Theil, C.G., Porush, I., and Law, R.D.; U.S. Pat. No.
time. 3,014,844 (1961).
Inhalation toxicity must also be considered 25. Abramson, B., Greif, N.I., and Silson, J.E.: U.S. Pat.
even though the product may be intended for No. 3,095,355 (1963).
topical administration. This can be accom¬ 26. Young, J.G., Thiel, C.G., and Laursen, G.A.: Nona-
queous Aerosol Dispersions. Midwestern Regional
plished by exposing test animals to vapors Meeting, Industrial Pharmacy Section, American
sprayed from an aerosol container. Pharmaceutical Association, Chicago, IL, October
1962.
27. Sciarra, J.J.: Pharmaceutical aerosols. In The Theory
and Practice of Industrial Pharmacy. 2nd Ed. Edited
by L. Lachman et al. Lea & Febiger, Philadelphia,,
References 1976, p. 281.
28. Cutie, A.J., and Sciarra, J.J.: Aerosol Age, 27:26, Oc¬
1. Goodhue, L.D., and Sullivan, W.M.: U.S. Pat. No. tober 1982.
2,321,023 (1943). 29. Sciarra, J.J.: Testing of aerosols. In The Science and
2. Sciarra, J.J.: Aerosols. In Prescription Pharmacy. 2nd Technology of Aerosol Packaging. Edited by J.J.
Ed. Edited by J.B. Sprawls. J.B. Lippincott, Philadel¬ Sciarra and L. Stoller. John Wiley and Sons, New
phia, 1970, p. 280. York, 1974, p. 301.
3. Sanders, P.A.: Handbook of Aerosol Technology. 2nd 30. Sampling Procedures and Tables for Inspection by
Ed. Van Nostrand Reinhold, New York, 1979, p. 19. Attributes, Mil-Std-105D, U.S. Dept, of Defense,
4. Root, M.J.: Aerosols. In Advances in Cosmetic Tech¬ Washington, DC, April 29, 1963.
nology. Vol. 1. Edited by R. Goldemberg. Drug and 31. Sciarra, J.J.: Quality control for pharmaceutical and
Cosmetic Industry, Ne.w York, 1978, p. 97. cosmetic aerosol products. In Quality Control in the
5. Aerosol Propellant Data Book. E.I. duPont de Pharmaceutical Industry. Vol. 2. Edited by M.S.
Nemours and Company, Wilmington, DE, 1967. Cooper. Academic Press, New York, 1973, p. 1.
6. Sciarra, J.J.: Aerosols. In Remington's Pharmaceuti¬ 32. CSMA Aerosol Guide. 6th Ed. Chemical Specialties
cal Sciences. 16th Ed. Mack Publishing, Easton, PA, Manufacturers Association, Washington, DC, March
1980, p. 1614. 1971.
7. Flanner, L.: Vapor Pressures of Solvents and Propel¬ 33. Young, J., Porush, I., Thiel, C., et al.: J. Am. Pharm.
lant Mixtures. Allied Chemical Corp., General Chem¬ Assoc., Sci, Ed., 49:72, 1964.
ical Division, Morristown, NJ, 1959. 34. Richman, M., and Shangraw, R.: Aerosol Age, 11:45,
8. Obarski, H.: Steel aerosol containers. In The Science September 1966.
and Technology of Aerosol Packaging. Edited by J.J. 35. Tollin, B.: The Determination of Particle Size of Aero¬
Sciarra and L. Stoller. John Wiley and Sons, New sols—A Review. Selected Pharmaceutical Research
York, 1974, p. 151. References. Vol. I. Smith Kline & French Laborato¬
9. Industry Specifications for Fabricated Aerosol Cans. ries, PA, 1960.
In CSMA Aerosol Guide. 6th Ed. Chemical Special¬ 36. Kanig, J., and Mintzer, H.: Measurement of Particu¬
ties Manufacturers Association, Washington, DC, late Solid in Aerosol Systems. Aerosol Technicom-
March 1971, p. 37. ment. Vol. Ill, No. 2. Aerosol Techniques, Inc., Mil¬
10. Johnsen, M.A.: Aerosol Age, 7:20, June 1962. ford, CT, 1960, p. 1.
11. Johnsen, M.A.: Aerosol Age, 7:29, July 1962. 37. Porush, I., Thiel, C., and Young, J.: J. Am. Pharm.
12. Johnsen, M.A.: Aerosol Age, 8:39, August 1962. Associ., Sci. Ed., 49:70, 1960.
13. Johnsen, M.A.: Aerosol Age, 9:39, September 1962. 38. Sciarra, J.J., and Cutie, A.: J. Pharm. Sci., 67:1428,
14. Mesrobian, R.B.: Aerosol Age, 19:19, July, 1974. 1978.
15. Sciarra, J.J.: Aerosol Age, 9:74, December 1964. 39. Johnsen, M.A., Dorland, W.E., and Dorland, E.K.:
16. Sciarra, J.J.: Aerosol Age, 10:39, January 1965. The Aerosol Handbook. Wayne E. Dorland, Caldwell,
17. Cutie, A.J., Ertefaie, S., and Sciarra, J.J.: Aerosol Age, NJ, 1972, p. 377.
29:24, March 1984. 40. The USP XX/NF XV, The United States Pharmaco-
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805:195, 1981. 1023.

618 • The Theory and Practice of Industrial Pharmacy

 21

Sterilization
KENNETH E. AVIS and MICHAEL J. AKERS

Sterilization is the process designed to produce a to a thermally sensitive product to enhance the
sterile state. The traditional concept of the ster¬ effectiveness of a low-temperature sterilization
ile state is the absolute condition of total de¬ process; thereby decomposition is prevented
struction or elimination of all living microorgan¬ while the combined effect of the antibacterial
isms. This concept has given way to the reality and the heat provide reasonable assurance that
that sterile is a term that must be given relative the product will be sterilized.
connotation and that the probability of having Microorganisms exhibit varying resistance to
achieved the absolute can only be predicted on sterilization procedures. The degree of resist¬
the basis of kinetic projection of microbial death ance varies with the specific organism. In addi¬
rates. Therefore, sterility in the absolute sense tion, spores, the form that preserves certain or¬
cannot be shown to have been achieved, but ganisms during adverse conditions, are more
rather, can be approached with an increasing resistant than vegetative forms of the organism.
probability of success as a sterilization process is The data given in Table 21-1 illustrate the vary¬
improved. With terminal methods of steriliza¬ ing resistance of different spores to moist and
tion of a parenteral product, particularly steam dry heat. Therefore, the conditions required for
under pressure, a probability of no more than a sterilization process must be planned to be le¬
one nonsterile unit in a million (10-6) is readily thal to the most resistant spores of microorgan¬
achievable. Even greater levels of assurance can isms normally encountered, with additional
be achieved with current technology. In this treatment designed to provide a margin of safety
chapter, sterile indicates a probable condition of against a sterilization failure.
complete freedom from viable microorganisms After consideration of the principles of micro¬
with the limitations just expressed; these limita¬ bial death and their relationship to validation of
tions are developed more fully later in the chap¬ sterilization processes, the processes of interest
ter. The term aseptic indicates a controlled proc¬ in industrial pharmacy are studied in this chap¬
ess or condition in which the level of microbial ter under the two main divisions of physical
contamination is reduced to the degree that mi¬ processes and chemical processes. Particular em¬
croorganisms can be excluded from a product phasis is placed on the principles involved and
during processing. It describes an “apparendy” on applications of the processes to pharmaceu¬
sterile state. ticals. For further details of sterilization pro¬
Persons responsible for carrying out steriliza¬ cesses, reference should be made to one or more
tion procedures must be acutely aware of the of the standard textbooks on this subject.1-4
degree of effectiveness as well as the limitations
of each sterilization process. They must also
understand that these processes may have a del¬ Validation of Sterilization
eterious effect on the material to be sterilized. In
the processing of pharmaceuticals, it is often Processes
nfecessary to reach a compromise between the All sterilization processes (thermal, chemical,
most effective sterilization procedure and one radiation, and filtration) are designed to destroy
that will not have a significant adverse effect or eliminate microbiologic contaminants present
upon the material to be sterilized. For example, in a product. The official test for sterility of the
it may be necessary to add an antibacterial agent product is a destructive test on a selected sam-

61S
Table 21-1. Times Required for Lethal Effect on Bacterial Spores by Thermal Exposure

Time (min.)

Moist Heat Dry Heat

Organisms I00°C 110°C 121°C 120°C 140°C 170°C

B. anthracis 5-15 _ _ _ 180 _

Cl. botulinum 330 90 10 120 60 15
Cl. welchii 5-10 — — 50 5 7
Cl. tetani 5-15 — — — 15 —

Soil bacilli >1020 120 6 — — 15

pie; thus, the task of proving that all units of a or dose units of sterilant exposure. For example,
product are sterile must involve the employment after 5 min of product exposure to a tempera¬
of probability statistics. The statistics of proba¬ ture of 12TC, the microbial population was
bility depend on such parameters as the length reduced from 2 x 10s to 6 x 103. Then, the D
or degree of exposure to the sterilant, the type value at 121°C is:
and number of microorganisms present, the de¬
sired level of microbial destruction or elimina¬
tion, and the resistance of the microorganism(s) °121 log(2 x 10s) - log(6 x 103) 3'28 mm
presented to the sterilization process.
In recent years, the pharmaceutical industry Thus, at 121°C, the microbial population is de¬
has intensified its efforts to quantitate the rate creased by 90% every 3.28 min.
and extent of microbial destruction or elimina¬ D values have been defined precisely for vari¬
tion. The Food and Drug Administration has ous microorganisms contained in certain envi¬
stated in its current good manufacturing prac¬ ronments (liquids and solid surfaces) at specific
tice regulations that sterilization procedures temperatures for heat sterilization,5 and at direct
must be validated pertaining to (1) the design of exposure to cobalt-60 irradiation.6 D values can-
the equipment and the process used to produce
batch sterilization and (2) the confirmation with
reproducible data of a given probability level of
residual microbial contamination upon comple¬
tion of the sterilization process. Validation of
sterilization processes can be facilitated by using
quantitative, theoretically sound principles such
as microbial death kinetic expressions.

Microbial Death Kinetic Terms

An important term in expressing microbial
death kinetics for heat, chemical, and radiation
sterilization is the D value. The D value is the
time (for heat or chemical exposure) or the dose
(for radiation exposure) required for the micro¬
bial population to decline by one decimal point
(a 90%, or one logarithmic unit, reduction). The
D value may be estimated graphically, as shown
in Figure 21-1, or mathematically, as shown by
equation (1):

U
D =
log N0 - log Nu
(1)
Time at a Specific Temperature
where U is the exposure time or exposure dose, Time at a Specific Gas Concentration
under specific conditions, N0 is the initial micro¬ Dose of Gamma Radiation
bial population (product bioburden) and Nu is FIG. 21-1. Graphic representation of the semilogarithmic
the microbial population after receiving U time microbial death rate.

620 • The Theory and Practice of Industrial Pharmacy

not be defined precisely for microorganisms ex¬
posed to such gases as ethylene oxide because of
the complex interaction of heat, concentration of
gas, and relative humidity.7 D values are esti¬
mated for gas sterilization when it is possible to
keep heat and humidity values constant, varying
only the concentration of gas.
Other key terms used in the determination of
microbial death rates include microbial load, or
bioburden; the Z value; the F value; the F0 value;
and the probability of nonsterility. These terms
are defined in Table 21-2, and Z value plots are
shown in Figure 21-2.
The F0 value is a term widely used in steriliza¬
tion cycle design and validation. Its current ap¬
plication is limited to steam sterilization al¬
though an F value can be computed for any
thermal method of sterilization. The F0 value
can be defined by the following two equations:
T-121
F0 = At 2 10 10 (2)

where At is the time interval between product

temperature measurements T.

F0 = Diai (log N0 - log Nu) (3)

Temperature I'CI

where N0 and Nu are those terms defined previ¬ FIG. 21-2. Z value plots of log D versus temperature.
ously. Key—A: Z = 10°C for B. stearothermophilus spores ex¬
posed to steam sterilization.
The F0 value of equation (2) is obtained by
B: Z = 22°C for B. subtilis var niger spores exposed
physical measurement of product temperature to dry heat sterilization.
and substitution of that temperature for T in the C: Z = 54°C for E. coli endotoxin exposed to dry
exponent. For example, if the product tempera¬ heat sterilization.
ture was measured every 5 min from 0 to 30 min

Table 21-2. Definition of Key Terms Employed in Microbial Death Kinetics

Symbol Term Definition

N0 Bioburden The population or number of living microorganisms per defined unit,

surface, or system.
Z Resistance value The number of degrees (C or Fy required for a 1 log reduction in the
D value.

T, - T2
log D2 - log Dj
F(T,z) Sterilization process The equivalent time at temperature T delivered to a unit of product
or equivalent time calculated using a specified value of z.
F|

Fo Sterilization process The equivalent time at a temperature of 121°C delivered to a unit of

equivalent time product calculated using a z value of 10°C.

Nu Probability of The number of nonsterile units per batch or the theoretic or extrapo¬
nonsterUity lated number of living microorganisms per defined unit after a given
equivalent heating time U at a specific temperature T.

Nu = antilog (togNo--^)

STERILIZATION *621
and found to be 25°C, 110°C, 118°C, 120°C, estimate of the degree of destruction of
121°C, and 100°C, the F,) value would be: microorganisms, and thus the safest condi¬
tions for determining cycle time.
F0 = 5 min (0 + 0.079 + 0.501 + 0.794
+ 5.000 + 0.0079) At least three factors affect the F0 value. They
F0 = 5 min (6.382) are (1) the container characteristics: size, geom¬
F0 = 31.91 min etry, and heat transfer coefficient, (2) the prod¬
uct volume and viscosity, and (3) the size and
By definition, when the F0 value is used, the Z configuration of the batch load in the sterilizer.
value is assumed to be 10°C. This means that for F value equations can be applied to dry heat
every 10°C increase in product temperature, the sterilization although most materials sterilized
D value is decreased by 90%, or 1 log unit. by dry heat can be subjected to overkill tempera¬
Equation (3) is the biologic F0 equation be¬ ture-time cycles. The reference temperature T0
cause the F0 value is calculated after determin¬ would not be 121°C, of course, but it probably
ing the D121 value and the product bioburden, would be 170°C, since this temperature is speci¬
N0. The probability of nonsterility is whatever fied in the USP/NF XXI. The Z value would not
level is desired, usually a minimum of 10~6. be 10°C, but would be in the range of 22°C for
In general, equation (3) is applied under two the destruction of B. subtilis var niger spores on
circumstances. Given Di2i, N0, and Nu, the glass to 54°C for the destruction of endotoxin.8,9
F0 value is calculated. For example, if D121 = (See Fig. 21-2.)
1 min, N0 = 102, and Nu = 10-6, then: Aseptic processing also requires validation to
assure batch to batch consistency in producing a
F0 = 1 min (log 102 - log 10~6) given probability of product sterility. While D
F0 = 8 min and F0 values cannot be applied, a probability of
nonsterility levels can be obtained by process
Given D121, N0, and F0, the achieved level of simulation testing using microbiologic growth
nonsterility may be calculated. For example, if medium, a suitable type arid number of chal¬
D121 = 2 min, N0 = 102, and F0 = 8 min, then: lenge microorganisms, and a relevant number
of containers. The percent contamination level
(% C) is calculated as follows:
Nu = antilog (log N0 - -rf2-)
X ^121 '

Nu = antilog (log 102 - *c-SFC,“1 ®

Nu = 10-2
where NG is the number of undamaged con¬
tainers with microbial growth, NT is the total
F Value Applications number of containers filled, and ND is the num¬
ber of damaged contaminated containers. Proce¬
The importance of F0 values in steam sterili¬
dures for validation of aseptic fill for solution
zation cycle validation may be summarized as
drug products have been presented in a recent
follows:
publication by the Parenteral Drug Associa¬
tion.10
1. F0 relates the killing efficiency of the process
at any temperature to the killing effect pro¬
duced at the desired sterilization temperature
of 121°C.
Validation Steps
The actual validation of a sterilization process
2. F0 provides a single quantitative value de¬
must follow a logical, systematic series of steps
scribing the thermal exposure time of the
and procedures. The validation procedure for a
cycle to which the product was exposed
steam sterilization process may involve the fol¬
equivalent to 121°C.
lowing design:
3. F0 incorporates the contribution of the heat¬
ing and cooling portions of the temperature¬ 1. Certify that the sterilizer has been mechani¬
time profile during a cycle with the overall cally checked and qualified.11
lethal effect of heat upon microorganisms.
2. Select the most appropriate biologic indica¬
4. F0, if used to describe the lethal effect upon tor microorganism possessing the desired
microorganisms at the coolest location in the resistance to steam heat, while realizing the
sterilizer, represents the most conservative advantages and hazards of bioindicators.12

622 • The Theory and Practice of. Industrial Pharmacy

 3. Experimentally determine the D value and 8. Determine the percent contamination level
Z value of the selected bioindicator. according to equation (5).
4. Determine the distribution of heat in the 9. Repeat the process.
empty sterilizer, and identify the coolest lo¬
10. If percent contamination level is unaccepta¬
cation.
ble, for example, >0.1%, review all environ¬
5. Determine the distribution of heat of a de¬ mental test results, sterilization records, and
fined loading size and configuration and other data to determine what action needs to
identify the coolest location. be taken to attain a percent contamination
level of less than 0.1%.
6. Determine the penetration of heat into the
product units at the coolest location and at
suspected locations where heat penetration Physical Processes of
will be slowest.
Sterilization
7. Evaluate the effect of such cycle parameters
as time, temperature, and load configura¬
Thermal Methods
tion on the destruction of the bioindicator
and the magnitude of the F0 value. The lethal effectiveness of heat on microorga¬
nisms depends upon the degree of heat, the ex¬
8. Determine the sterilization process time posure period, and the moisture present. Within
required to achieve the desired F0 value the range of sterilizing temperatures, the time
and/or the desired probability level of bioin¬ required to produce a lethal effect is inversely
dicator destruction. proportional to the temperature employed. For
9. Repeat the process until satisfactory and re¬ example, sterilization may be accomplished in 1
liable replication is obtained. hour with dry heat at a temperature of 170°C,
but may require as much as 3 hours at a temper¬
10. Establish a monitoring program for periodic ature of 140°C. While it is common practice to
requalification of the sterilization cycle. identify cycle times in terms of the maximum
11. Finalize standard operating procedures and temperature hold time, total heat input may be
action levels should changes or problems computed in terms of F values, as explained pre¬
develop in the future. viously; however, the lethal effect must be com¬
puted in terms of the time during which the en¬
The validation procedure for an aseptic filtra¬ tire mass of the material is heated. The
tion process may involve the following design: mechanism by which microorganisms are killed
by heat is thought to be the coagulation of the
1. Properly evaluate the facility and critical protein of the living cell. The data given in Table
areas for proper equipment function, air 21-3 illustrate this principle, using the effect of
quality, and other engineering criteria. varying amounts of water on the temperature
required to coagulate egg albumin.13 The tem¬
2. Perform air and surface microbial tests in perature required is inversely related to the
the filling area to know reliably the back¬ moisture present. Further, experience in the
ground microbial contamination level. laboratory has confirmed that sterilization by
3. Select a sensitive microbial growth medium. thermal methods may be effected at lower tem¬
peratures in the presence of moisture.
4. Select the most appropriate challenge mi¬
Thermal methods of sterilization may conven¬
croorganism for aseptic filtration validation.
iently be divided into those accomplished by dry
5. Sterilize growth medium and all filtration heat and those by moist heat.
equipment by sterilization methods previ¬
ously validated. Table 21-3. Effect of Moisture and Heat on Egg

6. Conduct a process simulation test by filter¬ Albumin

ing a desired volume of microbial growth
Water Temperature
medium containing a known concentration Effect
(%) CC)
of challenge microorganism into an appro¬
priate number of previously sterilized con¬ 50 56 coagulation
tainers. 25 80 coagulation
6 145 coagulation
7. Incubate the filled containers at the proper
0 170 coagulation and oxidation
conditions with proper controls.

STERILIZATION • 623
 Dry Heat. Substances that resist degradation ture of 20°C or more may be found in different
at temperatures above approximately 140°C shelf areas of even small laboratory ovens of the
(284°F) may be rendered sterile by means of dry natural convection type.14
heat. Two hours exposure to a temperature of Forced convection ovens provide a blower to
180°C (356°F) or 45 min at 260°C (500°F) nor¬ circulate the heated air around the objects in the
mally can be expected to kill spores as well as chamber. Efficiency is greatly improved over
vegetative forms of all microorganisms. This natural convection. Temperature differences at
total sterilizing cycle time normally includes a various locations on the shelves may be reduced
reasonable lag time for the substance to reach to as low as ± 1°C. The lag times of the load ma¬
the sterilizing temperature of the oven chamber, terial therein also are greatly reduced because
an appropriate hold period to achieve steriliza¬ fresh hot air is circulated rapidly around the ob¬
tion, and a cooling period for the material to re¬ jects. The curves shown in Figure 21-3 illustrate
turn to room temperature. the difference in lag time for some of the same
Factors in Determining Cycle Time. The containers of com oil when heated in a natural
cycle time is composed of three parts: (1) the convection oven as compared with the same
thermal increment time of both the chamber oven equipped for forced circulation.14
and the load of material to be sterilized, assum¬ Another type of sterilizer is the tunnel unit
ing both start at room temperature, (2) the hold with a moving belt, designed to thermally steril¬
period at the maximum temperature, and (3) the ize glass bottles and similar items as they move
cooling time. The material lags behind the in¬ through the tunnel. The items are cooled with
creasing temperature of the chamber. The time clean air before they exit the tunnel, usually di¬
required for all of the material to “catch up” with rectly into an aseptic room and linked in a con¬
the temperature of the chamber is longer with tinuous line with a filling machine. Such units
larger quantites of material, poorer thermal con¬ require careful validation.15
ductance properties of the material, and lower Effect on Materials. The elevated tempera¬
heat capacity. The relationship of these factors tures required for effective hot air sterilization in
must be carefully determined during validation a reasonable length of time have an adverse ef¬
studies so that effective cycle times can be fect on many substances. Cellulose materials,
planned. such as paper and cloth, begin to char at a tem¬
The cycle time is most commonly prescribed perature of about 160°C (320°F). At these tem¬
in terms of the hold time, for example, 2 hours at peratures, many chemicals are decomposed,
180°C dry heat. The hold time may be shown by rubber is rapidly oxidized, and thermoplastic
sensors detecting the temperature of the cham¬ materials melt. Therefore, this method of sterili¬
ber at its coolest spot; however, a better indica¬ zation is reserved largely for glassware, metal¬
tion of the actual thermal condition is obtained ware, and anhydrous oils and chemicals that can
by sensing, usually with a thermocouple, the
coolest spot in the load of the material to be steri¬
lized. When such a location is used, and when
this coolest spot is known from previous valida¬
tion studies, the timing required for sterilization
is correctly programmable. It should be remem¬
bered that other parts of the load of material may
be heated for a longer period, and if it is ther¬
mally unstable, degradation could occur. There¬
fore, the thermal stability of the material to be
sterilized must be known and the optimum
method of sterilization selected to achieve effec¬
tive sterilization throughout the entire mass of
material while maintaining its stability and in¬
tegrity.
Sterilizer Types. The ovens used to achieve
hot air sterilization are of two types, natural con¬
vection and forced convection. Circulation
within natural convection ovens depends upon
the currents produced by the rise of hot air and
fall of cool air. This circulation can be easily FIG. 21-3. Rate of heating com oil in Pyrex liter bot¬
blocked with containers, resulting in poor heat tles in the same hot air erven with natural convection
distribution efficiency. Differences in tempera¬ (-•-) and forced circulation (—•—).

624 • The Theory and Practice of Industrial Pharmacy

withstand the elevated temperature ranges placing air downward, as illustrated by the grav¬
without degradation. Expansion of materials is ity displacement autoclave shown in Figure
also appreciable, as they are heated from room to 21-4. Objects must be placed in the chamber
sterilizing temperatures. Therefore, glassware with adequate circulation space around each
must not be wedged tightly in the oven cham¬ object, and so arranged that air can be displaced
ber, containers for oils must be large enough to downward and out of the exhaust line from the
permit expansion of the oil, and provision must chamber. Any trapped air, e.g., air in containers
be made for the expansion of other substances. with continuous sides and bottoms or in tightly
Advantage may be taken of the anhydrous wrapped packs, prevents penetration of the
state achieved with this method of sterilization steam to these areas and thus prevents steriliza¬
to provide dry glassware and metalware at the tion. The air trapped in this manner is heated to
end of an adequate heating cycle. Dry equip¬ the temperature of the steam, but hot air at a
ment and containers are essential in the manu¬ temperature of 120°C (248°F) requires a cycle
facture of an anhydrous product, but they are time of 60 hours to ensure a lethal effect on
also desirable to prevent dilution of an aqueous spores.16 A 20-min exposure at this temperature
product. Also, dry equipment can be kept sterile with hot dry air, therefore, would be entirely in¬
during storage more easily than wet equipment. adequate.
Further, dry heat effectively destroys pyrogens, Factors Determining Cycle Time. Spores
usually requiring about twice the hold time for and vegetative forms of bacteria may be effec¬
sterilization. tively destroyed in an autoclave employing
To maintain a sterile condition after steriliza¬ steam under pressure during an exposure time
tion, environmental contamination must be ex¬ of 20 min at 15 pounds pressure (121°C [250°F])
cluded. The openings of equipment must be or as little as 3 min at 27 pounds pressure
covered with a barrier material such as alumi¬ (132°C [270°F]). These time intervals are based
num foil. As an alternative, items to be sterilized on the assumption that the steam has reached
may be placed in a covered stainless steel box or the innermost recess of the material to be steri-
similar protective container.
Moist Heat. Moist heat is more effective
than dry heat for thermal sterilization. It should
be remembered, however, that normal moist
heat cycles do not destroy pyrogens.
As previously noted, moist heat causes the
coagulation of cell protein at a much lower tem¬
perature than dry heat. In addition, the thermal
capacity of steam is much greater than that of
hot air. At the point of condensation (dm point),
steam liberates thermal energy equal to its heat
of vaporization. This amounts to approximately
540 calories per gram at 100°C (212°F) and 524
calories per gram at 121°C (250°F). In contrast,
the heat energy liberated by hot dry air is equiv¬
alent to approximately only 1 calorie per gram of
air for each degree centrigrade of cooling. There¬
fore, when saturated steam strikes a cool object
and is condensed, it liberates approximately 500
times the amount of heat energy liberated by an
equal weight of hot air. Consequently, the object
is heated much more rapidly by steam. In addi¬
tion, when steam under pressure is employed, a
rapidly changing fresh supply of heat-laden
vapor is applied to the object being heated. This
is due both to the pressure under which steam is
applied and to the partial vacuum produced at
the site where steam is condensed, for it shrinks
in volume by about 99% as it condenses.
Air Displacement. The density of steam is FIG. 21-4. Cross-sectional diagram of the functional
lower than that of air. Therefore, steam enters parts of an autoclave. (Courtesy of American Sterilizer
an autoclave chamber and rises to the top, dis¬ Co.)

STERILIZATION • 625
 lized, and that the temperature of the material is unsealed containers and explosion of sealed con¬
held for at least one half of that time interval. In tainers.
the case of bottles of solution, the heat must be One method for rapid extraction of heat from
conducted through the wall of the container, sealed containers of solutions is to spray the con¬
raise the temperature of the solution to that of its tainers with gradually cooling water while the
environment, and generate steam within the pressure in the chamber is concurrently re¬
container from the water therein. Therefore, a duced. Another accelerated cooling method
significant lag time is involved before the solu¬ employs short pulses of high pressure steam in¬
tion reaches the sterilizing temperature. troduced into the loaded chamber. As the steam
The determination of lag time and its inclu¬ expands in the chamber it extracts heat from the
sion in the planned total cycle time is no less containers of solution. The steam is exhausted
important for moist heat sterilization than for from the chamber at a rate that provides for a
hot air sterilization, discussed previously. By gradual reduction of the pressure concurrent
way of illustration, it has been found that 1200 with the temperature reduction. By these meth¬
ampuls, each containing 5 ml of a solution, can ods, it is sometimes necessary to introduce
be effectively sterilized in an autoclave at 121°C pulses of air into the chamber to replace all or
(250°F) during an exposure time of 20 min. part of the steam so that the pressure around the
A single bottle containing the same total volume containers is not reduced too rapidly. By the
of solution (6 L) required an exposure of 60 min spray cooling method, it has been reported that
at 121°C (250°F).17 the cooling time for a load of 200 one-liter bottles
Air-Steam Mixtures. While air-steam mix¬ of solution may be reduced from about 20 hours
tures have a lower temperature and lower ther¬ to about 20 min.18
mal capacity than pure steam, the presence of A relatively new approach to a reduction in
air may be utilized to control the pressure in the the total heating cycle time has been the intro¬
chamber when flexible-walled containers of duction of a precycle vacuum. In a specially de¬
products are being sterilized. For example, plas¬ signed autoclave, a precycle vacuum of at least
tic bags of large-volume parenterals (LVPs) or 20 mm Hg is drawn. More recent studies have
collapsible tubes of aqueous jellies would swell shown that a double vacuum drawn in sequence
and burst in an autoclave utilizing steam only, prior to the heating cycle removes air more ef¬
particularly during the cooling phase. When air fectively from porous materials.19 The subse¬
is mixed with the steam and the air pressure is quent introduction of steam permits rapid pene¬
independently controlled, the pressure applied tration and load heating with complete
to the outside of the containers can be adjusted elimination of air pockets. Since the total heat¬
to equal the internal pressure so that the con¬ ing period is markedly reduced owing to the re¬
tainers do not burst. Because of the tendency of duction in the temperature increment time, a
steam and air to stratify, the mixture must be higher temperature (usually 135°C [275°F]) may
mixed continuously; this is usually accom¬ be employed with less deleterious effects on
plished by means of a blower. materials. This method is-particularly suited to
Approaches to Reduction of Cycle Time. operating room packs in hospitals, where the
Prolonged heating of most objects is detrimental total cycle time for large packs has been reduced
to the material. For example, fabrics and rubber from about 78 min by the conventional method
parts deteriorate with loss of tensile strength, to about 14 min. Such a method cannot be used
solutions may undergo adverse chemical for solutions or other objects that cannot with¬
changes, and metal objects may become pitted. stand the high vacuum employed.
Therefore, the total cycle time should be con¬ Lower Temperature Sterilization. Moist
trolled so that the heating period is not unneces¬ heat also is used for lower temperature steriliza¬
sarily prolonged. Usually, this is best accom¬ tion procedures. Temperatures of 100°C (212°F)
plished by shortening the cooling period. For or lower are used for these so-called marginal, or
nonsealed items of equipment or containers that fractional, methods. The term marginal origi¬
do not contain solutions, the steam may be ex¬ nates from the questionable reliability of the
hausted to the outside rapidly at the end of the processes. The term fractional is derived from
sterilizing cycle. Objects are thereby cooled rap¬ the fact that these processes are normally per¬
idly, particularly if removed from the autoclave formed by two or three exposures to moist heat,
chamber. Such a procedure cannot be employed alternated with intervals during which the mate¬
for solutions, whether sealed or unsealed in con¬ rial is held at room or incubator temperatures.
tainers, because the rapid release of chamber Fractional methods of sterilization such as
pressure would cause violent ebullition of the tyndaUization, employing a temperature of
hot solution, with spattering of the contents of 100°C (212°F), and inspissation, employing

626 • The Theory and Practice of Industrial Pharmacy

temperatures as low as 60°C (140°F), are rela¬ cepted,12 but their use as indicators for routine
tively effective in reducing the number of vege¬ process control is questioned by some. Among
tative forms of microorganisms, but are unrelia¬ the concerns are (1) lot to lot variability of the
ble against spores. For certain preparations, the resistance of the spores, (2) lot to lot variability
effectiveness of these processes may be im¬ in the number of viable spores, (3) difficulty in
proved by the inclusion of a bacteriostatic agent. obtaining pure cultures, and (4) the inherent
These marginal methods of sterilization should danger of placing viable spores in a sterilizer
be\reserved for substances that must be proc¬ load of materials for human use.
essed by a thermal method but that cannot with¬ Application of Thermal Methods of
stand higher temperatures without degradation. Sterilization. It is generally accepted that the
The assurance of sterility is comparatively low, most reliable thermal method of sterilization is
however. the use of moist heat under pressure. Therefore,
Wrapping Materials. Wrappings for equip¬ this method of sterilization should be employed
ment and supplies subjected to moist heat steri¬ whenever possible. Aqueous pharmaceutical
lization must permit easy penetration of steam preparations in hermetically sealed containers
and escape of air. They must also possess suffi¬ that can withstand the temperature of autoclav¬
cient wet strength so that they will not tear or ing can be rendered sterile and remain so indefi¬
burst during the process. After sterilization, the nitely unless tampering with the seal occurs.
wrapping must provide an efficient bacterial Nonaqueous preparations in sealed containers
barrier so that equipment remains sterile for a cannot be sterilized in this manner during a nor¬
reasonable time until used. In addition, mainte¬ mal cycle because no water is present within the
nance of sterility depends upon complete cover¬ container to generate steam and thereby effect
age of the contents of the pack, drying of the sterilization.
wrapping after the process, and a static air state Moist heat sterilization is also applicable to
within. Acceptable disposable process wrapping equipment and supplies such as rubber clo¬
materials include 20-lb weight Kraft paper, spe¬ sures, glassware, and other equipment with rub¬
cial parchment paper, and Tyvek. Reusable ber attachments; filters of various types; and
types'include close-weave nylon and Dacron. uniforms. To be effective, however, air pockets
Except for Kraft paper, all are low-lint materials. must be eliminated. This normally requires that
Indicators for Evaluating the Steriliza¬ the items be wet when placed in the autoclave.
tion Process. The duplication of proven ther¬ They also will be wet at the end of the sterilizing
mal methods of sterilization cannot be taken for cycle. When moisture can escape without
granted. Mechanical equipment as well as per¬ damage to the package, part of the moisture can
sonnel are subject to failure. Therefore, indica¬ be removed by employing an evacuation step at
tors should be used as a check on the duplication the end of the cycle. Even this process does not
of the conditions of a proven (validated) process, usually completely dry the equipment. There¬
locating the indicator where there is the greatest fore, when such equipment is used in process¬
impediment to the penetration of the heat. ing, allowance must be made for the diluting ef¬
Among the indicators available, the most fect of this water, or preferably, a small portion
widely used is the thermocouple. These indica¬ of the product may be used to rinse or flush the
tors are often connected to recorders so that a water out of the equipment. In some instances,
continuous record of the actual temperature at when dry equipment is required and it must be
the location of the thermocouple can be ob¬ sterilized by autoclaving, the equipment may be
tained. dried in a vacuum oven before use.
For autoclave sterilization, a variety of other Dry heat sterilization is used for containers
indicators also are used. These include wax or and equipment whenever possible because an
chemical pellets that melt at 121°C and paper adequate cycle results in sterile and dry equip¬
strips that are impregnated with chemicals that ment. High-speed processing lines recently de¬
change color under the influence of moisture veloped have included a hot-air tunnel for the
and heat. All of these have limited reliability for continuous sterilization of glass containers,
indicating the length of time that a temperature which are heated by infrared lamps or by electri¬
of 121°C has been maintained. cally heated, filtered, circulating air. Glass and
Resistant bacterial spores in sealed ampuls or metal equipment usually withstand dry heat
impregnated in dry paper strips are used as bio¬ sterilization without difficulty, although uneven
logic indicators. Their destruction is evidence of thermal expansion may cause breakage or dis¬
the intended effect of a sterilization process. tortion. Rubber and cellulosic materials undergo
Their use to prove the effectiveness of new ster¬ degradation, however. Certain'ingredients, such
ilizing equipment or processes is widely ac¬ as chemicals and oleaginous vehicles, to be used

STERILIZATION • 627
in sterile pharmaceutical preparations are some¬ The germicidal effectiveness of ultraviolet
times sterilized with dry heat at lower (usually light is a function of the intensity of radiation
140°C or less) temperatures. In such cases, it and time of exposure. It also varies with the sus¬
must be established that the heating cycle has ceptibility of the organism. The data in Table
no deleterious effects on the ingredients and 21-4 show some of this range of susceptibility.20
that the cycle time is adequate to achieve sterili¬ From these data, it can be seen that if the inten¬
zation. They^also must be carefully protected sity of radiation on a surface was 20 microwatts
after sterilization until incorporated aseptically per cm2, the minimum intensity usually recom¬
in the product to prevent contamination from mended, it would require approximately 1100
the environment. seconds exposure to kill B. subtilis spores, but
only approximately 275 seconds to kill
S. hemolyticus. The intensity of ultraviolet radi¬
ation can be measured by means of a special
Nonthermal Methods light meter having a phototube sensitive to the
Ultraviolet Light. Ultraviolet light is com¬ 2537 A wavelength.
monly employed to aid in the reduction of con¬ Maintenance and Use. To maintain maxi¬
tamination in the air and on surfaces within the mum effectiveness, ultraviolet lamps must be
processing environment. The germicidal light kept free from dust, grease, and scratches be¬
produced by mercury vapor lamps is emitted cause of the large reduction in emission inten¬
almost exclusively at a wave length of 2537 Ang¬ sity that will occur. Also, they must be replaced
strom units (253.7 millimicrons). It is subject to when emission levels decrease substantially
the laws for visible light, i.e., it travels in a (about 30 to 50%) owing to energy-induced
straight line, its intensity is reduced in propor¬ changes in the glass that inhibits the emission.
tion to the square of the relative distance it trav¬ Personnel present in areas where ultraviolet
els, and it penetrates materials poorly or selec¬ lights are on should be protected from the direct
tively. Ultraviolet light penetrates clean air and and reflected rays. These rays cause reddening
pure water well, but an increase in the salt con¬ of the skin and intensely painful irritation of the
tent and/or the suspended matter in water or air eyes. The American Medical Association has
causes a rapid decrease in the degree of penetra¬ recommended that the maximum safe human
tion. For most other applications, penetration is exposure for 1 hour be limited to 2.4 mw/cm.2
negligible, and any germicidal action is confined Ultraviolet lamps are used primarily for their
to the exposed surface. germicidal effect on surfaces or for their pene¬
Lethal Action. When ultraviolet light passes trating effect through clean air and water.
through matter, energy is liberated to the orbital Therefore, they are frequently installed in
electrons within constituent atoms. This ab¬ rooms, air ducts, and large equipment in which
sorbed energy causes a highly energized state of the radiation can pass through and irradiate the
the atoms and alters their reactivity. When such air, and also reach exposed surfaces. Water sup-
excitation and alteration of activity of essential
atoms occurs within the molecules of microorga¬
nisms or of their essential metabolites, the or¬
ganism dies or is unable to reproduce. The prin¬
Table 21-4. Intensity of Radiation at 2537 A
Necessary to Completely Destroy Certain Micro¬
cipal effect may be on cellular nucleic acids,
organisms
which have been shown to exhibit strong ab¬
sorption bands within the ultraviolet wavelength Energy
range. Organism (mw.-sec./cm.2)
The lethality of ultraviolet radiations has been
well established; however, it also has been Bacillus subtilis 11.000
shown that organisms exposed to ultraviolet ra¬ B. subtilis spores 22,000
diations can sometimes recover, a fact not sur¬ Eberthella typhosa 4,100
prising if the previously described theroy of le¬ Escherichia coli 6,600
thality is correct. Recovery has been increased Pseudomonas aeruginosa 10,500
by the addition of certain essential metabolites Saxcina lutea 26,400
to the culture, adjustment of the pH of the me¬ Staphylococcus aureus 6,600
Streptococcus hemolyticus 5,500
dium, or exposure to visible light shortly after
Sacchaxomyces cerevisiae 13,200
exposure to the ultraviolet radiations. Therefore,
Penicillium roqueforti 26,400
adequate exposure to the radiations must occur
Aspergillus niger 330,000
before reliance can be placed upon obtaining a
Rhizopus nigricans 220,000
sterilizing effect.

628 • The Theory and Practice of Industrial Pharmacy

 plies also have been sterilized when the limit of tltCTRON
INJICTOR
penetration has been carefully determined and
controlled so that adequate irradiation through¬
out has been achieved.
Ionizing Radiations. Ionizing radiations
are high-energy radiations emitted from radioac¬
tive isotopes such as cobalt-60 (gamma rays) or
produced by mechanical acceleration of elec¬
trons to very high velocities and energies (cath¬
ode rays, beta rays). Gamma rays have the ad¬
vantage of being absolutely reliable, for there
can be no mechanical breakdown; however, they
have the disadvantages that their source (radio¬
active material) is relatively expensive and the
emission cannot be shut off as it can from the
mechanical source of accelerated electrons. Ac¬
celerated electrons also have the advantage of
providing a higher and more uniform dose rate
output.
Electron Accelerators. Electron accelera¬
tors are of two general types, the linear and the
Van de Graaff accelerators. The principle of the
linear accelerator may be followed from Figure
21-5. Very high-frequency microwaves (radar)
collect electrons from a cathode and accelerate
them as they travel through the vacuum tube,
reaching almost the speed of light. The electrons
are emitted and directed to the target at an en¬
ergy range of 3 to 15 million electron volts
(meV). Since energy potentials of 10 meV or
higher may produce radioactive materials, linear
accelerators of more than 9 meV are not nor¬
mally used for sterilizing.
The Van de Graaff accelerators are capable of
energy potentials up to 3 meV. They utilize the FIG. 21-5. Operating principle of a linear electron accel¬
force exerted on a charged particle by a high erator. (Courtesy of High Voltage Engineering Corp.)
voltage potential in an electric field as a means
of direct particle acceleration.
Determination of Dosage. The dosage is which water molecules are transformed into
determined by the energy released by the highly energized entities such as hydrogen and
gamma rays or by the number of electrons that hydroxyl ions. These, in turn, bring about en¬
impinge on each square centimeter of absorbing ergy changes in nucleic acids and other mole¬
substance (the target). The rad is the unit of ab¬ cules, thus eliminating their availability for the
sorbed radiation, the unit of dosage now most metabolism of the bacterial cell. Ionizing radia¬
frequendy employed. It is arbitrarily defined as tions differ from ultraviolet rays in their effects
the absorption of 100 ergs of energy per gram of on matter primarily in that the former are of a
substance. The depth of penetration within a higher energy level, actually producing ioniza¬
target of a given dose is directly related to the tion of constituent atoms. Bacterial spores and
electron voltage of the source, and indirectly re¬ viruses are generally four to five times more re¬
lated to the density of the material to be irradi¬ sistant than vegetating bacteria and molds. A
ated. dose of 2 to 2.5 megarads, however, is consid¬
Lethal Action and Dosage. Ionizing radia¬ ered adequate to ensure sterility.21 Currently,
tions destroy microorganisms by stopping repro¬ there is no evidence of reactivation of microor¬
duction as a result of lethal mutations. These ganisms as has been found with ultraviolet light.
mutations are brought about by a transfer of ra¬ Applications for Sterilization. Accelerated
diation beam energies to receptive molecules in electrons or gamma rays may be used to sterilize
their path, the direct-hit theory. Mutations also select products by a continuous process. Most
may be brought about by indirect action in other product sterilization procedures must be

STERILIZATION • 629
performed in batches. Continuous-process steri¬ of membrane filters composed of materials hav¬
lization requires exacting control so that there ing high resistance to most pharmaceutical sol¬
are no momentary lapses in sterilizing effective¬ vents has further reduced this problem.
ness. Assurance of adequate dose delivery, com¬ As noted in Table 21-5A, B, membrane filters
plete and uniform coverage of the product, and are usually composed of plastic polymers,
adequate penetration have been achieved in the including cellulose acetate and nitrate, nylon,
effective and routine sterilization of sutures,22 polyvinyl chloride, polycarbonate, polysulfone
using a linear accelerator. Adequate dosage is and Teflon. Occasionally, sintered metals such
usually determined by the effect of the absorbed as stainless steel and silver are used when
energy, at the maximum determined depth of highly durable characteristics are required.
penetration, on photographic film, and/or on the Since most of the membrane filters are dispos¬
biologic indicator Bacillus pumilus. able, the problem of cleaning after use is limited
The use of radiation is increasing in fre¬ to the reusable filter housing and support
quency and extent as experience is gained with screen. These are usually made of stainless steel
this method, particularly for the sterilization of or tough plastic polymers that are cleaned rather
medical plastic devices. It has been given new easily. Careful attention must be given, how¬
impetus by the question raised by the Occupa¬ ever, to disassembly of the housing and scrub¬
tional Safety and Health Administration (OSHA) bing to remove any residues that might intro¬
on the safety of ethylene oxide and the low envi¬ duce contamination in subsequent use.
ronmental level now being permitted. Availabil¬ The membranes are usually rendered hydro¬
ity of facilities for this method, using both en¬ philic by treatment with a surface active agent at
ergy sources, is increasing. An individual the time of manufacture. If this is not done,
medical device or pharmaceutical manufacturer particularly at the lower porosities, an aqueous
may not justify the high cost of a facility for radi¬ solution cannot be forced through the filter
ation sterilization, but the increasing availability except under very high pressure. When nonwet¬
of centers performing contract services is mak¬ ting with water is desired, however, as with such
ing this method a more viable option. nonaqueous solvents as ethanol and inert gases,
A number of vitamins, antibiotics, and hor¬ the polymer is left in its hydrophobic form.
mones in the dry state have been successfully Function of Filters. Membrane filters func¬
sterilized by radiation. Liquid pharmaceuticals tion primarily by sieving, or by screening parti¬
are more difficult to sterilize because of the po¬ cles from a solution or gas, thus retaining them
tential effect of the radiations on the vehicle sys¬ on the filter surface. Because of the nature of
tem as well as the drug. membrane filters and their limited thickness,
Filtration. Filtration may be used for the there is little entrapment within the filter
removal of particles, including microorganisms, medium, this being a mechanism applicable to
from solutions and gases without the application the function of depth filters, such as those made
of heat. Ideally, filters should not alter the solu¬ of glass and paper. Membrane filters also func¬
tion or gas in any way, neither removing desired tion in some instances by electrostatic attrac¬
constituents nor imparting undesired compo¬ tion. This would apply particularly to the filtra¬
nents. This requirement essentially limits the tion of dry gases, in which electrostatic charges
types of filters currently employed to the poly¬ tend to increase because of the frictional effect
meric types listed in Table 21-5A, B. Further¬ of the flowing gas.
more, almost all of those currently in use with The pores, or holes, through any filter
parenteral solutions and gases are of the mem¬ medium consist of a range of sizes. For example,
brane type, that is, tissue-thin material remov¬ if a filter is designated as 0.2 micron porosity,
ing particles primarily by sieving. When a filter the porosity most commonly used to effect steri¬
does remove constituents from a solution such lization, the maximum mean pore diameter is
removal is usually due to the phenomenon of 0.2 micron, with many pores much smaller than
adsorption, which being a surface phenomenon, this and a few larger. The latter may have diam¬
occurs during only the first portion of the filtra¬ eters as large as 0.5 micron, but they are so few
tion, that is, until the surface of the filter is satu¬ in number that the probability of a microbial
rated with the adsorbed molecule or ion. The spore (commonly rated as being 0.5 micron in
most common attack on the filter itself is due to diameter) finding those few pores is highly
the solvent properties of the vehicle of certain remote. However, it must be recognized that
parenteral products. Since the most common there is a probability of this happening, even
solvent for parenteral solutions is water, and the though remote. Therefore, it is no longer accept¬
use of other types of solvents is limited, this usu¬ able to consider such filters an absolute means
ally is not a problem. Moreover, the development of sterilizing a solution. To increase the probabil-

630 • The Theory and Practice of Industrial Pharmacy

 *Bio-Rad Labs.—Richmond, CA 94804, Gelman Sconces—Ann Arbor, MI 48106; Millipore—Bedford, MA 01730; Nuclepore—Pleasanton, CA 94566; Pall Trinity Micro Corp.—Cortland, NY
<v co ba a) co co
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13045; Saitorius—Hayward, CA 94545; Schleicher & Schuell—Keene, NH 03431

Si is
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^UZATION • 633
STEJUI’
Table 21-5B. Comparative Characteristics of the Membrane Filters (0.2/xm porosity) Used for Sterili¬
zation

Approx. H20 Flow Rate

(ml/min./cm2 at Bubble Sterilization—
Trade Name Extractables 520mm Hg) Point (psig) Autoclavable

HYDROPHILIC

Versapor <3% 37 — No, ETO

AN Hydrophilic Acropor <3% 20 11* No, ETO
MF-Millipore <5% 15.6 55 No, ETO
SM 11307 < 0.3% 251 55 Yes
Membra-Fil <2% 18 50 Yes
BA83 1.5% 20 54 No, ETO
GA Metricel < 3% 20 45 Yes
Celotate — 15.6 55 No, ETO
OE66 1.5% 20 54 No, ETO
SM 11107 < 0.7% 201 50 Yes, and dry heat
SM 11607 negligible 251 50 Yes, and dry heat
RC 58 < 1.5% 251 54 Yes
Ultipor N66 negligible — 46 Yes
Nuclepore negligible 15 60 Yes
Uni-Pore negligible 26; — Yes
HT Tuffryn <3.5% 12 36 Yes, or limited dry heat
Durapore Hydrophilic negligible 15 45 Yes

HYDROPHOBIC

TF Teflon trace lot 131 Yes, and dry heat

Fluoropore trace 15t 131 Yes, and dry heat
TE 35 trace 15t 131 Yes, and dry heat
Filinert trace 20f 11.51 Yes, and dry heat
Emflon trace 4.65§ Forward flow testing Yes, and dry heat
Durapore negligible 15 181 Yes

’With kerosene.
tWith methyl alcohol.
|At 700 mm Hg A P.
§At 207 mm Hg A P.

ity of achieving a sterile filtrate, some research¬ filter if filtration time is prolonged, if there is a
ers are proposing that the solution be passed high pressure differential, or if there is frequent
through a series of two 0.2-micron porosity fil¬ fluctuation of the pressure.
ters. Others have suggested that a 0.1-micron Liquid Flow Through a Filter. The flow
porosity filter be used, but this would greatly rate of a liquid through a filter is affected by the
reduce the flow rate. size of the pores through the filter, the pore
Since membrane filters function primarily by volume (the proportion of open space to solid
sieving, particles of any kind in a solution are matrix), the surface area of the filter, the pres¬
retained on the surface. If the content is rela¬ sure differential across the filter, and the viscos¬
tively high, particles may accumulate on the ity of the liquid. Of these factors, the two most
surface and plug the filter so that the flow of practical ways to increase flow rate is to increase
solution decreases and perhaps stops. To avoid the surface area of the filter or the pressure dif¬
this problem, when solutions have a high con¬ ferential across the filter. There is a practical
tent of solids, particularly when the solids are limit to increasing the diameter of a disc filter;
deformable macromolecules, the solution can thus, if larger surface areas are required, a
best be processed by passing it through one or pleated filter in a cartridge form is often used. In
more prefilters, the first usually being a rela¬ this way, a large increase in surface area may be
tively porous depth filter. With depth filters, achieved within a relatively small overall dimen¬
particles may gradually migrate through the sion of the filter unit. Within the limits of the

632’The Theory and Practice of Industrial Pharmacy

physical strength of the filter and its housing, checked before use. The least complicated
the pressure differential can be increased to method for doing this is the bubble point test.
several hundred pounds per square inch. In This test is performed by applying air pressure,
pharmaceutical practice, however, the pressure or other gas pressure, to the upstream side of a
differential used is rarely more than 25 to 30 hydrophilic filter in which the pores are filled
pounds per square inch. Usually, positive, pres¬ with water. The pressure is gradually increased
sure is applied on the liquid upstream of the until bubbles pass through the filter and are
filter, but a vacuum may be drawn downstream detected in a liquid downstream. This bubble
of the filter. In the case of a vacuum, the maxi¬ point pressure is inversely proportional to the
mum differential achievable is one atmosphere, diameter of the pores, and thus is a measure of
or approximately 15 pounds per square inch. the largest pores. The filter manufacturer identi¬
Furthermore, the negative pressure in the fil¬ fies the appropriate test pressure for each pore
trate chamber makes it difficult to prevent the size, for example, 55 pounds per square inch
ingress of contamination from the environment. gauge for a hydrophilic membrane filter of 0.2
Therefore, for filtrations designed to render jxm porosity as given in Table 21-5. If there is
solutions sterile, it is preferable to apply pres¬ even a pinhole or similar defect in the filter,
sure upstream of the filter using a gas filtered to bubbling occurs at a much lower pressure than
be free from microorganisms. Any leakage that expected. For hydrophobic membranes, the
may occur in such a system causes loss to the filter is usually wet with ethanol or methanol
outside without contamination of the sterile fil¬ prior to application of the air pressure.
trate. For cartridge-type filters, it is practical to
Solutions having a high viscosity normally measure the diffusion of air, or other gas,
have a slow flow rate. In most instances, the rate through the water-filled pores of the filter
can be increased by warming the solution, medium because of the large surface area. Pres¬
thereby reducing its viscosity provided the sure is applied to the upstream side of the filter
warming does not have an adverse affect on the as specified by the manufacturer, at approxi¬
solution. mately 10% of the bubble test pressure. The air
As previously mentioned, the flow rate dissolves in the water in the pores of the mem¬
through a filter also depends on the relative pore brane and is released from the downstream side
volume of the filter. All filters must have a solid of the membrane at a rate that is directly related
matrix that forms the framework for the pores. to the pore size. This rate is measured by the
The lower the amount of solid matrix is in pro¬ volume of the air collected downstream or by the
portion to the pore Spaces, the higher are the loss of pressure from the upstream side as the
pore volume and the flow rate. air diffuses.
Types of Filters. Since the filter membranes A more direct test with respect to the ability of
are designed to be used once and then dis¬ a filter to retain microorganisms is the microbial
carded, they are disposable; further, filter hous¬ challenge test. A standardized culture contain¬
ings composed of plastic polymers, which are ing a large number of small microorganisms,
also intended to be disposable, are becoming such as Pseudomonas diminuta, is filtered. The
increasingly available. Thus, all after-use clean¬ objective is to provide a high probability of find¬
ing is eliminated. In addition, the membrane ing oversized pores in the filter by the challenge
filter is sealed into the housing by the manufac¬ of a large number of small microorganisms.
turer, so that the risk of leakage is minimal. Therefore, after filtration, the presence of bacte¬
Membrane filters are usually in the form of ria in the filtrate constitutes a failure of the filter
discs or pleated cylinders (cartridges). They to sterilize the liquid. This type of test is nor¬
range from 13-mm discs (approximately 0.8 mally a part of the quality control program of the
cm2) to 20-in. or longer cartridges (approxi¬ filter manufacturer for each lot of sterilizing
mately 0.84 M2). The housings are usually of porosity membrane from which filters are made;
stainless steel or of various plastic polymers. however, it is rarely used in the pharmaceutical
A few years ago, it was rather common prac¬ plant for individual filters.
tice to use filters that were reusable, such as Aseptic Processing. Sterilization of a solu¬
diatomaceous earth, sintered glass, and tion by filtration provides an extremely clean
unglazed porcelain. Because of the problems of solution, removing dirt particles as well as
adequate cleaning between uses and of testing, microorganisms in the micron size range. After
current applications of these filters are limited. sterilization, however, the filtrate must be trans¬
Testing of Filters. Although membrane fil¬ ferred from the receiver and subdivided into the
ters are tested and labeled by the manufacturer, individual final containers. The objective of this
the pore size and integrity of the filter should be process, known as aseptic processing, is to

STERILIZATION • 633
exclude every microorganism from all steps of development of the newer gaseous sterilizing
the process subsequent to filtration. Accom¬ agents, particularly ethylene oxide.
plishing this requires a rigidly controlled aseptic Ethylene Oxide. Ethylene oxide (EtO) is a
environment and technique. The difficulty of cyclic ether ([CF^O) and is a gas at room
maintaining such an aseptic condition is the temperature. Alone, it is highly flammable, and
greatest problem associated with sterilization by when mixed with air, explosive. Admixed with
filtration; however, for solutions that are inert gases such as carbon dioxide , or one or
adversely affected by heat, this may be the only more of the fluorinated hydrocarbons (Freons)
way in which sterilizationcan be accomplished. in certain proportions, ethylene oxide is ren¬
Aseptic processing is technically not a sterili¬ dered nonflammable and safe to handle. As a
zation process, but is mentioned here because of gas, it penetrates readily such materials as plas¬
its close involvement with sterilization by filtra¬ tic, paperboard, and powder. Ethylene oxide
tion. It is used for products that cannot be termi¬ dissipates from the materials simply by exposure
nally sterilized, that is, sterilized after they have to the air. It is chemically inert toward most solid
been sealed in the final container. (See also materials. On the other hand, in the liquid state,
Chapter 22.) as compressed in cylinders, ethylene oxide dis¬
solves certain plastic and rubber materials and
requires particular care in handling.
Chemical Processes of Sterilizing Process. Sterilization with ethyl¬
ene oxide involves a carefully validated proce¬
Sterilization
dure using a pressure chamber.24 The material
to be sterilized is placed in a room or chamber
Gas Sterilization and exposed to a relative humidity of up to 98%
Gas sterilization is not new. Such gases as for a period of 60 min or longer. It is then placed
formaldehyde and sulfur dioxide have been used in the chamber, previously heated to about 55°C
for sterilization for many years. These gases are (131°F), and an initial vacuum of approximately
highly reactive chemicals, however, and are dif¬ 27 in. Hg is drawn. The ethylene oxide is then
ficult to remove from many materials after expo¬ introduced, along with moisture, to achieve a
sure. Therefore, their usefulness is limited. Two relative humidity of 50 to 60%, to the pressure
newer gases, ethylene oxide and beta-propiolac- required to give the desired concentration of
tone, have fewer disadvantages than the older ethylene oxide (see Table 21-6), which is main¬
agents and therefore have assumed importance tained throughout the exposure period. Follow¬
in sterilization.23 Undoubtedly, the advent of ing the exposure period of 6 to 24 hours,
plastic materials and the need for a practical depending on the degree of contamination, the
method of sterilizing them have spurred the penetrability of the material, and the concentra-

Table 21-6. Exposure Conditions Used with Ethylene Oxide Mixtures at a Temperature of 55°C
(13TF)*

Ethylene Oxide Chamber

Commercial Mixture Content Concentration Pressures Minimum Exposure
Name (%) (mg/L) (Psig) Periods (hours)

Carboxidet 10 Ethylene oxide 450 28 6

90 Carbon dioxide

Oxyfume-20t 20 Ethylene oxide 670 18 4

80 Carbon dioxide 920 30 3

Cry-OxcideJ 11 Ethylene oxide 450 5 5

(Benvicide) 54 Trichlorofluoromethane 850 18 3
35 Dichlorodifluoromethane

Pennoxide§ 12 Ethylene oxide 650 7 4

88 Dichlorodifluoromethane

•Following a humidifying (60% relative humidity; dwell period of 60 min.

tUnion Carbide Chemicals Co., Niagara Falls, NY.
JThe Matheson Company, East Rutherford, NJ.
§Pennsylvania Engineering Company, Philadelphia, PA.

634 • The Theory and Practice of Industrial Pharmacy

 tion of EtO, the gas is exhausted, and a vacuum found, however, that certain materials—notably
of approximately 25 inches Hg is drawn. Filtered rubber, certain plastics, and leather—have a
air is then introduced into the chamber until strong affinity for ethylene oxide and may
atmospheric pressure is attained. require prolonged aeration, as long as 12 to 24
A heated chamber is used to decrease the time hours, before items made from these materials
required for this sterilization process. A temper¬ may safely be used. Tissue irritation may result
ature of 55°C (131°F) has no adverse effect on if the ethylene oxide is not entirely dissipated.
most substances. It has been suggested that a Concern also exists for the carcinogenic and
rise in temperature of 17°C permits the shorten¬ mutagenic properties of EtO and residues in
ing of the exposure period by about one half.25 materials for human use. Both the Occupational
Moisture also has been found to exert a signif¬ Safety and Health Administration (OSHA) and
icant effect on the sterilization process, although the FDA have been studying this matter. As a
reports have varied gready with respect to the consequence, OSHA has recently established an
conditions and the amount of moisture that are occupational exposure standard of 1 ppm of EtO
essential. It appears that a relative humidity as an 8-hour time-weighted average concentra¬
(RH) of 30% or more is essential for effective tion.
antibacterial activity. Studies have shown that Mechanism of Action. Ethylene oxide is
microorganisms must be hydrated if they are to believed to exert its lethal effect upon microor¬
be killed by ethylene oxide within the usual ganisms by alkylating essential metabolites,
cycle time. If significantly dehydrated previ¬ affecting particularly the reproductive process 23
ously, their rehydration may require several The alkylation probably occurs by replacing an
days’ exposure to relative humidities of 75% or active hydrogen on sulfhydryl, amino, carboxyl,
more.26 Moisture introduced into the sterilizing or hydroxyl groups with a hydroxyethyl radical.
chamber along with the gas may not adequately The altered metabolites are not available to the
hydrate the microorganism; the moisture must microorganism, and so it dies without reproduc¬
be absorbed by the surrounding material and ing.
penetrate the microorganism. Therefore, a mois¬ Application. Alkylation may also occur with
turizing dwell period at up to 95% RH should be drug molecules in pharmaceutical preparations,
the first step in every sterilizing cycle as an aid particularly in the liquid state. Therefore, ethyl¬
in the distribution and absorption of moisture by ene oxide sterilization of pharmaceuticals is
the material to be sterilized. The dwell period limited essentially to dry powders of substances
also aids in establishing a moisture equilibrium shown to be unaffected. It has extensive applica¬
within the chamber load, particularly for materi¬ tion, however, to plastic materials, rubber goods,
als that preferentially absorb moisture. and delicate optical instruments. It has also
The exposure conditions most frequently used been found that stainless steel equipment has a
with ethylene oxide are shown in Table 21-6. longer useful life when sterilized with ethylene
Note that concentrations higher than the mini¬ oxide instead of steam. The effective penetrabil¬
mum effective concentration of 450 mg per liter ity of ethylene oxide makes it possible to sterilize
of chamber volume reduce the exposure period. parenteral administration sets, hypodermic
The concentrations employed are directly needles, plastic syringes, and numerous other
related to the pressure of the various mixtures related materials enclosed in distribution pack¬
required to attain that concentration. Available ages of paperboard or plastic.
equipment may limit the pressure and thereby Although the cycle time for sterilization with
the concentration attainable. ethylene oxide is quite long and certain prob¬
In addition, note that liquid ethylene oxide is lems contributing to sterilization failures have
frequently used instead of the mixtures with yet to be elucidated, this method of sterilization
inert gases, thereby eliminating the necessity for has made it possible to sterilize many materials
high-pressure handling equipment. The liquid that would be virtually impossible to sterilize
is usually vaporized into the sterilizing chamber with other known methods.
previously evacuated to at least 720 mm (28 in.) Beta-propiolactone. Beta-propiolactone
Hg. In the absence of oxygen (in a vacuum) and ([CH2]2OCO) is a cyclic lactone and is a non¬
a spark, there is no danger of explosion with flammable liquid at room temperature. It has a
ethylene oxide. low vapor pressure, but since it is bactericidal
Normally, the dissipation of ethylene oxide against a wide variety of microorganisms at rela¬
from materials is accomplished readily at the tively low concentrations, no difficulty is experi¬
end of a sterilizing cycle by the evacuation fol¬ enced in obtaining bactericidal concentrations of
lowed by a short period of aeration, that is, expo¬ the vapor. It is an alkylating agent and therefore
sure to the normal atmosphere. It has been has a mode of action against microorganisms

STERILIZATION • 635
similar to that of ethylene oxide. Studies have sodium bicarbonate to the phenolic germicides
indicated that vapor concentrations of approxi¬ to prevent rusting. Higher concentrations of
mately 2 to 4 mg per liter of space are effective at disinfectants normally would be expected to be
a temperature not below 24°C (75°F) and a rela¬ more effectively bactericidal; however, concen¬
tive humidity of at least 70%, with an exposure trations are limited by the detrimental effect that
period of at least 2 hours.27 most of these solutions have on the surfaces to
The penetrability of beta-propiolactone vapor which they are applied. Chemical attack may be
has been found to be poor. Therefore, its princi¬ evidenced by such effects as pitting and rusting
pal use appears to be the sterilization of surfaces of metal surfaces and cracking and discoloration
in large spaces, such as entire rooms. of painted surfaces.
Select disinfectants, particularly glutaralde-
hyde and beta-propiolactone have been found to
improve the effectiveness of such physical
Surface Disinfection methods of sterilization as ultraviolet light and
The use of chemical disinfectants in the phar¬ ultrasonics. Other select combinations of chemi¬
maceutical industry is designed primarily to cal and physical sterilizing agents have shown
reduce the microbial population so that asepsis increased reliability as compared with either
can be maintained in a limited, controlled envi¬ agent alone.
ronment. Most disinfectants do not destroy Further details about the properties of the
spores during any reasonable contact period; many germicides available may be found in
therefore, they do not sterilize a surface. How¬ standard textbooks.1
ever, as adjuncts to thorough cleaning of sur¬
faces, disinfectants properly used may be
expected to provide an aseptic condition of the
Evaluation
surfaces involved. The effectiveness of each sterilization process
The effectiveness of a disinfectant depends on must be demonstrated prior to its use under
the nature of the surface, the nature and degree processing conditions. A thorough evaluation
of contamination, and the microbicidal activity must be carried out, both of the functional capa¬
of the agent employed. Hard smooth surfaces bilities of the equipment and of the process
are much easier to disinfect than rough porous methods under the most demanding conditions
ones. Since most disinfectants are not effective of operation. This aspect has been discussed at
against spores, only vegetative forms of microor¬ the beginning of the chapter under the heading
ganisms can be expected to be killed. The effec¬ “Validation of Sterilization Processes.”
tiveness of the agent will depend on the number Only when proved to be consistendy effective
of organisms present and their sensitivity to the can a particular procedure be considered a valid
agent. Therefore, it is essential to select an agent sterilization process. In addition, at frequent
that has been proven effective against the intervals during use, the equipment and meth¬
common contaminants. ods should be re-evaluated to ensure that they
Hundreds of disinfe'ctants have been made are continuing to function properly.
available commercially. Methods of evaluation
differ significantly; therefore, comparisons of
effectiveness are often quite difficult. In one
Sterility Tests
comparison of 16 commercial disinfectants Sterility tests are performed on products and
(identified by active constituents only) at least materials subjected to a previously validated
five were found to be ineffective by the screen¬ sterilization procedure. The results give evi¬
ing method proposed. The two most effective dence that the sterilization procedure has been
contained a combination of four phenolic com¬ repeated effectively; however, it is generally
pounds. agreed that the controls exercised over an entire
Spaulding has provided a valuable summary validated process give superior assurance of
of disinfectants.2® He recommends a 2% solu¬ effective sterilization. These tests are performed
tion of one of the phenolic germicide cleaners for on a sample selected to represent the entire lot of
floors and walls, and 1:1000 concentrations of material. The sample may be taken from among
quaternary ammonium solutions or 1 to 2% final packages or containers of a product, or as a
solutions of phenolic germicides for smooth hard portion from a bulk tank of liquid or from other
surfaces. If the object is metallic, he recom¬ bulk material.
mends that 0.2% sodium nitrite be added to the Details of the official test tube inoculation and
quaternary ammonium solutions and 0.5% filtration procedures, including modifications

636 • The Theory and Practice of Industrial Pharmacy

for certain special situations, axe found in the inadvertent contamination during the test. Such
USP. false results can be eliminated by the use of
Test Interpretations and Modifications. carefully and adequately trained personnel
The principal operative factor in the test is that a working in a properly controlled environment.
portion of the material to be tested is placed in In general, such results are expected to occur
an environment designed so that any microor¬ less than 1% of the time.
ganisms present and viable will grow. It is well Although these limitations exist, the test is
known, however, that microorganisms do not normally valid for detecting sterilization failures.
always reproduce or vegetate (spores) simply by The limitations of the test should be recognized,
being placed in what is thought to be a favorable however, and the test should not be expected to
environment. Attenuation resulting from ultra¬ yield more information than its design permits.
violet radiation or nonlethal exposure to heat, The USP recommends that more exhaustive
lack of stimulation often necessary to make testing be performed at planned intervals to
spores vegetate, and previous contact with a confirm the continued reliability of the steriliza¬
bacteriostatic agent are among the effects that tion procedures and of the testing methods.
may interfere with the growth of the organisms. More exhaustive treatment of this subject may
In such cases, a false negative result would be be found in the literature.30
obtained. Filtration Test Methods. The membrane
False negative results of a direct inoculation filtration technique now has been accepted by
test also may occur as a result of antibacterial the USP for large and small volume parenterals.
activity inherent in the product. In addition to Although a filtration technique is subject to a
those products in which a bacteriostatic agent substantial risk from environmental contamina¬
has been purposely included, such an effect may tion, it has certain distinct advantages, includ¬
arise from an excessively low pH, a high salt ing the filtering away of inhibiting substances
content, or antibacterial activity of the medicinal and the use of larger samples.
agent itself. Such antimicrobial effect may be Essentially, this method permits the use of a
determined by the introduction of viable micro¬ sample of the liquid being tested of almost any
organisms into tubes of culture medium with desired volume. The liquid is filtered through a
and without a serial dilution of an inoculum of sterile membrane filter of microbial retentive
the product. If comparable growth occurs in all porosity under strict aseptic environmental
tubes, the product is not antimicrobial (at least, conditions. The microorganisms are retained on
against the specific organism used). If less the filter, and the liquid under test passes into
growth occurs in some of the tubes containing the filtrate, thereby carrying away potentially
an inoculum of the product, a specific inactivat¬ inhibitory substances. In addition, the filter may
ing agent must be used in subsequent testing, or be rinsed with a sterile liquid, if necessary, to
a dilution ratio must be determined that will remove potentially inhibiting substances that
permit the microorganisms that are present to may have adhered to the microorganisms. The
grow. Preferably, the filtration procedure would filter is then placed in culture medium and incu¬
be used so that the product can be filtered away bated for growth.
from any viable microorganisms retained on the Personnel conducting sterility tests must be
filter. thoroughly trained in the techniques employed.
A false negative result also may be obtained if This requirement is even more stringent for
the microbial population is so small that the persons conducting membrane filter tests
inoculum taken from the product does not con¬ because of the more complex manipulative steps
tain a microorganism. Since the product had involved. Likewise, persons interpreting the
been exposed to a sterilization process, it is results from such tests must be thoroughly
conceivable that the microbial population may familiar with the limitations as well as the effec¬
have been greatly reduced, but not totally so. tiveness of the tests.
This reduction would be more likely to occur The sterilization procedure is the vital step in
with a marginal method of sterilization or with achieving a sterile product, yet all other proce¬
an aseptic procedure, although ideally, it should dures and conditions required for the manufac¬
not occur at all. Such false results are best over¬ ture of the product must be designed to comple¬
come by improving the reliability of the steriliza¬ ment this step. Good housekeeping, an
tion procedure, but in testing, they may be effectively controlled aseptic environment, a
remedied by increasing the number or size of controlled and identified bioburden of the prod¬
the sample. uct, a well-planned and controlled production
A false positive test result could be caused by process, and well-trained and dedicated person-

STERILIZATION • 637
nel for both production and testing are essential 11. Simmons, P. L.: Pharm. Tech., 3:69, 1979.
12. Myers, T., and Chrai, S.: J. Parenter. Drug Assoc.,
for the production of a sterile product. Only
34:234, 1980.
when all of these factors complement the find¬ 13. Lewith, S.: Arch, exper. Path. u. Pharmakol., 26:341,
ings from the sterility test can it be concluded 1890.
with confidence that the product is sterile. 14. Avis, K. E.: Am. J. Pharm., 129.T1, 1957.
15. Akers, M. J., Avis, K. E., and Thompson, B.: J.
Parenter. Drug Assoc., 34:330, 1980.
16. Bruch, C. W., Koesterer, M. G., and Bruch, M. K.:
Develop, in Indus. Microbiol., 4:334, 1963.
References 17. Brewer, J. H.: The Becton, Dickinson Lectures on
Sterilization. Seton Hall College of Medicine and
1. Block, S. S. (Ed.): Disinfection, Sterilization, and Dentistry, Jersey City, NJ, April 10, 1959.
Preservation. 3rd Ed. Lea and Febiger, Philadelphia, 18. Wilkinson, G. R., Peacock, F. G., and Robins, E. L.: J.
1983. Pharm. Pharmacol., 12.197T, 1960.
2. Gaughran, E. R. L., and Kereluk, K. (Eds.): Steriliza¬ 19. Wilkinson, G. R., and Peacock, F. G.: J. Pharm. Phar¬
tion of Medical Products. Johnson & Johnson, New macol., 13.-67T, 1961.
Brunswick, 1977. 20. Nagy, R.: Research Paper BL-P-8-0089-6G6-3, Oct.
3. Perkins, J. J.: Principles and Methods of Sterilization 9,1958, Westinghouse Electric Corp., Bloomfield, NJ
in Health Sciences. 2nd Ed. Charles C Thomas, 21. Ley, F. J., andTallentire, A.: Pharm. J. 195:216,1965.
Springfield, IL, 1969. 22. Artandi, C., and Van Winkle, W., Jr.: Nucleonics,
4. Phillips, G. B., and Miller, W. S. (Eds.): Industrial 17:86, 1959.
Sterilization. Duke Univ. Press, Durham, 1973. 23. Bruch, C. W.: Ann. Rev. Microbiol., 15:245, 1961.
5. Pflug, I. J., and Smith, G. M.: Survivor curves qf bac¬ 24. Halleck, F. E.: Med. Dev. & Diagn. Ind., 2:27, April
terial spores heated in parenteral solutions. In Spore 1980.
Research. Edited by A. N. Barker et al. Academic 25. Ernst, R. R., and Shull, J. J.: Appl. Microbiol., 10:337,
Press, London, 1976. 1962.
6. Pope, D. G., Tsuji, K., Robertson, J. H., and 26. Gilbert, G. L., Gambill, V. M., Spiner, D. R., et al.:
DeGeeter, M. J.: Pharm. Tech., 2:31, 1978. Appl. Microbiol., 12:496, 1964.
7. Robertson, J. H., Townsend, M. W., Allen, P. M., 27. Spiner, D. R., and Hoffinan, R. K.: Appl. Microbiol.,
et al.: Bull. Parenter. Drug Assoc., 31: 265, 1977. 8:152, 1960.
8. Molin, G., and Ostlund, K.: Can. J. Microbiol., 28. Ostrander, W. E., and Griffith, L. J.: Appl. Microbiol.,
22:359, 1976. 12:460, 1964.
9. Tsuji, K., and Harrison, S. J.: Appl. Environ. Micro¬ 29. Spaulding, E. H.: The Becton, Dickinson Lectures on
biol., 36:710, 1978. Sterilization. Seton Hall College of Medicine and
10. Technical Monograph No. 2, Parenteral Drug Associ¬ Dentistry, Jersey City, NJ April 1, 1958.
ation, Philadelphia, 1980. 30. Bryce, D. M.: J. Pharm. Pharmacol., 8:561, 1956.

638 • The Theory and Practice of Industrial Pharmacy

 22
Sterile Products
KENNETH E. AVIS

Sterile products are dosage forms of therapeutic tion of sterile products has become a highly spe¬
agents that are free of viable microorganisms. cialized area in pharmaceutical processing. The
Principally, these include parenteral, ophthal¬ standards established, the attitude of personnel,
mic, and irrifking preparations. Of the^, par¬ and the process control must be of a superior
enteral products are unique among dosage level.
forms of drugs because they are injected The organizational divisions normally respon¬
through the skin or mucous membranes into sible f°r the preparation of sterile products in the
internal body compartments. Thus, because pharmaceutical industry are product develop¬
they have Circumvented the highly efficient first ment, production, control, and packaging. The
lineof body defense, the skin and mucous mem¬ treatment of the subject matter in this chapter is
branes,TI^yTnust be~free fromlnicrobiarcon- in accordance with these four divisions of re¬
tamination and from toxic components as well sponsibility, with emphasis on the distinctive
as possess an exceptionally high leveTof purity. aspects of sterile product manufacturing. Partic¬
'TWcomponents and processes involved in the ular emphasis is placed on the production divi¬
preparation of these products must be selected sion, for it is in this division that the distinctive¬
and designed to eliminate, as much as possible, ness of sterile product processing is particularly
contamination of all types, whether of physical, evident.
chemical, or microbiologic origin. Requirements for components related to the
Preparations for the eye, though not intro¬ product formula and its stability are considered
duced into internal body cavities, are placed in in the product development section. Many of the
contact with tissues that are very sensitive to principles of product development, control, and
contamination. Therefore, similar standards are packaging are identical for sterile and nonsterile
required for ophthalmic preparations. products. Since some of these principles are
Irrigating solutions arb now also required to treated elsewhere in this text, only those that are
meet the same standards as parenteral solutions distinctive for sterile products are covered in
because during an irrigation procedure, sub¬ this chapter.
stantial amounts of these solutions can enter the The student may wish to consult other general
bloodstream directly through open blood vessels references for corollary reading.1-3
of wounds or abraded mucous membranes.
Therefore, the characteristics and standards
presented in this chapter for the production of Product Development
large-volume parenteral solutions apply equally The final objective in the development of a
to irrigating solutions. sterile product is the elicitation of a therapeutic
Sterile products are most frequently,solutions effect in a patient. Concentration on the details
or suspensions, but may even be solid pellets for of physical or chemical factors must not be al¬
tissue implantation. The control ot aprocess to lowed to take precedence over the prime consid¬
minimize contamination for a small quantity of eration, the use of the product in a patient.
such a product can be achieved with relative Parenteral preparations may be given by vari¬
ease. As the quantity of product increases, the ous routes: intravenous, intraspinal, intramus¬
problems of controlling the process to prevent cular, subcutaneous, and intradermal. When
contamination multiply. Therefore, the prepara¬ injection occurs via an intravascular route, corn-

639
plete drug availability occurs immediately; no rification beyond that obtainable in many com¬
absorption is necessary. For all other routes, at mercial products or by normal production proce¬
least a blood vessel wall, and usually one or more dures is often necessary. Not only may chemical
tissue cell walls, must be permeated before the or physical contaminants cause irritation to body
drug can enter the circulation. Most often, this tissues, but extremely small quantities may
occurs by passive diffusion and is most favorable cause degradation of the product as a result of
when the drug has both lipophilic and hydro¬ chemical changes, particularly during the heat¬
philic properties, with the former being predom¬ ing period when thermal sterilization is em¬
inant. With nonvascular injections, absorption ployed. For example, minute traces of copper
is also affected by such factors as the size and greatly accelerate the rate of oxidation of ascor¬
number of blood vessels supplying the tissue, bic acid in solution. These traces of copper may
the movement (exercise) of the tissue following come from the water vehicle, the chemical com¬
injection, the physical and chemical properties ponents, or even the container. Rigid specifica¬
of the drug, and such characteristics of the dos¬ tions must therefore be developed for all ingredi¬
age form as whether it is a solution, suspension, ents.
or emulsion, the nature of the vehicle, and its ->
pH. Once in the circulating blood, the physio¬
logic effect of a therapeutic agent is affected by Vehicles
the extent to which it distributes throughout the By far the most frequently employed vehicle
body, by the degree of binding to plasma pro¬ for sterile products is water, since it is the vehi¬
teins, and by its rate of elimination by hepatic cle for all natural body fluids. The superior qual¬
metabolism and/or renal excretion.4,5 ity required for such use is described in the
Intravenous and intraspinal preparations monograph on Water for Injection in the USP.
rarely~are given in a form"other than aqueous Requirements may be even more stringent for
5^utiaasrTHe~3angef oFiffockage of finecapil- some products, however.
laries, particularly in the brain, precludes the One of the most inclusive tests for the quality
use of forms other than solutions for intravenous of water is the total solids content, a gravimetric
administration, although emulsions have been evaluation of the dissociated and undissociated
given in which the particle size of the dispersed organic and inorganic substances present in the
phase is carefully controlled. The sensitivity of water. However, a less time-consuming test, the
nerve tissues generally precludes the use of any¬ electrolytic measurement of conductivity* of the
thing but the purest of solutions for intraspinal water, is the one most frequently usecTTnstanta-
jnedication,.Preparafiohs given intramuscularly, neous measurements can be obtained by im¬
^Beutaneously, orTntfaflbrmallyTan be admin- mersing electrodes in the water and measuring
istered~ai~solutions, ~suspensions, orjenmlsions. the specific conductance, a measurement that
EYeiTsttlid'pellets may beTmplantedsubcutane- depends on the ionic content of the water. The
ously or intramuscularly. The vehicles can conductance may be expressed by the meter?
range from Water for Injection, to glycols, to “scale as conductivity in micromhos, resistance
fixed oils. Although care must be exercised to ni megbhms, or ionic content as parts per mil-
avoid undue tissue irritation, mild local irritation hon (ppm)~of sodium chloride. The validity^of
is permissible at these injection sites. This measurement as anindicition of the purity
The nature of a preparation can influence sig¬ of the water is inferential in that methods of pro¬
nificantly the rapidity of onset of a therapeutic ducing high-purity water, such as_ distillation
effect from a drug, the duration of the effect, and and reverse osmosis, can be expected to remove
the form of the absorption pattern achieved. undissociated substances along with those that
Therefore, the development of the formulation are dissociated7~LJndissociated substances such
for a parenteral product must be integrated care¬ as"pyrogens, however, could be present in the
fully with its intended administration in a pa¬ absenceof ions and notbe disclosed bvthe test.
tient. -TfiereforeFTor contaminants other than ions,
The chemical and physical properties of a additional tests should be performed.
drug must be determined, its interaction with Additional tests for quality of Water for Injec-
any desired excipients must be studied, and the
effect of each step of the process on its stability
must be studied and understood.
"Bamstead Co., Div. of Sybron Corp., Boston, MA 02132;
Solvent systems suitable for sterile products Beckman Instruments, Inc., Cedar Grove, NJ 07009;
are limited to those that produce little or no tis¬ Coming Glass Works, Coming, NY 14830; Foxboro Ana¬
sue irritation; water is die most common. All lytical, Div. Foxboro Co., Burlington, MA 01803;
components must be of exceptional quality. Pu¬ Vaponics, Inc., Plymouth, MA 02360.

640 • The Theory and Practice of Industrial Pharmacy

tion with permitted limits are described in the Containers may be rendered free from pyrogens
USP monographs. When comparing the total" by adequate cleaning and heating, usually at
solids permitted for Water for Injection with that 210°C for 3 to 4 hours. Studies also have shown —.
for Sterile Water for Injection, one will note that that heating at 650°C for 60 sec destroys pyro- ^
considerably higher values are permitted for gens; however, autoclaving temperatures do not ,
Sterile Water for Injection. This is necessary J destroy pyrogens during a normal cycle. -4
because th<? latter product has been sterilized, Pyrogens sometimes can be removed from so¬
usually by a thermal method, in a container that lutions by adsorption on the surface of select
has. dissolved to some extent in the water. adsorbantsTbut the often concurrent phenome¬
Therefore, the solids content will be greater than non of the adsorption of solute ions or molecules
for the nonsterilized product. On the other hand, may prevent the use of such a method .Selective
the 10 ppm total solids officially permitted for solvent extraction methods are useful in the pro¬
Water for Injection may be much too high when duction of antibiotics where heavy pyrogen con¬
used as the vehicle for many products. In prac¬ tamination results from the fermentation proc-
tice, Water for Injection normally should not*l ess. New developments in ultrafiltration show^j'c!^
have a conductivity of more than 1 micromho (1 J promise of moving this process from limited re¬
megohm, approximately 0.1 ppm NaCl). J search applications in molecular separations to
Pyrogens. Water used in parenteral and irri¬ practical production processes, which may in¬
gating solutions should be free of pyrogens. To clude pyrogen separation and elimination.8,9 For
achieve this, proper controls must be main¬ most pharmaceutical preparations, however, it
tained in the preparation and storage of the is better to prevent pyrogenic contamination
water. than to attempt to remove pyrogens, a task that
Pyrogens are products of metabolism of micro¬ is difficult to accomplish without adversely af¬
organisms. Most bacteria and many molds and fecting the product.
viruses have been reported as producing pyro¬ The product development department there¬
gens. The gram-negative bacteria produce the fore must develop purity requirements for Water
most potent pyrogenic substances as endotox¬ for Injection which are sufficiently stringent for
ins. Chemically, pyrogens are lipid substances its use as a vehicle in the product most sensitive
associated with a carrier molecule, which is usu¬ to contaminants. Tests other than those for sol¬
ally a polysaccharide but may be a peptide. ids and pyrogenic content might be required,
About 1 hour after injection into man, pyrogens e.g., qualitative and quantitative tests for the
produce a marked rise in body temperature, presence of ions such is copper and iron.
chills, body aches, cutaneous vasoconstriction. Nonaqueous Solvents. In the formulation
and a rise in arterial blood pressure. Antipyretics of sterile pharmaceutical products, it is some¬
eliminate the fever, but not the other systemic times necessary to eliminate water entirely or in
effects of pyrogens. part from the vehicle, primarily because of solu¬
The fever response to pyrogens in rabbits is bility factors or hydrolytic reactions. A nonaque¬
the basis for the official pyrogen test, which is ous solvent must be selected with great care for
described later in this chapter. For further infor¬ it must not be irritating, toxic, or sensitizing,
mation, the reader is referred to the extensive and it must not exert an adverse effect on the
reviews on the nature and significance of pyro¬ ingredients of the formulation. The screening of
gens that have appeared in the literature.6,7 such a solvent must therefore include an evalua-
Source and Elimination of Pyrogen Con¬ rion of its physical properties, such asdensitv.
tamination. Pyrogens may enter a product by viscosity, miscibility and polarity, as well as its
any means that may introduce microorganisms sfablBfvTsoivenractivitv. and toxicity.10
or the products of their growth. The most likely '"SolventstHat are miscible with water, and thaFj
sources are water, contaminated solutes, and are usually used in combination with water as
containers. Water is free from pyrogens if it has
been distilled so that the condensed molecules
the vehicle, include dioxolanes, dimethyl*
acetamide, N-(/3-hydroxyethyl)-lactamide, butyl¬ 0
have gone through the vapor state protected ene glycol, polyethylene glycol 400 and 600,
from inadvertent contamination, and if the dis¬ propylene glycol, glycerin, and ethyl alcohol..
tillate has been collected and stored in a sterile Water-immiscible solvents include fixed oils,*
condition. To be pyrogen-free, solutes must be ethyl oleate, isopropyl myristate, and benzyl
prepared from vehicles free from pyrogens, and benzoate. The most frequently used nonacfueous.
must be stored in a manner designed to prevent solvents are polyethylene glycol, propylene gly¬
subsequent contamination. Opened containers col, and fixed oils. These solvents have been re¬
of solutes, capable of supporting the growth of viewed elsewhere,11,12 and the reader is referred
microorganisms, invite such contamination. to this review for further details.

STERILE PRODUCTS * 641

Solutes throughout the useful life of the product. There¬
fore, these agents must be selected with great
The physical and chemical purity of solutes care, and they must be evaluated as to their ef¬
used for sterile preparations must also be excep¬ fect upon the entire formulation. An extensive
tional. Obviously, contaminants entering a prod¬ review of excipients used in parenteral products
uct with a solute have the same effect as if they and the means for adjusting pH of these prod¬
entered via the vehicle. Even small traces of ucts has recently been published and should be
contaminants may be detrimEjffffirtn products, referred to for more detailed information.14
necessitating purification of the solute. For a Table 22-1 provides a list, adapted from that re¬
few substances (for example, ascorbic acid and view, of excipients commonly used in commer¬
calcium gluconate), special parenteral grades cial parenteral products.
are commercially available. Antibacterial Agents. Antibacterial agents
In addition, solutes should be free from micro¬ in bacteriostatic concentration must be included
bial and pyrogenic contamination. This entails in the formulation of products packaged in mul¬
not only proper quality of the chemical as pro¬ tiple dose vials, and are often included in formu¬
cured but storage conditions designed to prevent lations to b& sterilized by marginal processes jrr
contamination, particularly after a container has made by aseptic manipulation. The require¬
been opened. Preferably, production lots should ments of activity, stability, and"effectiveness of
be designed to use the entire contents of pack¬ antibacterial agents in parenterals have been
ages of chemicals whenever possible. reviewed 'in published papers.15-17
Added Substances. Substances added to a Antioxidants. Antioxidants, included in
product to enhance its stability are essential for many formulations to protect a therapeutic
almost every product.13 Such substances in¬ agent susceptible to oxidation, particularly
clude solubilizers, antimadants, chelating under the accelerated conditions of thermal ster¬
agents, buffers, tonicity contributors, antiEaete- ilization, may function in at least two ways., i.a,
rial agents, antifungal agents, hydrolysis inhibi¬ (1) by being preferentially oxidized (reducing
tors, antifoammg' agents, and numerous other agents) and thereby gradually used up, or (2) by
substances for specialized purposes. At the same Hocking an oxidative chain reaction in which
time, these agents must be prevented from'ad¬ theyare not usually consumed. In addition, cer¬
versely affecting the product. In general, added tain compounds have been found to act as syner-
substances must be nontoxic in the quantity gists, increasing the effectiveness of antioxi-
administered to the patient. They should not in¬ UarTTs, particularly those blocking oxidative
terfere with the therapeutic efficacy nor with the reactions. A fourth group of compounds are use¬
assay of the active therapeutic compound. They ful in this connection in that they complex with
must also be present and active when needed catalysts that otherwise would accelerate the

Table 22-1. Excipients Used for Commercial Parenteral Products

Excipients Concentration Range (%)

Antimicrobial Preservatives
Benzyl alcohol . / 0.5-10.0
Benzethonium chloride 0.01
Butylparaben 0.015
Chlorobutanol 0.25-0.5
Metacresol 0.1-0.25
Methylparaben 0.01-0.18
Myristylgamma picolinium chloride 0.17
Phenol 0.065-0.5
Phenylmercuric nitrate 0.001
Propylparaben 0.005-0.035
Thimerosal 0.001-0.02
Solubilizers, Wetting Agents, or Emulsifiers
Dimethylacetamide 0.01
Dioctyl sodium sulfosuccinate 0.015
Egg yolk phospholipid 1.2
Ethyl alcohol 0.61-49.0
Ethyl lactate 0.1
Glycerin 14.6-25.0

642 • The Theory and Practice of Industrial Pharmacy

 Excipients Concentration Range (%)

Solubilizers, Wetting Agents, or Emulsifiers—continued

Lecithin 0.5-2.3
PEG-40 castor oil 7.0-11.5
Polyethylene glycol 300 0.01-50.0
Polysorbate 20 0.01
Polvsorbate 40 0.05
Polysorbate 80 0.04-4.0
Povidone 0.2-1.0
Propylene glycol 0.2-50.0
Sodium desoxycholate 0.21
Sorbitan monopalmitate 0.05
Theophylline 5.0
Buffers
Acetic acid 0.22
Adipic acid 1.0
Benzoic acid and sodium benzoate 5.0
Citric acid 0.5
Lactic acid 0.1
Maleic acid 1.6
Potassium phosphate 0.1
Sodium phosphate mon basic 1.7
Sodium phosphate dibasic 0.71
Sodium acetate 0.8
Sodium bicarbonate 0.005
Sodium carbonate 0.06
Sodium citrate 4.0
Sodium tartrate 1.2
Tartaric acid 0.65
Bulking Substances or Tonicity Modifiers
Glycerin 1.6-2.25
Lactose 0.14-5.0
Mannitol 0.4-2.5
Dextrose 3.75-5.0
Sodium chloride varies
Sodium sulfate i.i
Sorbitol 2.0
Suspending Agents
Gelatin 2.0
Methylcellulose 0.03-1.05
Pectin 0.2
Polyethylene glycol 4000 2.7-3.0
Sodium carboxymethylcellulose 0.05-0.75
Sorbitol solution 50.0
Chelating Agents
■A Edetate disodium 0.00368-0.05
Edetate calcium disodium 0.04
Edetate tetrasodium 0.01
Local Anesthetics
Procaine HC1 1.0
Benzyl alcohol 5
Stabilizers
Creatinine 0.5-0.8
Glycine 1.5-2.25
Niacinamide 1.25-2.5
Sodium acetyltryptophanate 0.53
Sodium caprylate 0.4
Sodium saccharin 0.03

Adapted from Wang, Y.J., and Kowal, R.R.: J. Parent. Drug Assoc., 34:452, 1980.

STERILE PRODUCTS • 643

 oxidative reaction. Because of the differences in tic component, or reactions within the product,
action, combinations of these agents are some- Buffers must have the~capacity to maintain the
times used. In Table 22-2, the more commonly pH of the product against these influences, but
employed antioxidants are listed according to not enough to prevent the body fluids from over-
the above four groupings. The reader is referred whelming the buffer following administration,
to the literature for more details concerning an • In most cases, the biologic effectiveness of the
tioxidants and their activities.18-20 drug is maximum at or near the biologic Quid pH
It should also be mentioned that for those rather than at the stabilizing pH of the injected
products in which oxygen enters into a degrada- product.
tive reaction, an antioxidant effect can be Acetates, citrates, and phosphates are the
achieved by displacing oxygen (air) from contact principal buffer systems used, but buffer sys-
with the product. Usually, this is accomplished terns making use of other ingredients in the for-
by saturating the liquid with either nitrogen or mulation are often used to reduce the total num-
carbon dioxide and sealing the final container ber of ingredients in the product. Buffer systems
after displacing the air above the product with must be selected with consideration of their ef-
the gas. fective range, concentration, and chemical ef-
Higuchi and Schroeter have warned of the feet on the total product. These factors have
reactivity of bisulfites with drug molecules,21 Been reviewed by Windheuser.23
and Halaby and Mattocks have warned of the Tonicity Contributors. Compounds con-
potential toxicity of sodium bisulfite absorbed tributing to the isotonicity of a product reduce
from peritoneal dialysis solutions.22 the pain of injection in areas with nerve end-
Buffers. Buffers are added to maintain a re- ingSTHutfers may serve as tonicity contributors
quired pH for many products; a change in pH as well as stabilizers for the pH. Other added
may cause significant alterations in the rate of substances also contribute to the colligative
degradative reactions. Changes in pH may occur properties of the preparation. Whenever possible
during storage as a result of the dissolving of such dual activity is desirable.
glass constituents in the product, release of con¬ Although the freezing point depression of the
stituents from rubber closures or plastic compo- solution is most frequently used to determine
~nentsTn contact with the product, dissolving of whether a solution is isotonic, isotonicity actu¬
gases and vapors from the airspace in the con¬ ally depends on the permeabilifyofalivi.ng~sem-
tainer and diffusion through the rubber or plas- fpcrmeable membrane Ihat separates the solu¬
tion from a biologic cell sysfeinTMost frequently,
for sterile" pharmaceutical preparations, the
Table 22-2. Antioxidants Used in Sterile Prod¬ membrane concerned is the one enclosing the
ucts
red blood cells. Therefore, a preparation cannot
Usual be considered to be isotonic until it has been
Concentration tested in a biologic system. A hemolytic method,
Compound (%)
sing.red blood cells, has been described.24,25
Isotonicity values for various drugs have been
Antioxidants (reducing agents) recorded.26'29 Testing by such a method be¬
Ascorbic acid 0.02-0.1 comes even more important when all or part of
Sodium bisulfite 0.1-0.15 the water is replaced with another solvent, since
Sodium metabisulflte 0.1-0.15 dissociation is different when water is displaced
Sodium formaldehyde sulfoxylate 0.1-0.15 by another solvent. .
Thiourea 0.005
Antioxidants (blocking agents) *
Ascorbic acid esters 0.01-0.015
Containers
Butyl hydroxytoluene (BHT) 0.005-0.02 Containers are in intimate contact with the
Tocopherols 0.05-0.075 product. No container presently available is
Synergists totally nonreactive, particularly with aqueous
Ascorbic acid 0.01-0.05 solutions. Both the chemical and physical char¬
Citric acid 0.005-0.01 acteristics affect the stability of the product, but
Citraconic acid 0.03-0.45 the physical characteristics are given primary
Phosphoric acid 0.005-0.01 consideration in the selection of a protective
Tartaric acid 0.01-0.02 container.
Chelating agents Glass containers traditionally have been used
for sterile products, many of which are closed
Ethylenediaminetetraacetic acid salts 0.01-0.075 with rubber stoppers. Interest in plastic con-

644 • The Theory and Practice of Industrial Pharmacy

 tamers for parenterals is increasing, and such polypropylene. Polypropylene is most widely/
containers are being used for commercial oph¬ used. It is a linear polymer that can be produced /
thalmic preparations and intravenous solu¬ to be highly crystalline. Because of its crystalfin-(
tions.30 ity, it has high tensile strength, a high melting!
Plastic Containers. The principal ingredi¬ point of 165°C, and a relatively low permeability)
ent of the various plastic materials used for con¬ to gases and water vapor. It is translucent, abra¬
tainers is the thermoplastic polymer; the basic sion-resistant, and has a high surface gloss. It
organic structural unit for each type commonly will withstand normal autoclaving tempera¬
encountered in the medical field is given in tures. It must be stabilized with an antioxidant,
Table 22-3. Although most of the plastic materi¬ however, the type and concentration of which
als used in the medical field have a relatively low must be carefully controlled to avoid leaching on
amount of added ingredients, some contain a one hand or degradation of the plastic on the
substantial amount of plasticizers, fillers, an¬ other.
tistatic agents, antioxidants, and other ingredi¬ Autian has reviewed the characteristics and
ents added for special purposes. These ingredi-' use of plastic materials for parenterals.32 Inter¬
ents are not usually chemically bound in the est in the use of such materials for containers for
formulation and, therefore, may migrate out of. sterile products is increasing, but careful evalua¬
the plastic and into the product under the condi¬ tion of their potential interaction with products
tions of production and storage. Considerable with which they are in contact is essential.33
variability also has been encountered in the pu¬ Flexible polyethylene containers are used for
rity of the commercially available polymers. ophthalmic solutions to be administered in
As the name indicates, thermoplastic poly¬ drops, and flexible polyvinyl chloride bags for
mers melt at elevated temperatures. All of the intravenous solutions. 54 The Tatter have a partic-
polymeric materials listed in Table 22-3 except ulaFadvantage over glass bottles in that no air
low-density polyethylene and polystyrene can be from the patient’s bedside need enter the con¬
autoclaved if they have been formulated with a tainer as the liquid flows out; the bag simply col¬
low amount of plasticizers, although most of lapses. Xfae new group of polymers, the polyole-
them soften at autoclaving temperatures, and fins, have madepossi51g~the~~aevelopmenf of
care must be exercised to avoid fusing adjacent Bottles that are rigid enough in~FioId~ tKeir shape
surfaces or otherwise deforming them. Also during processing'But can collapse under atmos¬
listed in Table 22-3 are certain properties of the pheric pressure as outflow of a solutiorToccurs
plastic materials most commonly used for con¬ ctunng intravenous administration to a patient.
tainers and components in drug packaging. Thus, the characteristics of a rigid container are
These properties vary considerably with the type utilized during processing and handling, but the
* and amount of additive combined with the poly¬ advantage of collapsibifity of a flexible container
mer. is achieved for aseptic administration.
Plastic containers^ are used mainly because The USP has provided test procedures for
they are fight in weighlTare nonbreakable, and, evaluating the toxicity of plastic materials. Es¬
when low in additives, have low toxicity and low sentially the tests consist of three phases: (1)
reactivity with products. Tissue toxicity can implanting small pieces of the plastic material
occur from certain polymers, but additives are intramuscularly m rabbits, (2) injecting eluates
a more common cause. 1 Reactivity due to sorp¬ using sodii@ chloride injection, with and with¬
tion (absorption and/or adsorption) has been out alcohoifintravenouslyfin. mice, and injecting
found to occur most frequently with the polyam¬ eluates using polyethylefr^glycol 400 and ses-
ide polymers, but additives leached from any ofi2P ame oil intraperitoneally in mice, and (3) inject¬
the plastic materials may interact with ingredi¬ ing all four eluates subcutaneously in rabbits.
ents of the product. The reaction from the test samples must not be
Most polymers are adversely affected by the significantly greater than nonreactive control
elevated temperatures required for thermal ster¬ samples. Guess and Autian have discussed
ilization and have a relatively high permeability these tests in detail.35
for water vapor (Table 22-3). Significant perme¬ Glass Containers. Glass is still the pre¬
ation of gases, including oxygen, may occur with ferred material for containers for injectable
some materials, polystyrene having by far the products. Glass is composed principally of the
highest level of permeation of those fisted. silicon dioxide tetrahedron, modified physico-
A relatively new group of plastics, the nolv- chemically by such oxides as those of sodium,
olefirfsT "deserve special mention. The two of potassium, calcium, magnesium, aluminum,
interest today in the parenteral field are poly¬ boron, and iron. The two general types of glass
propylene and the copolymer polyethylene- are soda-lime and borosificate (see Table 22-3).

STERILE PRODUCTS • 645

Table 22-3. Comparative Properties* of Container Materials

Average Autoclavable
Material Structural Unit Density (Physical Stability)

Thermoplastic polymers
Polyethylene
Low density.. (—c h2—C H2—)n 0.92 ' No

High Density (—ch2—ch2—)n 0.96 Yes

Polypropylene (-CHCH3-CH2—)n 0.90 Yes

Polyvinyl chloride

Flexible (—CHC1—CH2—)n 1.2 Yes

(cautiously)
Rigid (—CHC1—CH2—)n 1.4 Yes
(cautiously)
Polycarbonate (—O—C6H5—C(CH3)2—c6h5—C02—)„ 1.2 Yes

Polyamide (nylon) (—CH2—(CH2)4—NHCO—)n 1.1 Yes

(repeatedly)
Polystyrene -- ( CH(C6H5) ch2 )n-- 1.05-_No

Polytetrafluoroethylene (-CF2-CF2—)„ 2.25 Yes

(Teflon) (repeatedly)

Glass
// o1 o1
Soda-lime I I
—0—Si—O—Si—O— In 2.48 Yes

V 0

Borosilicate
I o o
2.23 Yes
O—Si—O—Si—O-
I I
o o

Rubber compounds
Butyl (—CH2-C(CH3)=CH—(CH2)2—C(CH3)2-)n 1.3 Yes

Natural (—CH2-C(CH3)=CH—ch2—)n 1.5 Yes

Neoprene (—ch2—ch=ccl—ch2—)„ 1.4 Yes

Polyisoprene (—CH2—C(CH3)=CH—ch2—)n 1.3 Yes

Silicone (—Si(CH3)2—0—Si(CH3)2—0—)n 1.4 Yes

’General relationships that vary substantially with factors such as container material formulation, thickness of wall, and temperature.

646 • The Theory and Practice of Industrial Pharmacy

 Potential
Water Gas Reaction
Additives f Leachable Vapor Permeation With Physical
Present Constituentsf Permeation (02) ProductI Properties

Low Additives § High Low Low Translucent, flexible

(Low)
Low Additives § Low Low Low Translucent, semi-rigid
(Low)
Low Additives § Moderate Low Low Translucent, semi-rigid
(Low)

High Additives § High Low Moderate Transparent, flexible

(High)
Low Additives? High Low Low Transparent, rigid
(Low)
Low Additives? High Low Low Transparent, rigid
(Low)
Low Additives? High Low High Translucent, rigid,
(Low) tough
Low Additives? High High Moderate Transparent, rigid
(Low)
Low __ ._Additives? - Low _ Low Nil . Translucent, tough,
(Nil) rigid, temperature-
resistant

High K20, Na^O, MgO, None None High Optically clear, rigid
CaOJHigh)/

Low B203, Na20, CaO, None None Low Optically clear, rigid
(Low)

Moderate Additives|| Low Moderate Moderate Opaque, flexible

(Moderate)
High Additives|| Moderate Moderate High Opaque, flexible
(High)
High Additives|| Moderate Moderate High Opaque, flexible
(High)
High Additives|| Moderate Moderate Moderate Opaque, flexible
(High)
Moderate Additives! Very high Very high Low Translucent, flexible
(Moderate)

tSubstances added to modify the properties of the basic ingredient.

(General relationships are based upon an aqueous system but may be markedly affected by other solvent systems of the product.
§May include residues of plasticizers, antistatic agents, antioxidants and other ingredients added for special purposes.
||May include, residues of vulcanizers, accelerators, lubricants, inorganic fillers, and other ingredients added for special purposes.

STERILE PRODUCTS • 647

The glass that is most resistant chemically is since the quantity of alkaline constituents
composed almost entirely of silicon dioxide, but leached is small. The Water Attack test is used
it is relatively britde and can only be melted and > only with containeriTEat have beenexposed to
molded at high temperatures. Boric oxide some- jvsulfur dioxide fumes under controlled humidity
what modifies the above characteristics as it en- conditions. Such treatment neutralizes the sur-
ters the structural configuration, but most of the face alkaline oxides, thereby rendering the glass
other oxides apparently enter the spaces within more resistant chemically. This increased resist¬
the structure and reduce the strength of the in¬ ance is lost, however, if the container is sub¬
teratomic forces between the silicon and oxygen. jected to repeated autoclaving, hot air steriliza¬
Therefore, the latter oxides lower the melting tion, or hot detergent treatment.
point of the glass and are comparatively free to On the basis of the results from the official
migrate. Consequently, they also lower the tests, glass compounds are classified into four
chemical resistance of the glass; that is, they types, as shown in Table 22-4. The greatest
may migrate into a product over a prolonged pe¬ chemical resistance is provided by Type I, and
riod of contact, particularly with aqueous solu¬ the least by NP (nonparenteral) glass. It should
tions. In solution, the oxides may hydrolyze to be noted, however, that within these types, as
raise the pH, catalyze reactions, or otherwise well as Types II and III, a range of compositions
enter into chemical reactions. Glass flakes are are available. The chemical resistance of the
also sometimes produced as a result of the action glass influences the selection of the type to be
of the solution. These interactions are markedly used for various products. Table 22-4 provides a
accelerated during the elevated temperature brief summary of the general classes of products
required for autoclaving. used with the four glass types. Type I glass is^
Chemical Resistance. The USP provides preferred for most sterile products, but Types II
the Powdered Glass and the Water Attack tests and III may be used when the product has a
for evaluating chemical resistance of glass. The nonaqueous vehicle or the period of contact with
test results are measures of the amount of alka¬ the aqueous vehicle is brief, as with dry powders
line constituents leached from the glass by puri¬ reconstituted just prior to use, or if the nonreac-
fied water under controlled elevated tempera¬ tivity of the glass and product has been estab- j
ture conditions; the Powdered Glass test is lished. For further consideration of the interrela-
performed-on ground, sized glass particles, and tionships of glass with products, the reader i,sJ
the Water Attack test is performed on whole con- referred to the published literature.36,37
^ainers. The conditions of the test must be rig¬ Physical Characteristics. The protection of
idly controlled to obtain reproducible results light-sensitive products from the degradative

Table 22-4. USP Glass Types, Test Limits, and Selection Guide

Test Limits
Sizef ml of 0.02N
Type General Description* Type of Test (ml) H2S04 General Use

1 Highly resistant bo- Powdered All 1.0 Buffered and unbuffered

rosilicate glass Glass aqueous solutions.
All other uses.
II Treated soda-lime Water Attack 100 or less 0.7 Buffered aqueous solu¬
glass Over 100 0.2 tions with pH below 7.0
Dry powders, oleaginous
solutions.
III Soda-lime glass Powdered All 8.5 ' Dry powders, oleaginous
Glass solutions.
NP General-purpose Powdered All 15.0 Not for parenterals. For
soda-lime glass Glass tablets, oral solutions
and suspensions, oint¬
ments, and external liq¬
uids.

*The description applies to containers of this type 6f glass usually available.

tSize indicates the overflow capacity of the container.

648 • The Theory and Practice of Industrial Pharmacy

effect of ultraviolet rays may be one of the im¬ nally with silicone fluid to produce a hydropho¬
portant physical characteristics of a glass con¬ bic surface. To achieve permanency, the silicone
tainer. Ultraviolet rays can be completely filtered must be baked at a temperature of approxi¬
out by the use of amber glass; however, the color mately 150°C (300°F). This additional operation
of amber glass is produced largely by the pres¬ is justified for such applications as to reduce the
ence of iron oxide, traces of which may sub¬ adherence of heavy, costly suspensions or emul¬
sequently be leached into the product. If the sions or to increase slippage of a plunger in , a
product contains ingredients subject to iron cat¬ syringe barrel.
alyzed chemical reactions, amber glass cannot Container Use Considerations. The size of
be used. The product must then be protected single-dose containers is limited to 1000 ml by
from ultraviolet rays by means of an opaque car¬ the USP and multiple-dose containers to 30 ml,
ton surrounding a flint (colorless) glass con¬ unless permitted otherwise in a particular mon¬
tainer. ograph. The size limitation for multiple-dose
In addition to other physical characteristics, vials is intended to limit the number of entries
glass containers should have sufficient physical for withdrawing a portion of the contents of the
strength to withstand the high pressure differ¬ vial with the accompanying risk of microbial
entials that develop during autoclaving and the contamination of the remaining contents. The
abuse that occurs during processing, shipping, particular advantage of these containers is flexi¬
and storage; a low coefficient of thermal expan¬ bility of dosage offered the physician. Single¬
sion to withstand the thermal shocks that occur dose containers are intended to provide suffi¬
during washing and sterilization procedures; cient drug for just one dose, the integrity of the
transparency to facilitate inspection of the con¬ container being destroyed when opened so that
tents; and uniform physical dimensions to facili¬ it cannot be reclosed and used again. Single¬
tate handling by the mechanical machinery dose containers may range from liter bottles of
used for automatic production operations. intravenous solutions to 1-ml, or smaller, car¬
Glass containers may be manufactured by tridges. The desire for further reduction in the
drawing from glass tubing or by blow molding. risk of contamination, both bacterial and viral,
Ampuls, cartridges, and vials drawn from tubing and an increased control over the administra¬
have a thinner, more uniform wall thickness tion of drugs, paricularly in a hospital, have
with less distortion than containers made by led to the recent development of single-dose,
blow molding. The greater strength of blown disposable administration units. For most of
vials and bottles, however,,may be essential for these units, the product container is a glass car¬
handling by mechanical processing equipment. tridge with plastic and metal fitments separated
Large vials and bottles are made only by blow from immediate contact with the product.
molding. Rubber Closures. Rubber closures are used
The physical dimensions of glass containers to seal the openings of cartridges, vials, and bot¬
can readily be varied to meet design needs, espe¬ tles, providing a material soft and elastic enough
cially those made by blow molding. An example to permit entry and withdrawal of a hypodermic
is the double-chambered vial designed to con¬ needle without loss of the integrity of the sealed
tain a freeze-dried product in the lower chamber container. Figure 22-1 illustrates some of the
and the solvent in the upper chamber, separated styles of rubber closures and their relationship to
by a rubber disc. The modifications in cartridge typical containers.
shapes for use with various disposable dosage Composition and Reactivity. Rubber clo¬
units, and the wide-mouth ampuls with flat or sures* are compounded of several ingredi¬
rounded bottoms to facilitate filling dry materi¬ ents,38-39 principally, natural rubber (latex) and/
als or viscous liquids, also illustrate the varia¬ or a synthetic polymer; a vulcanizing agent, usu¬
tions in physical dimensions possible with glass ally sulfur; an accelerator, one of several active
containers. The development of the easy-open organic compounds such as 2-mercaptoben-
ampul several years ago, permitting opening zothiazole; an activator, usually zinc oxide; fill¬
without a file, was an important modification in ers, such as carbon black or limestone; and a
the physical structure of these containers, mar¬ variety of other ingredients such as antioxidants
keted under the name “Color-Break”* and and lubricants. These ingredients are combined
“Score-Break”! ampuls. by kneading them into a homogeneous plastic
Glass containers are sometimes coated inter- mass on a roller mill. The homogeneous com-

‘Faultless Rubber Co., Ashland, OH 44805; Tompkins

* Kimble, Division of Owens-Illinois, Toledo, OH 43601. Rubber Co., Plymouth Meeting, PA 19462; The West
tWheaton Scientific, Millville, NJ 08332. Company, Phoenixville, PA 19460.

STERILE PRODUCTS • 649

FIG. 22-1. Rubber closures associated with vials, bottles, and cartridges. Slotted vial closures on left, flanged vial closures
in center foreground, permanent hole bottle closure in center rear, and cartridge and disposable syringe closures Ion right.

pound is rendered fluid and then vulcanized in scribed intervals, samples are examined for
the desired shape by means of molds under high qualitative and quantitative evidence of chemi¬
pressure and temperature. cal or physical change either in the closure or in
In Table 22-3 are listed the elastomeric poly¬ the product.
mers most commonly used in compounding rub¬ Physical Characteristics. Several proper¬
ber closures, as well as some of their compara¬ ties of rubber closures are significant, particu¬
tive properties. larly elasticity, hardness, and porosity. Rubber
Ideally, closures should be completely nonre¬ closures must be sufficiendy elastic to provide a
active with the product with which they are in snug fit between the closure and the neck and
contact. No such ideal compound exists; there¬ lip of the glass container. They must also spring
fore, each rubber compound should be tested for back to close the hole made by the needle imme¬
compatibility with each preparation with which diately after withdrawal. Rubber closures must
it is to be used. Two general compatibility prob¬ not be so hard that they require an excessive
lems exist, namely, the leaching of ingredients pressure to insert the hypodermic needle, and in
from the rubber compound with subsequent re¬ doing so, must not produce a large number of
action with ingredients of the product, and the fragments as the hollow needle cuts through the
removal of ingredients from the product by sorp¬ closure (coring). Although porous, they should
tion by the rubber compound or by vapor trans¬ not permit the easy transfer of water vapor and
fer through the closure.40,41 gases in either direction. See Table 22-3 for gen¬
Although-compatibihty problems are encoun¬ eral comparisons. Minimal water vapor transfer
tered with relative frequency, it should not be is important, for example, to prevent the absorp¬
construed that rubber compounds invariably in¬ tion of water by freeze-dried products.
troduce such problems. Preliminary compatibil¬ Plastic or lacquer coatings are sometimes ap¬
ity usually is assessed by placing the rubber clo¬ plied to the surfaces that will be in contact with
sure in intimate contact with the product and the product. These coatings sometimes reduce
maintaining the samples at elevated tempera¬ vapor transfer, sorption, and leaching, but they
ture levels for planned periods of time. At pre¬ do not usually provide the complete barrier de-

650 • The Theory and Practice of Industrial Pharmacy

sired. Teflon liners have been shown to provide Although the contact time of the product with
an effective barrier against sorption and leach¬ the device is usually brief, it is intimate; there¬
ing.42 fore, compatibility between the device and the
The physical shapes of closures vary with product must be evaluated. For example, it has
their intended use. Several common shapes are been shown that insulin can be adsorbed by PVC
shown in Figure 22-1: the common flanged clo¬ tubing during the time of contact for administra¬
sure (center), slotted for freeze-dried products tive of an i.v. solution, approximately 6 hours.45
(left) or punctured for attachment of adapters for The materials used for devices are mostly the
infusion sets (center, rear), and the plunger type same as those used for containers, but may in¬
for use with cartridges (right). Disc closures pre¬ clude others if short term contact has been
assembled with aluminum caps are being used shown to be acceptable. For example, nylon and
to increase the speed of the operation in the silicone rubber are used for i.v. catheters, and
high-speed packaging of antibiotics and other stainless steeF is used for hypodermic needles.
drugs. Other designs are used as needed for par¬ Even aluminum is sometimes used for the hub
ticular application. and cannula of needles, but aluminum is much
Testing. Methods of testing for lot to lot uni¬ more reactive with some products than stainless
formity of rubber closures have been studied for steel. Parts of a device that do not come into con¬
many years, but because of the nature of rubber tact with the product, such as the clamp on an
compounds, consistent test results have been i.v. administration set, need not pass product
difficult to obtain. Progress has been made, how¬ stability evaluation.
ever, and the USP now describes physicochemi¬ All device components must be visibly clean,
cal and biologic tests, but without test limits. but the fluid path through the device should
The physicochemical tests on aqueous extracts meet the same rigid standards for cleanliness as
include pH, turbidity (nephelos), residue on dry¬ the product. Usually, this must be achieved dur¬
ing, iodine number, and heavy metals content. ing manufacture and assembly of the device
The biologic tests on saline, polyethylene glycol since final wet rinse or cleaning may be difficult
400, and cottonseed oil extracts include acute or impossible, owing to configuration of the de¬
and chronic toxicity in mice and rabbits. Further vice. Further, moisture residues may be detri¬
discussion of the purpose of these tests may be mental to stability, causing leaching or interfer¬
found in the hterature.43,44 ence with sterilization. Plastic particles from
molding or metal dust from the sharpening of
needles are examples of particulate matter that
must be eliminated. If solvents are used to as¬
semble component! of the device, care must be
Devices taken to eliminate any excess, especially in the
Devices, as considered here, are the various fluid path.
items of equipment used to convey the product Tests performed by representative sampling of
from its container into the body of the patient a lot of a finished device include those for toxic¬
or from one container to another; or the term ity as specified by the USP and functional tests
may refer to the containers themselves. Devices appropriate for the specific device'. The latter
associated with sterile products include the must be adequate to assure that a given, lot per¬
following: forms as intended in use, although the criticality
of a particular defect differs. Defects are usually
Administration sets for large volume expressed in terms of Acceptable Quality Levels
parenterals (LVPs) (AQLs); the more critical AQLs are less than 1.0.
Filter needles For example, split hubs of needles, would be
more critical than slight discoloration of tubing,
Hypodermic needles and may have AQLs of 0.065% and 2.5%, re¬
Hypodermic syringes spectively. Therefore, great care must be exer¬
In-line filters cised by quality control to prevent critical de¬
fects from being passed along to the user. For
Plastic irrigating solution bottles example, the integrity of the seal of the permea¬
Plastic LVPs containers tion section within a kidney dialysis unit is so
Plastic ophthalmic dropping bottles critical to its use that every unit must be tested
before it is released.
Transfer needles
Transfer sets

STERILE PRODUCTS • 651

Formulation formation, the reader is referred to the technical
literature.49-51
The formulation of a parenteral product in¬ Adding to the complexity of solvent selection
volves the combination of one or more ingredi¬ is the requirement that solvents to be injected
ents with a medicinal agent to enhance the con¬ must be of low toxicity to body tissue. .Ether is a
venience, acceptability, or effectiveness of the solvent for testosterone, but is highly irritating
product. Rarely is it preferable to dispense a to body tissue ancTcannot be used alone as a sol¬
drug singly as a sterile dry powder unless the vent for an injectable preparation. Frequendy,
formulation of a stable liquid preparation is not the desired solubility can be achieved with
possible. mixed solvents, e.g., the use of approximately
On the other hand, a therapeutic agent is a 40% ethanol in water to solubilize the digitalis
chemical compound subject to the physical and dvcosidesT-
chemical reactions characteristic of the class of Compounds that are dissolved in water are
compounds to which it belongs. Therefore, a often subject to degradative reactions, such as
careful evaluation must be made of every combi¬ hydrolysis, oxidation, decarboxylation, and race-
nation of two or more ingredients to ascertain mization. Formulation must be designed, in
whether or not adverse interactions occur, and if such cases, to minimize the degradative effects.
they do, of ways to modify the formulation so Often, these reactions are markedly affected by
that the reactions are eliminated or minimized. the pH of the solution. Epinephrine in solution
The formulation of sterile products is challeng¬ undergoes racemizatioriand oxidation, but if the
ing, therefore, to the knowledge and ingenuity of pH is maintained at 3.0 or lower, little reaction
the persons responsible.46-48 occurs.52 t he oxidation reaction can be further
The amount of information available to the reduced by displacing atmospheric oxygen with
formulator concerning the physical and chemi¬ an inert gas and adding(QJ% sodium metabisul-
cal properties of a therapeutic agent, particularly ifte as an antioxidant. Atropine sulfate rapidly
if it is a new compound, is often quite meager. hydrolyzes in solution, hut if the pH is main¬
Information concerning basic properties must tained with a~buffer system at about 3.5 to 4.0,
be obtained, including molecular weight, solu¬ "hydrolysis does not occur at a significant rate?3
bility, purity, colligative properties, and chemi¬ 'The use of a mixed solvent system often re¬
cal reactivity, before an intelligent approach to duces degradative reactions. Barbituric acid de¬
formulation can begin. Improvements in formu¬ rivatives hydrolyze readily in water, particularly
lation are a continuing process, since important at a low pH. It has been shown, however, that
properties of a drug or of the total formulation pentobarbital sodium is soluble and stable in a
may not become evident until the product has vehicle containing 60% polyethylene glycol 400
been stored or used for a prolonged time. How¬ and 10% ethanoHn water at a pH of 8.54
ever, because of the extensive test documenta¬ The aforementioned reactions do not occur in
tion required by the U.S. Food and Drug Admin¬ an anhydrous, nonpolar vehicle, such as fixed
istration (FDA), only outstanding formulations oil, although the presence of a small amount of
can be justified for continuance to the state of a water may permit slight reactions. Oleaginous
marketed product. injections are subjected, however, to the disad¬
The Solvent System. A parenteral thera¬ vantages of being viscous (thus difficult to ad¬
peutic agent is given by preference as a solution. minister, particularly in cold weather) and of
If aqueous, the solution is physiologically com¬ involving frequent incidence of pain upon injec¬
patible with body tissues, and the biologic re¬ tion.
sponse elicited should be reasonably predictable. Additives. A variety of ingredients may be
The high-dielectric constant -ofwater makes it added to a formulation to provide the required
stability and therapeutic efficacy. Several
hydrogen bonding potential brings about the so¬ classes of additives have been mentioned: anti¬
lution of such organic substances as alcohols, bacterial agents, antioxidants, buffers, and to¬
aldehydes, ketones, and amines. Conversely, nicity contributors.
water is a poor solvent for nonpolar compounds, Additives may be included in formulations for
such as alkaloidal bases, which require nonpolar purposes other than those already mentioned.
solvents. Since therapeutically active com¬ Chelating agents may be added to bind, in
pounds given by injection range in property nonionizable form, trace amounts of heavy met¬
from highly polar to nonpolar, solvents having als, which if free, would catalyze degradative
complementary properties must be employed if a changes. The chelating agent most commonly
solution is to be achieved. For further basic in¬ used is the trisodium or calcium disodium salt of

652 • The Theory and Practice of Industrial Pharmacy

 ethylenediamine tetraacetic acid in a concentra¬ One characteristic not as critical for ophthal¬
tion of about 0.05%. An interesting example of mics is freedom from pyrogens since pyrogens
the use of this chelating agent is the stabiliza¬ are not absorbed systemically from the eye; how- y
tion of thimerosal in poliomyelitis vaccine. Thi¬ ever, insofar as pyrogens are indicative of a mi- I
merosal is present as a bacteriostatic agent, but crobiologically clean process, they should not be j
Tt is unstable in the presence of cupric ions, the present.
breakdown products of which destroy the antige¬ Freeze-Dried Products. Solutions intended
nicity of the vaccine. The chelating agent stabi¬ to be freeze-dried must be aqueous, for the dry¬
lizes the thimerosal, and thereby stabilizes the ing process involves removal of water bv subli^~
vaccine.55 The heavy metals extracted from rub¬ mation. Since the solution is in existence for
ber closures also may be bound by the presence onlya brief period during processing, stability
of a chelating agent, reducing the possibility of problems related to the aqueous system are
reactions with ingredients in the formulation. practically nonexistent. However, the formula¬
Occasionally, with slighdy soluble salts it may tion must reflect the characteristics to be im¬
be desirable to reduce the solubility of the com¬ parted^ to the solid residue (cake) after dry¬
pound. For example, procaine hydrochloride ing,57,58 and those required of the solution after
reduces the solubility of procaine benzylpenicil- reconstitution at the time of use. Often, the drug
lin by the common ion effect, thereby helping to alone does not give sufficient solid residue or the
stabilize the crystal size in aqueous suspensions characteristics appropriate for the product;
of the antibiotic. therefore, substances often must be added to
Inert gases have been used to displace oxygen provide the characteristics desired. Among the
from a solution and reduce the possibility of oxi¬ characteristics required of a good cake are (1) a
dative changes in the formulation. Inert gases uniform color and texture, (2) a supporting ma¬
may be used to stabilize solutions in other ways. trix of solids sufficient to maintain essentially
For example, sodium bicarbonate injection de¬ the original volume after drying, and (3) suffi¬
composes, particularly during autoclaving, to cient strength to prevent crumbling during stor¬
produce sodium carbonate, carbon dioxide, and age. In addition, the nature and amount of solids
water. Saturation of the solution with carbon in the solution largely determine (1) the eutectic
dioxide inhibits this reaction and stabilizes the temperature of the frozen solution, the subzero
solution. temperature at which the frozen material will
Complexation sometimes occurs between an melt, which determines the temperature below
added ingredient and a macromolecule in the which the product must be held during freeze¬
formulation. The methyl and propyl esters of drying,59 (2) the rate of thermal and vapor trans¬
p-hydroxybenzoic acid have been found to com¬ fer through the product during the process of
plex with polysorbate 80 with a corresponding drying, and (3) the rate of solution of the product
decrease in antibacterial activity.56 Their effec¬ during reconstitution.
tiveness can be regained, however, if the The percentage of solids in the frozen plug
amount of the esters present is increased to off¬ should be between approximately 2 and 25%.
set the quantity bound by the nonionic surfac- Among the best salts for providing uniform crys¬
int. tal size, uniform color and texture, physical
Ophthalmic Preparations. Products to be strength, and rapid reconstitution are the mono¬
instilled into the eye, while not parenterals by basic and dibasic sodium phosphates. Sodium
definition, have many similar, and often identi¬ chloride is often used, but when used alone, the
cal, characteristics. The formulation of stable, cake tends to shrink markedly in volume and to
therapeutically active ophthalmic-preparations appear crusty and crumbly. When organic sub¬
requires high purity of ingredients as well as stances such as mannitol, sorbitol, sucrose, and
freedom from chemical, physical (particles), and gelatin are used to provide solids for the cake,
^ microbial contaminants. These preparations care must be taken during the heating, particu¬
usually require buffers to stabilize the pH of the larly during the terminal stages of drying, to
product, additives to render it isotonic or nearly avoid discoloration of the cake by charring.
so, and stabilizers such as antioxidants when Added substances required in the formulation
appropriate for the particular ingredients. Those must not be volatile under the conditions of dry¬
ophthalmics used in larger quantities, such as ing; therefore antibacterial agents such as phe¬
eye irrigants, or in the care of devices such as nol, chlorobutanol, and benzyl alcohol should
contact lenses are usually relatively uncompli¬ not be used.
cated solutions similar to large-volume parenter¬ Long-Acting Formulations. Long-acting
als. parenteral drug formulations are designed, ide-

STERILE PRODUCTS • 653

 ally, to provide slow, constant, and sustained re¬ and 5%, but may go as high as 30% in some
lease of a drug over a prolonged period of time, antibiotic preparations. The amount of solids
essentially to simulate and replace the more haz¬ and the nature of the vehicle determine the vis¬
ardous, continuous intravenous infusion of a cosity of the product, an important factor be¬
drug. Rarely, if ever, is the ideal achieved, but cause of syringeability, the facility with which
extensive research has resulted in depot dosage the product is passed in and out of a syringe.
forms that approach the desired goal. The property of thixotropy is sometimes utilized,
In one type of depot formulation, which is re¬ particularly with oleaginous suspensions, to pro¬
ferred to as “dissolution-controlled,” the rate of vide the sedimentation stability of a gelled prep¬
drug absorption is controlled by the slow dissolu¬ aration during storage and the syringeability of a
tion of drug particles, with subsequent release to fluid at the time of administration.
tissue fluid surrounding the bolus of product in Probably the most important requirement for
the tissue. The formation of drug salts with very parenteral suspensions is a small and uniform
low aqueous solubility is one of the most com- particle size.61 Various techniques are available
(pfrion approaches to this type of Tormnlation. for the reduction of particles, including dry or
Control of the particle size also can contribute to wet ball milling, micropulverization, fluid en¬
slow dissolution in that larger particles or crys¬ ergy grinding, ultrasonic insonation of shock-
tals dissolve more slowly than small crystals cooled saturated solutions, and spray drying.
with proportionately more surface area. Further, Small, uniform particles are required to give
the suspension of the drug particles in vegetable slow, uniform rates of sedimentation and pre¬
oils, and especially if gelled with substances dictable rates of dissolution and drug release.
such as aluminum monostearate, produces pro¬ Also, uniform particle size reduces the tendency
longed absorption rates. for larger crystal growth during storage, since it
Another type of depot formulation is produced has been found that relatively small crystals
by the binding of drug molecules to adsorbents. often tend to disappear and large crystals grow
Only the free portion, in equilibrium with that larger in a mixture. Such a change can cause
which is bound, can be absorbed. As drug is ab¬ caking of a suspension, difficult syringeability
sorbed, a shift in equilibrium is established, and because of the large particles and changes in the
the drug is slowly released from the bound state dissolution and drug release rate following injec¬
to the free state. This is particularly exemplified tion.
by the binding of vaccines to aluminum hydrox¬ The stabilization of a suspension for the pe¬
ide gel to provide a sustained release. A third riod between manufacture and use presents a
type of depot preparation is the encapsulation number of problems. As indicated, solids gradu¬
type, in which biodegradable or bioabsorbable ally settle and may cake, causing difficulty in
macromolecules such as gelatin, phospholipids, redispersion prior to use. Surface active agents
and long-chain fatty acids become a diffusion may aid in the preparation and stabilization of a
matrix for the drug. The drug is encapsulated suspension by reducing the interfacial tension
within the matrix, and release of drug molecules between the particles and the vehicle. Polysor-
is controlled by the rate of permeation out of the bate 80, lecithin, Emulphor EL-620* and
diffusion barrier and by the rate of biodegrada- Pluronic F-68t are among the surface active
tion of the barrier macromolecules. A fourth type agents that have been used in parenteral sus¬
(cV is the esterification type depot preparation, in pensions. The concurrent addition of a hydrocol¬
which esters ofadrug that are bioerodibie are loid, such as sodium carboxymethylcellulose,
synthesized. The esterified drug is deposited in may enhance the effect of the surfactant and
tissue at the site of injection to form a reservoir cause loss of surface charge of the dispersed par¬
of drug. The rate of drug absorption is controlled ticles, water repellency, and the tendency to ag¬
by the partitioning of the drug esters from the glomerate.62 The following is an example of
reservoir to tissue fluid and by the rate at which such a formulation:
the drug ester regenerates the active drug mole¬
cule. Often, these esters are dissolved or sus¬ Cortisone acetate, microfine 25 mg
pended in oleaginous vehicles, which further Polysorbate 80 (surface active agent) 4 mg
slow the release. Sodium CMC (protective colloid) 5 mg
Long-acting . parenteral drug formulations Sodium chloride (for tonicity effect) 9 mg
have been extensively reviewed in an article by Benzyl alcohol (antibacterial) 9 mg
Chien,60 which "should be consulted for more Water for Injection, to make 1 ml
details of this important type of dosage form.
Suspensions. The solids content of paren¬ *GAF Corp., New York, NY 10020.
teral suspensions usually ranges between 0.5 fWyandotte Chemicals Corp., Wyandotte, MI 48192.

654 • The Theory and Practice of Industrial Pharmacy

Among other protective colloids that have been than 0.2 ml rarely is used because tissue volume
employed are acacia, gelatin, methylcellulose, is small and compact; also, absorption is quite
and polyvinylpyrrolidone. slow owing to the lack of blood vessels. Volumes
Occasionally, parenteral suspensions may be of 1 ml or less may be injected subcutaneously,
improved by a slight increase in viscosity, either and only occasionally are volumes of more than
by increasing the amount of protective colloid or 2 ml given intramuscularly. Volumes of 10 ml or
by adding a compound such as sorbitol. In other less may be given intraspinally, but only by the
formulations, it has been found that flocculation intravenous route may large volumes be given
of the suspended particles has been necessary to safely, provided careful control of the rate of
prevent packing to a dense cake. The addition of administration is undertaken. It is not conven¬
selected ions that increase the surface charge of ient to administer a volume of more than 20 ml
the solid particles may cause them to form fluffy by a syringe, and usually it is not practical to set
aggregates. These setde rapidly, but to a large up an infusion unit for less than 250 ml.
sedimentation volume, which can easily be re¬ I so tonicitv is a characteristic that is probably
dispersed. Monosodium citrate has been used of greatest importance for intraspinal injections
effectively for such a purpose. because the circulation oFTfie cerebrospinal
A Emulsions. The principal problem in the for¬ fluid is slow, and disturbances of osmotic pres¬
mulation of parenteral emulsions is the attain¬ sure quickly cause headache and vomiting.
ment and maintenance of uniform oil droplets of Since intracutaneous injections are given
1 to 5 microns in size as the internal phase. With mostly for diagnostic purposes, nonisotonic solu¬
emulsions, separation of the phase does not tions may cause false signs of irritation.
occur as readily as with suspensions because the Isdtonicity is preferable for the comfort of the
difference in density between the oil and water patient, but is not essential for subcutaneous
is relatively small. One such product, an emul¬ and intramuscular injections. For the rapid ab¬
sion of a natural vitamin Kj, has been stabilized sorption of drugs given intramuscularly, a
with lecithin. slightly hypertonic solution may increase the
Intravenous nutrient emulsions that have rate by causing local effusion of tissue fluids.
been made contain, for example, 15% cotton¬ Usually, intravenous fluids should be isotonic,
seed oil, 4% dextrose, 1.2% lecithin, and 0.3% of although slow administration of a paratonic so¬
an oxyethyleneoxypropylene polymer, the latter lution may be performed safely if rapid dilution
two ingredients being the emulsifiers. The dis¬ with the blood occurs.
persed phase should have droplet sizes of less In general, only solutions of drugs in water
than 1 micron. The emulsion must be stable to may be given intravenously. Suspensions may
autoclaving. Elevated temperatures, however, not be given because of the danger of blockage of
tend to produce coalescence of the dispersed the small blood vessels. Aqueous or oleaginous
phase, and excessive shaking has caused accel¬ suspensions and oleaginous solutions cahnot
eration of the rate of creaming. Small amounts normally be given subcutaneously because of
of gelatin, dextran, and methylcellulose have the pain and irritation caused. Muscle tissue tol¬
been found to aid in stabilizing the emulsions, erates oils and suspended particles fairly well
but they are also adversely affected by elevated and is therefore the only route normally suitable
temperatures. for their administration.
The preparation of a parenteral emulsion is The administration of a drug deep into the
troublesome. It is made more difficult by the muscle tissue results in a pool of the product at
rigid requirement for particle size control to pre¬ the site of injection. From this depot, the drug is
vent emboli in blood vessels, by the limited released at a rate determined to a large extent by
choice of emulsifiers and stabilizers of low toxic¬ the characteristics of the formulation. Whether
ity, and by the preservation of the oil phase the solvent is aqueous or oleaginous affects the
against the development of rancidity. rate of absorption; oleaginous solutions are usu¬
Effect of Route of Administration. Paren¬ ally more slowly absorbed. Increasing the vis¬
teral preparations may be given by several cosity of solutions slows the absorption, as do
routes.63 The five most common are ^intrave¬ gelatin or polyvinylpyrrolidone in water and alu¬
nous, intramuscular, subcutaneous, intracuta- minum monostearate in oils. Utilizing modifica¬
neous.and intraspinal. tions of the drug molecule to render it less solu¬
The intended route of administration has a ble (for instance, the formation of various esters
marked effect on the formulation of a parenteral or salts) permits the production of stable suspen¬
product. The volume in which a dose of the drug sions, causing a marked reduction in the rate of
must be encompassed is one factor to consider. absorption of the drug from the depot. Thus, uti¬
For intracutaneous injections a volume of more lizing various modifications in formulation of

STERILE PRODUCTS • 655

the product makes it possible to retard the rate at change must go through the same approval
which a drug is released from a depot. steps as the original written SOP. Further, ex¬
Ophthalmic preparations are formulated in tensive records must be kept to give assurance
much the same way as parenteral solutions. The at the end of the production process that all
eye is particularly sensitive to irritation; there¬ steps have been performed as prescribed, an
fore formulation should be directed toward mini¬ aspect emphasized in the FDA’s Good Manufac¬
mizing irritation. Normally, clean aqueous solu¬ turing Practices.64 Such in-process control is
tions are preferable for ophthalmic use. essential to assuring the quality of the product,
Suspensions of solids have been used in the eye since these assurances are even more signifi¬
when the therapeutic need superseded the need cant than those from product release testing.
to avoid irritating effects, as for the suspensions The production of a quality product is a result of
of corticosteroids sometimes used. It. has been the continuous, dedicated effort of the quality
found that a foreign body sensation increases as assurance, production, and quality control per¬
the concentration of suspended particles, re¬ sonnel within the plant in developing, perform¬
gardless of size, approaches 5%. ing, and confirming effective SOPs.
This brief discussion of some of the factors To differentiate quality assurance from quality
involved in the formulation of parenteral dosage control, the former function is usually one of
forms has been intended simply to introduce the preplanning those factors that bear upon the
student to this important area. This area is quality of a product and is thus a preventative
changing steadily as the ingenuity of research development process. Quality control may in¬
pharmacists spurs the development of new and clude this aspect, particularly if there is only one
improved formulation aids and techniques. organizational group directly responsible for
quality in a plant, but it more likely concentrates
on those operations and tests that have been
Stability designed to evaluate the quality actually
General principles of evaluation for stability achieved in a product.
are discussed in Chapter 26. In this chapter, it is To enhance the visualization of the passage of
sufficient to mention that the previous consider¬ materials through the various steps of the pro¬
ation of ingredients and packaging components duction process, a flow diagram is provided in
in intimate contact with the product, and some Figure 22-2. In the initial step, the formula in¬
of the problems associated with formulation, gredients, container components, and process¬
draw attention to the necessity of evaluating the ing equipment that have been released for use
effect of all the components on the stability of are drawn from their respective storage areas.
the product, particularly when the product is The ingredients are compounded according to
subjected to the accelerating reactivity of ther¬ the master formula in an environment designed
mal sterilization. to maintain a high level of cleanliness. If the
product is a solution, it is filtered during transfer
to the aseptic filling room.
Production Process equipment and container components
The production process includes all of the are cleaned thoroughly according to required
steps from the accumulation and combining of specifications, are assembled in a clean environ¬
the ingredients of the formula to the enclosing of ment, and preferably, are sterilized and depyro-
the product in the individual container for distri¬ genated prior to use.
bution. Intimately associated with these proc¬ All equipment and supplies introduced into
esses are the personnel who carry them out and the aseptic filling area should be sterile (Fig.
the facilities in which they are performed. The 22-2), having come directly from the steriliza¬
most ideally planned processes can be rendered tion process, preferably through double-ended
ineffective by personnel who do not have the sterilizers (Fig. 22-3). When this is not possible,
right attitude or training, or by facilities that do packages, hose lines from equipment, and sup¬
not provide an efficiently controlled environ¬ plies should be passed through openings (ports)
ment. of minimal size that can be reclosed promptly,
To enhance the assurance of successful man¬ under aseptic conditions. Outer wrappings of
ufacturing operations, all process steps must be packages should be loosened and the contents
carefully reduced to writing after being shown to received, that is, the inner wrapping grasped, by
be effective. These written process steps are personnel already in the aseptic filling room.
often called standard operating procedures When double wrappings are not feasible, the
(SOPs). No extemporaneous changes are per¬ outer surfaces of boxes, packages, or equipment
mitted to be made in these procedures; any should be wiped with a disinfectant solution as

656 • The Theory and Practice of Industrial Pharmacy

 Supply Storage Controlled Clean Environment Aseptic Area Clean Area

they are transferred into the aseptic room. All standards imposed for the aseptic rooms or for
supplies must be introduced into the aseptic fill¬ the compounding room. Packaged products are
ing rooms in such a manner that the aseptic placed in quarantine storage until all tests have
state of these rooms is maintained, thereby pre¬ been completed and in-process control records
venting the introduction of environmental con¬ have been evaluated; then the product may be
tamination into the product while it is being released for distribution.
subdivided into individual containers. After
these containers are sealed, contamination can¬
not enter the container and product.
As shown in Figure 22-2, the product is sealed Facilities
in its final container within the aseptic room. It The facilities for the manufacture of sterile
is them transferred to the packaging area. This products should be designed for control of clean¬
area is maintained clean but need not meet the liness appropriate for each step. Near perfect

FIG. 22-3. Double-door sterilizing oven being loaded with clean equipment. The equipment will be removed sterile from
the other door in the aseptic area after the sterilization cycle. (Courtesy of Schering Corp.)

STERILE PRODUCTS • 657

cleanliness must be achieved in the aseptic fill¬ duction, and most importandy, contamination of
ing rooms. The surrounding areas should pro¬ the production area by maintenance operations
vide a buffer area in which standards of cleanli¬ and personnel.
ness are only slighdy lower than those for the These basic design and construction features
aseptic rooms. The prevention of contamination have been continued with the advent of HEPA-
must he. the primary objective in the design of filtered laminar airflow capabilities (to be dis¬
these facilities. cussed in the following section). Laminar air¬
To achieve such exceptional design and con¬ flow is most frequently added to a clean room to
struction standards, a knowledge of the purpose achieve greater environmental control in a local
of the facility must be coupled with the utiliza¬ area, such as in a workbench enclosure or over a
tion of the best construction materials and de¬ filling fine.
sign. The ceding, walls, and floors should be The reader is referred to the literature for a
constructed of material that is easy to clean and further discussion of the design, construction,
nonporous, to prevent the accumulation of de¬ and operation of facilities for the preparation of
bris and moisture.65 Probably one of the best fin¬ sterile products.67-69
ishes for rigid surfaces is the “spray-on-tile.” Environmental Control. Effective environ¬
This is a ceramic epoxy finish applied by spray¬ mental control, both physical and biologic, is
ing or painting to form a continuous, smooth, essential, but the level achievable is related to
seal coating on the ceiling and walls.66 The rig¬ the characteristics of the facility, as discussed
orous effects from continuous washing with de¬ previously. Further, rigid standards from plant
tergents and disinfectants, however, can cause to plant and from one geographic location to an¬
even this epoxy finish to degrade and wear or other are not appropriate. Allowance also must
peal. One of the best materials for floors is a ce- be made for variations in control associated with
ramic-plastic cement applied as a thick coat over seasonal conditions.
existing rigid flooring- to form a continuous, The standards of environmental control vary,
seated surfaces Another flooring material used depending on the area involved (clean-up, pack¬
increasingly in areas of less heavy traffic is sheet aging, compounding, or filling) and the type of
vinyl with heat-welded seams, coved to the side product being prepared. Unquestionably, the
walls and applied by adhesives on underlying entire area used for the preparation of a product
surfaces. Movable metal partitions are some¬ prepared aseptically (without terminal steriliza¬
times used to provide flexibility of room arrange¬ tion) must be maintained under the most rigid
ment, but they have the disadvantage of seams control that existing technology permits. If the
and joints, which are very difficult to seal. product is to be terminally sterilized, somewhat
Glass is often used in partitions to permit su¬ less rigid biologic control of the compounding
pervisory view of the operation, but more impor¬ and filling areas may be acceptable, but rigid
tantly, to provide more pleasant, better lighted, standards of cleanliness must be maintained.
less confining surroundings for the operators. High standards of cleanliness, excluding daily
Lighting fixtures should be recessed, and ex¬ use of the disinfecting procedures, are usually
posed piping or other dirt-collecting surfaces acceptable for the clean-up and packaging areas.
should not be tolerated. Furniture should be of Traffic Control. Excellence in environmen¬
nonporous, hard-surfaced materials, preferably tal control would be relatively easy to achieve
stainless steel. Counters should be suspended were it not for the necessity for personnel and
from the wall. supplies to move from one area to another.
Items of equipment that are difficult or impos¬ Therefore, a carefully designed arrangement to
sible to sterilize should be kept out of the aseptic control and minimize traffic, particularly in and
areas, if possible. If they must be used in the out of the aseptic areas, is essential. A floor plan
aseptic area, they should remain there and be for a sterile products facility is shown in Figure
continuously exposed to disinfecting processes. 22-4. Note that the only access directly from the
Whenever possible, operating machinery parts outside is to the personnel wash rooms, the
should be enclosed in stainless steel housing. equipment wash rooms, the nonsterile manufac¬
The mechanical servicing of electrical, gas, turing area, and the capping (packaging) area.
water, air ventilation, and other utility lines into Access by personnel to the aseptic corridor and
these areas requires careful planning. One of aseptic compounding and filling rooms is only
the most effective plans for this is to provide a through an airlock. Pass-through openings and
floor above, space beneath, or a corridor along¬ double-ended sterilizers are provided to permit
side of the production area where all service controlled passage of supplies from nonaseptic
connections can be accessible and properly to aseptic areas.
maintained. This prevents interruption of pro¬ Personnel should be permitted to. enter asep-

658 • The Theory and Practice of Industrial Pharmacy

 TOTAL CNCLOMO TLOOO MU • 10,011 U.M.
TOTAL Mono AIU C0VCH0 ■ to.na AO. TT.

FIG. 22-4. Floor plans for industrial sterile products production area. (Courtesy of Schering Corp.)

tic areas only after following rigidly prescribed in a laminar airflow facility than in one that is
procedures for removing their street clothing, not bathed with a constant clean airflow. All
washing their hands, and donning gowns, hats, cleaning equipment should be selected for its
shoes, facemasks, gloves, and other prescribed effectiveness and freedom from lint-producing
attire. Once they have entered the aseptic area, tendencies. It should be reserved for use in the
they should not be permitted to move in and out aseptic areas only.
of the area without regowning. Personnel as¬ Surface Disinfection. After thorough clean¬
signed to cleaning and packaging should be re¬ ing, all surfaces should be disinfected, at least in
stricted to these areas,, Unauthorized personnel the aseptic areas. An effective liquid disinfectant
Should never be permitted to enter the aseptic should be sprayed or wiped on all surfaces (see
area. , Chap. 21, “Sterilization”).
Housekeeping. Cleaning personnel must be Irradiation from ultraviolet lamps that are lo¬
irtibued with the philosophy that not one re¬ cated to provide adequate radiation intensity on
maining particle of debris is acceptable. Only the maximum extent of surfaces in a room and
with such an approach will the conditions be that are maintained free from dust and films fur¬
provided for achieving and maintaining proper ther reduces the viable microorganisms present
environmental control. It must also be recog¬ on surfaces and in the air. Ultraviolet rays may
nized that jnany, if not most, critical contami¬ be particularly useful to irradiate the inside, ex¬
nating particles are sub visual in size. posed surfaces of processing tanks, surfaces
All equipment and surrounding work area under hoods, the surface of conveyor belts, and
must be cleaned thoroughly at the end of the similar confined surfaces that are otherwise dif¬
working day. No contaminating residues from ficult to render aseptic; however, they cannot
the concluded process may remain. The ceiling, reach unexposed surfaces such as pipe connec¬
walls, and other structural surfaces must be tions to tanks, the underside of conveyors, and
cleaned with a frequency commensurate with the inside of containers.
the design of the facility, that is, less frequendy Ultraviolet lamps must be kept clean, and care

STERILE PRODUCTS • 659

must be taken to check for a decrease in effec¬ duced successively so that the air flows from the
tive emission, a natural occurrence due to a maximum security area to the hallway or other
change in the glass structure with aging. less critical areas for return to the filtration sys¬
Air Control. In any area occupied by person¬ tem. At the intake end of the system, fresh air,
nel, the air must be exchanged at frequent inter¬ usually about 25%, is continually introduced for
vals. Fresh outside or recycled air must first be the comfort and needs of the personnel. Further,
filtered to remove gross particulate matter. A the air is usually conditioned with respect to
spun glass, cloth, or shredded polyethylene fil¬ temperature and humidity for the comfort of the
ter* may be used for this preliminary cleaning personnel, and sometimes, to meet the special
operation. At times, more than one prefilter may requirements of a product.
be used in series, the first of quite large and the A relatively new air control system, based on
next of somewhat smaller pore size, to provide a laminar flow principles, has greatly improved
gradation of particle size removal from heavily The potential for environmental control of asep¬
contaminated air. To remove finer debris down tic areas. Currently, it is the only means avail¬
to the submicron range, including microorgan¬ able for achieving a Class 100 clean room. A
isms, a high efficiency particulate air fHFPA) Class 100 clean room is defined as a room in
filter, defined as at least 99.97% efficient in whicHTEe particle count in the air is not more
removing particles of 0.3 nm size and larger and than 100 per cubic foot of 0.5 nm and larger in
Composed of glass fibers and fillers! or electro¬ size. HEPA-filtered air is blown evenly out of the
static precipitators,]: may be employed. Air pass¬ entirebadroTTopof a workbench (Fig. 22-5), or
ing through these units can be rendered virtu¬ entire side or ceiling of a room. The airflow must
ally free from foreign matter. Another air be uniform in velocity and direction throughout
cleaning system § washes the air with a disin¬ 'any given cross-section of the area, being ex¬
fectant and controls the humidity at the same hausted from the opposite side. The air velocity
time. employed should be100 ± 20 ft/min. .Contami-
Blowers should be installed in the air ventila¬ nation is controlled because it is swept away
tion system upstream to the filters so that all with the airflow. .Any contamination introduced
dirt-producing devices are ahead of the filters. downstream from the filter, however, may be
The clean air is normally distributed to the re¬ carried to a critical working area located farther
quired areas by means of metal (preferably downstream. This may be caused by the im¬
stainless steel) ducts. Since it is practically im¬ proper placement of supplies, the manipulation
possible to keep these ducts as clean as required, of personnel, or discharge from operating equip¬
it is normally preferable to install HEPA filters at ment. Because the risk of introducing contami¬
the point where the clean air enters the con¬ nation in such a manner is generally considered
trolled room. Alternatively, the ducts may be to be less with vertical flow from ceiling-
replaced with a room (a plenum), usually above mounted HEPA filter units, vertical flow is most
the production area, into which clean air is frequently utilized to protect critical sections of
blown and then distributed through openings processing lines and similar activities.69'70 Hori-
into each of the process rooms. The entire ple¬
num can be kept clean and aseptic.
The clean, aseptic air is distributed in such a
manner that it flows into the maximum security
rooms at the greatest volume flow rate, thereby
producing a positive pressure in these areas.
This prevents unclean air from rushing into the
aseptic area through cracks, temporarily opened
doors, or other openings. The pressure is re-

"Pliotron Corp., Niagara Falls, NY 14302.

tAmerican Air Filter Co., Inc., Louisville, KY 40277;
Cambridge Filter Corp., Syracuse, NY 13221; Flanders
Filters, Washington, NC 27889; Weber Technical Prod¬
ucts, Lawrence, MA 01842.
tAmerican Air Filter Co., Inc., Louisville, KY 40277;
Electro-Air Div., Emerson Electric Co., McKees Rocks, PA
15136; Westinghouse Electric Corp., Sturtevant Div.,
Hyde Park, MA 02136.
§ Midland Ross Corp., Ross Air Systems Div., New Bruns¬
wick, NJ 08903. FIG. 22-5. Horizontal laminar airflow clean bench.

660 • The Theory and Practice of Industrial Pharmacy

 zontal flow, on the other hand, is used to protect usually utilized, involving two or more that best
processing lines and is used most frequently for identify the control achieved of the particular
workbenches.* Numerous reports have shown circumstances of a given environment.
the marked benefit of laminar airflow for con¬ Personnel. The people who produce sterile
trolling working environments, from small products usually are nonprofessional persons,
workbenches to entire rooms.71-75 supervised by those with professional training.
Although Class 100 work environments are To be effective operators, they must be inher¬
normally specified for the most critical aseptic ently neat, orderly, reliable, and alert, and have
and/or clean operations, achieving such levels of good manual dexterity. They should be apprecia¬
cleanliness is expensive and requires effective tive of the vital role that every movement has in
maintenance and monitoring. It should be rec¬ determining the quality of final product, i.e., its
ognized that not all operations associated with freedom from contaminants.
parenteral medications require such an environ¬ All employees should be in good health and
ment. To such an end, other classes are de¬ should be subjected to periodic physical exami¬
fined.76 For example, a Class 10,000 room is one nations. They should understand their responsi¬
in which the particle count is no more than bility to report the developing symptoms of a
10,000 per cubic foot of 0.5 /zm and larger in head cold, a sore throat, or other infectious dis¬
size. Such a cleanliness level is usually consid¬ eases so that they can be assigned to a less criti¬
ered suitable tor butter areas around Class 100 cal area until they have fully recovered.
worksiteslnwfiich operationsT sucfias" handling The attire worn by personnel in the aseptic
precleaned containers, process filtration, and areas usually consists of sterile coveralls, hoods,
aseptic gowning of personnel may be performed. face masks, and shoe covers. Sterile rubber
Still less stringent requirements would be ap- gloves also may be required.
plied to laboratories, stock staging areas, and fin- Personnel entering the aseptic areas should
ishjjackaging, where a Class 100,000 or similar be required to follow a definite preparatory pro¬
cleanliness level would usually he considered cedure.81 This should include removing at least
suitable. outside street clothing, scrubbing the hands and
The effectiveness of the environmental con¬ arms thoroughly with a disinfectant soap, and
trol system is normally monitored on the basis of donning the prescribed uniform. A full body
deviation, usually upward, from baseline counts water and soap shower would be essential in
determined from extensive testing by the envi¬ most biologic product processing plants—
ronmental control procedures utilized. Biologic usually, both when entering and leaving the
evaluation methods most frequently utilized are area to control contamination in both directions
summarized in Table 22-5 and include settling between personnel and the product. It must be
and surface contact nutrient agar plates, air recognized, however, that removing natural oils
impingement on nutrient media, and membrane from the skin temporarily increases particle
filtration, f77-79 Particulate matter evaluation shedding. An air shower for the fully attired
methods, also summarized in Table 22-5, in¬ worker may be used at times to blow away loose
clude membrane filtration]; and electronic parti¬ lint, although the disruptive air currents gener¬
cle counters. §80,81 A combination of methods is ated may be detrimental to overall air control. A
vibrating foot mat or a disinfectant foot bath also
may reduce the transfer of contamination.
*Air Control, Inc., Norristown, PA 19401; The Baker Co.,
Because people are continually shedding via¬
Inc., Sanford, ME 04005; Clean Room Products, Inc., Bay
Shore, NY 11706; Envirco, Albuquerque, NM 87107; ble and nonviable particulate matter from body
Flanders Filters, Inc., Washington, NC 27889; Laminaire surfaces,82 uniforms are worn to help control
Coip., Rahway, NJ 07065; Liberty Industries, Inc., Ber¬ this emission. Preferably, they are of the coverall
lin, CT 06037; Vecco International, Livonia, MI 48150. type and made of synthetic fibers such as Da¬
- JAndersen Samplers, Inc., Adanta, GA 30336; Flow Sen¬ cron. Dacron cloth is made of a continuous fiber,
sor; McLean, VA 22102; Folex-Biotest-Schleussner, Inc.,
which makes it essentially lint-free and in air
Moonachie, NJ 07074; Mattson-Garvin Co., Maidand, FL
32751; New Brunswick Scientific, Edison, NJ 08817. conditioned rooms, is acceptably comfortable.
JAMF-CUNO, Meridec, CT 06450; Gelman Sciences, Hats and masks are sometimes made of special
Inc., Ann Arbor, MI 48106; Millipore Corp-, Bedford, MA parchment paper and are discarded after use.
01730; Nuclepore Corp., Pleasanton, CA94566; Sartorius Spun polyethylene* has recently found favor as
Filters, Inc., Hayward, CA 94545. a material for uniforms.
§Air Techniques, Inc., Baltimore, MD 21207; Bausch &
Lomb, Rochester, NY 14625; Climet Instruments Co.,
Redlands, CA 92373; HIAC/Royco Instruments Div.,
Menlo Park, CA 94025; Phoenix Precision Instrument, *Tyvek, E. I. duPont de Nemours & Co., Wilmington, DE
Gardiner, NY 12525. 19898.

STERILE PRODUCTS *661

Table 22-5. Environmental Monitoring Methods

Method Principle of Operation Advantages Disadvantages

Biologic evaluation
Settling plates Gravitational fallout in a Uncomplicated. Only heavier particles
given time on a given Low cost. settle and are col¬
area. lected.
Irregularities in counts
due to wild air cur¬
rents, physical move¬
ments of personnel, j
etc.
Slit sampler Measured volume of air Measured volume of air Velocity of impaction
drawn through slit and sampled. likely to have lethal
impacted on nutrient Sampling related to time effect on vegetative
agar as plate turns. as plate turns. forms.
Drying effect may be le¬
thal to vegetative cells.
Must be used with ac¬
cess to electricity and
vacuum.
Centrifugal sampler Measured volume of air Measured volume of air Velocity of impaction
centrifugally blown on sampled. likely to have lethal
nutrient agar strip. Unit can be easily car¬ effect on vegetative
ried by hand and is forms.
battery-operated. Drying effect may be le¬
Unit head is sterilizable thal to vegetative cells.
and body sanitizable.
Cascade sieve sampler Measured volume of air Measured volume of air Velocity of impaction
cascaded through up sampled. likely to have lethal
to six plates of de¬ Permits gradation of par¬ effect on vegetative
creasing pore size and ticles by size. forms.
impacted on nutrient Must be used with ac¬
agar plates, with the cess to vacuum.
smallest particles col¬ Affected by high RH;
lected on the last best used with dry
plate. conditions.
Liquid impinger Measured volume of air Measured volume of air Liquid must be filtered
bubbled through liquid sampled. or plated to isolate
nutrient medium with Less lethal action on microorganisms.
impingement in liquid. vegetative forms since More complicated proce¬
impingement is in dure.
“soft” liquid. Time-consuming proce¬
Accepted as reference dure.
method.
Membrane filter sam¬ Measured volume of air Measured volume of air Additional step of mem¬
pler drawn through mem¬ sampled. brane being placed on
brane filter with parti¬ May be used also for nutrient agar in plate.
cles retained on sur¬ microscopic particle Air pockets under mem¬
face and filter then counting. brane prevent growth.
incubated on nutrient Drying effect of microor¬
agar plate. ganisms on membrane
is lethal to most vege¬
tative forms.
Vacuum source required.

i
662 • The Theory and Practice of Industrial Pharmacy

j
 Method Principle of Operation Advantages Disadvantages

Particulate matter evaluation

Membrane filter Measured volume of air Measured volume of air Counting and sizing re-
drawn through mem- sampled. quire experienced and
brane filter with parti- Particles microscopically trained microscopist.
cles retained on sur- visible and identifiable. Identification of particles
face. Particles can be sized requires experienced
and dimensionally de¬ and trained microscop¬
scribed. ist.
Time-consuming proce¬
dure.
Right angle light-scat- Particle in viewing cell Quantitative count of Sizing affected by light-
tering instrumental scatters light at right particles in measured scattering characteris-
counter angles from incident volume of air obtained. tics of particle surface.
light to photodetector Instant results given. No differentiation be-
tube. Range of sizes of parti- tween viable and non-
cles measured. viable particles.
Costly.
Near forward light- Particle in viewing cell Quantitative count of Sizing affected by light-
scattering instrumental scatters fight forward particles in measured scattering characteris-
counter from incident fight to volume of air obtained. tics of particle surface.
photodetector tube. Instant results given. No differentiation be-
Range of sizes of parti¬ tween viable and non-
cles measured. viable particles.
Greater intensity than More cosdy than other
other methods; there¬ methods.
fore, smaller particles
can be counted.

Personnel working in equipment wash rooms, The specifications for the quality of the water
sterilizing rooms, and packaging areas are nor¬ required have been discussed under the heading
mally required to don clean uniforms daily and “Vehicles,” earlier in this chapter.
to be conscious of cleanliness, but are not re¬ The specifications for a still should include (1)
quired to meet the special requirements for per¬ prepurification of feed water by chemical soften¬
sonnel entering the aseptic areas. ing, deionization, or filtration to improve the
quality of the distillate and reduce the frequency
of required cleaning due to insoluble scale in the
Processing boiler, (2) removal of entrained contaminants
The initial processing step is the procurement from the vapor before it is condensed by passage
of acceptable components (see Fig. 22-2). In a through an efficient baffle system, (3) ejection of
plant, the majority of components are requisi¬ volatile constituents from the top of the system
tioned from tested and approved stock, and are before the vapor is cooled so that they will not
then subjected to whatever processing steps are redissolve and appear in the condensate, (4)
required to prepare them for use. A few compo¬ construction of all surfaces that will come in
nents, such as Water for Injection, are manufac¬ contact with the vapor and condensate of a ma¬
tured to specifications as needed. terial that will not dissolve in even trace
Water for Injection. Water for Injection amounts, preferably pure tin, 304 stainless steel,
(WFI) usually is prepared by distillation in a still or borosilicate glass.
specifically designed to produce the high-quality In addition to conventional stills,* two types of
water required.83 84 Reverse osmosis, however, stills frequently used for the production of large
is a method that is now approved by the USP, volumes of water are the vapor compression
and it is receiving increasing attention and use.*

*AMSCO, Erie, PA 16512; Bamstead Co., Div. of Sybron *AMSCO, Erie, PA 16512; Bamstead Co., Div. of Sybron
Corp., Boston, MA 02132; Culligan International Co., Corp., Boston, MA 02132; Consobdated Machine Corp.,
Northbrook, IL 60062; Millipore Corp., Bedford, MA Boston, MA 02134; Coming Glass Works, Coming, NY
01730; Vaponics, Inc., Plymouth, MA 02360. 14830; Vaponics, Inc.. Plymouth, MA 02360.

STERILE PRODUCTS • 663

stills* and the multiple effect stills.tWhile they continuous circulation to avoid stagnation,
operate on somewhat different principles, both maintenance at elevated temperature, complete
utilize initially heated feed water and steam to isolation from all other piping systems, elimina-
conserve on energy consumption and cooling tion of elbows or other pockets in which water
water. Both types are capable of producing high- can stagnate for long periods, and a means of
purity water at rates of 50 to 1000 or more gal- thorough cleaning and sanitation at frequent
Ions per hour. intervals, as with clean steam or hot alkali.
A reverse osmosis system functions by apply- Cleaning Equipment and Containers,
ing pressure (usually 200 to 400 psi) to raw Equipment and containers to be used in the
water sufficient to force the permeation of water processing of a sterile product must be scrupu-
through a select semipermeable membrane in lously clean.87 New, unused containers and
the opposite direction from natural osmosis. The equipment are contaminated principally with
membranes most commonly used are composed dust, fibers, and chemical films, which usually
of cellulose esters or polyamides (nylon) and are ^are relatively easy to remove, often by rinsing
effective in retaining all macromolecules and|^Jt6nly. Debris that is more dangerous and more
85% or more of small ions such as Na+ and Cl“ y^'difficulTtcTremove may be present as a residue
Since pyrogens axe macromolecules, they H> from a previous use. Such debris usually must
should be retained as well as such viable parti- be removed by vigorous treatment with hot de-
cles as microorganisms. Greater efficiency and tergents.
reliability are achieved by passing the water In general, equipment used previously should
through two membranes in series. The accept- be scrubbed by hand immediately after use with
ance of reverse osmosis for the preparation of an effective detergent that does not leave a resi-
Water For Injection is increasing as experience due of its own. Whenever possible, equipment
is gained with the system and its characteristics should be disassembled so that each part can be
are understood more fully.85 thoroughly scrubbed and cleaned, with particu-
Storage and Distribution. The storage and lar attention given to screw threads, joints, and
distribution of WFI are as important as its pro- other dirt-collecting structures. Live steam can
duction.86 A closed system is desirable, with air sometimes be used to loosen debris effectively,
exchange through a filter that removes microor- particularly in areas that are not easily accessi-
ganisms, dirt, and vapors from the air as the ble. After cleaning, the equipment should be
tank is filled and emptied. Should microorgan- rinsed several times, with a final rinse with
isms gain entrance to the tank, they may be pre- WFI. Just prior to reuse, large clean tanks and
vented from multiplying by holding the temper- similar equipment should be rinsed thoroughly
ature of the water at 80°C by means of a steam with WFI. Reserving equipment for use with
coil in the bottom of the tank. Normally, WFI only one type of product reduces cleaning prob-
should not be held for more than 24 hours at lems.
room temperature before it is used, but if held at A new method for large tanks, pipe lines, and
80°C, continuous addition of fresh WFI as usage associated equipment that can be isolated and
occurs is common practice. The constant danger contained within a process unit has been devel¬
of microbial contamination, in spite of precau¬ oped and identified as a CIP (Clean in Place) I
tions, and subsequent development of pyrogenic system.88 Cleaning is accomplished primarily
substances in the water demand careful storage with high-pressure rinsing treatments delivered
requirements. automatically within the equipment. This is
The distribution of WFI from the storage tank usually followed by steam sanitization through
to the point of use may be by direct withdrawal the same system, although actual sterilization of
from the tank, or in large plants, through a pipe the entire system with attached components,
system. When a pipe system is used, special pre¬ such as filters, is being investigated.89
cautions must be followed to prevent contamina¬ For glass or metal equipment small enough to
tion, including construction with welded stain¬ be transported by hand, machine washing is
less steel pipe, a closed system preferably with possible. The glassware or metalware is auto¬
matically conveyed, usually in an inverted posi¬
tion, through a series of rigorous, high-pressure
*Aqua-Chem. Inc., Milwaukee, WI 53201; Bamstead Co., treatments, including hot detergent, hot tap
Div. of Sybron Corp., Boston, MA 02132; Mechanical water, and final rinses with distilled water. Be¬
Equipment Co., Inc., New Orleans, LA 70130.
cause many containers have restricted open¬
tAMSCO, Erie, PA 16512; Bamstead Co., Div. of Sybron
Corp., Boston, MA 02132; Finn-Aqua America, Inc., ings, it is essential that the treatments in any
Bellevue, WA 98007; Vaponics, Inc., Plymouth, MA washer be introduced through tubes into each
02360. container, with a smooth flow out. All parts of

664 • The Theory and Practice of Industrial Pharmacy

the machine coming in contact with the treat¬
ments must be noncorrosive so that metallic
contaminants from the machine are not depos¬
ited on the glassware.
When high processing rates are not required,
a cabinet type washer* embodying these princi¬
ples may be used. In such a machine, the ware
to be washed is held on a rack within a cabinet
while the machine automatically goes through
the sequence of treatments of the cycle.
Rinsing New Containers. In cleaning new
glassware, the detergent treatment is usually
eliminated, and with it, the risk of a detergent
residue. Without the detergent treatment, the
cycle is essentially a rinsing process. To loosen
debris by rinsing, alternating hot (preferably
clean steam) and cold treatments should be
used. Final rinses should be done with filtered FIG. 22-6. Rinser designed to clean vials by racks sized to
WFI. This sequence of treatments may be per¬ shipping cartons or by individual handling. Note laminar
formed on the machines described above or on a airflow to protect clean, wet vials. (Courtesy of University
rotary rinser, t The containers are inverted on of Tennessee.)
spindles in the front of the machine and carried
through a series of rinses in one rotation. For
ampuls or containers with a markedly con¬ through many rinsing operations and be depos¬
stricted opening that makes water drainage in¬ ited on glassware subsequently being processed.
complete, the final treatment is usually a blast of High-speed processing lines often are de¬
clean air to blow out remaining water. signed to clean containers by rinsing with clean
After cleaning, it is essential that the clean water, or sometimes simply with clean air,
containers be protected from dust and other par¬ under high pressure. The containers are
ticulates that might be present in the environ¬ shipped from the manufacturer on a support
ment. Therefore, the clean containers are often tray enclosed within a shrunken, tightly-fitted,
removed from the rinser and placed in clean polyethylene sheet to minimize the accumula¬
stainless steel boxes for sterilization under the tion of dirt during shipment. The cleaned con¬
protection of HEPA-filtered laminar airflow tainers are usually then fed by conveyor to hot¬
(Fig. 22-6).. air sterilizing tunnels, thereby minimizing han¬
Conveyor type rinsers,]: as shown in Figure dling of the containers, increasing speed of
22-7, have relatively high production rates. They processing, and allowing the clean sterile con¬
have an advantage over the above rinsers in that tainers to be delivered through-the-wall into the
they deliver the clean container at the opposite aseptic filling room.
end from that at which the unrinsed containers Cleaning Rubber and Plastic Com¬
are loaded. The delivery end can, therefore, be ponents. Rubber closures are usually washed
in an adjoining room (Fig. 22-7), away from the by mechanical agitation in a tank of hot deter¬
dust and dirt associated with packing cartons. gent solution (such as 0.5% sodium pyrophos¬
To eliminate the tedious handling of each in¬ phate) followed Dy a senelTof thorough water
dividual container, rack loading rinsers] § have rinses, the final rinse being WFI.90 The objec¬
been designed with rack sizes adapted to con¬ tive is to remove surface debris accumulated
tainer packing cartons. Such a rinser is shown in from the molding operation and from handling,
Figure 22-6. and leachable constituents at or near the sur¬
Minute quantities of oils, proteinaceous mate¬ face. Part of the debris is attracted and held on
rials, or other debris retained in the rinser from a the surface by electrostatic forces. Similarly,
previously used container could be carried plastic materials accumulate surface debris.
Abrasion may occur during agitation, result¬
ing in small, loose pieces of the rubber or plastic
‘Vemitron/Better Built, Carlstadt, NJ 07072. y> material. This problem is more acute with two-
tCozzoli Machine Co., Plainfield, NJ 07060; U:S. Bottlers
component closures, i.e., a rubber disc inserted
Machinery Co., Chicago, IL 60618; Vemitron/Better
Built, Carlstadt, NJ 07072. in an aluminum cap, because agitation usually
tCozzoli Machine Co., Plainfield, NJ 07060. causes more abrasion of the aluminum and pro¬
§Metromatic Products Corp., Oyster Bay, NY 11771. duces small aluminum fragments, which adhere

STERILE PRODUCTS • 665

FIG. 22-7. Conveyor rinser delivering clean vials to an adjoining clean room. (Courtesy of Schering Corp. and Cozzoli
Machine Co.)

tenaciously to the rubber disc or wedge between Sometimes, the closures are subjected to an
the disc and the cap. autoclave cycle as a part of the cleaning process.
Therefore, the multiple objectives for washing Such treatment aids in loosening surface debris
closures and other parts include loosening de¬ and also leaches from the closure some of the
bris, minimizing abrasion, and sweeping away extractives, thus reducing the subsequent con¬
the loosened debris. Household clothes washers tamination of the product. It should be remem¬
of the horizontal rotating basket type or the cen¬ bered, however, that excessive heating is detri¬
ter post agitator type have been used, but nei¬ mental to the life of rubber and thermoplastic
ther meets the requirements for an ideal washer materials.
for closures. More commonly today, the closures Particular attention should be given to the
are subjected to gentle agitation with air bub¬ cleaning of rubber and plastic tubing. When tub¬
bles,* basket rotation accompanied by spray ing is reused, adequate cleaning of the lumen,
rinsing,! or simple water movement followed by which is not readily accessible, may be virtually
extensive rinsing with WFI. Handling after impossible. When cleaning is necessary, special
cleaning must be done carefully to prevent parti¬ brushes may be helpful in reaching the lumen.
cle generation from abrasion and to prevent The safest approach is to retain the tubing for
pickup of dust and other particulate matter from reuse with the same product or to discard after
the environment. Therefore, the clean closures one use.
are often handled under the protection of HEPA- Sterilization of Equipment. In general,
filtered laminar airflow. equipment, containers, closures, and all other
components should be sterilized after cleaning
‘Production Equipment, Inc., Rochelle Park, NJ 07662. and prior to use. The principles and practices of
tlndustrial Washing Machine Corp., Matawan, NJ 07747. sterilization are discussed in Chapter 21.

666 • The Theory and Practice of Industrial Pharmacy

 Compounding the Product. The product included as near the outlet from the filler as pos¬
should be compounded under clean environ¬ sible to collect any lint or other particulate mat¬
mental conditions (see Fig. 22-2). Aseptic condi¬ ter picked up from the fines or equipment. It is
tions usually are not required since it may not be at the moment of filtration that a solution must
possible or feasible to sterilize some of the in¬ pass from a clean environment to an aseptic
gredients or the equipment, e.g., large tanks. environment (see Fig. 22-2), particularly if it has
Whenever possible, however, equipment and been sterilized by the filtration process.
ingredients should be sterile to reduce the mi¬ Filling Procedures. A liquid may be subdi¬
crobial load. vided from a bulk container to individual dose
The accuracy of compounding should meet containers more easily and uniformly than a
the rigid standards accepted in pharmaceutical solid. Mechanical subdivision of a mobile, low-
procedures, regardless of the batch size, recog¬ density liquid can be achieved with light-duty
nizing that small multiple errors may be addi¬ machinery, but viscous, sticky, or high-density
tive. In large batches, particular attention must liquids require much more rugged machines to
be given to achieving and maintaining homoge¬ withstand the pressure required to dispense
neity of solutions, suspensions, and mixtures, them.
maintaining a given temperature, and accelerat¬ Filling Equipment for Liquids. Certain
ing cooling. The order of mixing ingredients fundamental features are found on all machines
may become highly significant, for example, used for filling containers with liquids. A means
owing to the physical problem of distributing a is provided for repetitively forcing a measured
pH-adjusting ingredient throughout a large tank volume of the liquid through the orifice of a de¬
of liquid. Compounding problems for large livery tube designed to enter the constricted
batches of product often are different from those opening of a container. The size of the delivery
for small batches. tube is governed by the opening in the container
Good planning requires anticipation of rea¬ to be used, the viscosity and density of the liq¬
sonable stock needs for products so that a single uid, and the speed of delivery desired. The tube
large lot, instead of several small lots, may be must freely enter the neck of the container'and
prepared. If made in divided portions, each por¬ deliver the liquid deep enough to permit air to
tion is “a lot” requiring separate testing, thus escape without sweeping the entering liquid
multiplying the time and cost required. into the neck or out of the container. To reduce
Filtration of Solutions. Solutions must be the resistance to the flow of the liquid, the tube
filtered. The primary objectives of filtration are should have the maximum possible diameter.
clarification or sterilization of a solution. The Excessive delivery force causes splashing of the
two objectives differ principally in degree. Clari¬ liquid and troublesome foaming, if the liquid has
fication is termed “polishing,” and a highly pol¬ a low surface tension.
ished solution requires the removal of particu¬ The delivery of relatively small volumes of liq¬
late matter down to at least 3 microns in size. uids is usually obtained from the stroke of the
Further reduction in the size of the particulate plunger of a syringe. The stroke of the syringe
matter removed, to approximately 0.3 micron, forces the liquid through a two-way valve that
results in sterilization, the removal of viable provides for an alternate filling of the syringe
microorganisms and spores. Where the objective from a reservoir and delivery to a container. For
of filtration is sterilization, a highly polished so¬ heavy, viscous liquids a sliding piston valve pro¬
lution is concurrently produced. A solution hav¬ vides more positive action.
ing a high polish conveys the impression of ex¬ A drop of liquid normally hangs at the tip of
ceptional quality and purity, a highly desirable the tube after a delivery. When the container to
characteristic for a sterile solution. be filled is an ampul, withdrawal of the tube
The various types of filters employed for ster¬ without wetting the long restricted neck is al¬
ile products, their selection, and use have been most impossible, unless the hanging drop of liq¬
discussed in Chapter 7. uid is retracted. Thus, a retraction device is de¬
After filtration, the solution must be protected signed as a part of most filling machines.
from environmental contamination until it is Filling machines4 should be designed so that
sealed in the final container. Normally, this is the parts through which the liquid flows can be
best accomplished by collecting the filtrate in a
container that is a part of a closed system, with
‘Cozzoli Machine Co., Plainfield, NJ 07060; Mateer-Burt
air exchange through a bacteria retentive filter.
Co., Wayne, PA 19087; National Instrument Co., Inc.,
The filtrate is fed directly from the collecting Baltimore, MD 21215; Perry, Industries, Inc., Hicksvilie.
vessel to the filling machine through sterile hose NY 11802; Scientific Equipment Products Co., Baltimore.
connections. A secondary “in-line” filter is often MD 21218.

STERILE PRODUCTS • 667

 sure. It is usually equipped with an overflow
tube connected to a receiver to prevent excess
filling of the container.
Vacuum filling* is commonly used in faster
filling lines for large liquid volumes because it is
more adaptable to automation. A vacuum is pro¬
duced in a bottle when a nozzle gasket makes a
seal against the lip of the bottle to be filled. The
vacuum draws the liquid from a reservoir
through the delivery tube into the bottle. When
the liquid level reaches the level of an adjustable
overflow tube, the seal is mechanically loosened
and the vacuum released. Any liquid that had
been drawn into the vacuum line is collected in
a trap receiver and then returned to the reser¬
voir.
It is obvious that the accuracy and precision of
machine filling of sterile liquids vary with the
method. Therefore, a method is selected to pro¬
FIG. 22-8. Aseptic filling of vials with liquid under verti¬ vide the degree of accuracy and precision re¬
cal laminar airflow, followed by stoppering with forceps by quired by the nature of the product. A slight ex¬
hand. (Courtesy of University of Tennessee.)
cess is required in each container to provide for
the loss that occurs at the time of administration
easily demounted for cleaning and for steriliza¬ due to adherence to the wall of the container and
tion. These parts also should be constructed of retention in the syringe and hypodermic needle
nonreactive materials such as borosilicate glass lumen. A table of suggested excess volumes is
or stainless steel. Syringes are usually made of found in the USP.
stainless steel when the pressures required for The danger of overdosage as well as economic
delivery of viscous liquids or large volumes factors limit the amount of excess desirable in a
would be unsafe for glass syringes. given container. A reduction of only 0.01 ml of
Filling machines such as the one shown in unnecessary excess in each 1-ml ampul of a lot
operation in Figure 22-8 can be designed to pro¬ of 10,000 would yield approximately 100 more
vide high delivery volume precision. The stroke containers of product.
of the syringe can be repeated precisely; there¬ Emulsions and suspensions often require spe¬
fore, once a particular setting has been cali¬ cially designed filling equipment because of
brated for a delivery, high precision is possible. their high viscosity. To obtain a reasonable flow
The precision can be affected by certain operat¬ rate, high pressures must be applied, or con¬
ing factors, however, such as the speed of deliv¬ tainers with large openings must be used, to per¬
ery, the uniformity of speed, the expansion of mit the entry of large delivery tubes. Sometimes
rubber tubing connecting the valve with the de¬ jacketed reservoir tanks can be used to raise the
livery tube, and the rapidity of action of the temperature of the product and thereby lower its
valves. viscosity. It is normally necessary to keep sus¬
Sterile solutions of relatively low potency dis¬ pensions, and sometimes emulsions, constantly
pensed in large volume (up to one liter) do not agitated in the reservoir during filling, so that
normally require the precision of filling that is the product remains homogeneous and each
required for small volumes of potent injectables. subdivided unit contains the required amount of
Therefore, bottles of solution are usually filled by drug.
gravity, pressure, or vacuum filling devices. Filling Equipment for Solids. Sterile sol¬
Gravity filling is relatively slow, but is accom¬ ids, such as antibiotics, are more difficult to sub¬
plished in a simple manner. The liquid reservoir divide accurately and precisely into individual
is positioned above the filling line with a hose dose containers than are liquids. The rate of flow
connection from the reservoir to a shut-off de¬ of solid material tends to be slow and irregular,
vice at the filling line. The shut-off device is particularly if finely powdered. Small, granular
usually hand operated, and the bottles are filled particles flow most evenly. Containers with a
to graduations on the bottles. relatively large opening must be used; even so,
The pressure pump filler often is operated
semiautomatically and differs from the gravity ‘Perl Machine Manufacturing Co., Inc., Brooklyn, NY
filler principally in that the liquid is under pres¬ 11201; U.S. Bottlers Machinery Co., Chicago, IL 60618.

668 • The Theory and Practice of Industrial Pharmacy

the filling rate is slow, and the risk of spillage is usually can be minimized if uniform particle
ever present. For these reasons, the tolerances size of the solid is achieved and a small electric
permitted for the content of such containers current is used to neutralize the developing
must be relatively large. Suggested tolerances charge.
may be found tabulated in the USP. One type of machine* for delivering measured
Sterile solids can be subdivided into con¬ quantities of free-flowing material employs an
tainers by individual weighing. The operator can auger in the stem of the funnel-shaped hopper
use a scoop that holds a volume approximately (see Fig. 22-9). The size and rotation of the
equal to the weight required, but the quantity auger can be adjusted to deliver a regulated vol¬
filled into the container is finally weighed on a ume of granular material from the funnel stem
balance. This is a slow process. into the container.
When the solid is obtainable in a relatively In another filling machine^ (Fig. 22-10), an
free-flowing form, machine methods of filling adjustable cavity in the rlrh of the filling wheel is
may be employed. In general, these methods filledfhy vacuum as the wheel passes under the
involve the measurement and delivery of a vol¬ hopper. The contents are held by vacuum until
ume of the solid material, which has been cali¬ the cavity is inverted over the container, when a
brated in terms of the weight desired. Among jet of sterile air discharges the dry solids. This
the major problems in the use of such machines machine dispenses dry solids that flow less
are stratification of particles due to varying par¬ freely than those of other machines presently
ticle sizes, the development of electrostatic available.
charge within the mass of dry solid particles, the
formation of air pockets, and uneven flow due to "Chase-Logeman Corp., Hicksviile, NY 11501; Mateer-
clumping of the particles. These all result in Burt Co., Wayne, PA 19087.
uneven filling of the container. The problems tPerry Industries Inc., Hicksviile, NY 11802.

FIG. 22-9. High-speed automated aseptic processing line protected by a hood showing unscrambler turntable at left and
powder filler at right. (Courtesy of Lederle Laboratories Div., American Cyanamid Co.)

STERILE PRODUCTS • 669

 A

PRODUCT HOPPER

FIG. 22-10. A, Automated filling unit for dry solids. The operation is protected by hoods to maintain an aseptic environ¬
ment. B, The diagram represents the functioning parts with the unscrambler turntable at left, the filling machine, the
rubber closure inserting device, and the collecting turntable for the filled and stoppered vials at right. (Courtesy of Perry
Industries, Inc.)

670 • The Theory and Practice of Industrial Pharmacy

 Sealing. Containers should be sealed in the genated or coated with silicone to reduce the
aseptic area immediately adjacent to the filling friction. This makes it possible for a closure to
machine. In addition to retaining the contents of slide from a rotating or vibrating drum to the
a sterile product, sealing of containers assures bottom of a chute, where it is positioned over a
the user that it has not been opened. It is obvi¬ container, ready for insertion by a plunger or
ous that a sterile container that has been opened some other pressure device (Fig. 22-10). Stop¬
can no longer be considered to be sterile. There¬ pering can be done at production line speeds
fore, tamperproof sealing is essential. with such a machine.
Sealing Ampuls. Ampuls may be closed by Aluminum caps are used to hold rubber clo¬
melting a portion of the glass of the neck to form sures in place. Single caps may have a perma¬
either bead-seals (tip-seals) or pull-seals. Tip- nent center hole or a center that is tom away at
seals are made by melting sufficient glass at the the time of use to expose the rubber closure.
tip of the ampul neck to form a bead of glass and Double aluminum caps usually have an inner
close the opening. Pull-seals are made by heat¬ cap with a permanent center hole, which in use
ing the neck of a rotating ampul below the tip, is exposed when the entire outer cap is tom off.
then pulling the tip away to form a small, twisted The triple aluminum caps are used for large bot¬
capillary just prior to being melted closed. tles with rubber closures having permanent
The heating with a high-temperature gas- holes for attachment to administration sets. The
oxygen flame must be even and carefully con¬ inner cap with a permanent center hole remains
trolled to avoid distortion of the seal. Excessive in place during use to secure the rubber closure.
heating of air and gases in the neck causes ex¬ The thin disc is used in conjunction with a thin
pansion against the soft glass with the formation rubber disc to seal the holes through the closure.
of fragile bubbles at the point of seal. Open capil¬ The outer cap holds the disc in place and is tom
laries at the point of seal or cracks result in away at the time of use.
“leakers.” Pull-sealing is a slower process, but When applied, the bottom edge of an alumi¬
the seals are more reliable than those from tip¬ num cap is bent (crimped) around and under
sealing. Powder ampuls or other types having a the lip of the glass container. It cannot be re¬
wide opening must be sealed by pull-sealing. moved without destroying the cap, but perfora¬
Fracture of the neck of ampuls often occurs tions permit tearing away the portions of the cap
during sealing if wetting had occurred at the to be discarded preparatory to use. Single alumi¬
time of filling. Also, wet glass at the neck in¬ num caps may be applied by hand crimping de¬
creases the frequency of bubble formation and of vices,* but double or triple caps or large produc¬
unsightly and contaminating deposits of carbon tion lots require the use of heavy-duty motorized
or oxides as a result of the effect of the heat of crimping machines.!
sealing on the droplets of product. Automation of Processing. The need for
With some sensitive products, it may be nec¬ increased production rates for sterile products
essary to close the ampuls with pull-seals to pre¬ eventually justifies the cost of developing and
vent combustion products of the flame from en¬ operating automatic machinery. Unquestiona¬
tering the ampul at the time of sealing, as might bly, machines can be designed to carry out cer¬
occur with tip-sealing. In addition, it is some¬ tain operations more rapidly and with more reli¬
times necessary to displace the air in the space able repetition than can be performed by people.
within the ampul above the product to prevent A further advantage of mechanization in proc¬
decomposition. This may be done by introducing essing sterile products is the elimination of the
a stream of inert gas, such as nitrogen or carbon human body as a source of biologic contamina¬
dioxide, during or after filling with the product. tion; however, the contaminating effects of
Immediately thereafter, the ampul is sealed be¬ abraded particles, lubricants, and dirt from the
fore the gas can diffuse to the outside. moving parts of even the cleanest aseptic ma¬
Sealing Bottles, Cartridges, and Vials. chine must not be forgotten.
Rubber closures must fit the opening of the When machines are designed or used so that
container snugly enough to produce a seal, but the constant attention of a human operator is
not so snugly that it is difficult to position them required, the operation is identified as being
in or on the container. They may be inserted by
hand, using sterile forceps (see Fig. 22-8). A
faster hand method involves picking up the clo¬ "The West Company, Phoenixvilie, PA 19460; Wheaton
Scientific, Millville, NJ 08332; Production Equipment
sure and inserting it into a vial by means of a
Inc., Rochelle Park, NJ 07662.
tool connected to a vacuum line. tAluminum Co. of America, Pittsburgh, PA 15219; The
When closures are to be inserted by ma¬ West Company, Phoenixvilie, PA 19460; Wheaton Scien¬
chines, the surface of the closure is usually halo- tific, Millville, NJ 08332.

STERILE PRODUCTS • 671

semiautomatic. For automatic operation, ma¬ rapidly and cooled to an experimentally deter¬
chines are usually linked together by conveyor mined temperature below its eutectic point.
belts in an arrangement that requires little at¬ Most commonly, it would be frozen by a me¬
tention from an operator (Fig. 22-10). The un¬ chanical refrigeration device, often the refriger¬
scrambler or feed turntable lines up a large ated shelves in the freeze-drying chamber, at a
number of vials and feeds them one at a time to temperature of -50°C or lower.
the conveyor belt. The belt carries each vial in When the product is completely frozen and
sequence to the filling wheel, to the stoppering properly cooled, the chamber is sealed and evac¬
machine, and then out to the collecting turn¬ uated. The ice in the frozen product gradually
table. A crimping machine could be inserted sublimes from the frozen surface and is col¬
after the stoppering machine. This processing lected in a refrigerated condenser chamber or on
line has been permanently linked together. For plates within the chamber containing the prod¬
greater flexibility, each machine may remain a uct. As the ice leaves the product, the drying res¬
separate unit, linked together in use by conveyor idue maintains essentially its original volume
belt units in an arrangement suitable for a par¬ and becomes porous, owing to the loss of the ice
ticular process. molecules. This porous structure usually in¬
Automation of the entire process would con¬ creases the subsequent rate of solution of the
vey an empty dose container from its supply car¬ product as compared with the original material.
ton through the entire process until it is filled The rate of drying depends largely on the ther¬
with a product, labeled, and placed in the ship¬ mal conductance of the frozen product, the rate
ping carton. A portion of such a processing line at which the vapor can diffuse through the pro¬
is illustrated in Figure 22-9. In this fine, the gressively thicker layer of dried porous material,
vials are removed by operators from their protec¬ and the rate of transfer of the vapor through the
tive cartons or “shrink-packs” and given an air system to the condenser surface. It has been
rinse. A covered conveyor carries them at high said that the drying rate can be estimated as
speed through a sterilizing tunnel. They approximately one hour for each millimeter of
emerge, cooled, on the unscrambler turntable depth of the product. The theory of freeze drying
(left, Fig. 22-9) and are conveyed in sequence to is more fully discussed in Chapter 3 and in the
the dry solids filler (right, Fig. 22-9), the stop¬ literature.91-95
pering and capping machines, and then into the In production, large freeze driers* are usually
next room for packaging, all without contact operated by an automatic control system. By
with human hands. A compact fine of similar means of a thermocouple frozen in a sample of
concept for processing small ampuls and vials the product, the temperature curve of the sam¬
has been developed.* Such lines are usually lo¬ ple is duplicated in comparison with a curve
cated in an aseptic room with the critical por¬ experimentally found to produce a satisfactory
tions further protected with covers and bathed product. During processing, the shape of the
with HEPA-filtered air. An automated process¬ sample curve is adjusted primarily by the heat
ing fine such as this can be justified when high input, which provides the energy for sublima¬
production rates are- required. tion.
Sterilization of Product. A product must The product is usually processed until there is
be sterilized by the most reliable method possi¬ less than 1% moisture in the dried material.
ble. The methods of sterilization, their applica¬ After completion of the drying cycle, reabsorp¬
tion, and the bases for their selection have been tion of moisture must be prevented. The product
discussed in Chapter 21. must, therefore, be removed from the chamber
Freeze-Drying. Freeze drying (lyophiliza- and sealed as rapidly as possible under con¬
tion) is a drying process applicable to the manu¬ trolled low-humidity conditions.
facture of certain pharmaceuticals and biologi- Freeze driers also may be equipped for stop¬
cals that are thermolabile or otherwise unstable pering vials within the drying chamber. Special
in aqueous solution for prolonged storage peri¬ slotted rubber closures (see Fig. 22-1) are par¬
ods, but that are stable in the dry state. tially inserted into the neck of vials prior to
A product to be freeze-dried is prepared and freezing the product. The slots permit the es¬
handled as an aqueous solution or suspension in cape of water vapor from the vials during the
the same manner as discussed previously for an
aseptic fill. The aqueous preparation is frozen
‘Hull Corp., Hatboro, PA 19040; Industrial Dynamics,
Div. American Sterilizer Co., Erie, PA 16512; NRC Equip¬
ment Corp., Newton, MA 02161; Stokes Division, Penn-
*Hodes Lange Division, The West Co., Phoenixville, PA walt Corp., Philadelphia, PA 19120; The Virtis Co., Inc.,
19460. Gardiner, NY 12525; USIFROID, Norristown, PA 19401.

672 • The Theory and Practice of Industrial Pharmacy

drying cycle. At the end of the drying cycle a contents, thereby accentuating interchange if an
hydraulically operated plate or an expandable opening exists.
rubber diaphragm presses the closures firmly The leaker test is intended to detect incom¬
into the neck of the vials and seals them under pletely sealed ampuls so that they may be dis¬
vacuum. A butyl rubber compound is usually carded. Tip-sealed ampuls are more likely to be
used for these closures because of its low water incompletely sealed than are those that have
vapor permeability. been pull-sealed. In addition, small cracks may
Numerous biologic preparations, tissue sec¬ occur around the seal or at the base of the ampul
tions, and viable microorganisms are being pre¬ as a result of improper handling.
served in the freeze-dried state. Multiple vita¬ Leakers usually are detected by producing a
min combinations, antibiotics, and hormone negative pressure within an incompletely sealed
preparations are examples of pharmaceutical ampul, usually in a vacuum chamber, while the
products preserved by this method. ampul is entirely submerged in a deeply colored
dye solution (usually 0.5 to 1.0% methylene
blue). Subsequent atmospheric pressure then
Quality Control causes the dye to penetrate an opening, being
The responsibilities of the quality control de¬ visible after the ampul has been washed exter¬
partment have been discussed elsewhere in this nally to clear it of dye. The vacuum (27 inches
text (Chap. 27). The discussion here is limited to Hg or more) should be sharply released after 30
those aspects of this important function that are min. Only a tiny drop of dye may penetrate a
peculiar to sterile products. small opening.
The three general areas of quality control are A reported study has shown that detection of
incoming stock, manufacturing (processing), leakers is more effective when the ampuls are
and the finished product. For sterile products, immersed in a bath of dye* during the autoclav¬
incoming stock control encompasses routine ing cycle.96 This has the added advantage of ac¬
tests on all ingredients as well as special evalua¬ complishing both leaker detection and steriliza¬
tions such as pyrogen tests on WF1, glass tests tion in one operation. Capillaries of about 15
on containers, and identity tests on rubber clo¬ microns in diameter or smaller may or may not
sures. It also may be necessary to perform mi¬ be detected by these test methods.
crobial load (bioburden) tests to determine the Vials and bottles are not subjected to such a
number and types of microorganisms present. leaker test because the rubber closure is not
Process control in the manufacture of sterile rigid; however, bottles are often sealed while a
products involves all of the innumerable tests, vacuum is being pulled so that the bottle re¬
readings, and observations made throughout the mains evacuated during its shelf-life. The pres¬
manufacturing process of a product, including ence of a vacuum may be detected by striking
conductivity measurements during the distilla¬ the base of the bottle sharply with the heel of the
tion of WFI, confirmation of volume of fill in hand to produce the typical “water hammer”
product containers, recording of cycle time and sound. Another test is to apply'T'sjpark-tester
temperature for thermal sterilization of the prod¬ probe to the outside of the bottle, moving from
uct, and confirming the count and identity of the liquid layer into the air space. A blue spark
labels for the product. The production control discharge occurs if the airspace is evacuated.
includes all of the final assays and tests to which Clarity Test. Clarity is a relative term, the
the product is subjected. In addition to the usual meaning of which is markedly affected by the
chemical and biologic tests, a sterile product is subjective evaluation of the observer. Unques¬
subjected to a leaker test (when applicable), a tionably, a clean solution having a high polish
clarity test, a pyrogen test (when applicable), conveys to the observer that the product is of
and a sterility test. exceptional quality and purity. It is practically
Leaker Test. Ampuls are intended to pro¬ impossible, however, to prepare a lot of a sterile
vide a hermetically sealed container for a single product so that every unit of that lot is perfectly
dose of a product, thereby completely barring free from visible particulate matter, that is, from
any interchange between the contents of the particles that are 30 to 4(Lam and larger in size.
sealed ampul and its environment. Should capil¬ Consequently, it is the responsibility of the qual¬
lary pores or tiny cracks be present, microorgan¬ ity control department to detect and discard in¬
isms or other dangerous contaminants may dividual containers of a product that the ulti-
enter the ampul, or the contents may leak to the
outside and spoil the appearance of the package.
Changes in temperature during storage cause *Dye formula: F.D.&C. Red No. 1,0.5%; F.D.&C. Red No.
expansion and contraction of the ampul and 2, 0.1%; and sodium lauryl sulfate, 0.25% in water.

STERILE PRODUCTS * 673

mate user would consider to be unclean. light scattering,* light absorption,! and electri¬
Further, the USP states that good pharmaceuti¬ cal resistance! have been used to obtain particle
cal practice requires that all containers be visu¬ counts and size distribution.100-103 All of them,
ally inspected and that any with visible particles however, require destruction of the product unit
be discarded. In addition, for large-volume infu¬ to obtain the test sample, making them useful
sions, the USP has established a limit of 50 par¬ only for quality control testing. A method utiliz¬
ticles of 10 yam and larger and 5 particles of2o ing video image projection coupled with elec¬
/am and larger perTmTIIliter. ~ tronic circuitry detects moving particles without
"“Normally, manufacturers of parenteral solu¬ destruction of the product unit.104 Therefore, it
tions can meet the above standard with the tech¬ can be used for in-line detection of particles in
nology currently available. Further, product de¬ product units, but at present, its use is limited to
velopment, raw material quality control, and 1- to 5-ml containers.
process control have eliminated any potential for Pyrogen Test. The presence of pyrogenic
widespread particulate development. In any lot substances in parenteral preparations is deter¬
of product, however, there may be a few con¬ mined by a qualitative biologic test based on the
tainers having visible particles. These must be fever response of rabbits. Rabbits are used as the
detected by visual inspection and discarded. test animal because they show a physiologic re¬
Although particulate matter is of primary con¬ sponse to pyrogens similar to that of human be¬
cern in products given intravenously, all paren¬ ings. If a pyrogenic substance is injected into
teral products should be free from insoluble par¬ the vein of a rabbit, an elevation of temperature
ticles. Several years ago, it was shown that the occurs within a period of 3 hours. The specifica¬
formation of pathologic granulomas in vital or¬ tion limits and procedural details are given in
gans of the body can be traced to fibers, rubber the official test in the USR
fragments, and other solids present in intrave¬ The housing conditions and handling are crit¬
nous solutions.9' More recendy, a double blind ical to obtaining consistent results with rabbits
study has shown that the use of a final filter for in the test. Because of this, the use of rectal
the administration of intravenous solutions re¬ thermometers has largely been replaced by rec¬
duced the incidence of thrombophlebitis, a re¬ tal thermocouples, which remain in place
sult believed to be due to the elimination of throughout the test, eliminating the handling of
subvisual particles from the administered solu¬ the rabbits for individual temperature readings
tion.98 While there are unanswered questions (Fig. 22-11). By this method, one person can
relative to these toxic effects, these findings handle 100 or more animals a day as compared
have highlighted the importance of the prepara¬ with about 15 by the individual thermometer
tion of exceptionally clean parenteral products. method. Critical evaluations of pyrogen testing
Suspensions, emulsions, or dry solids, in addi¬ with rabbits may be found in the litera¬
tion to solutions, should be compounded and ture.105'106
processed under clean conditions to minimize Many medical agents, if present, interfere
the presence of foreign particles. with the test results because of their antipyretic
The visual inspection of a product container is or other interfering effects. Therefore, _the
usually done by individual human inspection of pyrogen test is performed on all vehicles used for
each externally clean container under a good injections, but only on those finished products
fight, baffled against reflection into the eyes, and that do not interfere with the test, that have a
viewed against a black and white background, high propensity for contamination with pyro¬
with the contents set in motion with a swirling gens, or that are given in large quantities. Con¬
action. A moving particle is much easier to see siderably greater danger exists from the injec¬
than one that is stationary, but care must be ex¬ tion of large volume solutions containing
ercised to avoid introducing air bubbles, which pyrogens than from small volumes. Also, the
are difficult to distinguish from dust particles. pyrogenic effect is less with intramuscular injec¬
To see heavy particles, it may be necessary to tion than with intravenous injection.
invert the container as the final step in inspec¬ Recently, an in vitro test method for pyrogens
tion. Although a human inspector is subject to has been developed utilizing the gelling property
reduction in efficiency by eye strain, fatigue, of the lysate of the ameboeytes of Limulus poly-
distractions, and emotional disturbances, visual
inspection can be done or 100% of the product
* Climet Instruments Co., Redlands, CA 92373; HIAC/
units and can be done at a level of discrimina¬
Royco, Menlo Park, CA 94025; Particle Technology. Inc.,
tion at least equal to that of the user.99 Sunnyvale, CA 94086.
Instrumental methods of evaluation for partic¬ tHIAC/Royco, Menlo Park, CA 94025.
ulate matter in liquids utilizing the principles of (Coulter Electronics, Inc., Hialeah, FL 33010.

674 • The Theory and Practice of Industrial Pharmacy

FIG. 22-11. Rabbits being subjected to a pyrogen test with temperatures being taken by rectal thermocouples connected to
an electric thermometer. (Courtesy of Wyeth Laboratories.)

phemus (the horseshoe crab).107 In the pres¬ specifications, however, i.e., what the limits
ence of pyrogenic endotoxins from gram-nega¬ should be and how the tests are to be utilized.110
tive bacteria, a firm gel is formed within 60 min Sterility Test All products labeled “sterile”
when incubated at 3TJJ~. Although only endo- must pass the sterility test, having been sub¬
toxinsTfbm gram-negative bacteria react in this jected to an effective process of sterilization. The
way, they constitute the majority and the most principles underlying this important test and the
potent of contaminating pyrogens. The limulus test procedure are discussed in Chapter 21.
amebocyte lysate (LAL) test has been found to
be 5 to 10 times more sensitive than the rabbit
Test and by the use of serial dilutions has been P
shown to be semiquantitative. There do not Packaging
seem to be large numbers of substances, other A thorough discussion of the packaging of
than proteins, that interfere with the reac¬ sterile products is beyond the scope of this chap¬
tion.108 The favorable results from many studies ter. A few pertinent facts are presented, how¬
have brought increasing acceptance of the LAL ever. The package is an extremely important
test for in-process testing and for selective prod¬ part of the product, for it presents the product to
uct release testing.109 The USP now contains the user. It must be particularly dignified, neat,
the specification's for a Bacterial Endotoxins and attractive in appearance if it is to convey to
Test designed to provide a means for estimating the user the quality, purity, and reliability that
the concentration of bacterial endotoxins pres¬ conformance to the aforementioned principles
ent in samples or on devices being tested. De¬ and procedures causes to be an inherent part of
bate is continuing on certain aspects of the test the product. The package also must accurately

STERILE PRODUCTS * 675

and completely provide the user with the infor¬ References
mation necessary for its use. The labeling
1. Avis, K. E.: Parenteral preparations. In Remington’s
should be legible and the identity and strength"' Pharmaceutical Sciences. 17th Ed. Edited by A. R.
ofTfiellrug clearlylEsfmguIsEable. This is par¬ Gennaro. Mack Publishing Co., Easton, PA, 1985, p.
ticularly difficult with the small containers used 1518.
for many sterile products. Furthermore, the- 2. Avis, K. E., and Levchuk, J. W.: Parenteral medica¬
package should protect the product against tions. In Dispensing of Medication, 9th Ed. Edited
by R. E. King. Mack Publishing Co., Easton, PA,
physical damage during shipping, handling, and 1984, p. 165.
storage and should protect light-sensitive sub~^ 3. Turco, S., and King, R. E.: Sterile Dosage Forms.
stances from ultraviolet radiation. 2nd Ed. Lea & Febiger, Philadelphia, 1979.
Further packaging requirements for injec¬ 4. Tse, F. L. S., and Welling, P. G.-. J. Parent. Drug
tions are given by the USP essentially as follows: Assoc., 34:409, 1980.
5. Tse, F. L. S., and Welling, P. G.: J. Parent. Drug
1. The volume of an injection in single-dose containers Assoc., 34:484, 1980.
6. Symposium on Pyrogens. J. Pharm. Pharmacol.,
should provide the amount specifled for administration at
6:302, 1954.
one time and in no case is more than one liter. This re¬ 7. Hahn, H. H., Chenk, S. F., Elfenbein, C. D. S., and
quirement is intended to minimize the likelihood of Wood, W. B., Jr.: J. Exp. Med., 131:710, 1970.
someone attempting to use at a later time a residue in a 8. Abramson, D., Butler, L. D., and Chrai, S.: J. Parent.
container after exposure to contamination from the envi¬ Sci. and Technol., 35:3, 1981.
ronment. 9. Rechen, H.C.: Pharm. Manuf., 1:29, 1984.
2. Preparations intended for intraspinal, intracistemal. 10. Reese, D. R.: Bull, Parent. Drug Assoc., 16(5): 11,
or peridural administration should be packaged only in 1962.
single-dose containers because of the sensitivity of nerve 11. Spiegel, A. J., and Noseworthy, M. M.: j. Pharm.
Sci. 52/917, 1963.
tissue to irritation from added substances such as anti¬
12. Carleton, F. J.: Bull. Parent. Drug Assoc., 23:142,
bacterial agents.
1967.
3. Normally, no multiple-dose container shall contain a 13. Scheindlin, S.: Bull. Parent. Drug Assoc., 20:61,
volume of injection more than Is sufficient to permit the 1966.
withdrawal of 30 ml, because larger volumes would pro¬ 14. Wang, Y. J., and Kowal, R. R.: J. Parent. Drug
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the potential for contamination. 35. Akers, M. J.: Pharm. Technol., 8:36, 1984.
4. Injections labeled for veterinary use are exempt 16. Lacbman, L., Urbanyi, T., and Weinstein, S.: J.
from the above limitation to single-dose containers, and to Pharm. Sci., 52:244, 1963.
17. Kohn, S. R., Gersbenfeld, L., and Barr, M.: J.
the volume of multiple-dose containers because large ani¬
Pharm. Sci., 52:967, 1963.
mals require larger doses than man.
18. Schroeter, L. C.: J. Pharm. Sci., 50:891, 1961.
19. Schou, S. A.: Am. J. Hosp. Pharm. 37.T53, 1960.
Details of labeling content requirements for 20. Chipault, J. R.: Antioxidants in foods. In Autoxida-
injections can be found in the USP. When a tion and Antioxidants. Vol. II, Edited by W, O.
label is applied to a container, it must be so ar¬ Lundberg. Interscience, New York, 1962.
ranged that a sufficient area of the container 21. Higuchi, T., and Schroeter, L.: J. Am. Pharm.
Assoc., Sci. Ed., 48:535, 1959.
remains uncovered to permit inspection of the 22. Halaby, S. F., and Mattocks, A. M.: J. Pharm. Sci.,
contents. While these packaging and labeling 54.-52, 1965.
stipulations apply specifically to official injec¬ 23. Windheuser, J. J.: Bull. Parent. Drug Assoc.,
tions, the Food and Drug Administration looks 17(5):1, 1963.
upon these as providing basic guidelines for all 24. Husa, W. J., and Adams, J.R.: J. Am. Pharm. Assoc.,
products. Sci. Ed., 33:329, 1944.
25. Grosicki, T. S., and Husa, W. J.: J. Am. Pharm.
The operation of the packaging department Assoc., Sci. Ed., 43.-632, 1954.
for sterile products is essentially the same as for 26. Hammarlund, E. R., and Pedersen-Bjergaard, K.: J.
other pharmaceutical packaging departments. Pharm. Sci., 50:24, 1961.
The overriding objective must be that every unit 27. Ansel, H. C.: ,4m. J. Hosp. Pharm., 23:25, 1964.
is properly labeled and packaged, with adequate 28. Hammarlund. E. R., and Van Pevenage, G. L.-. J.
controls to be assured that this is accomplished. Pharm. Sci., 55/1448, 1966.
29. Fassett, W. E., Fuller, T. S., and Hammarlund, E.
Throughout the entire manufacturing process R.: J. Pharm. Sci., 58:1540, 1969.
for a sterile product, the prevailing philosophy 30. Mulbns. J. D.: Bull. Parent. Drug Assoc., 22/38,
must be that no effort is too great to make the 1968.
finished product as nearly perfect as possible. 31. Autian, J.; J. Pharm. Sci., 53.1289, 1964.
32. Autian, J.: Bull. Parent. Drug Assoc., 22:276, 1968.
33. Eubanks, R., and Autian. J.: Am. J. Hosp. Pharm.
28:172, 1971.
34. Petrick, R. J., Loucas, S. P., Cohl. J. K.. and Mehl,
B.: Am. J. Hosp. Pharm., 34:357, 3977.

676 • The Theory and Practice of Industrial Pharmacy

35. Guess, W. L., and Autian. J.: Am. J. Hosp. Pharm. 73. Bowman, F. W.: Bull. Parent. Drug Assoc., 22:57,
21:260, 1964. 1968.
36. Majeske, J. P.: Bull. Parent. Drug Assoc., 16(4):1, 74. Hortig, H. P.: Bull. Parent. Drug. Assoc., 27:38,
1962. 1973.
37. Sanga, S. V.: J. Parent. Drug Assoc., 33:61, 1979. 75. Gross, R. I.: Bull. Parent. Drug Assoc., 30:143,1976.
38. Hopkins, G. H.: J. Pharm. Sci., 54:138, 1965. 76. Fed. Stand. No. 209B: Clean Room and Work Sta¬
39. Keim, F: Bull. Parent. Drug Assoc., 29:46, 1975. tion Requirements, Controlled Environment. Gen¬
40. Lachman, L., Urbanyi, T., and Weinstein, S.: j. eral Services Adm., Washington, DC, April 24,
Pharm. Sci., 52:244, 1963. 1973.
41. Hopkins, G.H.: Bull. Parent. Dnig Assoc., 29:278, 77. Whitfield, W. J.: Bull. Parent. Drug Assoc., 21:37,
1975. 1967.
42. Lachman, L., Pauli, W. A., Sheth, P. B., and 78. Loughhead, H. O., and Moffett, J. A.: Bull. Parent.
Pagliery, M.: J. Pharm. Sci., 55:962, 1966. Drug Assoc., 25:261, 1971.
43. Hartop, W. L.: Parent. Drug Assoc. Convention, 79. Delmore, R. P., Jr., and Thompson, W. N.: Med.
Nov. 2, 1966. Device &. Diagn. Ind., 3(2):45, 1981.
44. Hopkins, G. H.: Bull. Parent. Drug Assoc., 23:105, 80. Lieberman, A.: Med. Device & Diagn. Ind., 4(1 J:43,
1969. 1982.
45. Whalen, F. J., LeCain, W. K., and Latiolais, C.J.: 81. Useller, J. W.: Clean Room Technology. NASA SP-
Am. J. Hosp. Pharm., 36:330, 1979. 5074, Supt. of Documents U.S. Government Print¬
46. Parrott, E. L.: Drug & Cosm. Ind., 96:320, 1965. ing Off., Wash,, DC.
47. Macek, T. J.: Amer. J. Pharm., 137:217, 1965; 82. Heuring, H.: Contain. Control. 9(7):18, 1970.
138:22, 1966. 83. Klink, A. E., and Artiss, D. H.: J. Parent. Drug
48. Scheindlin, S.: Bull. Parent. Drug Assoc., 24:31, Assoc., 32:226, 1978.
1970. 84. DiSessa, P.: Pharm. Tech., 4:103, 1980.
49. Flynn, G. L.: 1. Parenter. Sci. andTechnol., 38:202, 85. Khimb, G. H.: Bull. Parent. Drug Assoc., 29:261,
1984. 1975.
50. Gorman, W. G., and Hall, G. D.. J. Pharm. Sci., 86. Artiss, D. H.: J. Parent. Drug Assoc., 32:89, 1978.
53:1017, 1964. 87. Anschel, J.: Bull. Parent. Drug Assoc., 31:47, 1977.
51. Lin, K. S., Anschel, J., and Swartz, C. J.: Bull. Par¬ 88. Grimes, T. L., Fonner, D. E., Griffin, J. C., et al.:
ent. Drug Assoc., 25:40, 1971. Bull. Parent. Drug Assoc., 31:179, 1977.
52. Hoevenaars, P. C. M.: Pharm. Weekblad., 100:1151, 89. Kovary, S. J., Agalloco, J. P., and Gordon, B. M.: J.
1965. Parenter. Sci. and Technol., 37:55, 1983.
53. Struhar, M.. Acta Fac. Bohemoslov., 9:99, 1964. 90. Anschel, J.: Bull. Parent. DrugAssoc., 31:302,1977.
54. Bodin, J. I., and Taub, A.: J. Am. Pharm. Assoc., Sci. 91. Meryman, H. T.: Ann. N.Y. Acad. Sci., 85:630,1960.
Ed., 44:296, 1955. 92. Mackenzie,A.P.:Bull.Parent.DrugAssoc.,20.T01,
55. Davisson, E. O., et al.: J. Lab. Clin. Med., 47:8, 1966.
1956. 93. DeLuca, P., and Lachman, L.: J. Pharm. Sci.,
56. Patel, N. K., and Kostenbauder, H. B.: J. Am. 54:617, 1965.
Pharm. Assoc., Sci. Ed., 47:289, 1958. 94. Couriel, B.: J. Parent. Drug Assoc., 34:352, 1980.
57. Gross, H. M.: Drug & Cosm. Ind., 75:468, 1954. 95. Jenning, T. A.: J. Parent. DrugAssoc., 34:109,1980.
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11(3):25, 1957. Pharm. Sci., 50:258, 1961.
59. DeLuca, P., and Lachman, L.: J. Pharm. Sci., 97. Garvan, J. M. and Gunner, B. W.: Med. J. Austral.,
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1981. Hosp. Pharm., 32:1001, 1975.
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Lippincott, Philadelphia, 1969, p. 108. 102. Hopkins, G. H., and Young, R. W.: Bull. Parent.
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ter 43:45077, Sept. 29, 1978. 103. Rebagay, T., Schroeder, H. G., Im, S., and DeLuca,
65. Meckler, M.: Contain. Control, 6(3):9, 1967. P. P.: Bull. Parent. DrugAssoc., 31:57, 1977.
66. Leuchten, W. E.: Bull. Parent. Drug Assoc., 17(2):6, 104. Louer, R. C., Jr., Russoman, J. A., and Rasanen, P.
1963. R.: Bull. Parent. Drug Assoc., 25:54, 1971.
67. Anisfeld, M. H., and Lovejoy, C. K.: J. Parent. Drug 105. Martin, W. J., and Marcus, S.: Appl. Microbiol.,
Assoc., 32:285, 1978. 12:483, 1964.
68. McQuillen, D. F.: Pharm. Technol., 5:44, 1981. 106. Personeus, G. R.: Pyrogen testing of parenteral
69. Hertzon, L.: Med. Device & Diagn. Ind., 4(1):29, pharmaceuticals. In Quality Control in the Pharma¬
1982. ceutical Industry. Vol. 2. Edited by M. S. Cooper.
70. Loughhead, H., and Vellutato, A.: Bull Parent. Drug Academic Press, New York, 1973, p. 239.
Assoc., 23:17, 1969. 107. Cooper, J. R., Hochstein, H. D., and Seligmann, E.
71. Whitfield, W. J., Mashbum, j. C., Neitzel, W. E., B., jr.: Bull. Parent. Drug Assoc., 26:153, 1972.
and Trujillo, L. C.: Basic Design Requirements for 108. Twohy, C. W., Duran, A. P., and Munson, T. E.: J.
Laminar Air Flow Dust Control Devices. SC-R-64- Parent. Sci. and Technol., 38:190, 1984.
145A, Sandia Corp., Albuquerque, NM, 1964. 109. Mascoli, C. C., and Weary, M. E.: J. Parent. Drug
72. Lamy, P. P., Davies, W. L., and Kitler, M.: Hosp. Assoc 33*81 1979
Pharm., 3:12, 1968. 110. Weary, M.: J. Parenter. Sci. and Technol., 38:20,
1984.

STERILE PRODUCTS • 677

 23
Pilot Plant Scale-Up
Techniques
SAMUEL HARDER and GLENN VAN BUSKIRK

Research and development personnel expend a layout of related functions should be taken into
considerable amount of effort developing drug account during the pilot plant phase with the
dosage forms with exacting specifications that intent to provide short-term and long-term effi¬
guarantee adequate physical and chemical sta¬ ciencies. The requirements, training, reporting
bility. These products, designed to deliver and relationships, and responsibilities of personnel
release a drug according to specific criteria, are also factors in successful product scale-up.1
have, up to this stage, been manufactured on a During the scale-up efforts in the pilot plant,
laboratory scale, or in intermediate-sized pilot production and process controls are evaluated,
plant equipment. Such equipment is usually validated, and finalized. In addition, appropriate
fairly standard and available in most laborato¬ records and reports are issued to support Good
ries. In addition to the obvious requirements of Manufacturing Practices (GMPs) and to provide
clinical efficacy and safety, the ability of the ex¬ the historical development of the production for¬
perimental formulation to be reproducibly man¬ mulation, process, equipment train, and specifi¬
ufactured on high-speed production equipment cations.
in a cost-effective manner is often the differenti¬ Often, meaningful product reprocessing pro¬
ating factor between a successful product and cedures can only be developed and validated at
one that is regarded as a research curiosity. To pilot plant scale. All critical features of a process
be successful, the product must be capable of must be identified so that as the process is
being processed and packaged on a large scale, scaled-up, it can be adequately monitored to pro¬
often with equipment that only remotely resem¬ vide assurance that the process is under control,
bles that used in the development laboratory. In and that the product produced at each level of
the pilot plant, a formula is transformed into a the scale-up maintains the specified attributes
viable, robust product by the development of a originally intended.
reliable and practical method of manufacture Each of the foregoing items is discussed in
that effects the orderly transition from laboratory more detail in the succeeding sections.
to routine processing in a full-scale production
facility.
Pilot plant studies must include a close exami¬ General Considerations
nation of the formula to determine its ability to
withstand batch-scale and process modification;
it must also include a review of a range of rele¬
Reporting Responsibilities
vant processing equipment to determine which The question of who should be responsible for
would be the most compatible with the formula¬ pilot plant studies has been debated at great
tion as well as the most economical, simple, and length with no clear resolution, as can be seen
reliable in producing the product. During this from the various reporting relationships in use
process, the availability of raw materials that within major pharmaceutical companies.2-4
consistently meet the specifications required to Pilot plant functions can be part of a research
produce the product must be determined. Pro¬ and development group with separate staffing.
duction rates and their relationship to immedi¬ This arrangement is designed to provide a hier¬
ate and future market requirements must be archy of responsibility to scale-up formulations
considered. The physical space required and the that have been developed by other formulators

681
 within research and development, thereby pro¬ ence within the group should encompass both
viding an opportunity for critique of formula/ formulation experience and process and equip¬
process that is independent of the initial formu¬ ment experience in the actual production envi¬
lation function. Alternatively, the formulators ronment. Personnel in the pilot plant must rec¬
who developed the product can take it into pro¬ ognize the intent of the formulator, and at the
duction and continue to provide support even same time, understand the perspective of pro¬
after the transition into production has been duction personnel. For these reasons, successful
completed. Proponents of this system cite the pilot plant organizations frequently include sci¬
advantage of historical continuity that comes entists with experience in both areas.
from this approach. Both of these first two struc¬ The type and level of education within the
tures stem from the premise that if the pilot group is important. Pharmaceutically trained
plant is a research responsibility, greater consid¬ scientists contribute fundamental strength to
eration is given to the preformulation and for¬ the function in their ability to assimilate the
mulation experiences obtained in the initial de¬ complex interrelationship between pharmaceu¬
velopment of a particular drug and its dosage tical processes and the potential impact on
form. chemical, physical, biochemical, and medical
Some companies prefer to have the pilot plant attributes of dosage forms. It is also important,
and technical service group organizationally however, that the group possess some engineer¬
separate from research and reporting instead to ing capability since the scale-up of many of the
the operations side of the business. The advan¬ processes involves engineering principles,
tage here may be that such a group would be which are usually not well covered in the normal
more operations-oriented, more pragmatic, and pharmaceutical training. In addition, it is be¬
more receptive to operations priorities. Manage¬ coming increasingly important for the group to
ment philosophy, the nature of a company’s contain individuals who are knowledgeable in
products, and the background experience of the both electronics and computers.5
personnel involved in pilot plant studies help The number of people in a pilot plant group
determine which arrangement is best for any depends on the number of products being sup¬
one particular organization at any point in time. ported and on the level of support required. An
A few companies have adopted a composite of experienced scientist with a knowledgeable
both approaches in hopes of achieving the best technician should be able to handle one major
attributes of both the research and development project, or two major projects simultaneously
and the operations-oriented systems. depending on their complexity, while at the
Whatever the reporting arrangement, the goal same time providing technical support for an
of a pilot plant is to facilitate the transfer of a additional group of marketed products.
product from the laboratory into production. The Many established companies have production
effectiveness of the pilot plant is determined by operators who have had many years of experi¬
the ease with which new products or processes ence with particular dosage forms and equip¬
are brought 'into routine production. This can ment, and supervisors who have had considera¬
best be achieved if a good relationship exists be¬ ble research experience. In such cases, the
tween the pilot plant group and the other groups support effort required of a pilot plant group
with which they interact, namely, research and would be much reduced. In such a company, the
development, processing, packaging, engineer¬ introduction of new products involving existing
ing, quality assurance/control (QA/QC), regula¬ technologies would require less support than the
tory, and marketing. introduction of a process involving new technol¬
ogy. On the other hand, companies who operate
their production facilities without the support of
Personnel Requirements extensively trained technical personnel, and in
The qualifications required for a position in a which the supervisory function is mainly ad¬
pilot plant organization are a blend of good theo¬ ministrative, can be expected to require consid¬
retic knowledge of pharmaceutics and some erably more support during introduction and
practical experience in the pharmaceutical in¬ scale-up of new products or processes and also to
dustry. In addition, the ability to communicate require substantially more continuing technical
well, both in speaking and in writing, and the support.
ability to develop good relationships with other
people axe important since experience and
knowledge are most useful when adequately and Space Requirements
effectively communicated. Practical experience A pilot plant has the following four types of
in pilot plant operations is invaluable. Experi¬ space requirements.

682 • The Theory and Practice of Industrial Pharmacy

 Administration and Information Proces¬ quate space for cleaning of pilot plant equip¬
sing. Documentation is important. Adequate ment. While some equipment can be cleaned in
office and desk space must be provided for both place, most equipment is better handled in a
the scientists and technicians. This should be dedicated cleaning area.
adjacent to the work area but sufficiendy iso¬ Storage Area. The fourth area and the one
lated to permit people to work without undue most often described as inadequate is storage
distractions. space. Separate provision should be made for the
Since the group is the link between research, storage of active ingredients and excipients.
operations, and other disciplines, members of These should be further segregated into ap¬
the group ffequendy meet with people from proved and unapproved areas according to
other departments and should have an area GMPs. There should be generous storage areas
available where three to four people can meet for in-process materials, finished bulk products
and discuss subjects of mutual concern. There from the pilot plant, and material from experi¬
should also be space for a computer terminal for mental scale-up batches made in production,
convenient data entry and retrieval as well as which for GMP reasons cannot be stored in oper¬
archives for stability data protocols and histori¬ ations storage areas. Space should be provided
cal files. for the storage of retained samples from pilot
Physical Testing Area. The second re¬ plant and experimental production batches. All
quired area is an adequate working area in of these space requirements are in addition to
which samples can be laid out and examined the controlled environment space allocated for
and where physical tests on these samples can storage of stability samples.
be performed. This area should provide perma¬ Finally, there should be storage for packaging
nent bench-top space for routinely used physical materials. These materials tend to be bulky, but
testing equipment (e.g., balance, pH meter, and since a common requirement of the scale-up
viscometer). function is to evaluate alternate suppliers of
Standard Pilot Plant Equipment Floor packaging materials, it is essential to provide the
Space. The third area is discrete plant space space required to store bottles, closures, tubes,
where equipment needed for manufacturing all vials, ampuls, etc. Here too, it would be prefera¬
types of pharmaceutical dosage forms is located. ble if the material could be segregated into ap¬
The equipment should be available in a variety proved and unapproved categories.
of sizes known to be representative of produc¬
tion capability. This arrangement helps assure
the quality of the scale-up data collected, while Review of the Formula
meeting the concern to be prudent with expen¬ A thorough review of each aspect of the for¬
sive materials. Intermediate-sized and full-scale mulation is important and should be carried out
production equipment is essential in evaluating early in the scale-up process. The purpose of
the effects of scale-up of research formulations each ingredient and its contribution to the final
and processes. Utilization of the area is most ef¬ product manufactured on small-scale laboratory
ficient when it is subdivided into areas for solid equipment should be understood. Then, the ef¬
dosage forms, semisolid products, liquid prepa¬ fects of scale-up using equipment that may sub¬
rations, and sterile products. Further subdivi¬ ject the product to stresses of different types and
sion of the areas should allow multiple opera¬ degrees can be more readily predicted, or recog¬
tions to be conducted simultaneously without nized when they actually occur. The need to
raising GMP concerns. modify the formulation during scale-up is not
Because the utilization of pilot plant equip¬ unusual. This should be done as early as possi¬
ment is sporadic and dependent on project as¬ ble in phase III trials to allow time to generate
signments, equipment should be made portable, meaningful long-term stability in support of a
where possible. The equipment can then be proposed new drug application (NDA). If these
stored in a relatively small area and brought out studies are not completed until after the applica¬
into suitable work areas for use. This system tion is made, long and costly delays in approval
helps relieve some of the congestion often found may result.
in pilot plant operations and provides more
working space around equipment that is in use.
Such a system also provides more space if equip¬ Raw Materials
ment is brought in for evaluation on a loan or One responsibility of the pilot plant function
rental basis. An essential requirement that is is the approval and validation of the active and
frequently neglected but that is important to all excipient raw materials used in pharmaceutical
pilot plant operations is the provision of ade¬ products. This is necessary because the raw

PILOT PLANT SCALE-UP TECHNIQUES • 683

materials used during small-scale formulation again, these can be made in the facilities of the
trials may not be representative of the large- equipment vendor if the equipment is not avail¬
volume shipments of materials used in large- able in-house, providing some indication of the
scale production, or because active ingredients, reliability of the extrapolation from the pilot
which may only have been prepared on a labora¬ plant to iarger production equipment. When the
tory scale, are also being subjected to scale-up to decision involves equipment available from sev¬
meet the rising needs of the product. Even eral vendors (e.g., fluid bed dryers), the next
though all analytic specifications are met, these step is to determine from the various vendors
larger lots of active ingredient may change in the advantages of their particular equipment.
particle size, shape, or morphology, resulting in Ease of cleaning should be considered, espe¬
different handling properties or differences in cially if multiple products are destined to be
bulk density, static charges, rate of solubility, manufactured in the equipment. The time re¬
flow properties, color, etc. The quality of active quired to tear down the equipment to clean and
ingredients needs to be verified because having change from one product to another should be
alternate suppliers is usually desirable. This is determined. In some instances, this can be
an important consideration for companies who longer than the actual time required to manu¬
purchase their active ingredients, because a sin¬ facture a batch, and if frequent changeovers are
gle supplier leaves the company vulnerable with anticipated, this becomes an important consid¬
respect to both supply and acquisition price. The eration. To evaluate these and other parameters
evaluation of alternate suppliers requires that accurately, trials should be run at the vendor’s
several batches of product be manufactured facilities. Such experiences help determine the
with these alternate materials and that their per¬ true capability of the equipment and the quality
formance in the formulation and the stability of of technical support available from the proposed
finished products be evaluated relative to the vendors.
standard product.

Production Rates
The immediate and future market require¬
Relevant Processing Equipment ments must be considered when determining
It is almost certain that most formulation de¬ the production rates and the type and size of pro¬
velopment work has been carried out on small, duction equipment needed. The size of the
relatively simple laboratory equipment. During equipment should be such that it is properly uti¬
subsequent scale-up, alternative manufacturing lized. The equipment and process should be
equipment should be considered. Based on the chosen so as to produce batches at a frequency
known processing characteristics of the product, that takes into consideration product loss in the
the equipment that promises to be the most eco¬ equipment during manufacture, the time re¬
nomical, the simplest, the most efficient, and quired to clean the equipment between batches,
the most capable of consistently producing prod¬ and the number of batches that will need to be
uct within the proposed specifications should be tested for release. To accommodate future
evaluated. For feasibility studies, if a particular growth, increased production capacity may be
technology is not available in-house, small-scale realized more economically through more effi¬
trials can be carried out at the various equip¬ cient utilization of smaller equipment than
ment vendors’ facilities. Then, when a decision through purchase of oversized equipment. For
has been made to use a particular process, the example, several smaller lots produced serially
selected pilot plant equipment needs to be ac¬ (without major clean-up) may be combined in a
quired. The size of this equipment should be final blend to make a single large batch.
such that experimental trials can be run that are
meaningful and relevant to the production-sized
batches that will eventually be made. If the pilot Process Evaluation
plant equipment is too small, the process devel¬ The previous sections have developed the
oped will not scale up well. If the equipment is product scale-up program to the point at which
too large, excessive costs will be incurred, espe¬ the manufacturing process has been proposed
cially if the product involves the use of a large and the equipment for production has been eval¬
quantity of a new and expensive active ingredi¬ uated, selected, installed, and debugged. The
ent. next step is to evaluate the process critically and
When a reasonable process has been devel¬ to optimize its performance based on that evalu¬
oped on the pilot plant equipment, intermediate¬ ation.6-9 Items that should be examined include
sized experimental batches should be run. Once the following:

684 • The Theory and Practice of Industrial Pharmacy

 Order of addition of components, including and in-process or end product specifications.
adjustment of their amounts Therefore, documentation obtained during proc¬
Mixing speed ess validation pan often be used predictively to
shorten the time required to identify the fac¬
Mixing time tors) in a process that has “drifted” from nor¬
Rate of addition of granulating agents, sol¬ mal.
vents, solutions of drugs, slurries, etc.
Heating and cooling rates
Filter sizes (liquids)
Preparation of Master
Screen sizes (solids) Manufacturing Procedures
Drying temperatures The manner in which the manufacturing di¬
rections, the chemical weigh sheet, the sam¬
Drying time pling directions, and the in-process and finished
product specifications are presented is of utmost
Knowledge of the effect of these important importance, as is the degree to which the pro¬
process parameters on in-process and finished cessing technician understands and complies
product quality is the basis for process optimiza¬ with them. The weigh sheet should clearly iden¬
tion and validation.10 The purpose of process tify the chemicals required in a batch. Further,
validation is to confirm that the selected manu¬ the weigh sheet should present these in the
facturing procedure assures the quality of the quantities and the order in which they will be
product at various critical stages in the process U9ed. To prevent confusion and possible errors,
and in the finished form,11 This is accomplished both names and identifying numbers for the in¬
by monitoring the within-batch variation of gredients should be used on batch records, and
measurable parameters, such as content uni¬ these should correspond with those on the bulk
formity, moisture content, and compressibility. raw material containers.
These data indicate where the process is per¬ The processing directions should be precise
forming as intended and where problem areas and explicit. They should be written in a style
may be found. that uses language and terms with which the
Parts of the process such as milling, mixing, operators are familiar. In writing the manufac¬
heating, cooling, drying, sterilizing, compacting, turing procedures, considerable input should
and filling, which cause some measurable come from the actual operators or from someone
change in the state of the material being proc¬ with current knowledge and experience in the
essed, need to be evaluated. Such process data weighing and processing areas. In accord with
should be accumulated for a series of batches GMPs, the batch records need to provide space
using a particular equipment configuration and to show the weighing and addition of each ingre¬
a well-documented process. If the data show dient with appropriate countersignatures for
that the process performs consistently at the each. A manufacturing procedure that becomes
critical steps to produce a product that falls a multipage document and takes the place of
within release specifications, then that process good operator training and a library of standard
has been validated. The process remains vali¬ operating procedures (SOPs) invites problems.
dated only if there are no changes in the for¬ Too detailed or wordy directions are cumber¬
mula, the quality of the ingredients, or the some, and too many sign-offs are as bad as too
equipment configuration.12 Changes in any of few. There are numerous examples in the in¬
these areas would have to be carefully evaluated dustry of problems arising because the operators
and a determination would have to be made as to will not read or follow highly detailed proce¬
the need and extent of revalidation required. dures. Experience has shown that when too
The personnel responsible for the process many signatures are required in a batch record,
should be adequately trained to be capable of they may not be signed off in the intended se¬
understanding the directions and to carry out quence during the manufacturing, but instead
the process as intended. are completed all at one time at the completion
The manufacturing process and quality con¬ of the process. When this occurs, the intention
trol information should be reviewed on an an¬ of verifing that each step was performed cor¬
nual basis, and if deemed necessary, some rectly is lost.
revalidation studies should be carried out to en¬ The batch record directions should include
sure that changes have not occurred.13 A vali¬ specifications for addition rates, mixing times,
dated process establishes a data base of cause- mixing speeds, heating and cooling rates, and
and-effect relationships between critical steps temperature, and appropriate ranges should be

PILOT PLANT SCALE-UP TECHNIQUES ■ 685

 given. The actual times, temperatures, and even these can and are interpreted differently by
speeds used should be documented. These can people in the FDA and in industry. Common
best be monitored and recorded by appropriate sense exercised by people who have a good theo¬
controller recorders, which free the operator to retic knowledge of pharmaceutical principles,
pay attention to the actual process and verify and who are technically competent and have
that all equipment is functioning properly and adequate relevant experience in manufacturing,
that the process is performing in a normal and guarantees compliance to GMP.
acceptable manner. Strip charts from the con¬ A checklist of GMP items that should be part
trollers are used to verify the compliance with of scale-up or new product or process introduc¬
the batch directions. tion includes the following:
The time and manner in which in-process and
finished product samples are to be taken from a Equipment qualification
batch, and the way in which they are handled Process validation
and stored, should be clearly specified within
the batch record. Samples improperly taken or Regularly scheduled preventative mainte¬
handled give rise to unreliable data that can re¬ nance
sult in lost time or can jeopardize the quality or Regular process review and revalidation
acceptability of a batch. When this occurs, batch Relevant written standard operating proce¬
reassay, special stability studies, reprocessing, dures
or extensive investigations are necessary to as¬
sure the quality of the batch before its release. The use of competent, technically qualified
In-process specifications included in the pro¬ personnel
cessing directions should be realistic but slightly Adequate provision for training of personnel
narrower than the finished product specifica¬ A well-defined technology transfer system
tion. If a specification is too broad, it cannot pro¬
vide the alert desired when something goes Validated cleaning procedures
wrong with the process. Too tight a specification An orderly arrangement of equipment so as to
results in the needless rejection of batches of ease material flow and prevent cross-contami¬
acceptable quality. nation
Finished product specifications set the stand¬
ards by which a product is evaluated and help
ensure that each batch manufactured delivers
the drug in the dose specified throughout the Transfer of Analytic Methods to
designated shelf-life of that product. Therefore,
when finished product specifications and re¬ Quality Assurance
lease specifications are set, they should take into During the scale-up of a new product, the ana¬
consideration the capability of the process, the lytic test methods developed in research must be
reliability of the test methods, and the stability transferred to the quality assurance department.
kinetics of the product. Early in the transfer process, the quality assur¬
It is obvious but often forgotten that the qual¬ ance staff should review the process to make
ity of a batch cannot be determined by the analy¬ sure that the proper analytic instrumentation is
sis of the small number of samples usually re¬ available and that personnel are trained to per¬
quired to meet compendial specifications (e.g., form the tests. Recovery studies on the product
content uniformity). These results are only a and on spiked placebo samples should be carried
valid estimate of the quality of a batch when out by different operators over a period of several
process validation studies have been conducted weeks to verify that the tests perform reliably
to establish the statistical integrity of the sam¬ and yield results with precision and accuracy
ple. Periodic revalidation, good manufacturing comparable to that obtained in research. If re¬
procedures, and monitoring of finished product quired, the assay method can be reformatted
test results via control charts are essential to and rewritten using terminology and procedures
maintaining consistent product quality. consistent with current quality assurance labo¬
ratory practice. To complete the transfer, re¬
search personnel should review the assay proce¬
GMP Considerations dure and the data obtained during the validation
The term Good Manufacturing Practices studies, to verify that the analytic methods have
means different things to different people. not been altered in a way that might affect the
There are FDA guidelines describing GMP, but reliability, precision, or accuracy of the tests.

686 • The Theory and Practice of Industrial Pharmacy

Product Considerations the tablet or capsule is small and the drug con¬
centration is relatively low in the blend. Ideally,
the dry blend should take place in the vessel
Solid Dosage Forms in which any subsequent processing such as
In scaling up the manufacture of tablets and granulation occurs. Not every manufacturing
capsules from experimental laboratory batch facility, however, has equipment with sufficient
sizes to intermediate- and large-scale produc¬ capacity to accommodate such a process. Conse¬
tion, each stage of the operation must be care¬ quently, a larger batch may be dry blended and
fully considered. A process using the same type then subdivided into multiple sections for the
of equipment performs quite differendy when granulation operation. Steps should also be
the size of the equipment and the amount of taken to ensure that all the ingredients (excipi¬
material involved is increased significandy. ent and active) are free of lumps and agglomer¬
Even such simple operations as loading a mixer ates prior to the dry blend. Failure to remove or
can become a complicated operation utilizing break up all agglomerates could cause flow prob¬
sophisticated equipment when large volumes lems through the equipment, creating non-
are involved. In some instances, scale-up may reproducible compression and encapsulation
involve a major process change that utilizes processes with a detrimental effect on the con¬
techniques and equipment that were either un¬ tent uniformity of the product. For these rea¬
suitable or unavailable on a laboratory scale. sons, screening and/or milling of the ingredients
The following are the typical unit operations prior to blending usually makes the process
involved in production of solid dosage forms. more reliable and reproducible.

Material Handling
Granulation
In the laboratory, materials are simply
To scale up a granulation process in the most
scooped, dumped, or poured by hand. This may
efficient manner, the purposes for granulating
also work well in some small- or intermediate¬
must be clearly understood. The most common
sized production operations, but in other inter¬
reasons given to justify granulating are (1) to
mediate- or large-scale operations, mechanical
impart good flow properties to the material so
means of handling these materials often become
that the tablet presses and encapsulators can be
necessary. These mechanisms range from sim¬
properly fed and a uniform tablet or capsule
ple post hoists or other mechanical devices for
weight maintained, (2) to increase the apparent
lifting, and tilting drums, to more sophisticated
density of the powders, and (3) to change the
methods of handling materials, such as vacuum
particle size distribution so that the binding
loading systems, screw feed systems, and meter¬
properties on compaction can be improved. A
ing pumps. The type of system selected also de¬
small amount of a potent active ingredient can
pends on the characteristics of the materials,
be dispersed most effectively in a carrier granu¬
e.g., density or static charge.
lation when the drug is dissolved in the granu¬
Any material handling system must deliver
lating solution and incorporated into the batch
the accurate amount of the ingredient to the in¬
during granulation. Use of the granulation proc¬
tended destination. Lengthy transfer lines may
ess to disperse an active ingredient is also com¬
result in material loss, for which there must be
monly cited as a reason to granulate.
accountability and compensation. If the system
Some pieces of equipment are more suitable
is used to transfer materials for more than one
than others for helping to develop the desired
product, steps must be taken to prevent cross¬
characteristics of a finished granulation. Tradi¬
contamination. This can be accomplished by the
tionally, wet granulation has been carried out
use of validated cleaning procedures for the
using sigma blade or heavy-duty planetary mix¬
equipment.
ers (Figs. 23-1 and 23-2). Production equipment
of this type equipped with large motors of 7 to 10
Dry Blending horsepower can process 100 to 200 kg of mate¬
Powders to be used for encapsulation, or to be rial. The weight of the material and the large
granulated prior to tabletting or encapsulation, shear forces generated by these powerful units
must be well blended to ensure good drug distri¬ affect not only the granulating time but also the
bution. Inadequate blending at this stage could amount of granulating fluid required relative to
result in discrete portions of the batch being ei¬ that used in experimental laboratory trials.
ther high or low in potency. This could result in Wet granulations can also be prepared using
drug content uniformity variation, especially if tumble blenders equipped with high-speed

PILOT PLANT SCALE-UP TECHNIQUES • 687

 1

FIG. 23-1. Sigma blade mixer. Inset shows the overlapping blades, which exert a folding and kneading action on the
granulation. The blades effectively move material from the sides of the chamber to the center. (Courtesy of Day Mixing Co.,
Div. of Littleford Bros., Inc.)

chopper blades (Figs. 23-3 and 23-4). High- ing, sizing, and lubrication in a continuous proc¬
shear mixers are often more effective in densify- ess in a single piece of equipment (Fig. 23-7).
ing light powders, but require large amounts of The advantages to using such equipment during
energy and have limited load size. There are scale-up of a product can be significant in terms
pieces of equipment available that combine the of space and manpower requirements. Closed
high-shear mixing action often required for good continuous systems have the added advantage
densification with the advantages of high-speed of less handling of materials, thereby reducing
choppers, which break up agglomerates and the danger of personnel exposure to potent ma¬
ensure uniform distribution of the granulating terials. This is especially important when potent
fluid and more controlled granule size (Figs. and potentially hazardous compounds are in¬
23-5 and 23-6). volved.
More recently, there has been a trend toward Binders are used in tablet formulations to
the use of multifunctional “processors.” These make powders more compressible and to pro¬
are units that are capable of performing all the duce tablets that are more resistant to breakage
functions required to prepare a finished granula¬ during handling. Some of these are added in the
tion, such as dry blending, wet granulation, dry¬ dry state and impart their binding properties

688 • The Theory and Practice of Industrial Pharmacy

FIG. 23-2. Planetary mixer. The beater revolves two to four times for each revolution of the head, providing double mixing
action. Each revolution of the head causes the beater to complete one revolution around the bowl. (Courtesy of Hobart
Corp.)

when exposed to the granulating fluid. Others pated during the formulation stage, the viscosity
are dissolved or dispersed in the granulating of the granulating solution can be adjusted so
fluid. In some instances, the binding agent im¬ that scale-up problems of this type can be
parts considerable viscosity to the granulating avoided. One way of avoiding this problem is to
solution, so that transfer of the fluid by either disperse some or all of the binding agent in the
pumping or pouring becomes difficult. During dry powder prior to granulating. The granulating
the scale-up of such a process, problems could liquid containing any remaining binder can then
be encountered during the addition of the gran¬ be easily pumped and metered into the batch
ulating agent to the powders being processed in during granulation.
enclosed equipment. If the problem is antici¬ Occasionally, nonaqueous solvents or solu-

PILOT PLANT SCALE-UP TECHNIQUES • 689

FIG. 23-3. Twin Shell blender. Material splits and refolds as the blender rotates, producing uniform blends. Various
intensifier bars can be added to handle specific applications. (Courtesy ofPatterson-Kelley, Co., Division ofHarsco Corp.)

tions that are composed of water and water- sistency and may have to be subdivided to a
miscible solvents are used to improve the granu¬ more granular and porous mass to facilitate dry¬
lating properties of a formulation or to disperse ing. This can be accomplished by passing the
poorly soluble drugs. While a reduced amount of wet mass through an oscillating type granulator
energy is required to remove the more volatile with a suitably large screen, (Fig. 23-8), or a
solvent(s) from the granulation, proper ventila¬ hammer mill with either a suitably large screen
tion and additional safety precautions (against or no screen at all (Fig. 23-9).
fire, toxicity, explosion) must be considered in
the selection and design of the equipment and
manufacturing area.14 In addition, solvent re¬ Drying
covery systems may be necessary to comply with The most common conventional method of
Environmental Protection Agency (EPA) or Oc¬ drying a granulation continues to be the circu¬
cupational Safety and Health Administration lating hot air oven, which is heated by either
(OSHA) regulations. steam or electricity, and in which the granula¬
Some granulations, when prepared in produc¬ tion is spread on paper-lined trays on a rack
tion-sized equipment, take on a dough-like con¬ truck, which is then wheeled into the oven

FIG. 23-4. Liquid-dispersion bar increases or “intensifies” speed and thoroughness of liquid-solid blends. (Courtesy of
Patterscm-Kelley, Co., Division of Harsco Corp.)

690 • The Theory and Practice of Industrial Pharmacy

 ' 1

FIG. 23-5. Large triangular-shaped plow blades and smaller high-speed choppers combine to provide intense mixing
action in the Littleford mixer. (Courtesy of Littleford Bros., Inc.)

where evaporative drying occurs. The important advantage is a reduction in drying time. Fluid¬
factors to consider as part of scale-up of an oven ized-bed drying times are usually less than 1
drying operation are airflow, air temperature, hour, compared with 8 hours or more in the con¬
and the depth of the granulation on the trays. If ventional ovens. Many products can also be dry
the granulation bed is too deep or too dense, the blended and granulated in a fluidized-bed
drying process will be inefficient, and if soluble granulator/dryer, further reducing the handling,
dyes are involved, migration of the dye to the and consequently the time, required to process a
surface of the granule may occur. During scale- batch. Scale-up of a fluidized bed drying opera¬
up of this operation, the granulation bed depth tion is more involved than scale-up of a circulat¬
should be carefully controlled and the drying ing hot air oven process.15,16 First, optimum
process monitored by the use of moisture and/or loads must be established. Then, rate of airflow
temperature probes in the granulation, or by fre¬ and inlet air temperature as well as the humidity
quent multipoint sampling of the granulation for of the incoming air must be established, since
moisture content throughout the drying phase. these all affect the drying time. If the air is
Drying times at specified temperatures and air¬ drawn from outside the plant without being con¬
flow rates must be established for each product, ditioned, the large seasonal variations in tem¬
and for each particular oven load. perature and humidity that may exist can alter
Fluidized-bed dryers are an attractive alterna¬ the drying process. Scale-up is further compli¬
tive to the circulating hot air ovens. Their main cated in that it has been shown that data from

PILOT PLANT SCALE-UP TECHNIQUES • 691

FIG. 23-6. High-shear pharmaceutical grade mixer/granulator. Inset shows detail of mixing bawl and blades. (Courtesy of
T.K. Fielder and Raymond Automation Company, Inc.)

small-scale batches (1 to 5 kg) cannot be used to process must be increased in capacity to accom¬
extrapolate processing conditions for interme¬ modate large, high-speed presses with more
diate-scale (100 kg) or larger batches. To obtain elaborate feed systems, it becomes important
a granulation comparable to that obtained on a that the equipment chosen can yield the desired
smaller scale, considerable experimentation and throughput while controlling the particle size
adjustments to the process are required.17 and size distribution of a granulation.
Compression factors that may be affected by
the particle size distribution are flowability,
Reduction of Particle Size compressibility, uniformity of tablet weight, con¬
Particle size, and especially particle size distri¬ tent uniformity, tablet hardness, and tablet color
bution, are important to the compression char¬ uniformity. A granulation with too large a parti¬
acteristics of a granulation. In the laboratory, cle size and insufficient fines is unable to fill the
hand screening or short-duration handling with die cavities uniformly during compression, and
small-scale milling equipment is used to obtain the weight of the tablets fluctuates considerably.
the desired particle size distribution prior to For colored granulations, the coarser the granu¬
compression or encapsulation. When such a lation, the more mottled the final tablet appear-

692 • The Theory and Practice of Industrial Pharmacy

FIG. 23-7. Schematic of a multifunction pharmaceutical processor. The system contains a solids mixing shell, which
includes a liquid dispersion bar. This unit is jacketed to allow heating and cooling. Material can be dried within the unit by
use of the vacuum canister and condenser. (Courtesy of Ortho Pharmaceutical Corporation.)

ance is. If too many fines are present, tablet screen size, and mill type). Compressibility or
weight variation occurs because of flow prob¬ encapsulation efficiency of the milled samples is
lems. Also, the tendency toward capping in¬ used to ascertain the milling conditions and tar¬
creases and is further exaggerated as the speed get mesh pattern for subsequent batches.
of the press is increased. Both oversized and Oscillating granulators of the type shown in
undersized granulations can adversely affect Figure 23-8 have long been used in the industry
tablet content uniformity. Particle size reduction to screen dried granulations. They work well if
of the dried granulation of production-size the oversized portion of the granulation includ¬
batches can be carried out by passing all the ing lumps or agglomerates is not too hard. Un¬
material through an oscillating granulator, a less care is exercised not to overfeed this type of
hammer mill, a mechanical sieving device, or in equipment, an excessive number of fines is pro¬
some cases, a screening device. When a screen¬ duced. Because the rub bars come in contact
ing device is used, the retained oversized portion with the screen, the wearing action may intro¬
must be milled and then returned to the batch. duce a small amount of fine metallic material
Screening-off procedures that mill only the over¬ into the batch. If a screen should break because
sized granulation require a final blending to en¬ of excessive wear, larger particles of potentially
sure uniformity throughout the batch. hazardous metal could be introduced into the
The most suitable piece of milling equipment granulation. The stainless steel screens com¬
to reduce granule particle size can only be cho¬ monly used today can be fabricated using special
sen by first determining the characteristics of ferrous metals, so that if a break should occur,
the unmilled granulation and then selecting that the fragments can be removed by passing the
piece of equipment that will produce the particle granulation through special magnetic devices or
size distribution necessary for the best perform¬ the compressed tablets through a metal check¬
ance during the compression or encapsulation ing device.
stages.14 Therefore, the first step in this process Hammer mills of the type shown in Figure
is to determine the particle size distribution of 23-9 are also frequently used to mill dried granu¬
the granulation using a series of “stacked” lations to a specified size distribution. They have
sieves of decreasing mesh openings. The per¬ a fairly rapid throughput, and the particle size
centage of a preweighed sample, which is re¬ distribution can be controlled by varying the
tained on a screen, gives a distribution profile screen size, the speed of the mill, the type and
that can be compared with milled samples pro¬ number of hammer blades used, and the rate of
duced by several mill conditions (e.g., speed, material feed. Usually, these mills are operated

PILOT PLANT SCALE-UP TECHNIQUES • 693

FIG. 23-8. Oscillating granulator. Oscillating motion of horizontal bars forces granulation through a screen, resulting in
uniform granules that are more easily dried. (Courtesy of Stokes Division-Pennu/alt Corp.)

at a medium to slow speed with the knives for¬ The use of perforated plates instead of wire
ward during sizing to prevent overmilling of the mesh screens also helps to reduce the chance of
granulation. To prevent a variable particle size metal contamination (Fig. 23-10).
distribution, a uniform feed rate must be main¬ Many of' the newer granulation operations
tained. This can best be achieved by a mechani¬ produce material with particle size distributions
cally controlled feed mechanism. Although the already quite close to the desired range. Then,
hammers do not come in contact with the the sizing operation only requires that a small
screen, normal wear or the passage of a hard amount of agglomerates be broken down. For
piece of granulation could cause the screen to this type of operation, the material can either be
break. Therefore, the screens should be care¬ subjected to a screening operation as described
fully examined before and after use to ascertain or be passed through a mechanical sieving oper¬
whether any metal contamination has occurred. ation, using equipment of the type shown in Fig-

694 • The Theory and Practice of Industrial Pharmacy

FIG. 23-9. Hammer mill (comminuting machine). The comminuting action occurs inside the mill head (see inset), where
the high-speed centrifugal force of the blades hurls the granulation through the screen, which is held in place at the
discharge port. (Courtesy of Fitzpatrick Co.)

ure 23-11. The advantage of using this type of cause of the enclosed nature of the equipment,
equipment is that there is no metal-to-metal little dust is created; consequently, material
contact during the screening process, so that the losses are low, and exposure of personnel to dust
possibility of metal contamination is reduced. is minimized.
Since there is also little milling action, the initial As part of the scale-up of a milling or sieving
particle size range is not significantly reduced. operation, the lubricants and glidants, which in
In addition, the throughput is rapid, and be- the laboratory are usually added directly to the
final blend, are usually added to the dried granu¬
lation during the sizing operation. This is done
because some of these additives, especially mag¬
nesium stearate, tend to agglomerate when
added in large quantities to the granulation in a
blender. To assure adequate distribution of these
dry additives, a preliminary dispersion of these
materials is often made during the sizing opera¬
tion. This part of the process must be carefully
optimized so that the lubricants are not over¬
mixed or undermixed during the screening and
subsequent blending operations.18,19

Blending
The type of blending equipment used in pro¬
FIG. 23-10. Perforated plate screens for hammer mills
(comminuting machines). Coarse screens (right) are used duction operations often differs considerably
for wet milling operations and finer screens (left) for dry from that used in the product development labo¬
milling. (Courtesy of Fitzpatrick Co.) ratories, and certainly differs greatly in size

PILOT PLANT SCALE-UP TECHNIQUES • 695

FIG. 23-11. Mechanical Sieving Equipment. A series of stacked screens inside the vibrating body of the classifier sepa¬
rates the granulation. Material is collected and discharged at the take-off spouts. (Courtesy of SWECO, Inc.)

Consequently, attention should be paid to the tent uniformity problems. Particle abrasion is
scale-up of this operation so that equipment of more likely to occur when high-shear mixers
the right design is used and blender loads, mix- with spiral screws or blades are used; however,
ing speeds, and mixing times are properly estab- even tumble blenders used for prolonged mixing
lished.20,21 In any blending operation, both seg- times can result in an excessive particle break-
regation and mixing occur simultaneously. 2 down as the free-falling particles impinge on
Both processes are a function of particle size, each other and on the blender walls,
shape, hardness, and density, and of the dynam- Variations that may occur in the bulk density
ics of the mixing action. Therefore, the charac- of the raw materials must be considered in se-
teristics of the different particles in the blend lecting a blender and in determining optimum
must be known, and the cause of segregation blender load. There is an economic incentive to
understood, so that the blending operation can maximize a batch size, but the maximum batch
be optimized and a uniform blend obtained.23 size to be blended should be conservatively cho-
A thorough understanding of the characteris- sen so as to allow latitude for the normal varia-
tics of the material to be blended helps to make a tion in granulation density. The failure to do so
full-scale production processing operation sue- eventually results in a low-density granulation
cessful and more efficient. A product with frag- that overfills the blender and in a loss of blend-
ile particles or agglomerates is more readily ing efficiency. Excessive granulation volumes
abraided, resulting in an excessive amount of have been documented as being responsible for
fines. These fines may mix improperly and poor content uniformity, poor lubrication of the
cause flow problems, and/or fill weight and con- granulation, and improper color dispersion.

696 • The Theory and Practice of Industrial Pharmacy

Specialized Granulation Procedures than originally directed. Alternatively, the time
may need to be increased if the mixing time is
shown to produce material with borderline uni¬
DRY BLENDING AND DIRECT COMPRESSION
formity. Muting time may also be important to
Since the preferred manufacturing procedure compressibility of the finished blend. Excessive
uses the simplest, least complicated equipment mixing time may fracture fragile excipients and
and requires a minimum amount of handling ruin their compressibility.
and operator time, any modification in a process The use of auxiliary dispersion equipment
that simplifies it is highly desirable. Processes within the mixer. An example is an intensifier
that yield free-flowing granulations without the bar or chopper blade in a twin-shell mixer.
aid of granulating solutions are desirable in that These increase the efficiency of dispersion of
they do not require the time and energy neces¬ solid and liquid ingredients added to the mix¬
sary to volatilize the solvent used in conven¬ ture. They also reduce agglomerates that may be
tional wet granulation procedures. With many of present in a material, thereby aiding the effi¬
the common excipients and even active drugs ciency of dispersion.
now available in a form that makes them directly The mixing action. Mixing action is deter¬
compressible, the possibility of dry blending and mined by the mechanics of the mixer and can
direct compression should be considered.24 only be changed by converting from one blender
Therefore, the simplest answer to granulation to another or by modifying the blender through
problems with some formulations could be to addition of baffles or plates, which would alter
avoid a granulation procedure by using a direct the mixing characteristics.
compression type of formula. The blender load. The amount of material vol¬
When exploring this option, a careful analysis ume to total mixer volume affects the efficiency
of particle characteristics that influence mixing of the blender. Each blender has an optimum
and segregation, such as size, size distribution, working volume and a normal working range.
shape, and static charge should be evaluated.25 Overloading a blender retards the free flow of
Scaling up a dry blending operation for a direcdy the granulation and reduces the efficiency of the
compressible formulation requires that special blender. Localized concentrations of the drug
attention be paid to blender loads, optimum mix¬ remain, causing content uniformity problems in
ing speeds, and the blending time required to the finished dosage form. Conversely, if the load
assure that the drug distribution within a batch is too small, the powders slide rather than roll in
is acceptable and consistent from batch to batch. a blender, and proper mixing does not occur, or
When a wet granulation is prepared, complete the time needed for uniform mixing of the pow¬
distribution of the active ingredients is achieved ders increases.
through a series of operations: dry blending,
granulation, milling, and lubrication, and if any
one step in this operation is inadequate to
SLUGGING (dry GRANULATION)
achieve content uniformity, the other processing
steps often compensate. This is not the case for a A dry powder blend that cannot be directly
single dry blend of a direcdy compressible for¬ compressed because of poor flow or compression
mula. Consequendy, optimization of the process properties may in some instances be processed
and validation of its performance are important. using a slugging operation. This is done on a
The following are aspects of the dry blending tablet press designed for slugging, which oper¬
operation of direcdy compressible materials that ates at pressures of about 15 tons, compared
can be adjusted to optimize the process. with a normal tablet press, which operates at
The order of addition of components to the pressures of 4 tons or less. Usually, extra-large
blender. As an example, a low-dose active ingre¬ tablet punches are used to form compressed
dient may be “sandwiched” between two por¬ slugs of the powdered material. This procedure
tions of direcdy compressible excipient in the is usually slow because the inherently poor com¬
blender to improve dispersion and/or to avoid pressibility of the powders requires slower press
loss to the surface of the blender. speeds to provide the extended compression
The mixing speed. Examples are blade rota¬ dwell time under load needed to hold the com¬
tion speed for a planetary type mixer, and mixer pacted material together. Slugs range in diame¬
tumbling or rotational speed for a twin-shell, ter from 1 inch, for the more easily slugged ma¬
cone-type, or similar type of mixer. terial, to f inch in diameter for materials that are
The mixing time. The mixing time can be de¬ more difficult to compress and require more
creased if available data show the materials to be pressure per unit area to yield satisfactory com¬
consistendy and uniformly mixed in less time pacts. After compression, the slugs are broken

PILOT PLANT SCALE-UP TECHNIQUES • 697

 down using either a hammer mill or an oscillat¬ to 10 tons per linear inch. Because of the simi¬
ing granulator to obtain a granulation with a larity in application, processes developed in the
suitable particle size distribution. If an excessive laboratory using a slugging operation might be
amount of fine powder is generated during the adapted to the roller compaction process involv¬
milling operation, the material must be screened ing a Chilsonator, such as that shown in Figure
and the “fines” recycled through the slugging 23-12. Materials of very low density require
operation. During scale-up of such an operation, roller compaction to achieve a bulk density suffi¬
the pilot plant scientist should pay particular at¬ cient to allow encapsulation or compression.
tention to the forces used for the slugging opera¬ One of the best known examples of this process
tion, the diameter of the punches, and the sub¬ is the densification of aluminum hydroxide.
sequent sizing and screening operations. The Pilot plant personnel should determine whether
optimization of these variables affects the parti¬ the final drug blend or the active ingredient
cle size and particle size distribution. could be more efficiently processed in this man¬
Granulation by dry compaction can also be ner than by conventional processing in order to
achieved by passing powders between two roll¬ produce a granulation with the required tablet¬
ers that compact the material at pressures of up ting or encapsulation properties.

Patents Pending
©The Fitzpatrick Company, Elmhurst, Illinois 1968

FIG. 23-12. Schematic of dry compaction operation. Dry material is fed to and compacted by a Chilsonator, then sized to
remove fines, which are recycled. The finished dry compacted granulation is ready for subsequent encapsulation or
compression. Inset shows actual size of a production unit. (Courtesy of Fitzpatrick Co. © The Fitzpatrick Company,
Elmhurst, IL, 1968.)

698 • The Theory and Practice of Industrial Pharmacy

Granulation Handling and Feed Systems both of which help to facilitate the compaction
The handling of the finished granulation in process. With advances in tablet press technol¬
the compression area can be a simple operation ogy, which provide better control of feeder
such as hand scooping the material from a drum mechanisms, precompression, and compression
into the press hopper, or for larger operations, a forces, many granulation problems or inadequa¬
cies can be overcome by making appropriate ad¬
sophisticated automated handling system using
vacuum or mechanical systems to convey the justments to the press. The handling and com¬
pression characteristics are important factors
granulation. For the latter system, studies
that must be considered in the selection of a tab¬
should be undertaken to determine the effect
let press. Output alone is not reason enough to
that this additional handling has on the content
select a press. Table 23-1 contains a partial list of
uniformity of the drug and on the particle size
presses available and their capabilities and fea¬
distribution. Segregation due to static charges
tures.
built up during vacuum and/or the mechanical
When evaluating the compression character¬
handling of the granulation can lead to problems
istics of a particular formulation, prolonged trial
with material flow through tablet press hoppers
runs at press speeds equal to that to be used in
and feed frames. This in turn makes it difficult
normal production should be tried. Only then
to control tablet weight, thickness, and hard¬
are potential problems such as sticking to the
ness. Poor content uniformity may be the final
punch surfaces, tablet hardness, capping, and
result.
weight variation detected. Such preproduction
More sophisticated material handling systems
trials in the pilot plant are important for identify¬
cause the added concern of cleanability. Long
ing these problems early in the scale-up process,
lengths of transfer tubes, valves, pneumatic
when changes are more easily made than during
pumps, vacuum canisters, cyclone traps, and
later production runs, when marketing require¬
other components of these systems must be en¬
ments may make it difficult to interrupt produc¬
gineered for efficient and total cleaning. Well-
tion schedules to modify the ibrmulation.
written, documented, and validated cleaning
High-speed tablet compression depends on
procedures are essential for such a system.
the ability of the press to interact with granula¬
tion so that a certain series of operations is suc¬
Compression cessfully performed. The granulation must be
delivered to the die feed system at an adequate
The ultimate test of a tablet formulation and
rate. The granulation delivery must not be inter¬
granulation process is whether the granulation
rupted, nor should the flow rate vary. The de¬
can be compressed on a high-speed tablet press.
livery system must not change the particle size
During compression, the tablet press performs
distribution. The system must not cause segre¬
the following functions:
gation of coarse and fine particles, nor should it
induce static charges, which would retard the
1. Filling of empty die cavity with granulation.
flow of the granulation and could cause the ac¬
2. Precompression of granulation (optional). tive ingredient to become segregated.26 The die
feed system must be able to fill the die cavities
3. Compression of granulation.
adequately in the short period of time that the
4. Ejection of the tablet from the die cavity and die is passing under the feed frame. The smaller
take-off of compressed tablet. the tablet, the more difficult it is to get a uniform
fill at high press speeds. The granulation must
The means by which these functions are ac¬ have good flow properties, a good particle size
complished varies, depending on the design of distribution, and a relatively small mean particle
the press. Machine design also determines the size to facilitate rapid but uniform fill of the die
usable range of compression forces at which the cavities. For high-speed machines, induced die
machine can safely operate, and the press speed feed systems are necessary. These are available
at which output can be optimized without nega¬ with a variety of feed paddles and with variable
tive impact on tablet quality. speed capabilities, so that the optimum feed for
Sometimes, because of raw material charac¬ every type of granulation can be obtained.
teristics or formulation constraints, a particular After the die cavities have been filled with
product cannot be successfully compressed at granulation, the excess is removed by the feed
the upper speed range of a press. When this oc¬ frame to the center of the die table. If the feed
curs, the press speed is reduced, or a slower frame has been overfilled and not all of the ex¬
press is used, to allow more time for the dies to cess granulation is moved to the center of the die
fill and to extend the dwell time of compression, table, this excess may be thrown from the table

PILOT PLANT SCALE-UP TECHNIQUES • 899

Table 23-1. Compression Rates of Typical Production Presses

Max. Tablet Number

Diameter of Tablets
Model (in.) Stations per Min

Colton 216 Vi 16 600-800

Colton 233 Vs 33 2500-4000
Colton 241 7/l6 41 3000-5000
Stokes B-2 7/»S 22 450-900
Stokes BB-2 Vs 27 800-1400
Stokes BB-2 Vie 33 1000-1700
Stokes 540 % 35 800-2400
Stokes 541 41 1000-2700
Stokes 551 Vie 51 1200-3700
Stokes 552 TriPact 7/l6 51 3000-5000
Stokes UltraPress 565-1 Vie 65 3500-10,000
Stokes UltraPress 565-2 % 53 2900-8100
Stokes Eagle-3 5/l6 41 2150-6150
Stokes Eagle-2 % 53 2800-8000
Stokes Eagle-1 7/l6 65 3500-10,000
Manesty Betapress % 16 700-1500
Manesty Betapress 13/32 23 100-2000
Manesty ExPress x20 1 20 800-2000
Manesty ExPress x25 % 25 1000-2500
Manesty ExPress x30 7/l6 30 1200-3000
Manesty Rotapress 7/l6 55 1300-5000
Manesty Rotapress Vs 45 1100-4300
Manesty Rotapress Mark III 7/l6 69 3300-10,000
Manesty Unipress 75/l6 20 970-2420
Manesty Unipress Vs 27 1300-3270
Manesty Unipress 7As 34 1640-4120
Fette Perfecta 3000 1S/i6 37 2200-4400
Fette Perfecta 3000 Vs 45 2700-6750
Fette Perfecta 3000 Vi 55 3300-8250
Fette Perfecta 1000 Vs 28 560-2100
Courtoy R100 15/ie 24 288-2300
Courtoy R100 Vs 30 360-2880
Courtoy R100 Vi 36 1260-4400
Kilian LX IS/l6 15 270-1350
Kilian LX Vs 21 400-2260
Kilian TX Vs 30 330-3150
Kilian TX Vi 40 440-4200
Kilian RX 'VlS 41 660-5500
Kilian RX Vs 51 830-7660
Kilian RX Vi 67 1080-10,000
Kikusui Gemini Vs 55 2200-7700
Kikusui Gemini %* 67 2680-9380
Kikusui Hercules 1 Vi 18 450-1080
Kikusui Hercules 15/l6 29 725-1740
Korsch PH230 Vs 17 up to 1850
Korsch PH230 Vi 20 up to 2200
Korsch PH336 Vs 36 up to 3600
Korsch PH343 Vi 43 up to 4300
Korsch PH423 1 Vi 23 368-2300
Korsch PH431 'Vis 31 500-3100
Korsch PH447 Vl6 47 750-4700

700 • The Theory and Practice of Industrial Pharmacy

 by the centrifugal force of the rotating die table. pacted, and in order for a tablet to form, bonds
For this reason, the clearance between the within the compressible material must be
scraper blade and the die table must be carefully formed.28 The forces that give rise to strong co¬
set. Too large a gap results in large granulation hesive bonds within the material also exist at the
losses, especially if the granulation contains a lot tablet interfaces and may result in adhesive
of fines. Too close a setting causes scoring of the bonds between the punch and die surfaces and
die table and metal contamination of the, prod¬ the tablet. Embossing on the punches tends to
uct. accentuate sticking. A good internal lubricant
Compression of the granulation usually oc¬ system is necessary to prevent sticking of the
curs as a single event as the heads of the tablet to the metal surface of the punches or die.
punches pass over the lower and under the If the granulation is adequately and properly
upper pressure rollers. This causes the punches lubricated, the tendency for sticking and bind¬
to penetrate the die to a preset depth, compact¬ ing of the tablet to the punch face can be elimi¬
ing the granulation to the thickness of the gap nated. Magnesium stearate and calcium stearate
set between the punch surfaces. The rapidity' are the most commonly used tablet lubricants.
and dwell time in which this event occurs is de¬ The level at which they should be employed and
termined by the speed at which the press is ro¬ the degree to which they need to be blended
tating and by the size of the compression rollers. with the granulation must be determined exper¬
The larger the compression roller, the more imentally. Too high a level of lubricant or
gradually the compression force is applied and overblending can result in a soft tablet, a de¬
released. The tendency toward capping in a for¬ crease in the wettability of the powder, and an
mulation can often be reduced by slowing down extension of the dissolution time.18,19
the press speed or using presses with larger The design and condition of the punches can
compression rollers. Granulations that are diffi¬ also be the cause for sticking. Embossing on the
cult to compress and that have a tendency to cap punch faces often causes sticking if the em¬
can often be more effectively compressed on a bossed letters, numbers, or symbols are too high,
press with a series of pressure rollers that impart if the angle of the embossing is too steep, or if
a stepwise increase in pressure, thus allowing the comers are too sharp. New punches often
entrapped air to escape gradually rather than as have to be “run in” over a 4- to 8-hour period
-an abrupt event at the end of a single-step com¬ before they can run cleanly. Microscopic nicks
pression. or pits in the punch faces can also cause stick¬
Courtoy has developed a tablet press that ing.
is capable of minimizing capping by a unique Binding at the die walls can sometimes be
compression system whereby pressure is ap¬ overcome by designing the die to be 0.001 to
plied to the punch heads by pressure rollers 0.005 inch wider at the upper portion than at the
that are pneumatically loaded. Instead of the center in order to relieve pressure during ejec¬
pressure profile being the customary sine wave tion.
( ) it becomes more of a square wave
( J-UL )• Thus, the dwell time at the point
of maximum pressure is prolonged considerably. Tablet Coating
Subjecting the tablet to the maximum compres¬ Tablet coating, which at one time consisted of
sion force for an extended time period reduces sugar coating in conventional coating pans, has
the tendency of the tablet to cap and permits undergone many changes because of new devel¬
running a problem granulation at higher than opments in coating technology and changes in
normal press speeds.27 safety and environmental regulations. The con¬
The final event in the compression process is ventional sugar coating pan has given way to
the ejection of the compressed tablet from the perforated pans or fluidized-bed coating col¬
die cavity. This involves the separation of the umns. The development of new polymeric mate¬
upper punch from the upper surface of the tablet rials has resulted in a change from aqueous
and withdrawal from the die cavity. The lower sugar coating to solvent film coating, and more
punch face then moves up through the die cav¬ recently, to aqueous film coating.
ity, breaking the tablet free from the die wall and Film coating is a specialized operation, and
forcing it out of the die cavity. As the die table although film coating systems can be developed
rotates, a take-off bar positioned just above the in a laboratory, the final coating process needs to
table forces the tablet to separate from the lower be defined on production scale equipment.29 A
punch face and sweeps the tablet off the press properly designed core tablet greatly facilitates
table into a collection chute. the success of scale-up. The tablets must be suf¬
During compression, the granulation is com¬ ficiently hard to withstand the tumbling to

PILOT PLANT SCALE-UP TECHNIQUES • 701

which they are subjected in either the coating abrasion can be minimized by controlling the
pan or the coating column. Tablet designs with length and diameter of the center spouting col¬
sharp edges or flat surfaces should be avoided umn and controlling the force of the air fluidiz¬
because they are difficult to coat. Engraved sur¬ ing the tablets.
faces also make coating more difficult. This With the advent of computers and microproc¬
problem can be minimized, however, if the en¬ essors, automated processing systems are avail¬
gravings are kept shallow and the cuts are an¬ able to make tablet coating a more controlled and
gled to avoid sharp edges. Some tablet core ma¬ reproducible process than it was several decades
terials are naturally hydrophobic, and in these ago, when tablet coating was considered an art
cases, film coating with an aqueous system may rather than a science.
require special formulation of the tablet core
and/or the coating solution.
Encapsulation for Hard Gelatin Capsules
A film coating solution may have been found
to work well with a particular core tablet in a The manufacturing process for encapsulated
small laboratory coating pan or column, but may products often parallels that for tablets. Both
be totally unacceptable on a production scale. tablets and capsules are produced from ingredi¬
This difference in performance is due to the in¬ ents that may be either dry blended or wet gran¬
creased pressure and abrasion to which the tab¬ ulated to produce a dry powder or granule mix
lets are subjected when the batch size is large, with a uniformly dispersed active ingredient. To
and to differences in the temperature and hu¬ produce capsules on today’s high-speed equip¬
midity environment to which the individual tab¬ ment, the processed powder blend must have
lets are exposed during the coating and drying the particle size distribution, bulk density, and
cycles. These differences are predictable from compressibility required to promote , good flow
basic engineering equations that describe tem¬ characteristics and to result in the formation of
perature and humidity gradients and transfer compacts of the right size and of sufficient cohe¬
within the coating system. Operating conditions siveness to be filled into capsule shells.
that must be established for either a pan or col¬ Equipment used in capsule filling operations
umn operation are optimum tablet load, operat¬ involves one of two types of filling systems. En-
ing tablet bed temperature, drying airflow rate capsulators manufactured by Zanasi or Martelli
and temperature, and the solution application form slugs in a dosator (a hollow tube with a
rate. The atomizing nozzles for typical pharma¬ plunger to eject the capsule plug), while the op¬
ceutical applications can be high-pressure air¬ erating system of the Hofliger-Karg machines is
less or air-atomizing. For airless sprayers, the based on formation of compacts in a die plate
size and shape of the nozzle aperture is impor¬ using tamping pins to form a compact. With
tant. For air-atomized sprayers, the atomizing both systems, the most common problems en¬
air pressure and the liquid flow rate are critical countered in scale-up involve bulk density, pow¬
factors in establishing proper spraying charac¬ der flow, compressibility, and lubricant distribu¬
teristics. A high airflow yields a fine spray, but it tion. The common problem of weight variation
also creates more turbulence and causes a spray can be caused by the poor flow characteristics of
drying effect. The coating solution can be the granules, which may in turn be due to the
sprayed continuously or intermittently. If it is bulk density and particle size distribution of the
sprayed intermittently, the cycles must be timed granules. Weight variation may also be caused
to prevent the rotation of dry uncoated or par¬ by plugs sticking to the dosator plunger surfaces
tially coated tablets, which would result in abra¬ or die walls because of inadequate lubrication.
sion and edge chipping of the tablets and a poor Overlubrication of the granules may result in
quality coating. weight variation problems because the softer
Not only do chipping and abrasion affect those plugs that axe formed may not be completely
tablets damaged, but the debris formed adheres transferred to the capsule body.
to the other tablets in the batch, thus ruining the Overly lubricated capsule granules are also
whole pan or column load. In addition to in¬ responsible for delaying capsule disintegration
creasing tablet hardness, the use of appropriate and dissolution, which may result in reduced
baffles in the coating pans can further reduce bioavailability. As in tablet operations, prolonged
chipping and abrasion. These baffles prevent trials of many hours using multiple batches are
the tablet bed from sliding instead of rolling, and required before a process can be judged as ac¬
they also redistribute the weight of the tablet ceptable for routine production. The size and
load, and spread the weight more uniformly over type of equipment used in blending, granulat¬
the entire tablet bed. In a column operation, the ing, drying, sizing, and lubrication of capsule

702 • The Theory and Practice of Industrial Pharmacy

granulations or mixtures can greatly influence ingredients. All equipment must be made of
the characteristics of the granulation and the suitable, nonreactive, sanitary materials and be
finished product. designed and constructed to facilitate easy
Because of the differences previously noted, cleaning. Liquid pharmaceutical processing
the type of encapsulating equipment chosen for tanks, ketdes, pipes, mills, filter housing, and so
routine production should dictate the properties forth are most frequently fabricated from stain¬
required of a powder blend. During testing de¬ less steel. Of the two types of stainless steel used
signed to determine the optimum process condi¬ in the industry (type 308 and 316), type 316 is
tions, the need for controlled environmental most often used because of its less reactive na¬
conditions must be considered. Many encapsu¬ ture. Stainless steel is not nonreactive, however,
lation processes are less reliable than antici¬ it does react with some acidic pharmaceutical
pated because the humidity in the processing liquids.31 When this situation is a concern, the
and encapsulation rooms is not adequately con¬ problem can be minimized by prereacting the
trolled. Left as an unknown variable, humidity stainless steel with an acetic acid or nitric acid
often has a significant effect on the moisture solution to remove the surface alkalinity of the
content of the granulation and on the empty gel¬ stainless steel. This procedure, known as passi¬
atin capsules. Granulation moisture content can vation, may need to be repeated at periodic in¬
be important to chemical or physical stability of tervals. For example, if an alkaline cleaning
the finished product, and uncontrolled moisture agent is being used between batches of a reac¬
leads to machine problems of flow and sticking tive product, passivation may need to be re¬
during material transfer and filling. Empty gela¬ peated before the subsequent batch can be pre¬
tin capsules have a recommended storage condi¬ pared.
tion of 15 to 25°C and a relative humidity of be¬ Interaction with metallic surfaces can be min¬
tween 35 and 65%. This condition is designed to imized by use of glass or polytetrafluoroethylene
minimize moisture absorption or loss, and the (Teflon) liners. Although these are highly inert
resultant changes in physical dimensions, dur¬ surface materials, they have the obvious disad¬
ing the encapsulation operation. During encap¬ vantages of cracking, breaking, flaking, and
sulation, the processing room humidity should peeling, with resultant product contamination.
be controlled to within 45 and 55%. At higher
humidities, the capsules may swell because of
the moisture absorbed. This may make separa¬
tion of the capsule parts more difficult and inter¬
Suspensions
fere with the transport of the capsule throughout Suspensions require more attention during
the encapsulation process. Low humidity condi¬ scale-up than do simple solutions because of
tions make the capsules brittle and increase additional processing needs. The addition and
their static charge, thereby seriously interfering dispersion of suspending agents, which on a lab¬
with the encapsulation operation. oratory scale may merely involve sprinkling the
material into the liquid vortex, may require use
of a vibrating feed system or other novel ap¬
Liquid Dosage Forms proach when production scale batches are in¬
In the discussion that follows, liquid pharma¬ volved.32 A powder eductor may facilitate the
ceuticals encountered in the pilot plant are de¬ addition of a material that tends to clump during
fined as nonsterile solutions, suspensions, or the process or that is difficult to disperse. In
emulsions. Scale-up of each of these presents a some instance, suspending agents that are diffi¬
different set of processing concerns that must be cult to disperse can be successfully incorporated
considered. Sterile liquids represent an addi¬ by making a slurry with a portion of the vehicle.
tional, unique class of pharmaceutical products; The suspending agent in a concentrated slurry
these are covered elsewhere within this book. is easier to wet and can be more completely dis¬
Simple solutions are the most straightforward persed using a high-shear mixer in a smaller
to scale up, but then require tanks of adequate volume of the vehicle. Such a slurry facilitates
size and suitable mixing capability.30 Most rapid and complete hydration of the suspending
equipment has heating/cooling capabilities to agent when added to the larger portion of the
effect rapid dissolution of components of the vehicle. The time and temperature required to
system. Adequate transfer systems and filtration hydrate suspending agents is often critical; and
equipment are required, but they must be moni¬ unless the hydration process is complete before
tored to assure that they can clarify the product other ingredients are added, the quality of the
without selectively removing active or adjuvant suspension is adversely affected.

PILOT PLANT SCALE-UP TECHNIQUES • 703

 Active ingredients in a suspension must be lected from the outer edge of the vacuum cham¬
uniformly dispersed throughout the batch. The ber.
best dispersion procedure to use in the produc¬ Unwanted and discolored particulate material
tion process depends on the physical character¬ in a batch can come from the raw materials or be
istics of the active ingredients. If they wet easily, introduced from the bags, cases, and drums in
disperse readily, and tend not to agglomerate, a which the raw materials were supplied. Even
simple addition of the chemicals at a convenient when all precautions are taken, some unwanted
stage in the manufacturing process is appropri¬ material may find its way into the product dur¬
ate. If the active ingredients are difficult to wet ing manufacturing, so that filtration of the fin¬
or tend to agglomerate, however, other methods ished suspension through an appropriate size
for adding these ingredients must be sought. screen is a normal batch processing step. The
One is to prepare a slurry with a wetting agent mesh size chosen must be capable of removing
and with the aid of high-shear mixing equip¬ the unwanted foreign particulates but should
ment. Another method is to pretreat the hard-to- not filter out any of the active ingredients. Such
wet material by blending it in a high-shear pow¬ a sieve can only be selected based on production
der blender with one or some of the liquid in¬ batch size trials. Most active ingredients have
gredients, possibly with a surfactant included. particle sizes less than 10 microns with almost
This converts a bulky material, which is difficult none over 25 microns. Therefore, when dealing
to handle because of static charges, to a dense, with particulates, screens of 150 mesh, having
readily wettable powder, which is much easier to openings of around 100 microns, remove un¬
handle. Such approaches minimize wetting dif¬ wanted suspended materials that are below the
ficulties and eliminate the formation of dry ag¬ easily visible range without retaining the sus¬
glomerates in the finished product. If these ag¬ pended active ingredient(s),
glomerates should occur, the air trapped in this At the completion of the batch, the transfer
dry material may cause the product to “cream” and filling of a finished suspension should be
(separate), thereby causing physical instability carefully monitored. If suspensions are not con¬
or poor content uniformity. stantly mixed or recirculated during transfer
In preparing pharmaceutical suspensions, the processes, they may “settle out” and thereby
type of mixers, pumps, and mills, and the horse¬ adversely affect the uniform distribution of the
power of the motors, should be carefully selected active ingredient.
based on scale-up performance.33 The equip¬
ment must be selected according to the size of
the batch and the maximum viscosity of the
product during the manufacturing process. As Emulsions
an example, the use of an appropriate type of Emulsions are disperse systems similar to
mixer is important because if the mixer is un¬ suspensions except that the dispersed phase is a
dersized, the obvious problems of inadequate finely divided immiscible liquid instead of a
distribution or excessive production time result-. solid. The dispersed phase is usually made up of
Mixing at too high a speed can result in the in¬ oils or waxes that may be in either a liquid or
corporation of an excessive amount of air into solid state. Manufacturing of liquid emulsion
the product. Air that is entrapped in the product products entails specialized procedures, and as a
as very small bubbles is difficult and time- result, scale-up, into production equipment in¬
consuming to remove, and if not removed, can volves extensive process development and vali¬
affect the physical and chemical stability of the dation. Processing parameters and procedures
product and/or the reproducibility of the filling that must be adjusted and controlled for the var¬
operation. If air entrapment is a problem that ious types of emulsions include temperature,
cannot be rectified with process or equipment mixing equipment, homogenizing equipment,
modifications, the air can be removed using a in-process or final product filters, screens,
vacuum unit such as the Versator (Fig. 23-13). pumps and filling equipment. The degree to
During operation of a Versator, product is drawn which the emulsion is refined by the reduction
into a vacuum chamber through an inlet line, of the globule size of the internal phase affects
where it is spread onto the center of a high¬ the physical properties of the emulsion, such as
speed rotating disc. The centrifugal force pro¬ appearance and viscosity, as well as the physical
duced by the rotation of the disc causes the stability of the product. Manufacturing systems
product to form a thin film on the disc surface. that utilize high-shear mixers are more likely to
As the film thins and moves toward the outer lead to air entrapment and may adversely affect
edge of the vacuum chamber, the entrapped air the physical and chemical stability. Conversely,
is drawn off, and the deaerated product is col¬ the use of vessels that can be operated with the

704 • The Theory and Practice of Industrial Pharmacy

FIG. 23-13. The Versator consists of a vacuum chamber and a high-speed revolving disc. During operation, material is
spread into a thin film by the centrifugal force of the disc, and deaeration is achieved under vacuum. If desired, the unit
can be pressurized to create entrainment of gas. (Courtesy of the Cornell Machine Co.)

contents under a controlled vacuum avoids the suspensions or emulsions is not adequate to pro¬
problem of unwanted aeration. The filtration of duce a homogeneous ointment or cream. For
an emulsion to remove particulates originating these products, the mixing equipment must be
from the raw materials or introduced during pro¬ capable of effectively and continuously moving
cessing can affect the quality of the emulsion. the semisolid mass from the outside walls of the
The unwanted particulates are most efficiently mixing kettle to the center and from the bottom
removed by filtering the separate oil and water to the top of the ketde. This action is required
phases before emulsification. both to distribute the ingredients and to bring
about a rapid and efficient heat transfer to and
from the product during the heating and cooling
Semisolid Products steps.
Pastes, gels, ointments, and creams are The power required to carry out the mixing
closely related to suspensions, liquids, and operation varies gready during the manufactur¬
emulsions except that they are products with ing sequence and is direcdy related to changes
higher viscosities. The scale-up of these prod¬ in the viscosity of the product. Motors used to
ucts involves many of the same factors that drive the mixing system of semisolid manufac¬
must be considered in the scale-up of the com¬ turing equipment must be sized to handle the
parable lower viscosity products already dis¬ product at its most viscous stage. Motors that
cussed, but the high viscosity renders certain drive the mixers used to disperse or dissolve
aspects of the scale-up of semisolid products components that have been added early in the
more critical. As an example, the natural turbu¬ manufacturing sequence, when product viscos¬
lence created by the mixers used to make liquid ity is low, may be required to operate at a slower

PILOT PLANT SCALE-UP TECHNIQUES • 705

 speed to prevent splashing of the intermediate the effect of sample conditions such as tempera¬
phases. For this reason, most semisolid equip¬ ture, processing history of the sample, and age.
ment is designed to provide variable speed mix¬ The more of these variables that can be con¬
ing. trolled, the more accurate the interpretation will
Many processing steps such as the mixing of be of the effects of processing conditions on the
oil and water phases during emulsification pro¬ viscosity of the product.34
cessing, component homogenization, addition of The most critical processing steps that need to
active ingredient, and product transfer are usu¬ be carefully evaluated and controlled during the
ally carried out at carefully predetermined tem¬ manufacture of a cream are the emulsification of
peratures. The working temperature range at the two phases and the dispersion of any sus¬
which these operations are carried out are usu¬ pended active ingredients. Pharmaceutical
ally critical to the quality of the final product. In equipment used in the homogenization of the
the formation of a cream, the aqueous phase and emulsion and dispersion of suspended active
oil phase must be heated to a temperature above ingredients includes various types of high-shear
the solidification point of the oil phase, and then mixers, homogenizers, and colloid mills, sup¬
emulsified. Failure to have both phases at the plied by a number of different manufacturers.
correct temperature results in a poor-quality One of the most common pieces of equipment
product with improperly dispersed wax. Conse¬ used for these purposes is a colloid mill consist¬
quently, an accurate understanding of the heat ing of a fixed stator plate and a high-speed rotat¬
transfer characteristics of the system and the ing rotor plate. Material drawn or pumped
temperature gradient throughout the batch is through an adjustable gap set between the rotor
important. and stator is milled or homogenized by the phys¬
Reliance on the temperature recorded by a ical action, and centrifugal force is created by
single sensor at a fixed point in the mixing ves¬ the high-speed rotation of the rotor, which oper¬
sel is often misleading. Unacceptably wide ates within 0.005 to 0.010 inch of the stator (Fig.
ranges in product viscosity are frequently the 23-14). Sonic homogenization equipment ac¬
result of inadequate temperature control during complishes emulsification by imparting suffi¬
the critical emulsification steps. Improper tem¬ cient energy to the material through rapidly vi¬
perature control can have an adverse effect on brating vanes that break up a liquid stream into
the particle size of poorly soluble active ingredi¬ small, discrete droplets.
ents. If these are added at too high a tempera¬ Transfer pumps for semisofid products must
ture, the solubility may be artificially increased, be able to move viscous material without apply¬
creating a metastable product. On subsequent ing excessive shear and without incorporating
cooling, crystal growth or recrystallization may air. Pumps designed to meet these criteria are
occur from the saturated solution. This recrys¬ known as positive displacement pumps (Fig.
tallized material may be a different polymorphic 23-15). They are available from many sources
form or a different crystal type or size. The result with subtle differences in design, but they all
may be a change of particle size distribution, operate using a rotating member inside of a
yielding a gritty, less elegant product, or one close fitting stationary housing. They are self¬
with altered stability or biologic activity. priming and can create adequate head pressure
Many cream formulations and some gel prod¬ to force product through long transfer lines and
ucts are shear-sensitive. Handling such prod¬ filtration equipment. In choosing the size and
ucts during transfer from the manufacturing type of pump for a particular operation, product
kettle to holding tanks or to the filling fines re¬ viscosity, desired pumping rate, product com¬
quires that attention be given to the amount of patibility with the pump surfaces, and the
shear that such products will encounter. pumping pressure required should be consid¬
Changes in measured viscosity are frequently ered.
seen when viscous products are pumped
through long transfer fines or are filtered to re¬
move unwanted particulates. Because of this,
the relationship between shear stress and the Suppositories
measured viscosity values of the product must The manufacture of suppositories on a labora¬
be understood. When carrying out such evalua¬ tory scale usually involves the preparation of a
tions, the pilot plant scientist needs to remem¬ molten mass, the dispersion of drug in the mol¬
ber that most viscometers determine relative ten base, and the casting of the suppositories in
viscosity rather than an absolute viscosity. a suitable mold. When the mold has been ade¬
Therefore, the accurate evaluation of the effect quately cooled, it is opened, and the supposito¬
of a process change on viscosity must recognize ries are removed. Such an operation provides fit-

706 • The Theory and Practice of Industrial Pharmacy

FIG. 23-14. Operational flow pattern of rotor-stator homogenizer. Product flows by gravity or may be pumped through
inlet connection (A) coming in contact with rotor (B) and is forced through first-stage processing gap (C) by high-shear
impellers on front face of rotor (B). These impellers, in addition to providing intense shearing action, furnish a pumping
force to move product across the periphery of the rotor (B). After traversing the periphery of the rotor (B), the product flaw
direction is reversed so that it is countercurrent to centrifugal force. The product then flows inward across the second-stage
area between rotor (B) and stator (D) and is discharged through outlet opening (E). (Courtesy of APV Gaulin, Inc.)

tie experience that is relevant to new processes tunnel, and removed from the mold, and (3) the
used in large-scale production of a suppository product is packaged in an off-line wrapping or
product. However, many commercial supposito¬ blistering operation. A detailed discussion of this
ries are still produced by a fusion method in operation and processing equipment can be
which (1) a molten mass is prepared, (2) the found in Chapter 19, “Suppositories.”
suppository is molded, cooled in a refrigeration The manufacturing and packaging processes

FIG. 23-15. Schematic representation of a positive displacement pump. The helical rotor moves inside the double helical
stationary housing, creating a progressing cavity, which moves the material. (MOYNO Quick Displacement Progressing
Cavity Pump, courtesy of Fluids Handling Division of Robbins & Myers, Inc.)

PILOT PLANT SCALE-UP TECHNIQUES • 707

for suppositories have recently been simplified The precise temperature control required af¬
to a one-stage operation. This new technology fects the design and type of mixing system used
eliminates many of the troublesome molding, in the melting and holding tank. The vessel in
cooling, and unmolding steps of the older tech¬ which the mass is prepared may require high-
nology. The basic improvement of the newer shear mixing capability to break up agglomer¬
processing equipment is that the molten suppos¬ ates of the active ingredient and to disperse the
itory mass is filled into formed PVC or foil shells, active ingredient effectively throughout the mol¬
which serve both as the mold and finished pack¬ ten base. The equipment should also be capable
age. Such a process eliminates many of the prob¬ of providing gentle stirring action that will effec¬
lems encountered during the removal of the tively keep the active ingredients well dispersed.
suppository from the two-piece molds in which Transfer of the molten mass to the filling
they were formed on the older equipment. The heads, of the suppository machine must be done
extra work and equipment required to complete through heated lines. When a separate holding
the off-line packaging operation of wrapping or tank is used, this must be jacketed and should
blistering are also eliminated. be part of a recirculating loop designed to pre¬
The manufacture of suppositories using mod¬ vent settling of the active ingredient and con¬
em equipment can be divided into several oper¬ gealing of the mass.
ations involving first the manufacture of the Any extraneous particulate material that may
molten suppository mass and then the molding be present in the molten mass can be removed
and packaging of the suppository. using an in-line filter of an appropriate mesh
size. Most active ingredients in suppositories are
less than 10 microns in size, so 100-mesh filters
Preparation of the Molten Suppository Mass with openings of approximately 70 microns pro¬
The preparation of the suppository mass on a vide filtration without retention of the active
production scale involves heating various wax¬ ingredients. The filter’s ability to remove extra¬
like components of the suppository base to a neous material but not hold back any of the drug
temperature at which they become molten. The should be validated by a series of carefully moni¬
higher melting components should be placed in tored pilot plant trials. Extensive sampling and
the manufacturing kettle first and the lower analysis of suppositories over an extended time
melting ingredients added when the first com¬ period designed to mimic production conditions
ponents are almost completely in the molten of filtration, holding, recirculation, and filling
state. To avoid overheating the waxes and alter¬ are required to show that the active ingredient is
ing their melting points, this operation should not retained. In addition, extensive visual in¬
be carried out in jacketed vessels in which the spection of filtered suppository mass is required
jacket temperature can be controlled. The best to show that the filter is efficient in removing
systems allow monitoring of both the tempera¬ unwanted material.
ture of the vessel jacket and the molten contents
of the vessel. Systems in which only live steam
or cold water are available to regulate the tem¬ Molding and Packaging
perature of the molten suppository mass are Current suppository manufacturing technol¬
almost impossible to control within the fairly ogy utilizes equipment that forms, fills, and
narrow temperature ranges required to produce seals the suppositories in a continuous process.
a continuous source of well-controlled heating The mold for the suppositories is formed from
and cooling water. The normal operating range special thermoplastics sheets of PVC, polyethyl¬
is 35 to 65°C, with temperatures of 45 to 65°C ene, and aluminum foil laminates. A variety of
used for melting and mixing of the suppository problems can occur during the forming of the
base material and temperatures of 35 to 45“C shells. These can be minimized by careful atten¬
used during addition of active ingredients and tion to the temperature and dwell times used
during molding (filling). Since the viscosity of during the formation of the molded cavities. In¬
suppository masses is normally temperature- appropriate temperatures or dwell times that are
dependent, the filling operation should be con¬ either too short or too long produce inadequate
ducted at a temperature just above the solidifica¬ mold shells that may leak because of improper
tion point. Settling of suspended material during seals. The temperature of the mass during filling
cooling is prevented through both the increased is also important. If the molten mass is filled at a
viscosity and the reduced time required to solid¬ temperature more than a few degrees above the
ify the mass. Because this is the most critical congealing point, a hole forms in the center of
step, the working range of temperature is often the suppository upon cooling, owing to excessive
no larger than ±3°C around the set point. contraction. Filling at too low a temperature

708 • The Theory and Practice of Industrial Pharmacy

causes clogging of the transfer lines and filling spatial separation, cleanliness, design, cleana-
nozzles and results in erratic fill weights. There¬ bility; dust, temperature, and humidity con¬
fore, the temperature of the molten mass in the trol)
hopper and lines must be carefully controlled, Adequacy of storage space for in-process,
and the mass constantly stirred or recirculated, quarantine, and approved bulk finished goods
to maintain the mass within a narrow tempera¬ storage.
ture range.
After filling, the shells pass through a cooling Controls for preventing product mixup and
tower where the suppositories are allowed to so¬ cross-contamination.
lidify before the ends of the PVC or aluminum Label storage, approval, dispensing, and ac¬
shell are sealed. Then the strips of suppositories countability procedures and controls.
are trimmed and cut into the specified length. Packaging equipment utilization, mainte¬
The temperature in the cooling tower deter¬ nance, cleaning, and use controls.
mines the cooling rate of the suppositories. If
the temperature is too low and the cooling rate Packaging component control procedures.
too fast, the suppositories can become britde. Structure and function of the quality control
Sufficient scale-up trials should be run to opti¬ unit, including personnel, training, SOPs, and
mize the process so that the temperature of the responsibilities.
product throughout the process is maintained at Warehouse space, separation of products, con¬
the level required for the particular formulation. trol procedures, and environmental controls.
Record control policies.
Contract Manufacture
After all of these checklist items have been
On occasion, scale-up or manufacture of a discussed to everyone’s mutual satisfaction, the
product may need to be done at an outside con¬ visiting team can complete discussions of divi¬
tract manufacturer. The reasons for considering sion of responsibilities between the originating
contract manufacture include the needs for ad¬ company and the contract vendor. These discus¬
ditional manufacturing capacity, highly special¬ sions should be finalized in a comprehensive
ized technology, or specialized equipment. document that outlines all areas of responsibility
When choosing a contractor, consideration and that can serve as the basis for followup in¬
should be given to the experience, capability, vestigations by the pilot plant scientist and/or
and reputation of the contractor within the in¬ the quality control department.
dustry. 5 In addition, the technical competence Technical fact-finding missions of this type
of the contractor’s personnel and compliance to can underscore the unique characteristics of the
good manufacturing practices are important fac¬ pilot plant scientist, whose scientific expertise,
tors in the choice of a vendor. Before pilot-size knowledge of production equipment and proc¬
batches or larger are prepared at an outside facil¬ esses, awareness of GMPs and SOPs, and ability
ity, a team of personnel who are knowledgeable to critically evaluate facilities, personnel, and
and experienced in production, QA, QC, and procedures are key components to the direction
GMP should visit the potential contract manu¬ of subsequent negotiations.
facturer. The site visit should include an in-
depth assessment of facilities, equipment, per¬
sonnel, and policy. The following checklist of
items to be reviewed originates from the Good
References
Manufacturing Practices regulations as set forth 1. Rhodes, C.T.: Pharm. Tech., 5:30, 1981.
2. Cooper, J.: Drug Dev. Commun., 1:1, 1974-1975.
in the Code of Federal Regulations (21
3. Nash, R.A.: Chemtech, 6:240, 1976.
CFR211): 4. Wray, P.E.: Management Science Conference for the
Pharmaceutical Industry, Purdue University, Lafay¬
Review of procedures, facilities, and person¬ ette, IN, September 1974.
nel (training and documentation) involved in 5. Lloyd, K.A.: Chem. Ind., 3:108, 1977.
acquisition, storage, testing, and handling of 6. Estes, G.K., and Luttrell, G.H.: Pharm. Tech., 7:74,
raw materials (excipients and actives). 1983.
7. Loftus, B.T.: Pharm. Ind., 42:1202, 1980.
Equipment availability, utilization, and main¬ 8. Ridgway, K.: Pharm. J., 205:265, 1970.
tenance; documentation of equipment opera¬ 9. Harder, S.W.: Pharm. Tech. 8:29, 1984.
tor training, equipment cleaning procedures, 10. Jeffries, J.: Interphex 82, Conference Papers, Brigh¬
ton, England, May 1982.
and equipment calibration.
11. Melliger, G.W.: Pharm. Ind., 42:1199, 1980.
Adequacy of manufacturing facilities (size, 12. Berry, I.R.: Pharm. Tech., 5:38, 1981.

PILOT PLANT SCALE-UP TECHNIQUES *709

13. Feature article. Drug Cosmet. Ind., 127:44, 1980. 24. Gioia, A.: Pharm. Tech., 4:65, 1980.
14. Fowler, H.W.: Manuf. Chem., Aerosol News, 40:29, 25. Greco, G.T.: Drug Dev. Indus. Pharm., 8:565, 1982.
1969. 26. Gold, G., and Palermo, B.T.: J. Pharm. Sci., 54:310,
15. Campy, D., et al.: J. Pharm. Pharmacol., 26.-76P, 1965.
1974. 27. Ritter, A., and Sucker, H.B.: Pharm. Tech., 4:59,
16. Ceschel, G.C., et al.: Farmaco Ed. Prat., 36:281, 1980.
1981. 28. Jetzer, W., et al.: Pharm. Tech., 7:33, 1983.
17. Leuenberger, H.: Acta Pharm. Technol., 29:274, 29. Stetsko, G., et al.: Pharm. Tech., 7:50, 1983.
1983. 30. Carstensen, J.T., and Mehta, A.: Pharm. Tech., 6:64,
18. Shab, A.C., and Mlodozeniec, A.R.: J. Pharm. Sci., 1982.
66:1377, 1977. 31. List, P.H.: Dtsch. Apoth. Ztg., 117:451, 1977.
19. Proost, J.H., et al.: Int. J. Pharm., 13:287, 1983. 32. Hansford, D.T., et al.: Powder Technol., 26:119,
20. Rees, J.E.: Manuf. Chem. Aerosol News, 46:23,1975. 1980.
21. Staniforth, J.N., et al.: J. Pharm. Pharmacol., 33:175, 33. Garrison, C.M.: Chem Eng., 90:63, 1983.
1980. 34. Fujiyama, Y., et al.: J. Soc. Cosmet. Chem., 21:625,
22. Llovd, P.J., et al.: J. Soc. Cosmet. Chem., 21:205, 1970.
1970. 35. Wasserman, M.D.: Drug Cosmet. Ind., 119:43, 1976.
23. Egermann, H.: Int. J. Pharm., Tech. Prod. Mff., 3:59,
1982.

710 • The Theory and Practice of Industrial Pharmacy

 24
Packaging Materials Science
CARLO P. CROCE, ARTHUR FISCHER, and RALPH H. THOMAS

In the pharmaceutical industry, it is vital that packaging material are its fragility and its
the package selected adequately preserve the weight.
integrity of the product. The selection of a pack- Composition of Glass. Glass is composed
age therefore begins with a determination of the principally of sand, soda-ash, limestone, and
product’s physical and chemical characteristics, cullet. The sand is almost pure silica, the soda-
its protective needs, and its marketing require- ash is sodium carbonate, and the limestone, cal-
ments. The materials selected must have the fol- cium carbonate. Cullet is broken glass that is
lowing characteristics: (1) they must protect the mixed with the batch and acts as a fusion agent
preparation from environmental conditions, for the entire mixture. The composition of glass
(2) they must not be reactive with the product, varies and is usually adjusted for specific pur-
(3) they must not impart to the product tastes or poses. The most common cations found in phar-
odors, (4) they must be nontoxic, (5) they must maceutical glassware are silicon, aluminum,
be FDA approved, (6) they must meet applicable boron, sodium, potassium, calcium, magne-
tamper-resistance requirements, and (7) they sium, zinc, and barium. The only anion of con-
must be adaptable to commonly employed high- sequence is oxygen. Many useful properties of
speed packaging equipment. glass are affected by the kind of elements it con-
Owing to the broad scope of the subject, a de- tains. Reduction in the proportion of sodium
tailed treatment of the science of packaging as ions makes glass chemically resistant; however,
related to pharmaceuticals cannot be adequately without sodium or other alkalies, glass is diffi-
covered in this chapter. To give the reader a gen- cult and expensive to melt. Boron oxide is incor-
eral understanding of this subject, however, porated mainly to aid in the melting process
basic topics have been selected for discussion. through reduction of the temperature required.2
These are limited to the protective function of Lead in small traces gives clarity and brilliance,
commonly used packaging materials, their limi- but produces a relatively soft grade of glass. Alu-
tations, and their possible interaction with vari- mina (aluminum oxide), however, is often used
ous drugs. to increase the hardness and durability and to
increase resistance to chemical action.

Glass Containers
Glass is commonly used in pharmaceutical Manufacture of Glass
packaging because it possesses superior protec- Four basic processes are used in the produc¬
tive qualities, it is economical, and containers tion of glass: blowing, drawing, pressing, and
are readily available in a variety of sizes and casting." Blowing uses compressed air to form
shapes. It is essentially chemically inert, imper- the molten glass in the cavity of a metal mold,
meable, strong, and rigid, and has FDA clear- Most commercial bottles and jars are produced
ance. Glass does not deteriorate with age, and on automatic equipment by this method. In
with a proper closure system, it provides an ex- drawing, molten glass is pulled through dies or
cellent barrier against practically every element rollers that shape the soft glass. Rods, tubes,
except light. Colored glass, especially amber, sheet glass, and other items of uniform diameter
can give protection against light when it is re- are usually produced commercially by drawing,
quired. The major disadvantages of glass as a Ampuls, cartridges, and vials draacn from tubing

711
have a thinner, more uniform wall thickness, cially in a damp atmosphere or with extreme
with less distortion than blow-molded con¬ temperature variations, the wetting of the sur¬
tainers. In pressing, mechanical force is used to face by condensed moisture (condensation) re¬
press the molten glass against the side of a mold. sults in salts being dissolved out of the glass.
Casting uses gravity or centrifugal force to cause This is called “blooming” or “weathering,” and
molten glass to form in the cavity of the mold. in its early stages, it gives the appearance of fine
Colored Glass—Light Protection. Glass crystals on the glass. At this stage, these salts
containers for drugs are generally available in can be washed off with water or acid. Type II
clear flint or amber color. For decorative pur¬ containers are made of commercial soda-lime
poses, special colors such as blue, emerald glass that has been de-alkalized, or treated to
green, and opal may be obtained from the glass remove surface alkali. The de-alkalizing process
manufacturer. Only amber glass and red glass is known as “sulfur treatment” and virtually pre¬
are effective in protecting the contents of a bot¬ vents “weathering” of empty bottles. The treat¬
tle from the effects of sunlight by screening out ment offered by several glass manufacturers
harmful ultraviolet rays. The USP specifications exposes the glass to an atmosphere containing
for light-resistant containers require the glass to water vapor and acidic gases, particularly sulfur
provide protection against 2900 to 4500 ang¬ dioxide at an elevated temperature. This results
stroms of light.4 Amber glass meets these speci¬ in a reaction between the gases and some of the
fications, but the iron oxide added to produce surface alkali, rendering the surface fairly resis¬
this color could leach into the product. There¬ tant, for a period of time, to attack by water. The
fore, if the product contains ingredients subject alkali removed from the glass appears on the
to iron-catalyzed chemical reactions, amber surface as a sulfate bloom, which is removed
glass should not be used. when the containers are washed before filling.
Glass for Drugs. The USP and NF describe Sulfur treatment neutralizes the alkaline oxides
the various types of glass and provide the pow¬ on the surface, thereby rendering the glass more
dered glass and water attack tests for evaluating chemically resistant.
the chemical resistance of glass. The test results Type III—Regular Soda-Lime Glass. Con¬
are measures of the amount of alkalinity leached tainers are untreated and made of commercial
from the glass by purified water under controlled soda-lime glass of average or better-than-aver-
elevated temperature conditions. The powdered age chemical resistance.
glass test is performed on crushed grains of a Type NP—General-Purpose Soda-Lime
specific size, and the water attack test is con¬ Glass. Containers made of soda-lime glass are
ducted on whole containers. The water attack supplied for nonparenteral products, those in¬
test is used only with type II glass that has been tended for oral or topical use.
exposed to sulfur dioxide fumes under con¬
trolled conditions.
Type I—Borosilicate Glass. In this highly Plastic Containers
resistant glass, a substantial part of the alkali Plastics in packaging have proved useful for a
and earth cations are replaced by boron and/or number of reasons, including the ease with
aluminum and zinc.5 It is more chemically inert which they can be formed, their high quality,
than the soda-lime glass, which contains either and the freedom of design to which they lend
none or an insignificant amount of these ca¬ themselves. Plastic containers are extremely
tions. Although glass is considered to be a virtu¬ resistant to breakage and thus offer safety to
ally inert material and is used to contain strong consumers along with reduction of breakage
acids and alkalies as well as all types of solvents, losses at all levels of distribution and use.
it has a definite and measurable chemical reac¬ Plastic containers for pharmaceutical prod¬
tion with some substances, notably water. The ucts are primarily made from the following poly¬
sodium is loosely combined with the silicon and mers: polyethylene, polypropylene, polyvinyl
is leached from the surface of the glass by water. chloride, polystyrene, and to a lesser extent, pol¬
Distilled water stored for one year in flint type ymethyl methacrylate, polyethylene terephthal-
III glass (to be described) picks up 10 to 15 parts ate, polytrifluoroethylene, the amino for¬
per million (ppm) of sodium hydroxide along maldehydes, and polyamides.6
with traces of other ingredients of the glass. The Plastic containers consist of one or more poly¬
addition of approximately 6% boron to form type mers together with certain additives. Those
I borosilicate glass reduces the leaching action, manufactured for pharmaceutical purposes
so that only 0.5 ppm is dissolved in a year. must be free of substances that can be extracted
Type II—Treated Soda-Lime Glass. When in significant quantities by the product con¬
glassware is stored for several months, espe¬ tained therein. Thus, the hazards of toxicity or

712 • The Theory and Practice of Industrial Pharmacy

physical and chemical instability are avoided. mize airborne dust accumulation at the surface
The amount and nature of the additives are de¬ bottle during handling, filling, and storage.
termined by the nature of the polymer, the proc¬ These antistatic additives are usually polyethyl¬
ess used to convert the plastic into the con¬ ene glycols or long chain fatty amides and are
tainers, and the service expected from the often used at 0.1 to 0.2% concentration in high-
container. For plastic containers in general, ad¬ density polyethylene.
ditives may consist of antioxidants, antistatic Polypropylene. Polypropylene has recently
agents, colors, impact modifiers, lubricants, become popular because it has many of the good
plasticizers, and stabilizers. Mold release agents features of polyethylene, with one major disad¬
are not usually used unless they are required for vantage either eliminated or minimized. Poly¬
a specific purpose. propylene does not stress-crack under any con¬
ditions. Except for hot aromatic or halogenated
solvents, which soften it, this polymer has good
resistance to almost all types of chemicals, in¬
Materials cluding strong acids, alkalies, and most organic
At present, a great number of plastic resins materials. Its high melting point makes it suita¬
are available for the packaging of drug products. ble for boilable packages and for sterilizable
A general description of the more popular ones products. Lack of clarity is still a drawback, but
are presented here.1,3,7-9 improvement is possible with the construction
Polyethylene. High-density polyethylene is of thinner walls.
the material most widely used for containers by Polypropylene is an excellent gas and vapor
the pharmaceutical industry and will probably barrier. Its resistance to permeation is equiva¬
continue to be for the next several years.10,11 It lent to or slightly better than that of high-density
is a good barrier against moisture, but a rela¬ or linear polyethylene, and it is superior to low-
tively poor one against oxygen and other gases. density or branched polyethylene. One of the
Most solvents do not attack polyethylene, and it biggest disadvantages of polypropylene is its
is unaffected by strong acids and alkalies. britdeness at low temperatures. In its purest
Lack of clarity and a relatively high rate of per¬ form, it is quite fragile at 0°F and must be
meation of essential odors, flavors, and oxygen blended with polyethylene or other material to
militate against the use of polyethylene as a con¬ give it the impact resistance required for pack¬
tainer material for certain pharmaceutical prep¬ aging.
arations. Despite these problems, polyethylene Polyvinyl Chloride (PVC). Clear rigid poly¬
in all its variations offers the best all-around pro¬ vinyl chloride bottles overcome some of the defi¬
tection to the greatest number of products at the ciencies of polyethylene. They can be produced
lowest cost. with crystal clarity, provide a fairly good oxygen
The density of polyethylene, which ranges barrier, and have greater stiffness. In its natural
from 0.91 to 0.96, directly determines the four state, polyvinyl chloride is crystal clear and stiff,
basic physical characteristics of the blow- but has poor impact resistance. It can be soft¬
molded container: (1) stiffness, (2) moisture- ened with plasticizers. Various stabilizers, anti¬
vapor transmission, (3) stress cracking, and oxidants, lubricants, or colorants may be incor¬
(4) clarity or translucency. As the density in¬ porated. Polyvinyl chloride is seldom used in its
creases, the material becomes stiffer, has a purest form. It is an inexpensive, tough, clear
higher distortion and melting temperature, be¬ material that is relatively easily processed. It
comes less permeable to gases and vapors, and must not be overheated because it starts to de¬
becomes less resistant to stress cracking. The grade at 280°F, and the degradation products are
molecular structure of high-density material is extremely corrosive. Polyvinyl chloride yellows
essentially the same as that of low-density mate¬ when exposed to heat or ultraviolet light, unless
rial, the main difference being fewer side a stabilizer is included by the resin supplier. It is
branches. virtually impossible to process vinyls at elevated
Since these polymers are generally suscepti¬ temperatures without a stabilizing agent. From
ble to oxidative degradation during processing the standpoint of clarity, the best stabilizers are
and subsequent exposure, the addition of some the tin compounds, but the majority cannot be
antioxidant is necessary. Usually levels of hun¬ used for food or drug products. Dioctyl-tin mer-
dreds of parts per million are used. Antioxidants captoacetate and maleate compounds have been
generally used are butylated hydroxy toluene or approved by the FDA, but these have a slight
dilauryl thiodipropionate. odor, which is noticeable in freshly blown bot¬
Antistatic additives are often used in bottle tles. Other acceptable stabilizers (sulfur, cal¬
grade polyethylenes. Their purpose is to mini¬ cium, and zinc salts) have a yellowish cast,

PACKAGING MATERIALS SCIENCE *713

which makes the plastic hazy and undesirable. practical toughness), general-purpose polysty¬
In the formulation of PVC compounds with cal¬ rene may be combined with various concentra¬
cium-zinc stabilization materials, all ingredients tions of rubber and acrylic compounds. Certain
are used in concentrations below their maxi¬ desired properties diminish with impact polysty¬
mum extractable concentrations. rene, e.g., clarity and hardness. The shock re¬
Polyvinyl chloride is an excellent barrier for sistance or toughness of impact polystyrene may
oil, both volatile and fixed alcohols, and petro¬ be varied by increasing the content of rubber in
leum solvents. It retains odor and flavors quite the material, and often these materials are fur¬
well and is a good barrier for oxygen. Rigid poly¬ ther classified as intermediate-impact, high-
vinyl chloride is a fairly good barrier for moisture impact, and super-impact polystyrene.
and gases in general, but plasticizers reduce Nylon (Polyamide). Nylon is made from a
these properties. Polyvinyl chloride is not af¬ dibasic acid combined with a diamine. Since
fected by acids or alkalies except for some oxi¬ there are many dibasic acids and many different
dizing acids. Its impact resistance is poor, espe¬ amines, there is a great variety of nylons. The
cially at low temperatures. type of acid and amine that is used is indicated
Much of the concern about the safety of plas¬ by an identifying number; thus, nylon 6/10 has
tic products has focused on polyvinyl chloride six carbon atoms in the diamine and ten in the
plastics and on compounds that are derived from acid. Nylon and similar polyamide materials can
vinyl chloride monomer. Its possible incrimina¬ be fabricated into thin-wall containers. Nylon
tion in the development of cancer of the liver can be autoclaved and is extremely strong and
(angiosarcoma) in some persons exposed to quite difficult to destroy by mechanical means.
vinyl chloride monomer and polyvinyl chloride Important to the widespread acceptance of nylon
during manufacture has received widespread is its resistance to a wide range of organic and
interest. Thus far, it seems that the only suspect inorganic chemicals. As a barrier material, nylon
is vinyl chloride, and the disease is not associ¬ is highly impermeable to oxygen. It is not a good
ated with polyvinyl chloride itself. Major reduc¬ barrier to water vapor, but when this character¬
tions in the amount of residual vinyl chloride istic is required, nylon film can be laminated to
monomer have been achieved by PVC produc¬ polyethylene or to various other materials.
ers; the use of PVC for the fabrication of plastic Its relative high-water transmission rate and
bottles now represents the fastest growing appli¬ the possibility of drug-plastic interaction have
cation use of PVC in the United States/2 PVC reduced the potential of nylon for long-term stor¬
may also be used as a skin coating on glass bot¬ age of drugs. Nylon 6, Nylon 6/6, Nylon 6/10,
tles. This is accomplished by dipping the bottle Nylon 11, and certain copolymers are cleared by
in a PVC plastisol and curing the coating, which FDA, subject to limitations or extractables.
produces a shatter-resistant coating over the Polycarbonate. Polycarbonate can be made
glass bottle.12 into a clear transparent container. This rela¬
Polystyrene. General-purpose polystyrene is tively expensive material has many advantages,
a rigid, crystal clear plastic. It has been used by one being its ability to be sterilized repeatedly.
dispensing pharmacists for years for containers The container is rigid, as is glass, and thus has
for solid dosage forms because it is relatively low been considered a possible replacement for glass
in cost. At present, polystyrene is not useful for vials and syringes. It is FDA-approved, although
liquid products. The plastic has a high water its drug-plastic problems have not been investi¬
vapor transmission (in comparison to high- gated adequately. It is only moderately chemi¬
density polyethylene) as well as high oxygen cally resistant and only a fair moisture barrier.
permeability. Depending on the methods of The plastic is known for its dimensional stabil¬
manufacture and other factors, polystyrene con¬ ity, high impact strength, resistance to strain,
tainers are easily scratched and often crack low water absorption, transparency, and resist¬
when dropped. Polystyrene also easily builds up ance to heat and flame.
a static charge; it has a low melting point Polycarbonate is resistant to dilute acids, oxi¬
(190°F) and therefore cannot be used for hot dizing or reducing agents, salts, oils (fixed and
items or other high-temperature applications. volatile), greases, and aliphatic hydrocarbons. It
Polystyrene is resistant to acids, except strong is attacked by alkalies, amines, ketones, esters,
oxidizing acids, and to alkalies. It is attacked by aromatic hydrocarbons, and some alcohols.
many chemicals, which cause it to craze and Polycarbonate resins are expensive and conse¬
crack, and so it is generally used for packaging quently are used in specialty containers. Since
dry products only. the impact strength of polycarbonate is almost
To improve impact strength and brittleness five times greater than other common packaging
(both of which are sometimes referred to as plastics, components can be designed with thin-

714 * The Theory and Practice of Industrial Pharmacy

ner walls to help reduce cost. Polycarbonate arti¬ ture barrier of polypropylene coupled with the
cles can be subjected to repeated sterilization in enhanced gas barrier of ethylene vinyl alcohol.
steam or water without undergoing significant Coextruded resins are providing packaging al¬
degradation. ternatives for products that previously were
Acrylic Multipolymers (Nitrile Poly¬ packaged only in glass.
mers). These polymers represent the acryloni¬ High-barrier plastics that may compete with
trile or methacrylonitrile monomer. Their glass and metal containers may be available
unique properties of high gas barrier, good through a new processing technology developed
chemical resistance, excellent strength proper¬ by Du Pont Co. This technology involves dis¬
ties, and safe disposability by incineration make persing nylon in a polyolefin resin so that the
them effective containers for products that are final polymer matrix contains a unique laminar
difficult to package in other polymers. Their oil arrangement of nylon platelets, which provide a
and grease resistance and minimal taste transfer series of overlapping barrier walls. Reportedly,
effects are particularly advantageous in food this technique produces a plastic, which, when
packaging. This medium cost material produces compared with the polyolefins, demonstrates a
a fairly clear container (not as brilliant as sty¬ 140-fold increase as a barrier against certain
rene). The use of nitrile polymers for food and hydrocarbons and an eightfold increase as a bar¬
pharmaceutical packaging is regulated to stand¬ rier for oxygen.
ards set by the Food and Drug Administration.
The present safety standard is less than 11 ppm
residua] acrylonitrile monomer, with allowable
migration at less than 0.3 ppm for all food prod¬ Drug-Plastic Considerations
ucts. A packaging system must protect the drug
Polyethylene terephthalate (PET). Poly¬ without in any way altering the composition of
ethylene terephthalate, generally called PET, is the product until the last dose is removed. The
a condensation polymer typically formed by the selection of a suitable package for a drug is not
reaction of terephthalic acid or dimethyl tereph¬ an easy task, inasmuch as an error can lead to
thalate with ethylene glycol in the presence of a serious consequences.
catalyst. Although used as a packaging film Drug-plastic considerations have been divided
since the late 1950s, its growth has recendy es¬ into five separate categories: (1) permeation,
calated with its use in the fabrication of plastic (2) leaching, (3) sorption, (4) chemical reaction,
botdes for the carbonated beverage industry. and (5) alteration in the physical properties of
The development of the biaxially oriented PET plastics or products.6-8,14-17
bottle has had a major impact on the bottling of Permeation. The transmission of gases,
carbonated beverages, accounting for an esti¬ vapors, or liquids through plastic packaging
mated annual resin usage of approximately 350 materials can have an adverse effect on the
million pounds. Its excellent impact strength shelf-fife of a drug. Permeation of water vapor
and gas and aroma barrier make it attractive for and oxygen through the plastic wall into the
use in cosmetics and mouth washes as well as in drug can present a problem if the dosage form is
other products in which strength, toughness, sensitive to hydrolysis and oxidation. Tempera¬
and barrier are important considerations. Fur¬ ture and humidity are important factors influ¬
thermore, the resin has been sanctioned for over encing the permeability of oxygen and water
25 years by the FDA for food contact applica¬ through plastic. An increase in temperature re¬
tions and has been the recipient of a favorable flects an increase in the permeability of the gas.
environmental impact statement.13 Great differences in permeability are possible,
Other Plastics. Coextruded resins are being depending on the gas and the plastic used. Mole¬
used to fabricate botdes and thermoformed blis¬ cules do not permeate through crystalline zones;
ters with barrier characteristics not previously thus, an increase in crystallinity of the material
attainable with single resins, resin blends, or should decrease permeability. Two polyethylene
copolymers. Coextrusion technology permits the materials may therefore give different permea¬
use of high-barrier resins, such as ethylene vinyl bility values at various temperatures.
alcohol, which could not be used alone because Materials such as nylon, which are hydrophil-
of either cost or physical or dimensional instabil¬ fic in nature, are poor barriers to water vapor,
ity. The resins used in the coextrusion can be while such hydrophobic materials as polyethyl¬
selected to provide optimum performance char¬ ene provide much better barriers.
acteristics for the particular product needs. A Studies have also revealed that formulations
coextrusion such as polypropylene/ethylene- containing volatile ingredients might change
vinyl-alcohol/polypropylene provides the mois¬ when stored in plastic containers because one or

PACKAGING MATERIALS SCIENCE *715

more of the ingredients are passing through the ents, temperature, length of contact, and area of
walls of the containers. Often, the aroma of cos¬ contact.
metic products becomes objectionable, owing to Chemical Reactivity. Certain ingredients
transmission of one of the ingredients, and the that are used in plastic formulations may react
taste of medicinal products changes for the same chemically with one or more components of a
reason. drug product. At times, ingredients in the for¬
The plastic container also may have an influ¬ mulation may react with the plastic. Even
ence on the physical system making up the micro-quantities of chemically incompatible
product. For example, certain water-in-oil emul¬ substances can alter the appearance of the plas¬
sions cannot be stored in a hydrophobic plastic tic or the drug product.
bottle, since there is a tendency for the oil phase Modification. The physical and chemical
to migrate and diffuse into the plastic. alteration of the packaging material by the drug
A clearance of a plastic material from one product is called modification. Such phenomena
manufacturer does not necessarily mean that as permeation, sorption, and leaching play a role
the same type plastic from another blow-molder in altering the properties of the plastic and may
is equally satisfactory. Each bottle manufacturer also lead to its degradation. Deformation in poly¬
has combined his own additives with the basic ethylene containers is often caused by permea¬
plastic, and each method of processing can be tion of gases and vapors from the environment
sufflciendy different to seriously affect the sta¬ or by loss of content through the container walls.
bility of a product. Thus, after ascertaining that Some solvent systems have been found to be re¬
a plastic from one bottle manufacturer is satis¬ sponsible for considerable changes in the me¬
factory for the product, the drug or toiletry man¬ chanical properties of plastics. Oils, for example,
ufacturer should insist that the bottle manufac¬ have a softening effect on polyethylene; fluori-
turer does not alter the components of the nated hydrocarbons attack polyethylene and pol¬
plastic bottle formulation or in any way alter the yvinyl chloride. Changes in polyethylene caused
blow-molding process for fabricating the con¬ by some surface-active agents have been noted.
tainer. In other cases, the content may extract the plas¬
Leaching. Since most plastic containers ticizer, antioxidant, or stabilizer, thus changing
have one or more ingredients added in small the flexibility of the package. Polyvinyl chloride
quantities to stabilize or impart a specific prop¬ is an excellent barrier for petroleum solvents,
erty to the plastic, the prospect of leaching, or but the plasticizer in polyvinyl chloride is ex¬
migration from the container to the drug prod¬ tracted by solvents. This action usually leaves
uct, is present. Problems may arise with plastics the plastic hard and stiff. Sometimes, this effect
when coloring agents in relatively small quanti¬ is not immediately perceptible because the sol¬
ties are added to the formula. Particular dyes vent either softens the plastic or replaces the
may migrate into a parenteral solution and cause plasticizer; later, when the solvent evaporates,
a toxic effect. Release of a constituent from the the full stiffening effect becomes apparent.
plastic container to the drug product may lead to
drug contamination and necessitate removal of
the product from the market. Selection of Proper Material
Sorption. This process involves the removal Some of the items to be considered in choos¬
of constituents from the drug product by the ing the plastic njaterial are listed in Tables 24-1,
packaging material. Sorption may lead to serious 24-2, and 24-3.
consequences for drug preparations in which Also to be taken into consideration is the po¬
important ingredients are in solution. Since tential effect of wall thickness, which relates to
drug substances of high potency are adminis¬ barrier requirements of the package for its in¬
tered in small doses, losses due to sorption may tended shelf-life.
significantly affect the therapeutic efficacy of
the preparation. A problem commonly encoun¬
tered in practice is the loss of preservatives.
Collapsible Tubes
These agents exert (heir activity at low concen¬
tration, and their loss through sorption may be
great enough to leave a product unprotected Metal
against microbial growth. The collapsible metal tube is an attractive con¬
Factors that influence characteristics of sorp¬ tainer that permits controlled amounts to be dis¬
tion from product are chemical structure, pH, pensed easily, with good reclosure, and adequate
solvent system, concentration of active ingredi¬ protection of the product. The risk of contamina-

716 •The Theory and Practice of Industrial Pharmacy

tion of the portion remaining in the tube is mini¬ functional characteristics. Plastic tubes have a
mal, because the tube does not “suck back.” It is number of inherent practical advantages over
light weight and unbreakable, and it lends itself other containers or dispensers. They are (1) low
to high-speed automatic filling operations. in cost, (2) light in weight, (3) durable, (4) pleas¬
Any ductile metal that can be worked cold is ant to touch, (5) flexible, facilitating product dis¬
suitable for collapsible tubes, but the most com¬ pensing, (6) odorless and inert to most chemi¬
mon ones in use are tin (15%), aluminum cals, (7) unbreakable, (8) leakproof, and (9) able
(60%), and lead (25%). Tin is the most expen¬ to retain their shape throughout their use. In
sive, and lead is the cheapest. Since tin is the addition, (10) they have a unique “suck-back”
most ductile of these metals, small tubes are feature, which prevents product ooze. If too
often made more cheaply of tin even though the much product is dispensed with one squeeze,
metal cost is higher. Laminates of tin-coated relaxation of hand pressure permits the product
lead provide the appearance and oxidation re¬ to be sucked back into the tube. If this feature is
sistance of straight tin at lower prices. undesirable for fear of contamination, plastic
The tin that is used for this purpose is alloyed tubes designed to avoid suck-back are available.
with about 0.5% copper for stiffening. When Thus, the suck-back feature of plastic tubes can
lead is used, about 3% antimony is added to in¬ be an advantage or a disadvantage. When the
crease hardness. Aluminum work hardens when tube is partly empty, however, this feature is a
it is formed into a tube, and must be annealed to nuisance, because the air must be expelled be¬
give it the necessary pliability. Aluminum also fore the product can be dispensed.
hardens in use, sometimes causing tubes to de¬ The sidewall of a plastic tube is extruded
velop leaks.1 under heat and pressure as a continuous hose¬
Tin. Tin containers are preferred for foods, like tubing and then is cut to length. The neck
pharmaceuticals, or any product for which pu¬ and shoulder are molded and joined to the tube
rity is a paramount consideration. Tin is the in a separate automatic process. The tube is
most chemically inert of all collapsible tube met¬ then decorated, mostly by offset printing. The
als. It offers a good appearance and compatibility tubes are capped with the bottoms remaining
with a wide range of products. open for filling, after which they are heat-sealed
Aluminum. Aluminum tubes offer signifi¬ to become as strong as any other part of the tube.
cant savings in product shipping costs because The most common types of material currently
of their light weight. They provide the attractive¬ employed in plastic tubes are low- and high-
ness of tin at somewhat lower cost. density polyethylene. The former is less expen¬
Lead. Lead has the lowest cost of all tube sive and used more extensively. High-density
metals and is widely used for nonfood products polyethylene offers more protection than the
such as adhesives, inks, paints, and lubricants. uncoated low-density type. Coated high-density
Lead should never be used alone for anything polyethylene is only slightly more protective
taken internally because of the risk of lead poi¬ than the coated low-density type, because in
soning. With internal linings, lead tubes are both instances, the coatings serve as a prime
used for such products as fluoride toothpaste. barrier.
Linings. If the product is not compatible Other materials include polypropylene and
with bare metal, the ir.eerier can be flushed with vinyl, but relatively high costs and various tech¬
wax-type formulations or with resin solutions, nical problems have limited their use.
although the resins or lacquers are usually
sprayed on. A tube with an epoxy lining costs
about 25% more than the same tube uncoated. Laminations
Wax linings are most often used with water- Permeation problems associated with plastic
base products in tin tubes, and phenolics, epox¬ tubes, and corrosion and breakage problems
ides, and vinyls are used with aluminum tubes, experienced with metal tubes, have led to the
giving better protection than wax, but at a emergence of a third type of collapsible tube, the
higher cost. Phenolics are most effective with laminated tube. This tube, constructed of a lami¬
acid products; epoxides protect better against nation containing several layers of plastic,
alkaline materials. paper, and foil, is fabricated from flat, printed
stock. This lamination, which is specifically tai¬
lored to the product requirements, is welded into
Plastic a continuous tube by heat sealing the edges of
This distinctive style of package, like its coun¬ the lamination together in a machine called a
terpart, the metal collapsible tube, excels in “sideseamer.” The tube is cut to length, and the

PACKAGING MATERIALS SCIENCE *717

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718 • The Theory and Practice of Industrial Pharmacy

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Table 24-2. Plastics Used for Drug Bottle Packaging
Water Vapor
Rate g/100 FDA
Sq in/24 hr Oxygen Perm. Bottle Cost Accept¬
Material @ 100°F, cc/100 sq. in. Relative to ability
(Density) Inertness 95° RH @ 73°F/mil HDPE for Foods

HIGH-DENSITY PE Outstanding 0.5 120 1 Yes

(0.955)
LOW-DENSITY PE Excellent 1.1 450 1.5 Yes
(0.920)
POLYSTYRENE Very poor 10.0 380 1.1 Yes
(1.05)
RIGID PVC Poor 2.7 15 2 Yes (some
(1.35) formulations)

POLYPROPYLENE Good to 0.4 230 1.3 Yes

(0.90) excellent

NYLON 6, 10 Good 2.9 3 3.0 Yes

(MO)

POLYCARBONATE Poor 14.0 230 3.5 Yes

(1.20)
ACRYLIC MULTI¬ Fair 11.5 30 2.1 Yes
POLYMERS (1.10)

From Pinsky, J.: High-density polyethylene gets nod in Army Drug Packaging Study. Package Engineering, November, 1967.

head is injection-molded onto the tube. The Closures

head is typically molded of low-density polyeth¬ The closure is normally the most vulnerable
ylene. Since some permeation through this and critical component of a container insofar as
molded head is possible, a head insert, made of stability and compatibility with the product are
urea formaldehyde, can be molded into the head concerned. An effective closure must prevent
to reduce product permeation. the contents from escaping and allow no sub¬
Although not as impermeable as metal tubes, stance to enter the container. The adequacy of
the laminated tube does provide a satisfactory the seal depends on a number of things, such as
level of barrier protection for a number of prod¬ the resiliency of the liner, the flatness of the
ucts. Laminated tubes initially served the denti¬ sealing surface on the container, and most im¬
frice market but today are also found in pharma¬ portant, the tightness or torque with which it is
ceuticals, depilatories, hand creams, hair care applied. In evaluating an effective closure sys¬
products, and denture adhesives.12 tem, the major considerations are the type of
container, the physical and chemical properties
Table 24-3. Factors in Selecting a Liner of the product, and the stability-compatibility
requirements for a given period under certain
1. Compatibility (chemical resistance) conditions.
2. Appearance, caliper, etc. Closures are available in five basic designs:
3. Gas- and vapor-transmission rates—WVTR, oxygen, (1) screw-on, threaded, or lug, (2) crimp-on
C02, etc. (crowns), (3) press-on (snap), (4) roll-on, and
4. Removal torque (5) friction. Many variations of these basic types
5. Heat resistance exist, including vacuum, tamperproof, safety,
6. Shelf-life child-resistant, and linerless types, and dis¬
7. Economics penser applicators.18
From Tang, T.: Liners and seals for closures. Modem Packaging Threaded Screw Cap. When the screw cap
Encyclopedia. Volume 46, No. 12, McGraw-Hill, Inc., New York, is applied, its threads engage with the corre¬
1973, page 225. sponding threads molded on the neck of the bot-

720 • The Theory and Practice of Industrial Pharmacy

 Color Toughness/ Outstanding Outstanding
Clarity Impact Advantages Disadvantages

Colorless, Excellent Inertness, low cost, Semi-opaque, transfer of taste ingredients,

translucent low WVT, toughness high dilute solution absorption
Colorless, Excellent Squeeze property, Flexibility, relatively poor barrier
hazy inertness, low cost to nonpolars, high WVT
Colorless, Poor Clarity, stiffness, low cost High WVT, susceptibility to cracking,
clear poor impact
Colorless, Fair Clarity, stiffness, 10-12 ingredients are possible; difficult
clear 02 barrier, retention of processability, solvent susceptibility
nonpolar materials
Colorless, Good (poor Inertness, low cost, Low-temperature britdeness, tendency
clear at 40°F and ESCR resistance to unzip, highly stabilized content
below)
Colorless, Excellent Good barrier for Cost, water absorption,
hazy nonpolars, tough, borderline for water-based materials
good 02 barrier
Colorless, Outstanding Very tough, clear, Cost, susceptibility to solvent cracking,
clear good oxygen barrier poor WVT, poor barrier
Colorless, Good Clarity, fair oxygen Poor WVT, blushes,
clear-hazy barrier, good for oils poor barrier

tie. A liner in the cap, pressed against the open¬ Crown Caps. This style of cap is commonly
ing of the container, seals the product in the used as a crimped closure for beverage bottles
container by overcoming sealing surface irregu¬ and has remained essentially unchanged for
larities, and provides resistance to chemical and more than 50 years.
physical reaction with the product being sealed. Roll-On Closures. The aluminum roll-on
The screw cap is commonly made of metal or cap can be sealed securely, opened easily, and
plastics. The metal is usually tinplate or alumi¬ resealed effectively. It finds wide application in
num, and in plastics, both thermoplastic and the packaging of food, beverages, chemicals, and
thermosetting materials are used. Metal caps are pharmaceuticals. The roll-on closure requires a
usually coated on the inside with an enamel or material that is easy to form, such as aluminum
lacquer for resistance against corrosion. or other light-gauge metal.
Almost all metal crowns and closures are Resealable, nonresealable, and pilferproof
made from electrolytic tinplate, a tin-coated steel types of the roll-on closure are available for use
on which the tin is applied by electrolytic deposi¬ on glass or plastic bottles and jars. The packager
tion. purchases these closures as a straight-sided,
Lug Cap. The lug cap is similar to the threadless shell and forms the threads on the
threaded screw cap and operates on the same packaging line as an integral part of the filling
principle. It is simply an interrupted thread on operation.
the glass finish, instead of a continuous thread. The roll-on technique allows for dimensional
It is used to engage a lug on the cap sidewall and variation in the glass containers; each roll-on
draw the cap down to the sealing surface of the closure precisely fits a specific container.
container. Unlike the threaded closure, it re¬ Pilferproof Closures. The pilferproof clo¬
quires only a quarter turn. sure is similar to the standard roll-on closure
The lug cap is used for both normal atmos¬ except that it has a greater skirt length. This
pheric-pressure and vacuum-pressure closing. additional length extends below the threaded
The cap is widely used in the food industry be¬ portion to form a bank, which is fastened to the
cause it offers a hermetic seal and handles well basic cap by a series of narrow metal “bridges.”
in sterilization equipment and on production When the pilferproof closure is removed, the
lines. bridges break, and the bank remains in place on

PACKAGING MATERIALS SCIENCE • 721

the neck of the container. The user can reseal Table 24-4. Permeation Rate of Liner Facings*
the closure, but the detached band indicates that
Facing Water Alcohol
the package has been opened. The torque neces¬
sary to break the bridges and remove the cap is Polyethylene, 2-mil 0.07 0.06
nominal. Saran, 75-gauge 0.07 0.08
Non-Reus able Roll-On Closures. In some Aluminum foil, 1-mil 0.04 0.12
packaging applications a reusable cap is not de¬ Tinfoil, 1-mil 0.09 0.20
sired. Non-reusable caps require unthreaded Polyester, 50-gauge 0.12 0.10
glass finishes. The skirts of these closures are Vinylite 0.20 0.03
rolled under retaining rings on the glass con¬ Solvent-resistant 0.23 0.61
tainer and maintain liner compression. Closures Yellow oil 0.28 0.85
of this type have tear-off tabs that make them
"Loss in grams from a 2-oz bottle with 22-mm cap with cork-
tamperproof and pilferproof.
backed liner, 13 weeks at room temperature.
From Hanlon, J. F.: Handbook of Packaging Engineering.
McGraw-Hill, Inc. New York, 1971.

Closure Liners
A liner may be defined as any material that is
inserted in a cap to effect a seal between the clo¬ Torque Testing
sure and the container. Controlling cap tightness on a packaging line
Liners are usually made of a resilient backing with a torque tester can prevent evaporation or
and a facing material. The backing material leakage of the product, breakage of a plastic
must be soft enough to take up any irregularities molded closure, and application of a cap too tight
in the sealing surface and elastic enough to re¬ to be removed. The Owens-Illinois torque tester
cover some of its original shape when removed is an instrument commonly used for this pur¬
and replaced. It is usually glued into the cap pose.
with an adhesive, or the cap can be made with
an undercut, so that the liner snaps into place
and is free to rotate. Rubber Stoppers
Factors in Selecting a Liner. Many factors Rubber is used in the pharmaceutical indus¬
have to be considered before an effective liner try to make stoppers, cap liners, and bulbs for
can be selected (Table 24-4). The most impor¬ dropper assemblies. The rubber stopper is used
tant consideration is that the liner be chemically primarily for multiple-dose vials and disposable
inert with its product, so that the latter is pro¬ syringes. The rubber polymers most commonly
tected against any possible change in purity or used are natural, neoprene, and butyl rubber.
potency. In the manufacture of rubber closures, certain
Gas and vapor transmission rates are usually performance expectations require certain in¬
relative and depend chiefly on the shelf-life re¬ gredients. The types of ingredients commonly
quired for the product. If the period between found in a rubber closure are:
packing and consumer use is expected to be
long, low transmission rates are necessary. Rep¬ Rubber
resentative permeation rates are presented in
Vulcanizing agent
Table 24-4.
Homogeneous Liner. These one-piece lin¬ Accelerator/activator
ers are available either as a disk or as a ring of Extended filler
rubber or plastic. Although they are more expen¬
sive and more complicated to apply, they are Reinforced filler
widely used for pharmaceuticals because their Softener/plasticizer
properties are uniform and they can withstand Antioxidant
high-temperature sterilization.
Heterogeneous or Composite Liners. Pigment
These are composed of layers of different mate¬ Special components, waxes
rials chosen for specific requirements. In gen¬
eral, the composite liner consists of two parts: a Since the composition of rubber stoppers is
facing and a backing. Usually, the facing is in complex and the manufacturing process compli¬
contact with the product, and the backing pro¬ cated, it is common to encounter problems with
vides the cushioning and sealing properties re¬ certain rubber formulas. For example, when the
quired. rubber stopper comes in contact with parenteral

722 • The Theory and Practice of Industrial Pharmacy

solution, it may absorb active ingredient, anti¬ is more expensive than the phenolics, but the
bacterial preservative, or other materials, and heat resistance and other properties of urea
one or more ingredients of the rubber may be make it shitable for premium items. Elegant col¬
extracted into the liquid. These extractives ors are obtainable with urea because the translu-
could (1) interfere with the chemical analysis of cency gives brightness and color depth. Urea
the active ingredient, (2) affect the toxicity or plastic is available in an unlimited range of col¬
pyrogenicity of the injectable product, (3) inter¬ ors and is a hard, brittle material that is odorless
act with the drug preservative to cause inactiva¬ and tasteless. Being a thermosetting plastic,
tion, and (4) affect the chemical and physical urea can withstand high temperatures without
stability of the preparation so that particulate softening, but it chars at about 390°F. It absorbs
matter appears in the solution. water under wet conditions, but such absorption
has no serious effect on the plastic.
Urea is not affected by any organic solvents,
but it is affected by alkalies and strong acids. It
Plastic Closures has good resistance to all types of oils and
The two basic types of plastics generally used greases. Although urea can withstand elevated
for closures are thermosetting and thermoplastic temperature, it cannot be steam-sterilized. Parts
materials. They differ greatly in physical and may shrink as much as 0.003 inch after mold¬
chemical properties, and fundamentally differ¬ ing.
ent manufacturing methods are used for each Thermoplastic Resins. Since their intro¬
type.3 duction, thermoplastics have become widely
Thermosetting Resins. Phenolic and urea used in the manufacture of closures. Polysty¬
thermosetting plastic resins are widely used in rene, polyethylene, and polypropylenes are the
threaded closures. The thermosetting plastic materials used in 90% or more of all thermoplas¬
first softens under heat and then cures and tic closures. Each material has specific perform¬
hardens to a final state. Shaping must occur in ance advantages, and the particular resin used
the first stage of softening, because after curing depends on the physical and chemical properties
there is no further mobility, even upon reappli¬ desired for the application and on the particular
cation of heat and pressure. During the molding product being packaged.
process, thermosets undergo a permanent
chemical change, and unlike thermoplastic ma¬
terials, they cannot be reprocessed. Since parts
Tamper-Resistant Packaging
that are improperly molded must therefore be In 1982, the vulnerability of over-the-counter
discarded, thermosetting materials are usually (OTC) or nonprescription drug products to ma¬
fabricated by compression molding. The manu¬ licious adulteration was dramatically and tragi¬
facturing process is relatively slow, but allows cally demonstrated with the tainting of Tylenol
better control and quick response to change in capsules with cyanide, which led to the deaths
temperature and material flow. of several people. Public concerns about the
Phenolics. Phenolic molding compounds are safety of drug packaging led to various proposals
available in different grades and in dark colors, by local municipalities for legislation regarding
usually black or brown. Phenolics are used when tamper-resistant packaging. To respond as
a hard sturdy piece is needed, and when dark quickly as possible to the safety concerns raised
colors can be tolerated. regarding OTC pharmaceutical packaging, and
Rigidity, heat, chemical resistance, and to assist the FDA in providing a consistent na¬
strength are the outstanding properties of the tional standard governing tamper-resistant
phenolics. Color limitation is the main draw¬ packaging, the Proprietary Association, a trade
back, although coatings are available at a pre¬ association for the Proprietary Pharmaceutical
mium price. As a closure, the phenolic can with¬ Industry, provided recommendations to the
stand the torquing forces of the capping FDA, which were subsequently incorporated
machines and maintains a tight seal over a long into FDA regulation 21 C.F.R. Parts 211, 314,
period of time. and 700, which covers tamper-resistant packag¬
The phenolics are resistant to some dilute ing of OTC drugs.
acids and alkalies and are attacked by other, es¬ The legislation enacted has had one of the
pecially oxidizing, acids. Organic acids and re¬ greatest impacts on the packaging of pharma¬
ducing acids usually do not have any effect. ceuticals in recent history. The requirement for
Strong alkalies decompose phenolics. tamper-resistant packaging is now one of the
Urea. This thermosetting resin is a hard major considerations in the development of
translucent material that takes coloring well. It packaging for pharmaceutical products. As de-

PACKAGING MATERIALS SCIENCE • 723

fined by the FDA, “a tamper-resistant package is the flexibility of pursuing new packaging tech¬
one having an indicator or barrier, to entry nologies that meet the objectives of the FDA rul¬
which, if breached or missing, can reasonably be ing.
expected to provide visible evidence to con¬
sumers that tampering has occurred. Tamper-
resistant packaging may involve immediate- Film Wrapper
con tainer/closure systems or secondary-con¬
tainer/carton systems or any combination Film wrapping has been used extensively over
thereof intended to provide a visual indication of the years for products requiring package integ¬
package integrity when handled in a reasonable rity or environmental protection. .Although film
manner during manufacture, distribution, and wrapping can be accomplished in several ways
retail display.” and varies in configuration from packaging
The visual indication is required to be accom¬ equipment to packaging equipment, it can be
panied by appropriate illustrations or precau¬ generally categorized into the following types:
tionary statements to describe the safeguarding
mechanism to the consumer. To reduce the pos¬ End-folded wrapper
sibility that the security mechanism can be re¬ Fin seal wrapper
stored after tampering, the FDA also requires
Shrink wrapper
either that the tamper-resistant feature be de¬
signed from materials that are generally not
readily available (e.g., an aerosol system), or that End-Folded Wrapper
barriers made from readily obtainable materials The End-Folded Wrapper is formed by push¬
carry a distinctive design or logo that cannot be ing the product into a sheet of overwrapping
readily reproduced by an individual attempting film, which forms the film around the product
to restore the package. and folds the edges in a gift-wap fashion as in¬
The following package configurations have dicated in Fig. 24-1A. The folded areas are
been identified by the FDA as examples of pack¬ sealed by pressing against a heated bar. Because
aging systems that are capable of meeting the of the overlapping folding sequence of the seals,
requirements of tamper-resistant packaging as the film used must be heat-sealable on both sur¬
defined by FDA regulation 21 C.F.R. Parts 211, faces. Materials commonly used for this applica¬
314, and 700: tion are cellophane and polypropylene. Cello¬
phane, which is regenerated cellulose, is not
inherently heat-sealable but requires a heat-seal
1. Film wrappers
coating to impart heat-sealing characteristics to
2. Blister package the film. This is usually accomplished by coating
3. Strip package the cellophane with either polyvinylidene chlo¬
ride (PVDC) or nitrocellulose. Since PVDC also
4. Bubble pack provides a durable moisture barrier, PVDC
5. Shrink seals and bands coated cellophane is often used for the
overwrapping of products that are sensitive to
6. Foil, paper, or plastic pouches moisture. Cellophane offers excellent machina-
7. Bottle seals bility and crystal clarity, and for many years was
the only clear film available for this type wrap¬
8. Tape seals ping. In the early 1970s, polypropylene came
9. Breakable caps onto the scene and represented a lower-cost al¬
ternative to cellophane. Because of the different
10. Sealed tubes handling characteristics of polypropylene, initial
11. Aerosol containers problems were experienced in obtaining satis¬
factory machinability. Machine modifications
12. Sealed cartons
and the redesign of equipment led to the gradual
replacement of cellophane by polypropylene, so
The use of any of these concepts does not neces¬ that polypropylene now dominates the market¬
sarily constitute compliance with the FDA rul¬ place for this application. Heat-sealing charac¬
ing. The manufacturer must determine that the teristics are imparted to polypropylene by the
particular package concept provides tamper re¬ use of heat-sealable acrylic coatings or by the
sistance for the manufacturer’s specific product. addition of heat-sealable modifiers to the resin
By the same token, manufactures are not limited itself.
to the packaging concepts listed here, but have To be tamper-resistant, the overwap must be

724 * The Theory and Practice of Industrial Pharmacy

 11 (C)
FIG. 24-1. Film wrapper systems. A, End-folded wrapper. B, Fin seal wrapper. C, Shrink wrapper.

well sealed and must be printed or uniquely dec¬ would accordingly deface the carton, making the
orated to exclude the possibility of having an al¬ carton unsuitable for re-use.
ternate overwrap substituted in its place. The
printed surface of the carton being overwrapped
Fin Seal Wrapper
may also be coated with a heat-sensitive varnish,
which causes the overwrap to bond permanently Unlike the end-folded wrapper configuration,
to the paperboard carton during the sealing of fin seal packaging does not require the product
the overwrap. The removal of the overwrap to act as a bearing surface against which the

PACKAGING MATERIALS SCIENCE • 725

overwrap is sealed. The seals are formed by Blister Package
crimping the film together and sealing together When one thinks of unit dose in pharmaceuti¬
the two inside surfaces of the film, producing a
cal packaging, the package that invariably comes
“fin” seal (Fig. 24-IB). Since the seals are
to mind is the blister package. This packaging
formed by compressing the material between
mode has been used extensively for pharmaceu¬
two heater bars (or nipping the film between tical packaging for several good reasons. It is a
pressure rollers) rather than sealing against the packaging configuration capable of providing
package, much greater and more consistent excellent environmental protection, coupled
sealing pressure can be applied, and conse-
with an esthetically pleasing and efficacious
quendy, better seal integrity can be accom¬
appearance. It also provides user functionality in
plished. For this reason, fin sealing has primar¬
terms of convenience, child resistance, and now,
ily been used when protective packaging is
tamper resistance.
critical. Since the surface of the heat seal does
The blister package is formed by heat-soften¬
not come in contact with the heated sealing bars
ing a sheet of thermoplastic resin and vacuum¬
on the packaging equipment, much more tena¬
drawing the softened sheet of plastic into a con¬
cious heat sealants, such as polyethylene or Sur-
toured mold. After cooling, the sheet is released
lyn,* can be used. With good seal integrity, the
from the mold and proceeds to the filling station
overwrap can be removed or opened only by
of the packaging machine. The semi-rigid blister
tearing the wrapper.
previously formed is filled with product and lid¬
ded with a heat-sealable backing material. (Fig.
Shrink Wrapper 24-2). The backing material, or lidding, can be of
Film overwrapping can also be accomplished either a push-through or peelable type. For a
with the use of a shrink wrapper. The shrink push-through type of blister, the backing mate¬
wrap concept involves the packaging of a prod¬ rial is usually heat-seal-coated aluminum foil.
uct in a thermoplastic film that has been The coating on the foil must be compatible with
stretched and oriented during its manufacture the blister material to ensure satisfactory seal¬
and that has the property of reverting back to its ing, both for product protection and for tamper
unstretched dimensions once the molecular resistance. Peelable backing materials have
structure is “unfrozen” by the application of been used to meet the requirements of child-
heat. The shrink wrap concept has a diversity of resistant packaging. This type of backing must
uses in packaging, one of which is its use as an have a degree of puncture resistance to prevent
overwrap. In this case, the shrink film is usually a child from pushing the product through the
used in roll form, with the center folded in the lidding and must also have sufficient tensile
direction of winding (Fig. 24-1C). As the film strength to allow the lidding to be pulled away
unwinds on the overwrapping machine, a pocket from the blister even when the lidding is
is formed in the center fold of the sheet, into strongly adhered to it. To accomplish this, a ma¬
which the product is inserted. An L-shaped terial such as polyester or paper is used as a
sealer seals the remainder of the overwrap and component of the backing lamination. Foil is
trims off the excess film. The loosely wrapped generally used as a component of the backing
product is then moved through a heated tunnel, lamination if barrier protection is a critical re¬
which shrinks the overwrap into a tightly quirement; however, metallized polyester is re¬
wrapped unit. The materials commonly used for placing foil for some barrier applications. A peel¬
this application are heat-shrinkable grades of able sealant compatible with the heat-seal
polypropylene, polyethylene, and polyvinyl chlo¬ coating on the blister is also required since the
ride. Since the various heat-shrinkable grades of degree of difficulty of opening is a critical pa¬
film have different physical characteristics such rameter for child-resistant packaging. The use of
as tear and tensile strength, puncture resist¬ peelable backing materials for blister packaging
ance, and shrinking forces, selection of the par¬ must be carefully evaluated to ensure that peel
ticular material used must be based upon spe¬
cific product considerations so that the shrink
wrap provides suitable integrity without crush¬
ing or damaging the product. The major advan¬ TRANSPARENT BLISTER-^,
tages of this type of wrapper are the flexibility
and low cost of the packaging equipment re¬
quired.
BACKING MATERIAL-*
*Du Pont’s Ionomer Resin. FIG. 24-2. Blister pack.

726 • The Theory and Practice of Industrial Pharmacy

 Table 24-5. Barrier Properties of Laminations

Oxygen Water-vapor
Material Transmission* Transmission t

0.002 saran/0.006 PVC 0.6 0.092

0.0015 Aclar/0.002 PE/0.0075 PVC 1.0
0.0015 Aclar/0.0075 PVC 1.1 0.035
0.002 PE/0.0075 PVC 1.3
0.0075 PVC 1.9
0.002 PE/0.005 PVC 2.6
0.005 PVC 2.7
0.001 nylon 25.0

*cc/24 hr/100 sq in. at 77°F, 50% RH.

tg/24 hr/100 sq in. at 95°F, 90% RH.
From Hanlon, J. F.: Handbook of Packaging Engineering. New York, McGraw-Hill, Inc.,
1971.

strengths are sufficient to meet tamper-resist¬ Since the sealing is usually accomplished be¬
ance objectives. tween pressure rollers, a high degree of seal in¬
Materials commonly used for the thermo- tegrity is possible. The use of high-barrier mate¬
formable blister axe polyvinyl chloride (PVC), rials such as foil laminations or saran-coated
PVC/polyethylene combinations, polystyrene, films, in conjunction with the excellent seal for-
and polypropylene. For commercial reasons and
because of certain machine performance char¬
Table 24-6. Moisture Barrier Properties of Flex¬
acteristics, the blisters on most unit dose pack¬
ible Materials
ages are made of polyvinyl chloride. For added
moisture protection, polyvinylidene chloride Water-Vapor
(saran) or polychlorotrifluoroethylene (Aclar) Material Transmission*
films may be laminated to PVC. The moisture
barrier of PVC/Aclar is superior to that of saran- Aclar (fluorohalocarbon):
coated PVC, especially under prolonged and ex¬ 22A, 1 mil 0.055
tremely humid storage conditions. Listed in Ta¬ 22A, l‘/2 mil 0.046
bles 24-5 and 24-6 are several commonly used 22C, 1 mil 0.045
thermoformable blister materials and a compari¬ 22C, 2 mil 0.028
son of their protective qualities. 33C M> mil 0,040
33C, 1 mil 0.025
33C, 2 mil 0.015
Strip Package Cellulose acetate, 1 mil 80.000
A strip package is a form of unit dose packag¬
Cellophane:
ing that is commonly used for the packaging of 140K 0.400
tablets and capsules. A strip package is formed 195K 0.450
by feeding two webs of a heat-sealable flexible 195M 0.650
film through either a heated crimping roller or a
Polyester, 1 mil 2.000
heated reciprocating platen. The product is
dropped into the pocket formed prior to forming Polyethylene:
the final set of seals. A continuous strip of pack¬ Low-density, 1 mil 1.300
ets is formed, generally several packets wide High-density, 1 mil 0.300
depending on the packaging machine’s limita¬ Polypropylene, 1 mil 0.700
tions. The strip of packets is cut to the desired Polyvinyl chloride, 1 mil 4.000
number of packets in length (Fig. 24-3). The Rubber hydrochloride, 1.2 mil 1.000
strips formed are usually collated and packaged Saran (PVDC), 1 mil 0.200
into a folding carton. The product sealed be¬ Two-ply waxed glassine paper 0.500
Waxed glassine paper 3.000
tween the two sheets of film usually has a seal
Waxed sulfite paper 4.000
around each tablet, with perforations usually
separating adjacent packets. The seals can be in *g loss/24 hr/100 sq in./mil at 95°F, 90% RH.
a simple rectangular or “picture-frame” format From Hanlon, J. F.: Handbook of Packaging Engineering.
or can be contoured to the shape of the product. McGraw-Hill, Inc., New York, 1971.

PACKAGING MATERIALS SCIENCE • 727

 oriented tube in a diameter slightly larger than
the cap and neck ring of the bottle to be sealed.
The heat-shrinkable material is supplied to the
bottler as a printed, collapsed tube, either pre¬
cut to a specified length or in roll form for an
automated operation. The proper length of PVC
tubing is slid over the capped botde far enough
to engage both the cap and neck ring of the bot¬
tle (Fig. 24-4). The bottle is then moved through
a heat tunnel, which shrinks the tubing tightly
around the cap and bottle, preventing the disen¬
gagement of the cap without destroying the
shrink band. For ease of opening, the shrink
bands can be supplied with tear perforations.

Foil, Paper, or Plastic Pouches

The flexible pouch is a packaging concept ca¬
pable of providing not only a package that is
tamper-resistant, but also, by the proper selec¬
mation, makes this packaging mode appropriate tion of material, a package with a high degree of
for the packaging of moisture-sensitive prod¬ environmental protection. A flexible pouch is
ucts. usually formed during the product filling opera¬
A number of different packaging materials are tion by either vertical or horizontal forming, fill¬
used for strip packaging. For high-barrier appli¬ ing, and sealing (f/f/s) equipment.
cations, a paper/polyethylene/foil/polyethylene In the vertical f/f/s operation, a web of film is
lamination is commonly used. When product drawn over a metal collar and around a vertical
visibility is important, a heat-sealable cello¬ filling tube, through which the product is
phane or a heat-sealable polyester can be used. dropped into the formed package (Fig. 24-5).
Also, the front and back of the package may use The metal filling tube also acts as a mandrel,
dissimilar materials. The choice of material used which controls the circumference of the pouch
depends on both product and equipment re¬ and against which the longitudinal seal is made.
quirements. The formation of this seal, which can be either a
fin seal or an overlap seal, converts the packag¬
ing film into a continuous tube of film. Recipro¬
Bubble Pack
cating sealers, orthogonal to the logitudinal seal,
The bubble pack can be made in several ways crimp off the bottom of the tube, creating the
but is usually formed by sandwiching the prod¬ bottom seal of the package. The product drops
uct between a thermoformable, extensible, or through the forming tube into the formed pack¬
heat-shrinkable plastic film and a rigid backing age. The reciprocation sealer moves up the film
material. This is generally accomplished by tube a distance equal to the length of the pack¬
heat-softening the plastic film and vacuum¬ age and forms the top and final seal of the pack-
drawing a pocket into the film in a manner simi¬
lar to the formation of a blister in a blister pack¬
age. The product is dropped into the pocket, SHRINK TUBING
which is then sealed to a rigid material such as
heat-seal-coated paperboard. If a heat-shrink¬
able material is used, the package is passed
through a heated tunnel, which shrinks the film
into a bubble or skin over the product, firmly at¬
taching it to the backing card.

Shrink Banding
The shrink band concept makes use of the
heat-shrinking characteristics of a stretch-
oriented polymer, usually PVC. The heat-shrink-
able polymer is manufactured as an extruded, FIG. 24-4. Shrink banding (tubing).

728 • The Theory and Practice of Industrial Pharmacy

 seal wrapper illustrated in Figure 24-IB can be
considered a type of horizontal f/f/s packaging
system.
" To provide the degree of package integrity re¬
quired for tamper-resistant packaging on both
horizontal and vertical equipment, inner-
surface-to-inner-surface sealing should be used.
This permits the use of such effective sealants
as polyethylene, ethylene vinyl acetate (EVA),
and Surlyn, which when properly sealed must
be tom apart to access the product. These seal¬
ants must be used as part of a lamination con¬
structed to provide the necessary characteristics
for the proper performance of the packaging
material. The outside surface of the lamination
should provide a good printing surface and
should be thermally stable since it comes into
direct contact with the heater bars. The outside
surface material is also used as the substrate
carrier, which gives the lamination the mechan¬
ical characteristics necessary for the machining
and handling of the package. The most com¬
monly used film for a substrate carrier is paper.
Polyester, nylon, and cellophane are also used if
age. This top seal of the package becomes the transparency, puncture resistance, or gloss are
bottom seal of the next package and the process desired.
repeats itself. Since vertical f/f/s machines are For moisture- and oxygen-sensitive products,
gravity-fed, they are primarily used for liquid, foil is commonly used as part of the film lamina¬
powder, and granular products. tion, with the foil sandwiched between the outer
The horizontal flfls system is generally used ply and the heat seal layer. Such laminations as
for products of smaller volume, which are more paper/polyethylene/foil/polyethylene and polyes¬
amenable to the flatter fonnat of the packages ter/polyethylene/foil/polyethylene are commonly
produced by this type of equipment. In this sys¬ used for high-barrier applications. Metallized
tem, the web of film is folded upon itself rather polyester is replacing foil for some high-barrier
than around a tube. As the folded film is fed hor¬ packaging applications because of its lower cost,
izontally through the equipment, a reciprocating excellent appearance, and flexural endurance.
platen creates pockets in the film by making ver¬
tical separation seals. The product is then placed
into each pocket and the final top seal is made
(Fig. 24-6). Packages formed on horizontal f/f/s Bottle Seals
equipment typically have a three-sided perime¬ A bottle may be made tamper-resistant by
ter seal, but other variations are possible, de¬ bonding an inner seal to the rim of the bottle in
pending on the type equipment used. The fin such a way that access to the product can only

FIG. 24-6. Horizontal form/fill/seal system.

PACKAGING MATERIALS SCIENCE • 729

be attained by irreparably destroying the seal. product. The paper used most often is a high-
Various inner seal compositions may be used, density lightweight paper with poor tear
but the structures most frequently encountered strength. Labels made of self-destructing paper
are glassine and foil laminations. are available; these cannot survive any attempt
Typically, glassine liners are two-ply lamina¬ at removal once they have been applied. To re¬
tions using two sheets of glassine paper bonded duce further the possibility of removing the label
together with wax or adhesive. The inner seals intact, perforation or partial slitting of the paper
are usually supplied inserted in the bottle cap can be made prior to application so that the label
and held in place over the permanent cap liner tears readily along those weak points if any at¬
by either a friction fit into the cap or a slight tempt is made to remove it.
application of wax, which temporarily adheres
the seal to the permanent cap liner. If glue-
mounted inner seals are to be used, glue is ap¬ Breakable Caps
plied to the rim of the bottle prior to the capping Breakable closures come in many different
operation. The application of the cap forces the designs. The roll-on cap design used in the past
inner seal into contact with the glued bottle rim for carbonated beverages uses an aluminum
and maintains pressure during glue curing and shell, which is placed over the bottle neck dur¬
until the cap is removed. When the botde cap is ing the capping operation. The cap blank is held
removed, the inner seal is left securely anchored on the bottle under pressure while rollers crimp
to the bottle rim. and contour the bottle tread into the cap blank.
Pressure-sensitive inner seals can also be The bottom portion of the cap is rolled around
used. The pressure-sensitive adhesive is coated and under the locking ring on the bottle neck
on the surface of the inner seal as an encapsu¬ finish. This lower portion of the cap blank is
lated adhesive. During the capping operation, usually perforated so that it breaks away when
the torque pressure ruptures the encapsulated the cap is unscrewed, which serves as a visible
adhesive, which then bonds the inner seal to the sign of prior opening. A ratchet-style plastic cap
rim of the bottle. One type of pressure-sensitive is also commonly used for a number of different
inner seal is constructed of thin-gauge styrene products. In this design, the bottom portion of
foam innerseal material coated on one side with the closure has a tear-away strip, which engages
a specially formulated torque-activated adhe¬ a ratchet on the bottle neck. To remove the clo¬
sive. The adhesive has minimal surface tack, sure, the bottom portion of the closure must be
but when applied with a properly torqued cap, it tom away to disengage the ratchet and allow the
provides excellent adhesion to both glass and removal of the cap.
plastic bottles.
A third method of application uses a heat-
sensitive adhesive that is activated by high-
frequency induction. This type of application Sealed Tubes
requires the use of aluminum foil as part of the Collapsible tubes used for packaging are con¬
inner seal composition. Once the cap is applied, structed of metal, plastic, or a lamination of foil,
the bottle is passed under an induction coil, paper, and plastic. Metal tubes are still used for
which induces high-frequency resonation in the those products that require the high degree of
foil. The frictional heat that is generated acti¬ barrier protection afforded by metal. Most of
vates the heat-seal coating and bonds the liner to these are made of aluminum and are usually
the bottle. This type of seal can only be used coated to eliminate compatibility problems be¬
with plastic caps since metal caps would inter¬ tween product and package. Puncture inserts,
fere with the induction sealing of the inner seal. which are usually made of aluminum 3 to 5 mil
To meet the tamper-resistant criteria, the inner thick, are used to seal the tube opening for
seals must be printed or decorated with a unique tamper resistance.19 These inserts have to be
design. The seal must also be bonded suffi¬ punctured and pried out to gain access to the
ciently to ensure that its removal would result in product. Extruded plastic tubes are widely used
destruction of the seal. for those products that are compatible with the
limited barrier characteristics of plastic. . These
tubes are usually constructed of polypropylene
Tape Seals or polyethylene. For high-barrier packaging,
Tape sealing involves the application of a metal or laminated tubes are used. Laminated
glued or pressure-sensitive tape or label around tubes are constructed of a multilayer lamination
or over the closure of the package, which must made of foil, paper, and plastic specifically tai¬
be destroyed to gain access to the packaged lored to the product requirements. The lamina-

730 • The Theory and Practice of Industrial Pharmacy

tion is used for the body of the tube with the plished in a number of ways. The most prevalent
head injection molded onto the tube. Since the method has been the use of the “tuck end” de¬
head is injection-molded, any number of designs sign. The tuck end design feature allowed the
are available that must be cut or broken to gain ends of the carton to be held closed by the physi¬
access to the product. These seal end designs cal engagement of the side tabs at the open end
are usually molded of low-density polyethylene. of the carton, with the slits placed in the carton
The tubes are filled from the other end and are tuck or lid. This design feature, which has been
sealed either by crimping the end in the case of prevalent in the folding carton industry because
metal tubes, or by induction sealing in the case of its functionality and compatibility with high¬
of plastic or laminated tubes. Additional infor¬ speed packaging equipment, is no longer consid¬
mation can be found under the heading “Col¬ ered an acceptable closure mechanism for OTC
lapsible Tubes,” a previous section in this chap¬ products. If tuck end cartons are to be used, they
ter. must be augmented with some other form of
tamper-resistant packaging such as film over¬
wrapping, tape sealing or glue sealing the car¬
Aerosol Containers ton. Seal end cartons differ from tuck end car¬
tons in that rather than using the mechanical
The aerosol container used for pharmaceuti¬
interlocking design of the tuck end to close the
cal products is usually made of drawn alumi¬
carton, externally applied glue or hot melt is
num. The inside of the container can be spe¬
used to provide carton sealing.
cially coated if product compatibility is a
problem. A hydrocarbon propellent in its cooled
liquid phase is added to the container along with FDA Regulations
the product, and a spray nozzle contained in a
When the FDA evaluates a drug, the agency
gasketed metal ferrule is crimped over the open¬
must be firmly convinced that the package for a
ing of the aerosol container. A length of polyeth¬
specific drug will preserve the drug’s efficacy as
ylene tubing, called a dip tube, is attached to the
well as its purity, identity, strength, and quality
inside of the spray nozzle and dips into the prod¬
for its entire shelf life. Under the provisions of
uct, drawing product into the spray nozzle when
the Federal Food, Drug and Cosmetic Act, how¬
the sprayer is activated. The spray nozzles are
ever, no specifications or standards for con¬
usually metered to allow a specific dose to be
tainers or container closures are provided.
dispensed with each spray. The design of the
Under the Act, it is the responsibility of the
aerosol package makes it inherently tamper-
manufacturer to prove the safety of a packaging
resistant. See Chapter 20 for a further discus¬
material and to get approval before using it for
sion on aerosol containers.
any food or drug product.
The FDA does not approve containers as such,
but only the materials used in the container. A
Sealed Cartons list of substances considered “Generally Recog¬
Folding paperboard cartons have been used as nized As Safe” (GRAS) has been published by
a secondary package for OTC products for many the FDA. In the opinion of qualified experts they
years. The popularity of this packaging mode is are safe under specified conditions, assuming
based on both functional and marketing consid¬ they are of good commercial quality.
erations. With the advent of mass marketing of A material that is not included under GRAS or
OTC products in the self-service sections of prior sanction, and is intended to be used with
larger stores, shelf presence and product stack- food, must be tested by the manufacturer, and
ability became a dominant consideration in the the data must be submitted to the FDA.
package design. The mass distribution of fragile The FDA has published regulations (part 133)
products also placed a requirement on the sec¬ that implement the Current Good Manufactur¬
ondary package for the prevention of breakage ing Practice requirements of section 501 (a) of
during distribution. Labeling requirements in the Act.
many cases exceeded the limited copy area pro¬ Part 133.9 of these regulations sets forth crite¬
vided by the label on the primary container and ria with respect to product containers, which
consequently required additional copy area to be manufacturers, processors, packers, or holders
provided as either inserts or carton panels. All of of drugs use as guidelines. The specific FDA
these considerations were addressed with the regulation relative to drugs states that “con¬
use of a folding carton to contain the primary tainers, closures and other component parts of
package. drug packages, to be suitable for their intended
The closure of folding cartons can be accom¬ use, must not be reactive, additive or absorptive

PACKAGING MATERIALS SCIENCE • 731

to an extent that the identity, strength, quality or 3. Modem Packaging Encyclopedia and Planning
purity of the drug will be affected.” Guide. Vol.,46. McGraw-Hill, New York, 1973.
Any drug container must be approved for such 4. United States Pharmacopoeia XIX. Mack Publishing,
Easton, PA. 1975.
use, along with the drug, before going on the 5. Bacon, F. R.: The Chemical Durability of Silicate
market. 1116 drug manufacturer must include Glass. The Glass Industry. Vol. 49. 1968.
data on the container and package components 6. Cooper, J.: Plastic Containers for Pharmaceuticals
in contact with the pharmaceutical product in Testing and Control. World Health Organization Pub¬
its New Drug Application (NDA). If the FDA can lication, No. 4, 1974.
determine that the drug is safe and effective, 7. Autian, J.: J. Pharm. Sci., 52:1, 1963.
8. Autian, J.: J. Pharm. Sci., 52:105, 1963.
and that the package is suitable, it approves the 9. Modem Plastics Encyclopedia. Vol. 49. McGraw-Hill,
drug and package. Once approved, however, the New York, 1972-1973.
package may not be altered in any manner with¬ 10. Athalye, A. S.: Popular Plastics, 16:28, 1971.
out prior FDA approval. 11. Pinsky, J.: Package Engineering, 12:74, 1967.
In the case of plastics, most resin manufactur¬ 12. Package Engineering Encylcopedia. Cahners, Bos¬
ers maintain Master Files on their resins with ton, 1982.
13. Modem Plastics Encyclopedia. Vol. 61. No. 10A.
the FDA. Upon request from the resin manufac¬ McGraw-Hill, New York, 1984-1985.
turer, the FDA uses this fiie as a reference to 14. Autian, J.: Drug and Cosmetic Industry, 102:47, 54,
support a New Drug Application that which a 79, 1968.
drug manufacturer files. 0 15. Autian, J.: Bull. Par. Drug Assn., 19:142, 1965.
More detailed presentations on FDA regula¬ 16. Griffin, R. C., and Saccharow, S.: Principles of Pack¬
tions are included in Chapter 27, “Quality Con¬ age Development. Ari Publishing, Westport, CT,
1972.
trol and Assurance,” and Chapter 28, “Drug 17. Varsano, J., and Gilbert, S. G.: Packaging of Pharma¬
Regulatory Affairs.” ceuticals in Plastic Containers and Films. Packaging
Institute Report, October, 1968.
18. Source Book for Closures. Packaging Institute, New
York, 1969.
References 19. A Look at 11 Solutions to O-T-C Tamper Packages.
Package Engineering. Cahners, Volume 27, No. 13.,
1. Hanlon, J. F.: Handbook of Packaging Engineering. December 1982.
McGraw-Hill, New York, 1971. 20. Plastics Packaging for Drug Products—The Regula¬
2. Bacon, F. R.: Specifications of Glass Containers for tory Story. The Society of the Plastics Industry Man¬
Pharmaceutical Use. Owens-Illinois Co., 1970. ual, New York, 1967.

732 • The Theory and Practice of Industrial Pharmacy

_25
Production Management
J. V. BATTISTA

Pharmaceutical manufacturing has long been particular area of responsibility. The deliberate
recognized as a major industry in the United contamination of drugs recendy experienced in
States. Its contribution to our economy is illus¬ the distribution chain has added a new dimen¬
trated by the fact that it employs 158,000 peo¬ sion to the responsibilities of production and has
ple,* has a combined annual sales in human further emphasized the necessity of close and
products of $12.9 billion, and has the second continuous cooperation between industry, FDA,
highest return on sales. When compared with all and others in the protection of the public.
industries in the U.S. with regard to profit, most
pharmaceutical corporations rank within the
first 100 companies in profitability and invest Good Manufacturing Practices
proportionally more than others in research and
development. In this regard, recent advances in (GMP)
biogenetics and gene modifications are ushering To deliver to the public lifesaving drugs of the
in a new era in disease treatment and the manu¬ highest quality and purity, the pharmaceutical
facture of pharmaceuticals. Clearly, then, the industry traditionally has cooperated with the
combination of marketing, research, manufac¬ Food and Drug Administration (FDA), even in
turing, finance, and sales reflects a high degree recent years, when the regulatory agencies have
of professional 'management within the indus¬ become increasingly restrictive. The combined
try. efforts of industry and government are reflected
Production in a pharmaceutical company con¬ in the Good Manufacturing Practices Regulation
sists of the creation and maintenance of a clearly (GMP) of 1971.1 More recently, the FDA has
defined organization and makes effective and increased surveillance by introducing the Inten¬
coordinated use of personnel, land, buildings, sified Drug Inspection Program (IDIP) and the
and equipment, including the management of Drug Enforcement Administration (DEA). In
inventory assets. All of these activities are per¬ addition, the definition of drugs has been ex¬
formed in accordance with the highest stand¬ panded to include devices and diagnostic prod¬
ards and at the lowest total cost. ucts.
Before a new product can be marketed or an
existing product significantly improved, the pro¬
duction department together with research,
product development, sales, and marketing de¬ Personnel
partments must define and agree upon costs, The time-worn phrase, “Quality must be built
profits, marketing dates, and product quality. into a product and cannot be inspected in,” has a
All manufacturing in the pharmaceutical in¬ serious and particular application in pharma¬
dustry must be done in compliance with the ceutical production. The quality control depart¬
FDA Good Manufacturing Practices Regulations ment can monitor production and indicate when
(GMP); hence, all production personnel should a process is deviating from control standards,
understand GMP, at least as it applies to their supply statisical data and constructive com¬
ments, and help in producing a quality product,
but the production department bears the ulti¬
‘This refers to those in the field of ethical products only. mate responsibility for quality. If a product fails,

733
the production department is required to find and checked, and that during all steps in the
and correct the problem. manufacturing process, all containers, drying
Production is further supported by the engi¬ racks, and other equipment should clearly state
neering department, which must participate in the product name and lot number as well as the
such matters as the selection of equipment to process stage. In packaging operations, a well-
ascertain that contact surfaces are hot reactive conceived line purgation system should ensure
or additive. Its services are basic in the matter of that all materials from a previous batch have
location of equipment and adequacy of dust been removed and that the new package order is
pickup to prevent cross-contamination. Those in properly identified with respect to the correct
the engineering department should also be con¬ labeling as well as the batch number.
cerned with the air quality in sterile operations, Shipping and distribution departments should
the design and configuration of buildings to per¬ ship only approved materials and should deal
mit adequate storage and cleaning, proper sew¬ effectively with problems related to recording lot
age disposal, adequacy of potable water, and the numbers on invoices, which is so critical in the
like. development of a product recall system. Proper
The GMP Regulations, although quite specific stock rotation and all other controls exercised at
in some areas, can generally be regarded as the producing location must also be provided
broad and subject to wide interpretation by both and monitored at every warehouse and branch
the regulatory agencies and management in in¬ location. Warehousing personnel should under¬
dustry, as well as by operating personnel. In stand the importance of any quarantine system
addition to adequate training and experience, for supplies and should never deliver unap¬
the Regulations state that personnel should proved materials to a processing department. In
have “adequate information concerning the rea¬ large operations, it may be difficult to place ap¬
son for the application of pertinent provisions of proval labels on every bag, drum, or container,
the GMP ... to their respective functions.” and any substitute system must be clearly un¬
Comprehensive on-the-job training of both derstood, be foolproof, and be acceptable to FDA.
hourly and supervisory personnel should in¬ For these and other reasons, each employee
clude interpretation of the Regulations as they must clearly understand why accuracy, cleanli¬
apply to job responsibilities. ness of operations, and strict adherence to in¬
In most cases, the quality of production in one structions are necessary.
department has an important effect on the oper¬ Written operating procedures are required
ations of another, and employees should be under the Regulations, and they are considered
trained to understand such interrelationships. helpful in an employee training program. A well-
For example, if the tablet department is produc¬ documented system and standardized proce¬
ing a product at the low end of the tablet hard¬ dures not only help personnel training, but also
ness range, in turn causing excessive tablet provide a basis for the development of a self¬
breakage during packaging, then one depart¬ inspection program that will permit auditing of
ment is transferring problems to another depart¬ operations by production management from
ment, thereby making the problem more diffi¬ time to time to ensure continuing compliance. A
cult and expensive to correct. typical self-inspection program for a packaging
operation can be found in Eastern Regional Pro¬
ceedings of PMA-FDA Seminar on “Quality As¬
Training surance in Drug Manufacturing."2
It would be difficult to exaggerate the impor¬
tance of personnel training. Since GMP touches
on all areas of manufacturing, participation by General Facilities
engineering, quality control, materials handling, Sections 133.3 and 133.4 of the GMP Regula¬
warehousing and distribution, purchasing, and tions indicate the far-reaching effect GMP has
other departments is a necessary step in ensur¬ on buildings and equipment in terms of cross¬
ing compliance. contamination, sanitation, construction materi¬
The training of hourly personnel in the manu¬ als, environmental impact, equipment selection,
facturing area is particularly important, since and other factors. The value of land, buildings,
new employees may find themselves in a rela¬ and equipment represents one of the highest
tively technical environment, dealing with po¬ investments in assets by a pharmaceutical com¬
tent or dangerous chemicals, and working with a pany. Improvements to avoid cross-contamina¬
system of weights and measures that is unfamil¬ tion and other important problems, combined
iar to them. GMP clearly states that all materials with higher costs of construction materials and
going into a batch must be properly identified labor, have caused building costs to escalate to a

734 • The Theory and Practice of Industrial Pharmacy

general average of $100 per square foot, with Table 25-1. Facilities Cost as Percentage of
some specific departments running over $200 Total Assets
per square foot in 1982.
Land, Buildings,
Equipment % of Total
Cost (In Millions of Dollars) Assets

As an illustration of the importance of facili¬ American Home

ties, the depreciated asset values of land, build¬ Products 770 25
ings, and equipment of a few companies have Warner-Lambert Co. 843 30
been tabulated from 1984 annual reports (Table Merck 1913 42
25-1). Lilly 1280 35
Such high expenditures in new facilities or in G. D. Searle 496 30
the refurbishment of existing ones makes it Schering Plough 912 36
imperative that investments provide the best
operations consistent with company policy and
GMP requirements. Creating the best facilities
and selecting the best equipment, therefore, re¬ Space Allocation
quire a continuing cooperative effort between As important as the provision of adequate
production people who know the process param¬ space for production is the proper space alloca¬
eters and engineering people who can provide tion for each operation. A departmental analysis
the necessary designs. Such a cooperative effort of space allocation is beyond the scope of this
avoids design and contruction mistakes, which section, but a comparison of some major areas is
may be expensive and difficult to correct at a of interest.
later date. For example, it is best to invest in the The data in Table 25-2 represent the facilities
right type of flooring for a particular area rather of a major pharmaceutical company whose oper¬
than incur high annual maintenance costs in ations extend to more than 45 countries and
cleaning or patching floors not properly specified over 140 plants. Included in the tabulation are
for that area. Manufacturing areas have literally some domestic and international operations rep¬
miles of service piping and ductwork overhead resenting prescription products (Items 1,5,6, 7,
and along walls, and such exposed services re¬ & 8); proprietary products (Item 4); and for gen¬
sult in high cleaning costs to avoid contaminat¬ eral comparative purposes, Items 2 and 3, which
ing both the products and work areas below. represent a combination of proprietaries and/or
Concealment of such construction errors is ex¬ mints and chewing gum operations.
pensive. It is obvious that the production department
In view of continuing escalation of construc¬ and the warehouse occupy most of the space.
tion costs and high cost of borrowing, companies One might also observe that plants 6, 7, and 8,
with old or underutilized facilities have devel¬ whose total size is less than 500,000 square feet,
oped rationalization strategies in which opera¬ require 21 to 39.3% of the total area for produc¬
tions have been consolidated into one or more tion. In plants occupying more than 500,000
plants and some facilities have been sold. square feet (1,3, and 5), however, a significantly
Construction materials, dust collection, and larger percentage of the plant (i.e., over 40%) is
other facilities are discussed in greater detail devoted to production.
later in this chapter. The same table shows little percentage differ-

Table 25-2. Space Allocation (Thousand Square Feet)

Production Warehouse
Total Office (%) (%) Other

1. 1652.6 159.7 756.5 (45.7) 367.7 (22.2) 368.7

2. 615.8 7.5 163.3 (26.5) 196.3 (31.8) 248.7
3. 595.8 23.1 270.5 (45.4) 172.1 (28.8) 130.1
4. 502.7 23.4 128.3 (25,5) 300.7 (59.8) 50.3
5. 502.6 24.5 207.3 (41.2) 215.5 (42.8) 55.3
6. 304.5 40.9 84.4 (27.7) 70.5 (23.1) 108.7
7. 286.2 16.7 57.3 (21.0) 77.1 (26.9) 135.1
8. 77.7 3.2 30.6 (39.3) 16.0 (20.5) 27.9

PRODUCTION MANAGEMENT • 735

ence in the space occupied by the warehouse, One of the most significant steps taken to pro¬
regardless of plant size. The only exceptions are vide industry-wide information in these areas
plant 5, which includes a significantly larger was a survey made by the Production and Engi¬
biologic operation, and plant 4, which is a pro¬ neering Section of the Pharmaceutical Manufac¬
prietary operation and has the highest ware¬ turing Association (PMA) in 1967 and updated
housing occupancy of plants over 500,000 in 1973. This publication is entitled “Survey of
square feet and the smallest production area— Current Manufacturing Practices in the Drug
just a reversal of the space allocations in phar¬ Industry,” and it is divided into three chapters—
maceutical manufacturing. This operation is Personnel, Buildings, and Equipment. In re¬
dominated by a few high-volume proprietaries sponse to questionnaires sent out to both large
that require large continuous manufacturing and small members of PMA, a detailed summary
operations, thus minimizing space needs for of information has been compiled that repre¬
production while increasing the size of ware¬ sents a cross section of practices and materials
housing areas. utilized in the industry.
Plant 2 is a combination of high-volume Table 25-3 provides a departmental checklist
proprietaries and gum operations, a substantial with a selection of materials that have proven
number of which require large-batch and con¬ durable over the years for walls, floors, and ceil¬
tinuous operations. The result is a production ings. Levels of lighting and general air-condi¬
area that is slightly smaller than the warehouse. tioning requirements are also listed. In the se¬
Plant 3, a pressed mints and gum operation, is lection of construction materials, initial costs are
largely automated, but the massive equipment only a partial consideration, since maintenance
occupies considerable space. On the other hand, enters into the total cost.
although there is a high volume of case goods, The selection of decorating colors in the man¬
the product is small and compact, and less space ufacturing and office areas is important, espe¬
is needed for the warehouse. cially in plants with few or no windows. The sec¬
In addition to space allocation by these broad tional use of different colored paints in long
categories, GMP Section 133.3 (Buildings) corridors avoids a tunnel-like impression; and
states that adequate space must also be provided the hanging of washable wallpaper in such areas
for the following: (1) orderly placement of equip¬ as the packaging room provides both pleasant
ment and materials to minimize mixups or surroundings and low maintenance costs.
cross-contamination; (2) receipt and storage of
all material in a quarantine area prior to use;
(3) holding of rejected materials; and (4) manu¬ Dust Collection and
facturing and processing operations and others.
Cross-Contamination
Cross-contamination constitutes an ever¬
Environmental Factors present danger in pharmaceutical manufactur¬
ing. Identification and removal of its causes
Materials, Lighting, and Air- have had a profound effect on plant layout as
well as on the design and construction of pro¬
Conditioning Specifications duction areas. In many cases, a reassessment of
Section 133.3 and subsection (b) of GMP refer dust collection requirements and specifications
to adequate cleaning, construction, lighting, has been necessary. For example, the develop¬
ventilating, and other important factors in a pro¬ ment of increasingly sensitive test methods for
duction operation. Since the word “adequate” is penicillin, coupled with the awareness that
used throughout GMP, one cannot be specific some individuals are extremely sensitive io this
with respect to the amount of lighting in each antibiotic, necessitated a complete relocation of
department, the type of ventilation, or the mate¬ penicillin production into a separate facility
rials of construction for floors and walls. away from all other operations to avoid possible
Based on personal preference and on the ex¬ cross-contamination.
periences of other companies, a choice can be T^pes of Dust-Collecting Systems. Al¬
made from an enormous array of available mate¬ though many types of dust collectors are avail¬
rials. These decisions are important when a new able, the selection of equipment should be based
building is being designed, but become ex¬ primarily on its intended application. Cyclone
tremely difficult in the redesigning of an old fa¬ collectors, for example, have limited application
cility, in which case ceiling heights, wooden in pharmaceutical production except for their
floors, and other outmoded features must be use in a spray-drying operation in which large
taken into consideration. volumes of powder are processed on a continu-

736 • The Theory and Practice of Industrial Pharmacy

 X X X XXX X

X X X X X X X X X X X

3 I
XXX X X X X X X X X X X

-> §
a
§

X X X X X X X X X X

XXX XX X X X X X X X 8 x X X

XXX X X X X X X X X X

: -e
Table 25-3. Facilities Guide for GMP

j -S' XXX XX X X X X X X X

Ibg
__ *2
c3 co G fi M t

l
CD 3
I JH 3 8. Stl
1 * I -3 ti S SS
■3 ^ •a S 1
“gj-
I 111;
c/5 w > O >
9» S’ 1 8 S
IsIlS
■i II
’Sib E
3
5 B Is?
li £05 #
J O* tj
<

PRODUCTION MANAGEMENT • 737

ous basis. On the other hand, replaceable filters, dust collectors are the replaceable filter, cloth
cloth bags, wet scrubbers, and high-efficiency bag, and HEPA types. In large operations, the
particulate air filters (HEPA), or a combination collectors are placed on the roof or on a mezza¬
of some of these, are commonly used. nine. These air filters are rated on an efficiency
Wet Collectors. A wet scrubber operates by basis as defined by the National Bureau of
mixing the dust-laden air stream with water in Standards (NBS) and the American Filter Insti¬
an enclosed chamber, which discharges the ef¬ tute (AFI), utilizing the Dioctyl-phthalate (DOP)
fluent into the sewer or treatment plant. A test method. Figure 25-1 illustrates a DOP effi¬
Rotoclone operates by spraying the air in the col¬ ciency table for particles in the 0.3-micron
lector and mixing it by means of high-speed pad¬ range. For example: Astrocel would be rated at
dles. This type of scrubber is efficient and uses a 99.97% efficiency, but selection of Varicel 50
minimal amount of water. Both systems are par¬ lowers efficiency to 35%. Other tables are avail¬
ticularly effective when a dye is used as the able for various particle sizes.
component of a dosage form, and it is therefore HEPA filters are effective at 100% in particle
necessary to prevent trace quantities from con¬ ranges of a few microns, and at one time, these
taminating nearby operations. Either process were used exclusively in sterile operations to
can be used when water-soluble, volatile sol¬ reduce particulate matter. The current empha¬
vents are used in pharmaceutical manufactur¬ sis on reducing cross-contamination, however,
ing, since the entrained vapors are diluted with has resulted in their use in many dry-product
water to a safe level of concentration. operations, such as granulating, tableting, and
Filters, Bags, and High-Efficiency Partic¬ capusle filling.
ulate Air Filter. The most commonly used The handling of products containing at-

„ -, f 99.99
100%-' 99.971 ASTROCEL \_99.999
(INIT. EFFICIENCY)
ELECTRO-PAK 95
90% 95 BIOCEL

ELECTRO-CELL
(IN IT. EFFICIENCY) 80-85
VELOCITY INFLUENCES EFF.
HUI 80%
80-85 DRI-PAK, NO. 100

70%
-| 65 1 VARICEL 90

60%

50%—-{~50l DRI-PAK, NO. 90

40%
VARICEL 50
]{
jj |\ DRI-PAK, NO. 60
30%

20%

L0%

0%
FIG. 25-1. DOP efficiency. Dioctyl-phthalate aerosol averaging 0.3 microns. Determinations made by light-scattering
method. Average value over life of media unless otherwise noted.

738 • The Theory and Practice of Industrial Pharmacy

tentuated viruses requires the use of HEPA fil¬ about 200 to 300 cfm at a minimum velocity of
ters with no return air circulation as a minimum 2000 feet per minute.
precaution. When viable pathogenic viruses or
other dangerous organisms are being processed,
it is best to incinerate all exhaust air at a temper¬ A Guide to Pharmaceutical
ature above 800°F.
Departmental Specifications. In addition
Manufacturing Facilities
to selecting the correct type of dust collector for The following information on manufacturing
each department, it is desirable to provide the facilities provides a guide to good manufacturing
air volume and velocity required for the collector practices for a number of pharmaceutical opera¬
to do its job effectively. One of the most common tions.
failures in dust collection is an insufficient air
velocity to carry all particles from the pickup lo¬
cation to the collector, and the most sophisti¬ Chemical Weighing
cated unit can become ineffective, especially if it This first important step in the manufacturing
is located some distance away from the pickup process has been receiving an increasing
location. For example, the dust pickup stations amount of attention because of possibilities for
on a tablet press should handle not only the fine cross-contamination and misbranded products
and coarse granulation, but also broken tablet due to incorrect ingredients or quantities. Many
pieces that may have been picked up on the companies have adopted a central weighing de¬
turntable or placed there by the press operator. partment to service all of the processing areas.
Chemical Weighing. Figure 25-2 shows a The advantages of this system are the centrali¬
typical weighing operation, with units located in zation of responsibility, the avoidance of dupli¬
booths, each equipped with a dust collection cating weighing facilities, and lower labor costs.
hood. Although a point-of-use collector may be After an item is weighed and properly initialed
used, a central unit gives better results when a on the batch sheet by the weigher, check-
large room is required or when several weighing weighed and initialed by a checker, and properly
booths are used. In such cases, HEPA filtration packaged and identified, additional weighing at
should be used. The hood for each 14x15 foot the point of use is usually unnecessary. A chem¬
booth should have a capacity of 4500 cfm with a ical weighing department should be designed to
face velocity in excess of 150 feet per minute. provide supervision, checkers, proper weighing
Tablet Granulating and Compressing. equipment, lighting, dust collection, and ade¬
Since granulating operations use several differ¬ quate sanitation.
ent pieces of equipment, each with its own High-potency drugs such as steroids and alka¬
unique problems, dust collection can best be loids should be weighed in a separate room
described in general terms. If the area is air- equipped with absolute filters to avoid even min¬
conditioned, it is possible to minimize cost by imal cross-contamination. This room could also
reusing 85% of the air, provided an HEPA filter be used for weighing dyes (see Fig. 25-2).
is used. Flexible 3- or 4-inch hoses should have Sinks and drain boards should be convenien¬
an air capacity of 200 to 300 cfm and a linear tly located to facilitate frequent cleaning of
velocity of more than 2500 feet per minute for measuring equipment. Cabinets should be pro¬
best results. When applied to tablet presses, vided for the storage of utensils.
however, at least 450 cfrn and a velocity of over Vacuum hoses should be available in the
3000 feet per minute are needed. weighing area immediately adjacent to the
Coating and Tablet Packaging. A typical weighing booths so that the tops of drums and
42-inch coating pan should have a supply inlet other containers can be cleaned free of dust be¬
of 200 cfm and an exhaust of 300 cfm when fore they are opened for removal of contents.
standard ducts axe used. Absolute filters are Balances and scales having the proper capac¬
preferable if 85% of the air is to be recirculated. ity and sensitivity needed for weighing opera¬
If solvent-type film coating is performed in a tions should be specified, and arrangements
conventional Accela Cota or Pellegrini pan, not made for frequent calibration. Printing scales
only does air volume have to be increased sub¬ that record weights on formula sheets and con¬
stantially, but the discharged air must be treated tainer labels should also be provided.
to conform to local and government environ¬ Meters should be used when liquid materials
mental standards. are transferred from storage tanks directly to
Flexible hoses used at tablet counters, powder manufacturing tanks. Each quantity should be
fillers, and cottoning machines should handle recorded on batch sheets, either manually or by

PRODUCTION MANAGEMENT • 739

 AtemrR ABos/B <31*1*1
4IHK,

CHEM. WETI^M R*0£>M

«>um*Tie.

FIG. 25-2. Top, Two weighing booths together with enclosed room for weighing steroids and the like. Bottom, Work bench
and hood, which should be connected to dust collector.

740 • The Theory and Practice of Industrial Pharmacy

means of a printing system. The meters should than tabletting costs when compared on a cost-
be calibrated and checked periodically. per-thousand-tablet basis.
A washing facility (Fig. 25-3) should be avail¬
able for cleaning portable equipment such as
Tablet Granulating granulators and mills. To facilitate cleaning
In general, several different products are in of nonportable equipment, such as fluid-bed
production at any given time. The numerous driers, mixers, etc., each room should be pro¬
steps in the granulating procedure increase the vided with floor drains and a pitched floor
possibilities of cross-contamination, incorrect (} inch per foot) as well as hot and cold water
product identification, and/or mixups. To elimi¬ and steam for special cleaning jobs. Particular
nate these possibilities, a separate room or booth attention should be devoted to the cleaning of
is recommended for each step. Thus, more drying racks and trays, which should be de¬
space is required and maintenance costs are signed for easy cleaning and made of stainless
higher because the equipment and each room steel or other nonrusting material.
must be thoroughly cleaned between operations. If the department is not air-conditioned, all
In many cases, the cleaning costs are buried in windows should be screened against the en¬
the indirect labor category, when truly it repre¬ trance of insects.
sents changeover costs as in a packaging opera¬ The aforementioned precautions are equally
tion. applicable to the manufacturing of powders and
Compartmentalizing the granulating process bulk materials for capsule filling.
has, unfortunately, fragmented the operation
and increased space, capital, and labor costs.
Granulating should be considered a unit opera¬ Tablet Compressing
tion composed of closely integrated manufactur¬ Booths or Rooms. Separate rooms for tablet
ing steps, and process development work should machines have now become a necessary design
be directed to this area for cost reduction and feature to avoid cross-contamination. When spe-
process improvement. Such effects help reduce cal low-humidity conditions are necssary to en¬
granulating costs, which are invariably higher sure product stability, a chemical unit employ-

>-DOST C«?l-U.BCTk9U (TVr)

^cHWVfrio.

FIG. 25-3. Typical granulating room showing separation of milling, blending, and granulating areas. Note drain in each
area.

PRODUCTION MANAGEMENT • 741

ing lithium or silica gel is satisfactory for relative cleaned and prepared for the next product. A
humidity levels below 20%. Such rooms should room should be made available nearby for the
have special low vapor transmission treatment cleaning of presses and replacement of punches
of walls and should be equipped with air locks. and dies for the next product.
Since it is now common practice to place'each The exact number of tablets produced is com¬
tablet press in its own separate location when in pared to the expected yield by a process called
operation, the rooms can all be the same size or reconciliation. A major discrepancy between
vary in size to accommodate the smallest and theoretic and actual yeilds signifies that an error
largest presses. When large volumes are being may have been introduced at some stage of the
produced, for instance, it is practical to have a procedure. To discover the discrepancy, rotary
booth or room large enough to accommodate two presses should be equipped with automatic
or more tablet machines for the same batch (Fig. counters, which can be set to place the same
25-4). The booth walls should extend from floor number of tablets in each bulk drum, thereby
to ceiling and may be made of tile up to the four- facilitating accountability calculations and tak¬
or five-foot level, with a glass or transparent par¬ ing physical inventory. A schematic drawing of a
tition extending it to the ceiling. Tile or other simple mechanical counter for a double rotary
hard surfaces in these booths should be used press is represented in Figure 25-5. The double
sparingly, since they contribute to the noise rotary press is equipped with a gate that is acti¬
level. Space should also be provided for in-proc¬ vated by a signal after a container is filled with a
ess testing equipment such as balances and tab¬ preset number of tablets to divert subsequent
let hardness testers. tablets into a second container placed nearby.
Tablet Presses. Each press should be In this regard, commercial equipment is avail¬
mounted on metal frames so that it can be able that not only will count tablets but also will
moved by lift trucks into a cleaning area. The monitor and adjust presses to conform to weight
number of booths or rooms needed in the com¬ standards.
pressing department usually does not equal the
number of tablet presses on hand, since all
presses are not likely to be in operation at the Tablet Coating
same time. Once a batch has been completed, Traditionally, tablet coating has been consid¬
the machine should be removed promptly from ered an art and has required a rather lengthy
the booth and replaced with one that has been apprenticeship. The process is noisy and dusty,

ohm* im uncrng.4
- own* cjujynat

-SVUPWlkj® &TYU P«3TH ARRAMS&MBWT

FIG. 25-4. Two booth sizes designed to accommodate single or small rotary presses or larger slugging or multi-layer
presses.

742 • The Theory and Practice of Industrial Pharmacy

 MODIFIED ROWAN
COUNTER ttCXIS
thereby improving dust collection and reducing
cross-contamination hazards.
Polishing cans of either the metal or cloth type
should be isolated from the general coating oper¬
ation, and any solvent-laden exhaust should be
sufficiently diluted with air to meet fire and en¬
vironmental standards of safety.
Adequate cleaning of floors and equipment
can be a problem in coating operations because
of dust and the frequent use of dyes. Sufficient
floor drains should be provided for this purpose,
and pumps should be used for the transfer of
wash water from coating pans to either floor
drains or nearby sinks. For large operations in
which coating solutions made with dyes are for¬
mulated, it is desirable to have a small adjacent
room equipped with a sink and mixing equip¬
ment for this purpose.
FIG. 25-5. Mechanical tablet counter for a double rotary If coated tablets are imprinted with a mono¬
press. gram or a product identification number, each
printing machine should be in a separate booth
to avoid cross-contamination. If an in-line, one-
and since one person operates about five pans, it at-a-time printing machine is used, each ma¬
is a labor-consuming and somewhat inefficient chine should be equipped with an electric eye or
procedure. In recent years, a number of techno¬ other counting device to count tablets as they
logic developments have removed some of the move down the discharge chute. Such devices
“art” and substituted automated techniques that give the official yield and can be used for prod¬
have increased pan sizes and improved the dry¬ uct reconciliation. In addition, if it is necessary
ing cycles. Automated spray coating is now to inspect coated tablets, the inspection equip¬
available, and new products as well as old ones ment should be placed in separate booths.
are being given a film coating or an abbreviated
thin sugar coating applied by mechanical rather
than manual methods.
These technologic changes have necessitated Manufacturing of Liquids
a new approach to the design and layout of a In locations where oral, external, or cosmetic
coating department, but some of the fundamen¬ preparations are made, it is necessary to have
tal considerations still apply. For example, re¬ separate facilities for each group. If this is not
gardless of coating pan size or of whether coat¬ possible, a separating wall should be constructed
ings are applied manually or by spraying, the to isolate one group from another, thereby pre¬
pans are placed in line and may be freestanding venting cross-contamination and the transfer¬
or enclosed (Fig. 25-6). Dust collection consider¬ ence of odors.
ations as previously described are still important Special attention should be given to the de¬
even though some new designs in pans vent the sign and installation of equipment and washing
dust through the back of the pan. facilities, especially those used for products that
Enclosing pans in groups of five or more offers are susceptible to microbiologic contamination.
some advantages. The enclosure muffles the Sanitary pumps and fittings should be used, to¬
noise level to acceptable limits. This is particu¬ gether with stainless steel tubing with snap-on
larly helpful in a large coating operation when connections, to facilitate easy removal and
the noise level approaches the maximum per¬ cleaning. Troughs should also be available to
mitted under the OSHA (Occupational Safety permit the cleaning and soaking of piping and
and Health Administration) maximum average transfer lines on an overnight basis. They
(80 decibels). The noise level can also be re¬ should be made of materials that withstand com¬
duced in open pans by the use of insulating ma¬ mercially available detergents and germicidal
terial or foam around the outside of the coating solutions, e.g., stainless steel.
pan, but product temperature control is thus Although the use of potable water is necessary
rendered more difficult. As indicated in Figure in all operations, it is particularly important in
25-6, each pan can be equipped with a window liquid manufacturing. If deionizers and other
that can be closed during dusty operations, water treatment equipment are used, special at-

PRODUCTION MANAGEMENT • 743

 &Vmt WN mx=t-<5~S*C> Wtt

S-L.eVAT>£>M 'A1
•ScWSMATfeS-
FIG. 25-6. Top, An enclosed bank of coating pans. Polishing pans should be in a different location from coating pans.
Bottom, Differences between open and enclosed pans.

744 • The Theory and Practice of Industrial Pharmacy

tention must be given to routine microbiologic tions, a wall or movable partition between pack¬
and chemical testing. Storage tanks and piping aging lines has been used.
used for bulk storage of such liquids as glycerin The choice of straight lines or U-shaped lines
and mineral oil should be constructed to facili¬ can be made only on the basis of department lay¬
tate examination as well as cleaning. out or line speeds. If U-shaped lines are se¬
Good Manufacturing Practices requires accu¬ lected, essential materials-handling activities
rate yields for liquid preparations and reconcilia¬ that are not related to actual filling or labeling,
tion of yields as in solid dosage forms. If the for both the input and output sides of the U,
same tanks are used to manufacture more than should be performed outside the department
one product, liquid meters and tank calibrations (Fig. 25-7). This arrangement not only elimi¬
are important to product reconciliation. In many nates noise, heavy traffic, and paper dust, but
cases, it is practical to install on each tank load also helps to reduce air-conditioning loads in the
cells that provide readout of its contents. packaging department.
Manufacturing tanks located on either side or Straight packaging lines, on the other hand,
around a work platform or gantry should- be suf- do not lend themselves to such an arrangement,
ficiendy far away from each other to avoid cross¬ since the output end of the line must be pro¬
contamination, especially when dry powders are vided with shipping cases and case-sealing ma¬
an ingredient. The elevated platforms should be chinery, and all finished products must be car¬
sufficiently large to permit the positioning of ried out of the room with lift trucks.
pallets or raw materials around the tanks and For operations in which there are considera¬
still provide sufficient room for the separation of ble numbers of labels of the same size or color,
adjoining tanks. the concept of roll labeling equipment versus cut
labels should be explored carefully. Roll labels
have many advantages over cut labels in avoid¬
Packaging ing mislabeling or label mixups in either the
Packaging lines should be far enough apart to label-printing operations or the storage and han¬
prevent cross-contamination, product mixup, or dling of labels in packaging. As the name im¬
other serious problems. Normally, a separation plies, when the continuously printed sheet of
of 15 to 20 feet is adequate, and in some opera¬ labels comes off the printing press, it is slit, and

FIG. 25-7. U-shaped lines with bottle filling and case sealing external to department. Distance between lines is 25 ft, and
a divider can be used for separation when needed.

PRODUCTION MANAGEMENT • 745

each row of labels is wound into a roll around a ment of pallets is also advisable to minimize in¬
center spool. Each label also has an identifying sect infestation.
mark on it that not only provides correct label A quarantine area for incoming raw materials
identification, but also allows electronic count¬ and packaging components is necessary, and an
ing, thereby permitting good label reconciliation. enclosed quarantine area must be provided for
If cut labels must be used, label-scanning raw materials, packaging components, bulk
equipment should be provided for label identifi¬ products, and finished goods that have been re¬
cation either before the labeling operation, at the jected for failure to meet various standards.
labeling machine, or at both times.
Labels should be stored in an air-conditioned
room, and in winter, the air should be humidi¬
fied to maintain a relative humidity of about
Shipping and Receiving
50% to avoid overdrying of labels. The room Constant movement of materials in and out of
should have sufficient space for storage of in¬ the building subjects this area to the greatest
serts and be subdivided to separate approved possibility of insect and rodent infestation. This
from unapproved labels and inserts in accord¬ is particularly troublesome in tropical areas and
ance with GMP (see Fig. 25-7). when night operations are in progress. Air cur¬
The department should be equipped with an tains have been used to prevent flying insects
adequate number of sinks to permit washing of from coming into the building, but their effec¬
measuring utensils such as graduates and pack¬ tiveness is somewhat limited.
aging line equipment parts. Usually, one sink is When an inside dock is provided, it should be
sufficient for two lines. large enough to permit both the trailer and the
The cleaning of dry products filling equip¬ tractor to park inside the building. Overhead
ment by vacuum or compressed air should be doors can be used to close off the dock area.
conducted during shutdown hours when the Each opening at the loading platform where
danger of cross-contamination is minimized. trucks back into an outside wall should be
Whenever compressed air is used for cleaning, equipped with compressible receptacles that ef¬
the equipment should be removed from the line fectively seal the truck’s opening with the entry
if possible or completely enshrouded during the port into the building.
cleaning operation. Only approved finished goods should be kept
Space should be available for use by depart¬ in the shipping area. Items awaiting quality con¬
mental and/or quality control line inspectors for trol approval should be kept in the quarantine
the storage of counting boards, graduated cylin¬ area. If this is not possible, a system that clearly
ders, torque testers, and other in-process testing identifies approved finished goods in the ware¬
equipment; also, cabinets should be provided for house must be used.
clean utensils and parts. Alcohol and other combustible solvents should
A staging area should be available for the stor¬ be stored in explosion-proof rooms equipped
age of packaging equipment not in use and ma¬ with special fire protection facilities. If narcotics
chine change parts, and facilities for cleaning and other dangerous drugs are handled, vaults
and dismantling packaging equipment should approved by the Drug Enforcement Administra¬
also be provided. tion (DEA) must be used for storage of finished
goods as well as for in-process materials. It is
advisable to have the alarm signal connected
directly with the nearest police station.
An inspection center immediately adjacent to
Warehousing the receiving dock should be provided where
Since warehousing is normally the largest facilities for the examination of incoming mate¬
operation in the plant in terms of area, special rials are made available. This can be used by the
attention should be focused on maintaining quality control department for statistical inspec¬
cleanliness, freedom from infestation, and or¬ tion and the sampling of raw materials and fin¬
derliness. The entire warehousing area should ishing supplies. The area should have lighting of
be cleaned as often as necessary to maintain not less than 150 footcandles. The inspection
sanitary conditions. Mechanical floor washers center should also be equipped with sinks and
may be used in large facilities. From time to other facilities for washing test equipment, and
time, wooden pallets are subject to spillage of space should be provided for storage of retained
materials, and an area in which to clean pallets samples for quality control as well as permanent
should be provided. Occasional pesticide treat¬ production records.

746 • The Theory and Practice of Industrial Pharmacy

 Dust collection hoses should be provided to safety stock (see “Concepts of the Order Point
clean the tops of containers prior to placement in System,” later in this chapter).
the general warehouse. Inventories are classified as follows:

1. Materials. These are such chemicals as active in¬

Materials Management gredients, diluents, and excipients needed to manu¬
facture intermediates or components of the finished
The role of materials management is to con¬
product. Included in this category and best shown
vert the sales forecast into a production forecast separately are finishing supplies such as containers,
and then into raw materials, finishing supplies, labels, caps, and shippers needed in the packaging
intermediates, equipment loading, and labor operation.
hours. It is then necessary to see that all of these 2. Components. These are parts or sub-assemblies
are available at the right time and place to maxi¬ needed for the final assembly of the end product (e.g.,
mize the use of company assets and provide the bulk tablets awaiting packaging).
best customer service with the lowest inventory 3. Work-in-Process. As the name implies, these are
investment. To do this effectively, there must be materials and components on which work is being
done.
control over purchasing, receiving, shipping,
4. Finished. Goods. These are the salable items, sam¬
warehousing, and distribution as well as produc¬ ples, or other promotional items held in inventory
tion planning and scheduling, and continuous awaiting customer orders or made for specific custom¬
liaison is needed with production, marketing, ers.
sales, and quality control departments.
Materials management has the dual responsi¬
bility of determining the amount of inventory as Inventory Management
well as its accountability. Inventories are an It is customary in any production operation to
important part of a company’s working capital consider return on investment in buying capital
and are reported to stockholders in the annual equipment, and many appropriation requests
report. are turned down if the rate of return is too low.
Activities most identified with materials man¬ Commitments for inventories must be consid¬
agement are production planning and inventory ered in the same way, and obviously, the pur¬
control. Production and inventory control prin¬ chase and holding of a one-month supply of an
ciples were developed from statistical or mathe¬ item gives a better return on investment and
matical approaches. More recendy, the evolu¬ inventory turnover than a two-months supply.
tion of operations research has permitted many This is an oversimplification since there are
production and inventory control problems to be many costs associated with inventory decisions,
expressed mathematically, and statistical proba¬ for example, ordering costs, out-of-stock costs,
bility theories have provided new methods for clerical costs, computer costs, and quality con¬
solving complex business problems by means trol costs; others are too numerous to list here.
of a computer. In this regard, the selection of Examination of the annual reports of several top
computer hardware and the development or pharmaceutical companies that have the great¬
purchase of software systems are important re¬ est return on equity shows that inventories can
sponsibilities of the materials management represent anywhere from 35 to 80% of working
department to ensure that any management in¬ capital, and some of these have worldwide in¬
formation system provides timely and accurate ventories approaching $700 million! Not only
data on thousands of daily transactions occur¬ does it cost money to acquire inventory, it also
ring in manufacturing and related operations. costs money to hold it until used.
A generally accepted method of quantifying
inventory costs is as follows:
Inventories
Basically, inventories are needed to satisfy Inventory Carrying Cost Breakdown (%)
future demands, and the pharmaceutical indus¬ Cost of money 11.0“
try has relatively long process cycle times and Storage and handling 8.5
procurement lead times. The inventories may be Obsolescence 4.4
described as a combination of fluctuations in Taxes 1.0
anticipation, lot size inventories, and invento¬ Insurance 0.1
ries to cover movement of materials from one 25.0
location to another. All of these are affected by
fluctuations in demand and manufacturing lead
times, which are covered by reserve stock or ‘Currently about 15.0%.

PRODUCTION MANAGEMENT • 747

 PARETO CURVE
A practical illustration of the importance of this
quantification is as follows:

Average Worldwide Inventories

$280,000,000
Inventory Carrying Cost at 25%
$ 70,000,000/yr
A 10% reduction in investment would save
$ 7,000,000.
Inventory reduction would release in cash
$ 28,000,000.

Obviously, a well-managed inventory can exert

considerable financial leverage, and inventory
reduction can release much needed cash which
the corporation can invest in more profitable
ventures and reduce borrowing.
The inventory investment, however, must al¬
ways take into consideration its effect on out-of-
stock situations as well as the desired customer
service level. Table 25-5 (p. 754) demonstrates ABC ANALYSIS

the relationship between safety stocks and vari¬ FIG. 25-8. Pareto curve. Graph shows that 40% of items
ous customer service levels. can account for 90% of total value.

The ABC Concept

items fall on the curve at 90% of the total inven¬
One of the most important and simplest tools tory value, and other relationships can easily be
used for inventory management is the ABC clas¬ calculated from the curve-
sification of inventories. This classification is Each item, such as raw materials, can be ex¬
based on a principle first outlined in the late pressed as the total annual procurement value
1800s by V. Pareto, an Italian engineer and in descending order for easy classification.
mathematician. In its simplest terms, it states
that in a large population in which many items Combined % of Total
are involved, relatively few items account for the Annual Annual Cumulative
major part of activity. For example, 15% of the Items Value Value (%)
highest-value items in inventory amounts to 1-4 $1,800,000 36 36
70% or more of the total inventory value. An¬ 5-6 600,000 12 48
other 25% of medium-value items accounts for 7-30 500,000 10 58
an additional 20% of inventory value. Therefore, 31-40 1,600,000 32 90
the combined A and B values, which amount to 41-200 500,000 10 100
only 40% of the total items, nevertheless repre¬ $5,000,000
sent a combined value of 90% of the total inven¬
tory. The remaining 60% of items represents a This table shows that the first 30 items (15%
small value. These are classified as A, B, and C, of 200) represent 58% of the total annual value.
respectively. This means that when there are a The next group of 31 through 40 items repre¬
substantial number of items to be controlled, sents an additional 32%. This means that in this
emphasis should be given to A and B items, particular illustration, by closely following 30
since on the average, they constitute the major raw materials that could be classified as A items,
portion of total inventory value. By concentrat¬ 58% of the total annual value would be covered.
ing attention on the management of A & B By examining 10 items that can be given a B
items, one is in effect covering about 90% of the classification, an additional 32% would be cov¬
inventory value. Inventory levels of C items ered. Therefore, by closely watching 40 items
should be given little attention and can even be out of 200, there would be a coverage of 90% of
kept at a high level since they contribute only a the total annual value. Obviously, little attention
small percentage to the raising or lowering of needs to be given to items 41 through 200, since
inventories. they represent only $500,000 and 10% of total
Figure 25-8 shows that 40% of all inventory annual purchases.

748 • The Theory and Practice of Industrial Pharmacy

Inventory Reporting and Analysis Conversion of General Inventory
Since inventories are reported in dollars, the Dollars to Months of Supply
figures are of little value unless they are related
The cumulative monthly forecasted cost of
to something, such as the ratio to cost of goods.
goods sold, which equals the inventory dollars,
A commonly used expression is “Turnover”
gives the equivalency in months of supply:
(TO), or “Stock Turn Rate” (STR), which shows
the relationship of inventories to the amount of
goods that could be produced from those figures Example: If the total inventory is $10 million
when related to factory door cost on an annual and finished goods total $6 million, what are the
basis: equivalents in a month’s supply?

Forecasted Cost of Goods Sold (millions)

„ „ = COST OF GOODS IN PERIOD Cumulative
tu or otn cosx 0F INVENTORY ON HAND
January 2 2
February 2 4
If the annual cost of goods is $20,000,000 and 3 7
March
the inventory is $10,000,000, the STR is 2.0, April 2 8
meaning that the inventory “turns over” twice a May 2.5 11.5
year. Such information is generally given to the June 3.1 14.6
top people in management to provide a general
inventory view, but at best, it shows an incom¬ By subtracting finished goods from the total in¬
plete picture. ventory, the remaining balance must be supplies
In addition, a STR of 2.0 for one division of a and work-in-process. Since the $10 million in¬
company or one group of products may be com¬ ventory falls between April and May, by interpo¬
pletely unacceptable to another division or lation, this works out to be 4.4 months.
group, which may be producing large-volume
consumer products and may expect inventories Total Finished Supplies and
to be turned over more often. What the STR of Inventory Goods Work-in-Process
2.0 is really showing is that there is a 6-months $10 million $6 million $4 million
total inventory on hand. 4.4 mo 2.64 mo 1.76 mo
Inasmuch as inventories are on hand to take 6/10 x 4.4 4/10 x 4.4
care of future sales demands, it is not accurate to
relate today’s inventories to a previous cost of Carried to its logical conclusion, such a report
goods. An expression of inventory dollars as they should be broken down further into individual
relate to forecasted sales would be more realistic. products or product groups representing A or B
To control and analyze inventories properly, it items to ensure that inventories that are not in
is best to develop a relationship to inventory dol¬ line or are above inventory policy limits will
lars as well as to the length of time such inven¬ clearly show, so that investigation and further
tory will last, expressed in number of months’ action can be taken (Table 25-4). Such a report
supply. If it is established that a 10 million dollar issued monthly provides meaningful informa¬
inventory is too high, this figure by itself does tion to all managerial personnel in materials
not permit proper inventory analysis to deter¬ management, production, sales, and accounting,
mine in which categories the high inventory since it covers A and B items and therefore most
occurs. This can be done as follows. of the inventory investment.

Table 25-4. Inventory and Months of Supply by Product Classification

Description
Raw Materials Fin Supplies In Process Bulk Finished Goods
by M$ Mos M$ Mos M$ Mos
M$* Mos M$ Mos
Classification

Product-A 73.0 2.2 81.4 2.7 11.5 .2 48.7 1.1 239.8 2.3
Product-B 10.8 1.6 6.2 1.8 14.2 1.3 24.0 2.1 40.0 2.9
25.6 2.4 31.0 2.2
Product-B 12.4 .9 4.8 3.2 19.3
If
*$ in thousands.

PRODUCTION MANAGEMENT • 749

Sales Forecasting plest approach is to assume that demand is
steady and that sales for any new period will be
The importance of a well-planned, well- the same as for the current period. Simple aver¬
executed sales forecast deserves emphasis, be¬ aging, then, is not realistic; it treats all data
cause therein lies the basis for many business equally, since there is no way of emphasizing or
decisions. A sales forecast dictates future per¬ “weighting” some portion of the data.
sonnel, equipment, and warehousing require¬ Weighted Averaging. Arithmetic averages
ments. It also generates the inventory invest¬ “weight” all data in terms of previous sales,
ment plan and determines the amount of cash which can be called the old forecast, and since
needed to operate the business. At the same inventories are for future sales, no means is pro¬
time, purchasing personnel are apprised of the vided for “weighting” future requirements. If
amounts needed, so that they can arrive at the the average weekly sales for last year were 100
best prices and delivery dates. pieces and the first week’s sales for the new year
Responsibility for Sales Forecasts. With were 70, it would be unreasonable to “weight”
few exceptions, sales forecasts are made by the these numbers equally in forecasting future
marketing staff, and this perhaps is as it should sales. If a “weighting factor” of 1 was used (same
be. They should know the conditions in the mar¬ as 100%), it would be logical to recognize more
ketplace and be able to assess the effects of com¬ “weight” in the 52 weeks of last year’s data than
petition, advertising and promotion, changes in in one week of the new data in computing the
prices, and the size of the sales force in view of new forecast. For instance, consider the follow¬
fluctuating demands. Poor forecasting can have ing:
serious ill effects on production operations. The
production staff, on the other hand, continually The Weighted Average
calls attention to violent changes in sales de¬
First Week
mands as they affect operations. Sometimes
forecast inaccuracies are offered as an excuse Simple Weighted
Average Average
for problems in production management. When
inventories are too high, the forecast often is “Old forecast” = 100 x 0.5 = 50 x 0.9 -90
blamed for not meeting the plan, and people are (Avg/52 wks)
either laid off, or worse, kept on and underuti¬ Sales = _70 x 0.5 = 35 x 0.1 = _7
lized, thereby increasing costs and reducing (Latest wk) 170 Avg 85 Avg 97
labor efficiency. Sometimes the problems are
due to forecast inaccuracies and sometimes to Second Week
errors in production planning. Both groups (Using Weighted Average)
should get together to resolve significant differ¬
Old forecast = 97 x 0.9 = 87
ences.
Sales (2nd wk) = 105 x 0.1 = 11
Since sales forecasts have an effect on so
New forecast = 98
many other operations, those operations most
affected should be represented in the forecasting
procedure. The materials management staff In the foregoing example, the average weekly
holds a pivotal position in this regard, inasmuch sales for the past 52 weeks (old forecast) plus the
as it must be alert to significant variations be¬ latest sales total 170, the average being 85.
tween forecasted demands and actual sales. When an equal weight of 0.5 (50%) is given to
Techniques. Basically it is more accurate to each number, the result is an average of 85.
forecast for a large group of items than for any Why should the average of 52 weeks of data be
one item. It is easier, for example, to forecast the given the same weighting as data for one week?
total sales of all the thyroid products in the line This is not a good method.
than to predict how many botdes of 65-mg 100s In the same illustration, one may wish to give
will be sold. Obviously, a forecast of tomorrow’s the 52 weeks (old forecast) a value of 0.9 (90%)
sales can be more accurate than a prediction of and the new one a value of 0.1 (10%): the results
sales two years hence. Additionally, forecasting would produce a new forecast of 97 instead of
should not be thought of in absolute terms, and 85. This in turn can be developed into forecasts
every forecast should include an estimate of for the ensuing weeks, a system well suited to
error. Before the forecast system is used, the computer application.
method should be tested, especially in statistical Exponential Smoothing—First-Order
forecasting, in which trends, seasonality, and Equation. From the foregoing, it can be seen
randomness must be taken into consideration. that it is possible to assign different weighting
Averaging. Simple Averaging. The sim¬ values to averages, and this is particularly useful

750 * The Theory and Practice of Industrial Pharmacy

on moving averages when dealing with averages should be noted and expressed as a plus or
of 3 months, 6 months, 39 months, and so on. In minus value from the actual. These monthly
exponential smoothing, such values range from deviations are then added without regard to the
0 to 1 using a, which is called a smoothing con¬ sign and divided by the time period being meas¬
stant. Thus, to produce a new forecast, the old ured. This is called mean absolute deviation
forecast, the current demand, and a selected (MAD).
value of a are needed. This can be expressed as
follows and is commonly referred to as the first- For example—Forecast 1500
order equation. Time period
New forecast = (1 - a) old forecast + a new (Wk or Mo) Sales Deviation
demand. Accordingly, if the old forecast is 100,
1 1200 -300
current demand 120, and an assigned a 0.2, 2 1500 —
then: 3 1900 +400
4 1700 +200
(1) New forecast = (1 - 0.2) 100 + 0.2 (120)
5 1600 + 100
= 80 + 24
= 104
MAD = = 200 Units
(2) If a is changed to 0.5 D

New forecast = (1 - 0.5) 100 + 0.5 (120)

= 50 + 60 The error can also be expressed statistically by
= 110 calculating the standard deviation, but this is
time-consuming and requires much computa¬
In (1), the a of the old forecast has a value of
tion. There is an approximate relationship that
80, and in (2), when a is changed to 0.5, the
is expressed, however:
value drops to 50. Thus, it can be seen that as
the a value increases, the old average of 100 is Sigma = 1.25 x MAD
progressively discounted and has less weighting,
whereas the new data give more weighting since
which would give 250 units in the example
it moves from 24 to 60.
given above.
Forecast accuracy is best when data of 2 or 3
If the MAD is watched, the forecast error is
years are available; however, exponential
monitored frequently. This monitoring prevents
smoothing can be used to advantage in forecast¬
overproduction or underproduction and can be
ing for new products for which little prior sales
used as a “tracking signal” to report significant
history exists. As was seen before, the higher the
variations, which in turn would result in produc¬
a value, the less weighting there is on the old
tion or forecast changes.
forecast, so that on new products high a values
Trends and Seasonality in Forecasts. In
can be used to limited advantage. The following
the event of a definite sales trend, the use of the
table shows the equivalency of assigned a values
first-order equation produces forecast error dif¬
to months of data.
ferences, which on a cumulative basis gets
larger and larger. In such cases, the method of
Alpha Values vs.
Equivalent Moving Average3
“least squares” can be used; however, it is some¬
times easier to use second-order smoothing. For
Alpha Equivalent those readers interested in statistical forecast¬
0.500 3 ing, the book by R. G. Brown is recommended.4
0.400 4
0.333 5
0.250 7 Economic Lot Size or Order
0.200 9
0.100 19
Quantity (EOQ)
0.050 39 It is not uncommon to have tens of thousands
0.010 199 of items in inventory, so that materials manage¬
ment personnel must decide how much to buy
As stated before, in any forecasting system the and when each item should be delivered, as well
forecast error should always be measured by as when intermediates and finished products
plus or minus differences between actual versus should be made. With excessively high invento¬
forecasted sales. ries, too much cash is tied up, investment oppor¬
Mean Absolute Deviation (MAD). As a tunities are lost, and obsolescence may be in¬
measure of forecast error, the monthly differ¬ creased. Production and marketing staffs tend to
ences between actual and forecasted sales favor high inventories to get longer production

PRODUCTION MANAGEMENT *751

runs, avoid back orders, and provide the best Order Size vs. Total cost^

customer service levels.

Fixed costs such as set-up and clean-up times
are the same no matter how large or small the
batch size or the packaging run is. Obviously,
the more frequently an item is bought, the lower
the carrying cost is, but such costs as quality
control increases if something is purchased
every month, as opposed to every third month.
Using simple figures for ease in calculation,
the following trial and error method shows the
EOQ.

Total Annual Cost for Various Order Quantities

Assume:
1. Annual usage of 12,000 units L_
2. Unit cost of $3.00
3. Cost of carrying inventory 10% per year
4. Ordering costs per order $50. Order quontity

FIG. 25-9. Graph shows relationship of changes in order¬

I. Assume a delivery of 500 kg. Cost ing costs and inventory carrying cost to total costs. (Data
■from Plossl and Wight.5)
Annual fixed costs
(24 orders/yr x $50) $1,200
Annual cost of carrying inventory

x 3 x 10%)
75 that as order quantities go up, so do carrying
Total annual costs
costs, but ordering costs go down. The total cost
1,275
curve shows that total costs decrease with in¬
II. Assume a delivery quantity creasing ordering quantities to a minimum of a
of 1,000 kg.
$200 ordering quantity, after which total costs
Annual fixed costs 600 increase with larger lot sizes because of the in¬
Annual cost of carrying inventory 150 creasing effect of inventory carrying costs. In
Total annual costs 750 this case, a $200 order quantity has a total cost
III. Assume a delivery quantity
of $20, but if a $50 order quantity were used, the
of 2,000 kg. total cost would be twice as much or $40.
The EOQ Formula. Considering the thou¬
Annual fixed costs 300 sands of inventory items, a trial and error
Annual cost of carrying inventory 300
method would be impractical; in its place, the
Total annual costs 600
EOQ equation can be used.
IV. Assume a delivery quantity
of 3,000 kg.
EOQ =
Annual fixed costs 200
Annual cost of carrying inventory 450
Total annual costs 650 where A is the annual usage in dollars, S is the
V. Assume a delivery quantity ordering costs in dollars, and I is the inventory
of 4,000 kg. carrying costs expressed as a decimal.

Annual fixed costs 150 Since the foregoing equation shows the least
Annual cost of carrying inventory 600
cost expressed in dollars, the least cost can be
Total annual costs 750
calculated directly as follows by substituting the
'Average inventory is half the lot size. figures used in the trial and erroi illustration.

Therefore, when a 2,000-kg delivery quantity

is ordered, the annual fixed costs and the annual
carrying costs are equal, resulting in the lowest
total annual costs. The interrelationship of the However, using the same example, if the num¬
costs are illustrated in Figure 25-9, which shows ber of units that give the lowest cost is required,

752 • The Theory and Practice of Industrial Pharmacy

the equation is expressed as follows: The order point system represents an attempt
to predict on the basis of past data. It is best used
when there is an independent demand. For ex¬
ample, one only produces finished goods in re¬
sponse to depletion of inventories resulting from
where A is the annual usage in units, S is the sales demands, and therefore a sales forecast is
order cost in dollars, I is the inventory carrying required. However, the components in finished
costs expressed as a decimal, and U is the cost of goods, such as raw materials and finishing sup¬
one unit. plies, need to be purchased only when supplies
needed to produce the finished goods need to be
12 x 12000 x 50 replaced. These requirements can be calculated.
EOQ= V-oT~x""3-
Even so, the purchasing department should be
given adequate notice. The order point system
= V4,000,000 = 2000 Units calculates the quantity and delivery date for
each item separately and independently of the
The EOQ equation shows that the most eco¬ other items that must also be used as part of the
nomical lot size is a function of the square root of production.
the annual usages of items expressed in dollars. In addition to the fact that the square root
The square root relationship also shows in a approach does not balance with lot size or the
general way how much inventories should in¬ other items needed simultaneously, it is not
crease if the sales of a product increases by 20%. time-phased and assumes that some inventory
Obviously, the inventory should not be in¬ should be replenished as soon as it is depleted. If
creased by 20%, and the maximum would be the 1,000 kg of a raw material is consumed in Feb¬
square root of 20. ruary and no further material is needed until
Generally speaking, the application of the June, the order point system dictates immediate
EOQ formula for ordering and lot sizing result in replenishment, and a large inventory may re¬
good materials management. At times, however, sult.
its inappropriate use may lead to increased in¬ Concepts of the Order Point System. The
ventories and costs, since EOQ quantities may following are three basic concepts of the order
not balance with quantities needed for lot sizes. point system.
Set-up costs are also an important factor, and a 1. safety stock. The function of safety stock
technique called LIMIT (Lot-size Inventory is to ensure the best level of customer service
Management Interpolation Techniques) can be and to keep back orders to a minimum. Such
used. stock is necessary because all forecasting tech¬
For additional information on lot-size inven¬ niques have errors, which are generally ex¬
tory and EOQ, the reader is deferred to Plossl,7 pressed as MAD or in standard deviations, and
and to Plossl and Wight.® safety stock compensates for such errors. The
calculation of safety stock is based on the normal
distribution curve and its relationship to the de¬
sired customer service level. If the MAD or stan¬
Inventory Management Systems dard deviation of forecast error is known, the
In managing inventories, two sets of tech¬ order quantity is multiplied by either of these
niques can be used in a manufacturing opera¬ figures, and the result equals the reserve or
tion: (1) statistical inventory control or order safety stock. For example, if the weekly forecast
point, (2) material requirements planning is 500, the MAD is 200 units, and a 98% service
(MRP). is desired, the reserve stock should be 512 units
Statistical Inventory Control vs. Material (Table 25-5). This is derived by multiplying the
Requirements Planning. As indicated earlier 200 units of MAD by 2.56. The use of standard
in this chapter, the concepts of mathematical deviation results in a smaller number. Either of
probability, operations research, the Pareto these figures added to the 500 units of weekly
curve, exponential smoothing, and EOQ all indi¬ forecast results in 1,012 units or 910 units,
cate that mathematical expressions can be ap¬ which in turn defines the order point. Obvi¬
plied in the field of inventory and production ously, this should be applied only When there is
control. When properly used, all constitute sta¬ a random demand.
tistical inventory control, or the order point sys¬ Additionally, the MAD column in the table
tem which most companies are using today. Be¬ shows the enormous increase in safety stocks
fore examining its three basic concepts, a closer needed when moving from a 90% to a 99.9%
inspection of the system is necessary. service level.

PRODUCTION MANAGEMENT • 753

Table 25-5. Safety Factors for Normal Distribution

Safety Factor Using:

Service Level Standard Mean absolute
(% Order cycles vilo stockout) deviation deviation

50.00 0.00 0.00

75.00 0.67 0.84
80.00 0.84 1.05
84.13 1.00 1.25
85.00 1.04 1.30
89.44 1.25 1.56
90.00 1.28 1.60
93.32 1.50 1.88
94.00 1.56 1.95
94.52 1.60 2.00
95.00 1.65 2.06
96.00 1.75 2.19
97.00 1.88 2.35
97.72 2.00 2.50
98.00 2.05 2.56
98.61 2.20 2.75
99.00 2.33 2.91
99.18 2.40 3.00
99.38 2.50 3.13
99.5 0 2.57 3.20
99.60 2.65 3.31
99.70 2.75 3.44
99.80 2.88 3.60
99.86 3.00 3.75
99.90 3.09 3.85
99.93 3.20 4.00
99.99 4.00 5.00

Adapted from Plossl and Wight .5

2. order point. Figure 25-10 shows that at 3. order quantity. The EOQ formula previ-
some point in time, 25,000 items are in inven- ously described assumes gradual inventory de-
tory, and as the weeks pass, the inventory is con- pletion, so that the lot size inventory is equal to
sumed as shown on the downward sloping line. half the order quantity.
This consumption continues until the inventory Material Requirements Planning (MRP),
reaches a predetermined level or ordering point, As stated previously, the order point system is
at which time a replenishment quantity is or- best applied when the demand is independent,
dered. This system assumes that usage is uni- as for finished goods. A more sophisticated and
form; thus, the average inventory is equal to mature approach to production and inventory
one-half the order quantity. The lead time, of control is the recognition of the principles of in¬
course, is that time lapse between placement of dependent versus dependent demand, first ex-
an order and the time it is received and approved pressed by Dr. Orliky of IBM in 1965. When the
by quality control. Since both demand and lead _ demand is for all components that “go into” an
time vary, the reserve stock is really established item, material requirements planning is a far
to take care of both. Accordingly, the order point more satisfactory technique,
is equal to the sum of the anticipated demand If an item such as a bulk tablet is made infre-
during lead time plus the reserve stock. In Fig- quently, or at least not on a continuous basis,
ure 25-10, during the five weeks of lead time, and is made in a large batch, the demand is oc-
about 5,000 units will be depleted from stock, casional, and immediate replenishment of the
and this amount plus the reserve of 10,000 units raw materials may not be necessary, or in, fact,
indicate an order point of 15,000. It must be may be undesirable. An order point system
remembered that randomness of demand during would immediately replenish any or all of the
lead time and gradual inventory depletion are raw materials, but in requirements planning,
the underlying assumptions. ordering would be postponed until the next

754 • The Theory and Practice of Industrial Pharmacy

i
 35 i

30 4
DELIVERY
MAXIMUM
INV. LEVEL

AVERAGE
INV. LEVEL

ORDER POINT
MINIMUM

INV. LEVEL

RESERVE

TIME IN WEEKS
FIG. 25-10. Graphic representation of order point.

scheduled production day, in consideration of In an MRP system, the gross requirements are
the lead time. In other words, in addition to broken down by quantity and required date as
holding orders until needed, this method also follows:
establishes the next requirement date and is
said to be time-phased. Under these conditions, Required Date Needed
if there is a sudden change in quantity or date, 50 1/3
the frequent updating in an MRP system per¬ 30 2/14
mits changing in sufficient time to avoid prob¬ 70 3/4
lems. 100 3/27
There are three general principles to remem¬ 50 4/25
ber for an effective MRP: 300

1. The materials plan must be revised fre¬ It is assumed that it is now January 2, and
quently to react to changes in requirements. that the lead time is four weeks. Actually, the
100 ordered for immediate delivery in the order
2. The smaller the time period used, the more point system do not need to be ordered until the
effective the materials plan wiill be. last week in February. The 50 needed on Janu¬
3. The materials plan must extend over a long ary 3 are already on hand, whereas the 150 on
enough period to cover the longest lead time order will cover 2/14, 3/4, and half of 3/27. By
of any component. time-phasing the order, the material was
brought in only when needed, thereby contribut¬
The following example illustrates the differ¬ ing to reduction of inventory and inventory car¬
ence in order point versus MRP: rying costs.

On hand 50
Plus on order 150
200 Cost Controls
Less gross requirement 300 From the sales forecast, the materials man¬
Net requirement -100 agement group generates a production forecast
that takes into account seasonality, deals and
In an order point system, 100 units are promotions, introduction of new products or
needed immediately, and no one knows when product sizes, and other factors that create a
the 150 on order axe needed, but presumably, demand on inventory, equipment, and person¬
they are needed immediately also. nel. This information in turn permits the devel-

PRODUCTION MANAGEMENT • 755

opment of the operating or expense budgets for sales forecasts, and batch sheets for each prod¬
each department. The information thus pro¬ uct give the exact formula and quantity of all
vided is applicable to a standard cost accounting raw materials.
system, which in its simplest terms, means that In addition to this, and in conformance with
individual item costs, as well as labor and bur¬ GMP, the batch sheet shows actual bulk yields,
den rates, have been fixed or standardized for a which can be compared with the theoretical
period of time, usually a calendar or fiscal year. yields, adjusted to take care of normal losses
during manfuaeturing. A materials usage vari¬
ance report is issued for each department and
The Three Elements of Cost Table 25-7 explains the cumulative results for
The basic elements of cost are materials, tabletting through the month of May. This re¬
labor, and burden; the last item is sometimes port expresses a favorable or unfavorable vari¬
referred to as “overhead.” ance for each product, and it can be seen that
1. Materials. Based on the needs expressed this department shows a net favorable variance
in the production forecast, the purchasing de¬ of $7,018. The value of this report, however, is
partment negotiates contracts and price ar¬ that it shows the variances for each product, two
rangements, and ascertains the standard cost for of which show losses in excess of $2,000—a sit¬
each item. These standard costs form the basis uation that should be further examined.
of a monthly price variance report, which not A similar report covers variances in materials
only measures the effectiveness of purchasing, usage in the packaging department (Table 25-7).
but also monitors changes in cost. This monitor¬ In this case, these variances are expressed by
ing is paticularly important in the pharmaceuti¬ packaging fine, with respect to both variations in
cal industry, in which materials represent the bulk such as tablets and liquid products, and
largest part of the cost of goods. variations in finishing supplies. For example,
The purchase price variance report shown in the May report shows that there was a total un¬
Table 25-6 is for the month of April and shows a favorable bulk variance of $15,399 in the pack¬
favorable ($74,800) cumulative total variance aging department and an unfavorable variance
through the four-month period for three pperat- of $27,796 in finishing supplies.
ing divisions of the company as well as for adver¬ In all cases, the accounting, production, and
tising. For Division B, for example, there is a quality control departments have agreed on a
favorable variance of $10,200 for the month of standard yield as compared with theory, and it
April and $33,200 total of all divisions. Since probably has been derived on the basis of statis¬
each division shows a favorable purchase price tical analysis with losses built into the cost sys¬
variance, their purchases are generally within tem. Variances in finishing supplies are derived
the standard cost predicted. However, to permit by comparing the finished goods produced in
better analysis of price variances, the figures are packaging with the amount that should have
broken down into major categories, such as raw been consumed on the packaging order and with
materials, certain classes of finishing supplies, losses on the packaging line. Both reports show
and others, to help pick out favorable and unfa¬ that product losses on bulk can be quite expen¬
vorable price variances. sive, and differences in yields between process¬
By categories, for example, the report shows ing and packaging point to the need for precision
that raw materials were purchased below stan¬ in the yielding of bulk tablets, liquids, and oint¬
dard costs, showing a savings of $30,100 for the ments by using counters on tablet presses or
month of April and a total savings of $43,300 meters and load cells in other areas, a practice
over a four-month period. This would indicate that will help in GMP reconciliation of bulk.
that the purchasing division is doing a good job, As stated previously, the biggest item in phar¬
and if the savings turn out to be substantial at maceutical cost-of-goods is materials. Reports
year’s end, perhaps selected raw materials cost such as those illustrated are furnished to each
standards could be revised downward next year. operating department for the department head
In general, it is desirable to have a favorable to analyze quickly and decide which products
price variance, but on the other hand, a variance Should be studied further so that problems can
that is too high might indicate poor estimation be corrected.
on the part of the purchasing division; it would In the control of materials costs, the variances
overstate or understate the cost of goods. are budgeted as a hedge against unforeseeable
Another control occurs in the usage of materi¬ price changes. The report described in this sec¬
als during production. From the production fore¬ tion is helpful to both purchasing and produc¬
cast, production planning determines the num¬ tion departments, as it points to problems and
ber of batches of each product needed to meet permits their correction. Of course, the informa-

756 • The Theory and Practice of Industrial Pharmacy

 O
■§> o
CQ

^(N (N CO C0(Nt-^O5Cpt>;i-jC>(NpC0
CO CO CO ID cocdddd'cancirHiD
^'—'co <m r-t ^ CO ^ CQ w^ ^

CO CD CQ M r- co CO CD 00 in o CO q 1—| _ CD q j—t CQ t"-

■i § / \ o CD d o»
■66- CO LD
o
CO
in cd CO o
CD CD in CO
q
CO
d CD CD in cd
CO CQ m r- CO CD
CD
CQ
oo
CO
cd
o
CD
CD
o
CO
§o K—' 05 in CD CQ CO CQ i> l“H ’—i q CD 1> CD
CD ** 00*’ cq~ ** •-J* CO*"

—o 05<0 cd *—j oo C0LqoJpCQp05C0LO--00 CQ in CD !q

CO CD CO rtr-!cdcd^iDcbo3CO(Nod in 00 cd !in
IJ £ t£- (M CN !N Is- lOOinCKNID'-'LOSNN CQ CO O CD LO
^ o> in <N tO CO CM t> «■* *-< 1—' ■q CD_
^ s cd —r (N •-T f-T CO
q

^ c- cq 05 ! q cq —< oo q in ■ ' O N t q ^ 03
^,^6 M CO 6 oi^iri cd cd ■ ' -J cd cao in
CO CQ CO
Table 25-6. Purchase Price Variance Report (In M Dollars)

00 GO CD O qriCCcqn-cN-HiNciq o
•I /-> cq i> d-^rcd,^cdt>c^'^r'^p’^ris^ CO CQ
l> 00 CO OOOCNCDC-CO'^rCNcOCDCO CO
GO CO ® H CQ CD

i—H CD o CD CO oo c- CD t> r-M o CQ o CD LO CD q in q CO

8 q D CQ t> q CO 05 d cd cd d •d CQ o 00 ■^r cd cd CQ d
3 ! £ -tbO- CD c- CQ CD t"- CQ CD CD CQ CO CD CQ 05 CO CD
00 CD in in CQ CQ CD ■^r in
31« q- 03 of
q
) Denotes favorable variance.

CO C/f CO
a ■o 13 13
13
<ffl o •S 8 o g> | ■g *C I < T)5bf) Cfl T3tuO8
73
S a h t3 TO
05 ^ 05 ^ 05 5L,
f2
CO CO CO 15 S q
CO i -S > •§ -s
•> > V ^ £ ^ 2 i§ I s __ _ __
c8Da;0aS0rt0c30qj C q ;s q ;a o
ST)
(

5Sa< CQ tf CQ Wfc JCQOUUU< q q q

PRODUCTION MANAGEMENT • 757

Table 25-7. Summary—Tabletting, Granulating, and Packaging Cost Performance (Year to Date)

Tabletting and Granulating Cost Performance

Material Std. Hrs.

Product Usage Delivered Labor Lost Total Cost
Name Variance To Invty. Performance Time Over Std.

$ $ $ $
“A” 116 615 912 1028
“B” (1493) 948 147 (1346)
“C” 1392 648 (79) 1313
“D” 866 877 579 1445
Etc. 2211 546 1025 3236

2568 375 1574 4142

(896) 401 166 (730)
(4869) 187 436 (4433)
1992 1992
Totals $(7018) 9042 10130 1992 5104

Packaging Cost Performance

Mat’l Usage Var. Std. Hrs.

Line Packaging Delivered Lab. Lost Total Cost
No. Line Descrip. Bulk Fin. Supply To Invtry. P erf. Time Over std.

$ $ $ $ $
1 Tablet 1 345 3406 3767 468 1185 5404
2 2 4446 1574 3257 1234 1404 8658
3 3 (56) 1668 3559 2350 1774 5736
4 4 2553 (2498) 15190 1277 (2229)
5 5(976) 927 1668 3827 1468 6249
6 6(380) (1864) 4569 1152 1370 (725)
7 7 (432) 732 5713 3497 2459 6256

24~ (141) 42 832 133 191 225

25 8531 1738 14649 12877 6612 29758
26 233 727 3567 3092 2300 6402
Totals 15399 27796 31512 36272 110979

tion is important to the accounting department item is expressed as the number of direct labor
and to management as well. hours needed to produce 1,000 bulk tablets or
2. Labor. Direct Labor. In any manufac¬ 1,000 bottles of 100’s for every product made,
turing operation, the management and careful including promotional samples. This informa¬
use of the labor force are important for cost con¬ tion is important to several groups, e.g . the ac¬
trol as well as for the stability and happiness of counting department, production planning, and,
the work force. In most companies, the number of course, the operating managers.
of hours required in each department for pro¬ Indirect Labor. It is easy to identify the di¬
duction of most items is known either by virtue rect labor needed for an item, but to arrive at the
of historical information or as a result of time true cost, indirect labor hours are needed. They
studies by industrial engineers. The latter stan¬ are difficult to measure, however. In some
dard is more practical, of course, since the his¬ plants, the indirect labor has not been ade¬
torical data do not necessarily reflect the most quately identified, and in some departments, it
efficient method of production. In either case, represents a high percentage of the total require¬
the production of any bulk or finished goods ments. Without indirect labor hours, it would be

758 • The Theory and Practice of Industrial Pharmacy

 difficult to analyze and control available hours of laundry for uniforms, maintenance department
work and to use the labor force efficiently. If a charges, travel, membership dues and seminars,
serviceman is bringing caps and bottles to three and the like. An important item in each depart¬
packaging lines, his function represents some mental budget is operating supplies. In the par¬
indirect labor to each of the lines. Whenever enteral department, for example, would be in¬
possible, it would be best to allocate such time to cluded the cost of ethylene oxide used in
the products on each line rather than completely sterilization and the replacement of HEPA fil¬
lose its identity and cost by putting it into the ters. Repairs and maintenance, as well as sup¬
indirect labor class, thereby spreading the cost plies used for production equipment such as
over the rest of the products. punches and dies, must be estimated since
The indirect labor costs that cannot be put these can add substantially to the budget.
into a work standard should be attributed to a Fixed Burden. In addition to the operating
specific purpose, so that they can be identified departments, others such as engineering, qual¬
and controlled. Some examples are the costs of ity control, materials management, and all de¬
mechanics, servicemen, equipment cleaning, partments reporting to each of them also prepare
line changeover, quality control inspectors, and operations budgets, and the expenses and labor
operation of the label room in a packaging de¬ costs form the overhead to be charged in the
partment. In a department such as packaging, manufacturing costs. In addition, the costs of
which may employ 200 to 300 people, the indi¬ fuel, electricity, land and real estate taxes, and
rect labor could amount to several hundred depreciation on the building and equipment. In
thousand dollars a year; therefore, each category the case of quality control, efforts have been
should be budgeted and compared against actual made by some companies to allocate as much
costs on a monthly basis. cost as possible directly into production depart¬
Another cost to watch is the use of direct labor ments to get as close as possible to true costs.
for an indirect labor job. The use of direct labor With a little effort, it is practical in some quality
people for such work should be minimized, since control services to assign reasonably accurate
they have a labor rate higher than indirect labor labor cost and expenses to some production
people and would contribute to increasing the areas. As a simplified illustration of this, if some¬
labor cost. one is keeping a facility and requires rabbits to
Every effort should be made to lower the per¬ test for the presence of pyrogens, the cost of this
centage of indirect labor to total labor for good can be allocated to the parenteral department,
cost control. Each labor category should be ex¬ which requires this service. This principle is not
amined periodically to see if it can be placed into unlike identifying indirect labor into the direct
a time standard. category, and in the example used, it avoids
It is in the interest of efficiency to break the spreading the cost of pyrogen testing over the
work standard down into job skills, e.g., machine other cost centers, which do not use this service.
operators, table workers, and mechanics, since
in the scheduling of production these services
must be available when required. References
3. Burden. There are two types of burden, 1. Federal Register, 36:133, 1971.
direct and fixed. 2. Quality Assurance in Drug Manufacturing. Eastern
Direct Burden. Categorized as direct burden Regional Proceedings of PMA-FDA Seminar, Rutgers
University, March 1969, Workshop No. E., p. 55.
are such expenditures as supervision and cleri¬
3. Pecham, H. H.: Effective Materials Management.
cal help; lost time; premium on overtime; vaca¬ Prentice Hall, Englewood Cliffs, NJ, 1972, p. 30.
tion, holiday, and sick pay; and such employee 4. Brown, R. G.: Statistical Forecasting for Inventory
benefits as hospitalization, insurance, and re¬ Control. McGraw-Hill, New York, 1959.
tirement benefits. 5. Plossl, G. W., and Wight, O. W.: Production and In¬
Additional items falling into direct burden are ventory Control, Principles and Techniques. Prentice
Hall, Englewood Cliffs, NJ, 1967.
controllable expenses incurred in the operation
6. Management of Lot-Size Inventories. American Pro¬
of each department and commonly called operat¬ duction and Inventory Control Society, Chicago, 1963.
ing expenses. 7. Plossl, G. W.: Manufacturing Control. The Last Fron¬
These expenses would include such items as tier for Profits. Reston Publishing, Reston, VA, 1973.

PRODUCTION MANAGEMENT * 759

_26
Kinetic Principles and Stability
Testing
LEON LACHMAN, PATRICK DELUCA, and MICHAEL J. AKERS

The importance of stability testing in the devel¬ ing with this Section is 314.1(8)(p) under New-
opment of pharmaceutical dosage forms is well Drug Applications, and requires “a‘ complete
recognized in the pharmaceutical industry. In¬ description of and data derived from studies of
creased filings of Abbreviated New Drug Appli¬ the stability of the drug, including information
cations (ANDA) and Paper New Drug Applica¬ showing the suitability of the analytical method
tions (PNDA) by generic and nongeneric drug used.” It further states that stability data should
manufacturers have resulted in an increase in be submitted for the new substance, for the fin¬
submissions of stability data to the Food and ished dosage form in the container in which it is
Drug Administration (FDA). With the coming of to be marketed, and, if it is reconstituted at the
the biotechnologic age, and as bioengineered time of dispensing, for the solution so prepared.
products become ready for testing in humans, It requires that an expiration date appear on the
stability test data for these compounds are re¬ label to preserve the identity, strength, quality,
quired as part of the submissions of Investiga¬ and purity of the drug until it is used. In fact it
tional New Drug Applications (INDs) to the states, “if no expiration date is proposed, the
FDA to assure their quality and'safety. This in¬ applicant must justify its absence.”
crease in stability testing has come at a time in Further, the FDA current Good Manufactur¬
which the empiric methods have, for the most ing Practices (GMP) regulations under sections
part, been replaced by a more scientific ap¬ 211.166 and 211.167 set forth basic guidelines
proach to stability evaluation using various ap¬ for stability for all drugs, and the requirement
propriate physical and chemical principles. for expiration dates on pharmaceutical products.
From a regulatory consideration, there are No drug product in a container-closure system is
several sections of the Federal Food and Drug indefinitely stable, and the manufacturer or
and Cosmetic Act that relate to the stability of packer of a drug product is responsible for deter¬
pharmaceutical products. Section 505(b)(4) con¬ mining the stability characteristics for each of
cerns itself with preservation of the characteris¬ the products. In the preamble to the Good Man¬
tics of the new drug and is the basis for requir¬ ufacturing Guidelines published in the Federal
ing stability data in the new drug application. Register of September 29, 1978,1 the Commis¬
Section 501(a)(2)(B) concerns itself with drug sioner of the FDA indicated that valid expiration
adulteration. A drug is considered adulterated if dates must be established for all drug products.
it does not meet the quality and purity charac¬ In a 1983 FDA survey of regulatory actions, it
teristics that it is represented to possess. Section was reported that 22% of GMP violations in¬
505(h) states that a drug shall be deemed to be volved problems with laboratory controls, and
misbranded if found by the Health Education that the most common deficiencies involved sta¬
and Welfare Agency to be liable to deterioration bility testing requirements of section 211.166.2
unless it is packaged in such form and manner, Deficiencies included failures to have written
with its label bearing a statement of such pre¬ stability testing protocols, inability to support
cautions, as are necessary for the protection of product expiration dates, inadequate number of
the public health. stability test batches, and use of assays that were
Of the three sections mentioned, the one that not stability-indicating.
pertains most directly to stability testing of drugs The application of certain physicochemical
is Section 505(b)(4). The FDA Regulation deal¬ principles in the performance of stability studies

760
has proved to be of considerable advantage in A has reacted. Until this occurs, the degradative
the development of stable dosage forms. Only reaction does not depend on the total concentra¬
through this approach is it possible to accurately tion of drug, but only on the portion that is in
and adequately make use of data obtained from solution, resulting in a zero-order reaction.
exaggerated storage conditions for the purposes The rate of decomposition of the drug can be
of predicting the stability at normal shelf storage described mathematically as follows:
for extended periods of time. It is extremely im¬
portant that the pharmaceutical manufacturer Rate of concentration decrease =
accurately predict the shelf stability of a new
product from accelerated storage data, because
of the considerable economic advantage gained
in marketing a new product as soon as possible
after formulation. A sound stability testing pro¬ where: Ca = concentration ofreacting material A
gram is possible only if personnel are skilled in k = proportionality factor = reaction
employing these principles and if appropriate rate
equipment is available. t = time

Since Ca is a constant, x, the amount of A react-

Theoretic Considerations ing> is identified as:
Degradative reactions in pharmaceutical for¬
mulations take place at definite rates and are
chemical in nature. They depend on such condi¬
tions as concentration of reactants, temperature,
Integration of equation (3) yields:
pH, radiation, and catalysts. An effective and
efficient study of these reactions requires the
x = kt + constant (4)
application of chemical kinetic principles.
If the data from a stability study followed a
zero-order reaction, a plot of x versus t, as shown
Order of Reaction in Figure 26-1, results in straight line plots with
In many cases, by stating the order of the re¬ the slope equal to k. The value k would indicate
action, the manner in which the rate of a reac¬ the amount of drug that is degrading per unit
tion varies with the concentration of the reac¬ time, and the intercept of the line at time zero is
tants can be defined. For the most part, the equal to the constant in equation (4).
degradation of pharmaceuticals can be treated In the solid state, many drugs decompose ac¬
as zero-order, first-order, or pseudo-first-order cording to pseudo-zero-order rates as reactions
reactions, even though many of the pharmaceu¬ occur between the drug and moisture in the
tical compounds degrade by complicated mecha¬ solid dosage form. The system behaves as a sus¬
nisms. Consequently, the lower-order reaction pension, and because of the presence of excess
types are treated in detail here, and only minor solid drug, the first-order reaction rate actually
consideration is given to higher-order reactions. becomes a pseudo-zero-order rate, and the drug
Zero-Order Reaction. When the reaction loss rate is linear with time. The rate expression
rate is independent of the concentration of the
reacting substance, it depends on the zero power
of the reactant (Rate = k°C) and therefore is
considered to be of the zero-order reaction. In
this type of reaction, the limiting factor is some¬
thing other than concentration, for example, sol¬
ubility or absorption of light in certain photo¬
chemical reactions. When solubility is the
factor, only that amount of drug that is in solu¬
tion undergoes degradation. This can be de¬
picted as follows:

A (solid) A (sol)-* B (1)

As drug is consumed in the degradative reac¬ FIG. 26-1. A representative zero-order plot of the amount
tion, more drug goes into solution until all solid of drug reacting vs. time.

KINETIC PRINCIPLES AND STABILITY TESTING ' 761

becomes similar to that in equation (3) except Integrating equation (5) in the following form:
that k is K', which indicates the pseudo-zero-
order reaction rate. Pseudo-zero-order rates of
reaction frequently occur with drugs formulated --^ = kdt (6)
as pharmaceutical suspensions.
Garrett and Carper,3 in their study of the color we obtain:
stability of a liquid multisulfa preparation,
showed that the color loss at 500 m/z followed -In Ca = kt + i, (7)
zero-order kinetics. The graph in Figure 26-2
presents their data at several elevated tempera¬ where i is the constant of integration. Convert¬
tures. The straight line plots show that the deg¬ ing from the natural logarithm (In) yields:
radation is behaving according to zero-order ki¬
netics, and the slopes of their lines represent the k
rate of degradation at the particular tempera¬ -log Ca = -- — t + constant (8)
tures.
First-Order Reaction. When the reaction
Using the above equation for a first-order re¬
rate depends on the first power of concentration
action, a straight line is produced when the loga¬
of a single reactant (rate = kCa), it is considered
rithm of the concentration Ca is plotted against
to be first-order. In this type of reaction, a sub¬
time, as shown in Figure 26-3. The velocity or
stance decomposes directly into one or more
reaction rate constant, k, can be calculated by
products (A —» products). The rate of reaction is
multiplying the slope of the line by 2.303. The
directly proportional to the concentration of the
higher the temperature, the greater is the k
reacting substance and can be expressed mathe¬
value, as evidenced by the steepness of the
matically in the following form:
slopes.
Integration of equation (5) between the limits
Hate of concentration decrease =
Ci and C2 and T and t2 results in the following:

= kCa (5)
(9)

-(In C2 - In CO = k(t2 - tj) (10)

1 . Cj 2.303 . Cj
(11)
ta - G n C2 ta - tj °g C2

FIG. 26-2. Plot of optical absorbance of extracted color

against time at 40°, 50°, 60°, and 70°C at 500 mg. (From
Garrett, E, R., and Carper, R. F.: J. Am. Pharm. Assoc., Sci. FIG. 26-3. Representative degradation curves for a mate¬
Ed., 44:515, 1955.) rial deteriorating according to first-order kinetics.

762 • The Theory and Practice of Industrial Pharmacy

 These equations permit the calculation of the 2.303 , _ 100 _ 0.104
rate of decomposition of a substance between ho%- k fog 90 - k
any time interval (t2 - tj) if the concentration of
drug at these two times is known. _ 0.104
tio% - k (16)
Where tj is the time at beginning of the reac¬
tion, t0 is the time at concentration C0, and t2 is or (17)
tio% = 0.152 tx/2
any time t at concentration C, then equation
(11) can be expressed as follows: It is important to note here that the ti/2 or t10%
is concentration independent. In other words, it
2.303 , C0 takes the same time to reduce the concentration
k= (12)
—los c" of drug from 0.1 moles to 0.05 moles as it would
to go from 0.001 moles to 0.0005 moles.
Use of this expression permits the calculation As a result of the foregoing discussion, it is
of the rate of reaction k, by determining the con¬ obvious that knowledge of the specific rate con¬
centration of drug remaining at any time t. stant, k, permits an estimation of the amount of
Equation (11) or (12) can be used to ascertain drug that degrades within a given time. The
whether the reaction is following first-order ki¬ graph in Figure 26-4 indicates the approximate
netics by determining k at several time intervals interrelationship between k and the time elaps¬
and noticing whether the values are essentially ing until 10 or 50% of the drug is decomposed.
constant. Equation (12) is also written as fol¬ Pseudo-First-Order Reaction. If a reaction
lows: rate depends on the concentration of two reac¬
tant species (rate = k Ca Cb or k = Ca Ca or
2.303 . a k Ca2), it would be of a second order. A pseudo-
k=
~108&r^o (13)
first-order reaction can be defined as a second-
order or bimolecular reaction that is made to
Where a = C0, x = amount reacting in time t, behave like a first-order reaction. This is found
and (a - x) the amount remaining after time t. in the case in which one reacting material is
The constant k is called the reaction velocity present in great excess or is maintained at a con¬
constant, or more frequently, the specific reac¬ stant concentration as compared with the other
tion rate. For a first-order reaction, it is a num¬
ber that expresses the fraction of the material
reacting in a unit of time and may be expressed
in reciprocal seconds, minutes, or hours. For
example, when k has a value of 0.001 sec"1, the
material is decomposing at a rate of 0.1% per
second.
The time necessary for a fraction of the mate¬
rial to degrade can be readily calculated. The
half-life, t1/2, of a drug is the time required for
50% of the drug to degrade and can be calcu¬
lated as follows:

2.303 , Co _ 2.303 100

tl/9. — log
k log C k 50

2.303 0.693
log 2 = (14)
k

0.693
therefore tm = (15)

In the pharmaceutical field, the time required

for 10% of the drug to degrade is an important FIG. 26-4. Approximate interrelationship between rate
value to know, since it represents a reasonable constant, k, and. the time elapsing until 10% or 50% de¬
limit of degradation of active ingredients. The composition. (Redrawn from Schou, S. A.: Pharm. Acta
t10% value can be calculated as follows. Helv., 34:309, 1959.)

KINETIC PRINCIPLES AND STABILITY TESTING • 763

substance. Under such circumstances, the reac¬ Influence of pH on Degradation
tion rate is determined by one reactant even The magnitude of the rate of hydrolytic reac¬
though two are present, since the second reac¬
tions catalyzed by hydrogen and hydroxyl ions
tant does not exhibit a significant change in con¬
can vary considerably with pH. Hydrogen ion
centration during the degradative reaction. An
catalysis predominates at the lower pH range,
example of such a situation is the hydrolysis of
whereas hydroxyl ion catalysis operates at the
an ester catalyzed by hydroxyl ion. If the hy¬
higher pH range. At the intermediate pH range,
droxyl ion concentration is high as compared
the rate can be independent of pH or catalyzed
with the concentration of the ester, the reaction
by both hydrogen and hydroxyl ions. The rate
behaves as a first-order reaction and can easily
constants in this pH range are usually less, how¬
be followed by assay for residual ester. A similar
ever, than those at higher or lower pH values. To
approach, and one more frequently employed, is
determine the influence of pH on the degrada¬
to keep the pH constant through the use of. ap¬
tive reaction, the decomposition is measured at
propriate buffers.
several hydrogen ion concentrations. The pH of
An example of a drug that obeys pseudo-first-
optimum stability can be determined by the plot¬
order kinetics is cefotaxime sodium.4 As shown
ting of the logarithm of the rate constant versus
in Figure 26-5, semilogarithmic plots of cefotax¬
pH, as illustrated by the pH profile in Figure
ime sodium concentration versus time result in
26-6. The point of inflection of such a plot repre¬
linear relationships at various pH levels demon¬
sents the pH of optimum stability. Knowledge of
strating first-order rate of hydration (log ki vs. t).
this point is extremely useful in the develop¬
Acid catalysis occurs at ^ pH 4, and base cataly¬
ment of a stable dosage form, provided the pH is
sis occurs at > pH 8, in which the concentra¬
within safe physiologic limits. Studies of this
tions of H+ and OH- respectively are high com¬
type can be performed at elevated temperatures
pared with the concentration of cefotaxime
so that data can be obtained in as short a time as
sodium. possible. The shift of this point of inflection
caused by temperature elevation is usually not
of sufficient magnitude to affect seriously the
conclusions drawn from such data. The plot in
Figure 26-7 gives an actual example in which
the point of inflection for methyl-DL-a-
phenyl-2-piperidylacetate served as a guide in
the development of a stable injectable solution.

o
x
V)
tr
g
x \ PH OF

FIG. 26-5. Observed pseudo-first-order plots for the deg¬

radation of I at various pH values, 25°, and g = 0.5. Key:
V/
□, pH 5.52; O, pH 3.93; A, pH 7.93; O, pH 2.23; ■, pH
8.94; •, pH 0.48; A, pH 9.89. (From Berge, S. M., et al: J. I 2 3 4 5 6 7
Pharm. Sci., 72:59, 1983. Reproduced with permission of pH
the copyright owner, the American Pharmaceutical Associ¬
ation.) FIG. 26-6. pH Inflection plot of maximum stability.

764 • The Theory and Practice of Industrial Pharmacy

 zoo Arrhenius:

k = Se"Ha/RT (18)

where: k = specific rate of degradation

R = gasconstant(1.987caloriesdegree-1
mole-1)
T = absolute temperature
S = frequency factor

The constant of integration in the Arrhenius

equation has been designated as the frequency
factor. This value is a measure of the frequency
of collisions that can be expected between the
reacting molecules for a given reaction. Loga¬
rithmically, it may be expressed as follows:

lnk=—^- + lnS (19)

Converting to log]0:
pH
FIG. 26-7. pH Dependency of the hydrolysis of methyl AHa 1
log k = - + log S (20)
DL-a-phenyl-2-piperidylacetate at 80°. (From Siegel, S., 2.303 R T
et ai: J. Am. Pharm. Assoc., Set. Ed., 48:431, 1959.)

where log S can be considered a constant.

Influence of Temperature on From equation (20), a plot of log k versus

Degradation AHa
yields a slope equal to - from which the
In order for the rate constants or velocity of 2.303R
degradation to be of use in the formulation of value for the heat of activation can be calculated.
pharmaceutical products, it is necessary to eval¬ The heat of activation (AHa) represents the en¬
uate the temperature dependency of the reac¬ ergy the reacting molecules must acquire to
tion. This permits the prediction of the stability undergo reaction. The higher the value for the
of the product at ordinary shelf temperature heat of activation, the more the stability is tem¬
from data obtained under exaggerated condi¬ perature-dependent. The graph in Figure 26-8
tions of testing. According to rule-of-thumb represents a plot of k values obtained at several
methods, the rate of reaction is said to double for elevated temperatures. Since the plot is linear,
each 10° rise in temperature. Although this rule the prediction of stability at shelf temperature is
may serve as a fairly accurate estimate for cer¬ possible by extrapolating the curve to the lower
tain preparations, it is not generally applicable. temperatures and reading off the k value for the
Therefore, to assign an overall factor for the in¬ lower temperature. Once the k value is obtained,
fluence of temperature on the acceleration of it can be used to estimate the time for t]0% deg¬
reactions is foolhardy. Some deterioration reac¬ radation with the aid of equation (16).
tions are not measurably influenced over a 10° In the event that the data available are more
temperature range, while others undergo rapid limited, for example, if the rate constants at two
degradative changes. The recommended proce¬ elevated temperatures or at one temperature
dure is to set up a planned schedule of acceler¬ and the heat of activation are known, it is still
ated tests for each formulation in order to ascer¬ possible to obtain an estimate of the rate con¬
tain the temperature dependency of the stant at a lower temperature by treating equation
chemical changes in the product undergoing (19) to yield equation (22).
evaluation. Using the differential form of equation (19):
The most satisfactory method for expressing
the influence of temperature on reaction ve¬ d In k AHa
(21)
locity is the quantitative relation proposed by dt RT2

KINETIC PRINCIPLES AND STABILITY TESTING • 765

 nius equation has been used by pharmaceutical
scientists in predicting room temperature stabil¬
ity of drug products based on higher tempera¬
ture rates of degradation, there are a variety of
situations in which Arrhenius predictions can
be erroneous or invalid.5,6 Higher temperatures
may evaporate solvents, thus producing unequal
moisture concentrations at different tempera¬
tures. At higher temperatures, there is less rela¬
tive humidity and oxygen solubility, thus hin¬
dering the predictability of room temperature
stability of drugs sensitive to the presence of
moisture and oxygen. For disperse systems, vis¬
cosity is decreased as temperature is increased,
and physical characteristics may be altered, re¬
sulting in potentially large errors in prediction of
stability. Different degradation mechanisms
may predominate at different temperatures,
thus making stability prediction marginal at
best.
Simplified Techniques for Stability
Prediction. Simplified graphic techniques
have been employed to predict the breakdown
that may occur over prolonged periods of storage
at normal shelf conditions. Free and Blythe de¬
FIG. 26-8. Temperature dependency of degradation rates.
scribe such a technique for liquid products
where the decomposition behaves according to
the genera] kinetic laws.7,8 For example, the
Upon integration between the limits kj and k2 plots in Figure 26-9 show that the degradation is
and Tj and T2, the following equation results: following a first-order reaction. The time for the
loss lines at the several temperatures to reach
AHa / T2 - Tj' 90% of the theoretic potency is noted by arrows
(22) on the curve. These time values at different
2.303 R V T2 • T:
temperatures are plotted in Figure 26-10, and
The utility of the temperature dependency re¬ the time for 10% loss of potency at room temper¬
lationship depends on the controlling mecha¬ ature can be obtained from the resulting straight
nisms of degradation. Preparations that degrade line by extrapolation to 25°C. If the extrapolated
through solvolytic processes, e.g., reactions in data in Figure 26-10 show that the time to reach
solution, usually have heats of activation in the
range of 10 to 30 kcal/mole. Here, considerable
advantage may be taken of the significant in¬
creases in rate of reaction that result with tem¬
perature elevation. On the other hand, if diffu¬
sion or photolysis are the rate determining steps
of the reaction, the heat of activation is only of
the magnitude of 2 to 3 Kcal/mole, and little ad¬
vantage is gained by accelerated temperature
studies in prediction, since the temperature ef¬
fect on rate is small. For reactions such as pyrol¬
ysis of polyhydroxylic materials, in which the
heat of activation can be of the magnitude of 50
to 70 kcal/mole, the rate of degradation, which
may be great at elevated temperatures, may not
be of any practical significance at the tempera¬
tures of marketing and storage of the pharma¬
FIG. 26-9. Values of tI0% at several temperatures, (From
ceutical preparation. Blythe, R. H.: Product Formulation and Stability Predic¬
Limitations of Arrhenius Relationship tion. Presented at the Production Section of the Canadian
for Stability Prediction. Although the Arrhe¬ Pharm. Mfgrs. Assoc., April 1957.)

766 • The Theory and Practice of Industrial Pharmacy

 90" 80” 70* 60” *5* 37* ill

■ma-mruM u/ajsolute t)

FIG. 26-12. Two-year shelf-life goal reference decomposi¬

I/ABSOLUTE TEMPERATURE tion. (From Kennon, L.: J. Pharm. Sci., 53:815, 1964. Re¬
FIG. 26-10. Plot of tI0% values vs. absolute produced with permission of the copyright owner.)
temperature(From Blythe, R. H.: Product Formulation
and Stability Prediction. Presented at the Production Sec¬
tion of the Canadian Pharm. Mfgrs. Assoc., April 1957.) now takes about twice as long to fall below 90%
of labeled claim during shelf storage.
90% potency at room temperature is too rapid to Kennon describes the construction of certain
provide an adequate shelf life for the product, it kinetic paths, which can be used for purposes of
is possible to determine the overage required for comparison during formulation development
the product to maintain at least 90% potency for work.9 Using standard kinetic equations, he cal¬
a prescribed time. This is accomplished by draw¬ culated the paths that reactions would follow if a
ing the loss line representative of the 90% po¬ 10% potency loss in two years at room tempera¬
tency value at room temperature, as shown in tures were permitted. By choosing activation
Figure 26-11. Then a line is drawn parallel to energies of 10 and 20 kcal/mole, both of which
this from the desired shelf life back to “0” days. are conservatively low, and by plotting the time
The example shown in Figure 26-11 indicates in months that a formulation would take to drop
that by the use of a 10% overage, the product to 90% potency versus 1/T, one arrives at Figure
26-12. Table 26-1 presents the data used in Fig¬
ure 26-12.
If the potency of the formulation is found to
remain above 90% of its original concentration

Table 26-1. Maximum and Minimum Time at

Which Potency Must Be at Least 90% of Label
Claim at the Temperature Indicated in Order to
Predict a Shelf-Life of Two Years at Room Tem¬
perature.

Temperature Maximum Minimum

37° 12 months 6.4 months

FIG. 26-11. Plot of average and normal loss curves. (From 45° 8.3 months 2.9 months
Blythe, R. H.: Product Formulation and Stability Predic¬ 60° 4.1 months 3 weeks
tion. Presented at the Production Section of the Canadian 85° 6 weeks 2.5 days
Pharm. Mfgrs. Assoc., April 1957.)

KINETIC PRINCIPLES AND STABILITY TESTING • 767

after storage at the various temperatures for cer¬ TEMPERATURE(K)
tain periods of time given in the graph and table, 320 326 332 338 344
there is good assurance that the formulation will
meet the requirement of a two-year shelf-life.
Thus, if the assays are over 90% of original con¬
centration at the minimum times shown (indi¬
cated by the 20 Kcal/mole line on the graph) at
the respective temperatures, in all probability,
the assays will be over 90% after two years at
room temperature. If the assays remain over
90% at the maximum times shown (indicated by
the 10 Kcal/mole line on the graph), it is a cer¬
tainty (kinetically speaking) that a potency of
over 90% will be maintained after two years at
room temperature.
It is evident from the foregoing discussion FIG. 26-13. The concentration-time-temperature curve
that considerable information can be gained on for the degradation of aspirin in 0.1N HCl at 40-70°C.
the stability characteristics of a drug through the Key: O, experimental points; —, mathematical fit (correl¬
use of certain physicochemical principles. Since ation coefficient = 0.9999). (Redrawn from Waltersson,
J. 0., et ai: Acta Pharm. Suec., 19:327, 3982.)
most pharmaceutical preparations are complex,
the degradation reaction may be complicated by
possible interaction of the several ingredients in
and the predicted rate constant at room temper¬
the formulation. It becomes impractical and is
ature is calculated. The advantage of non¬
usually unnecessary to perform thorough basic
isothermal kinetic studies is the short time pe¬
kinetic studies on the final formulation.to obtain
riod required to generate the data for estimating
an estimate of the shelf-life of the product. It
stability. Disadvantages include the need for
usually is sufficient to follow the degradation or
programmable and sophisticated temperature
some property of the degradation as a function of
control equipment and the decrease in experi¬
time at several elevated temperatures, usiijg the
mental accuracy in predicting product shelf-life.
kinetic expressions presented, and then to extra¬
Discussions of kinetic expressions pertaining
polate the data to ambient conditions to obtain
to complex mechanisms, general acid-base reac¬
an estimate of the shelf-life of the product. This
tions, and the influence of ionic strength are not
is demonstrated with practical examples in the
treated in detail but are briefly presented in a
section of this chapter entitled “Chemical and
general manner to provide the reader with an
Physical Stability Testing of Pharmaceutical
awareness of the additional factors that can con¬
Dosage Forms.”
tribute to the stability of a drug.
Thermal stability of pharmaceutical solutions
and suspensions can be estimated by apply¬
ing an accelerated nonisothermal kinetic General Acid-Base Catalysis of
method.10,11 At suitable intervals, time and tem¬
perature are recorded, and samples of drug prod¬ Degradation
uct are placed in a thermostated water bath Buffer salts are commonly used in the formu¬
whose temperature is increased at programmed lation of pharmaceutical liquids to regulate the
intervals. The drug samples are assayed and pH of the solution. Although these salts tend to
plotted at log concentration versus time at a par¬ maintain the pH of the solution at a constant
ticular temperature. The points of the level, they can also catalyze the degradation.
nonisothermal degradation curve, shown in Fig¬ Therefore, it is necessary to evaluate the effect
ure 26-13, are fitted according to a polynomial of buffer concentration on the stability of the
regression equation: preparation in addition to the effect of hydrogen
and hydroxyl ion concentrations. Common
f(t) = a + bt + ct2 + dt3 buffer salts such as acetate, phosphate, and
borate have been found to have catalytic effects
where f(t) is the concentration function, and a, on the degradation rate of drugs in solution. As
b, c, and d are coefficients. The rate constants at examples, Figures 26-14 and 26-15 illustrate the
each temperature are then calculated from the catalytic effects of citrate and phosphate buffers
first derivative of this equation, which repre¬ on cefadroxil degradation at various pH.
sents the slope of the tangent line at each point To determine whether a particular formula¬
of the curve. Arrhenius plots are then generated, tion is catalyzed by the buffer system employed,

768 • The Theory and Practice of Industrial Pharmacy

 the ionic strength is kept constant, and the con¬
centration of buffer is altered, while the ratio of
the buffer salts is kept constant to maintain the
pH. If the degradation reaction is found to be
influenced by the different concentrations of
buffer, then the reaction is considered to be gen¬
eral acid and base catalyzed. In such a case, the
concentration of the buffer ratio should be kept
as low as possible to diminish this catalytic ef¬
fect.

Influence of Ionic Strength on

Degradation
The rate of reaction can be influenced by the
ionic strength of the solution in accordance with
the following equation:

log k = log ko + 1.02 ZAZB Vu (23)

TOTAL CITRATE, M where ZA + ZB are the charges carried by the

FIG. 26-14. Plots of pseudo-first-order rate constant vs. reacting species in solution, u, the ionic
total citrate buffer concentration far cefadroxil degrada¬ strength, k, the rate constant of degradation, and
tion at various pH values, 35°, and ionic strength 0.5. (Re¬ ko, the rate constant at infinite dilution. The
drawn from Tsuji, K., et al.:J. Pharm. Sci., 70:1120, 1981. ionic strength (u = VSc.z,2) is defined as half
Reproduced with permission of the copyright earner, the the sum of the terms obtained by multiplying
American Pharmaceutical Association.)
the concentration of each of the ionic species
present in the solution by the square of its va¬
lence. Plotting the logarithm of the reaction
rates versus the square root of the ionic
strength, as illustrated in Figure 26-16, can de¬
termine whether an increase in ionic strength
increases, reduces, or has no effect on the degra¬
dation rate.
The concentration of salt employed in a liquid
pharmaceutical formulation can increase or de-

TOTAL PHOSPHATE, M
FIG. 26-15. Plots of pseudo-first-order rate constant vs.
total pksopkate buffer concentration for cefadroxil degra¬
dation at various pH values, 35°, and ionic strength 0.5.
(From Tsuji, K., et al.: J. Pharm. Sci., 70:1120, 1981. Re¬
produced with permission of the■ copyright owner, the FIG. 26-16. Dependence of reaction rates on ionic
American Pharmaceutical Association.) strength.

KINETIC PRINCIPLES AND STABILITY TESTING • 769

 "o tively charged ester is being reacted with the
x negatively charged hydroxyl ion.
Z For concentrated solutions, equation (23)
s must be expanded to include interactions be¬
'lu
tween ionic species.

Complex Reactions
Although most degradative reactions occur¬
ring in pharmaceutical systems can be treated
0.7 0.82 0.94 1.06 1,18 1.30 1.42 1.54
by the simple zero-order, first-order, and pseu¬
>fr do-first-order kinetics, as previously discussed,
there are certain pharmaceutical formulations
FIG. 26-17. Influence of ionic strength on the velocity of
hydronium-ion-catalyzed reaction. (From Siegel, S., et al.: that exhibit more complicated reactions. These
J. Am. Pharm. Assoc., Sci. Ed., 48:431, 1959.) have opposing, consecutive, and side reactions
along with the main reaction. In most instances,
the extent of the simultaneous reactions is small
crease the degradation rate of the drug in solu¬ in comparison with the main reaction and can
tion or have no effect. When the drug is posi¬ be neglected. These more complicated reactions,
several of which are now briefly described, in¬
tively charged and is undergoing hydrogen ion
catalysis, an increase in ionic strength caused by clude opposing or reverse reactions, consecutive
the addition of a salt, such as sodium chloride, reactions, and side or competing reactions.
causes an increase in the rate of degradation, as Opposing Reactions. The simplest case of a
reversible reaction is that in which both reac¬
shown in curve 1, Figure 26-16. A decrease in
the rate of degradation results if the positively tions are of the first order, as illustrated by the
charged drug is undergoing hydroxyl ion cataly¬ following:
sis, and the ionic strength is increased by addi¬
tion of a salt as shown in curve 3, Figure 26-16. A *=* B (24)
If the drug undergoing degradation is a neutral
molecule, changes in ionic strength by the addi¬
tion of a salt would have no effect on the rate of A somewhat more complicated reversible reac¬
gradation, as shown in curve 2, Figure 26-16. tion is one in which the forward reaction is of a
The graph in Figure 26-17 shows the in¬ first-order type and the reverse reaction of a
fluence of increasing the ionic strength on the second-order type, as demonstrated by the
degradation rate of a positively charged following:
drug; namely, methyl-DL-a-phenyl-2-piper-
idylacetate undergoing hydronium-ion-cata-
lyzed degradation. A ?=s B + C (25)
A negative salt effect on the degradation rate
is illustrated in Figure 26-18, in which a posi- When the forward and reverse reactions are
both of the second-order type, the reaction takes
on the following form:
i
o
A + B <=* C + D (26)
k1

Reversible reactions of this type are quite

common, but usually, the reverse reaction is
ignored because the concentration is not signifi¬
cantly affected. An example of this is expressed
by the following:

ch3cooh + C2H5OH
>nr ±5 ch3cooc2h5 + h2o
FIG. 26-18. Influence of ionic strength on the velocity of
the hydroxyl-ion-catalyzed reaction. (From Siegel, S., Initially, the reverse reaction can be ignored, but
et al: ]. Am. Pharm. Assoc., Sci. Ed., 48:431, 1959.) as the reaction proceeds, and the concentration

770 • The Theory and Practice of Industrial Pharmacy

of water and ethyl acetate increases, both reac¬ versus time (t), a straight line is obtained, and k
tions influence equation (26). is then obtained by multiplying the slope of the
Since this has been given as a first example of line by 2.303/(a - b).
a second-order reaction, a brief discussion of Consecutive Reactions. When the stages
this type of reaction is presented. For equation of a consecutive reaction occur at rates of about
(26), the rate of reaction is proportional to the the same magnitude, each stage must be consid¬
concentration of the two reacting substances A ered In the kinetics of the overall reaction. The
and B for the forward reaction and C and D for simplest case is one in which both consecutive
the reverse reaction. For the forward reaction, if processes are of the first order, as illustrated by
a and b represent the initial concentration of the the following equation:
two reacting substances, and if x denotes the
moles of A and B in each liter reacting in the A B C (32)
interval of time t, then the velocity of the reac¬ In the consecutive reaction, if k2 is considerably
tion is expressed by the equation: greater than k], B can be considered an unstable
intermediate, and the rate determining step for
dx
= k(a - x)(b - x) (27) the overall reaction would be the conversion of A
to B. The overall reaction could then be treated
by first-order kinetics.
When A and B are present in equal concentra¬
Side Reactions. In some processes, the re¬
tions, a = b:
acting substance can be removed by two or more
Hv reactions occurring simultaneously, as depicted
~ = k(a - x)2 (28) by the following equation:

Integrating equation (28) yields:

(33)
1 dx
= dt
k (a - x)2
I 1 In general, side or competing reactions are
= t + constant
k (a - x) more common to organic chemistry. The organic
chemist routinely deals with the production of
For t = 0, constant = (since x = 0 at t = 0).
ka several compounds from two reactants; how¬
ever, through the proper manipulation of condi¬
1 x tions (e.g., pressure, temperature, concentra¬
k (29)
t a(a - x) tion) the desired product predominates. An
example of a competing reaction is the nitration
The half-life or time for 50% degradation (tj/2) of bromobenzene to produce ortho, meta, and
can be calculated by substitution. para nitrobenzene as follows:
Since x = '/2a at the half-life, substituting into Br Br
equation (29) results in the following equation:
NO,
.“-T5T <30>

Integrating equation (27), in which concen¬ Br

trations of A and B are not equal, the following
equation results:
+ 3H20
1 b(a - x) NO
kt = •In
a-b a(b - x)
Br
or

2,303 b(a - x)
(31)
t(a - b) 'log a(b - x)
b(a - x)
In such a reaction, plotting the log
a(b - x) NO,.

KINETIC PRINCIPLES AND STABILITY TESTING • 771

 Purified insulin degrades by two mecha¬ amide linkage are anesthetics, antibiotics, vita¬
nisms—deamidation and polymerization.12 mins, and barbiturates.
These degradation reactions may occur as con¬ Ester Hydrolysis. The hydrolysis of an ester
secutive and side reactions according to the fol¬ into a mixture of an acid and alcohol essentially
lowing scheme:13 involves the rupture of a covalent linkage be¬
tween a carbon atom and an oxygen atom. Al¬
k± though some of these hydrolyses can be effected
B
in pure water, in the majority of cases, the pres¬
ence of a catalyst is needed to promote the reac¬
* D (34)
tion. These catalysts are invariably substances of
ks a polar nature, such as mineral acids, alkalies, or
C
certain enzymes, all of which are capable of sup¬
where: A = insulin plying hydrogen or hydroxyl ions to the reaction
B = desamido insulin mixture. The alkaline hydrolysis of an ester does
C = polymerized insulin not differ essentially from an acid-catalyzed hy¬
D = polymerized desamido insulin drolysis, except that it is irreversible, and there¬
fore quantitative, because the resultant acid is at
The relative rates of deamidation and polymeri¬ once neutralized. On the other hand, the acid-
zation are pH- and temperature-dependent. This catalyzed hydrolysis of esters is reversible and
example of a complex reaction is probably repre¬ may be made essentially complete in either di¬
sentative of the complexity of degradation mech¬ rection by an excess of water or alcohol.
anisms that are seen with polypeptides pro¬ Of the numerous schemes presented to repre¬
duced by genetic engineering and developed as sent the hydrolysis of esters by either alkali or
pharmaceutical dosage forms. acid, the one given by Walters is perhaps the
clearest to visualize.14
For both the alkali- and acid-catalyzed hydro¬
lysis, it is evident that the ester is cleaved at the
Degradative Pathways acyl-oxygen linkage, that is, between the car¬
Although the decomposition of active ingredi¬
ents in pharmaceutical dosage forms occurs
through several pathways, i.e., hydrolysis, oxida¬ bonyl carbon V C / and the oxygen of
tion-reduction, racemization, decarboxylation, C2H5 (O - C2H5). This type of cleavage takes
ring cleavage, and photolysis, those most fre¬ place for most ester hydrolytic reactions.
quently encountered are hydrolysis and oxida¬ In practice, the general scheme employed to
tion-reduction. Consequently, this section treats denote ester hydrolysis is as follows:
these two important degradation processes in
detail and only briefly reviews the others. O

R1—C—OR + H+ + OH" -*
ester
Hydrolysis
Many pharamaceuticals contain ester or O
amide functional groups, which undergo hydro¬ t I'
lysis in solution. Examples of drugs that tend to R1—C—OH + HOR
degrade by hydrolytic cleavage of an ester or acid alcohol

772 • The Theory and Practice of Industrial Pharmacy

 Alkali Catalyzed Acid Catalyzed

O O
I I
ch3—c—oc2h5 rate-determining ch3—c-o—c2h5
t addition of ionic
OH--'' catalyst H-*

II I
0~ o

ch3—c—o—c2h5
t I
i H

O"
I
ch3-c- -o-c2h5
Combination of' ion with
HO H water gives this unstable
intermediate, which
immediately breaks down
to acid or salt and alcohol.
O

CH3—C + O—C2H5

HO H

This holds true for either acid- or alkaline-cata- kinetic expressions have been employed in the
lyzed reactions. study of the degradation of drugs by ester hydro¬
The general form of the kinetic equations to lysis, but at times, second-order kinetic expres¬
express acid- or base-catalyzed hydrolysis is as sions have been employed.
follows: A number of reports in the literature deal with
detailed kinetic studies of the hydrolysis of phar¬
maceutical ingredients containing an ester
-k(ester)(H*)
group in the molecule. Probably one of the earli¬
est and most thorough studies was performed on
—'jt—'* - -k (ester)(OH~) aspirin by Edwards.15 He studied the degrada¬
tion of aspirin in various buffer solutions and
treated the overall reaction as pseudo-first-order.
These equations denote second-order reactions,
but in studying degradation reactions of this
O
type, it is possible to treat them as pseudo-first-
order reactions. This is done by keeping the C—CH3
OH- or H+ at a considerably higher concentra¬ + H20
tion than the ester concentration or by keeping
the H+ or OH- concentrations essentially con¬
stant through the use of buffers. This would OH
cause the previous equation to reduce to: .0
OH
^^jl-COOH
+ ch2-i— cf\
OH

which represents a kinetic expression for a first- The data in Table 26-2 represent a summary of
order reaction. Whenever possible, first-order the rates of degradation over a wide pH.

KINETIC PRINCIPLES AND STABILITY TESTING • 773

Table 26-2. Aspirin Hydrolysis at Varying pH
at 17°C

pH k (days 1) pH k (days J)

0.53 0.578 6.0 0.120

1.33 0.0835 6.98 0.10
1.80 0.045 8.00 0.13
2.48 0.0267 9.48 0.321
2.99 0.0343 10.5 1.97
4.04 0.088 11.29 13.7
5.03 0.130 12.77 530

From a plot of the log k versus pH as pre¬

sented in Figure 26-19, Edwards was able to
postulate a reaction mechanism and determine
the influence of pH on the degradation. The pH
of optimum stability is at 2.4. At a pH of 5 to 7,
the degradation reaction was essentially pH-
independent, and at a pH above 10, the stability
of aspirin was found to decrease rapidly with
increase in pH. In the area in which the degra¬
dation is pH-independent, there are several re¬
actions going on, each causing an effect of its
own resulting in a cancellation of the effect of FIG. 26-19. Overall velocity constant for aspirin hydroly¬
H+ and OH", which gives a uniform rate over sis at 17°C as a function of pH. (From Edwards, L. ].:
this pH range. Trans. Farad Soc., 46:723, 1950.)
Although the use of pseudo-first-order kinet¬
ics is sufficient to define and study the degrada¬ dation have been under study. The following are
tion of aspirin, the hydrolysis of aspirin proceeds factors to be considered:
through a complex mechanism over the pH 1. pH. If physiologically permissible, the so¬
range studied, consisting of six different degra- lution of the drug should be formulated as close
dative pathways as shown below. as possible to its pH of optimum stability. In the
Other pharmaceutical materials that have event that the hydrolytic degradation of the drug
been reported to degrade through ester hydroly¬ is general acid and base catalyzed, that is, that
sis are procaine, atropine, and methyl p-amino- the degradation is catalyzed by the acid and
benzoate. basic species of the buffer salt in addition to H+
These examples serve to illustrate the impor¬ and OH", the buffer concentration should be
tance of chemical kinetic studies in evaluating kept at a minimum.
the degradative pathways and overall stability of 2. Type of Solvent. Partial or full replacement
pharmaceutical compounds containing an ester of water with a solvent of lower dielectric con¬
group in the molecule. stant generally causes a considerable decrease
As a result of the realization that a considera¬ in the velocity of ester hydrolysis.16"26 Examples
ble number of drugs degrade through ester hy¬ of these nonaqueous solvents are ethanol, gly¬
drolysis, methods to enhance the stability of cols, glucose, and mannitol solutions and substi¬
pharmaceuticals undergoing this type of degra- tuted amides.

CH3COOC6H4COOH + H30+ HOC6H4COOH + CH3COOH + H+ (at low pH)

CH3COOC6H4COOH + H20 ^ HOC6H4COOH + ch3cooh (uncatalyzed)
CH3COOC6H4COOH + OH" ^ HOC6H4COOH + CH3COO"'
(pH independent)
HOC6H4COO" + ch3cooh
CH3COOCsH4COO" + H30+ HOC6H4COOH + ch3cooh
CH3COOC6H4COO" + h2o HOC6H4COOH + CH3COO"'
(uncatalyzed)
HOC6H4COO" + CH3COOH
CH3COOC6H4COO" + OH" HOC6H4COO" + CH3COO" (at high pH)

774 • The Theory and Practice of Industrial Pharmacy

 3. Complexation. The hydrolytic rates may be Table 26-3. Influence of Surfactant on Benzo¬
influenced in two ways by complex formation, caine Degradation at 30°C Using 0.04N NaOH
namely, by either steric or polar effects. Obvi¬
ously, the attachment of a large caffeine mole¬ Half-Life (t!/2) Ncmionic Cationic Anionic
cule, for example, on a benzocaine molecule, in Minutes (%) (%) (%)
can greatly affect the frequency and ease of en¬ 0
64 0 0
counter of the ester with various catalydc spe¬ 18& 1.33
cies (H+, OH-) through steric hindrance. The 324 3.3
reaction also may be affected by the electronic 57 0.067
influence of the complexing agent, which can 425 1.34
alter the affinity of the ester carbonyl ion for the 650 2.46
catalytic species. In general, the steric effect 420 1
would be expected to decrease the hydrolytic 1150 5
rate, whereas the electronic effect may increase
or decrease the reaction velocity.
on the rate of hydrolysis of esters.32 He found
that nonionic, cationic, and anionic surfactants
stabilize the drug against base catalysis, as evi¬
denced by the data in Table 26-3.
A 5% sodium lauryl sulfate solution (anionic)
caused an 18-fold increase in the half-life of
benzocaine. The association of benzocaine close
I to the anionic head group of the surfactant made
CH3
a definite barrier to the approach of the hydroxyl
Caffeine group into the micelle and attack on the ester
linkage. When 2.46% cetyl trimethyl ammo¬
nium bromide in solution (cationic) is used, a
tenfold increase in the half-life of benzocaine
results. This effect is rather interesting, but can
possibly be explained by the fact that although
the negatively charged hydroxyl ion is attracted
Benzocaine by the cationic group, it apparently cannot pene¬
trate beyond this polar head into the deeper con¬
There have been several reports on the influ¬ fines of the micelle wherein the benzocaine ap¬
ence of complexing agents in retarding the hy¬ pears to be held. When a nonionic surfactant at
drolytic deterioration of esters.27-30 Higuchi and 3.3% concentration is used, only about a four¬
Lachman,27 Lachman et al.,28 and Lachman fold to fivefold increase in half-life was obtained
and Higuchi29 have shown that caffeine com¬ for benzocaine, indicating that the nonionic sur¬
plexes with local anesthetics, such as benzo¬ factant is a less effective stabilizer than the ani¬
caine, procaine, and tetracaine, cause a reduc¬ onic or cationic ones. Because of the relatively
tion of the velocity of their hydrolytic high degree of hydration at the surface of the
degradation. These investigators have also nonionic surfactant micelle, it would appear that
shown that the complexed fraction of the ester considerable hydrolytic attack could take place
undergoes essentially no degradation. within the micelle, as well as in the aqueous
Consequently, if it were possible to complex phase. However, this explanation of micelle pro¬
the total amount of drug in solution, it might be tection against hydrolytic degradation of phar¬
possible to stabilize it completely. Because of the maceutical compounds warrants further explo¬
limited solubility of caffeine, it has not been pos¬ ration.
sible to accomplish this in the studies employing 5. Modification of Chemical Structure. A
the hydrochloride salts of the local anesthetics. number of reports in the literature show that
Guttman reported that the velocity of the base- certain substituents added to the alkyl or acyl
catalyzed decomposition of riboflavin was de¬ chain of aliphatic or aromatic esters or to the
creased by the presence of caffeine in solution.31 benzene ring of aromatic esters cause a decrease
It was found that the vitamin in its complexed in the hydrolytic rate.33-38 This may be attrib¬
form with caffeine possessed negligible reactiv¬ uted to a steric and/or polar effect of the substit¬
ity toward alkaline hydrolysis. uent group. For example, by increasing the
4. Surfactants. Using benzocaine as an exam¬ length of, or by branching, the acyl or alkyl
ple, Riegelman studied the effect of surfactants chain, the rate of hydrolysis of the ester usually

KINETIC PRINCIPLES AND STABILITY TESTING • 775

 Nonionic Anionic Cationic

©S.r-e

Drug located at The free negative charges Presence of + ends attracts

periphery of repel incoming OH- ions. OH- at low concentration.
micelle. At higher concentration, the
attached OH- shields the
drug from OH-

decreases, owing to steric hindrance. However, bility by forming less soluble salts or esters of the
if an electrophilic or nucleophilic group is intro¬ drug.42-44 Usually, only the fraction of the drug
duced into the acyl or alkyl side chain of ali¬ that is in solution undergoes hydrolytic degrada¬
phatic or aromatic esters, or on the benzene ring tion. Garrett, in his study with acyl-salicylates,
of aromatic esters, the rate of hydrolysis can be found that a compound that shows rapid hydro¬
increased or decreased by the electronic effect of lysis in solution may be made to exhibit better
these groups.39,40 For example, alkaline hydroly¬ stability than a more stable analog by reducing
sis of aromatic esters is promoted by the pres¬ its solubility.44
ence of electrophilic groups on the benzene ring Transient derivatives are nontoxic additions to
(halogen or N02), which attract electrons away drug molecules, such as hydrolyzable esters,
from the reaction site (ester groups). The hydro¬ which remain intact long enough to improve the
lysis is retarded, on the other hand, by nucleo¬ drug bioavailability and then cleave to allow the
philic groups (CH3, OCH3, and NH2), which parent compound to exert its recognized biologic
cause electrons to move toward the point of reac¬ activity. A transient derivative is a more soluble
tion.32 The reverse effect would be found in the and/or stable form of the parent compound and
case of hydrogen-ion-catalyzed hydrolysis of aro¬ permits better absorption for improved and more
matic esters. reproducible bioavailability. In this case, the
In general, base-catalyzed hydrolytic reactions drug modification undergoes biotransformation
are more affected by polar effects of substituents or hydrolysis at physiologic pH to yield the active
than is acid-catalyzed hydrolysis. On the other form of the drug.
hand, the steric retardation of acid-catalyzed Monoesters of the antibiotics lincomycin and
hydrolysis caused by substituents is greater than clindamycin have been prepared to render solu¬
for base-catalyzed hydrolysis. The total effect ble and stable compounds suitable for injection.
produced by substituents in alkaline hydrolysis, At pH 7.4, the antibiotics undergo biomodifica¬
however, is considerably greater than the effect tion to yield the active undissociated forms.
produced in acid ester hydrolysis.41 This is prob¬ Monoesters of lincomycin with faster rates of
ably accounted for by the fact that in alkaline hydrolysis were found to have greater in vivo
ester hydrolysis, both polar and steric effects of antibacterial activity 45-46
the substituents occur, whereas in acid ester
hydrolysis, the polar effect is almost negligible.
In pharmaceutical practice, it is generally not
possible to employ substituents on the drug mol¬
ecule for improving stability against hydrolytic
cleavage of the ester group, because in most
cases, these substituents also have an effect on
the physiologic activity of the drug molecule.
The dipivalate ester of epinephrine, however,
helps to protect the catechol ring from undergo¬
ing oxidation, thus enhancing the stability of the
topical ophthalmic solution of epinephrine.
6. Salts and Esters. Another technique that is
sometimes employed to increase the stability
of pharmaceuticals undergoing degradation H Rj
through ester hydrolysis is to reduce their solu¬ Lincomycin, R groups = OH

776 • The Theory and Practice of industrial Pharmacy

 Substitution of a hexanoate group: blood levels for the 3-phosphate, which are prob¬
ably related to the rate and degree of hydrolysis.
O Amide Hydrolysis. Pharmaceutical com¬
pounds containing an amide group can undergo
—O—C—C5Hji hydrolysis in a manner similar to that of an ester
type compound. Instead of the acid and alcohol
in the 2 position gives rise to hydrolysis rates at that form as a result of ester hydrolysis, hydro¬
pH 7.4 in intestinal fluid, which are significantly lytic cleavage of an amide results in the forma¬
greater than hexanoate substitution in the 3, 4, tion of an acid and an amine.
or 7 positions. The difference in enzymatic hy¬
drolysis rates is attributed to the different steric
and electronic environments of the four hy¬ O H
droxyl groups. Steric hindrance at the 2 position I I ,
R—C—N—R1 + H20 ->
was also demonstrated by the observation that
(3,3-dimethyl) butyrate hydrolyzed much more amide
slowly than the hexanoate ester.
O
The phosphate esters of clindamycin undergo
biomodification to release the active undissoci¬ 'I
R—C—OH + H2N—R1
ated form. The inactive compound, clindamycin
acid amine
phosphate, on treatment with dephosphorylat-
ing enzymes affords the active compound clin¬
damycin.47 Figure 26-20 shows the percentage Because of the relatively greater stability of
of hydrolysis of clindamycin phosphate esters in amides as compared with structurally similar
various enzymatic systems. The 3-phosphate esters, there is considerably less information in
ester was found to hydrolyze much more slowly the literature on quantitative chemical kinetic
and much less extensively than the 2-phosphate studies pertaining to the hydrolytic stability of
ester. An in vivo study in rats revealed lower such compounds. Pharmaceuticals such as nia-

FIG. 26-20. Percentage of hydrolysis of clindamycin phosphate esters in enzyme systems.

1. Clindamycin—2—P04 in alkaline phosphatase.
2. Clindamycin—2—P04 in rat liver homogenate.
3. Clindamycin—2—P04 in human plasma.
4. Clindamycin—3—P04 in alkaline phosphatase.
5. Clindamycin—3—P04 in rat liver homogenate.
6. Clindamycin—3—P04 in human plasma. (From Brodasky, T. F., and Lewis, C. J.: Antibiot, 25:230, 1972.)

KINETIC PRINCIPLES AND STABILITY TESTING • 777

cinamide, phenethicillin, barbiturates, and
chloramphenicol degrade by amide hydrolysis.
In a report on the stability of salicylamide and
some N-substituted derivatives, Kosky postu¬
lated both basic and acid hydrolysis as mecha¬
nisms for degradation.48 The basic hydrolysis
proceeded as follows:

O
II , slow
R—C—NHR1 + OH- ?—=-

o- O
I fast I
R—C—NHR1 R—C—OH + RJ.NH-
I
OH
fast
O
RC—CT + R‘NH0

The rate-determining step in the hydroxide-

ion-catalyzed reaction is the nucleophilic attack
by the hydroxide ion.
The acid hydrolysis was as follows:
FIG 26-21. Pseudo-first-order plot of the hydrolysis of
O amides in 1.0N perchloric acid at 90°. Key: 1, benzamide;
2, salicylamide; 3, N-(2-diethylaminoethyl) benzamide; 4,
RC— NHR1 + HoO+ — salicylanilide; 5, N-(2-diethylaminoetkyl) salicylamide
hydrochloride; 6, N-(2-dimethylaminoethyl)-salicylamide
.0 hydrochloride; 7, N-(2-diiscrpropylaminoethyl)-salicyT
amide hydrochloride; 8, N-isopentylsalicylamide; 9,
RC—NH2R1 + H20 ~= N-propylsalicylamide. (From Kosky, K. T.: ]. Pharmaceut.
Set, 58:560, 1969.)
O
I fast
R—C—NH2R cylamide was more stable in basic than acidic
medium, probably owing to the protection af¬
forded by the negative charges on the phenolate
H ion. The N-alkyl and N-amino alkylsalicyla-
H mides were highly resistant to acid and base
hydrolysis. This appeared to be due to combined
o
steric hindrance by the hydroxyl group in the
RC—OH2 + r'nh2 — ortho position and the alkyl and aminoalkyi
group on the nitrogen.
The methods available for retarding deteriora¬
RC—OH + R’NHJ tion through amide hydrolysis are similar to
those presented under ester hydrolysis. The re¬
The mechanism for acid hydrolysis of amides placement of all or part of the water with solvent
requires that substituents should exert only of lower dielectric constant would generally in¬
weak polar effects, but that when suitably situ¬ crease the stability of the pharmaceutical prepa¬
ated, they should exert strong steric effects. The ration toward hydrolysis. Contrary to this gener¬
effect of alkyl and aminoalkyi substituents on alization, Marcus and Taraszka found that
the amide nitrogen in retarding the rate of acid aqueous solutions of chloramphenicol contain¬
hydrolysis of salicylamide appears to be due pri¬ ing up to 50% propylene glycol had no effect on
marily to steric hindrance. improving the stability of this antibiotic over
As can be seen in Figure 26-21 in the acid that obtained with solutions of the antibiotic in
medium, salicylanilide was more stable than sal¬ water.49 In fact, a slight increase in the rate of
icylamide, which in turn was more stable than reaction was observed. Consequently, as illus¬
benzamide. Aminoalkyi substituents on the ni¬ trated in this study, it is unwise to make a blan¬
trogen increased the stability of benzamide. Sali- ket assumption that replacement of all or part of

778 • The Theory and Practice of Industrial Pharmacy

the water in a pharmaceutical preparation en¬
hances the stability of an active ingredient. In¬
stead, each situation must be individually evalu¬
ated with due consideration given to the
mechanism of degradation. An instance in
which the use of propylene glycol was found to
retard amide hydrolysis is given in a report by
Bodin and Taub,50 who show that the stability of
pentobarbital in solution is effectively enhanced
by the use of a propylene glycol solvent system.
Ring Alteration. A hydrolytic reaction can
proceed as a result of ring cleavage with subse¬
quent attack by hydrogen or hydroxyl ion. Ex¬
amples of drugs that have been reported to un¬
dergo hydrolysis by this mechanism include
hydrochlorothiazide, pilocarpine, and reserpine.
Quite often, equilibrium kinetics is associated »•
with such mechanisms.
FIG. 26-22. pH-Rate profile of the hydrolysis of hydro¬
chlorothiazide at 60°C. (From Mollica, J. A., Rehm, C. R.,
and Smith, ]. B.: J. Pharm. Sci., 58:635, 1969. Reproduced
with permission of the copyright owner.)

ion and hydroxyl ion.52 Although uncertainty

exists as to whether both the hydrogen ion and
hydroxide ion catalysis are equilibrium proc¬
esses, the concentration of pilocarpate and
pilocarpic acid are influenced by pH. One of the
+ HCHO schemes postulated for the cyclic mechanism is
as follows:
i>n2
II

Mollica et al. reported that the hydrolysis of

hydrochlorothiazide involved reversible kinetics
in which the rate of forward reaction was influ¬
enced by pH, but the equilibrium constant was Pilocarpine
independent of pH.51 The hydrolytic reaction
was reported to proceed by ring opening to form
an imine, which undergoes attack by water or
hydroxide ion to yield a carbinolamine interme¬
diate, which further decomposes to formalde¬
hyde and 4-amino-6-chloro-m-benzenedisul-
fonamide, as shown by the following scheme:

I^R-N = CH2 ^
R - NH - CH2OH ^ II + HCHO

The observed pH profile for hydrochlorothiazide, Pilocarpine is relatively stable in solutions of

illustrated in Figure 26-22, is relatively complex acidic pH, kH = 1.35 x 10-1 liters/mole/hr. As
and cannot be explained by ionization of reac¬ the pH increases, pilocarpine progressively be¬
tants, but lends itself to Schiff base formation comes unstable, 1^>h = 7-56 x 102 liters/mole/
and hydrolysis. hr. Phosphate and carbonate buffers catalyze
The hydrolysis of pilocarpine in aqueous solu¬ the degradation, whereas borate does not. The
tion has been reported to involve a cyclic equilib¬ addition of methylcellulose improves the stabil¬
rium process, which is catalyzed by hydrogen ity slightly.

KINETIC PRINCIPLES AND STABILITY TESTING * 779

Oxidation-Reduction Hydroperoxide Decomposition:
The oxidative decomposition of pharmaceuti¬
ROOH -> RO + OH
cal compounds is responsible for the instability
of a considerable number of pharmaceutical
preparations. For example, steroids, vitamins, Termination:
antibiotics, and epinephrine undergo oxidative
degradation. These reactions are mediated ei¬ R02’ + X-> inactive products
ther by free radicals or by molecular oxygen. R02 + R02-* inactive products
Because of the complexity of oxidative processes
and their sensitivity to trace metal and other The initiation of this reaction can be produced
impurities, it is difficult to reproduce them and by the thermal decomposition of substances nat¬
to establish mechanisms for the reactions. Con¬ urally present or added to the reaction mixture
sequently, many reports dealing with oxidation- or possibly by fight. As shown above, termina¬
reduction reactions are qualitative in nature tion of the reaction may take place by combining
rather than quantitative. two R02 • radicals or by X, a free radical inhibi¬
A substance is said to be oxidized if electrons tor. In the latter case, X generally converts the
are removed from it. Thus, a substance is oxi¬ peroxy radical R02 • to a hydroperoxide and be¬
dized when it gains electronegative atoms or comes a resonance stabilized radical incapable
radicals or loses electropositive atoms or radi¬ of continuing the chain. Generally free radicals
cals. Oxidation often involves the addition of can best be terminated by a free radical inhibitor
oxygen or the removal of hydrogen. The simplest (e.g., sodium metabisulfite, thiourea, cysteine
type of oxidation is, therefore, the elimination of hydrochloride), since otherwise the product of
an electron, as in the process: recombination of radicals could contain suffi¬
cient energy to redissociate the molecule. In
Fe++ -* Fe+ + + + e" autoxidative reactions, only a small amount of
oxygen is needed to initiate the reaction, and
where the ferrous ion is oxidized to the ferric thereafter, oxygen concentration is relatively
ion.
unimportant.
The most common form of oxidative decompo¬
Heavy metals, particularly those possessing
sition occurring in pharmaceutical preparations
two or more valency states, with a suitable oxi¬
is autoxidation, which involves a free radical dation-reduction potential between them (cop¬
chain process. In general, autoxidation may be
per, iron, cobalt, and nickel) generally catalyze
defined as the reaction of any material with mo¬
oxidative deteriorations. These metals reduce
lecular oxygen. Free radicals are produced by the length of the induction period (the time in
reactions involving homolytic bond fission of a
which no measurable oxidation occurs) and in¬
covalent bond, so that each atom or group in¬
crease the maximum rate of oxidation. They can
volved retains one of the electrons of the original
affect the rates of chain initiation, propagation,
covalent bond. This may be depicted as follows: and termination, as well as the rate of hydroper¬
oxide decomposition. In each case, their major
A:B —-* A- + B- function is to increase the rate of formation of
CH3:CH3 -> 2CH3 free radicals.
Many oxidations are catalyzed by hydrogen
These radicals are highly unsaturated and read¬ and hydroxyl ions. This can partly be ascribed to
ily take electrons from other substances, causing the fact that the redox potential for many reac¬
oxidation. The autoxidation of an organic sub¬ tions depends on pH. This is particularly true for
stance RH by a free radical chain process can be pharmaceutical compounds falling under the
simply described as follows: classification of weak acids. The system qui-
none/hydroquinone may be taken as a classic
Initiation: example to illustrate this point.

activation
RH light, heat R- + (H)

Propagation:

R' + 02--> R02

R02' + RH -» ROOH + R-

780 • The Theory and Practice of Industrial Pharmacy

 The oxidation potential may be expressed by Table 26-4. Common Drugs That are Reported
the following simplified version of the Nemst to React with Oxygen
equation:
Amikacin Novobiocin
Apomoiphine p-Aminobenzoic acid
E = Eo + log —' Csu^none Ascorbic acid Paraldehyde
^ '^hydroquinone Chlorpromazine and other Penicillin
phenothiazines Pentazocine
where Eo is the so-called standard potential, E is Cyanocobalamin Phenylephrine
the actual potential, 2 equals the number of Dexamethasone Physostigmine
Dobutamine Prednisolone
electrons taking place in the change from the
Epinephrine Prednisone
ox-form to the red-form, and 0.06 is a calculated
Edrophonium Procaine and related amides
approximate constant.53 It can be seen from this
Ergometrine Reseipine
equation that an increase in the concentration of Gentamicin Resorcinol
hydrogen ions causes an increase in the value of Heparin Riboflavin
E. This means that the red-form of the system is Hydrocortisone Streptomycin
less readily oxidized when the pH is low. Since Isoamyl nitrite Sulfadiazine
pharmaceuticals that undergo deterioration Isoproterenol Thiothixene
through oxidation are generally in the red-form, Kanamycin Terpenes
minimum decomposition is usually found in the Methyidopate Tetracyclines
pH range of 3 to 4. Metaraminol Thiamine
Although the oxygen concentration is of im¬ Metoclopramide Tobramycin
portance in the autoxidation process, its signifi¬ Morphine Turbocurarine
cance is usually not adequately considered. Neomycin Vitamin A
When studying the rate of the reaction for an Norepinephrine Vitamin D
oxidation at different temperatures, it is neces¬ Vitamin E
sary to consider both the direct effect of the tem¬ From Akers, M. J.: J. Parenter. Sci. Tech., 36:223, 1982.
perature and the effect of temperature on the
oxygen content (concentration of oxygen) of the
liquid. For example, the transfer of a preparation an accelerated decomposition of prednisolone,
from storage at 15 to 5°C, with a temperature which was first thought to be due to buffer con¬
coefficient of 2 for a 10°C change, causes the centration.55 By studying the oxidative degrada¬
rate to be reduced to half its initial magnitude, tion with and without 0.1% disodium salt of eth-
owing to the direct temperature dependence of ylenediamine tetraacetic acid at different buffet
the reaction. Simultaneously, the concentration concentrations, it was found that the solutions
of oxygen increases by about 25%, usually re¬ not containing any chelating agent degraded
sulting in an increased rate of oxidation. Exam¬ more rapidly as the buffer concentration in¬
ples of pharmaceuticals that degrade through creased, while the buffered solutions containing
oxidative pathways are shown in Table 26-4. chelating agent showed that the rate of degrada¬
For the most part, oxidative degradations of tion was independent of the concentration of the
pharmaceutical compounds follow first-order or buffer. This is clearly shown by the graphs in
second-order kinetic expressions. Guttman and Figure 26-23.
Meister studied the base-catalyzed degradation These investigators also studied the influence
of prednisolone and found that the degradation of pH on the stability of prednisolone in borate
exhibited a first-order dependency on steroid
concentration.54 The rate of prednisolone disap¬
pearance from aqueous solutions increased with Table 26-5. Rate Constants for the Base-Cata¬
an increase in hydroxyl ion concentration under lyzed Degradation of Prednisolone at 35°C in the
both aerobic and anaerobic conditions; however, Absence and Presence of Air
the reaction mixture exposed to air showed more
rapid degradation of prednisolone (Table 26-5). Normality of ka (Anaerobic) ka (Aerobic)
For example, at a hydroxide ion concentration of NaOH Hr-1 Hr-1
0.01N, the rate constant for the overall degrada¬
0.01 0.0311 0.0589
tion obtained under anaerobic conditions was
0.02 0.0531 0.0839
approximately half the value of that obtained
0.03 0.071 0.110
when no precautions were taken to exclude air
0.04 0.103 0.097
from the system.
0.05 0.120 0.110
Trace metal impurities in buffer salts caused

KINETIC PRINCIPLES AND STABILITY TESTING * 781

 occurred more rapidly from systems that were
not protected by chelating agents. Using a phos¬
phate buffer system, it was found that the solu¬
tions containing the chelating agent showed
enhanced stability, beginning at pH 5 over the
solutions without chelating agent. In addition,
the pH dependency from 5 to 8 was very small
for the system containing chelating agent, but
considerable for the system without it. It is inter¬
esting to note that the influence of pH on the
metal catalyzed reaction in phosphate buffer
was somewhat different from the borate buffer.
Rancidity, which can affect nearly all oils and
fats, is a widely known term covering many typi¬
cal off-flavors formed by the autoxidation of un¬
saturated fatty acids present in an oil or fat.
These off-flavors have a more or less distinct
odor and are due to the volatile compounds that
MOLARITY OF BORIC ACID
are formed upon oxidation of the oils and fats.
FIG. 26-23. The effect of buffer concentration on the rate
These volatile compounds are generally short-
of prednisolone degradation in the presence and absence of
sequestrene Na2 at 30°, pH 10, and ionic strength 0.2. Key:
chain monomers that are formed by cleavage of
O, no EDTA; 0, 0.1% EDTA. (From Oesterling, T. O., and the nonvolatile hydroperoxide primary oxidation
Guttman, D. E.: J. Pharm. Sci., 53:1189, 1964.) product. The free radical mechanism shown
here depicts the oxidation of oils and fats that
takes place in the presence of atmospheric oxy¬
buffer with and without chelating agent. The gen, light, and trace amounts of catalysts.
chelating agent was found to have little effect on Determination of iodine numbers can be em¬
the degradation rate up to a pH of 8; but at ployed as an indication of whether oxidation has
higher pH, the disappearance of prednisolone taken place across the double bond.

R'—CH2—CH=CH—R" + 02 * R'—CH—CH=CH—R" + H02-

R'—CH—CH=CH—R" + 02 » R'— CH—CH=CH—R"

O—O
I
R'—CH—CH=CH—R" + R'—CH2—CH=CH—R" »

O—OH
I
R'—CH—CH=CH—R" + R'—CH—CH=CH—R"

O—OH
I
2R'—CH—CH=CH—R" » R'— CHO + R"—CH=CH • + • OH
hydroperoxide nonvolatile

R"_CH=CH—CHO—R' + • OH
volatile
or
/

o
2R'—C—CH=CH—R" + 2 • OH
I
H

782 • The Theory and Practice of Industrial Pharmacy

 The stability of pharmaceutical compounds Table 26-6. Antioxidants Commonly Used for
undergoing oxidative degradation can be in¬ Aqueous Systems
creased by several approaches.
Oxygen Content. Since, in many cases, oxi¬ Sodium sulfite Ascorbic acid
dative degradation of a drug takes place in aque¬ Sodium metabisulfite Isoascorbic acid
ous solution, it is helpful to keep the oxygen con¬ Sodium bisulfite Thioglycerol
tent of these solutions at a minimum. In a study Sodium thiosulfate Thioglycolic acid
Sodiuih formaldehyde Cysteine hydrochloride
to determine the oxygen content of water pre¬
sulfoxylate Acetylcysteine
pared and treated by different techniques, it was
Sulfur dioxide
found that water in equilibrium with atmos¬
pheric oxygen contains 5.75 ml per liter of oxy¬
gen at 25°C and 9.14 ml per liter of oxygen at
4°C, and that all free oxygen is expelled from oxidants in complex pharmaceutical systems.
water at 100°C.56 Freshly distilled water col¬ The effectiveness of an antioxidant or the com¬
lected direcdy from the distillation apparatus parative value of various antioxidants for a par¬
and stored at 4°C in closed containers contains ticular pharmaceutical preparation is best ac¬
V4 to Vs the oxygen content of water saturated complished by subjecting the pharmaceutical
with oxygen from the atmosphere. Boding and system with the antioxidant to standard oxida¬
cooling this freshly distilled water to 20°C re¬ tive conditions and periodically assaying the for¬
sults in almost a twofold increase in the oxygen mulation for both drug and antioxidant. Al¬
content of the water; however, if the water is though this method may require maximum
cooled in an atmosphere essentially free from effort, it yields the most useful information.
atmospheric oxygen, there is no increase in oxy¬ It should be remembered that because of the
gen content. To obtain water that contains a complexity of free radical oxidative processes
minimum amount of free oxygen, water after it and their sensitivity to trace amounts of impuri¬
is first boded is purged with carbon dioxide or ties, attempts to compare the effectiveness of
nitrogen gas. The oxygen content of water antioxidants among different pharmaceutical
treated with carbon dioxide is reduced to systems are of limited validity.
0.45 ml per liter at 20°C. Antioxidant materials used in pharmaceutical
Since most oxidative degradations of pharma¬ systems are listed in Tables 26-6 and 26-7.
ceutical compounds are probably autoxidative in Water-soluble antioxidants act by preferen¬
nature and involve chain reactions that require tially undergoing oxidation in place of the drug.
only a smad amount of oxygen for initiating the Oil-soluble antioxidants serve as free radical
reaction, reduction of oxygen concentration acceptors and inhibit the free radical chain proc¬
alone is not sufficient in many cases to prevent ess. Sulfurous acid salts consume molecular
degradation from occurring. The traces of oxy¬ oxygen present in solution. Structurally, other
gen left may be sufficient to start a chain reac¬ antioxidants have the property of losing a hydro¬
tion. Consequendy, it is necessary to add agents gen free radical and/or an electron.
such as antioxidants and chelating agents to ob¬ The effectiveness of these antioxidants can
tain acceptable protection against oxidative deg¬ depend on the concentration used, whether they
radation. are used singularly or in combination, the solu¬
Antioxidants. Antioxidants are added to tion pH, and the package integrity and nonreac¬
pharmaceutical formulations as redox systems tivity.
possessing higher oxidative potential than the Although sodium metabisulfite has been used
drug that they are designed to protect, or as extensively in the past and is still used to a con¬
chain inhibitors of radical induced decomposi¬ siderable extent as an effective antioxidant, re¬
tion. In general, the effect of antioxidants is to cent reports have indicated that the antioxidant
break up the chains formed during the propaga¬
tion process by providing a hydrogen atom or an
electron to the free radical and receiving the Table 26-7. Antioxidants Commonly Used for
excess energy possessed by the activated mole¬ Oil Systems
cule.
Ascorbyl palmitate Butylated hydroxy
Although the selection of an antioxidant can
Hydroquinone toluene
be made on sound theoretic grounds based on
Propyl gallate Butylated hydroxy anisole
the difference in redox potential between the
Nordihydroguaiaretic a-tocopherol
drug and antioxidant, electrometric measure¬
acid Lecithin
ments only rarely predict the efficiency of anti-

KINETIC PRINCIPLES AND STABILITY TESTING *783

activity of this substance is inhibited by a num¬ dation, found that when boric acid was added to
ber of compounds, that it actually undergoes the solution, a marked stabilization of epineph¬
degradation itself, and that it potentiates the rine took place.60 They postulated that this stabi¬
degradation of epinephrine.57-60 lizing effect of boric acid was due to chelate for¬
The effectiveness of bisulfite as an antioxi¬ mation between boric acid and the catechol
dant in typical pharmaceutical systems depends grouping of epinephrine.
on the ease with which this compound is oxi¬ The epinephrine is able to form a one-to-one
dized in comparison with the drug it is to pro¬ chelate through its dihydroxy structure, as fol¬
tect. Substances that inhibit bisulfite oxidation lows:
may exert important effects on the overall stabil¬
ity of the product by decreasing the antioxidant
effect of bisulfite. It has been postulated that the
mechanism by which these substances inhibit
sulfite activity is through the formation of coor¬
dination compounds between inhibitor and bi¬
sulfite. Typical substances that can inhibit the
oxidation of bisulfite are mannitol, phenols, in¬
organic anions, aldehydes, ketones, and alka¬
loids.
It has been shown that bisulfite reacts with
epinephrine to form a colorless, inactive epi¬
nephrine sulfonate, which thus indicates the
need for caution in using bisulfite in formula¬ In the presence of boric acid, the rate of sulfite
tions without performing adequate studies to attack is reduced as the hydrogen ion concentra¬
determine its effect on active ingredients.59 tion decreases. The half-life for epinephrine
These investigators showed that a substantial under the reaction conditions at pH 6.0 in the
breakdown of epinephrine takes place in the absence of boric acid was found to be 195 hours,
presence of bisulfite as depicted in Figure 26-24. whereas in the presence of boric acid, the half-
Higuchi and Schroeter reported that the degra¬ life was found to be 267 hours. At pH 7.5, how¬
dation of chloramphenicol induced by bisulfite ever, the half-life of epinephrine was found to be
appears to be considerably more complex than 74 hours in the absence of boric acid and 1,270
that found with epinephrine.58 Loss of optical hours in its presence. It was postulated that epi¬
activity was found to occur at a much faster rate nephrine is increasingly chelated by the boric
in the presence of bisulfite. acid molecules as the pH is made more alkaline,
Riegelmen and Fisher, in their study to stabi¬ and that the chelated epinephrine is far less sus¬
lize epinephrine against sulfite-catalyzed degra- ceptible to sulfite attack than free epinephrine.
The effectiveness of antioxidants can be en¬
hanced through the use of synergists such as
chelating agents.
Chelating Agents. Chelating agents tend to
form complexes with the trace amounts of heavy
metal ions inactivating their catalytic activity in
the oxidation of medicaments. Examples of
some chelating agents are ethylenediamine iet-
raacetic acid derivatives and salts, dihydroxy-
ethyl glycine, citric acid, and tartaric acid.
pH. It is also desirable to buffer solutions
containing ingredients that are readily oxidiza-
ble to a pH in the acid range. This causes an
increase of the oxidation potential of the system
with a concurrent increase in stability when oxi¬
dations are catalyzed by hydrogen or hydroxyl
FIG. 26-24. Percentage of epinephrine remaining in 0.1% ions. The pH of optimum stability in the acid
(0.0055 molar) solutions containing 0.1% sodium bisulfite range, however, must be determined experi¬
(0.0096 molar) buffered at pH 4.0 with 0.1 molar acetate or
citrate. The solutions were stored in sealed, evacuated
mentally for each drug.
ampuls at 80°. (From Schroeter, L. C., Higuchi, T., and Solvents. Solvents other than water may
Schuler, E. E.: J. Am. Pharm. Assoc., Sci. Ed., 47:724, have a catalyzing effect on oxidation reactions
1958.) when used in combination with water or alone.

784 • The Theory and Practice of Industrial Pharmacy

 For example, aldehyde, ethers, and ketones may qualitative in nature. Only within recent years
influence free radical reactions significantly. have photodegradative studies been performed
on a quantitative basis. In photodegradative re¬
actions, second-order, first-order, and zero-order
Photolysis reactions are possible.
Felmeister and Dischler studied the
Consideration of the decomposition of phar¬ photodecomposition of chlorpromazine hydro¬
maceutical compounds resulting from the ab¬ chloride at 253.5 mp. and derived the mecha¬
sorption of radiant energy in the form of light nism for the free radical-mediated deterioration
has become more important in recent years be¬ of chlorpromazine.61 The ultraviolet irradiation
cause of the complex chemical structure of of chlorpromazine causes the degradation to pro¬
many new drugs. Degradative reactions, such as ceed through a semiquinone free radical inter¬
oxidation-reduction, ring rearrangement, or mediate. The semiquinone free radical dispro-
modification and polymerization, can be brought portionates in aqueous media in both the
about by exposure to light at particular wave absence and the presence of dissolved oxygen,
lengths. According to the equation E = though the loss of free radical is slightly faster in
2.859 x 105/A Kcal per mole, the shorter the the presence of oxygen. The loss in concentra¬
wave length (A) of light, the more energy is ab¬ tion of chlorpromazine versus photons of light
sorbed per mole. Consequendy, the radiations per liter absorbed shows that degradation follows
absorbed from the ultraviolet and violet portions zero-order kinetics.
of the light spectrum are more active in initiat¬ Hamlin et al. studied the photolytic degrada¬
ing chemical reactions than those absorbed from tion of alcoholic solutions of hydrocortisone,
the other longer wave length portions of the prednisolone, and methylprednisolone exposed
spectrum. to ordinary fluorescent lighting.62 The plots in
In a large number of systems that are photo- Figure 26-25 show that the degradation follows
lyzed, free radicals are products that undergo first-order kinetics and that prednisolone and
subsequent reactions. If the molecules absorb¬ methylprednisolone show about the same rate of
ing the radiation take part themselves in the degradation, whereas hydrocortisone degrades
main reaction, the reaction is said to be a photo¬ about V7 the rate of the other two steroids.
chemical one. Where the absorbing molecules Hence, the two double bonds present in prednis¬
do not themselves participate directly in the re¬ olone and methylprednisolone make these ste¬
action, but pass on their energy to other mole¬ roids more susceptible to light-catalyzed degra¬
cules that do, the absorbing substance is said to dation than the one double bond in the A ring of
be a pkotosensitizer. hydrocortisone.
The kinetics of photochemical reactions is
more complicated than the kinetics of thermal
reactions because more variables are involved.
The intensity and wave length of light and the
size and shape of the container may greatly af¬
fect the rate of reaction. A photochemical reac¬
tion may be accompanied by a thermal reaction
that is identical to the photochemical reaction
opposite to it, or entirely different in character. A
photochemical reaction may produce a catalyst,
which then causes a thermi reaction to proceed
at a measurable rate. Sometimes an induction
period is necessary while a sufficient quantity of
catalyst is being accumulated, to make the reac¬
tion proceed with a measurable velocity. A ther¬
mal reaction, once started, may continue after
the illumination is stopped, giving an aftereffect.
The energy available in a photochemical reac¬
tion is much greater than in a thermal reaction, FIG. 26-25. First-order plots of the photolytic degrada¬
and this fact often changes the character of the tion of steroids when exposed to laboratory fluorescent
reaction. lighting. Hydrocortisone: X, INH assay; O, V. V. assay.
Prednisolone: A, INH assay; □, U. V. assay. Methylpredni¬
As a result of the complexity of photolytic re¬
solone; •, INH. (From Hamlin, W. E., Chulski. T., John¬
actions, investigations in this area of pharma¬ son, R. H., and Wagner, J. G.: J. Am. Pharm. Assoc, Sci.,
ceutical stability have been, for the most part, Ed., 49:253, 1960.)

KINETIC PRINCIPLES AND STABILITY TESTING • 785

Racemization Table 26-8. Rates of Decrease of Absorbance of
Prepared Extract at 500 mpt per Hour (k)
In such a reaction, an optically active sub¬
stance loses its optical activity without changing °c (k)
its chemical composition. This reaction can be
important to the stability of pharmaceutical for¬ 40 0.00011
mulations, since the biologic effect of the dextro 50 0.00028
form can be considerably less than that of the 60 0.00082
levo form. For example, levo-adrenaline is 15 to 70 0.00196
20 times more active than dextro-adrenaline.
Solutions of levo-adrenaline form a racemic mix¬
temperature dependency of the degradation can
ture of equal parts of levo- and dextro-adrenaline
be obtained. Information of this type, obtained
with a pharmacologic activity just over half that
from exaggerated test conditions of short dura¬
of the pure levo compound.
tion, permits the determination of the chemical
The kinetics of racemization may be studied
stability of an active ingredient or ingredients,
in a manner similar to hydrolytic reactions. By
colorants, and antimicrobial preservatives for
determining the rate constant, temperature de¬
extended shelf storage.
pendency of the reaction, and dependence of the
The color stability of a multisulfonamide prep¬
reaction on pH, it is possible to establish the op¬
aration was determined in this fashion. By the
timal conditions for storage of the preparation.
use of colorimetric measurements of samples
Racemization reactions, in general, undergo
subjected to thermally accelerated degradation,
degradation in accordance with first-order ki¬
it was possible to predict the color stability of the
netic principles. The racemization of a com¬
preparation at room temperature, with data ob¬
pound appears to depend on the functional
tained in about 25 days.1
group bound to the asymmetric carbon atom;
The arithmetic plots in Figure 26-2 present¬
aromatic groups tend to accelerate the racemiza¬
ing the change in absorbance at 500 mp versus
tion process.
time are linear, indicating that color loss is fol¬
lowing a zero-order reaction. The slopes of these
lines were obtained, and they indicate the rate of
Chemical and Physical Stability change of color with time. These rate constants
Testing of Pharmaceutical are summarized in Table 26-8.
From the data in this table, Arrhenius plots
Dosage Forms were made and are shown in Figure 26-26. The
Chemical Stability. The information pre¬ linear nature of the curve indicates its utility in
sented thus far has illustrated that it is possible, predicting the rates of color loss at lower temper¬
through the use of chemical kinetic principles, atures. The rate constants at the lower tempera¬
to study the degradation of an active drug in so¬ tures obtained from this plot are summarized in
lution accurately, as well as determine the Table 26-9.
mechanism responsible for the degradation. A
more complicated situation arises when one at¬
tempts to study the stability of one or more drugs
in a liquid pharamaceutical dosage form. Be¬
cause of the multiplicity of ingredients in most
pharmaceutical formulations, there exists the
possibility of interactions taking place, as well as
each ingredient having different degradative
characteristics. The ideal situation would be to
study the degradation pattern of each ingredient
in the mixture individually. This is, of course,
difficult, time-consuming, and expensive to ac¬
complish. Fortunately, it is not necessary for
purposes of stability prediction to determine the
mechanisms of degradation. In general, it is pos¬
sible to evaluate the stability of any component
FIG. 26-26. Plot of the logarithm of the rate of decrease in
of a pharmaceutical preparation by determining
absorbance of extracted color -per hour against the recipro¬
some property of the degradation as a function of cal of the absolute temperature (T) as obtained at 500 mp.
time. If this function can be linearized in accord¬ (From Garrett, E. R., and Carper, R. F.: J. Am. Pharm.
ance with chemical kinetic reaction orders, the Assoc., Sci. Ed., 44:515, 1955.)

786 • The Theory and Practice of Industrial Pharmacy

Table 26-9. k Values Determined from Arrhe¬ and first-order kinetic treatment of the data, it
nius Expression was possible to determine the pH of optimum
stability, as well as the concentration of ascorbic
k, Absorbance acid to provide for a shelf-life of two years for the
°c dec/hr product. It was possible to make this estimation
from 30 days of accelerated temperature study.
20 0.0000115
25 0.0000209 The predicted stability was subsequently corrob¬
30 0.0000363 orated by room temperature data.63
Swintosky et al. used chemical kinetics to pre¬
dict the shelf-life of oral penicillin G procaine
suspensions from elevated temperature storage
These rate constants can then be used to de¬ conditions.35 The degradation of penicillin in
termine the time when the color has reached an saturated procaine penicillin solutions was
undesirable level. For example, to predict the found to follow a first-order reaction. Using in¬
time for the absorbance to fall to 0.225 (At) from formation obtained from the Arrhenius plot of
a zero time value of 0.470 (Ao), the zero-order the stability data at several elevated tempera¬
kinetic equation At = Ao - kt is used. At 20°C, tures and the solubility of penicillin at these
the rate constant (k) from Table 26-9 is 1.15 x temperatures, the authors were able to prepare
105 (absorbance decrease/hour). Rearranging aqueous suspensions of procaine penicillin of a
the above equation to find the time, the absorb¬ predictable shelf-life that would be far in excess
ance reads 0.225 at 20°C: of that observed in solution, since only that frac¬
tion of the penicillin in solution undergoes deg¬
-At + Ao radation.
W ” k It has been shown that vitamin A acetate and
palmitate encased in gelatin, acacia, and like
= -0-225 + 0.470
substances, when tabletted into conventional
1.15 x 10“5 uncoated tablets and/or chewable tablets, follow
a pseudo-first-order degradation scheme.64 An
= 21,304 hours Arrhenius plot of the data obtained at several
= 887 days elevated temperatures for vitamin A palmitate is
shown in Figure 26-27. This linear plot of the
The predicted times for 20°, 25°, and 30°C are logarithm of the pseudo-first-order rate con¬
summarized in Table 26-10. stants obtained at elevated temperatures versus
The thermal degradation of ascorbic acid, vita¬ absolute temperature permits an estimation of
min B12, folic acid, vitamin A, d-pantothenyl al¬ the rate constants at room temperature (25°C),
cohol, and thiamine hydrochloride in a liquid and thus an estimation of the shelf-life of the
multivitamin preparation was studied by use of vitamin in the tablet. If the rate constant is
either zero-order or first-order treatment of the
data. It was possible to predict the stability of the
.vitamin components maintained at room tem¬
perature from the data obtained from samples
stored under accelerated test conditions.
The stability of ascorbic acid in a liquid o/w
multivitamin emulsion containing sodium fluo¬
ride and vitamins A, B6, D, and C as active in¬
gredients was studied under accelerated storage
conditions to predict its shelf-life. With zero-

Table 26-10. Duration of Color (Corresponding

to Estimated Point of Rejection of Absorbance of
Extract, A = 0.225)

°Centigrade Time
FIG. 26-27. Rate constants (k = week-1) for pseudo-first-
20° 887 days (ca. 214 yr) order rate constants of vitamin A palmitate beadlets in
25° 488 days (ca. 114 yr) dry-slugged, mannitol-base, multivitamin cheivable tablet.
Log k is plotted against reciprocal absolute temperature.
30° 281 days (ca. % yr)
(From Carstensen, J. T.: J. Pharm. Sci., 51:100, 1964.)

KINETIC PRINCIPLES AND STABILITY TESTING • 787

 1
placed into equation (16), the t10% at 25°C is ob¬ alteration to provide derivatives having high
tained. The relative stabilities of several vitamin melting points, and hence greater stability,
A derivatives in the solid state are demonstrated should prove a useful tool to the pharmaceutical
by the zero-order plots of their degradation in formulator of solid dosage forms in instances
Figure 26-28.65 It was postulated that the degra¬ where drug degradation poses a serious prob¬
dation occurs almost exclusively in a liquid film lem.
at the surface of the crystal. The relative amount The influence of active constituents and tablet
of material in the liquid state may be expected in diluents on the stability of phenylephrine hydro¬
these instances to determine, in some large chloride in a solid state was studied in accord¬
manner, the rate of degradation. The fraction of ance with chemical kinetic principles. For the
material in the liquid state is related to the melt¬ most part, phenylephrine hydrochloride was
ing point of the pure crystalline solid by the fol¬ found to degrade in accordance with zero-order
lowing equation: kinetics. Such studies made possible the scien¬
tific development of multi-ingredient tablet for¬
mulations containing phenylephrine hydrochlo¬
ride at optimal stability.
Statistical Techniques in Predicting
where Xj is the mole fraction of solvent (the liq¬ Thermal Stability. In the last few years, it has
uid phase), Lf is the molar heat of fusion, R, the become standard procedure to use.statistics in
gas constant, and Tm the melting point of the determining the validity of the Arrhenius treat¬
pure solid. It is evident from the plots in Figure ment of data.
26-28 that in a series of vitamin A derivatives, Statistical aspects of the Arrhenius treatment
the compound having the highest melting point of kinetic data and the prediction of stability
is generally the most stable, all other factors have been covered by Carstensen and Su.66 The
being equal. Consequently, the use of chemical authors demonstrated that when decomposition
is less than 10%, which is the case for many
drugs of intermediate stability and certainly
those for which a New Drug Application (NDA)
is being considered, zero-order and first-order
degradation axe practically indistinguishable,
and statistical methods are greatly facilitated by
the use of zero-order kinetics. Of importance is
the necessity to employ at least four points to
obtain reasonable accuracy in applying the Ar¬
rhenius treatment and making an extrapolation.
The degree of accuracy can be calculated, and
Garrett has shown there is a substantial differ¬
ence between three points and more than three
points.67 In addition, the “longer” the extrapola¬
tion, the larger the scatter of points. For exam¬
ple, Carstensen demonstrated that if only the
data shown in Table 26-11 at the three highest
temperatures were used to predict stability at
25°C, using least squares for plotting, then:

log lq25.c) = [0.0353 - 7] ±1.6740

Table 26-11. Rate Constants of Degradation of

Diazepam Injection

FIG. 26-28. Solid state degradation of vitamin A com¬ t°C looorr 105fe, (hr-') y = 5 + log k,
pounds at 50°. Key: A, Vitamin A benzahydrazone, m.p.
181-182°; ■, vitamin A succinate triphenylguanidine 121 2.54 176 2.2455
salt, m.p. 140.0-140.5°; •, vitamin A 3,4,5-trimethoxy- 110 2.61 84.3 1.9258
benzoate, m.p. 85-86°; A, vitamin A nicotinate, m.p. 100 2.68 33.1 1.5198
93-94°; □, vitamin A phthalimido-N-acetate, m.p. 111- 85 2.81 10.0 1.0000
112°; O, vitamin A acetate, m.p. 57-58°. (From Guillory, 70 2.92 2.15 0.3324
J. K., and Higuchi, T. J.: J. Pharm. Sci., 51:100/1962.)

788 • The Theory and Practice of Industrial Pharmacy

which corresponds to: all cases, the predicted potency was found to
agree closely with the potency determined for
k(25°c) of 2.30 X 10-9 to 5.12 x 1(T6 samples stored at the temperature for as long as
a year. The estimates were found to be well
The interval is of several orders of magnitude, within the limits of error of prediction and the
and at the higher rate constant (the least stable), 95% confidence limits of a single assay.
the drug remaining after two years would be cal¬ To facilitate data processing and statistical
culated to be 81.6%. treatment of stability information, computer pro¬
If all the data in Table 26-11 are employed, grams have been developed and are commer¬
however, then: cially available.* Digital and analog computer
programs have been employed to simulate drug
log = [0.2257 - 7] ±0.2937 decomposition induced during linear noniso-
thermal stability studies.70,71
which corresponds to: Stability Data Generation and Handling.
In the past few years, stability testing has been
k(25°C) of 8.51 x 10“8 to 3.30 x 10"7 revolutionized by two highly technologic ad¬
vancements—high pressure liquid chromatog¬
The interval is much narrower, and at the raphy (HPLC) methodology for analyzing drug
higher rate constant, the drug remaining after product stability, and the computer for stability
two years would be calculated to be 98.7%. data acquisition, storage, analysis, and report¬
If an Arrhenius plot of the data at the three ing. Since the FDA has become more demand¬
highest temperatures listed in Table 26-11 is ing in its requirements that product expiration
constructed and 95% confidence lines are in¬ dates be based on stability data obtained using
cluded, the graph shown in Figure 26-29 re¬ stability-indicating assay methods and such data
sults. The dotted lines represent the high and analyzed by valid statistical calculations, HPLC
low limits around the extrapolated solid line. and the computer have become essentially in¬
The further away the actual experimental points dispensable tools for fulfilling these require¬
are from the extrapolation, the greater is the var¬ ments.
iation. This emphasizes the inaccuracy that re¬ Most assay methods described in the official
sults from attempts to extrapolate over too wide compendial drug monographs are not stability-
a temperature range. indicating, that is, the assay is not capable of dif¬
Both Garrett and McLeod et al. used statistical ferentiating intact drug from one or more of its
procedures to determine the degree of confi¬ degradation products. In other words, the assay
dence to be held in the predicted stability of a lacks specificity for the active ingredient. Nearly
pharmaceutical preparation;68’69 the data they all new drug products being developed today use
used were based on accelerated storage tests. In HPLC as the method of choice for analyzing the
stability of the dosage form. HPLC can separate
and quantitate the active ingredient from its
degradation products in the dosage form. Many
of the older analytic methods used as official
assay methods are gradually being changed to
the more specific, sensitive, and accurate HPLC
method.
One disadvantage of HPLC methodology is
that it is time-consuming; however, this can be
overcome through automation. Thus, the role of
the computer has reached new heights in man¬
aging stability testing programs. Not only can
the computer control the analytic process for
generating stability data, but also it has become
essential in all aspects of data manipulation and
reporting.
Physical Stability. Although there are a
considerable number of reports in the literature
FIG. 26-29. Arrhenius plot of degradation of diazepam in
ampul solution with high and low limits. (From Carsten-
sen, }. T., and Su, K. S. W„- Bull. Parenteral Drug Assn., *EDP Technology Inc., 1532 Third Street, Santa Monica,
25:287, 1971.) CA 90401 The Upjohn Company, Kalamazoo, MI.

KINETIC PRINCIPLES AND STABILITY TESTING • 789

concerned with chemical stability testing of ac¬
tive ingredients in pharmaceutical dosage
forms, there is a conspicuous scarcity of reports
dealing with physical stability testing. From
both pharmaceutical and therapeutic stand¬
points, physical changes in the dosage form
upon storage can be as serious as chemical in¬
stability of the active ingredients, sometimes
more so. Examples of physical changes that can
take place are crystal growth, change in crystal
form, increase or decrease in dissolution rate
and disintegration times, cracking of emulsions,
caking of suspension, color fading, color devel¬
FIG. 26-30. Logarithm of apparent rate constants k of
opment, and sediment or swirl development in drug A, taken from Table 26-12 and plotted as a function of
solutions. Crystal growth in a suspension can reciprocal absolute temperature. (From Carstensen, ]. T.,
result in a change in the rate of absorption and Johnson, J. L., Valentine, W., and Vance, ]. ].: ]. Pharm.
possibly in ineffective therapeutic levels. Crystal Sci., 53:1050, 1964.)
growth in an ointment or cream can cause skin
irritation as well as poorer absorption. A change
in crystal form of a steroid in suspension can ceeded to plot 0t versus the product of time and
result in the formation of a therapeutically inac¬ intensity (Fig. 26-31). The value for 0, was ob¬
tive form of the drug. tained from the equation (1 - Rt)2/2Rt where R,
Tablets. There have been several studies is the measured reflectance of the tablet. The
concerned with the influence of temperature consistency of the slopes (k values) at the three
and light on the color stability of tablets. In one different concentrations shows that the fading of
investigation, the effect of temperature on the the dye at the surface of the tablet is first-order.
rate of darkening of tablet dosage forms was in¬ By using the product of time and intensity, each
vestigated, and it was found that the darkening intensity condition was found to be on the same
was following either zero- or first-order kinetics, straight line for any given concentration. The
depending on the drug and tablet formulation.72 general first-order equation for the straight line
For example, for tablet of drug A, which dark¬ plots in Figure 26-31 is:
ened in accordance with first-order kinetics, the
Arrhenius plot is given in Figure 26-30, and the In 0t = -ktl + In 0t'
data in Table 26-12.
The linearity of the Arrhenius plot permits where 0t (Kubelka-Munk function of the tablet)
extrapolation to 25°C from the elevated tempera¬ is the 0 calculated at time, t, and 0,' is the 0t at
tures. With this information, it is possible to es¬ t = 0. By determining the times at which objec¬
timate the extent of darkening at room tempera¬ tionable fading took place under high light in¬
ture at extended storage periods. Everhard and tensity, it is possible from these time-intensity
Goodhart,73 using certain relationships devel¬ values to calculate the time for objectionable
oped by Kubelka,74 quantitated the relationship fading at lower intensities encountered under
of light-catalyzed fading of colored tablets as a normal shelf storage conditions, using the above
function of time and light intensity. Since fading equation (Table 26-13).
is proportional to the product of time, t, and in¬ Nyquist, et al. reported on the use of acceler¬
tensity of the light, I, these investigators pro- ated light-temperature-humidity conditions in

Table 26-12. Drug A

Temp 10?IT Mo x-Value 100 k

(t°C) (ok-1) Log x/x0*
Stored (%) Log x (Mo-1)

5 — 21 34.78 1.54133 _ _

55 3.05 1 35.06 1.54481 0.00348 3.48 ± 0.7

45 3.145 3 35.06 1.54481 0.00348 1.15 ±' 0.23
37 3.225 6 35.07 0.54494 0.00361 0.62 ± 0.12
26 3.355 16 34.88 1.54258 0.00125 0.08 ± 0.04

*5° Value used for reference.

790 • The Theory and Practice of Industrial Pharmacy

 FIG. 26-32. Decrease in blood levels when an aged tablet
FIG. 26-31. Plots.of 9t vs. the product of time and inten¬ (-rather than a fresh tablet (—■), teas administered
orally to human beings.
sity. Key: 9,11 footcandles; A, 50 footcandles; ■. 80 foot-
candles; ▼, 655 footcandles. Top line, 0.06% dye; middle
line, 0.03%; bottom line, 0.015% dye. (From Everhard,
M. E., and Goodhardt, F. W.:J. Pharm. Sci., 52:281, 1963.) It is unwise and dangerous to assume that a
tablet formulation exhibiting good drug absorp¬
tion will remain so throughout its shelf-life. This
predicting light stability and in establishing a can be illustrated by the curves in Figure 26-32,
rapid method of evaluating light stability of in which the blood levels are plotted for an aged
white tablets.75 Exposing tablets to a fadeometer tablet and for one newly prepared. It is evident
combined with color measurement in a tri- that aging of this tablet formulation results in a
stimulus colorimeter was found to be a rapid considerable change in drug availability.
method for evaluating light stability of white tab¬ Disperse Systems. The physical stability of
lets under various temperature and humidity an emulsion or suspension can be influenced by
conditions. factors affecting the chemical stability of the
If the dissolution rate of the active ingredient emulsifier, suspending agent, antioxidant, mi¬
from the tablet or the tablet disintegration time crobiologic preservative, and active substance,
were to increase under extended shelf storage of as well as the physical characteristics of the dis¬
the tablet formulation, the therapeutic effective¬ perse system.
ness of the tablet medication could be seriously It is an established fact that the degree of sta¬
affected. In general, a decrease in therapeutic bility of an emulsion may be measured by the
efficacy would take place because the active in¬ variation of the distribution of sizes of the dis¬
gredient would be less readily available for ab¬ persed droplets with time. An emulsion ap¬
sorption. proaching the unstable state is characterized by
The effect of storage of phenobarbital and the appearance of large globules as the result of
phenacetin tablets on the rates of dissolution coalescence and aggregation of small globules.
has been studied for three tablet formulations.68 Lloyd has employed the relationship between
Tablets prepared with gelatin or polyethylene reflectance of colored emulsions and the surface
glycol 6,000 as granulating agents changed little average diameter of their disperse phase to eval¬
during storage, whereas tablets prepared with uate different emulsion stabilizers and study the
carboxymethylcellulose underwent a significant kinetics of emulsion coalescence.76 Oil-in-water
increase in dissolution rate. emulsions containing 50% volume of the dis-

Table 26-13. Time Required For Objectionable Fading at Low Light

Intensities as Calculated From Accelerated Light Conditions

Concentration
of Dye Hours at Calcd. Hours Calcd. Hours
(% w/w) 540 fc at 50 fc at 10 fc

0.060 17 180 920

0.030 7 75 380
0.015 2 20 110

fc = footcandles

KINETIC PRINCIPLES AND STABILITY TESTING *791

persed phase and different starches, starch de¬ where:
rivatives, water-soluble gums, and surfactants
were used. The oil phase was colored with the , c
red dye, Scarlet B. Reflectance of the emulsions C _ (6f)k
was determined at 450 m/a and the surface aver¬
age particle diameters of the internal phase was Based on the data in Figure 26-33, emulsion
determined by microscope. Upon plotting sur¬ stability was evaluated by determining the
face average particle diameter on logarithmic change in average particle diameter with time
paper, a linear relationship becomes apparent as through reflectance measurements of the sam¬
shown in Figure 26-33. ple at designated time intervals. The data from
The relationship between percentage of re¬ this study are summarized in the semilog plot
flectance (R) and surface average particle diam¬ Figure 26-34. The portions of the curves during
eter (D) is expressed as follows: the periods of active coalescence approximate
straight lines. Since specific interfacial area sim¬
Log R = — k log D + log c ulates a concentration factor (interfacial areas
per unit volume of oil), the coalescence behavior
or alternatively as: of the emulsion system in Figure 26-34 simu¬
lates a first-order reaction and can be used to
estimate the physical stability of an emulsion at
extended storage periods.
Van den Tempel measured the rate of coagula¬
where k and c are constants characteristic of the tion of o/w emulsions according to the following
emulsion. Surface average particle diameter was simplified equation:
shown to be inversely related to specific interfa¬
cial area (A) of a given emulsion as follows:
n n0

where f is the volume fraction of the dispersed

phase. Thus, the reflectance is proportional to
the specific interfacial area of the emulsion
raised to k power.77

R = c'Ak

FIG. 26-33. Reflectance of various emulsion systems vs. FIG. 26-34. Stability of paraffin oil emulsions containing
surface-average particle diameter. (From Lloyd, N. E.: ]. various starches and starch derivatives. (From Lloyd,
Colloid Sci., 14:441, 1959.) N. £.: J. Colloid Sci., 14:441, 1959.)

792 • The Theory and Practice of Industrial Pharmacy

where n is the number of particles in a unit vol¬ uation. The equation for sedimentation was re¬
ume at time t, n0 is the number of particles at ported as:
time to, and a is the rate of decrease of particle
dV
concentration.78 Plotting — versus time results = k(l - V)V1/2
dt
in a linear relationship (Fig. 26-35). The' data
plotted in this figure show the rate of decrease of Integration of the equation gives:
particle concentration (coagulation) in an emul¬
sion stabilized with dioctyl sodium sulfosucci- i + Vv
kt = log
nate. l - Vv
While it is undoubtedly fundamental to study
emulsion stability on the basis of size frequency By determining the half-life, the time for half
analysis, the practical commercial aspect of sta¬ the volume to separate, it is possible to readily
bility is the observation of creaming and/or sepa¬ compare a series of emulsions.
ration of water and oil in an emulsion. Factors To study demulsification of oil-in-water and
involved in this observation are vibration, head water-in-oil emulsions, the internal phase was
space of gas, temperature, globule size, density colored, and the volumes of separated internal
of the phases, viscosity of the external phase, phase were measured colorimetrically at differ¬
gelling, and other changes in the emulsifying ent times.80 A graphic evaluation of the rate of
agent with aging. internal phase separation revealed that the rela¬
A scheme for expressing separation changes tionship of the percentage separated to time is
quantitatively is presented.79 The separation of exponential (Fig. 26-36). The straight lines ob¬
oil or water of quantity dV in time t depends on tained by this log-log plot indicate the following
time and the amount of emulsion still emulsified
equation:
(1 - V), as well as the height at which the emul¬
sified globule must travel to reach the separation
x = kya
layer and make the separated portion of the
phase clear. This height is proportional to V in a log x = log k + a log y
cylindric vessel; however, the sedimentation
velocity is not proportional to the height, but to a In demulsification time (seconds)
power of this, which can theoretically be be¬
tween 0 and 1, and is usually 0.5. Errors of ±3%
were reported to accompany this method of eval-

log(Q demulsification time (seconds)

FIG. 26-36. Plots showing the rates of demulsification of
FIG. 26-35. Decrease of particle concentration in emul¬ several emulsion systems. (From Menczel, E.,
sions with time. (From Van den Tempel, At.: Rec. Tran. Rahinowitz, At., and Madjor, A.: Am. J. Pharm., 132:335,
Chim., 72:433, 3953.) 1960.)

KINETIC PRINCIPLES AND STABILITY TESTING • 793

where y is the percentage of separated internal
phase, x is time, and k and a are constants that
differ from one emulsion system to another.
Whatever the rate of separation of the internal
phase, the demulsification is at first nonap-
parent, and then it becomes apparent. It was
assumed that the rate of demulsification was
equal at both the nonapparent and apparent
stages (negative and positive y axis of Figure 26-
36) for emulsions consisting of considerable vol¬
umes of internal phase dispersion; the separa¬
tion of 1% internal phase (In = 0) renders the
demulsification perceptible. A perceptible
demulsification axis (PDA) was suggested,
which is actually the demarcation point between
apparent and nonapparent demulsification; the FIG. 26-38. Increase of oil coalescence as a function of
less the rate of demulsification, the more time is time for “bad,” curve A, and “good,” curves B, C, D, oil-
needed to reach the PDA. If the slope of the in¬ water emulsions. The symbols and ultracentrifugal rpm at
30° are: 0, 59,780; O, 52,640; •, 47,660. (From Garrett,
ternal phase separation is drawn upward and
E. R.:J. Pharm. Sci., 51:35, 1962.)
extended into the nonapparent stage, the inter¬
ception points (k) with the perceptible axis of
demulsification indicate the degree of emulsion bad emulsion was found to separate oil almost
stability. When the same exponential time units instantly following a first-order rate of separa¬
are used for the x axis, as well as for the PDA, tion. A good emulsion exhibited an induction
the higher the value for k, the more stable is the period during which no detectable oil separation
emulsion. took place, followed by an accelerated rate of oil
The ultracentrifuge has been suggested as a separation as depicted in Figure 26-38.
means to measure o/w emulsion stability.81 By The viscosity aging characteristics of suspen¬
determining the emulsion clearing or separation sions and suspending agents were studied by
at different centrifugal speeds and plotting the Levy.82 The viscosity degradation curve for so¬
logarithm of this data versus time, the straight dium alginate XR-C is shown in Figure 26-39,
line plots shown in Figure 26-37 are obtained. A and it appears to follow a first-order degradation.
For sodium alginate, the effect of concentration
on stability was found to be negligible in the con¬
centration range studied; however, in the case of
sodium carboxymethylcellulose, there was a pro¬
nounced effect of concentration on the viscosity

FIG. 26-37. Examples of clearing of oil-water emulsion

from i.v. emulsion at various centrifugal speeds. Plots of
the logarithm of the distance of the emulsion-water bound¬
ary from the center of the rotor against the time of ultra-
centrifugation in seconds at 30°. The symbols and corre¬
sponding rpm are: —O—, 12.590; —•—, 15220; FIG. 26-39. The viscosity stability of sodium alginate
—O— 20,410; —O—, 24,630; '35.600. (From XR-C at several concentrations. (From Levy, G.: J. Pharm.
Garrett, E. R.: J. Pharm. Sci., 51:35, 1962.) Set, 50:429, 1961.)

794 • The Theory and Practice of Industrial Pharmacy

 tion rather than equal viscosity was performed,
the formulator would receive a distorted picture
of their relative stabilities.
None of the several methods described for
evaluating the physical stability of disperse sys¬
tems considered the temperature dependency of
the parameters employed. For accurate utiliza¬
tion of the data from exaggerated temperature
storage, the relationship of the change in these
parameters at the different temperatures must
be determined. It is realized, however, that for
emulsions and suspensions, it may not be possi¬
ble to exaggerate the temperatures to the extent
done for solutions. In disperse systems, the
physical properties at temperatures above a cer¬
tain point could be completely different from
FIG. 26-40. The decrease in the apparent viscosity of sev¬ those that would exist at normal temperatures of
eral concentrations of sodium carboxymethylcellulose storage. For example, in formulations exhibiting
(M. W. 75,000) as a function of time. (From Levy, G.: J. thixotropic properties, a rise in temperatures
Pharm. Sci., 50:429, 1961.) above a certain value would cause a change in
the properties of the preparation into a gel struc¬
ture. In this physical form, the preparation
stability as shown in Figure 26-40. Increase in would exhibit parameters that could not be ex¬
polymer concentration results in a decrease in trapolated to those that would exist in the nor¬
the rate of viscosity change. mal system. However, it is felt that through the
The plots in Figure 26-41 compare the stabil¬ use of elevated temperatures that are not as high
ity of sodium carboxymethylcellulose of various as those employed for chemical reactions, valid
average molecular weights by plotting viscosity temperature dependency data could be obtained
half-lives versus initial apparent viscosity. The that would be useful in the estimation of the
vertical line in the figure serves to compare the physical stability of a product at normal storage
viscosity half-lives of the three polymer types at conditions.
a given apparent viscosity. It was indicated that A significant challenge confronting pharma¬
if a comparison of solutions of equal concentra- ceutical development and analytic scientists is
the testing of new drug delivery systems for
physical and chemical stability. Since most new
delivery systems involve polymeric systems, pro¬
tein, and genetically engineered substances,
standards need to be developed for these sys¬
tems, and new tests, specifications, and equip¬
ment are required to evaluate such systems.

Influence of Packaging
Components on Dosage Form
Stability
Faulty packaging of pharmaceutical dosage
forms can invalidate the most stable formula¬
tion. Consequently, it is essential that the choice
of container materials for any particular product
be made only after a thorough evaluation has
been made of the influence of these materials on
INITIAL APPARENT VISCOSITY the stability of the product and of the effective¬
(BROOKFIELD UNITS xIO-8) ness of the container in protecting the product
during extended storage under varying environ¬
FIG. 26-41. The viscosity half-life (V1/2) of sodium car¬
boxymethylcellulose solutions at 49° as a function of the mental conditions of temperature humidity, and
initial apparent viscosity. (From Levy, G.: J. Pharm. Set., light.
50:429, 1961.) The materials most commonly employed as

KINETIC PRINCIPLES AND STABILITY TESTING • 795

container components for pharmaceutical prep¬ Table 26-15. Extraction of Alkali
arations include glass, metal, plastic, and rub¬
Extraction as
ber.
Glass Treatment mg Na20
Glass. Of these four materials, glass has
been the container of choice for pharmaceutical Annealed in absence of S02 2.9
dosage forms because of its resistance to decom¬ Annealed in presence of S02 0.9
position by atmospheric conditions or by solid
and liquid contents of different chemical compo¬
sition. Furthermore, by varying the chemical
composition of glass, it is possible to adjust the treated glass. The suggested reason for the
chemical behavior and radiation properties of greater resistivity of this glass is that a layer of
the glass. positively charged hydrogen ion glass forms,
Although glass exhibits many advantages over causing the development of a compacted layer
other packaging materials, it has two principal on drying and the expulsion of water. The diffu¬
faults, namely, the release of alkali and the re¬ sion of sodium through such a layer is greatly
lease of insoluble flakes to liquids stored in the retarded; hence, the extraction by water would
container. The USP XX acknowledges that alkali be considerably reduced.
ions can be released for each of four types of In recent years, a number of drugs have been
glass listed in the USP compendium, as shown developed that are of high potency, and conse¬
by the data in Table 26-14. quently, of low dosage. The stability of these
By decreasing the soda content in the glass or drugs can be readily affected by the release of
replacing the sodium oxide with other oxides, it soluble alkali from glass containers. As a safety
has been possible to overcome the undesirable factor, whenever the dosage form is a liquid, the
property of glass releasing alkali cations into so¬ solution should be buffered to eliminate any ef¬
lution. This is exemplified by the borosilicate fect due to possible change in pH if some alkali
glass in Table 26-14 as compared with the gen¬ were released from the glass.
eral purpose soda-lime glass. Sometimes, insoluble flakes have been found
Several approaches have been used to in¬ to appear in solutions stored in glass containers.
crease the resistance of glass to alkali release by The type of glass employed plays a major role in
surface treatment. One method consists of treat¬ whether flake formation takes place. For exam¬
ing the surface of soda-lime glass to produce a ple, flake formation may occur in nonborosili-
fire-polished skin of silica, which is more resis¬ cate glass immediately after autoclaving,
tant than the inner layers of glass. This surface- whereas in borosilicate glass, it occurs at tem¬
treated glass is represented bv Type II glass in peratures much higher than those normally
Table 26-14. used for autoclaving.
Another approach is to treat the surface of the Glass containers may possess various addi¬
glass with sulfur dioxide in the presence of tives, such as oxides of boron, sodium, potas¬
water vapor and heat.83 This causes the surface sium, calcium, iron, and magnesium which alter
alkali to react with the sulfur dioxide, and the physical and chemical properties of the glass.
glass becomes more resistant, as shown by the For example, when formulating sulfate salts,
data in Table 26-15, for 5-hour extractions per¬ (drug substances or antioxidants) the glass con¬
formed with boiling water for treated and un- tainer should have minimal amounts of calcium

Table 26-14. Glass Types and USP Test Limits

Limits

General ml of
Type Description* Type of Test Size (ml)f 0.02 N Acid

I Highly resistant borosilicate glass Powdered glass All 1.0

II Treated soda-lime glass Water attack 100 or less 0.7'
over 100 0.2
III Soda-lime glass Powdered glass All 8.5
IV General purpose soda-lime glass Powdered glass All 15.0

*Description applies to containers of the type of glass usually available.

tSize indicates overflow capacity of the container source. (Data from USP XX/NF XV, United States Pharmacopeial Convention, Inc.,
1982, p. 949.)

796 • The Theory and Practice of Industrial Pharmacy

Table 26-16. Parenteral Solutions Containing Barium Sulfate Crystals

Source of
Type of Sulfate or
Product Glass Container Bisulfite Ions

Procaine hydrochloride, 2% 30-ml vial Antioxidant

Kanamycin sulfate, 0.5 g/2 ml 2-ml vial Drug
Meperidine hydrochloride, 100 mg/ml 1-ml vial Antioxidant
Magnesium sulfate, 5 g/10 ml 10-ml vial (plunger) Drug
and rubber closure
Atropine sulfate, 0.5 mg/ml 1-ml ampul Drug
Promethazine hydrochloride, 25 mg/ml 1-ml ampul Antioxidant

From Boddapati, S., Butler, D. L., Im, S., and DeLuca, P. P., J. Pharm. Sci., 69:608,1980. Reproduced with permission of the copyright
owner, the American Pharmaceutical Association.

and barium to prevent the formation of insoluble physical or chemical changes due to the radiant
inorganic salts.84 Table 26-16 shows six paren¬ energy of light. Light radiations can cause color
teral solutions containing barium sulfate crys¬ development or color fading and potentiate an
tals, which were identified by polarizing micros¬ oxidation-reduction reaction, resulting in drug
copy, scanning electron microscopy with degradation, rancidity of oil formulations, and
energy-dispersive x-ray analysis, micro-x-ray flavor and odor loss. Products exhibiting physi¬
powder diffraction, and micro Ramon spectros¬ cal and chemical changes resulting from the ef¬
copy. Figure 26-42 shows the crystals from two fects of radiant energy can, in most instances, be
Solutions. On the basis that barium sulfate adequately protected by the use of special glass
forms in situ,85 the sulfate ions appear to origi¬ containers. Flint glass, which is the most widely
nate from the union of the drug and/or the bisul¬ used multipurpose container material, has the
fite ion of the antioxidant. The barium ions orig¬ disadvantage of being transparent to light rays
inate from the borosilicate glass, which can above 300 m/a. As a result, amber glass, which
contain up to 5% BaO.86 has the property of shutting out certain portions
Flakes are also likely to occur with phosphate, of the light spectrum, has been used extensively
citrate, tartrate, and alkaline solutions. Pretreat¬ by the pharmaceutical industry. The transmis¬
ment of the containers with dilute acid solution sion curves for flint and amber glass shown in
was found to delay flake formation. Figure 26-43 show that although flint glass
Many pharmaceutical preparations exhibit transmits significantly from 300 m/a, amber

A B
FIG. 26-42. Scanning electron micrographs of barium sulfate crystals isolated from procaine hydrochloride (A) and
atropine sulfate (B) (1000 x , 20 kv). (From Boddapati, S., Butler, D. L., Im, S., and DeLuca, P. P: J. Pharm. Sci., 69:608,
1980. Reproduced with permission of the copyright owner, the American Pharmaceutical Association.)

KINETIC PRINCIPLES AND STABILITY TESTING • 797

 Table 26-18. Chemical Assay for Residual Anti¬
histamine from Solutions Stored in Clear and
Amber Glass Ampuls

Assay (%)

Time (Weeksj Clear Glass Amber Glass

0 100 100
4 83 98
8 64 98
FIG. 26-43. Transmission curves for typical flint and
amber glass.
The amber color of the glass is imparted by the
addition of iron and manganese oxides, cations
glass does not begin to transmit to any apprecia¬ that are known to catalyze oxidative reactions.
ble extent until 470 my. Since it is known that Studies have shown that these ions are ex¬
the photochemical activity of the light radiations tracted from the glass,87 and that the decomposi¬
drops off with increasing wave length, it would tion rates of several drugs—thiomerosol,88
be expected that the amber container would af¬ amitriptylene,89 and L-ascorbic acid90—are en¬
ford a product better protection against light hanced in amber glass containers.
than the flint glass. This is illustrated by the fol¬ The Parenteral Drug Association has pub¬
lowing examples. lished guidelines on the processing and selec¬
The data in Table 26-17 show the protective tion of glass containers.91 Various surface treat¬
effect of amber glass on the fading of dyes from ments are used to improve chemical resistance
the surface of tablets stored in flint and amber and decrease alkalinity. For example, exposing
glass bottles. hot containers to sulfur dioxide reduces sodium
The results in Table 26-18 summarize the content at the surface, and a brief treatment
stabilizing properties of amber glass on the pho¬ with ammonium bifluoride effectively cleans the
tochemical degradation of an antihistamine in¬ surface by dissolving a portion of it.
jectable solution exposed to exaggerated illumi¬ Plastics. Although glass has many desirable
nation. The solutions stored in clear glass am¬ properties, recent years have seen the use of
puls show a 36% loss of antihistamine concen¬ more and more containers having all or part of
tration, while those in amber glass show their structure composed of plastic for the stor¬
essentially no loss in drug concentration. age of pharmaceutical preparations. It should be
The protective effect of amber glass on the realized that the term plastic denotes a consider¬
darkening of sulfonamide tablets exposed to ex¬
able group of high-molecular-weight polymers,
aggerated lighting is shown in Table 26-19, each having different physical and chemical
where reflectance data are given for the surface properties. They include polyethylene, polypro¬
of the sulfonamide tablets. It is evident that the pylene, polystyrene, polyvinylchloride, and sev¬
tablets darken with storage, since the reflec¬ eral others. Any particular plastic may be avail¬
tance values decrease substantially when the able in different densities or may be modified by
tablets are exposed to light in an open dish. Vi¬ certain additives that affect its chemical and
sual observation of these tablets indicated that
they had taken on a yellow-tan color; however,
for the tablets stored in amber bottles, no signifi¬
cant change in reflectance took place, and visual
Table 26-19. Influence of Light on the Photo¬
sensitivity of a Sulfonamide Tablet Formulation
observation showed no apparent darkening.
% Reflectance at 450 mu

Table 26-17. The Amount of Dye (%) Faded per Time (Weeks) Open Disk Amber Bottle
Day When Irradiated Under Exaggerated Inten¬
0 52.6 52.6
sity
2 41.3 52.3
FD&C DSrC 4 35.6 53.6
Glass Sample Blue #1 Yellow *10 6 31.7 53.8
8 28.9 52.9
Flint 12.9 38.1 10 25.4 —

Amber 4.6 6,2 12 23.8 51.5

798 • The Theory and Practice of Industrial Pharmacy

physical properties. Only through studying the The property of plastics to sorb materials from
stability of the plastic container with the product solution can cause loss of drug, antibacterial
for which it is to be used is it possible to be cer¬ agent, or other materials from solution. The
tain that the plastic has no effect on the prepara¬ curves in Figure 26-44 show the degree of bind¬
tion and that the preparation or one of its ingred¬ ing of several commonly used antibacterial pre¬
ients has no effect on the plastic. servatives when solutions of these preservatives
A chief disadvantage of plastic containers, as are in contact with the nylon barrel of a disposa¬
compared with glass, is the problem of permea¬ ble syringe.95 In nearly all instances, after one
tion in two directions, namely, from the solution week’s storage at 30°C, over 60% of the preserv¬
in the container through the plastic into the ative is bound. When these same preservatives
ambient environment and from the ambient have been evaluated with polyethylene and poly¬
environment through the plastic into the prepa¬ styrene barrels, essentially no binding has been
ration. In addition, materials can be leached found. This clearly illustrates the importance of
from the plastic container into the liquid prepa¬ selecting the correct plastic material for a partic¬
ration, materials from the preparation can be ular use.
adsorbed or absorbed onto and into the plastic Stability tests performed on Vioform Lotion
container, and in certain instances, the contents packaged in plastic containers showed that the
of the container can chemically or physically Vioform was being sorbed by the container. Lin¬
react with the plastic components of the con¬ ing of the container with an epoxy resin elimi¬
tainer, causing container deformation. The de¬ nated this problem. This is illustrated by the
gree of permeation, leaching, sorption, diffusion, data summarized in Table 26-20, which pres¬
and chemical reactivity varies considerably from ents reflectance data of the inside wall of the
one plastic material to another. lined and unlined container. A decrease in the
The stability of a product packaged in a plastic reflectance of the container wall is indicative of
container can be affected in several ways, owing Vioform sorption by the plastic since a yellow
to container permeability. The chemical, as well surface reflects less light than a white surface.
as the physical, stability of the tablet dosage This is further substantiated by the increase in
form can be influenced considerably by penetra¬ reflectance of the lotion with storage, indicating
tion of water vapor from the atmosphere into the that the lotion is becoming lighter because of the
container. Penicillin tablets were found to de¬ loss in Vioform content.
grade in polystyrene containers, owing to perme¬ Although the epoxy lining was effective in
ation of water vapor.92 Oxygen and carbon diox¬
ide in air can permeate through plastic
containers, catalyzing the degradation of drugs
that are prone to oxidation or hydrolysis. A tetra¬
cycline suspension was found to change in color
and taste, owing to permeation of air through
the walls of a polyethylene container.93
Plastic containers, when used for emulsion
preparations, must be thoroughly evaluated for
physical and chemical changes of the emulsion,
as well as for physical changes in the container.
It has been reported that certain materials in an
emulsion have a tendency to migrate toward the
polyethylene wall, causing either a change in
the emulsion or a collapse in the container.94
Since polyethylene has a tendency toward elas¬
tic recovery, air is continuously drawn into the
plastic container, increasing the chance of oxi¬
dation and drying out of the preparation. In the
case of an emulsion, the air can cause the emul¬
sion to break down, owing to dehydration or oxi¬
dation of the oil phase. This phenomenon of
package “breathing” is a major cause of product
deterioration during storage in plastic con¬ TIME (hours)
tainers. It can also be responsible for the loss of FIG. 26-44. Binding of antibacterial preservatives by
flavor and perfume ingredients from products nylon as a function of time. (From Marcus, E., et al: ]. Am.
packaged in plastic containers. Pharm. Assoc., Sci. Ed., 43:457, 1959.)

KINETIC PRINCIPLES AND STABILITY TESTING • 799

 Table 26-20. Sorption of Vioform by the Plastic Container from the
Lotion When Stored at 40°C.

Reflectance in %

Unlined Container Lined Container

Time (Weeks) Lotion Container Lotion Container

0 60.0 55.0 63.0 54.5

1 60.0 48.0 61.5 53.0
2 61.0 49.5 63.0 53.0
3 65.0 50.0 61.5 54.0
4 — 49.0 63.0 53.0

eliminating the problem with Vioform lotion, it well as whether the coating completely covers
was not effective in preventing the sorption of the underlying material. In addition, the coating
the antibacterial agent, phenylmercuric acetate, must be evaluated for ease of cracking and sol¬
from solution as illustrated by the data in Table vent resistance.
26-21. Tin and tin-coated tubes are usually employed
It is evident from the results presented in Ta¬ because of their unreactive properties, although
bles 26-20 and 26-21 that linings are not always it has been reported that tin tubes can be cor¬
effective and must be evaluated separately for roded by chlorides or acid conditions. Vinyl and
each product. The ineffectiveness of the lining cellulose lacquers are applied to tin to increase
could be attributed to sorption of the lining itself their utility.
by the preservative or to the presence of imper¬ Coated and uncoated aluminum tubes are
fections, such as pinholes in the lining, which being used, but are not always satisfactory. It
permit penetration of the lining to the plastic. has been reported that aluminum reacts with
Metals. In addition to glass and plastic, cer¬ fatty alcohol emulsions to form a white encrusta¬
tain metals are also employed as containers for tion.96 Such tubes were also found to be unsta¬
pharmaceutical products. Disperse systems, ble for mercury-containing compounds. It has
having a consistency of a soft paste, gel, cream, been stated that uncoated aluminum tubes are
or ointment, can be conveniently packaged into deleteriously affected when used for prepara¬
collapsible tubes. Metals commonly used for tions outside the pH range of 6.5 to 8.O.97 The
such tubes are tin, plastic-coated tin, tin-coated application of an epoxy lining to the internal sur¬
lead, aluminum, and coated aluminum. Tubes faces of aluminum tubes was found to make
constructed of a single material can readily be them more resistant to attack.
tested for stability with a product. Tubes having Whether the container is made of glass, plas¬
coatings present additional problems, since it tic, or metal, it still requires a closure to contain
must be established whether the coating mate¬ the contents effectively. In addition to forming
rial is sufficiently inert for the preparation, as an effective seal on the container, the closure

Table 26-21. Loss of Phenylmercuric Acetate from Solution Stored in

Lined and Unlined Polyethylene Bottles

% Preservative Lost

Unlined Container Epoxy-Lined Container

Time (Weeks) 25°C 40°C 25°C 40°C

0 0 0 0 0
1 10.0 29.3 12.4 24.6
2 11.5 38.5 — 27.0
3 20.0 35.8 15.4 37.7
4 20.0 46.2 23.9 43.9
8 33.2 57.7 Tin 58.5
12 33.7 70.0 33.2 68.8

800 • The Theory and Practice of Industrial Pharmacy

should not react chemically or physically with
the container contents to sorb material from the
contents or leach material to the contents.
Rubber. Rubber of varying composition is
used in pharmaceuticals and biologicals as stop¬
pers, cap liners, and parts of dropper assemblies.
A major use of the rubber stopper is that of a
closure for multiple-dose vial solutions for injec¬
tions. The problems that can be encountered by
having rubber stoppers in contact with the liq¬
uid in the vial are the sorption of active ingredi¬
ent, antibacterial preservative, or other materi¬
als into the rubber, and the extraction of one or
more components of the rubber into the vial so¬
lution.
The data in Table 26-22 illustrate the influ¬
ence of various rubber closures on the loss of the
antimicrobial preservative chlorobutanol from FIG. 26-45. Leaching of extractives from rubber stoppers
on multiple dose vial solutions.
vial solutions. It is evident from these data that
the closures have a marked deleterious effect on
preservative concentration at all temperatures.
At 60°C, after 12 weeks of storage, the vials stop¬ of three years, would no doubt cause further
pered with neoprene closures and stored in an leaching of extractives in solution.
inverted position show only 8.5% residual con¬ If an epoxy lining is applied to rubber stop¬
centration of chlorobutanol, whereas the ampuls pers, a considerable reduction results in the
under the same conditions of storage contain amount of extractive leached from the stopper
72.4%. by the water for injection in the vials, but there
The curves in Figure 26-45 show that extract¬ is essentially no effect on the sorption of pre¬
ives from the natural rubber closures used to servative from solution. However, the use of
stopper vials containing water for injection were Teflon-coated rubber stoppers essentially pre¬
leached into the water when the vials were auto¬ vents sorption and leaching of the rubber stop¬
claved. It is evident from the absorption spectra per.
of the extractives in the vial solutions that even The presence of rubber closure extractives in
normal autoclaving at 115<IC, 10 psi for 30 min the vial solutions could interfere with the chem¬
causes appreciable extractive to enter the water ical analysis of the active ingredient, affect the
for injection. Subsequent storage of these vials toxicity or pyrogenicity of the injectable prepara¬
at room temperature for the shelf-life of the tion, interact with the drug or preservative to
pharmaceuticals, which at present is an average cause inactivation or loss of stability, and cause

Table 26-22. Influence of Various Closures on Residual Concentration of Chlorobutanol iti Vial Solu¬
tions After Storage

Stopper Composition

Natural Rubber Neoprene Polymer Butyl Polymer

Storage Ampul
Temp Time Control Upright Inverted Upright Inverted Upright Inverted
(°C) (wk) (%) (%) (%) (%) (%) (%) (%)

25 12 100 81.00 78.7 87.3 81.0 68.1 63.8

40 2 100 76.6 63.8 61.7 59.6 68.1 61.7
— 12 97.9 74.5 57.5 53.2 46.8 66.0 66.0
50 2 97.9 59.6 57.5 57.5 46.8 66.0 61.7
— 12 91.5 57.5 42.5 46.8 38.3 59.6 57.5
60 2 95.8 57.5 53.2 51.0 46.8 51.0 48.9
— 12 72.4 57.5 42.5 29.8 8.5 46.8 46.8

KINETIC PRINCIPLES AND STABILITY TESTING • 801

physical instability to the preparation, owing to good as the original package and that all
the presence of particulate matter in the solu¬ product specifications can be maintained
tion. throughout the dating period.
Good Manufacturing Practices and Expi¬
ration Dating. Good Manufacturing Practice
(GMP) requirements for drug stability (Section References
211.166), expiration dating (Section 211.137),
1. Federal Register, 43:45077, 1978.
and FDA guidelines for stability studies (Section 2. The Gold Sheet, 17, Cole Palmer Werble, October
98), contain significant and specific information 1983.
related to conducting stability studies and as¬ 3. Garrett, E. R., and Carper, R. F.: J. Pharm. Sci.,
signing expiration dates.98 The important fea¬ 44:515, 1955.
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Pharm. Sci., 72:59, 1983.
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must be based on data obtained from an ap¬ 7. Free, S. M.: Considerations in Sampling for Stability.
propriate stability testing program. Presented before the American Drug Manufacturers
Association, November 1955.
2. Such a stability program would include: 8. Blythe, R. H.: Product Formulation and Stability Pre¬
(a) numbers and sizes of containers per sam¬ diction. Presented at the Production Section of the
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container-closure system at appropriate 10. Waltersson, J. O., and Lundgren, P.: Acta Pharm.
Suec., 20:145, 1983.
storage condition(s); 11. Waltersson, J. O., and Lundgren, P.: Acta Pharm.
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at least three production batches, to be 12. Schlechtrull, J., et al.: Insulin II. In Handbook of
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Verlag, New York, 1975, p. 760.
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obtained using reliable and specific stability- 14. Walters, W. A.: Physical Aspects of Organic Chemis¬
try. 4th Ed. Van Nostrand, New York, 1959, p. 332.
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4. Tentative expiration dates can be assigned J. Chem. Soc., 129:2863, 1926.
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accelerated studies are scientifically sound 19. Germuth, F. G.: J. Am. Pharm. Assoc., 20:568, 1931.
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802 • The Theory and Practice of Industrial Pharmacy

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51:100, 1962.

KINETIC PRINCIPLES AND STABILITY TESTING • 803

_27
Quality Control and Assurance
LEON LACHMAN, SAMIR A. HANNA, and KARL LIN

The concept of total quality control refers to the sponsibility from manufacturing for producing a
process of striving to produce a perfect product quality product can result in imperfect composi¬
by a series of measures requiring an organized tion, such as ingredients missing, subpotent or
effort by the entire company to prevent or elimi¬ superpotent addition of ingredients, or mixup of
nate errors at every stage in production. Al¬ ingredients; .mistakes in packaging or filling,
though the responsibility for assuring product such as product contamination, mislabeling, or
quality belongs principally to quality assurance deficient package; and lack of conformance to
personnel, it involves many departments and product registration. Quality assurance person¬
disciplines within a company. To be effective, it nel must establish control or checkpoints to
must be supported by a team effort. Quality monitor the quality of the product as it is proc¬
must be built into a drug product during product essed and upon completion of manufacture.
and process design, and it is influenced by the These begin with raw materials and component
physical plant design, space, ventilation, cleanli¬ testing and include in-process, packaging, label¬
ness, and sanitation during routine production. ing, and finished product testing as well as batch
The product and process design begins in re¬ auditing and stability monitoring.
search and development, and includes prefor¬
mulation and physical, chemical, therapeutic,
and toxicologic considerations. It considers ma¬ Sources of Quality Variation
terials, in-process and product control, including Because of the increasing complexity of mod¬
specifications and tests for the active ingredi¬ em pharmaceutical manufacture arising from a
ents, the excipients, and the product itself, spe¬ variety of unique drugs and dosage forms, com¬
cific stability procedures for the product, free¬ plex ethical, legal, and economic responsibilities
dom from microbial contamination and proper have been placed on those concerned with the
storage of the product, and containers, packag¬ manufacture of modem pharmaceuticals. An
ing, and labeling to ensure that container clo¬ awareness of these factors is the responsibility of
sure systems provide functional protection of all those involved in the development, manufac¬
the product against such factors as moisture, ture, control, and marketing of quality products.
oxygen, light, volatility, and drug/package inter¬ A systematic effective quality assurance pro¬
action. Provision for a cross referencing system gram takes into consideration potential raw ma¬
to allow any batch of a product to be traced from terial, in-process, packaging material, labeling
its raw materials to its final destination in the and finished product variables.
event of unexpected difficulties is required.

Quality Assurance Control of Quality Variation

The assurance of product quality depends on
more than just proper sampling and adequate Raw Materials Control
testing of various components and the finished Good raw material specifications must be
dosage form. Prime responsibility of maintain¬ written in precise terminology, must be com¬
ing product quality during production rests with plete, must provide specific details of test meth¬
the manufacturing department. Removal of re¬ ods, type of instruments, and manner of sam-

804
pling, and must be properly identified. Table procedures are found in the Code of Federal
27-1 lists general tests, limits, and other physi¬ Regulations, Title 21, Section 211.42. It simply
cal or chemical data for raw materials related to states that “components” be received, sampled,
identity, purity, strength, and quality. Table 27-2 tested, and stored in a reasonable way, that re¬
presents the quality assurance monograph for jected material be disposed of, that samples of
acetaminophen, USP, as an example of a spe¬ tested components be retained, and that appro¬
cific raw material quality assurance monograph. priate records of these steps be maintained. In
The FDA Current Good Manufacturing Prac¬ practice, the manufacturer physically inspects
tices (CGMP) covering raw material handling and assigns lot numbers to all raw materials re-

Table 27-1. Raw Material Quality Assurance Monograph

A. (Raw Material Name)

1. Structural formula, molecular weight
2. Chemical name(s)
3. Item number
4. Date of issue
5. Date of superseded, if any, or new material
6. Signature of writer
7. Signature of approval

B. Samples
1. Safety requirement
2. Sample plan and procedure
3. Sample size and sample container to be used
4. Preservation sample required

C. Retest Program
1. Retesting schedule
2. Reanalysis to be performed to assure identity, strength, quality, and purity

D. Specifications (wherever applicable)

1. Description
2. Solubility
3. Identity
a. Specific chemical tests such as related alkaloids, organic nitrogen basis, acid moiety, or inorganic salt tests;
sulfate, Chloride, phosphate, sodium, and potassium tests; or other spot organic and inorganic chemical
tests as needed.
b. Infrared absorption
c. Ultraviolet absorption
d. Melting range
e. Congealing point
f. Boiling point or range
g. Thin-layer, paper, liquid, or gas chromatography
4. Purity and quality
a. General completeness of solutions, pH, specific rotation, nonvolatile residue, ash, acid-insoluble ash, resi¬
due on ignition, loss on drying, water content, heavy metals, arsenic, lead, mercury, selenium, sulfate,
chloride, carbonates, acid value, iodine value, saponification value.
b. Special quality tests, particle size, crystallinity characteristics, and polymorphic forms
c. Special purity tests, ferric in ferrous salts, peroxides and aldehydes in ether and related degradation prod¬
ucts
5. Assay, calculated either on anhydrous or hydrous basis
6. Microbial limits, especially for raw materials from natural sources

E. Test Procedures
1. Compendial, USP, or NF references
2. Noncompendial, detailed analytical procedure, weights; dilutions; extractions; normality; reagents; instrumen¬
tation used and procedure, if any; calculations

F. Approved Suppliers
1. List of prime suppliers and other approved alternative suppliers, if any

QUALITY CONTROL AND ASSURANCE • 805

Table 27-2. Acetaminophen, USP, Quality Assurance Specifications

Item Number Date of Issue Superseded Written by Approved by

001 Jan. 1, 1984 New J. Doe T. Mullen

Sampling Plan Retest Program

Containers
to be
Containers # Sampled Schedule Tests

1 All 2 yr Identity IR
2-5 All p-aminophenol
6-10 6 assay
11-18 7
19-28 8
29-100 9
101 10

HO

C8H9N02 Mol. wt. 151.16

Chemical Formula
4'-Hydroxyacetanilide, p-hydroxyacetanilide, p-acetaminidophenol, p-acetaminophenol, p-acetylaminophenol, N-acetyl-
p-aminophenol

Specifications
Description White, odorless, crystalline powder, possessing a slightly bitter taste
Solubility Soluble in boiling water and in sodium hydrdxide TS, freely soluble in alcohol
Identity A-IR Scan conforms to reference standard
B-UV Scan conforms to reference standard
C-FeCl3 Violet-blue color is produced
Melting range 168-172°C
pH (saturate solution) 5.3-6.5
Water NMT 0.5%
Residue on ignition NMT 0.1%
Chloride NMT 0.014%
Sulfate NMT 0.02%
Sulfide No coloration or spotting of the test paper occurs
Heavy metals NMT 0.001%
Readily carbonizable No more color than Matching Fluid A
substances
Free p-aminophenol NMT 0.005%
p-Chloroacetanilide NMT 0.001%
Assay 98.0-101.0% on the anhydrous basis
Completeness of solution 1 g/20 ml methanol is not less clear than an equal volume of methanol examined
similarly

Test Procedures
For all tests, see USP XXI, United States Pharmacopeial Convention, Rockville. MD, 1980.

Approved Suppliers
1. S. B. Penick & Co., Lyndhurst, NJ
2. Mallinckrodt, Raleigh, NC

806 • The Theory and Practice of Industrial Pharmacy

 ceived and quarantines them until they axe ap¬ or by all three methods. Caution must be exer¬
proved for use. Each raw material is sampled cised in testing antibiotic raw material to assure
according to standard sampling procedures and that it is not altered during the sampling proce¬
is sent to the quality control laboratory for test¬ dure. The sample must be taken in a relatively
ing according to the written procedures (Table dry atmosphere, relatively free from dust, and
27-2). If acceptable, it is moved to the release free of both chemical and microbial airborne
storage area, after being properly stickered to contamination, and exposure must be reduced
indicate the item number, name of material, lot to minimal time of sampling. Special attention
number, date of release, reassay date, and signa¬ should be given to the assay for potency of anti¬
ture of the quality assurance inspector. It is re¬ biotic raw materials. Since the potency value in
tested as necessary according to an established terms of micrograms per milligram obtained for
schedule to assure that it still conforms to speci¬ this material is used in calculating the number
fications at time of use. of grams or kilograms required for the working
Quality assurance personnel should keep formula procedures, it is recommended that at
preservation samples of active raw materials least two separate weighings of such antibiotic
that consist of at least twice the necessary quan¬ raw material powder be assayed on each of three
tity to perform all tests required, to determine different days (six different assays using six dif¬
whether the material meets the established ferent weighings). If all the individual results
specifications. These preservation samples are not within the normal distribution of the
should be retained for at least 7 years. Approved group or show too much variance, additional
materials should be rotated so that the oldest assays should be performed until a mean po¬
stock is used first. Any raw material not meeting tency is obtained with confidence limits of
specifications must be isolated from the accepta¬ ±2.5% (or better) at P = .05.
ble materials, stickered as a rejection, and re¬
turned to the supplier or disposed of promptly.
OTHER ACTIVE MATERIALS
To verify the supplier’s conformance to specifi¬
cations, further supporting assurance by means The current editions of the USP and NF con¬
of on-site periodic inspections are pertinent to tain monographs on most therapeutically active
the total quality of raw materials. This procedure materials used in manufacturing. Since there is
assures that cross-contamination does not take such a wide variance in the nature of the active
place because of improperly cleaned equipment ingredients used in manufacturing, it is impos¬
or poor housekeeping practices; otherwise, con¬ sible to summarize briefly the testing of those
taminants could go undetected because specifi¬ raw materials. One of the most important deci¬
cations generally are not designed to control the sions to be made in raw material control is the
presence of unrelated materials. In general, raw degree of purity to be maintained for each mate¬
materials may be classified into two groups: (1) rial. It is not uncommon to find an appreciable
active or therapeutic and (2) inactive or inert. variation in the degree of purity between sam¬
ples of the same raw material purchased from
different commercial sources. The selection
Active or Therapeutic Materials
must then result in the highest purity practical
for each raw material, consistent with safety and
ANTIBIOTICS
efficacy of the final dosage form. In general, a
Antibiotics are one of the few drugs for which typical raw material currently found in a com¬
the official analytic method appears in the Code pendium has a purity requirement of at least
of Federal Regulations. The USP and NF refer to 97%. Its specifications normally include solubil¬
the Code of Federal Regulations for specifica¬ ity, identification, melting range, loss on drying,
tions and analytic methods given in the individ¬ residue on ignition, special metal testing, spe¬
ual monographs for each antibiotic. The Code of cific impurities that are pertinent to the method
Federal Regulations, Title 21, Chapter 1, Parts of synthesis of each individual raw material, and
436 to 436.517 and Parts 442 and 455 contain assay. The methods of assay are usually chemi¬
the analytic method specifications for all antibi¬ cal in nature.
otics approved for human use in the United It should be understood that these compendial
States. The number of tests required varies from tests are intended as the minimum required
one antibiotic to another. The data in Table 27-3 from a legal point of view. For certain products,
specify the tests required by the Code of Federal it may be necessary to require that the active
Regulations for some antibiotics. ingredient specifications he far tighter than
Testing of antibiotics is usually performed ei¬ those of the comparable compendial standard.
ther chemically, microbiologically, biologically, Raw materials cannot be adequately evaluated

QUALITY CONTROL AND ASSURANCE • 807

 uoitmoy
oi/padS

sfimiq g
piqoxoijq S

“ C ‘B
>.2 3

imiimni
snoanbrmof^

uoiimBajmsiQ

axnvuadmaj^
j.0 af>uv}j
fraiyajy

spisffl Room

uoijiufi; no anpisay

,/jpssy 703 ^
9UlUiWlfixoapli[{
.ftossy x
ou^diuopoj
fyiuiipisfuj x
27-3. Tests of Some Antibiotics

dinisioy$

aoi h
z
Table

808 • TTie Theory and. Practice of Industrial Pharmacy

and controlled without special instrumentation Table 27-4. Colorants
such as spectrophotometry; potentiometric
titrimetry; column, gas (GLC), paper, thin-layer, Colorant Restriction on Use
and high-pressure liquid chromatography
FD&C'. Blue #1 Permanent listing for use in
(HPLC); polarography; x-ray diffraction; x-ray
foods, drugs, and cosmet¬
fluorescense; spectrophotofluorimetry; calorim¬ ics
etry; and radioactive tracer techniques. No less Blue #2
demanding are the tests required for microbio¬ Green #2
logic assay, pharmacologic assay, and safety Red #3 Provisional listing for use in
testing. For certain products, even when highly foods, drugs, and cosmet¬
purified and well characterized raw materials ics
are involved, specifications should include addi¬ Red #40
tional critical tests, such as particle size, crystal Yellow #5
shape, and crystalline versus amorphous forms. Yellow #6
Any of these characteristics could affect the D&.C: Blue #6
safety or effectiveness of the final dosage form. Green #5
It is a CGMP requirement that all raw materials, Green #6
active or inactive, be assigned a meaningful Orange #5
reassay date that assures the purity and potency Orange #10
of the raw material at time of use. This confirms Orange #17 Provisional listing for use in
drugs and cosmetics
the continued stability of each raw material.
Red #6
Red #7
Inactive or Inert Materials Red #21
Red #22
Inactive or inert materials usually make up
Red #27
the major portion of the final dosage form. Red #28
Therefore, their physical characteristics, such as Red #30
color, odor, and foreign matter, are as important Red #8
as their chemical purity. Among other important Red #12
specifications of inactive or inert materials are Red #19 Provisional listing for use in
particle size, heavy metal content, arsenic, sele¬ drugs and cosmetics with
nium, water content, microbial limit, foreign restriction of NMT 0.75
matter, residue on ignition, and pH. mg to be ingested on a
Approved certified water-soluble Food, Drug daily basis
and Cosmetics (FD&C) dyes, or mixtures Red #33
thereof, or their corresponding lake, may be Red #36 J
used to color oral dosage forms. The color in oral Yellow #10 Provisional listing for use in
dosage forms is mainly a means of identification. drugs and cosmetics
The FDA determines and approves colorants for Lakes of the above:
use in food and drugs with recommendation of Annatto Permanent listing for use in
limits, if any. Table 27-4 lists selected colors and foods, drugs, and cosmet¬
FDA restrictions on their use. A typical analysis ics
Carotene
of a color contains identity tests and tests of total
Caramel Permanent listing for use in
volatile matter, heavy metals, water-insoluble
foods, drugs, and cosmet¬
matter, synthesis impurities, arsenic, lead, and
ics and provisional listing
total color. An FD&C color lake analysis contains
for use in cosmetics
additional tests for chloride, sulfate, and inor¬
Carmine Permanent listing for use in
ganic matter. foods, drugs, and cosmet¬
If a flavored oral dosage form is desired, fla¬ ics
vors or volatile oils may be used. Flavors or vola¬ Titanium dioxide Permanent listing for use in
tile oils are usually tested for refractive index, drugs and cosmetics
specific gravity, solubility, and alcohol content,
if any. A GLC chromatogram can be used as a Data from Food and Drug Administration, Federal Register.

“fingerprint” for each specific flavor to help in

assuring the supplier’s continuous compliance
to specifications. Knowledge of the presence of personnel to assure compliance with FDA color¬
any synthetic FD&C dyes in a flavor formula is ant regulations.
important for the formulator and quality control The most popular sweetening agents used are

QUALITY CONTROL AND ASSURANCE • 809

sucrose, glucose, mannitol, lactose, crystalline and rodents. People are the mainstay of any
and liquid sorbitol, and such artificial sweeten¬ plant housekeeping and sanitation program.
ing agents as saccharin, sodium saccharin, cal¬ Consequently, personal cleanliness and proper
cium saccharin, and aspartame. haircovering and clothing should be required.
Testing for unwanted impurities resulting Floors, walls, and ceilings should be resistant to
from synthesis side reaction in the manufactur¬ external forces, capable of being easily cleaned,
ing procedure is essential in the analysis of and in good repair. Adequate ventilation, proper
sweetening agents, for example, furfuraidehyde temperature, and proper humidity are other
in lactose, and reducing sugars in mannitol. important factors. Ventilation in manufacturing
Sweetening agents are usually tested for water departments is usually designed so that dust can
content, heavy metals, residue on ignition, arse¬ be contained and removed. In such depart¬
nic, and special tests such as specific rotation, mental operations, dust collectors, air filters,
melting range, selenium, and readily car- and scrubbers to clean the air are checked on a
bonizable substances. routine schedule. Air quality monitoring at the
work station could indicate the adequacy of
these elements.
In-Process Items Control The water supply may be potable, distilled, or
Conformance to compendial standards as the deionized, and must be under adequate pressure
sole basis forjudging the quality of a final dosage to keep the water flowing. Deionization units
form can be grossly misleading. Obviously, a should be monitored, and the resins changed or
compendial monograph could never cover all regenerated frequently, to deliver water of con¬
possibilities that might adversely affect the qual¬ sistently high chemical and microbial quality as
ity of a product. The difficulty lies in part in the per written compendial or inhouse specifica¬
fact that final dosage forms are frequently pro¬ tions.
duced in batches of hundreds of thousands or Quality assurance should review and monitor
even millions of units. The numbers of units the following programs, based on written proce¬
assayed at the end of the process is not likely to dures that specify the details of each:
be representative of more than a small fraction
of the actual production. Sanitation: Example is shown in Table 27-5
There is a real and significant difference be¬ for one insecticide.
tween a finished product compendial standard Cleaning: Building and equipment.
and the quality assurance of the manufacturing Ventilation: Filter conditions and changes;
process. The FDA-CGMP regulations emphasize pressure gauge; humidity moni¬
environmental factors to minimize cross¬ toring; temperature monitoring;
contamination of products and errors in labeling microbial monitoring (Table 27-6);
and packaging, and the integrity of production light intensity.
and quality control records; however, they do lit¬ Water; Release at point of use after
tle to minimize within-batch and batch-to-batch checking by quality control;
variation in the output of production. Therefore, proper flushing period and/or vol¬
it is an important function of the in-process ume before water use.
quality assurance program to ensure that fin¬
ished dosage forms have uniform purity and
Manufacturing Working Formula
quality within a batch and between batches.
Procedures (MWFP)
This is accomplished by identifying critical steps
in the manufacturing process and controlling Documentation of the component materials
them within defined limits. and processing steps, together with production
operation specifications and equipment to be
Quality Assurance Before Start-Up used, make up the MWFP.
A working formula procedure should be pre¬
pared for each batch size that is produced. To
ENVIRONMENTAL AND MICROBIOLOGIC CONTROL
attempt expansion or reduction of a batch size
AND SANITATION
by manual calculations at the time of production
To assure that finished dosage forms meet cannot be considered good manufacturing prac¬
high standards of quality and purity, an effective tice.
sanitation program is required at all facilities Quality assurance personnel must review and
where such products are manufactured. A suc¬ check the working formula procedures for each
cessful extermination program must be enforced production batch before, during, and after pro¬
within and outside the plant to control insects duction for the following details:

810 • The Theory and Practice of Industrial Pharmacy

Table 27-5. Quality Assurance Operating Procedure

Page No.

Date Supersedes

NEW Sanitation Control—Pest Control

Written Checked
by by

Certox: Insecticide

Type of action
Kills on contact
Formula Approximate %
Petroleum distillates 71.8%
Technical piperonyl butoxide* 12.0
Pyrethrine 1.2
Inert ingredients 15.0

Dilution
Dilute 1 gallon of concentrate with 4 gallons of water.

Time interval
To be used once weekly after working hours on Friday evenings.

Area designation
Floor and drains

Equipment
Spray unit for Certox
Certox concentrate
Safety equipment

Removal of waste materials

Removal of waste materials remaining in the spray units after exterminating shall be the responsibility of the extermi¬
nator.

Effectiveness inspection
It will be the responsibility of the quality assurance department to perform routine area checks to ascertain the
effectiveness of the frequency of spraying.
It will be the responsibility of the area supervisor, however, to take necessary action immediately upon seeing any
infestation.

Special restrictions and cautions

1. Foods should be removed or covered during treatment.
2. Do not store or use near heat or open flame.
3. Apply only as designated on area designation assignments.

Toxicity in humans
Severe allergic dermatitis and systemic allergic reactions are possible.

Toxic symptoms
Large amounts may cause nausea, vomiting, tinnitus, headache, and other CNS disturbances.

Government status
EPA Registration Number: 1748-110
Since Certox presents no significant toxicity problem, no tolerance data are available.

“equivalent to 9.6% (butylcarbityl) (6-propyl-piperonyl) ether and 2.4% related compounds.

Signature and date of issue given by a respon¬ form, item number, lot number, effective date
sible production or quality assurance em¬ of document, reference to a superseded ver¬
ployee. sion (if any), amount, lot, and code numbers
Proper identification by name and dosage of each raw material utilized.

QUALITY CONTROL AND ASSURANCE *811

Table 27-6. Environmental Control in Manufacture of Oral Dosage Forms

Product Lot No.

Room _ Date exposed -

Time of Incubation Date

Media_ Exposure_ temperature_°C read

Duration _

1 —Location of Plate Exposure Plate no. Colony Count

2—Location of Air Sampler (m3 air/hr) Plate no. Colony Count

Comments

Microbiologist _ Supervisor

Date Reported _

Initialing of each step by two of the operators proper reassay dates should be allowed to enter
involved. the production department. Raw materials in¬
Calculations of both active and inactive mate¬ tended for use in specific products should be
rials, especially if there have been any correc¬ stacked and stored together in an approximate
tions for 100% potencies for active ingredients staging area with proper identification (name,
used. dosage form, item number, lot number, weight,
and signatures).
Starting and finishing times of each operation.
Equipment to be used and specification of its
set-up. MANUFACTURING EQUIPMENT
Proper labeling of released components and Quality assurance personnel must ensure that
equipment, indicating product name, manufacturing equipment is designed, located,
strength, lot number, and item number. and maintained so that it facilitates thorough
cleaning, is suitable for its intended use, and
RAW MATERIALS
minimizes potential for contamination during
Quality assurance should check the original manufacture. Manufacturing equipment and
containers of released raw materials for cleanli¬ utensils should be thoroughly cleansed and
ness before they axe taken to the production de¬ maintained in accordance with specific written
partment. Most raw materials, however, are directions. Whenever possible, equipment
weighed in an environmental control weighing should be disassembled and thoroughly cleaned
area, where they are transferred to a secondary to preclude the carryover of drug residues from
container that circulates only inside the produc¬ previous operations. Adequate records of such
tion department. This secondary container procedures and tests, if appropriate, should be
should be properly labeled with a sticker that monitored by quality assurance employees. It is
bears all the information on the original con¬ good manufacturing practice to use laboratory
tainer label. Only released raw materials with checks whenever possible to detect trace quanti-

812 • The Theory and Practice of Industrial Pharmacy

ties of drugs if products containing such drugs The specified in-process procedure is to be
were produced on specific equipment prior to checked, at each step in the process, according
cleaning. to written in-process quality assurance proce¬
Prior to the start of any production operation, dures.
the quality assurance personnel should ascer¬ Quality assurance personnel should verify
tain that the proper equipment and tooling for and document the proper equipment, addition of
each manufacturing stage are being used. ingredient, mixing time, drying time, filtering,
Equipment must be identified by labels bearing and mesh size of sieves used in screening.
the name, dosage form, item number, and lot At certain points, samples are to be taken to
number of the product to be processed. Equip¬ the quality control laboratory for potency assay
ment used for special batch production should and any other testing that is necessary to ensure
be completely separated in the production de¬ batch uniformity and purity.
partment, and all dust-producing operations Containers of in-process raw materials are la¬
should be provided with adequate exhaust sys¬ beled with product name, item number, lot
tems to prevent cross-contamination and recir¬ number, and gross, tare, and net weights of the
culation of contaminated air. contents.
Weighing and measuring equipment used in
production and quality assurance processes,
COMPOUNDING
such as thermometer and balances, should be
calibrated and checked at suitable intervals by Quality assurance personnel are responsible
appropriate methods; records of such tests for ascertaining that all containers of raw mate¬
should be maintained by quality assurance and rials are properly labeled and staged in the com¬
production personnel. Examples for such cali¬ pounding staging area, that they are clean, and
bration methods are given in Table 27-7. that manufacturing equipment is properly iden¬
tified as to product, strength, item number, and
Quality Assurance At Start-Up lot number.
The production process begins with the set-up
of the manufacturing equipment to prepare the
RAW MATERIALS PROCESSING
finished dosage form within the specified limits
Only released, properly labeled raw materials for the particular product. At each significant
axe allowed in the in-processing area. Depend¬ step in the procedure, quality assurance person¬
ing on the nature of the product, quality assur¬ nel verify that the process is being performed in
ance personnel should check and verify that the accordance with the written directions and is
temperature and humidity in the area are within conforming to required standards.
the specified limits required for the product. If A variable group of tests that are widely used
the temperature and/or humidity is beyond the for in-process controls measure characteristics
specified limits, production must be informed including physical appearance, color, odor,
and corrective actions taken. thickness, diameter, friability, hardness, weight
variation, disintegration time, volume check,
viscosity and pH. Such in-process tests are de¬
Table 27-7. Quality Assurance Calibration Pro-
signed to ensure control of problems that can
cedure
arise during finished dosage form manufactur¬
Page No. ing.
Current Good Manufacturing Practices re¬
Date Supersedes Calibration of Thermometers quire that in-process quality assurance be ade¬
Written Checked quately documented throughout all stages of
by by manufacturing. Throughout the production run,
in-process samples are removed and tested, and
Thermometers (to be checked every 6 months) data are recorded on special forms as specified
in the product’s in-process monograph. The
1. Employ suitable USP melting point standards for number of samples taken for testing and the
the range of the thermometer to be tested. type of testing obviously depend on the size of
2. Use USP method class I to determine the actual the batch and the type of product. If deviation
melting range of the standards. from the specified limits occurs, the necessary
corrective action is taken and recorded, and a
3. Tag the thermometer with calibration date, next cal¬
resample is taken and tested to determine
ibration date, temperature correction, if any, and
whether the quality attribute of the product is
signature of the person conducting the test.
now within the limits. In some instances, as in

QUALITY CONTROL AND ASSURANCE • 813

the case of compendial weight variation or pH issued; however, all labels must be accounted
specifications, the deviation is such that units for at the end of the operation, and unused labels
produced prior to the corrective action are iso¬ must be accounted for before their destruction.
lated, accounted for, and rejected. If the lot number and expiration date of the
In addition to the foregoing, portions of the product are not going to be printed directly on
initial, final, and in-process samples are used for the line, the labels are run through a printing
collecting average run samples for the quality machine, which imprints the lot number and
control laboratory to perform final batch analysis expiration date. The labels are recounted and
and release. placed in a separate container with proper iden¬
tification for future transfer to the packaging
department. The packaging department then
PACKAGING MATERIALS CONTROL
requests, according.to the packaging form, the
The USP defines the container closure system product to be packaged, along with all packaging
as that device that holds the drug and is or may components, such as labels, inserts, bottles,
be in direct contact with the drug. The immedi¬ vials, ampuls, stoppers, caps, seals, cartons, and
ate container is that which is in direct contact shipping cases. Quality assurance personnel
with the drug at all times. The closure is a part of inspects and verifies all packaging components
the container. and equipment to be used for the packaging op¬
Packaging materials should not interact phys¬ eration to ensure that it has the proper identifi¬
ically or chemically with the finished product to cation, that the line has been thoroughly
alter the strength, quality, or purity beyond cleaned, and that all materials from the previous
specified requirements. The compendium pro¬ packaging operation have been completely re¬
vides specifications and test procedures for light moved. Proper reconciliation and disposition of
resistance: well-closed, tightly closed, and four the unused and wasted labels should occur at
different types of glass containers. the end of the packaging operation.
Specifications and test methods are designed
for containers on the basis of tests performed on
the product in the container. The following fea¬ FINISHED PRODUCT CONTROL
tures are to be considered in developing con¬ Specifications. Final testing of finished
tainer specifications: product is made in the quality control laborato¬
ries. These tests are designed to determine com¬
Properties of container tightness. pliance with specifications. Thus, the testing of
Moisture and vapor tightness regardless of the finished product for compliance with prede¬
container construction. termined standards prior to release of the prod¬
uct for packaging and subsequent distribution is
Toxicity and chemical/physical characteristics
a critical factor for quality assurance. This test¬
of materials needed in container construction.
ing, along with in-process testing, assures that
Physical or chemical changes of container each unit contains the amount of drug claimed
upon prolonged contact with product. on the label, that all of the drug in each unit is
Compatibility between container and product. available for complete absorption, that the drug
is stable in the formulation in its specific final
Good Manufacturing Practices require that container closure system for its expected shelf-
stability data be submitted for the finished dos¬ life, and that dosage units themselves contain
age form of the drug in the container closure no toxic foreign substances.
system in which it is to be marketed. Normally, the design of test parameters, pro¬
cedures, and specifications is made during prod¬
uct development. It is a good manufacturing
LABELS CONTROL practice to base such parameters on experiences
Production control issues a packaging form developed from several pilot and production
that carries the name of the product; item num¬ batches. Furthermore, the results of these stud¬
ber; lot number; number of labels, inserts, and ies should be subjected to statistical analysis
packaging materials to be used; operations to be where appropriate, to appraise the precision and
performed, and the quantity' to be packaged. A accuracy of each procedure correctly for each
copy of this form is sent to the supervisor of label characteristic. In the long run, with additional
control, who in turn counts out the required production experience, specifications may possi¬
number of labels. Since labels may be spoiled bly be modified to upgrade product specifica¬
during the packaging operation, a definite num¬ tions.
ber in excess of that actually required is usually Bulk Product Testing. Each lot of bulk

814 * The Theory and Practice of Industrial Pharmacy

product should be tested to ensure identity, corded. The areas of record keeping include:
quality, potency, and purity. Quality assurance
authorizes the release for further processing Individual components, raw materials, and
based on actual physical, chemical, and/or bio¬ packaging materials. Master formula and pro¬
logic laboratory testing. cedure.
Tests required by the official compendia on Batch production.
the ingredients and the dosage form applies to
all manufacturers of a specific compendial prod¬ Packaging and labeling operation.
uct. The manufacturer frequently employs alter¬ Laboratory in-process and finished control
native methods that are more accurate, specific, testing.
or economical than those in the compendia. Proper signing and dating by at least two indi¬
The manufacturer is not required to employ
viduals independendy for each operation in
the official analytic procedures as long as the the proper spaces.
quality of his product complies with the com¬
pendial requirements. In the case of a legal Reconciliation of materials supplied with
action, however, the compendial procedures amounts of tablets produced, taking into ac¬
become the referee procedures for determining count allowable loss limits.
compliance.
Quality Assurance During Packaging Before releasing the product for distribution,
Operation. If the quality control laboratory quality assurance should evaluate the batch rec¬
analysis confirms that the product complies with ords of all in-process tests and controls and of all
specifications, and if the quality assurance audit tests of the final product to determine whether
indicates that manufacturing operations are sat¬ they conform to specifications.
isfactory, the bulk product is released to the
packaging department, and production control is
notified. Packaging operations should be per¬ Concept of Statistical Quality
formed with adequate physical segregation from
product to product. Quality assurance personnel Control
should periodically inspect the packaging fines Statistical quality control (SQC) has been de¬
and should check filled and labeled containers fined as the monitoring of quality by application
for compliance with written specifications. of statistical methods in all stages of production.
Some packaging operations, especially those Statistical methods of investigation based on the
using high-speed equipment, are fitted with au¬ theory of probability may be used for estimating
tomated testing equipment to check each con¬ parameters, for performing tests of significance,
tainer for fill and label placement. Alternatively, for determining the relationship between fac¬
an operator may visually inspect all packages fed tors, and for making meaningful decisions on
into the final cartons. Quality assurance should the basis of experimental evidence. The selec¬
perform an independent inspection and select tion of an appropriate method essentially de¬
finished preservation samples at random from pends on the type of measurement, the sam¬
each lot. The preservation samples should con¬ pling techniques, the design of the experiment,
sist of at least twice the quantity necessary to and the type of sample distribution (normal, bi¬
perform all tests required to determine whether nomial, or Poisson).
the product meets its established specifications. SQC has been used to serve (1) as a basis for
These preservation samples should be retained improved evaluation of materials through more
for at least 1 year after the expiration date and representative sampling techniques, and (2) as a
should be stored their original package under means of achieving sharper control in certain
conditions consistent with product labeling. manufacturing processes. The procedures con¬
Quality assurance personnel should also se¬ sist of properly sampling the product, determin¬
lect an appropriate size sample of the finished ing the quality variation of the sample, and from
package product and send it to the analytic con¬ this data, making inferences to the entire batch
trol laboratory for final testing. under investigation. Once the characteristic
Auditing. Good Manufacturing Practice re¬ data pattern of a process has been determined,
quires that the manufacturing process be ade¬ the pattern can be utilized to predict the limits
quately documented throughout all stages of the within which future data can be expected to fall
operation. The history of each task, including as a matter of chance, and to determine when
the starting materials, equipment used, person¬ significant variations in the process have taken
nel involved in production and control until place. The objective is to determine whether the
completed packaging is complete, should be re¬ major source of observed variation is due to

QUALITY CONTROL AND ASSURANCE • 815

“chance variation,” which is inevitable during sumption of a normal frequency distribution
the manufacturing process, or to “assignable curve.
causes,” which can usually be detected and cor¬ The normal distribution is defined completely
rected by appropriate methods. by two parameters: the mean and the standard
Any program of production and inspection has deviation. The observed mean (X) is the arith¬
its own unique chance causes of variation, metic average of a series of values and is calcu¬
which cannot be controlled or eliminated and lated by dividing the sum of such values by the
often cannot be identified. This variation repre¬ number of values (N) in the series. It is ex¬
sents a pool of small individual variations for pressed as:
which limits can be established. On the other
hand, the assignable causes can usually be iden¬
tified by statistical techniques, for example, the
detection of an outlier or a trend or pattern. As¬
signable causes, by definition, are associated X is the best measure of the central value of a
with something special and assignable, such as normal distribution and is an estimate of the
excessive variations caused by a specific ma¬ theoretic mean (ji). For quantitative expression
chine, a specific batch of material, or a con¬ of the dispersion or scatter about the central
tainer. Therefore, the use of SQC permits the value for establishing an estimate of variation
evaluation of the magnitude of “chance varia¬ among the values, the range (R) and the stan¬
tion” and the detection of “assignable variation” dard deviation (S) are commonly employed. The
of product quality. This may be detected by range is calculated as the arithmetic difference
means of quality control charts. between the largest and the smallest value in a
group of data. The standard deviation of the
sample (s) is an unbiased estimate of the stan¬
Normal Frequency Distribution dard deviation of the population (S) and is calcu¬
There are many types of variation patterns in lated from the following formula:
product quality. The most common pattern of
data distribution is the normal curve, a symmet¬ /S(X-X)»
ric, bell-shaped curve. By plotting the relative
s~ V N - 1 (2)
frequency of the data obtained from a large
number of results along the vertical axis against
the magnitude of the measured characteristic, The standard deviation is a measure of the vari¬
such as tablet weight or chemical assay, on the ation expressed in the same units of measure¬
horizontal axis, a normal frequency distribution ment as the original values. Furthermore, if the
curve is often obtained, as shown in Figure 27-1. distribution of measurements is normal, it per¬
Most statistical techniques are based on the as- mits delineation of a zone or range within which
a given portion of the original observations nor¬
mally fie. Thus, as seen in Figure 27-1, about
68% of all results fall within one standard devia¬
tion (±ls) on either side of the mean, 95.5%
within two standard deviations (±2 s), and
99.7% within three standard deviations (±3 s).
When sampling from a normal distribution, X
and s are independent of each other, i.e., the dis¬
persion or scatter as measured bv s is indepen¬
dent of the magnitude of the X. Figure 27-2
shows a series of normal probability distribu¬
tions whose mean values are the same, but
whose standard deviations differ. Such distribu¬
tions are so constructed that the total area under
each curve is unity, or 100%; thus, segments of
area under the curve represent probabilities.
Both the range (R) and standard deviation (s)
are measures of the variability among individu¬
als in a group. Although R is a less efficient mea¬
MEASURED MAGNITUDE sure of that variability, there is a definite rela¬
FIG. 27-1. A normal frequency distribution curve charac¬ tionship between the two values. In fact, it is
terized by the mean (p) and the standard deviation (S). possible to obtain an estimate of s from R by di-

816 • The Theory and Practice of Industrial Pharmacy

 aids in controlling and analyzing physical,
chemical, analytic, or biologic parameters of a
product, such as (1) weight variation of tablets
and capsules; (2) thickness of tablets; (3) vol¬
ume of liquid filling in a container; (4) the num¬
ber or percentage of defects in parenteral prod¬
ucts; and (5) the number or fraction of defects in
a sample of packages emanating from a packag¬
ing operation. Any measurements that could
form the basis of acceptance or rejection of the
product would be amenable to surveillance via
the control chart.
MEASURED MAGNITUDE Control charts are useful in highlighting
trends for intra- and inter-batch variation by fol¬
FIG. 27-2. Frequency distributions with the same mean
but different standard deviation.
lowing a moving mean value of a specification,
as for tablet hardness or assay. There are two
basic types of quality control charts: charts
based on variable and charts based on attributes.
viding R by an appropriate divisor, the numeri¬
Attribute charts refer to go or no-go situations in
cal value of which depends on the sample size
which each sample inspected is tested to deter¬
(N). Divisors (D) for selected N are presented in
mine whether it conforms to the requirements;
Table 27-8. If it is known that the mean sample
variable charts are based on a continuous distri¬
range calculated from a series of samples, each
bution of measurements that can, in a sense,
containing N = 4 items, has the value 6.3, then
measure degrees of unacceptability. A quality
the standard deviation for the distribution of
control chart by variables or by attributes devel¬
individual items can be estimated as s =
oped on the basis of certain quality characteris¬
6.3/2.1 = 3.0. If s for the distribution of individ¬
tics serves as an aid in keeping the product in
ual items in a certain population is 4.0, the
mean sample range in samples of N = 7 could control.
The application of control charts to manufac¬
also be estimated from Table 27-8 as R = 2.7 x
turing processes can best be described by means
4.0 = 10.8. Estimations of the standard devia¬
of the following examples:
tion from the range are used quite extensively in
industrial statistics.
Control Charts by Variables
Example 1. During the automatic filling of a
Quality Control Charts parenteral solution in vials, control of the vol¬
Control charts have been employed for various ume filled during a production run should be
pharmaceutical operations and may be used as established and maintained. One vial was taken
at random from each of the four needles of the
filling machine at designated times and the av¬
Table 27-8. Divisors for Estimating Standard erage and range of this subgroup of four was
Deviation from the Range computed. The numerical data obtained for the
process control record is summarized in Table
Sample Size [N] Divisor [D] 27-9 and graphically depicted in Figure 27-3.
The upper curves of Figure 27-3 and X (mean)
2 1.1
charts and the lower curves are R (range) charts.
3 1.7
The lines connecting the points serve only to aid
4 2.1
in visualizing the trend. The upper and lower
5 2.3
2.5
control limits for the average (UCLX and LCLX)
6
7 2.7
of the filled volume were calculated as shown on
8 2.8 the lower part of Table 27-9, using the formulas:
9 3.0
10 3.1 UCLX = I + A2R (3)
15 3.5
LCIX = X - A2R (4)
30 4.0
50 4.5
where X, the grand_average, is the arithmetic
100 5.0
average of all the X; R, the average range, is cal¬
500 6.0
culated as the arithmetic average of the values of

QUALITY CONTROL AND ASSURANCE • 817

Table 27-9. Process Control Record of Automatic Filling of a Parenteral Solut ion in Vials from Four
Filling Needles of Machine (Label Fill is 10 ml; Required Fill is 10.5 ml)

Volume of Solution Filled (ml)

Time the Vial -
is Sampled Needle A Needle B Needle C Needle D X R

Day 1
8:30 a.m. 10.7 10.5 10.6 10.5 10.58 0.2
9:20 10.5 10.5 10.8 10.7 10.63 0.3
10:15 10.5 10.9 10.5 10.5 10.60 0.4
11:25 10.8 10.5 10.5 10.5 10.58 0.3
1:00 p.m. 10.5 10.7 10.5 10.5 10.55 0.2

2:00 10.5 10.8 10.5 10.5 10.58 0.3

3:10 10.6 10.5 10.9 10.6 10.65 0.4
4:00 10.5 10.5 10.7 10.7 10.60 0.2

Day 2
8:20 a.m. 10.5 10.7 10.7 10.5 10.60 0.2
9:30 10.6 10.5 10.8 10.5 10.60 0,3
10:15 10.7 10.8 10.8 10.7 10.75 0.1
11:30 10.5 10.6 10.6 10.6 10.58 0.1
1:10 p.m. 10.4 10.5 10.5 10.8 10.55 0.4
2:20 10.5 10.6 10.4 10.9 10.60 0.5
3:30 10.6 10.6 10.5 10.8 10.63 0.3

Calculation:
X = Grand average = 10.60
R = Average range = 0.28
UCLj = X + A2R = 10.60 + (0.73)(0.28) = 10.80
LCLj = X -_A2R = 10.60 - (0.73X0.28) = 10.40
UCLr = D^R = (2.88X0.28) = 0.64
LCLr = D3R = (0)(0.28) = 0

R; and A2, the factor for using the range to calcu¬ The upper and lower control limits for the
late three standard deviation limits for the aver¬ range (UCLR and LCLr) were calculated from
age, is a constant that for subgroups of four has the formulas:
the value of 0.73. A2 for selected sample sizes
(N) are presented in the last column of Table UCLr = D4 • R (5)
27-10.
LCLr = D3 • R (6)

where D3 and D4, the factors to calculate three

Table 27-10. Factors for Estimating the Three
standard deviation limits for the range, are con¬
Standard Deviation Limits
stants, which for subgroups of four in this case
Factors have the values of 0.00 and 2.28, respectively.
Factors for
Sample for D3 and D4 for selected sample sizes (N) are tabu¬
R Chart
Size X Chart lated in Table 27-10.
(N) d3 d4 (A2) Control charts are depicted in Figure 27-3 are
characterized by a vertical axis that has a scale
2 0.00 3.27 1.88 of varying measurement, such as a mean (X),
3 0.00 2.57 1.02 range (R), standard deviation (s), or fraction
4 0.00 2.28 0.73 unacceptable (p), and a horizontal axis that is
5 0.00 2.11 0.58 time-oriented. Each point in the control chart
6 0.00 2.00 0.48
represents a value obtained from a selected
7 0.08 1.92 0.42
number of items referred to as a subgroup.
8 0.14 1.86 0.37
These values are plotted in sequence. The con¬
9 0.18 1.82 0.34
trol charts as shown in Figure 27-3 consist of a
10 0.22 1.78 0.31
solid and two horizontally parallel lines on either

818 • The Theory and Practice of Industrial Pharmacy

FIG. 27-3. Control chart for automatic filling of a parenteral solution in vials. The upper curves are x (mean) charts and
the lower curves are R (range) charts.

side of the solid line. The central solid line is the frequently used in conjunction with a range or
target value or the historical process average standard deviation chart. The control chart for
and/or range. The two dotted parallel lines indi¬ ranges (R chart) indicates the variation present
cate the limits within which practically all the in a set of samples. It is advantageous to plot
observed results should fall as long as the proc¬ both the X and R charts together, because one
ess is under normal variation (statistically con¬ may be in control and the other may show exces¬
trolled). The upper dotted line is the upper con¬ sive variation.
trol limit (UCL), which is normally three Example 2. The performance of the filling
standard deviations above the center line. Like¬ machines for filling by weight a relatively vis¬
wise, the lower line is the lower control limit cous parenteral suspension in multiple dose
(LCL) and is three standard deviations below containers can be followed with control charts.1
the center line. Figure 27-4 shows a control chart on the per¬
If the process is in control, the six standard formance of two machines in filling a batch of
deviations spread between the upper and lower the material. Two samples were removed from
control limits encompass 99.7% of the values in the production flow and weighed approximately
a normal distribution with its mean at the center every 20 min, and the average and range meas¬
line. This is the case for the example shown in urements were used to construct the control
Figure 27-3. The control chart of Figure 27-3 is chart in Figure 27-4. It can be seen that Ma¬
said to show evidence of “control,” since all chine A is filling vials within the predicted lim¬
points fall within the designated control limits. its, the averages being within the control limits.
The control chart for averages (X chart) is a Machine B shows large variation, however, as
measurement of the central tendency. Approxi¬ can be seen in the range chart as well as by
mately half of the values are above the average points indicated outside the control limits on the
while the other half are located below it. This average chart. Since the measured values fall
would be expected if random variation is present outside the limits, causes for the process being
and the process is under control. Control charts out of control, which may be assignable, must be
that are used for plotting sample averages are investigated. Some possibilities of the assignable

QUALITY CONTROL AND ASSURANCE *819

FIG. 27-4. Control chart containing the x and R charts on comparative performance of two filling machines for a
parenteral suspension.

causes are filling machine connections, filters, Control Charts by Attributes

filling heads, and automatic measuring equip¬ As mentioned, when a record shows only the
ment. number of articles conforming and the number
Assuming that the assignable causes for the of articles failing to conform to any specified re¬
out-of-control behavior in Machine B are found quirement (go or no-go) it is said to be a control
and corrected, it still may be desirable to reduce record by attributes. It is obvious that most rou¬
the variation as observed in the range charts of tine inspections of manufactured pharmaceuti¬
Machines A and B. This would allow the estab¬ cal products, such as the inspection of paren¬
lishment of narrower control limits on the aver¬
teral products or counting of broken tablets in a
age chart, thus making it possible to reduce the
bottle, are inspections for attributes. The inter¬
overfill and still maintain the same degree of
est is in the number of flaws or fraction defective
assurance of meeting the specifications. Upon
per batch. Thus, the weakness of attribute meas¬
intensive process investigation and improve¬
urements is that gradation of quality cannot be
ment, it was possible to narrow the control limits
measured. In general, variable charts are more
on the average chart as shown in the control
sensitive than attribute charts, although the lat¬
chart of Figure 27-5. It is worth noting here that
ter are usually easier to implement. To employ
the control limits were narrowed on both X and
control charts for attributes, a plan with desira¬
R charts as compared to those of Figure 27-4.
ble properties would include the following:
Thus, the process was brought into closer statis¬
tical control, with the fill weight variation being
minimized. 1. Samples should be chosen at random.

820 • The Theory and Practice of Industrial Pharmacy

FIG. 27-5. Control chart containing the x and R charts on performance of tuio filling machines after process investigation
and improvement. Note that the control limits were narrowed on x and R charts as compared to that of Figure 27-4.

2. For easier evaluation there should be a fixed (3) computing the average fraction defective, P,
number of samples (n) taken each time for obtained by dividing the total number of defec¬
inspection. Each tablet or ampul inspected is tives found by the total number of units in¬
considered a sample. spected in a series of batches:
3. Each sample is evaluated so that the sample
is accepted or rejected, i.e., each tablet or 2d
P
ampul is either good or defective. 2n (8)
4. Each sample must be independent, i.e., each
(4) calculating the upper and lower control lim¬
tablet or ampul, good or defective, has noth¬
its, UCL and LCL, through the following formu¬
ing to do with another tablet or ampul to
las:2
cause it to be good or defective.

The essential steps in constructing the control UCL = P + P) (9)

charts for fraction defective are: (1) recording
the number inspected, n, and the number of
defectives found, d; (2) computing the fraction LCL = P - (10)
defective, p, which is the ratio of the number of
defectives found to the total number of units ac¬
tually inspected in the batch, and which is ex¬ If n is different for different batches, upper
pressed as: and lower control limits will vary from
batch to batch. To calculate the limits, first
d_ the value of 3VP(1 - P) is computed. The
P=
n (7) value of the square root of n is calculated

QUALITY CONTROL AND ASSURANCE • 821

 for each_ batch and divided into tion defective, has been plotted in Figure 27-6.
3\/P(l — P) to obtain the value of the The numerical values of three standard devia¬
three standard deviations for the batch, 3s, tions (3s) for each individual batch in this par¬
that is: ticular example are considered to be constant,
since n for each batch changes only slightly. The
3VP(1 - P) LCL may be set at zero if only high values of p
3s
Vn
(11) are of concern. Because all points fall within the
control limits, as seen in Figure 27-6, the prod¬
uct is said to be in statistical control.
and (5) plotting of P’s on a control chart with P Example 2. During the automatic packaging
as the average and control limits calculated as of a tablet product in containers, control of the
previously shown. number of broken tablets in a container released
Example 1. The example used for illustrat¬ from packaging lines should be established and
ing the control chart (p chart) for percentage maintained. By sampling containers from each
fractional defective for a parenteral product is batch at random and inspecting and recording
shown in Figure 27-6. The process control rec¬ the percentage unacceptable for each batch,
ord accumulated from 10 batches of the product data may be accumulated. Occasionally, it may
and the computation of p, P, 3s, UCL, and LCL be observed that batches are out of control (P >
employing equations (7) to (11) are summarized UCL) during the accumulation of data, as
in Table 27-11 for constructing Figure 27-6. shown in the p chart of Figure 27-7. Batches 6,
The inspectors are required to detect and re¬ 13,16, and 18 are out of control. After all assign¬
move the defective samples, which may be char¬ able causes have been corrected, these rejected
acterized by: (1) broken ampuls or vials; (2) batches should be eliminated, and a new set of
presence of particulate matters such as lint, dirt, P, UCL, and LCL values should be calculated for
glass fragment, and other foreign suspended a new p chart.
matter; or (3) imperfections in the glass. The All methods and procedures set forth for qual¬
number of defectives found in the batch in¬ ity control administration should be strictly fol¬
spected was recorded, and the fraction defective lowed, since changes may cause significant vari¬
of the batch was computed. Percentage defec¬ ation in the data being collected. When data are
tive (100 P), a more convenient value than frac¬ being recorded, any conditions that have

BATCH
FIG. 27-6. Control chart (p chart) for percentage of defective units inspected for a parenteral product.

822 • The Theory and Practice of Industrial Pharmacy

Table 27-11. Process Control Record and Control Limits Calculated (for Ten Batches of a Parenteral
Product)

Number Number Fraction

Inspected Defective Defective
Batch # (n) (d) (P) 3S UCL LCL

1 4956 84 0.0170 0.0059 0.0254 0.0136

2 4924 71 0.0144 0.0059 0.0254 0.0136
3 4900 120 0.0245 0.0059 0.0254 0.0136
4 4883 &8 0.0201 0.0059 0.0254 0.0136
5 4891 114 0.0233 0.0059 0.0254 0.0136
6 4952 88 0.0178 0.0059 0.0254 0.0136
7 4905 109 0.0222 0.0059 0.0254 0.0136
8 4897 72 0.0147 0.0059 0.0254 0.0136
9 4868 95 0.0197 0.0059s 0.0255 0.0135
10 4845 103 0.0213 0.00596 0.0255 0.0135
Calculation: 2n = 49021
Sd = 954
84
P = = 0.0170 = 1.70%
4956
954
P 0.0195 = 1.95%
49021
3V0.0195[1 - 0.0195]
3S : 0.0059 = 0.59%
V4956
UCL = P + 3S = 0.0195 + 0.0059 = 0.0254 = 2.54%
LCL = P - 3S = 0.0195 - 0.0059 = 0.0136 = 1.36%

FIG. 27-7. Control chart (p chart) for percentage of broken tablets in plastic containers.

QUALITY CONTROL AND ASSURANCE * 823

changed since the last sample was taken should
also be recorded. These include such items as
changes in machine settings and operators. In
general, the control chart is plotted initially
without the benefit of control limits. When suffi¬
cient historical data from at least 10 to 12
batches have been collected, the control limits
computed are reasonably reliable, and the con¬
trol chart can be established for future batches.
As the new batches of the product are produced,
the inspection data are plotted on the control
chart. Close attention to control charts indicates
to manufacturing personnel and control inspec¬
tors whether the product is of poor quality.

Quality Level and Inherent

Variability
The ideal state of a statistically controlled
process or situation is one in which both the
quality level, as reflected by averages in X chart,
and the inherent variability, as indicated by
ranges in R chart, remain within limits pre¬
dicted from ordinary variation. This is illustrated
in Figure 27-8D, where the process is in the
ideal state of statistical control. This situation is FIG. 27-8. Examples of product quality variation during
manufacturing. Key: A, luck of control due to a shifting
not always ideal in practice, however, and lack of
quality level; B, lack of control due to changes in inherent
control may be indicated in the following three variability; C, lack of control due to changes in both qual¬
different situations: (1) the inherent variability ity level and inherent variability; and D, an ideal statisti¬
remains essentially constant, but the quality cally controlled process.
level shifts from time to time as shown in Figure
27-8A; (2) the level of quality may remain essen¬
tially constant, but the inherent variability population in order to make inferences to the en¬
changes from time to time, a situation illustrated tire population. The object of sampling and sub¬
in Figure 27-8B; and (3) both quality level and sequent testing, in the present context, is to pro¬
inherent variability shift together as depicted in vide an effective check on the quality of the
Figure 27-8C. Through the use of a control product or substances being processed. Repre¬
chart, basic variability of the quality parameter, sentative of materials to be sampled are drug
average level of the quality characteristic, and substances, raw materials, intermediate prod¬
the consistency of the performance of the prod¬ ucts, and final products before, during, and after
uct are easily visualized. Since the control chart manufacturing and packaging operations. The
provides a continuous monitoring of a process, it quality control inspector must be empowered to
sounds a warning signal quickly when the prop¬ sample at any point or stage of manufacturing
erty being measured falls outside the control and packaging operations. Proper methods of
limits. As a result, steps can be taken promptly sampling and adequate number and size of sam¬
to remedy any indication of trouble before future ples are needed for an effective quality assur¬
batches or the remainder of a current batch are ance program, since the judgment “accept” or
manufactured. Thus, the control chart indicates “reject” is made on the basis of the sample, irre¬
when a process is out of control, but does not spective of the conditions in the remainder of
necessarily indicate the exact manner in which the batch.
a shift in quality level or inherent variability oc¬ Although controlled manufacturing and pack¬
curs. aging systems provide the largest measure of
quality assurance, the quality level of final dos¬
age forms has to be tested and inspected. The
Sampling and Sampling Plans degree of uniformity in content of any compo¬
Sampling may be defined as the process of nent in a dosage form is subject to an additive
removing an appropriate number of items from a effect of the variabilities of the process steps. To

824 • The Theory and Practice of Industrial Pharmacy

obtain a value representative of the total popula¬ level or levels. A sampling plan indicates the
tion, the sample taken is most important. An number of units of product from each batch to
improper sample may result in a value that can be inspected (sample size or series of sample
be biased and in error. Careful consideration of sizes) and the criteria for determining the ac¬
the design of the sampling plan enables these ceptability of the batch. The inspection level de¬
errors to be kept to a minimum. The only possi¬ termines the relationship between the batch size
ble way to avoid such sampling errors is to do a and the sample size and is to be determined by
100% inspection. This normally cannot be at¬ the responsible authority.
tained practically and can also introduce errors The most common and distinct methods of
due to personnel fatigue arid other related inspection are single and double sampling meth¬
human factors. Even if it is possible to perform ods. In single sampling, only the specified sam¬
100% inspection, good sampling plans are pre¬ ple size is inspected before a decision is reached
ferred for efficient inspection. regarding the disposition of the batch, and the
A good statistical sampling plan should be able acceptance criterion is expressed as an accept¬
to pass a high percentage of acceptable batches ance number. In double sampling, a second
and reject the unacceptable ones. The number sample for inspection is permitted if the first
of unacceptable units are controlled to rigid fails, and two acceptance numbers are used—
standards by the stringency of the sampling the first applying to the observed number of
plan. The variety of sampling plans, procedures, defectives for the first sample alone,and the sec¬
and tables that can be constructed is unlimited. ond applying to the observed number of defect¬
The advantages and disadvantages of each of ives for the first and second samples combined.
several possible choices should be carefully Triple and multiple samplings are merely exten¬
weighed from both theoretic and practical view¬ sions of the foregoing.
points. Frequently, the ease of implementation The following example illustrates the double
weighs more heavily than the statistical proce¬ sampling method. A sample of 50 tablets is
dure because overall costs and ease of applica¬ taken. If it contains no more than two defectives,
tion may be more important. Sometimes, trials the batch is accepted. If it contains four or more
of alternative procedures under actual operating defectives, it is rejected. If it contains more than
conditions may bring to light unanticipated fac¬ two but less than four defectives, a second sam¬
tors that result in the adoption of a plan that ple size of 50 is taken. If the two samples com¬
seems less efficient in theory. The choice of the bined contain less than four defectives, the
most advantageous plan is determined after ex¬ batch is accepted.
periences have been accumulated. The construction of a statistical sampling plan
Sampling plans based on data from measure¬ normally requires that four basic quality stand¬
ments of attributes or variables may be con¬ ards be specified: (1) an acceptable quality level
structed. As discussed previously, attribute data (AQL) (e.g., a batch of tablets is considered to be
refer to go or no-go situations in which each accepted if it contains 2% or less unacceptable
piece inspected is examined or tested to deter¬ tablets) (2) an unacceptable quality level (UQL)
mine whether it conforms to the requirements (e.g., the same batch of tablets is said to be re¬
imposed by specifications; variable sampling is jected if it contains 4% or more unacceptable
based on a continuous distribution of measure¬ tablets); (3) the risk or error, designated as a
ments, which can, in a sense, measure degrees (Producers’ Risk), which is the probability of re¬
of unacceptability covering the gray zone be¬ jecting a good batch; and (4) the risk or error,
tween accepted and rejected situations. designated as (Consumers’ Risk), which is the
For practical purposes, the work involved in probability of accepting a bad batch. In general,
designing a sample plan may be greatly reduced the sampling scheme should be designed in
or eliminated by use of a series of government- such a way that the a and [i errors are appropri¬
sponsored sampling plans such as MIL-STD- ately shared by the producer and the consumer.
414 for variables sampling plans,3 and MIL- The usual approach is the determination of
STD-105D for attribute sampling plans.4 In desirable AQL, UQL, a, and f) and subsequent
addition to providing a savings in time, these computation of the sample size and acceptance
books have gained acceptance by industry criteria. If the AQL and UQL are close together
throughout most of the United States. These and a and are very small, as in the case of
publications provide sampling procedures and low-dose or potent drugs, a large sample is re¬
related reference tables for use in planning and quired for a suitable sampling plan. Conversely,
conducting inspection. Acceptability of a batch ffie plan calls for few samples if the AQL and
is determined by the use of a sampling plan as¬ UQL are far apart and a and /3 are large. A con¬
sociated with the designated acceptable quality venient graphic method of presenting these

QUALITY CONTROL AND ASSURANCE *825

risks, a and jS, is through the operating charac¬ since the curve crosses the 10% abscissa at the
teristic (OC) curves, which are graphs illustrat¬ 90% ordinate. By a similar operation, batches of
ing the ability of a sampling plan to discriminate UQL = 40% will be accepted only 8% (j8) of the
between acceptable and unacceptable batches. time. By referring to the appropriate table of
For every sampling plan, there is an OC curve. MIL-STD-414, the sample size was found to be
The OC curve is prepared by plotting the per¬ N = 10, and the acceptability criteria (or esti¬
centage of batches of a given quality that is ex¬ mated percentage unacceptable) that balances
pected to be accepted versus the quality of sub¬ the risks is 21.06%. Therefore, the final statisti¬
mitted batches expressed as percentage cal plan takes the following form. Select 10 tab¬
unacceptable. lets at random from an inspection batch, and
For characteristics that may be measured on a individually assay each tablet. From these ten
continuous scale and for' which quality may be determinations, estimate the percentage unac¬
expressed in terms of percentage unacceptable, ceptable in the batch. The batch will be accepted
the MIL-STD-414 may be used as a source of if this estimate does not exceed 21.06% unac¬
statistical plans if the measurements are ran¬ ceptable. Otherwise, the batch will be rejected.
dom and independent observations follow a nor¬ Figure 27-9B shows an OC curve,5 where one
mal distribution. To illustrate the application of would pass that quality at least 95% of the time
MIL-STD-414, a hypothetical example for (a = 5%) if the submitted batch of material con¬
teaching purposes is employed.5 The tolerances tains 10% or less unacceptable units (AQL =
of pure drag contained in the tablets in question 10%). This same OC curve shows that a batch
were set at 93 to 107% of the labeled amount, 20% or more unacceptable (UQL = 20%) would
and the desired quality characteristics of the tab¬ not pass more than 10% of the time (/} = 10%).
lets produced were specified at AQL = 10%, For this example, a sample size of 85 tablets is
UQL = 40%, a = 10% and /3 = 8%. By search¬ required. An ideal OC curve,5 illustrating perfect
ing through the OC curves of MIL-STD-414, discrimination but unrealistic stringency, is
Figure 27-9A was found, which most nearly cor¬ shown in Figure 27-9C. To obtain such a curve,
responds to these requirements. From this OC the entire batch of products would have to be
curve, one learns that batches of AQL =10% examined.
will be accepted 90% (a = 10%) of the time, The five characteristics (AQL, UQL, a, /3, and
N) operating within a variable sampling plan
can be seen graphically from the operating char¬
acteristic curves for sampling plans at N = 10.
As shown in Figure 27-10, the horizontal scale
running from 0 to 100% is the quality of submit¬
ted lots in the percentage defective, i.e., the per¬
centage of the units in a lot that fall outside the
established tolerances for the product. The verti¬
cal scale, which also runs from 0 to 100%, is the
percentage of lots of a stated percentage unac¬
ceptable that are expected to be accepted under
the sampling plan. For the OC curve of Figure
27-10, labeled AQL = 4%, for example, it is
shown that a lot that is 4% unacceptable will be
accepted 90% of the time [a = 10%] at N = 10,
and a lot that is 20% unacceptable [UQL =
20%] will be accepted 20% of the time [/3 =
20% ] at N = 10. At a given AQL, these plans are
designed to greatly enlarge a probability of ac¬
cepting a batch if the batch has AQL or a smaller
percentage unacceptable. Figure 27-10 shows
that when AQL of the product is raised, the per¬
centage unacceptable that can be tolerated is
also increased at the given a level and sample
size.
The operating characteristic curves for sam¬
pling plans at AQL =1% are illustrated in Fig¬
FIG. 27-9. Examples of operating characteristic curves. ure 27-11. It should be noted that there are dif-

826 • The Theory and Practice of Industrial Pharmacy

FIG. 27-10. Operating characteristic curves for sampling plans at N = 10.

FIG. 27-11. Operating characteristic curves for sampling plans at AQL = 1%.

QUALITY CONTROL AND ASSURANCE • 827

ferent curves for different sample sizes. For the pie is found, 100% testing is resumed until p
OC curve labeled N = 10, it can be seen that a tablets in succession are again found free ofde-
lot with 1% unacceptable [AQL = 1%] will be fect. For example, using a rotary tabletting press
accepted 90% of the time or conversely rejected of 25 punches to manufacture a batch of a mil¬
10% of the time [a = 10%]. A lot that is 20% lion tablets, let p be 50 (to contain two tablets
unacceptable [UQL = 20% ] will be accepted 5% from each punch) and f be one tablet in ten
of the time [fS = 5%]. As shown in Figure 27-11, thousand. The Dodge plan then calls for testing
at a given a level and AQL, the percentage unac¬ an additional 100 tablets, thus bringing the total
ceptable of the submitted lot that can be toler¬ to 150 tablets if no operation problem is found
ated is decreased by increasing the sample size. and if the process is under control. The two ad¬
It shows that plans at a given AQL are more dis¬ vantages offered by this sampling plan are (1) it
criminating with larger sample sizes; for exam¬ reduces the amount of testing necessary when
ple, it will accept good lots and reject bad lots a compressing proceeds as designed and pre¬
greater percentage of the time. dicted, and (2) it increased the chances for de¬
When operating characteristic curves were tection and correction if the tablets fall out of
developed for the compendial weight variation specification.
specifications, a batch of tablets containing a In the application of sampling plans to phar¬
total of 5% underweight and overweight tablets maceutical dosage forms, homogeneity of the
were found to have 93% probability of being ac¬ samples must be emphasized. For homogeneous
cepted when samples of 10 tablets were em¬ dosage forms such as oral or parenteral solu¬
ployed. The relations depicted in Table 27-12 tions, samplings are ordinarily taken with a sam¬
show that a larger sample size increases accept¬ ple size as small as one unit. If a drum of a pow¬
ance probability. These data were obtained on dered drug or excipient is known to be
the basis of a million-tablet batch. homogeneous, then for statistical putposes it
The same curves showed that a batch with can be thought of as a solution, and single or
20% unacceptable tablets had a probability of duplicate samples are considered sufficient to
passing the weight Variation test 40%, 23%, 4%, provide a reliable response. Semisohd dosage
and 0% of the time as the sample size increased forms such as ointments, creams, and suspen¬
from 10 to 20 to 50 to 100 tablets. sions may be considered statistically as resem¬
Tablets are often manufactured in batch sizes bling oral or parenteral solutions when they are
consisting of a million units. For practical pur¬ assumed to be homogeneous. To verify homoge¬
poses, these batches represent infinite popula¬ neity, it is frequently necessary to take more
tions, and relatively large sample size is required than one sample from semisolid dosage forms.
to gather significant data. For such a batch, Knowledge and/or indication of the presence of
samples ranging up to 200 units are required heterogeneity allows the batch to be treated sta¬
according to the MIL-STD-414 variable sam¬ tistically as having an infinite population of vari¬
pling plan. able components.
The Dodge sampling plan is distinctive in that Statistical sampling has worked well in con¬
it is continuous in nature, requiring at the start trolling the quality of printed material. Statisti¬
that 100% of the tablets be consecutively tested cal sampling plans with a sensitivity in the
until p tablets in succession are found to be range of 1 to 5% unacceptable were considered
without defect.6 Then 100% testing is discontin¬ adequate for inspection of packaging supplies
ued, and a fraction, f, of the tablets is checked by several years ago; however, sensitivity of 0.1%
random sampling. When an unacceptable sam- for defects that interrupt high-speed packaging
lines would be desirable. When problems such
as these arise, sampling schemes must be modi¬
fied, since the cost of sampling and inspecting
Table 27-12. Relation of Sample Size to Accept¬ 3000 to 5000 units would be prohibitive, and the
ance Probability cost of manufacturing certain products with
such a low level of defectiveness would be high.
Size of Samples Acceptance Although attribute sampling plans are the
(No. of tablets) Probability (%) simplest to use and to enforce, variable sampling
plans that yield more information are increasing
10 93
in importance. This is especially true with auto¬
20 95
mation of the in-process quality control func¬
50 98
tions during the manufacturing and packaging
100 99
operations.

828 • The Theory and Practice of Industrial Pharmacy

Control and Assurance of pride in performance and showing the impor¬
tance of the contributions of these individuals in
Manufacturing Practices producing products that could be lifesaving, the
The factory inspection provision of the 1962 risk of errors can be minimized. In reality, this is
Amendments to the Food, Drug, and Cosmetic the basis for tne so-called control of quality by
Act empowered the FDA to inspect drug manu¬ the zero-defect concept, which operates through
facturing sites (in which drugs are processed, prevention rather than detection of the mistakes
manufactured, packaged, and stored) for compli¬ by properly directing and motivating personnel.
ance with accepted standards of operations, Quality work and products result from this ap¬
practices, and sanitation. The regulations pro¬ proach.
mulgated as a result of the 1962 Amendments It is essential that qualified personnel be em¬
require a complete and full description of the ployed to supervise the formulation, processing,
controls the manufacturer employs in the prepa¬ sampling, testing, packaging, and labeling of the
ration of dosage forms for clinical trials as well as drug product, and that competent staff be placed
of the marketed products routinely produced. in charge of the maintenance of machinery,
The law recognizes that Current Good Manufac¬ equipment, and sanitation. The qualified per¬
turing Practices (CGMP) with the attendant sonnel are persons who by virtue of education,
quality control procedures, are paramount to the training, and experience have the knowledge
production of quality products. As a result, the and ability to execute the technologic assign¬
FDA has required pharmaceutical manufactur¬ ments. The key personnel involved in the manu¬
ers to commit themselves to a method of manu¬ facture and control of the drug should assume
facturing and quality assurance for each prod¬ the responsibility of assuring that the drug and
uct. The manufacturer should have performed the dosage form they are handling have the de¬
sufficient control tests to permit an evaluation of sired characteristics. The responsibility for
the adequacy of the manufacturing, processing, keeping the manufacturing process within the
and packaging operations. CGMP regulations of the FDC Act must be dele¬
The first CGMP regulations were issued in gated to the people directly involved with the
1963, one year after the enactment of the 1962 various aspects of the process and their immedi¬
Kefauver-Harris Drug Amendments. Although it ate supervisors. The supervisors are required to
took about eight years (1971) to revise them, provide the necessary direction and control of
they are in no way stagnant. In fact, the word the operation and be available at all times in case
“current,” in referring to CGMP, suggests that a question or a problem arises. The operating
they are dynamic, and the regulatory agency personnel should have the necessary authority
constantly updates and maintains them in rela¬ to sign the manufacturing documents for each
tion to the current state of the art and science of process for which they are responsible. The doc¬
drug manufacturing practices in the industry. ument is then countersigned by the supervisor.
The next revision of the CGMP took place in The signature and endorsement should appear
1978, and these are in effect at present. on the proper worksheet at the completion of a
The successful application of CGMP is com¬ production operation.
plex but possible if the systems governing the Equipment and Buildings. Equipment and
various phases of personnel, equipment, build¬ buildings used in the manufacture, processing,
ings, control records, and production procedures packaging, labeling, storage, or control of drugs
are at the state of proper planning and control. It should be of suitable design, size, construction,
should be kept in mind that CGMP is an aid and and location and should be maintained in a
by no means a substitute for a good total quality clean and orderly manner.
assurance program. The building should provide adequate space
Personnel. One criterion for a successful for the orderly placement of materials and
quality assurance program is the encourage¬ equipment to minimize any risks of mixups or
ment of quality consciousness in the personnel cross-contamination between the drugs, excipi¬
of the entire company. Proper selection, train¬ ents, packaging, and labeling from the time the
ing, and motivation of production, packaging, materials are received to the time the products
and control personnel are vital to produce qual¬ are released. Adequate lighting, ventilation, dust
ity pharmaceuticals consistently. The degree to control, temperature, and humidity should also
which the desired quality for the product is at¬ be provided. To avoid conditions unfavorable to
tainable is proportional to the attitudes or de¬ the integrity and safety of the product, other
sires of the individuals working in production, considerations may be required for particular
packaging, and control. By building a sense of operations and products, such as bacteriologic

QUALITY CONTROL AND ASSURANCE • 829

controls for preventing microbial contamination, 6. Appropriate statements of theoretic yield at
for sanitizing work areas for parenteral prepara¬ various stages and the termination of pro¬
tions, and for preventing the dissemination of cessing.
microorganisms from one area to another or
7. Manufacturing and control instructions,
from previous manufacturing operations.
specifications, precautions, and special nota¬
The desired characteristics of equipment for
tions to be followed.
producing quality products are numerous, and
they differ from machine to machine; however, 8. A detailed description of the closures, con¬
the equipment should be of suitable size, accu¬ tainers, labeling, packaging, and other finish¬
racy, and reproducibility. Their surfaces should ing materials.
be inert, nonreactive, nonabsorptive, and nonad¬
ditive so that the identity, purity, and quality of Batch Production Record. Batch produc¬
the drug substance and other components are tion records should be prepared, maintained,
not affected to any significant extent. The equip¬ and controlled for each batch of product. In gen¬
ment should be constructed to facilitate adjust¬ eral, they should be retained for a period of ap¬
ment, cleaning, and maintenance to assure the proximately five years after distribution has
precision, reliability, and uniformity of the proc¬ been completed. The batch production record
ess and product, and to assure the exclusion of shall contain an accurate reproduction of the
contaminants from previous and current manu¬ manufacturing formula, procedure, and product
facturing and packaging operations. specifications from the correct master formula
Control of Records. The records, such as procedure to be used in the production of a batch
master formula and batch production records, of product. These batch records are then sent to
should be prepared and maintained in accord¬ each of the departments involved in the produc¬
ance with established procedures. tion, packaging, and control of the product. The
Master Formula Record. Master formula records include dates, specific code or identifica¬
records for each product should be prepared, tion numbers of each ingredient employed,
endorsed, and dated by a competent and respon¬ weights or measures of components and prod¬
sible individual and should be independently ucts in the course of processing, results of
checked, endorsed, and dated by another com¬ in-process and control testing, and the endorse¬
petent and responsible individual. The informa¬ ments of the individual performing and super¬
tion contained in the records should be provided vising each step of the operation.
in a format and language that will not be misin¬ In addition, a lot number is assigned that per¬
terpreted by the operating personnel and the mits the identification of all procedures per¬
supervisor, to assure that each batch of a prod¬ formed on the lot and their results. This lot
uct can be identically reproduced. number appears on the label of the product. This
Although the content and format may differ procedure facilitates a search for the details of
from product to product, the master formula rec¬ manufacture and control history of any particu¬
ord shall include the following information: lar product.
Control of Production Procedures. To
1. The name of the product, a description of the ensure that products have the intended charac¬
dosage form, and its strength. teristics of identity, strength, quality, and purity,
production and the related in-process quality
2. The complete list of ingredients, designated control (IPQC) procedures should be rigidly fol¬
by whole names and codes sufficiently spe¬ lowed as required by the master formula record
cific to indicate any special characteristic. or the batch production record. To a large extent,
3. The quantity by weight or volume of each IPQC is concerned with providing accurate, spe¬
ingredient, regardless of whether it appears cific, and definite descriptions of procedures to
in the finished product. If variations in the be employed from the receipt of raw materials to
quantity of a particular ingredient are permit¬ the release of the finished dosage forms. It is a
ted, as is sometimes necessary in the prepa¬ planned system to identify the materials, equip¬
ration of a dosage form, an adequate state¬ ment, processes, and operators; to enforce the
ment should be provided in the record. flow of manufacturing and packaging operations
according to the established rules and practices;
4. The standards or specifications of each ingre¬
to minimize human error or to detect the error if
dient used in the product. and when it does occur; and to pinpoint the re¬
5. An appropriate statement concerning any cal¬ sponsibility to the personnel involved in each
culated excess of an ingredient. unit operation of the entire process. In general,

830 • The Theory and Practice of Industrial Pharmacy

 the in-process control procedures are usually affect its quality and to prevent errors during
rapid and simple tests or inspections that are processing. Only the most commonly practiced
performed when the manufacturing of a product methods for parenterals, solid dosage forms (tab¬
batch is in progress. They are used to detect var¬ lets and capsules), and semisolid preparations
iations from the tolerance limits of the product (ointments, creams, and lotions) are briefly de¬
so that prompt and corrective action can be scribed.
taken. The in-process control procedures and For parenteral products, the in-process quality
tests should be openly discussed, experimentally controls are (1) checking the bulk solution, be¬
justified, written in detail, properly explained, fore filling, for drug content, pH, color, clarity,
and in particular, rigidly enforced once they are and completeness of solution; (2) checking the
established. filled volume of liquids or the filled weight of
For the convenience of discussion, the actual sterile powders for injection in the final con¬
production procedures are subdivided and dis¬ tainers at predetermined intervals during filling;
cussed as manufacturing control and packaging (3) testing for leakage of flame-sealed ampuls;
•control. (4) subjecting the product to physical examina¬
Manufacturing Control. Although the tion (visually or mechanically) for appearance,
scope and structure of the manufacturing con¬ clarity, and particulate contamination; (5) exam¬
trol operation differs appreciably from company ining the sterility indicator placed in various
to company, it is possible to highlight their com¬ areas of the sterilizer for each sterilization opera¬
mon elements. The production planning depart¬ tion; (6) submitting the product for sterility test¬
ment issues the formula and manufacturing ing or other predetermined biologic tests to es¬
worksheets bearing an identification number, tablish the safety and other parameters of the
tide of product, and the names and quantities product.
for all ingredients, together with a complete de¬ The in-process quality controls for solid dos¬
scription of the procedures to be followed, the age forms are (1) determining the drug content
precautions to be taken, the equipment to be of the formulation; (2) checking the weight vari¬
used, the lot sizes to be processed, and the suita¬ ation for tablets and capsules at predetermined
ble in-process controls to be undertaken. intervals during manufacturing; (3) checking
Material tickets for each raw material are writ¬ the disintegration and/or dissolution time, hard¬
ten and issued by the production department to ness, and friability of the tablets at least during
the department of material stores, where the the beginning, middle, and end of production or
orders are filled and verified. After the materials at prescribed intervals during manufacturing;
have been sent to the production department (4) testing soluble tablets for compliance with
and checked similarly, the pattern of control solution time requirements; and (5) examining
takes shape as production proceeds. The addi¬ products by line inspection or other equally suit¬
tion of raw materials to the batch is verified and able means and removing the defective units
countersigned by a qualified person. Notation is prior to packaging.
made on the manufacturing worksheet of the For semisolid preparations, the following in-
identifying number of each ingredient as it is process controls are available: (1) checking for
used, and each unit operation is checked off as it uniformity and homogeneity of drug content
is performed. An appropriate label is attached to prior to the filling operations; (2) determining
each container or piece of equipment in use to the particle size of the preparation when appro¬
identify its contents and to ensure that the priate; (3) checking the appearance, viscosity,
in-process stage is properly designated. Any de¬ specific gravity, sediment volume, and other
viation from standard operating conditions, no physical parameters at prescribed intervals;
matter how small, should be reported to both (4) testing for filling weight during the filling
production and control personnel responsible for operation; and (5) testing for leakage on the fin¬
the product. ished jars or tubes.
The in-process checking during manufactur¬ At the completion of the manufacturing proc¬
ing plays an important role in the auditing of the ess as well as in-process stages, actual yields are
quality of the product at various stages of pro¬ checked against theoretic value, and the repre¬
duction. Duties of the auditor or the control in¬ sentative samples are withdrawn for laboratory
spector consist of checking, enforcing, and re¬ testing by the control inspector according to the
viewing procedures and suggesting the change predetermined sampling plan. The operators
for upgrading the procedures when necessary. actively performing the process, their supervi¬
The primary objective of an IPQC system is to sors, and the control inspector must all verify
monitor all the features of a product that may that the entire operation was accomplished in

QUALITY CONTROL AND ASSURANCE • 831

the prescribed manner. Occasionally, materials absence of foreign drugs and labels, adequacy of
in bulk storage are sampled at random and are the containers and closures, and accuracy of la¬
examined to determine that no detectable beling. Proper reconciliation and disposition of
change has taken place, and that the batch is the unused and wasted labels should occur at
satisfactory for final packaging. the end of the packaging operation. The yield
The batch production records and other must be justified against the theory represented
needed documents are then delivered to the by the batch size of the starting materials. Suita¬
quality control office, together with the with¬ ble and reasonable procedures should be estab¬
drawn samples of the product. These records lished for action to be taken when an unex¬
and test results are reviewed for conformance to plained discrepancy exists between the number
specifications and CGMP. The bulk finished of labels issued and the number accounted for
products are held in quarantine until they are on the finished product. The common approach
released for packaging by quality control person¬ is for key personnel to prevent distribution of the
nel. batch in question, and of other batches of prod¬
Packaging Control. At some time before the ucts that were packaged during the same period
manufacture of a product is completed, a pack¬ of time, until a satisfactory explanation can be
aging record bearing an identification number is obtained for the discrepancy.
issued to the packaging section. This record Validation. The terms validation and qualifi¬
specifies the packaging materials to be used, cation have, in recent years, become familiar in
operations to be performed, and the quantity to connection with pharmaceutical processes.
be packaged. Simultaneously, requisitions are Qualification is generally related to equipment
issued for the products to be packaged and for and is used to determine whether the equip¬
the packaging and printed materials, such as ment operates as it was designed to in a repro¬
labels, containers, inserts, brochures, cartons, ducible manner. Validation of a process is the
and shipping cases. demonstration that controlling the critical steps
The packaging operation unites the product, of a process results in products of repeatable at¬
container, and label to form a single finished tributes (e.g., content uniformity) or causes a
unit. Not only must individual package compo¬ reproducible event (e.g., sterilization).
nents be correct, but they must also be assem¬ The concept of applying a systems approach to
bled correctly. Prior to the start of a packaging pharmaceutical manufacture and control, re¬
operation, the control inspector and packaging quiring validation of the process and qualifica¬
supervisor must check and verify the line to en¬ tion of equipment, facilities, personnel, and so
sure that it has been thoroughly cleaned and forth, received considerable impetus when it
that all materials from the previous packaging was recognized by both the FDA and industry
order have been completely removed. In addi¬ that sampling and testing of finished products
tion, various pieces of packaging equipment are alone cannot provide the necessary assurance of
stripped down, cleaned, and examined when an drug product quality within and between
order is finished. The bulk of the product and batches. The customary sample size in end
each of the packaging components should be product testing does not provide sufficient sta¬
checked, endorsed, and dated by qualified pack¬ tistical validity for high product quality; it alone
aging personnel with the cooperation of a control cannot verify that the various factors in the sys¬
inspector. In practice, only the exact number of tem intended to assure quality within and be¬
labels required for a batch, including a small tween batches of product are functioning as they
excess, should be delivered to the labeling area were designed to function. Such verification can
after careful and meticulous inspection of each only be accomplished through identifying the
label. critical components of the system and imple¬
In the packaging area, a large group of people menting control tests for these components,
work on several different products simultane¬ which when taken as a whole, demonstrate that
ously, using high-speed packaging equipment. their characteristics are repeatable from batch to
Therefore, the operation should be performed batch of product. Consequendy, a validated
with adequate physical segregation of products. process is a systematic, documented program
Dosage forms of similar color, size, and shape that provides a high degree of assurance that a
should not be scheduled consecutively on a line. specific process will consistendy produce a prod¬
Tablets of similar shape should not be scheduled uct meeting its predetermined specifications
on the neighboring packaging lines at the same and quality attributes.
time, even though the size or color may be dis¬ The FDA, in its program guidance manual to
similar. Proper on-line inspection should be FDA investigators, defines a validated manufac¬
made during the packaging operation to ensure turing process as follows:

832 ■ The Tkeory and Practice of Industrial Pharmacy

“A validated manufacturing process is one that has rejections or recalls after market introduction
been proved to do what it purports or is represented to are serious and can be easily detected and mini¬
do. The proof of validation is obtained through collec¬ mized by an effectively administered quality
tion and evaluation of data, preferably, beginning
testing program. Therefore, the testing of the
from the process development phase and continuing
finished products for compliance with the estab¬
through into the production phase. Validation neces¬
sarily includes process qualification (the qualification lished standards prior to release of the material
of materials, equipment, systems, building, person¬ for distribution is a critical factor for quality con¬
nel), but it also includes the control of the entire proc¬ trol and assurance. The testing indicates the
esses for repeated batches or runs.” possible deviations from perfection that occur in
the batch. Product quality assurance is not com¬
The FDA interprets Subpart F Section plete with the release of the batch, however. The
211.100(a) and 211.110(a) of the Current Good stability of the product in the marketed package
Manufacturing Regulations for drug products to should be repeatedly reconfirmed by actual
mean that pharmaceutical processes must be physical, chemical, and biologic tests performed
validated. These two sections of the regulations on several representative batches of the product
are presented: over the period of its expected shelf-life. The ac¬
tivities associated with the control of the dosage
Section 211.100(a)—“There shall be written proce¬ form after manufacture are discussed briefly in
dures for production and process control designed to this section.
assure that the drug products have the identity,
strength, quality and purity they purport or are repre¬
sented to possess. Such procedures shall include all Types of Specifications
requirements in this subpart. These written proce¬
dures including any changes, shall be drafted, re¬ The element of potential hazard to public
viewed and approved by the appropriate organiza¬ health and the risk of violating stringent and
tional units and reviewed and approved by the quality exacting statutes render specification writing for
control unit.” the pharmaceutical industry quite unique. The
Section 211.110(a)—“To assure batch uniformity and main purpose of establishing specifications is to
integrity of drug products, written procedures shall be' ensure that the characteristics of the finished
established and followed that describe the in-process dosage forms conform to appropriate standards
controls, and tests or examinations to be conducted on of identity, purity, potency, quality, safety, and
appropriate samples of in-process materials of each efficacy.
batch. Such control procedures shall be established to The first four types of specifications (i.e.,
monitor the output and to validate the performance of identity, purity, potency, and quality) are dis¬
these manufacturing processes that may be responsi¬
tinctively analytic in nature and are embodied in
ble for causing variability in the characteristics of in-
process material and drug product.”
specifications known as drug standards. Exam¬
ples of tests for standard of identity, purity, and
quality are shown in Table 27-13. These drug
The documentation, including protocols, data,
standards may be further delineated and illus¬
and results obtained from process validation and
trated by citing the typical examples in the fol¬
equipment qualification are important, since the
lowing sections.
validation performed should be auditable by an
appropriate responsible individual who, after
reviewing the records, should be able to certify Standard of Identity
the validation of the process to produce products Identity tests are usually the distinctive quali¬
to defined attributes consistendy provided that tative chemical methods used to confirm the
the system validated is not altered. actual presence of the compound. For some
drugs, microbiologic and pharmacologic tests
also may be employed. Examples are:
Control and Assurance of
Finished Products 1. The infrared absorption spectrum for chloro¬
thiazide dispersed in mineral oil exhibits
Good manufacturing practices, well-defined
maxima only at the same wavelengths as that
specifications, sound sampling procedures, and
of a similar preparation of chlorothiazide ref¬
efficient process controls do not in themselves
erence standard.
constitute an overall quality control program.
Unless the testing procedures by which the 2. Ouabain, when dissolved in sulfuric acid,
product quality is finally measured are estab¬ produces a dark red color by transmitted light
lished on an equally sound basis, the entire sys¬ and shows a greenish fluorescence in re¬
tem may be deficient. Product failures causing flected light.

QUALITY CONTROL AND ASSURANCE • 833

Table 27-13. Examples of Tests for Standards of Identity, Purity, and Quality
Standard of Identity Standard of Quality Standard of Purity

Color formation Absorbance Color and/or odor

Precipitation Refractive index Clarity and/or color of solution
Decomposition Optical rotation Acidity or alkalinity
Derivative formation Specific gravity Acid of alkali
Infrared spectra pH Inorganic salt
Ultraviolet spectra Viscosity Heavy metals
Visible spectra Melting point or range Foreign matter
Specific reactions Saponification value Residue on evaporation
Cations or anions determination Acid value Readily carbonizable substances

3. The ultraviolet absorption spectrum of pro¬ 2. A solution of ouabain yields no precipitate

pranolol hydrochloride in methanol exhibits with tannic acid or with iodine to indicate the
maxima and minima at the same wave¬ absence of alkaloids.
lengths as that of a similar preparation of ref¬
3. The residue on ignition of propranolol hydro¬
erence standard. The respective absorptive
chloride is not more than 0.1%.
values at the maximum wavelength do not
differ by more than 2.5%. 4. After drying quinidine gluconate at 105° for 1
hour, it loses not more than 0.5% of its
4. A solution of quinidine gluconate in dilute
weight.
sulfuric acid exhibits a vivid blue fluores¬
cence. On the addition of a few drops of hy¬
Based on USP XXI, standard of purity of sev¬
drochloric acid, the fluorescence disappears.
eral drug substances and their dosage forms is
tabulated as illustrated in Table 27-14. Each
Standards of Quality drug substance has its specific contaminant or
Quality tests are usually the physical methods impurity specified at different maximum allowa¬
used to measure accurately the characteristic ble limits. The limit may be as low as 0.003% of
properties of the drug. Results are expressed as a p-chlorophenol in clofibrate or as high as 5.0%
permissible range of values for a measured prop¬ of related alkaloids in ergotamine tartrate. The
erty of the drug. Examples are: same contaminant or impurity present in differ¬
ent drug substances may not have the same
1. The specific notation of propranolol hydro¬ maximum allowable limit. For example,
chloride is between -1.0° and +1.0° calcu¬ m-aminophenol is a common impurity found in
lated on the dried basis. aminosalicylic acid, and its alkali salts at a maxi¬
mum allowable limit of 0.25% and 0.20% re¬
2. A solution of quinidine gluconate is
spectively. The maximum allowable limits of
dextrorotary.
levarterenol is 4.0% in epinephrine and 2.0%
3. The refractive index of clofibrate is between in epinephrine bitartrate. The limits for
1500 and 1505 at 20°. diazotizable substances in various diuretic thia¬
zide compounds range from 1.0% in hydrochlo¬
4. The specific gravity of ethanol is between
rothiazide to 2.5% in trichlormethi^zide. In con¬
0.812 and 0.816 at 15.56°
trast to this situation, however, the limit for
4-epianhydrotetracycline is 2.0% regardless of
Standards of Purity whether the drug substance is from tetracycline,
Purity tests are generally designed to estimate tetracycline hydrochloride, or tetracycline phos¬
the levels of all known and significant impurities phate complex.
and contaminants in the drug substance under The same situation exists for the maximum
evaluation. These standards are numerically allowable limit of contaminant or impurity in
expressed as maximum tolerable limit or the dosage forms of the same drug substance. As
absence of an impurity or contaminant based on shown in the last column of Table 27-14, the
the prescribed methods. Examples are: limits of nonaspirin salicylates in aspirin tablets,
aspirin suppositories and aspirin buffered tablet
1. The maximum tolerable limit of diazotizable are 0.3%, 1.0%, and 3.0% respectively. The
substances of chlorothiazide is 1.0%. maximum allowable 4-epianhydrotetracycline

834 • The Theory and Practice of Industrial Pharmacy

 Maximum Allowable Limit (%)

■\j' d d ■g *■ O P <U & JV

^232^^ n>
j .« .< r<i 3 S S 3
■§1111111
oj H H H ros , §bbb-§ bbb
^S^bbbbs tr‘«o)<uriaja;aj
Table 27-14. Standard of Purity of Drug Substances and Their Dosage Forms Listed in USP XXI

CGG GGG
ObbbtNrirJ-COC .oooooooo
^OOOOOOOC ImZZZ-ZZZ

LO O O O ID O <N
(N(N(N(NHq!NH © O in LO CD LO o qqqicqqqqoqiqq
dddddodd *-« d o d d -4 I'dlOlNdHHHHHHNO O H o (N CN

Data compiled from USP XXI, United States Pharmacopeial Convention, Rockville, MD, 1980.
Contaminant or Impurity

4-Epianhydrotetracycline
&
a S 0) ”0 cti cti
2 T3 o <n *3L c % is h
oooo£j0rt£ Q« ’C
= 3 |
ccccgc.y^ 8 i. ’ 3
£ X 'SL _ v ^ w
I ■§ "c
) J 7'S
I ^ <? § -O rt S’ p
22 2 g £i T3 g N J3 s
!II!||T| O N O.S 5
2-32 § S £ §
% 'S *2 mu
2 v 2 a 2.
9 '2 1 < I Is 1 53 g o w w
sees^slz 3"1. 5 S a. S
; fa CU ^ TJ-

Tetracycline phosphate complex

6
Drug Substances

£■§ |
a; u a) m <U Q3
s|l| £ 3 -Td -a <u
cd3 5 9 'T8
co Ph o 3 S 2 8 S
5 O
■i 1 T3 2 i hi “ E
s g « #2 j|'S£
>-> >-> >-*
y o <j (J CO 11 g s -g | 8I S E I 2 is II
3 3 3 3 Mr o
all 111 55J2S |E8
<9 E §
Q c aw (U03O2U uO>,
4) <u iS c ^ 11 ■§ §1^
2 3 9?
s
11 g, h
Q< Q< H aS09
e -2 ’o 'O o "5
Sjs ?. >r >p ;c 2 ■sJSfi
fa fa Ed fa W BUUlIhfc ££££

QUALITY CONTROL AND ASSURANCE • 835

limit is prescribed at 3.0% for tetracycline hy¬ Its content of dihyroquinidine gluconate is
drochloride capsules, injections, and tablets; not more than 20.0% by weight of its content
however, none is described for ophthalmic sus¬ of total alkaloid salt, calculated as:
pensions, topical solutions, and ophthalmic
ointments. A similar situation is found for C20H24N2O2.C6H12O7.
azathioprine, with the maximum limit of
mercaptopurine set at 3.0% for azathioprine in¬ Examples of standards of potency for several
jection, but no limit described for the tablet dos¬ drug substances and their dosage forms are
age form. Even more striking is the fact that the listed in USP XXI and are demonstrated in Table
maximum limit for some contaminant or impu¬ 27-15. For drug substance, most of the chemi¬
rity is set for drug substance but is not required cally synthesized raw materials have a lower
for its dosage forms. Examples are mercap¬ specification limit of at least 97% potency with
topurine in azathioprine, p-chlorophenol in the exception of antibiotics such as chloram¬
clofibrate, p-chloroacetanilide in phenacetin, phenicol, ampicillin, and tetracycline hydrochlo¬
levarterenol in epinephrine, and diazotizable ride, which in general have a lower potency limit
substances in most of the diuretic thiazides. of 90% or more. As shown in Table 27-15, differ¬
ent dosage forms of the same drug substance are
Standards of Potency assigned the same specification limits, such as'
90.0 to 130.0% for chloramphenicol capsules,
Potency tests are assays that estimate the
ophthalmic solutions, and ophthalmic oint¬
quantity of active ingredient in the drug. Em¬
ments, and 95.0 to 110.0% for all dosage forms
ploying physical, chemical, biologic, pharmaco¬
containing promazine hydrochloride. As shown
logic, or microbiologic means, these quantitative
in Table 27-15, however, different dosage forms
tests yield the strength or potency of the drug
of the same drug substance may be assigned dif¬
substance. Examples are:
ferent specification limits as well. Using ephed-
rine sulfate as an example, limits are 90.0 to
1. Chlorothiazide contains not less than 98.0%
110.0% for syrups, 92.0 to 108.0% for capsules,
and not more than 100.5% of C7H6C1N304S2,
95.0 to 105.0% for injections, and 93.0 to
calculated on the dried basis.
107.0% for tablets and nasal solutions. It should
2. Ouabain contains not less than 95.0% and be noted that the positive and negative specifica¬
not more than 100.5% of C29H440j2.8H20. tion limits are generally symmetric around the
potency for most of the dosage forms. Therefore,
3. Propranolol hydrochloride contains not less
in many cases, the potency range is expressed in
than 98.0% and not more than 101.5%
the form of 100 ±10% or 100 ±7% than 90 to
of C16H2iN02.HC1 calculated on the dried
110% or 93 to 107%.
basis.
A drug substance is suitable for use if the to¬
4. Quinidine gluconate contains not less than tality of data derived from these four attributes
99.0% and not more than 100.5% of total al¬ shows that it meets all of the specifications.
kaloid salt, calculated on the dried basis as: In general, specifications should provide for
the maintenance of reasonable standards, while
C2oH24N202.CgH]207 allowing a sensible degree of latitude for manu-

Table 27-15. Standard of Potency of Different Dosage Forms Having Same Limits
Standard of Potency Expressed as Percentage of Claim

Drug Substance Raw Material Dosage Forms

Amitriptyline HC1 99.9-100.5 90.0-110.0 (Injection, tablet)

Chloramphenicol >90.0 90.0-130.0 (Capsule, ophthalmic solution, ointment)
Chlorpromazine HC1 98.0-101.5 95.0-105.0 (Injection, syrup, tablet)
Digoxin 97.0-103.0 95.0-110.0 (Injection, elixir, tablet)
Fluphenazine HC1 97.0-103.0 95.0-110.0 (Injection, oral solution, elixir, tablet)
Griseofulvin 90.0-105.0 90.0-115.0 (Oral suspension, tablet, capsule)
Meperidine HC1 98.0-101.0 95.0-105.0 (Injection, syrup, tablet)
Reserpine 97.0-101.0 90.0-110.0 (Injection, elixir, tablet)
Promazine HC1 97.0-101.5 95.0-110.0 (Injection, oral solution, syrup, tablet)

Data compiled from USP XXI, United States Pharmacopeia! Convention, Rockville, MD, 3980.

836 • The Theory and Practice of Industrial Pharmacy

Table 27-16. Utilization of Historical Batch ment of drug substance, excipients, reagents,
Data to Guide the Specification for Standard of packaging, and printed materials. The incoming
Purity materials and the finished products are checked
against the specifications to an extent sufficient
Drug substance: An experimental to determine the compliance and the acceptabil¬
antihypertensive ity of the materials and products. Therefore, the
Proposed limit 1% of an impurity specifications set forth as the standard should be
of purity:
discriminating enough to differentiate good or
Method: High-pressure liquid
acceptable material from inferior or rejectable
chromatography for an
material. The specifications should be practical
impurity
and realistic, however, and they should reflect
Detection limit: 0.1%
those parameters necessary to define the prod¬
Batch record: 0.2 0.2 0.3 0.1 <0.1
0.3 <0.1 0.1 0.1 0A uct as well as to permit manufacture of the prod¬
Acceptable limit: 0.6% uct to a defined quality level. In developing
“House” limit: 0.5% specifications for purchased material, the ven¬
dor’s capability to supply the material should
also be considered.
facturing variations or tolerances, and accepta¬ In the development of specifications, the fol¬
ble latitude for analytic errors, particularly in lowing objectives should be carefuHy consid¬
control techniques. To guide in the appropriate ered: (1) to ascertain which physical, chemical,
development of specifications, historical data and biologic characteristics of dosage form are
critical, which are important, which are helpful,
accumulated from batch analyses of the drug
substance or the drug product are usually the and which are not particularly important but are
best source. The relevance of historical batch useful; (2) to decide which dosage form charac¬
records to establish meaningful specifications is teristics shall be established as the criteria for
illustrated in Table 27-16 for standard of purity, evaluating routine production batches; (3) to
establish the appropriate test methods for evalu¬
and in Table 27-17 for standard of potency, re¬
spectively. Proposed limits usually become ac¬ ating the selected criteria; and (4) to determine
ceptable limits, which must be realistic and rele¬ the acceptable tolerances and limits for each of
vant to the actual historical batch analysis the dosage form characteristics.
record and to the sensitivity or reproducibility of In deciding the elements that will contribute
method. to the making of a satisfactory specification for a
Specifications and procedures that are de¬ drug, the first question to be asked must always
be “For what purpose is the specification
signed to test the product quality consist of a se¬
needed?” No single set of requirements meets
ries of statements and methods of evaluating the
all possible situations.
physical, chemical, and biologic characteristics
of the dosage form. The in vivo clinical testing of
lot to lot of product is replaced, out of necessity, Specifications for New Products
with a series of in vitro laboratory tests, which
During the development of any new drug,
are correlated to reflect the clinical performance
there must be a rigorous investigation of both
of the drug substance formulated in the product.
the chemical and physical properties of the ma¬
Specifications are also used in the procure-
terial. A knowledge of the synthetic and appro¬
priate testing by nuclear magnetic resonance,
Table 27-17. Utilization of Historical Batch infrared spectroscopy, and mass spectrometry
Data to Guide the Specification for Standard of route usually provides strong evidence of struc¬
Potency. ture, together with hints as to the identity of pos¬
sible by-products that might be present. Specific
Drug substance: Antihypertension chemical reactions may give further confirma¬
Proposed potency limits: 93.0-107.0% tion of structure. As frequently happens, possi¬
Method: Chloroform extraction ble contaminants bear a close structural rela¬
followed by UV spectro- tionship to the drug substance. Two percent or
photometry 3% of such substances may produce no readily
Reproducibility: ±2% detectable effect even by infrared spectroscopy.
Batch record: 99.3 98.4 103.4 97.9 101.3
It is necessary to recognize the presence of im¬
98.9 101.8 99.7 98.6 100.4
purities present at such low levels, however,
Acceptable limits: 95.0-105%
because the contaminant might have an unde¬
“House” limits: 96.0-104%
sirable or even harmful effect. Thus, it is reason-

QUAUTV CONTROL AND ASSURANCE • 837

able that its presence should be defined and con¬ and identify impurities. There are two major
trolled. kinds of impurities: product-nonspecific impuri¬
Although, ideally, a drug should be absolutely ties, which are introduced externally into the
pure, this is generally not feasible in practice. A product during processing, and product-specific
more practical approach is to require that the impurities, which appear as by-products or de¬
material to be subjected to pharmacologic and graded products of the drug substances as well
clinical trial is prepared to be as pure as is eco¬ as excipients used in the product. Therefore, the
nomically reasonable and then characterized as test parameters should be designed, and the
fully as possible with respect to its impurity con¬ testing procedures for the specifications should
tent. If the trials prove satisfactory and accepta¬ be established, so that the tests are capable of
ble, then the aim should be to ensure that subse¬ detecting product-specific as well as product-
quent batches of material should be at least as nonspecific impurities.
‘’clean” as the trial material. It is essential that Today, many countries require the establish¬
the total identity of the material being used, in¬ ment of interim specifications when the product
cluding both its major and minor constituents, is registered for clinical trials. Therefore, the
be known. Only in this way can the results of analytic methodology for the drug in a dosage
clinical trials be meaningful for a new drug. form must be developed at the initial stages of
product development. The early provisional
Specifications for Well-Established Products specifications may be less rigorous than subse¬
quently provided since they are often based on
It is important to bear in mind that material
experiences from only a few small batches. Sel¬
synthesized on a pilot scale for clinical trial work
dom does a drug manufacturer base his specifi¬
may not be the same as material synthesized in a
cations on observations made on a single devel¬
full-scale manufacturing process, especially in
opment batch. The stability, potency, and other
respect to its pattern of minor constituents.
critical characteristics of the product should be
What is a tolerable level of impurity in a drug?
finalized only after several pilot and production
This question, of course, has no answer. Every
batches have been produced. The results of
impurity in each drug must be considered as a
these studies should be subjected to statistical
separate and individual case. If the impurity has
analysis to appraise correctly the magnitude of
been shown to have, or is suspected to have,
the variation involved for each characteristic,
undesirable properties, it should be limited as
thereby establishing firm specifications for each
rigorously as possible.
characteristic. A specific method of analysis
must be developed early in the program to per¬
Official Specifications form stability studies adequately. Even at this
The manufacturer’s specifications are de¬ stage, the experience with the product is usually
signed to be applied to the drug at the time of still limited.
manufacture or quite shortly thereafter. An offi¬ A description of the tests and reagents for var¬
cial specification, on the other hand, should be ious official drugs and their dosage forms are
designed to apply to the material at any time available from the official compendia. From con¬
during its period of possible use. An official tent uniformity to dissolution tests, and from
specification is likely to be somewhat less strin¬ identity tests to assay procedures, each section
gent, especially with regard to changes due to outlines specific procedures that are mandatory
slight decomposition. As an obvious example, a for the proper control of the product.
manufacturer’s release specification for content All drug specifications fisted in pharmaco¬
of free salicylic acid in aspirin would need to be peias have been verified in collaborating labora¬
considerably more stringent than that of a phar¬ tories of pharmaceutical companies and aca¬
macopoeia, which applies to the shelf-life of the demic institutions. The pharmacopoeia issued
drug. for a country is the legal standard of that nation.
There is another complicating factor arising The specifications in a pharmacopoeia are so
when the specification is intended to apply to designed that the tests and the requirements for
the drug independent of its source. A specifica¬ acceptance are applicable to all manufacturers’
tion developed for the drug using a particular products. This means that anyone who manu¬
manufacturing process that is designed to limit factures a product of that type should conform
certain known impurities may fail to control with those specifications. It should be recog¬
other impurities that might arise by use of a dif¬ nized that the specifications set in the compen¬
ferent route of synthesis. dium are minimum standards to which the
Specifications for a product are developed not product is expected to conform at any time dur¬
only to assure product quality but also to detect ing its expiry date period. A partial list of official

838 • The Theory and Practice of Industrial Pharmacy

Table 27-18. Partial List of Pharmacopeias and cial United States Pharmacopeia, Official Home¬
Other Books of Standards opathic Pharmacopeia of the United States, Offi¬
cial National Formulary, or any of their
Country Pharmacopeia or Other Standards supplements.
The complexity of quality control testing can
Federal Republic Deutsches Arzneibuch and
be more clearly understood from the quality con¬
of Germany supplements
France Pharmacopee Francaise
trol profiles of a hypothetical parenteral dosage
Japan The Pharmacopeia of Japan form containing sulfadimethoxide as an active
Sweden Pharmacopeia Nordica ingredient (Table 27-19), and a hypothetical tab¬
Switzerland Pharmacopeia Helvetica and its let dosage form containing glutethimide as the
supplements active ingredient (Table 27-20). For manufac¬
Union of Soviet State Pharmacopeia of the Union turing the parenteral sulfadimethoxide injec¬
Socialist of Soviet Socialist Republics tion, there are seven items or raw materials to be
Republics tested and cleared by quality control laboratory
United Kingdom British Pharmacopeia; according to the specifications designed for each
The Pharmaceutical Codex item. There are approximately 70 tests required
United States The United States Pharmaco- prior to the release of these seven items for com¬
of America peia/National Formulary; Code pounding. Similarly, a large number of tests are
of Federal Regulations, 21 required to accept eight items for fabricating
Foods & Drugs glutethimide tablets. There are approximately
World Health Pharmacopeia Internationales 80 tests that need to be performed to determine
Organization the acceptability of these eight ingredients.
Based on the examples shown in Tables 27-19
compendia from several countries and WHO is and 27-20, the average number of quality control
presented in Table 27-18. A compendium is a tests required to accept or reject a raw material
collection of monographs of drug substances and is approximately ten. It is evident that the total
drug products. “Official” as used in “official number of tests required by the official com¬
compendium” signifies governmental authoriza¬ pendia on the ingredients in the dosage form are
tion. As defined in the FD&C Act of 1938, the numerous. In addition to these tests are added
phrase “official compendium” means the Offi¬ the quality control tests on the finished dosage

Table 27-19. Quality Control Profile of Various Raw Materials Used in a Proposed Parenteral Sulfon¬
amide Injection

Item Function Tests Required

Sulfadimethoxine, NF XVI Antibacterial Appearance; solubility; identity; melting range; ultraviolet absorp¬
tion; loss on drying; residue on ignition; content of heavy met¬
als; assay.
Glycerine, USP XXI Cosolvent Appearance; solubility; identity; color; specific gravity; residue on
ignition; contents of chloride, sulfate, arsenic, and heavy met¬
als; limit of chlorinated compound; readily carbonizable sub¬
stances; limit of fatty acids and esters.
Benzyl alcohol, NF XVI Preservative Appearance; solubility; identity; specific gravity; distilling range;
refractive index; residue on ignition; limits for aldehyde and
chlorinated compounds.
Sodium bisulfite, NF XVI Antioxidant Appearance; solubility; identity; contents of arsenic, iron, and
heavy metals; assay.
Disodium edetate, USP XXI Chelator Appearance; solubility; identity; pH; loss on drying; contents of
calcium and heavy metals; assay.
Sodium hydroxide, NF XVI pH adjuster Appearance; solubility; identity; insoluble substances and organic
matters; contents of potassium and heavy metals; assay.
Water for injection, USP XXI Solvent Appearance; reaction; chloride, sulfate, ammonia, calcium, car¬
bon dioxide and heavy metals; total solids and oxidizable sub¬
stances; pyrogen test.

Data compiled from USP XXI/NF XVI, United States Pharmacopeia! Convention, Rockville, MD, 1980.

QUALITY CONTROL AND ASSURANCE • 839

Table 27-20. Quality Control Profile of Various Raw Materials Used in a Proposed Glutethimide
Tablet

Item Function Tests Required

Glutethimide, USP XXI Depressant Appearance; solubility; identity; melting range; ul¬
traviolet absorption; loss on drying; residue on
ignition; assay.
Tragacanth, NF XVI Binder Appearance; identity; karaya gum; microbial limits,
arsenic, lead, heavy metals.
Lactose, USP XXI Diluent Appearance; solubility; identity; specific rotation;
residue on ignition; heavy metals; clarity and
color of solution, microbial limits, pH, water, alco¬
hol soluble residue.
Talc, USP XXI Glidant Appearance; identity; loss on ignition; acid-soluble
substances; water-soluble iron; reaction and solu¬
ble substances.
Magnesium stearate, NF XVI Lubricant Appearance; solubility; identity; loss on drying; lead
content; assay.
Polyethyleneglycol 4000, NF XVI Binder and lubricant Appearance; solubility; viscosity; completeness and
color of solution; pH, acidity; average molecular
weight; residue on ignition; arsenic; heavy met¬
als, limit of ethylene glycol and diethylene glycol,
ethylene oxide average molecular weight.
Alcohol, USP XXI Solvent Appearance; solubility; specific gravity; nonvolatile
residue; water-insoluble substance; aldehydes and
other foreign organic substances; methyl ketones,
methanol and other alcohol content; fusel oil con¬
stituents, amyl alcohol and nonvolatile, car-
bonizable substances.
Purified water, USP XXI Solvent Appearance; reaction; heavy metals content, total
solids; bacteriologic purity, oxidizable substance,
carbon dioxide, calcium ammonia, sulfate, chlo¬
ride, pH.

forms of sulfadimethoxide Injection and gluteth¬ ponent of the container is glass or plastic. The
imide tablets according to the product specifica¬ official compendium provides for several types
tions. of glass and several classes of plastic to be used
Procedures in the compendium apply to all with various pharmaceutical products. Exam¬
manufacturers of a particular product, whereas ples of quality control profiles of three major
the quality control procedures of the manufac¬ packaging materials are shown in Table 27-21.
turer are intended to apply specifically to his Specifications designed for containers are mean¬
own product. The pharmaceutical industry fre¬ ingful only if they have been selected on the
quently employs alternative methods, which basis of tests performed on the product in the
may be more accurate, specific, sensitive, and .container. The following features are to be con¬
economical than those in the compendium. The sidered before container specifications are set:
manufacturer is not required to employ proce¬ (1) physical changes of container upon pro¬
dures in the official compendium as long as the longed contact with the product; (2) moisture
quality of his product ultimately meets the re¬ and gaseous permeability of the container;
quirements fai the compendium for identity, (3) compatibility between the container and the
quality, potency, and purity. In the case of a product; and (4) toxicity and safety.
legal action, the test methods in the compen¬
dium are the basis for determining compliance.
Container components should not interact Testing Program and Method
physically or chemically with the product to alter Total quality assurance certifies that each re¬
its identity, purity, quality, or potency beyond ceived lot of raw material or each manufactured
the official allowances. Usually, the major com¬ batch of product meets the established quality

840 • The Theory and Practice of Industrial Pharmacy

Table 27-21. Quality Control Profile of Various Packaging Materials USP XXI/NF XVI

Item Function Test Required

1. High-density poly- Containers for cap- Multiple internal reflectance, thermal analysis, light transmis-
ethylene containers sules and tablets sion, water vapor permeation, extractable substances, nonvola¬
tile residue, heavy metals.
2. Glass
Highly resistant. Parenteral use Light transmission, chemical resistance—powdered glass test.
borosilicate glass
(Type II)
Treated soda-lime Acidic and neutral Light transmission, chemical resistance—water attack at 121°
glass (Type II) parenteral prepara¬ test.
tion
Soda-lime glass Parenteral and Light transmission, chemical resistance—powdered glass test.
(Type III) nonparenteral prep¬
aration
General purpose Nonparenteral arti¬ Light transmission, chemical resistance—powdered glass test.
soda-lime glass cles, i.e., oral or
topical use
3. Elastomeric closure Parenteral use Biologic test—acute systemic toxicity, intracutaneous reactivity;
for injection physicochemical test—turbidity, reducing agents, heavy met¬
als, pH change, total extractables.

Data compiled from USP XXI/NF XVI, United States Pharmacopeia! Convention, Rockville, MD, 1980.

standards. It provides for the authorization of means. The standard purity statement for the
the release of the approved raw materials for active ingredient in the dosage form usually per¬
manufacturing, and the release of the manufac¬ mits a wider variation than that for the active
tured product to the market, based on actual lab¬ ingredient itself. Through purity and identity
oratory testing-physical, chemical, microbio¬ tests, the quality of the drug alone is established,
logic, and at times, biologic. and its level of impurities restricted, as in the
Outlines of various quality control tests for dif¬ limiting tests for chloride, sulfate, and heavy
ferent properties of the product are presented metals. The assay measures the concentration of
here to illustrate the scope of various laboratory this previously accepted drug in the dosage
testing. form.
When a physicochemical assay method is not
1. Physical and chemical tests—Tests for ap¬ possible, a macrobiologic or microbiologic proce¬
pearance, color, odor, identity, optical rota¬ dure is employed. Biologic testing of drugs may
tion, specific gravity, pH, solubility, viscosity, be quantitative or qualitative in nature; it uti¬
disintegration time hardness, friability, aver¬ lizes intact animals, animal preparations, iso¬
age weight or volume per unit, weight or vol¬ lated living tissues, or microorganisms. Biologic
ume variation, content uniformity, dissolu¬ methods are employed in the following situa¬
tion profile, polymorphic form, particle size, tions: (1) when adequate chemical assay has not
moisture content, and assay for active ingred- been devised for the drug substances, although
ient(s), impurities, contaminants, or degrada¬ its chemical structure has been established
tion products. (e.g., insulin); (2) when chemical structure of
the drug substance has not been fully elucidated
2. Biologic and microbiologic tests—Macrobio¬ (e.g., parathyroid hormone); (3) when the drug
logic or microbiologic assays, and tests for is composed of a complex mixture of substances
potency, safety, toxicity, pyrogenicity, steril¬ of varying structure and activity (e.g., digitalis
ity, histamine, phenol coefficient, antiseptic and posterior pituitary); (4) when it is impossi¬
activity, and antimicrobial preservative effec¬ ble or impractical to isolate the drug from its in¬
tiveness tests. terfering substances, although the drug itself
can be analyzed chemically (e.g., isolation of vi¬
Most therapeutic agents are substances of tamin D from certain irradiated oils); (5) when
known chemical structure or composition and the biologic activity of the drug substance is not
can be assayed by quantitative physicochemical defined by the chemical assay (as when active

QUALITY CONTROL AND ASSURANCE • 841

and inactive isomers of methylphenidate cannot standard, although other methods of computa¬
be differentiated by the chemical method); and tion have been devised to improve the reliability
(6) when specificity, sensitivity, or practicality of the results.
dictates the use of biologic rather than chemical Increasing emphasis on microbiologic attri¬
assay procedures. butes of nonsterile products has generated addi¬
The accuracy of biologic tests does not ap¬ tional responsibility in the quality control of raw
proach that which is expected with good chemi¬ materials, especially those derived from animal
cal methods. Accuracy within ±20% of the true or botanical origin. In recognition of this in¬
value is good, and within ±10% is excellent, for creased concern regarding the possible contami¬
most bioassays. Consequently, it is useful and nation of nonsterile products with pathogenic or
advisable to supplement the biologic tests with otherwise objectionable microorganisms, the
select physicochemical tests when possible. USP XXI has included microbiologic quality
Some official quantitative and qualitative bio¬ control test procedures. These are designed to
logic tests are summarized in Tables 27-22 and monitor nonsterile drug products for possible
27-23 respectively. Some biologic tests require adulteration with microorganisms such as Sal¬
as long as a month for completion; others may monella species, Escherichia coli, certain spe¬
take only a few hours. Therefore, bioassays are cies of Pseudomonas, and Staphylococcus au¬
often expensive and inconvenient. reus. Medicinal substances of natural and
To minimize the source of error resulting from mineral origin are likely to be contaminated with
animal variation during biologic tests, reference bacteria, while synthetic medicinal substances
standards or pure drug substances and standard tend to be bacteriologically clean in comparison.
reference preparations are used, where possible, Nevertheless, solutions, suspensions, and semi¬
for comparison of their potency with the potency solid dosage forms of these synthetic medicines
of unknown preparations to be tested. A refer¬ tend to acquire bacterial contamination from
ence standard is the specific active principle of excipients, manufacturing processes and envi¬
the drug in its purest obtainable form. The prin¬ ronment, and containers. At the present ume,
ciple of using tests in which reference materials there are many monographs in the USP XXI re¬
are employed is based upon successive testing of quiring freedom from one or more of the afore¬
the unknown and standard preparations on two mentioned organisms. Typical examples are
groups of similar animals, as in the case of digi¬ given in Table 27-24.
talis and tubocurarine, or on the same animal or The microbial flora associated with various
organ, as in the case of posterior pituitary and raw materials can vary considerably. Standard
epinephrine. The potency of the unknown can plate-counting procedures are familiar and pop¬
therefore be expressed as a percentage of the ular methods. In addition, broth enrichment

Table 27-22. Partial List of Official Quantitative Biologic and Microbiologic Tests
Biologic Tests
Drug and Dosage Form Test Animal(s)
Insulin Rabbit
Digitalis and the related Pigeon
cardiac glycosides
Parathyroid Dog
Posterior pituitary Rat
Tubocurarine chloride Rabbit

Microbioloijic Tests
Drug and Dosage Form Test Organism(s)
Microbiologic assay
Calcium pantothenate Lactobacillus plantarum
Cyanocobalamin Lactobacillus leichmannii
Penicillin Staphylococcus aureus
Other antibiotics (Varied according to the antibiotics)
Antimicrobial preservatives Antimicrobial preservations—effectiveness
Candida albicans, Aspergillus niger,
Escherichia coli, Pseudomonas aeruginosa,
Staphylococcus aureus

842 • The Theory and Practice of Industrial Pharmacy

Table 27-23. Partial List of Official Qualitative Biologic Tests

Products to be Tested Test

Preparations of liver or stomach Antianemia tests

Antiseptics, disinfectants, fungicides, germicides Antibacterial tests
Preparations containing toxoids Antigenic test
Water, USP Bacteriologic purity
tests
Gelatin Bacterial content
Protein hydrolysate injection Biologic adequacy
test
Protein hydrolysate injection Nonantigenicity test
Diagnostic diphtheria toxin, influenza virus vaccine, and smallpox vaccine Potency tests
Parenteral products, radioactive pharmaceutical, transfusion and infusion Pyrogen test/bacterial
assemblies endotoxin test
Most antibiotics, transfusion and infusion assemblies Safety tests
Parenteral and ophthalmic products, antibiotics, sutures, all surgical dressings, Sterility tests
transfusion and infusion assemblies
Chloramphenicol, streptomycin, chlorotetracycline, tetracycline, liver injection Test for depressor
substances
Adrenal cortex injection Test for pressor sub¬
stances
Suramin sodium and preparations containing toxoids Toxicity tests
Pharmaceutical articles, from raw materials to finished products Microbial limit tests

Table 27-24. Typical Pharmaceutical Materials Required by Official Compendia to Ensure Freedom
from Specific Objectionable Microorganisms

USP XXI

Absence of Absence of Absence of Absence of

Escherichia Coli Salmonella Escherichia Coli Salmonella and Pseudomonas
and Salmonella

Alumina and magnesia oral Dehydrocholic acid Gelatin Chymotrypsin

suspension
Aluminum hydroxide gel Digitalis capsules
Pectin Pancrelipase
Milk of magnesia Thyroid Activated charcoal
Trypsin (crystallized)
Pancreatin

NF XVI

Absence of Salmonella,
Absence of Escherichia Coli,
Absence of Escherichia Coli Staphylococcus Aureus, and
— Salmonella and Salmonella Pseudomonas Aeruginosa

— Acacia Starch
Agar Alginic acid Caramel

Data compiled from USP XX1/NF XVI, United States Pharmacopeial Convention, Rockville, MD, 1980.

QUALITY CONTROL -AND ASSURANCE • 843

procedures are used to detect low levels of mi¬ fungi are usually objectionable since these orga¬
croorganisms. The following categories of raw nisms have been implicated as agents of dis¬
materials are often contaminated with various eases in foods. Further examples of objectiona¬
microbial flora and should be thoroughly investi¬ ble microorganism contamination are tabulated
gated: processed water, colors, dyes, pigments, in Table 27-25.
talcs, starches, clays, fillers, natural gums, and Microbiologic testing of sterile products (in¬
thickening agents. It is important to consider jection and ophthalmic) for the antimicrobial
the pharmaceutical process when a limit is es¬ efficacy of added antimicrobial agents, for steril¬
tablished for the number of microorganisms per ity, and for pyrogenicity are discussed in detail
gram of raw material. Samples should be taken in Chapters 21, “Sterilization,” and 22, “Sterile
throughout the production cycle on a random Products.”
basis to evaluate the microbiologic spectrum of Traditionally, pyrogen testing is performed on
the process. This serves as an indicator of sani¬ rabbits, and observations are made for febrile
tation and good manufacturing practices. response. A recent innovation in pyrogen testing
The final dosage form is often statistically is the use of an in vivo limulus amebocyte lysate
sampled and tested for microbiologic attributes. (LAL) test, which is capable of detecting the
Here again, the absence of pathogens is impor¬ more potent endotoxin pyrogens. Manufacturers
tant, and the total count gives a measure of mi¬ of nonantibiotic injectable products may substi¬
crobiologic normality. The hazard of microbial tute the LAL test for the official rabbit pyrogen
contamination is related to the intended area of assay as an end product endotoxin test immedi¬
use for the product. For parenteral products, the ately upon a supplemental submission to the
dictum is that any viable microorganism is a FDA, provided that the firm has validated the
health hazard. Even for orally administered test for the particular drug product. On the other
products, the presence of E. coli and Salmonella hand, antibiotic drug makers and manufacturers
species are always objectionable, and the pres¬ of biologicals who change manufacturing con¬
ence of Pseudomonas species, C. albicans, En- trols are required to submit to the agency for
terobacter species and mycotoxin-producing advance approval a full statement describing the

Table 27-25. Partial List of Objectionable Organisms in Pharmaceuticals

Intended Area of Examples of Objectionable Organisms

Product Application
Always Objectionable Usually Objectionable

Oral products Escherichia coli Pseudomonas sp.

Salmonella sp. Enterobacter sp.
Enterotoxigenic Staphylococcus aureus
Myocotoxin-producing fungi
Candida albicans
Parenteral products Any viable microorganism
Ophthalmic preparations Pseudomonas aeruginosa Other Pseudomonas sp.
Staphylococcus aureus
Genitourinary tract products Escherichia coli Klebsiella sp.
Proteus mirabilis Acinetobacter anitratus
Serratia marcescens
Pseudomonas aeruginosa
Pseudomonas multivorans
Products for surface wounds Pseudomonas aeruginosa
and damaged epithelium Staphylococcus aureus
Klebsiella sp.
Serratia marcescens
Pseudomonas multivorans
Pseudomonas putida
Clostridia perfringens
Topical products Pseudomonas aeruginosa Pseudomonas multivorans
Staphylococcus aureus Pseudomonas putida
Klebsiella sp. Clostridia perfringens
Serratia marcescens Clostridia tetani
Clostridia novyi

844 • The Theory and Practice of Industrial Pharmacy

 proposed change supported by the validated praisal of the data and optimal confidence in the
data. results. If the error in the analytic methods em¬
An important aspect of dosage form control is ployed for product testing is not understood, the
the safety or toxicity test that is performed on possibility of rejecting a finished product may be
the finished dosage form to guard against adven¬ due to the test methods and not to inferior prod¬
titious adulterations of pharmaceuticals. Ana¬ ucts.
lytic assays of drugs may not detect impurities or Occasionally, outside laboratories may be
errors unforeseen in formulation, whereas in used to augment the testing capacity and capa¬
vivo testing may qualitatively show a change in bility of the manufacturer. It is advisable that
a predetermined response to a specific drug dos¬ the facilities and personnel of the outside labora¬
age. tories be evaluated before they are engaged. The
The use of reference standards has been ex¬ quality control personnel of the manufacturer
tended beyond biologic assays, so that today they should evaluate and endorse the results submit¬
are required for many pharmacopeial assays and ted by the outside laboratories.
tests. This reflects the extensive use of modem
chromatography and spectrophotometry, which
require measurements relative to a reference Quality of Analytic Methodologies
standard to attain accurate and reproducible re¬ The quality of a method has to be character¬
sults. For example, a set of standards is provided ized, monitored, measured, and validated. The
for checking the reliability of apparatus used for nature of the analytic methods may be physical,
melting point determinations. There are also chemical, microbiologic, biologic, or a combina¬
pure specimens of steroids suitably diluted with tion of these types.7'® The quality of analysis is
an inert diluent for use in the chromatographic built in during its design stage, validated in its
identification of steroids. development stage, and confirmed in its utiliza¬
Reference standards are prepared and distrib¬ tion stage.
uted by the USP. A similar program providing Parameters of Quality Analysis. The se¬
international standards is maintained by the lection of an analytic method may be based on
World Health Organization, which is concerned one or more of the following quality criteria or
mainly with standards for serums, vaccines, tox¬ parameters, which serve as the foundations of a
ins, vitamins, and endocrine extracts. In gen¬ quality analysis:
eral, the critical characteristics of the specimens
selected as standards are determined indepen¬ 1. Specificity
dently in three or more laboratories.
2. Sensitivity (limit of detection)
The traditional and conventional gravimetric
and volumetric assay methods are being sup¬ 3. Linearity
plemented by newer instrumental methods.
4. Precision
Pharmaceutical analysis now includes such
techniques as partition or absorption chromatog¬ 5. Accuracy
raphy, gas-liquid chromatography, high pres¬
6. Ruggedness
sure liquid chromatography, ultraviolet and
infrared spectrophotometry, complexometry, 7. System Suitability
chelatometry, nonaqueous titrimetry, fluoro-
metry, polarography, differential scanning calo¬ These important quality parameters of an ana¬
rimetry, x-ray spectroscopy, nuclear magnetic lytic method are briefly described in this section.
resonance, autoradiography, thermogravimetric Specificity is an important quality criterion.
analysis, and mass spectroscopy. Thus, the ana¬ Analysis of a component of a mixture may inter¬
lytic work required may range from the stand- fere with other components of the mixture. If
- ardized elemental analysis of the compound to this occurs, the analytic method is nonspecific
the highly specialized and sophisticated chemi¬ for the component under investigation. With a
cal or instrumental functional group determina¬ specific method, the concentration of the com¬
tion. ponent can be completely measured regardless
Just as there are differences between samples of what other compounds are present in the
and between replicate determinations on the sample. Ideally, for chromatographic analysis, a
same sample, there are also variations between specific method should be capable of resolving
technicians, instruments, and laboratories. from the peak of interest all other components,
These variations for the most part can be meas¬ including impurities, contaminants, excipients,
ured, and their significance determined. Such and degradation products. In general, baseline
knowledge provides for the most accurate ap¬ resolution from other peaks or spots is accepted

QUALITY CONTROL AND ASSURANCE • 845

as adequate resolution for good specificity. It is dard within the acceptable assay range of the
not necessary, however, to have clean baseline method.
separation among components that are not to be Precision is a quality criterion referred to the
quantified. Furthermore, the integrity of the reproducibility of measurement within a set
peak should be verified by collecting the peak number of independent replicate measurements
fraction and chromatographing it by another sol¬ of the same property. Thus, it refers to the dis¬
vent system or chromatographic method. It can persion of a set about its central value and is
also be further verified by wavelength-ratio tech¬ generally expressed as the standard deviation of
niques for direct comparisons to a standard. a series of measurements obtained from one
Sensitivity pertains to the ease of detection. sample. Usually, the precision of a method is
Analysts usually try to develop methods in established during the development stage by the
which sensitivity has a constant value in a range multiple analyses of samples judged to be typical
as large as possible. Limit of detection gives the of the material that is to be analyzed. These
minimum concentration of a component that analyses usually do not account for any addi¬
can be detected by the analytic method. As a tional sources of variation such as day-to-day
rule, whenever a sample contains a compound fluctuation, laboratory-to-laboratory variation,
in a very low concentration, the signal from the small modification in technique, varying skill of
instrument will be small. Therefore, uncertainty analysts, undetected operational or instrumental
exists as to whether the signal comes from noise factors, and other unexpected systematic errors.
produced by the instrument, from the method, Methods used to estimate the precision within
or from the actual component to be measured. a batch suffer from certain drawbacks. The most
This gives rise to the term limit of detection. The straightforward consists in the replicate analysis
analyst should determine the lowest detectable of a few selected samples and the subsequent
quantity of major component of interest at the calculation of the standard deviation. Unless
most sensitive instrument settings. This detec¬ random sampling is used, the samples selected
tion limit is usually taken to be twice the signal- may not be representative of the batch. In any
to-noise ratio. For determining the detection analytic system, the precision of determination
limit of minor components, the analyst must varies over the concentration range of the sam¬
determine the smallest amount of contami¬ ples. This fact must be taken into account if the
nants, impurities, precursors, or degradation concentration range is wide. In a system in
products quantifiable as weight percent of major which the substance determined occurs in the
component in the presence of this major compo¬ same matrix in all the samples, the standard
nent. This limit of detection is usually taken as deviation of measurement increases with con¬
ten times the signal-to-noise ratio; however, the centration, usually as a linear function. If all the
minimum quantifiable levels of these sub¬ duplicate determinations were made within a
stances should be no more than 50% of the limit batch of analyses, the method would give an es¬
set in the specifications for these substances. timate only of the within-batch precision rather
Linearity of method gives the characteristic than of the overall characteristics of the analytic
trend of such parameters as absorbance, peak system. If the same procedure were used on
height, peak area, or response ratio as a function many successive batches, a valid estimate of the
of concentration of component to be measured. overall variance would be obtained, consisting of
At least five different concentrations of a stan¬ the sum of the within-batch variances and the
dard solution should be employed and spanned variance due to any systematic differences be¬
80 to 120% or even 50 to 150% of the expected tween batches.
working concentration range. By plotting the Table 27-26 illustrates the precision data for
concentration versus response, the linearity of the three sulfonamide assays in trisul-
the observed data points can be visualized. The fapyramidine suspensions by a stability-indicat¬
test of linearity can be accomplished by fitting ing high pressure liquid chromatographic
the data points to a curve of the form: (HPLC) method of analysis.9 Analyses were per¬
formed by two analysts over a 2-day period, and
y = mx" + b results were calculated as percentage of theory
on a weight basis. Each sample represents a
For perfect linearity, n = 1. Once the concentra¬ freshly prepared suspension, and as shown in
tion-response equation is known, one can calcu¬ Table 27-26, the relative standard deviations
late the maximum error to be expected from ranged from ±2.1 to ±3.1%.
deviations in linearity and the possible error to An example of a precision study during a
be anticipated from use of a single point stan¬ method transfer from research laboratory to rou-

846 • The Theory and Practice of Industrial Pharmacy

Table 27-26. Precision Data for Trisul- licates of a representative composite sample
fapyrirnidines in a Suspension Containing containing 18 to 24 times the amount of drug
200 mg of Each Drug per 5 ml by a Stability- needed for one assay. A separate determination
Indicating HPLC Method. of the precision of the system is made, consider¬
ing only the error attributable to the operating
Theoretic Percentage system and not the error attributable to sample
Sample Sulfadiazine Sulfamethazine Sulfamerazine handling and preparation. The measure of sys¬
tem precision is performed by repeatedly analyz¬
1 105.0 103.5 103.8 ing aliquots of a single standard solution, record¬
2 105.6 104.0 103.5 ing responses, and calculating the relative
3 106.6 104.1 103.8 standard deviation of the response.
4 100.6 99.6 102.1 Accuracy is defined as the closeness of a
5 107.6 109.6 112.2 measured value to its true value. It normally re¬
6 106.7 103.4 107.3 fers to the difference between the mean of the
7 104.7 105.3 106.4
set of results and the value accepted as the true
8 106.6 105.7 108.0
or correct value for the quantity measured. As a
Mean 105.4 104.4 105.9 rule, results of analysis of the unknown are com¬
SD ±2.2 ±2.8 ±3.3 pared with the results obtained from the analy¬
sis of standards or reference materials. The ana¬
RSD, % ±2.1 ±2.7 ±3.1
lyst should prepare six samples of drug in matrix
From Elrod, L., Cos, R. D., and Plasz, A. C.: J. Pharm. Sci., spanning 80 to 120% or even 50 to 150% of the
161:71, 1982. Reproduced with permission of the copyright expected content, assaying each of those syn¬
owner, the American Pharmaceutical Association.
thetic samples. The acceptance criterion in the
accuracy test is expressed in terms of the stan¬
dard deviation of the method as determined in
tine microbiologic laboratory for an erythromy¬ the precision test, since the deviation from the¬
cin dosage form is illustrated in Table 27-27. ory depends on the error inherent in the method
In general, the quality control laboratory de¬ itself. As acceptance criteria, recovery of drug
termines the precision of the method on six rep¬ expressed as percentage of theory must be ± 4s

Table 27-27. Comparison of Microbiologic Assay of Erythromycin Dosage Form at Two Different
Laboratories.

Concentration of Erythromycin Potency Found

Claimed Routine Laboratory Research Laboratory

Level Sample —--
Erythromycin Cone. (%) Designation Day 1 Day 2 Day 1 Day 2

80 a 77 79 79 84
b 85 77 85 86
c 80 86 70 86
d 78 80 80 80
e 83 84 78 84
f 81 79 79 87
100 a 102 108 94 120
b 105 103 108 92
c 97 110 108 102
d 101 107 115 102
e 104 102 97 106
f 98 108 105 115
120 a 130 135 115 147
b 132 118 110 140
c 133 130 124 120
d 128 127 111 140
e 131 133 117 133
f 130 130 122 126

QUALITY CONTROL AND ASSURANCE • 847

of the theoretic value at all levels where s is the the relative standard deviation is calculated to
relative standard deviation obtained in the preci¬ indicate the system’s precision as compared
sion test. The range of 4s units is intended, and with the historical data. The second part of each
preferred, to cover the additional error possibly system-suitability test is the system’s powers of
introduced in preparing the synthetic samples resolution. The most useful measurement of
for accuracy testing. such power is the calculation of the resolution
Ruggedness tests describes the influence of between two closely eluting chromatographic
small but reasonable alterations in the proce¬ peaks for which the resolution is considered crit¬
dures of the quality of analysis.10 ical. Normally, the separation between the peak
Examples of these minor variations are source of interest and a second peak eluting close to it is
and age of reagents, concentration and stability chosen as the resolution factor to be calculated.
of solutions and reagents, heating rate, ther¬ Although system-suitability tests are recom¬
mometer errors, column temperature, humidity, mended for all HPLC methods, it is suggested
voltage, fluctuation, variations of column to col¬ that they can be used in some manner for all
umn, plate to plate, analyst to analyst and in¬ analytic methods adopted for drug products.
strument to instrument, and many others. Eight With the background knowledge of specificity,
measurements suffice to investigate seven vari¬ sensitivity, linearity, precision, accuracy, and
ables when the appropriate experimental design ruggedness of an analytic method, it is relatively
is employed. The various types of interlaboratory easy to derive the confidence and reliability of
checks should be carried out to ensure that the the analytic data obtained with the method.
analyst who developed the method is not the With the use of a formal validation procedure
only one who can obtain satisfactory results and a system-suitability test, each new method
from the procedure, and that all details are writ¬ is sure to meet the same performance standards,
ten into the testing directions and are not inad¬ minimizing the problems encountered in daily
vertently omitted. With the widespread use of routine analysis and in interlaboratory method
automatic injectors for HPLC systems, it is nec¬ transfer or method change.
essary to check and validate the length of time To select an appropriate method, the analyst
for which prepared solutions or reagents are should have a thorough knowledge of the physi¬
stable. The stability of these solutions should be cochemical properties of a drug, degradation
checked over a period of 12 to 24 hours if an products, degradation mechanisms, and degra¬
automated method of running samples over¬ dation reaction rates. One can then develop a
night is practiced in the laboratory. specific method suitable for monitoring the sta¬
System-suitability tests help to answer the bility of an active ingredient or formulation. The
question, “How good and reliable is the perform¬ methodology used for kinetic studies (solid state
ance of a given analytic system on a given day?” or solution) can generally be considered scientif¬
FDA and the compendia have recommended ically suitable for monitoring decomposition.
system suitability tests for inclusion in all HPLC For the purpose of this brief presentation, sta¬
procedures.11,12 System, in this context, means bility-indicating methods are classified as elec¬
all components of the analysts, hardware, sol¬ trometric methods, solvent extraction methods,
vents, and electronics considered together. spectrophotometric methods, and chromato¬
System-suitability tests are composed of a sys¬ graphic methods.
tem’s precision measurement and a system’s Electrometric Methods. Titrimetric meth¬
powers of resolution measurement to check the ods (aqueous or nonaqueous) that can be used
performance of the analytic system on a given for the precise analysis of the active ingredient
day. System-suitability testing differs from most often do not offer the desired specificity for
method validation testing. Validation of analytic the analysis of pharmaceutical products. If the
method is generally initiated at the method de¬ decomposition products do not interfere with
velopment stage and is finalized by demonstrat¬ the titration, however, e.g., formation of non-
ing that the method is scientifically sound and basic degradation products of an organic amine
technically adequate for a particular drug. or amine hydrochloride, then one may be able to
Therefore, validation is often done only once. utilize titrimetry. Alternatively, by employing
System-suitability testing should be on a contin¬ suitable extraction procedures for eliminating
uing basis, however. possible interferences from excipients and/or
The measurement of system precision is most decomposition products, one can use titrimetry
easily made by employing replicate aliquots of for monitoring the stability of products.
the same solution. Signal responses such as Solvent Extraction Methods. It is possible
peak height, peak area,, and response ration de¬ to extract acidic, neutral, or basic compounds
rived from these aliquots are determined, and selectively from organic solvents on the basis of

848 • The Theory and Practice of Industrial Pharmacy

the partition behavior of their ionized and un¬ Table 27-28. Some Applications of HPLC to
ionized species. The USP/NF compendia utilize Pharmaceutical Products
a double-extraction procedure as the preferred
method of analysis for organic nitrogeneous Mode of HPLC Drug Substance or Type of Product
bases. This procedure provides some degree of
Anion exchange Ampicillin, barbiturates, prosta¬
specificity, because it may possibly remove com¬ glandins A2 and B2
pounds that are neutral or acidic or that have Cation exchange Imidazolines, tetracyclines, tri-
more polar substituents that could arise upon sulfapyrimidines, xanthines
degradation. It does not, however, eliminate iso¬ Anion and cation Water-soluble vitamins, anal-
mers or other closely related basic substances. exchange gesics such as aspirin and
Therefore, the validity of this approach for moni¬ acetaminophen
toring stability should be demonstrated prior to Absorption Benzodiazepines, carbamazepine,
its utilization. phenytoin, phenobarbital,
Spectrophotometric Methods. Direct riboflavin
spectrophotometric determination such as color¬ Partition Corticosteroids
imetric analysis or ultraviolet determination is Reversed phase Ergotamine, nortriptyline, pro-
widely used in pharmaceutical analysis but usu¬ partition caine, synthetic estrogens
ally lacks selectivity. The selectivity or specific¬ Ion exchange and Androsterone and dehydroepi-
ity can be improved through separation or by reversed phase androsterone
reaction of an appropriate functional group. For partition
example, the reactions that produce a colored
product are generally measured in the visible
region of the spectrum. As examples of colori¬
metric analysis, carboxylic acid derivatives such
as lactams, amides, lactones, and esters are con¬ ambient or low temperatures. Of various chro¬
verted to the corresponding hydroxamic acids by matographic techniques employed in stability
reacting with hydroxylamine hydrochloride in evaluations, GLC and HPLC provide the most
an alkaline medium. The hydroxamic acid is useful quantitative information.
then allowed to react with ferric chloride in the Stability-Indicating Methods. One of the
presence of dilute acid to produce red-violet fer¬ major characteristics for a quality analytic
ric hydroxamate for colorimetric determination. method for pharmaceuticals is its ability to de¬
Owing to its limited sensitivity, IR analysis is termine distinctively the parent compound from
primarily used for identification of decomposi¬ the degradation products. The current trend in
tion products and has found few quantitative stability-indicating methods is based on direct
applications in stability evaluation. An increas¬ chromatography or derivatization chromatogra¬
ing number of applications are being found for phy. These approaches are used extensively in
nuclear magnetic resonance (NMR) spectros¬ stability evaluation of pharmaceutical products.
copy, since it offers specificity along with sim¬ When it is not possible to determine the intact
plicity of operation, hut it, too, lacks sensitivity drug direcdy because of interfering substances,
and precision. it is desirable to precede the final analysis with a
Chromatographic Methods. Many sta¬ separation procedure. This step can be solvent
bility-indicating methods entail some form of extraction or chromatographic separation.
chromatography: paper, thin-layer (TLC), col¬ The USP and NF provide yet another ap¬
umn, gas (GLC), and liquid (HPLC). The latter proach to evaluating stability. This approach
two techniques not only offer sharp separation entails monitoring the content of a decomposi¬
but also provide precise methods of quantitation. tion product, e.g., salicylic acid in aspirin and
Less than a decade ago, paper chromatography disulfonamide in hydrochlorothiazide, while uti¬
was used extensively in pharmaceutical analy¬ lizing an assay for the drug itself that may not be
sis. This technique has rapidly given way to totally stability-indicating. In some ways, this
TLC, GLC, and HPLC. Of these three tech¬ approach provides a more rigorous control of
niques, HPLC has the most widespread applica¬ product stability. In the examples cited, the
tion. Several applications of recent interest are presence of 1 to 4% of a decomposition product
summarized in Table 27-28. With this tech¬ render the item unsuitable; thus, much tighter
nique, a compound can be chromatographed in limits are being applied to these products as
several ways, and most important, the volatility compared with those that must meet the rubric
required for GLC is not a limitation. The prob¬ limits for potency. These examples also illus¬
lems due to thermal instability are not encoun¬ trate that different standards are used to define
tered because most separations are carried out at product stability.

QUALITY CONTROL AND ASSURANCE • 849

 Automated Continuous System flow systems and operating under a variety of
conditions. On the other hand, an analytic
for Assay Procedures scheme devised for a particular automated sys¬
Automation usually enhances the quality, tem may not be readily transposable for use ei¬
quantity, and efficiency of an operation. Its in¬ ther with a manual procedure or with other
troduction into the analytic laboratory has dra¬ types of automated equipment.
matically changed the traditional look, capabil¬ Compendial methods for testing drugs are
ity, precision, and acceptability of most of our based largely on ultraviolet absorption measure¬
conventional analytic disciplines. The use of ments. After extraction of dilution, the sample
automated instrumentation of pharmaceutical must exhibit maxima and minima at the same
analysis, data handling, and data storage is cer¬ wavelengths as those of a similar solution of the
tainly on the rise. Within the last decade, and reference standard, and the respective wave¬
especially during the last few years, great strides length of maximum absorption should not differ
have been made in a diversity of instrumental significantly. Based on this principle, the Auto¬
approaches to automated chemical, microbio¬ analyzer, an automated continuous system for
logic, enzymatic, and other assays. Since auto¬ repetitive spectral scanning, was developed.
mated continuous testing has great potential use This equipment is capable of accepting tablet,
for routine testing, it is not surprising that some capsule, powder, solution, and suspension sam¬
pharmaceutical manufacturers are initiating ples for analysis as required. The Autoanalyzer
automated control methods that are capable of is, in fact, a mechanical chemist that can auto¬
sampling, analyzing, and accepting or rejecting. matically perform designated tests at a much
The use of these methods permits the analysts greater speed than a trained analyst. It has been
to cope with the increasing number of samples utilized to perform many chemical microbio¬
required to ensure product quality. Automated logic, biologic, and clinical tests, as well as to
continuous assay procedures enhance the relia¬ implement production in-process control.
bility of data and provide immediate feedback on Besides the Autoanalyzer produced by Tech-
process control with tremendous savings in nicon Company, there are other automated sys¬
time. tems for drug analysis, such as Titralyzer from
In the quality control laboratory, where a suf¬ Fischer Scientific Company. Recent advances in
ficiently large number of similar dosage forms or automation and computerization have improved
dosage units must be subjected routinely to the the efficiency and economics of laboratory per¬
same type of examination, automated methods formance. For example, numerous companies
of analysis provide for far more efficient and pre¬ have developed dedicated gas-liquid or high effi¬
cise testing than manual methods. Such auto¬ ciency liquid chromatographic systems that per¬
mated methods have been found especially use¬ mit on-line sample analysis and data handling.
ful in testing the content uniformity of tablets One such system utilizes an automatic sample
and capsules and in facilitating methods requir¬ injector, which is time-sequenced and con¬
ing precisely controlled experimental condi¬ nected to a gas-liquid chromatograph that has
tions. Many manufacturing establishments, as been preset for a specific analysis. The signal
well as the- laboratories of regulatory agencies, from the gas-liquid chromatographic detector is
have found it convenient to utilize automated digitized, and the computer automatically prints
methods as alternatives to pharmacopeial meth¬ out such parameters as retention time, area
ods. under the curve, and concentration of the drug.
As a general practice, before an automated Such automated data processing provides multi¬
method for testing an article is adopted as an ple analysis with minimum supervision and
alternative, it is advisable to ascertain that the with a savings in time. Dedicated gas-liquid
results obtained by the automated method are chromatographic systems are offered by such
equivalent in accuracy and precision to those companies as Hewlett-Packard and Waters Asso¬
obtained by the prescribed pharmacopeial ciates, Inc. These and other suitable automated
method. It is necessary to monitor the perform¬ procedures have been developed for the analysis
ance of the automated analytic system continu¬ of phenothiazine derivatives, erythromycin, tol¬
ally, by assaying standard preparations of known butamide, vitamins A and B6, amitriptyline hy¬
composition that have been frequently inter¬ drochloride, and various steroid dosage forms.
spersed among the test preparations. As previously discussed, HPLC is one of the
Many of the manual methods given in the most important analytic techniques to be given
pharmacopeia can be adapted for use in semi- various degrees of automation in recent years.
automated or fully automated equipment, incor¬ Its proven versatility and fast-growing ability to
porating either discrete analyzers or continuous supply fundamental information and quality

850 • The Theory and Practice of Industrial Pharmacy

control data have stimulated the development of sure that batches of the released product are
a completely automated HPLC system. In addi¬ maintained within specification limits through¬
tion, the great advances in minicomputer sci¬ out their stated period of shelf storage. Stability
ence and microprocessor technology, such as testing of the product during development and
Technicon Solid Prep Sample II and Peristaltic scale-up stages is employed to define the recom¬
Pump III, have provided the extra dimension mended expiration date and storage conditions
needed to automate fully most of the hardware for inclusion on the label and to establish a prod¬
components and flow-of-operation and data- uct stability profile. Therefore, quality control
management processes. The system has proved stability testing after product is released to the
to be successful for the routine analyses of fat- market is for the verification and confirmation of
soluble vitamins in more than nine different this profile.
multivitamin formulations. The productivity has The stresses and hazards to which products
been at least three times greater than the con¬ are exposed during their passage from the man¬
ventional manual procedures. The continuous ufacturing plant to the distribution chain and to
flow analyses with automated HPLC systems are the consumer can be environmental, mechani¬
especially useful in content uniformity analyses, cal, or contaminant in nature. Environmental
which require large volumes of samples. When stresses such as extreme temperatures, high
the microprocessor is properly programmed, the moisture, intense light, and radiation are com¬
system can be easily adapted for reliable, mon, and mechanical hazards such as vibration,
around-the-clock, unattended operation in each sudden drop, inversion, shock, and deformation
specific application. are not unusual. Elevated temperature, espe¬
Microbiologic assays have always been time- cially if coupled with high relative humidity, is
consuming and tedious. Following the success¬ known to cause and accelerate physical deterio¬
ful assay in fermentation media of streptomycin ration and chemical degradation. Mechanical
and penicillin (the first two antibiotics whose stresses have shown to cause such problems as
assay was automated), a variety of automated liquid spillage, tablet chipping, and package de¬
systems have been devised and applied success¬ formation and breakage. Therefore, quality con¬
fully in turbidimetric and respirometric assays. trol of the marketed product does not stop at the
For example, plates used in the microbiologic final release of the product from the manufac¬
assay of several antibiotics are being prepared turing site. A reserve sample of at least two
and read automatically, with the data recorded times the quantity of product required to con¬
magnetically and the results analyzed and re¬ duct all the quality control tests performed on
corded by computer. the batch of product should be retained for at
Among the requirements in the current USP/ least one year after the expiration date.
NF is a content uniformity test for tablets and Section 505-(b) of the CFR law as stated on
capsules containing 50 mg or less of active in¬ the New Drug Application Form specifically de¬
gredient. In the event that general strength dos¬ scribes the requirements for stability informa¬
age forms of the active ingredient are available tion as:
below and above 50 mg per tablet or capsule,
then all strengths require a content uniformity “A complete description of, and data derived from
test. It is only through the use of automated pro¬ studies of the stability of, the drug, including informa¬
cedures that the analytic burden is manageable. tion showing the suitability of the analytical methods
One may expound any number of good rea¬ used. Describe any additional stability studies under
way or contemplated. Stability data should be submit¬
sons to automate laboratory procedures. Auto¬
ted for any new drug substance, for the finished dos¬
mated systems may enable a laboratory to pro¬
age form of the drug in the container in which it is to
vide new services more quickly, with increased be marketed, and if it is to be put in solution at the
reliability, in greater abundance, or at lower cost. time of dispensing, for the solution to be prepared as
Any of these benefits may justify consideration directed. State the expiration date(s) that will be used
of an automated instrument. In any case, the on the label to preserve the identity, strength, quality,
total economic effect must be considered. and purity of the drug until it is used. If no expiration
date is proposed, the applicant must justify its ab¬
sence.”
Associated Activities
Stability Studies. There are legal, moral, Under the regulations for antibiotic drugs, an
economic, and competitive reasons, as well as expiration date is required for the product label
reasons of safety and efficacy, to monitor, pre¬ of any antibiotic drug. These regulations are de¬
dict, and evaluate drug product stability. The tailed in the Antibiotic Application, FD Form
aim of quality control stability testing is to en¬ 1675 (1/71), as follows:

QUALITY CONTROL AND ASSURANCE * 851

“A completed description of, and data derived from shelf-life stability of the product on production
stability studies of the potency and physical character¬ batches by taking the first several batches of the
istics of the drug, including information showing the product or by taking batches at certain intervals
suitability of the analytical methods used. Describe of time during the first year of manufacture, and
any additional stability studies underway or contem¬
in subsequent years at least one additional pro¬
plated. Stability data should be submitted for any new
duction batch, and subjecting them to extended
antibiotic, for the finished dosage form of the drug in
the container including a multiple-dose container in shelf-life testing at ambient storage conditions.
which it is to be marketed, and if it is to be put into At each sampling, which is generally performed
solution at the time of dispensing, for the solution pre¬ on a yearly or semiannual basis, the samples are
pared as directed. The expiration date needed to pre¬ tested for physical, chemical, and biologic prop¬
serve the identity, strength, quality, and purity of the erties according to the standards set forth in the
drug until it is used.” monographs of the official compendia or to the
specifications established by the manufacturer.
The most desirable stability data are from ac¬ The stability of the product should be evalu¬
tual shelf-life studies using products in the con¬ ated in the container in which it is marketed.
tainer-closure systems stored under labeled con¬ The expiration date and storage conditions
ditions. For introducing new products to the should appear on the label of the product. Expe¬
market, however, or for making material rience in the pharmaceutical industry has
changes in the process, formula, or container- shown that there can be a considerable delay
closure system of existing products, one cannot between the manufacture of a product and its
wait until all the needed stability data at room eventual utilization by the consumer. To avoid
temperature are generated. Therefore, appropri¬ deterioration of drugs and finished products
ately designed and executed short-term (e.g., during storage, the adequacy of warehouse and
3-month) accelerated stability studies have been other storage facilities requires proper attention.
accepted by the FDA as data bases for use in To assist in assuring the stability of the dosage
extrapolating longer room-temperature expira¬ forms during transportation and storage, indica¬
tion dates. Use of accelerated data is obviously tion of the proper storage condition should ap¬
not a substitute for actual shelf-life study. It is a pear on the label.
means of predicting shelf-life of a product based Since 1979, expiration dates have been re¬
on scientific principles and guided by experi¬ quired on prescription and over-the-counter
ence. This method of shelf-life prediction based drug products with limited exceptions. The FDA
on short-term accelerated stability data is cur¬ considers a product misbranded when it is la¬
rently well-utilized by pharmaceutical scientists. beled with an expiration date not supported by
An example is demonstrated in Table 27-29. suitable stability data. The expiration date of a
The manufacturer is asked to confirm the drug product must appear on the immediate

Table 27-29. Comparison of Shelf-life Predicted from Short-Term Accelerated Stability Study and
Shelf-Life Obtained by Long-Term Room Temperature Study

Shelf-Life Prediction, t (in Years)

10%

Extrapolated from
Short-Term Calculated from
Apparent Heat Accelerated Long-Term Room
of Activation Stability Testing Temperature
Parenteral Formulation (kcal/mole) Data Stability Data

Steroid A 22.1 3.4 3.4

Antihypertensive A 18.6 9.0 9.4
Antihypertensive B 17.4 11.5 18.5
Local anesthetic 30.4 14.6 14.6
hydrochloride
Diagnostic agent 26.3 20.0 28.2
Antidepressant 17.3 1.5 1.5
Antibiotic S (bio. assay) 28.5 1.3 1.3
Antibiotic V (chem. assay) 25.1 2.9 3.0
Sulfonamide G (suspension) 20.4 9.0 10.0

852 • The Theory and Practice of Industrial Pharmacy

 container and also on the outer package. When because of various defects or shortcomings, as
single dose containers are packaged in individ¬ discussed in Section 501 of the Federal FDC
ual cartons, however, the expiration date may Act. According to the law, a drug is considered
properly appear on the individual carton instead adulterated if it does not meet the quality and
of on the immediate product container. purity characteristics it is represented to pos¬
Furthermore, the current GMP regulations sess.
provide specific information as to the stability According to Section 502 of the Federal FDC
characteristics of pharmaceutical products and Act, the major reason for considering a drug to
their expiration dating. These GMP regulations be misbranded is the mislabeling of the product.
indicate that the Commissioner of the FDA con¬ To safeguard the manufacturer from marketing
cludes, “The interests of the consumers must be adulterated or misbranded products, the estab¬
served by the establishment of valid expiration lishment of a total quality control system con¬
dates for all products, and Sections 211.166 of cerned with the dosage form, package, and label¬
the GMP regulations set forth basic guidelines ing prior to release for distribution is essential.
for stability studies for all drugs, which studies Maintenance, Storage, and Retrieval of
will be used to establish expiration dates.” Records. The proper control of records (master
Product Identification Systems. To en¬ formula, batch production, and packaging rec¬
sure the quality of a product, the unit doses are ords) in manufacturing operations has been dis¬
(1) individually packaged and labeled and cussed in a previous section of this chapter.
(2) imprinted with an assigned code for the pur¬ Suitable maintenance storage and retrieval of
pose of identification. The first procedure is usu¬ records for dosage form control are mandatory in
ally termed the unit dose packaging concept. assuring product quality.
Single unit doses for medication—tablets, cap¬ Product distribution records should be orga¬
sules, or parenterals—are individually sealed in nized systematically for each manufactured
packages that have been imprinted with com¬ product. Complete records of the distribution of
plete identifying data. Thus, the danger of error each batch of product must be maintained in a
is substantially reduced. manner that would facilitate its recall if neces¬
The second procedure in identifying the prod¬ sary. Such records should include the batch or
ucts is called the unit code system. Various tech¬ control numbers identifying the batch of product
niques have been employed for this method. distributed, the date and quantity shipped, and
The codes vary in complexity, for example, a the name and address of the consignee. Such
system adopts alphabetical and numerical com¬ records should be retained for at least two years
binations. A drug product code composed of nine after the batch of product has been distributed or
characters to be used by pharmaceutical manu¬ at least one year after the drug’s expiration date,
facturers for inclusion in the National Drug whichever is longer.
Code Directory has been developed and has For the vast amounts of records maintained in
been used by the FDA to establish a uniform a quality assurance program, the storage and
code system for dosage forms. The nine-charac¬ retrieval of these records when needed can be
ter code would identify the labeler, the dosage time-consuming if done manually. The applica¬
form, the strength of the product, and the num¬ tion of computer systems in the storage and re¬
ber of product units in the package. In the case trieval of data in this area is inescapable.
of tablets or capsules, those parts of the code In general, records of data converted to digi¬
identifying the drug and its strength would be tized form are stored on computer tapes, cards,
used on each unit of the dosage form. Interest¬ or discs, or in case storage. The choice of storage
ingly, any product not identified would be medium depends on the volume, pattern of use,
termed misbranded unless compliance were type of data, and cost factors. Case memory is
impractical and the FDA granted an exemption. the fastest, most expensive and most accessible
Adulteration, Misbranding, and Counter¬ type of memory. Disc storage is available for
feiting. An adulterated, misbranded, or coun¬ large volumes of data, and its almost random
terfeited drug is a fraud to the public. Such prod¬ access features are particularly useful. Magnetic
ucts can seriously endanger the health and tape is compact and provides relatively cheap
safety of the person taking the medication, since storage. The main disadvantage of tape is that if
there is no guarantee that the ingredients are the data to be retrieved does not occur in the
safe, of highest quality, or of labeled potency. A same sequence as that in which it is stored on
situation of this nature may mislead the physi¬ the tape, the whole tape must be searched for
cian because his patient’s response may differ the requested information.
from the response expected. The importance of batch or control numbers
A drug product may be deemed adulterated must be re-emphasized. The establishment of

QUALITY CONTROL AND ASSURANCE • 853

these identification numbers for the products all levels of product distribution, from manufac¬
manufactured is the direct key by which the en¬ turer to ultimate consumer.
tire quality assurance program in production, Adverse Effects. Quality of marketed prod¬
control, storage, and distribution can be readilv ucts can be further ensured if competent per¬
unlocked. As an indirect assurance of the prod¬ sonnel are assigned to evaluate the significance
uct quality to the consumer, this identification and severity of each side reaction or adverse ef¬
number not only opens the correct file without fect reported by the physician who prescribes
delay should the need arise, but also facilitates the medicinals, the drug surveillance group of
recall of that particular product from the market the hospital, published scientific results, and
should it become necessary. even the regulatory agency. An effective product
Complaints. Suitable systems should be pro¬ information system should be established to
vided to investigate and follow up the com¬ evaluate and accumulate these reports on the
plaints regarding deteriorated, adulterated, mis¬ safety, potency, adverse reactions, clinical side
branded, or counterfeited products. Often, effects, and drug abuse problems of the mar¬
useful information can be generated from de¬ keted product and to prepare appropriate replies
tailed investigation of the reason for complaint; and reports in this area.
the investigation may be physical, chemical, or
biologic in nature. Complaints should be re¬
corded and carefully evaluated by competent Summary
and responsible personnel, and the complaint The professional, social, and legal responsibil¬
files should indicate the action taken. ities that rest with the pharmaceutical manufac¬
Return of Goods. Inevitably, a certain frac¬ turers for the assurance of product quality are
tion of distributed product is returned for one tremendous. It is only through well-organized,
reason or another. Returned products should be adequately staffed, and accurately performed
properly handled by capable individuals and cor¬ process and dosage form control before, during,
rectly recorded in a manner that prevents con¬ and after production that adequate quality as¬
fusion and the possibility of errors. On receipt, surance of the product can be achieved. It
each should be listed on an appropriate form, should be realized that no amount of dosage
giving the name and address of the sender, the form testing and control can maintain and as¬
batch or control numbers of the returned prod¬ sure product quality unless good manufacturing
uct, the reason for returning the product, and practices are implemented systematically and
the estimated condition of the product. The process control is practiced vigorously. Product
product should then be analyzed by physical, quality must be built into, and not merely tested
chemical, or biologic methods whenever possi¬ in, the product.
ble and stored in an orderly manner pending is¬ The pharmaceutical manufacturer assumes
suance of credit and a decision for disposal. the major responsibility for the quality of his
Recall Procedures. The need to establish an products. The manufacturer is in a position
effective drug recall system by the pharmaceuti¬ (1) to control the sources of product quality vari¬
cal manufacturers is evident inasmuch as hun¬ ation, namely materials, methods, machines,
dreds of recalls are made annually. In general, and men, (2) to ensure the correct and most ap¬
product recalls may be initiated by the manufac¬ propriate manufacturing and packaging prac¬
turer, by the regulatory agency, hy government tices, (3) to assure that the testing results are in
seizure through the courts, or by the manufac¬ compliance with the standards or specifications,
turer at the request of the regulatory agency. and (4) to assure product stability and to per¬
The last category applies to the majority of re¬ form other activities related to product quality
calls. If the products to be recalled have been through a well-organized total quality assurance
distributed only to the warehouses of the manu¬ system.
facturer or the distributor, the hazard to the pub¬ For the total quality assurance system to func¬
lic health may not be serious. The recall can be tion effectively, certain basic operational rules
effected rapidly and easily. When recall involves should be established and should always prevail.
the local pharmacist, the physician, or the pub¬ First, control decisions must be based solely on
lic, however, the problem becomes complicated, considerations of product quality. Second, the
and complete recall may be hampered. It then operation must adhere rigidly to the established
becomes necessary to enlist the aid of public standards or specifications as determined by
communication systems to reach the consumer. systematic inspection, sampling, and testing,
An effective system for product recall requires, and should constantly strive for improving the
in addition to the efforts of pharmaceutical man¬ levels of the current standards or specifications.
ufacturers, a careful system of record-keeping at Third, the facilities, funds for personnel, and

854 • The Theory and Practice of Industrial Pharmacy

environment necessary for personnel to perform (MIL-STD-414). Superintendent of Documents, U.S.
their responsibilities effectively should be ade¬ Government Printing Office, Washington, DC, June
1957, and Notice 1 of May 1968.
quately provided. Last but not least, the control
4. Military Standard Sampling Procedures and Tables
decisions should be independent administra¬ for Inspection by Attributes fMIL-STD-105-D). Su¬
tively, and they must not yield to, or be overruled perintendent of Documents, U.S. Government Print¬
by, production or marketing personnel under ing Office, Washington, DC, April 1963, Notice 1 of
any circumstances. Because the control decision November 1963, and Notice 2 of March 1964.
can involve the health of the consumer and the 5. Breunig, H. E. and King, H. P.: J. Pharm. Sci.,
51:1187, 1962.
reputation of the manufacturer, the climate nec¬ 6. Dodge, H. L.: Ann. Math. Statistics, 14:264, 1962.
essary for making judicious decisions is essen¬ 7. Zarembo, J. E., J. Assoc. Off. Anal. Chem., 65:542,
tial. In times of major disagreement, the control 1982.
decisions should be subjected to review only at 8. Kateman, G., and Pijpers, F. W.: Quality Control in
the highest level of management. Analytical Chemistry. Wiley-Interscience, New York,
1981.
9. Elrod, L., Cox, R. D., and Plasz, A. C.: J. Pharm. Sci.,
References 71:161, 1982.
10. Youden, W. J.: Statistical Techniques for Collabora¬
1. Noel, R. H.: Indus. Quality Control, 7:14, 1950. tive Tests. Association of Official Analytical Chem¬
2. Grant, E. L: Statistical Quality Control 3rd Ed. ists, Washington, DC, 1972.
McGraw-Hill, New York, 1964. 11. Roman, R.: Pharmacopeial Forum, 8:2237, 1982.
3. Military Standard Sampling Procedures and Tables 12. Guidelines for the Analytical Validation of HPLC
for Inspection by Variables for Percent Defective Method. Pharmacopeial Forum, 9:2789, 1983.

QUALITY CONTROL AND ASSURANCE • 855

 28
Drug Regulatory Affairs
WILLIAM R. PENDERGAST and RAYMOND D. McMURRAY*

The laws and regulations governing the pharma¬ mals; and (C) articles (other than food) intended to
ceutical industry were adopted to protect the affect the structure or any function of the body of man
consuming public by attempting to provide or other animals; and (D) articles intended for use as a
component of any article specified in clause (A), (B),
drugs of consistent quality, purity, and efficacy.
or (C); but does not include devices or their compo¬
The Federal Food, Drug and Cosmetic Act (the
nents, parts, or accessories.
Act) is a living document in that it is amended Label. Sec. 201(k):3 The term “label” means a dis¬
frequendy and interpreted constantly.1 The Act play of written, printed, or graphic matter upon the
may be imperfect, but careful attention to its immediate container of any article; and a requirement
provisions plus an effort of good faith by all per¬ made by or under authority of this Act that any word,
sons concerned with drug manufacturing can statement, or other information appearing on the label
produce the type of product for which the Act shall not be considered to be complied with unless
and its regulations strive. such word, statement, or other information also ap¬
Even though the applicable laws and regula¬ pear] s] on the outside container or wrapper, if any
there be, of the retail package of such article, or is
tions may change with regard to specifics, there
easily legible through the outside container or wrap¬
are, nonetheless, many constants applicable
per.
generally. This chapter serves as an overview of Labeling. Sec. 201(m):4 The term “labeling”
some of the more important laws and regula¬ means all labels and other written, printed, or graphic
tions. matter (1) upon any article or any of its containers or
The text describes the Federal Food, Drug and wrappers, or (2) accompanying such article.
Cosmetic Act, treats briefly other Federal acts New Drug. Sec. 201(p):s The term “new drug”
and regulations bearing on pharmaceutical means—(1) any drug (except a new animal drug or an
manufacturing, looks at the structure, powers, animal feed bearing or containing a new animal drug)
the composition of which is such among experts quali¬
and duties of the Food and Drug Administration
fied by scientific training and experience to evaluate
(FDA), describes state and local laws and regula¬
the safety and effectiveness of drugs, as safe and ef¬
tions, and finally, covers the protection of indus¬ fective for use under the conditions prescribed, rec¬
trial property and product liability. ommended, or suggested in the- labeling thereof, ex¬
cept that such a drug not so recognized shall not be
deemed to be a “new drug” if at any time prior to the
Definitions enactment of this Act it was subject to the Food and
The terms most commonly used in this chap¬ Drugs Act of June 30, 1906, as amended, and if at
ter are defined as they are in the Act: such time its labeling contained the same representa¬
tions concerning the conditions of its use; or (2) any
Drug. Sec. 201(g)(1):2 The term “drug” means drug (except a new animal drug or an animal feed
(A) articles recognized in the official United States bearing or containing a new animal drug) the compo¬
Pharmacopoeia, official Homeopathic Pharmacopoeia sition of which is such that such drug, as a result of
of the United States, or official National Formulary, or investigations to determine its safety and effective¬
any supplement to any of them; and (B) articles in¬ ness for use under such conditions, has become so
tended for use in the diagnosis, cure, mitigation, treat¬ recognized, but which has not, otherwise than in such
ment, or prevention of disease in man or other ani- investigations, been used to a material extent or for a
material time under such conditions.
New Animal Drug. Sec. 201(w):6 The term “new
* Deceased. animal drug” means any drug intended for use for ani-

856
mals other than man, including any drug intended for transportation of adulterated or misbranded or
use in animal feed but not including such animal poisonous or deleterious foods, drugs, medi¬
feed—(1) the composition of which is such that such cines, and liquors and for regulating traffic
drug is not generally recognized, among experts quali¬ therein.” This was the first concept of regulating
fied by scientific training and experience to evaluate
the introduction into interstate commerce of
the safety and effectiveness of animal drugs, as safe
unfit foods and drugs and was based on the
and effective for use under the conditions prescribed,
recommended, or suggested in the labeling thereof; Commerce Clause of the Constitution of the
except that such a drug not so recognized shall not be United States granting power to Congress “to
deemed to be a “new animal drug” if at any time prior regulate commerce with foreign nations, and
to June 25, 1938, it was subject to the Food and Drug among the several states.”8 The concept of mis¬
Act of June 30, 1906, as amended, and if at such time branding as well as adulteration thus was intro¬
its labeling contained the same representations con¬ duced into the law, and violation again was sub¬
cerning the conditions of its use; or (2) the composi¬ ject to seizure and confiscation.
tion of which is such that such drug, as a result of Even though the 1906 Act was a great step
investigations to determine its safety and effective¬
forward, it soon became apparent that prohibi¬
ness for use under such conditions, has become so
recognized but which has not, otherwise than in such
tions in the law were not sufficiently stringent.
investigations, been used to a material extent or for a The ever-expanding industrial economy, includ¬
material time under such conditions; or (3) which ing the practice of pharmacy on an industrial
drug is composed wholly or partly of any kind of peni¬ scale, made it apparent that even though
cillin, streptomycin, chlortetracycline, chlorampheni¬ amendments could be passed to fill specific
col, or bacitracin, or any derivation thereof, except gaps, there were areas requiring further con¬
when there is in effect a published order of the Secre¬ trols. Although the law prohibited crude adulter¬
tary declaring such drug not to be a new animal drug ation and misbranding of drugs, its less than
on the grounds that (A) the requirement of certifica¬
precise language did not provide a suitable vehi¬
tion of batches of such drug, as provided for in sec¬
cle for policing medical claims. For instance, an
tion 512(n), is not necessary to insure that the objec¬
tives specified in paragraph (3) thereof are achieved attempt was made in 1912 to plug this loophole
and (B) that neither subparagraph (1) nor (2) of this by an amendment prohibiting any false state¬
paragraph (w) applies to such drug. ment of curative or therapeutic effect on the la¬
Animal Feed. Sec. 201(x):7 The term “animal beling of drugs. This effort was thwarted when it
feed,” as used in paragraph (w) of this section, in sec¬ was held that that language required a showing
tion 512, and in provisions of this Act referring to such that there was fraudulent intent in making the
paragraph or section, means an article which is in¬ claim. Simply proving a medical claim to be false
tended for use for food for animals other than man and
was insufficient.
which is intended for use as a substantial source of
Another important defect of the 1906 Act was
nutrients in the diet of the animal, and is not limited
to a mixture intended to be the sole ration of the ani¬
that it did not require testing of new drug prod¬
mal. ucts to show their safety prior to marketing.
Spurred on by several unfortunate instances,
some involving deaths, due at least in part to the
Brief History of the Federal lack of pretesting, the current law was enacted
on June 27, 1938; the Federal Food, Drug and
Food, Drug, and Cosmetic Act Cosmetic Act. This is the basic federal law under
Approximately 100 years after its founding, which foods, drugs, medical devices, diagnostic
during the later phases of Reconstruction follow¬ products, and cosmetics are regulated today.
ing the Civil War, the Congress of the United Now, more than 45 years later, that Act begins to
States came to realize that all matters of public look like a patchwork quilt after many amend¬
health and safety could not be lodged solely in ments through the years, which have affected
the states, and that certain measures had to be both substance and procedure.9 Incidentally, the
taken to protect the population in these vital 1938 Act dropped its concern with liquor.
areas. On August 30, 1890, there was enacted a The 1938 Act contained the first “new drug”
law prohibiting the importation into the United provisions, which required that drugs not gener¬
States of adulterated or unwholesome food, ally recognized as safe, by experts qualified to
drugs, or liquors. Thus began the federal inter¬ make that judgment, under the conditions of
est in regulating unwholesome consumer prod¬ use stated on the label, had to be marketed
ucts. under a procedure by which a “New Drug Appli¬
In 1906, realizing the limitations of a statute cation” (NDA) was filed. The NDA had to con¬
concerned only with the importation of unfit tain convincing evidence to show that the drug
foods, drugs, and liquors, Congress passed the was safe for its intended purpose. The Act also
Wiley Act to prevent “the manufacture, sale, or provided the following;

DRUG REGULATORY AFFAIRS • 857

1. The label of each drug had to state the name of Kefauver-Harris Amendments
each active ingredient, and the amount of certain
specific substances, whether active or not, enu¬ The Drug Amendments of 1962 amended the
merated in the Act. basic 1938 Act in an attempt to establish
stronger controls over research manufacturing,
2. Therapeutic claims that were false or misleading
advertising, promotion, sale, and use of drugs,
were not actionable without a showing of fraudu¬
lent intent. and to ensure their quality, safety, and effective¬
ness.10
3. The manufacture and sale of devices were brought
under the law.
4. The Government was given limited authority to New Drugs
make factory inspection to ensure compliance with
the law. Probably the most significant provisions of the
1962 Drug Amendments relate to “new drugs.”
5. Cosmetics were brought under the law and were
The definition of a “new drug” was expanded
required to be nondangerous, and properly labeled
beyond that of the original 1938 definition, for
and packaged.
which lack of general recognition by qualified
Since 1938, the Act has carried a provision experts as to a drug’s safety for its intended pur¬
that the label of a drug must bear adequate di¬ pose was the sole criterion. Now the test was
rections for use. It became apparent in practice, that unless it was generally recognized by such
however, that certain drugs and drug products experts to be both safe and effective for its in¬
of necessity had to be administered by or under tended purpose, the product must seek approval
the direction of a licensed practitioner, because under the New Drug Application procedure set
of the inability of a layman to diagnose his condi¬ forth in the Act at Section 505. There was also
tion, choose an effective treatment, and recog¬ introduced into the law the concept of “substan¬
nize a cure or mitigation. Many products were so tial evidence of effectiveness,” which was de¬
restricted, but it was not until the Durham- fined to mean:
Humphrey Amendment of 1951 that the con¬
cept of a “prescription drug” was introduced into . . . adequate and well-controlled investigations, in¬
cluding clinical investigations, by experts qualified by
the Act. The Amendment was, in fact, an excep¬
scientific training and experience to evaluate the ef¬
tion to the provision that all drugs must bear fectiveness of the drug involved, on the basis of which
adequate directions for use on their labels. A it could fairly and responsibly be concluded by such
label bearing the so-called prescription legend, experts that the drug will have the effect it purports or
CAUTION, FEDERAL LAW PROHIBITS DIS¬ is represented to have under the conditions of use pre¬
PENSING WITHOUT PRESCRIPTION, by dint scribed, recommended, or suggested in the labeling or
of this exception, was deemed to bear adequate proposed labeling thereof.11
directions for use. The sale of these had to be
restricted to an order by a licensed practitioner, The Federal Food, Drug and Cosmetic Act, as
and the labeling on or within the package had to now written, prohibits the interstate shipment of
have adequate information for use from which a new drug that is not covered by an approved
such practitioner might safely prescribe the new drug application, unless such shipment is
drug. made for investigational purposes and is in ac¬
In the years immediately following World cordance with the regulations governing the use
War II, pharmaceutical research expanded rap¬ of investigational drugs, which are designed to
idly, and in ever-increasing numbers, more obtain evidence demonstrative of the safety and
drugs aimed at specific disease, primarily pre¬ effectiveness of an investigational pew drug for
scription products, became available. With the the purposes for which it is intended to be
great strides in research, production, and mar¬ used.12
keting in the pharmaceutical industry, there A drug may be considered “new” because of
grew an increasing concern among the federal its composition, its use, its dosage, or its dosage
lawmakers with the problem of the adequacy of form. It can readily be understood that a drug
procedures employed in the testing and distribu¬ that contains as its active ingredient a new
tion of these new drug products. In particular, chemical entity would be considered to be a new
there was concern for proof of effectiveness and drug; however, a drug may be new owing to the
for the need to ensure a clear disclosure of possi¬ composition of inactive ingredients, the propor¬
ble side effects along with a need to require ad¬ tion of ingredients, active or inactive, or the
vertising and promotion not only to be positive, combination of ingredients, active or inactive.
but also to point out the possible harmful side A drug’s recommended new use or change in
effects of these new drugs. recommended dosage, dosage form, or route of

858 * The Theory and Practice of Industrial Pharmacy

administration also can cause it to be considered the intended human subjects with special con¬
a new drug. The basis for a drug’s “newness” sideration for infants, pregnant women, or the
determines what steps must be taken to obtain aged; and (3) the expected effects of the drug in
an approved new drug application.13 humans.
Investigational New Drugs. The factor of Prior to the institution of clinical testing in
“newness” that requires the greatest amount of humans, a Notice of Claimed Investigational
work is the presence of a new chemical entity. Exemption for a New Drug (Form FD-1571)
The activities involved in obtaining new drug must be filed with the Food and Drug Adminis¬
approval in such instances are briefly set forth in tration by the sponsor. This form is also referred
the following paragraphs. (Forms FD-1571, FD- to as an IND, or investigational new drug appli¬
1572, and FD-1573, which are required for cation.
sponsorship of new drug clinical testing and This notice is required to set forth:
statements of the investigations are available
from the Food and Drug Administration, 1. The best available descriptive name of the drug,
5600 Fishers Lane, Rockville, MD 20852.) including, to the extent known, the chemical
After its synthesis, a new chemical entity is name and structure of any new drug substance (a
normally subjected to a “screening” process, new chemical entity).
which involves initial testing of the drug in a 2. A complete list of components of the drug.
small number of animals of different species
(usually three) plus microbiologic tests to detect 3. The quantitative composition of the drug.
any beneficial effects of the chemical. Although 4. The name and address of the supplier of any new
serendipity does play a certain part in this effort, drug substance if other than the sponsor (the per¬
the approach is generally quite controlled, based son or firm submitting the IND) and a description
on the known structure of the compound. Today, of the preparation (chemical synthesis or other
method of manufacture) of any new drug sub¬
in addition to the usual LD50 and acute and
stance.
chronic toxicity studies, tests involving teratoge¬
nicity, mutagenicity, and carcinogenicity are 5. A statement of the methods, facilities, and con¬
often conducted. trols used for the manufacture, processing, and
If the initial screening proves the new chemi¬ packaging of the new drug.
cal to be worthy of further investigation, more 6. A statement covering all information available to
extensive animal tests for its suspected proper¬ the sponsor derived from preclinical investiga¬
ties are conducted. If the properties are similar tions and any clinical studies and experience with
to those of a drug already on the market, the two the drug.
compounds may be tested against each other to 7. Copies of labels for the drugs and informational
determine their relative merits. material that will be supplied to investigators.
Animal tests are designed to determine: This material must describe the preclinical stud¬
ies with the drug and describe all relevant haz¬
ards, side effects, contraindications, and other in¬
1. The relative toxicity of the new chemical. formation pertinent to use of the drug by the
These tests would include acute toxicity and investigator.
LD50 tests to determine toxic dosage, as well 8. A description of the scientific training and experi¬
as median and long-term toxicity tests for ence considered appropriate by the sponsor to
harmful effects on the animal and on various qualify an investigator as a suitable expert to in¬
specific organs, such as the eyes, liver, and vestigate the drug.
brain. 9. The names and curriculum vitae of all investiga¬
2. The probable or possible effect of the chemi¬ tors.
cal in human drug use, including areas of in¬ 10. An outline of the planned investigations of the
terest for study, dosage, and probable side ef¬ drug in humans. These investigations are divided
fects. into three phases. The first two phases are termed
“clinical pharmacology” studies.
Animal tests or “preclinical investigations,” as
they are also termed, are designed with particu¬ Phase 1 is the initial introduction of the drug into
lar regard to possible future testing of the drug humans for the purpose of determining toxicity, me¬
in humans, or “clinical investigation.” tabolism absorption, elimination, safe dosage range,
Preclinical tests, therefore, are designed with and other pharmacologic action.
the following considerations: (1) the expected Phase 2 covers the initial trials for specific therapeutic
duration of administration of the drug to human effect and is conducted on a limited number of pa¬
beings; (2) the age groups and physical status of tients.

DRUG REGULATORS AFFAIRS • 859

Phase 1 and 2 studies are limited in nature and should tional testing are protected from unnecessary
be very closely controlled by the sponsor. risk, the FDA requires that the sponsor of any
Phase 3 is termed the “clinical trial” of the new drug such test have it reviewed and approved by a
and is intended to assess its safety and effectiveness board of nongovernment employees. This Board
in one or more particular indications. is directed to assure the protection of the rights
and welfare of any humans subject to such a
The regulations provide for a 30-day waiting test.
period, after which, if the FDA has not re¬ The FDA has detailed regulations describing
sponded negatively, the clinical trials may com¬ the makeup of those Boards, how they are to
mence. function, the records they are to keep, and their
Specific information on the planned studies role in the drug approval process.1 In brief,
for all phases of the investigation must be sub¬ there must be five members who cumulatively
mitted to the Food and Drug Administration in possess the requisite expertise to evaluate the
the IND before work is begun. These may be drug, the proposed tests, and the local commu¬
submitted sequentially and not necessarily con¬ nity attitudes toward such studies. Both sexes
currently. To avoid any delays at this point, most must be represented, there must be at least one
sponsors discuss the planned tests and the test member whose primary concerns are nonscien-
substance with the FDA beforehand. In this tific (such as a member of the clergy), and no
way, false starts and wasted efforts are mini¬ member of the IRB can have a conflicting inter¬
mized. est. The sponsor has the responsibility of select¬
The sponsor of an investigational new drug is ing this Board, but if it fails to meet FDA stand¬
required to: ards or fails to function according to FDA
regulations, the agency can refuse to approve
1. Keep records of shipment of the drug to each inves¬
any NDA incorporating a study done under the
tigator. supervision of such an IRB .15 Today, most major
institutions engaged in clinical research have at
2. Monitor the progress of the investigations of the least one IRB established.
drug and report on these investigations to the FDA
New Drug Application. In 1985, the FDA
at intervals not exceeding one year.
revised its regulations governing NDAs in a
3. Promptly investigate and report to the FDA and to number of ways designed to speed up the review
investigators findings associated with use of the process. These new regulations and the Agen¬
drug that may suggest significant hazards, contra¬
cy’s discussion of them appear in the Federal
indications, side effects, or precautions pertinent to
Register of February 22, 1985, beginning on
the safety of the drug.
page 7452. The sponsor, upon completion of a
4. Refrain from promoting the drug as being “safe” or sufficient amount of clinical work to demon¬
“effective.” strate the safety and effectiveness of the new
5. Obtain from clinical investigators a signed State¬ drug for the use or uses for which it is intended,
ment of Investigator form (Form FD-1572 for in¬ may then submit a new drug application (NDA)
vestigations in Phase 1 or 2 clinical pharmacology to the FDA (FD Form 356). This application
and Form FD-1573 for Phase 3 clinical trails), set¬ must include (1) detailed reports of the preclini-
ting forth the investigator’s curriculum vitae and
cal (animal) studies; (2) reports of all clinical
his commitments, some of which are:
(human) studies; (3) information on the compo¬
A. The investigator will maintain required records sition and manufacture of the drug and on the
of the study. controls and facilities used in its manufacture;
B. The drug will only be given to patients under and (4) samples of the drug and its labeling.
his supervision or under the supervision of Under the new rules, summaries of the data
named investigators responsible to him. must be provided, and the full case reports of
C. The investigator will: each person who received the drug are needed
(1) inform patients that they are involved in an only in limited circumstances.
investigational drug study, and Material previously submitted to the FDA in
(2) obtain their consent for this involvement the IND or in periodic reports must be included
except when this is not feasible or not in the by reference in the NDA.
best interests of the patient. NDAs for new chemical entities are usually
very involved submissions running into thou¬
An important facet of any clinical testing sands of pages in total. The information con¬
under an IND is its supervision by Institutional tained therein must be sufficient to justify the
Review Boards (IRBs). To assure, so far as possi¬ claims made in the proposed labeling for the
ble, that all humans subjected to the investiga¬ drug as to effectiveness, dosage, and safety, and

860 • The Theory and Practice of Industrial Pharmacy

 foreign data can be used. The exact wording that Certain other information must be transmit¬
may be used in the labeling of a drug usually is ted as soon as possible—in any event, within
decided by an exchange between the sponsor 15 working days of receipt. This information
and the FDA. would pertain to serious and unsuspected side
Once a new drug application is approved, any effects, injury, toxicity, sensitivity reaction, or
significant change in the manufacturing, con¬ incidents associated with clinical use, studies,
trol, packaging, or other physical properties of investigations, or tests, whether or not they are
the drug, or any change in its labeling that may determined to be attributable to the drug, or in¬
have an effect on safety and effectiveness rela¬ formation concerning any unusual failure of the
tive to either the drug itself or the manner in drug to exhibit its expected pharmacologic activ¬
which it is used must be covered by a supple¬ ity.
mental new drug application. Supplements to NDA. The 1985 rules also
The requirements of an NDA for prescription change the requirements for supplements. Sup¬
and over-the-counter drugs are similar. It is ex¬ plements are required if there is a proposed
tremely rare, however, that any new chemical change in the drug or its labeling (with excep¬
entity would be approved by the FDA for over- tions), and the changes cannot be put into place
the-counter sale for reasons of lack of sufficient until FDA approves them. Any number of these
data to support the safety in use of a totally changes may be made, but a separate submis¬
“new” drug. Since the basic test is the ability to sion must be made for each.
provide on the label adequate direction for use, The regulation provides for certain changes
most applications specifically for over-the- that can be made without the approval of a sup¬
counter drugs would tend to be supplemental plemental application, if such change is fully
applications, mainly on the particular showing described in the next periodic report. These
that the drug might be safely used without direct changes are:
medical supervision.
Once approved, several conditions must be 1. Any change made to comply with an official
met in connection with an NDA. First, advertis¬ compendium.
ing must be submitted to FDA on a routine
basis. It is especially important that introductory 2. A different container size or closure system
for solid oral dosage forms.
advertising be submitted with some promptness.
Second, reports of human clinical experience 3. Change in a description of a drug that does
are required on the following basis. The first re¬ not involve a change in a dosage strength or
ports are due at intervals of three months, begin¬ form.
ning with the date of approval of the application,
4. An editorial or minor change in labeling.
during the first three years, and annually there¬
after. 5. Deletion of a color ingredient.
Records reflecting clinical experience with the
6. Inclusion of additional specifications and
drug must be retained, and they must be avail¬
methods without deletion of those described
able for inspection. The reports required at the
in the approved application.
aforementioned intervals must include unpub¬
lished reports of clinical experience, studies, 7. Addition of reasonable expiration data based
investigations, and tests conducted by the appli¬ on FDA approved protocol.
cant or reported to him, unpublished reports of
animal experience, experience involving the It is a good general rule, when considering to
chemical, or physical properties of the drug, and make any material changes, to anticipate that a
any information that might affect the safety or supplement to the approved NDA will be needed
efficacy of the product. These may be submitted unless specifically covered by the language of
on Forms FD-1639, FD-2253, or FD-2252. the aforementioned enumerated exceptions.
The FDA requires immediate reporting of in¬ Abbreviated New Drug Applications. By
formation concerning any mixup in a drug or its regulation published in final form on April 24,
labeling with another article; information con¬ 1970, the Food and Drug Administration
cerning any bacteriologic or any significant amended Section 130.4 of the New Drug Regu¬
chemical, physical, or other changes, or deterio¬ lations,16 to provide for the filing of a short form
ration in the drug; or any failure of one or more NDA, where it is found that it is not necessary to
distributed batches of the drug to meet the spec¬ provide the FDA with all the information called
ifications established for it in the New Drug for in Section 505 of the Act. Findings may be
Application. This information could, of course, directed to specific drugs individually, or as in
form the basis for a recall. the case of the Drug Efficacy Study Implemen-

DRUG REGULATORY AFFAIRS • 861

tation (DESI) reviews, the DESI announcement For the first time, there is now in place a statu¬
may state that only the submission of an abbre¬ tory mechanism for obtaining FDA approval of
viated NDA may need to be made. Information generic equivalents of previously approved phar¬
submitted in an abbreviated NDA may be lim¬ maceuticals. Thus, the ANDA mechanism put
ited to a table of contents, label and labeling into place for pre-1962 products during the
copy, a statement as to the prescription or OTC course of the DESI review has now been ex¬
nature of the drug, and the components of the tended by statute to post-1962 drugs, subject to
new drug. In lieu of the broader NDA state¬ certain conditions.
ments concerning the full composition of the If the FDA agrees that a particular pharma¬
drug and a detailed description of the methods ceutical is appropriate for an abbreviated new
used in—and the facilities and controls- used drug application, companies wishing to market
for—the manufacture, processing, and packag¬ it can submit ANDAs, which usually contain
ing of the drug required under items 7 and 8 of bioequivalency data and certain other detailed
the NDA form, the following items are neces¬ information, to obtain agency approval. Full
sary: clinical studies are not needed. The processing
of abbreviated applications should proceed rap¬
1. Include the composition of the drug, stating the idly. As President Reagan has said, “[This] legis¬
name and amount of each ingredient, whether ac¬ lation will speed up the process of federal ap¬
tive or not, contained in a stated quantity of the proval of inexpensive generic versions of many
drug in the form in which it is to be distributed. brand name drugs, [and] make the generic ver¬
2. Identify the place where the drug will be manufac¬ sions more widely available to consumers . . ..”
tured, processed, packaged, and labeled and th6 He estimated that the American consumer
name of the supplier of the active ingredient(s). would save more than $1 billion over the ten-
3. Identify any person other than the applicant who
year period following 1984.
performs a part of those operations and designate The second section of the new law provides a
the part. mechanism to grant drug companies up to
5 years additional patent protection' for new
4. Include certifications from the applicant and from
drugs to compensate for some of the years of pa¬
any person identified in subdivision (3) of this sub-
paragraph that the methods used in, and the facili¬ tent life lost as a result of the time-consuming
ties and controls used for, the manufacture, pro¬ testing required by the FDA. Under this provi¬
cessing, packing, and holding of the drug are in sion, die Patent Office, working in collaboration
conformity with current good manufacturing prac¬ with FDA, can grant up to 5 years additional
tice in accord with Part 133 of this chapter (21CFR time of patent protection to certain new pharma¬
Section 133). ceutical entities depending on the length of time
5. Assure that the drug dosage form and components for which these entities were required to go
will comply with the specifications and tests de¬ through the regulatory review process. The
scribed in an official compendium, if such article is FDA, which is charged with the responsibility
recognized therein, or, if not listed or if the article for computing the regulatory review time period,
differs from the compendium drug, that the speci¬ will not grant any additional time for delays
fications and tests applied to the drug and its com¬ caused by the neglect or mistakes of the phar¬
ponents are adequate to assure their identity,
maceutical company.
strength, quality, and purity.
At the time of this writing, the FDA is only
6. Outline the methods used in, and the facilities, and beginning to implement the many provisions of
controls used for, the manufacture, processing, and this complex law, and no new regulations have
packing of the drug.
yet been promulgated specifying all of the details
that must be met. Many generic equivalents
If th.e, finding that the drug requires only an have already been approved for post-1962 drugs,
abbreviated'fiew drug application also specifies however, and undoubtedly, this new legislation
that there must be included adequate data to will encompass a large part of the efforts of many
assure the biologic availability of the drug, and pharmaceutical companies for years to come.
for preparations claiming sustained action, such New Animal Drugs and Animal Feed. Ef¬
data should show that the drug is available at a fective August 1, 1969, the Act was amended to
rate of release that will be safe and effective. include definitions of “new animal drug” and
Recent Legislation. In 1984, Congress “animal feed.”17 The same amendment, the Ani¬
passed the Drug Price Competition and Patent mal Drug Amendment of 1968, also added a new
Term Restoration Act of 1984. This bill promises section 512 to the Act, which requires applica¬
to have far-reaching effects on the pharmaceuti¬ tions for new animal drug to be filed with refer¬
cal industry. In brief, it provides the following. ence to new animal drugs and provides for cer-

862 • The Theory and Practice of Industrial Pharmacy

tain registrations of animal feeds containing tory procedures manual, which defines in even
new animal drugs. Regulations quite similar to greater detail the recall mechanism and FDA’s
those involving drugs for human use have been involvement in it. All companies manufacturing
adopted by the Bureau of Veterinary Medicine, or distributing pharmaceutical products should
and forms for an Animal New Drug Application have officials and employees that are fully in¬
and a Medicated Feed Application are Forms formed as to these regulations and FDA proce¬
FD-356V and 1800 respectively. dures, so that accurate and appropriate deci¬
Certification of Drugs. Insulin and antibi¬ sions can be made.
otics are the two classes of drugs requiring certi¬ The FDA classifies all recalls into one of three
fication, although certain antibiotics may be categories. Category I recall represents an emer¬
exempt from certification. The FDA, acting gency situation in which the drug poses a haz¬
under the mandate of the Act, has adopted regu¬ ard that is immediate, long-range, and life-
lations to ensure that each batch has the charac¬ threatening. Such recalls require special mecha¬
teristics of identity, strength, quality, and purity nisms and a close relationship with the FDA,
prescribed in such regulations. since a public warning must be issued, and the
Application for certification must be made to product must be recalled to the consumer level.
the Commissioner. For insulin, the information The second type of recall is Category II, a pri¬
that must be contained in a request for certifica¬ ority situation in which the consequences of the
tion is set forth in 21 CFR Section 164.2. offending drug remaining on the market may be
In 1982, the FDA published a regulation that immediate, long-range, or potentially life-threat¬
exempts virtually all antibiotics from the re¬ ening. In general, such recalls must be made to
quirement of obtaining batch certification.18 For the retail or dispensing level, and occasionally,
20 years, companies marketing approved antibi¬ the FDA issues press releases to inform the pub¬
otics had been required to submit assay results lic. The final recall classification is Category III.
and samples of each manufacturing batch for This is a routine situation in which the threat of
FDA testing and evaluation. The purpose of this life is remote or nonexistent. Such recalls in¬
exercise was to assure batch-to-batch integrity clude products that are technically illegal be¬
and uniformity, and this testing was paid for by cause they are adulterated or misbranded in
the companies involved and was both cosdy and some respect or another, for example, labeling
time-consuming (a batch could not be released violations not involving a health hazard. Such
for sale until FDA passed it). Apparendy finding recalls are required only to the wholesale level,
the exercise no longer justified, the FDA and press releases are usually not issued.
dropped it. Batch confirmation continued to be In addition to such formal recall mechanisms,
required for insulin products.19 there are occasions that require companies to
remove products from the market when there
are no violations of the law involved. This is
Recalls often done for reasons totally unrelated to the
While the FDA has no statutory authority to FDA or to the integrity of the product. It is im¬
require the recall of a pharmaceutical, the portant for companies to appreciate that such
agency nevertheless has published, in the inter¬ market withdrawals are not recalls and are not
est of public safety, extensive regulations con¬ subject to FDA regulations.
cerning recalls and has set up a detailed mecha¬ Removal of a product that is still entirely
nism for the recall of drugs from the under the direct control of the manufacturer,
marketplace. Recalling a drug is one of the most even though it may have been shipped interstate
difficult decisions facing a manufacturer or dis¬ to one or more branch warehouses, also is not
tributor, for such an act has important ramifica¬ classified as a recall, provided no stock has been
tions, ranging from a company’s relationships distributed to the trade. These removals are
with the FDA to potential product liability litiga¬ termed “stock recoveries” and do not appear on
tion. Therefore, recalls should be entered into the public recall fist. Usually, however, checks
only after the most careful evaluation of the are made on the adequacy of these retrievals to
problem, and once begun, they must be com¬ cover ultimate disposition of the merchandise.
pleted as rapidly and efficiently as possible. FDA
regulations provide extensive guidelines to de¬
termine (1) what products should be recalled Drug Efficacy Study
(and to what level) and (2) the precise mecha¬
nism for recall that would most likely achieve Implementation (DESI) Review
the desired goal. In addition to these regulations, A particularly controversial provision of the
the FDA has also made available its own regula¬ 1962 Amendments concerns drugs already on

DRUG REGULATORY AFFAIRS • 863

the market that had effective NDAs under the had been presented on the face of the petition¬
old law, i.e., during the period from 1938 to ing papers to require a hearing.
1962. A two-year period of grace was provided The apparent slowness with which the Food
for the manufacturer to supply substantial evi¬ and Drug Administration was implementing the
dence of effectiveness to support the claims on NAS/NRC Reports gave rise to litigation,
the previously cleared labeling, since the 1938 wherein the American Public Health Associa¬
Act required proof of safety only. tion and the National Council of Senior Citizens
To cope with the overwhelming burden of brought an action against the then acting Secre¬
such a review, FDA enlisted the services of the tary of the Department of Health, Education and
National Academy of Sciences, National Re¬ Welfare and the Commissioner of the Food and
search Council (NAS/NRC) to help. The NAS/ Drug Administration to make public all the re¬
NRC set up a series of panels to which drugs ports theretofore not public, and in addition, to
were assigned on the basis of the medical disci¬ speed up the process. 1 This resulted in a mem¬
plines in which they were used, e.g., Ophthal¬ orandum by Judge Bryant of the United States
mic Panel, Dermatology Panel, and Cardiology District Court for the District of Columbia,
Panel. Manufacturers of drugs affected were wherein the court concluded that there is no
invited to submit data to these panels in addition compelling reason why the NAS/NRC Reports
to the data already contained in their NDAs. not then public should not be immediately re¬
Upon an evaluation of these data, the panels leased, and that it would be an abuse of agency
rated the drugs on effectiveness for their labeled discretion to refuse to make such reports public.
indications as follows: In addition, the court would set a deadline for
the FDA to complete its evaluation of all drugs
1. Effective with regard to efficacy, and in October 1972,
Judge Bryant threw open to public inspection all
la. Effective, but ... 20
of the remaining reports. He set certain timeta¬
2. Possibly effective bles (1) for implementing either a removal of
less than effective classifications or a with¬
3. Probably effective
drawal of the NDAs, (2) for allowing certain
4. Ineffective drugs to remain on the market if good reason
w'as shown by the FDA, pending a longer-term
The panels worked independently, and fre¬ implementation, and (3) for requiring reports to
quently, a drug would be judged effective for one the Court of the progress of the DESI review
of its uses by one panel and less than effective, implementation program. Therefore, with the
i.e., ratings la through 4, for another of its uses exception of less than effective drugs, which
by another panel. These apparent differences may be continued past the cutoff date because of
were not resolved by joint panel meetings, but public health considerations, all implementation
were treated as independent judgments having would be finished by final order of FDA at least
equal weight. by October 10, 1976. The FDA did not appeal
The extent of the problem can be seen in the Judge Bryant’s ruling.
fact that the NAS/NRC Panels returned 2824 re¬ The FDA once again failed to perform under
ports covering approximately 3700 drugs manu¬ court order, and the plaintiffs went before Judge
factured by 237 companies. The Panels began Bryant for a further order, which resulted in a
submitting reports on October 11,1967, and the settlement stipulation calling for the final regu¬
last report was submitted on April 15,1969. The latory action in all cases to be taken by June
FDA attempted to implement these reports by 1984. The stipulation set certain priorities
publishing findings in the Federal Register, and within which the classes of drugs to be dealt
in the case of drugs that were probably or possi¬ with were specified. Periodic reports of progress
bly effective, the drug would be allowed to re¬ were to be made by the FDA to Judge Bryant.
main on the market for periods of 12 months In its own attempt to give some notice to prac¬
and 6 months respectively, to allow for further titioners that the drug they were planning to
clinical trials to support efficacy. After these pe¬ prescribe had received a rating of less than ef¬
riods, if no work had been done, a notice of with¬ fective by the NAS/NRC Panels, the FDA pro¬
drawal was prepared and published in the Fed¬ mulgated a regulation that became final on Feb¬
eral Register. This gave rise to requests for ruary 12, 1972. It required that the less than
hearings under the appropriate sections of the effective evaluation be called to the practition¬
Act. In all cases, hearings were denied based on er’s attention by including a statement promi¬
a finding by the Secretary that no issue of fact nently in the labeling, and surrounding it with

864 • The Theory and Practice of Industrial Pharmacy

an appropriate border. Since most package in¬ Supreme Court granted writs of certiorari, that
sert labeling is printed black on white, this regu¬ is, it agreed to hear argument on the issues.
lation promptly became known as the “Black They were resolved in June 1973.
Box” regulation. Thus, during the period of im¬ The first case is the so-called Bentex case.23
plementation ordered by Judge Bryant, all prod¬ In this case, a group of drug companies market¬
ucts rated less than effective must be so desig¬ ing pentylenetetrazol had filed suit against the
nated, in the “Indications” section of the FDA, alleging that their products were generally
package insert or on the label within an appro¬ recognized as safe and effective and therefore
priate border, as follows: were not new drugs. They asked to be exempt
from the regulatory results of an NAS/NRC
panel report, which had found that other compa¬
nies’ pentylenetetrazols, which were the subject
Based on a review of this drug by the National
of new drug applications, lacked substantial evi¬
Academy of Sciences/National Research
dence of efficacy. This meant that the question
Council and/or information, FDA has classi¬
before the court was whether a so-called “me-
fied the indication(s) as follows:
too” drug could be subject to the NAS/NRC re¬
(a statement of the probably or possibly effec¬
sults, even if it had never held an NDA and even
tive status in paragraph form appears here)
if it might meet the literal requirements of the
Final classification of the less than effective
grandfather clause. The Supreme Court held
indications requires further investigation.
that such products are subject to the NAS/NRC
results.
Thus, “me-too” products must meet the
From the beginning, enforcement of the NAS/ standards announced by the FDA for NDA
NRC findings was not without its problems; re¬ drugs, notwithstanding any other legal argu¬
solving these problems ultimately required re¬ ments that the “me-too” manufacturers might
course to the Supreme Court of the United make. The court held that the FDA has jurisdic¬
States. First, there was the spectre of the so- tion to decide, with administrative finality, the
called “grandfather clause” of the Kefauver- new drug status of individual drugs or classes of
Harris Bill, which it was claimed, protected cer¬ drugs. The FDA, according to the Supreme
tain drugs within its definition from ever having Court, should not be required to litigate on a
to be proven effective.22 Second, it was claimed case-by-case basis the new drug status of each
that certain drugs that were identical or similar drug on the market. All of this means that
to NDA drugs reviewed by NAS/NRC were unaf¬ henceforth FDA may say with great finality
fected by the findings of such review because whether a product is a new drug and, in particu¬
they had been marketed in imitation of such lar, can say that “me-too” products are new
drugs, but had not themselves had an NDA drugs and must come off the market if the NDA
(“me-too” drugs). This claim was made in the drug they are imitating is required to come off
face of FDA’s proposed notice in February and the market.
final notice in October of 1972 that DESI notices The second case before the Supreme Court
of findings were equally applicable to identical, involved a bioflavonoid product.2'* In this in¬
related, or similar drug products even though stance, a lower court had held that the courts
such products had never had an NDA. had jurisdiction to determine whether a product
Third, there was a controversy regarding was protected by the grandfather clause, and
which body, the FDA or the courts, had jurisdic¬ that the FDA did not have authority to decide
tion to decide whether a drug was a “new drug”— this question conclusively. The lower court also
that is, that it was not generally recognized as had held that the manufacturer’s own “me-too”
safe and effective. Finally, there was the ques¬ versions of its NDA drug were subject to the
tion whether a manufacturer had an absolute NDA procedures. The Supreme Court held that
right to a hearing before FDA prior to with¬ the phrase “any drug,” as used in the grand¬
drawal of his NDA or whether FDA could ad¬ father clause, is used in a generic sense, which
ministratively decide that no hearing was war¬ means that the “me-toos,” whether products of
ranted because, on the face of the documents the same or of different manufacturers, covered
offered in support of the drug, there was not by an effective NDA, are not exempt from the
“substantial evidence” of safety and/or efficacy. efficacy requirements of the 1962 Amendments.
These cases were fought vigorously through Thus, the grandfather clause has been further
the lower courts, and the importance of their narrowed so that it applies only to those drugs
outcomes was deemed to be so great that the that meet the definition in the grandfather

DRUG REGULATORY "AFFAIRS • 865

clause and are not “me-toos” of other drugs that opportunity to litigate the new drug issue before
did have NDAs. FDA, it may not later try to litigate it in another
The third decision involves the important forum, such as a federal court.
question of a drug company’s rights to adminis¬ A final chapter in this controversy, the status
trative hearings before the FDA. This is the of “me-too” or generic equivalent drugs, was fi¬
Hynson, Westcott, & Dunning decision.25 In nally decided in 1983. All through the late fifties
this case, a lower court had ruled that the com¬ and sixties, and well into the seventies, compa¬
pany had presented enough evidence, in its re¬ nies continued to market their unapproved ver¬
quest for a hearing to revoke a new drug applica¬ sions of drugs that had gone through the NDA
tion, to entitle that company to a hearing. In this process, relying on various legal arguments and
decision, the Supreme Court sustained the sum¬ an FDA policy of allowing such marketing—a
mary judgment mechanism instituted by FDA to policy that seemingly conceded that NDAs were
determine whether administrative hearings unnecessary for generic drugs. As the DESI
must be held. Under this mechanism, a drug Review moved on and the ANDA policy was put
company must present, in its hearing request, into effect, however, a more definitive resolution
substantial evidence that the drug is effective, of this problem was needed.
and if the FDA concludes that such evidence Following a series of lawsuits involving the
has not been presented, no hearing is granted, generic drug industry, one finally reached the
and the drug is removed from the market with¬ Supreme Court.27 There the Court ruled* that
out hearing. The Supreme Court has sustained generic versions of drugs that had gone through
this mechanism. In the event that the FDA de¬ an NDA process (be it NDA or ANDA) also had
nies a hearing, the Supreme Court has ruled to go through a similar procedure. The main rea¬
that a court of appeals, in reviewing this admin¬ son for this decision was the Court’s reliance on
istrative action, “must determine whether the the fact that changes in inactive ingredients
Commissioner’s findings accurately reflect the such as colors, stabilizers, binders, or the Hk&
study in question, and, if they do, whether the could affect the safety or efficacy of an active
deficiencies he finds conclusively render the ingredient. Thus, each should be separately ap¬
study inadequate or uncontrolled ...” proved by the FDA. With that ruling, the last
Perhaps the most important statement in the issue of the DESI Review was resolved, so that
Hynson, Westcott & Dunning decision regards a the question of whether there are any drugs that
problem other than hearing requests. It had long do not require FDA approval is largely academic.
been accepted that a drug could be an “old drug”
if there was sufficient expert medical opinion
declaring it to be generally recognized as safe
and effective. It was further thought that this
OTC Review
opinion could be just that—opinion—and need Another practice of FDA, similar to the NAS/
not be based on any particular type of scientific NRC reviews, is the appointment of panels of
data. The Supreme Court has now severely nar¬ experts to review the safety and efficacy of all
rowed this thinking and has ruled that a drug over-the-counter drugs (OTC drugs). As with
can be an old drug, based on a consensus of ex¬ the NAS/NRC, these OTC panels have been as¬
pert opinion, “only when that expert consensus signed products on a category basis, e.g., analge¬
is founded upon ‘substantial evidence’ as de¬ sics, antacids, and anesthetics. Each OTC panel
fined in Section 505(d).” This means that a drug is to review products in each category, as well as
can be an old drug only if there is substantial published literature and data supplied, on call,
evidence of efficacy by well-controlled studies from manufacturers. After the review, a “mono¬
that demonstrate that the product is in fact ef¬ graph” is to be published in the Federal Register
fective. Lower federal courts have followed this setting forth the panel’s evaluation of all the data
discussion, and there now remains no question and its decision regarding the ingredients that
as to the validity of this doctrine. may be included in products for the indications
The final case before the Supreme Court in¬ related to the panel’s investigation. The mono¬
volved CIBA.26 Here, a lower court had ruled graph will also set forth allowable claims, per¬
that the FDA had the authority, in an adminis¬ missible combinations, contents, and dosage
trative hearing, to determine whether a product ranges, as well as permissible dosage forms and
was a new or old drug. CIBA had appealed this routes of administration. Manufacturers may
decision. The Supreme Court held, in a manner request a hearing to add substances or change
consistent with the previous three decisions, any of the recommendations of the monograph,
that the agency does have such jurisdiction, and after which it will be published in the Federal
that, therefore, when a company has had one Register in final form and will become law. OTC

866 • The Theory and Practice of Industrial Pharmacy

preparations falling outside the monograph in ministration or application, in such manner and form,
any particular will be deemed to be new drugs as are necessary for the protection of users.
and will require approved NDAs.
This process is still underway, and while sev¬ “Adequate directions of use” has been defined
eral final monographs have been published,30 in the Regulations as meaning directions under
most remain in the administrative process— which the layman can use a drug safely and for
which some believe will not be finished before the purposes for which it is intended.29
the end of this century. The label of an over-the-counter drug must
name, but need not state the quantity of propor¬
tion of, the active ingredients, except for any
Further 1962 Drug Amendments habit-forming ingredient covered by Sec¬
Other provisions of the 1962 Amendments tion 502(d). The latter also requires that the
relate to: statement “Warning—May be habit forming”
appear on the label “in juxtaposition” with the
1. Immediate registration with the FDA upon name of such ingredient, or any of the sub¬
first engaging in the manufacture, repacking, stances specified in Section 502(e) of the Act.
or relabeling of drugs, and then registration Warning Notices. A drug may be deemed to
annually thereafter, with inspections to be be misbranded if it does not contain, in addition
made at least once every two years. to adequate directions for use, adequate warn¬
ings against use in certain pathologic conditions
2. Strengthened factory inspections with re¬
(or by children) in which its use may be danger¬
spect to establishments concerned with pre¬
ous to health, or warnings against unsafe dosage
scription drugs. or methods or duration of administration or ap¬
3. A requirement that procedures employed by plication, in such manner and form as are nec¬
manufacturers must conform to “current essary for the protection of users. Thus, a manu¬
good manufacturing practice.” This permits facturer, packager, or distributor must warn
the Government to be in a better position to against all known hazards. To aid in making
oversee operations without the necessity of these uniform, suggested warning statements
interstate shipment of a product, which for most known hazards are set forth in Sec¬
would be in violation of the law. tions 369 and 310.201 of the Regulations.30
These warning statements must contain the full
4. The “established name” or nonproprietary
meaning of those suggested, but need not use
name must be designated on the label.
the identical wording.
5. Prescription drug advertising must provide a Prescription Drugs. The specific require¬
“brief summary relating to side effects, con¬ ments for the labeling of a prescription drug are
traindications, and effectiveness” so as to set forth in Part 201.50, Subpart B of the Regula¬
give the physician a balanced picture of the tions. It need not bear “adequate directions for
desirability of its use. use” if it complies with the requirements set
forth in that Section, namely, speaking to the
6. All antibiotics are subject to certification pro¬
practitioner, it must bear “labeling,” on or within
cedures.
the package from which the drug is to be dis¬
pensed, that sets forth adequate information for
Labeling Requirements its use. This infonnation includes indications,
effects, dosages, routes, methods, frequency and
The following serve to summarize the princi¬ duration of administration, relevant hazards,
pal requirements for the labeling of both OTC contraindications, side effects, and precautions
products and prescription drugs subsequent to “ . . . under which practitioners licensed by law
the passage of the 1962 Drug Amendments. to administer the drug can use the drug safely
Over-The-Counter Drugs. The labeling for and for the purposes for which it is intended,
OTC products is governed by Section 502(f) of including all purposes for which it is advertised
the Federal Food, Drug and Cosmetic Act, or represented ...”
which states: With respect to all drugs, Section 502(b) of the
act requires the label to provide an accurate
Section 502. A drug . . . shall be deemed to be mis¬
statement of the quantity of the contents in
branded—Unless its labeling bears (1) adequate di¬
rections for use; and (2) such adequate warnings terms of weight, measure, or numerical coupt,
against use in those pathological conditions or by chil¬ as well as the name and place of business of the
dren where its use may be dangerous to health, or manufacturer, packer, or distributor.
against unsafe dosage or methods or duration of ad¬ The label of a prescription drug intended for

DRUG REGULATORY AFFAIRS • 867

oral administration must contain the quantity or Indications
proportion of each active ingredient. Contraindications
If the drug is intended for parenteral adminis¬ Warnings
tration, the quantity or proportion of all inactive Precautions
ingredients must also be stated on the label, ex¬ Adverse Reactions
cept that ingredients added to adjust the pH or Dosage and Administration
to make the drug isotonic may be declared by Overdosage (Where Applicable)
name and a statement of their effect. If the vehi¬ How Supplied
cle is water for injection, however, it need not be
specifically named. Optionally, the package insert may contain the
If the drug is for other than oral use, but is not following:
for parenteral use, e.g., ointment or suppository,
the names of all inactive ingredients must be set Animal Pharmacology and Toxicology
forth except that flavorings and perfumes may Clinical Studies
be designated as such without naming their spe¬ References
cific components.
Color additives may be designated as coloring and other special warnings or precautions pecu¬
without being specifically named, unless this is liar to that particular drug product, which must
required in a separate section of the color addi¬ appear conspicuously in the beginning of the
tive regulations, and trace amounts of harmless package insert for special attention by physi¬
substances added solely for individual product cians and by patients for purposes of safety.
identification need not be named. “Contraindications” warn against those condi¬
Warning Notices. The only specific warning tions in which the drug must not be used be¬
required on a prescription label or on the outer cause it may actually cause harm to the patient,
container of the package, if the label is too small as through aggravation of an existing condition
to accommodate this statement, is: “Caution: such as high blood pressure or glaucoma.
Federal law prohibits dispensing without pre¬ “Warnings” are utilized in connection with
scription.” those situations in which the use of the drug
Package Inserts. A package insert is not might cause a serious problem, such as causing
specifically required with any drug; however, abortion in a pregnant patient. “Precautions”
since all drugs, whether prescription or over- describe instances in which the use of the drug
the-counter, must bear labeling with adequate should be closely supervised to avoid undesired
directions for use if the label of the drug does not side effects that are annoying but not of a seri¬
permit sufficient space to set forth all the re¬ ous nature. “Adverse Reactions” warn the physi¬
quired information, a package insert must be cian to look for drug-related conditions that have
included to contain this required information. been known to occur even when the drug is used
Package inserts and labels containing directions at the recommended dosage level. These must
for use must include the date of the latest revi¬ be taken into account by the physician when he
sion of the piece. judges the benefit-to-risk ratio of the drug. Ad¬
In order to satisfy the requirements of Sec¬ verse reactions warned against need not appear
tion 201.100 of the regulations, package inserts in all patients at all times, but the physician
that are generally included in prescription drug must be made aware of the possibility in order to
packages must bear “adequate information for make a considered judgment in prescribing the
its use, including indications, effects, dosages, drug.
routes, methods, and frequency and duration of
administrations, and any relevant hazards, con¬
traindications, side effects, and precautions Drug Listing Act of 1972
under which practitioners licensed by law to By the terms of the Kefauver-Harris Amend¬
administer the drug can use the drug safely and ment of 1962, all producers of drugs and drug
for the purposes for which it is intended, includ¬ products were required to register their estab¬
ing all purposes for which it is advertised or rep¬ lishments with FDA.32 The effect of registration
resented.” In order to present the information in was twofold: (1) it gave the Food and Drug Ad-
a uniform manner, FDA has issued labeling pol¬ ministration an updated list of all legitimate
icies,31 setting forth the format, order, and sec¬ manufacturers, and (2) by the operation of the
tion headings for package inserts as follows: amendment, it required inspection of these pro¬
ducers at least once every two years. It did not,
Description however, provide the Food and Drug Adminis¬
Actions tration with a list of the types of drugs produced

868 • The Theory and Practice of Industrial Pharmacy

at each of these establishments, or with formu¬ integrity according to the requirements of the
las for the many thousands of such drugs. Since Act.
the 1962 Amendment required that drugs, “Current good manufacturing practice” is
whether prescription or over-the-counter, which nowhere defined in the Act or in the regulations.
were deemed to be less than effective come off The regulations concern themselves with spe¬
the market, FDA was faced with the almost in¬ cific criteria for buildings, equipment, person¬
surmountable job of locating all such drugs and nel, components, master formula and batch pro¬
taking appropriate action. Regulations have duction records, production and control
been promulgated, however, under Section 2 of procedures, product containers, packaging and
the Drug Listing Act to ensure that sufficient labeling, laboratory controls, distribution rec¬
data be sent to the FDA and be computerized for ords, stability, and complaint files.34
easy handling. These regulations had been promulgated
Once the data are fully computerized and under the general regulatory powers granted in
classes of drugs can be identified, the FDA in¬ Section 701(a) of the Act. Before the Supreme
tends to use the broad new powers, which it Court decisions of 1973, these regulations were
gained in June of 1973 by dint of the four land¬ thought to be interpretive only—not having the
mark Supreme Court decisions already cited, to force and effect of law. Now, however, it has
move against drug entities deemed to be less been held that Section 701(a) regulations do
than effective. With the DESI and OTC Reviews have such an effect, and therefore all regula¬
affecting virtually every drug currently on the tions adopted in final form by FDA must be con¬
market, and with the Supreme Court mandate, sidered as being a pronouncement of the law,
FDA feels it need not proceed on a case-by-case unless and until they are successfully chal¬
basis, but merely needs to locate violative drugs lenged in court.
and notify the producer that it intends to take It would be well, therefore, for the industrial
action. If the producer persists in marketing the pharmacist to know just what an FDA inspector
violative drug, not only will seizure and injunc¬ looks for,35 both in a sanitary inspection and in a
tion follow, but use of the criminal penalties of good manufacturing practice inspection. (These
the Act will increase. may take place separately, but are usually simul¬
taneous.) The generally accepted sanitary in¬
spection checklist is as follows:

Current Good Manufacturing 1. Human behavior

(a) Personal hygienic practices of the employees
Practice (GMP) (b) Supervision to which employees are subjected
Perhaps the most significant addition to the 2. Infestation
law is the concept of “current good manufactur¬ (a) Rats, mice, and other vermin
ing practice” (GMP). This is a requirement that (b) Flies, roaches, water bugs, and other insects
drugs, and the methods used in, or the facilities 3. Conditions of equipment and utensils
or controls used in their manufacture, process¬ (a) Provisions for cleaning these articles
ing, packing, or holding conform with those
4. Conditions of raw materials
practices that will assure that such drugs meet
(a) Sanitary conditions of water and ice supplies
the requirements of the Act as to safety, and
have the identity, strength, quality, and purity 5. Toilets, washing facilities, and their accessibility
characteristics that they purport or are repre¬ 6. The plant
sented to possess. If they do not, they are adul¬ (a) Surroundings, structure in relation to rodent
terated.33 and insect exclusion, cleanliness, and “cleana-
What does this mean to a manufacturing bility”
pharmacist? The requirement is so broadly 7. Waste disposal, including methods of sewage dis¬
stated that it casts a tremendous burden of proof posal of the plant and of other buildings in immedi¬
on the Food and Drug Administration, especially ate surroundings, when this information may be of
in cases where there are arguable variables in significance
methodology, procedure, or equipment. It also 8. Conditions of storage and handling of products,
casts a heavy burden on the industrial pharma¬ particularly those subject to insect and rodent in¬
cist, however, because it requires him to pro¬ festation after the finished product is produced
duce drug products by using manufacturing
practices that are both current and good. In other Under GMP, the inspector will concern him¬
words, he must keep up with advances and self with other aspects of pharmaceutical manu¬
adopt those that will increase assurance of drug facturing.

DRUG REGULATORY AFFAIRS • 869

 1. Buildings shall be maintained in a clean and or¬ products that have met the standards and specifi¬
derly manner and shall be of suitable size, con¬ cations established in their master production and
struction, and location to facilitate adequate control records shall be distributed; to prevent
cleaning and maintenance and proper operation mixups between drugs during filling, packaging,
in the manufacturing, processing, packing, label¬ and labeling operations; to assure that correct la¬
ing, or holding of a drug. bels and labeling are employed for the drug; and
to identify the finished product with a lot or con¬
2. Equipment used for the manufacture, processing,
trol number that permits determination of the his¬
packing, labeling, holding, testing, or control of
tory of the manufacture and control of the batch.
drugs shall be maintained in a clean and orderly
manner and shall be of suitable design, size, con¬ 9. Laboratory controls must include the establish¬
struction, and location to facilitate cleaning, ment of scientifically sound and appropriate spec¬
maintenance, and operation. ifications, standards and test procedures to assure
that components, in-process drugs, and finished
3. Personnel must be adequate in number and back¬
products conform to appropriate standards of
ground of education, training, and experience or
identity, strength, quality, and purity.
combination thereof to ensure that the drug has
the safety, identity, strength, quality, and purity 10. Distribution records must be kept so that the dis¬
that it purports to possess, and they must also be tribution of each lot of drug can be readily deter¬
in good health. mined to facilitate its recall if necessary, and so
that a first-in, first-out warehouse system can be
4. Components and other materials used in the
used.
manufacture, processing, and packaging of drug
products and materials necessary for building and 11. Stability of finished drug products must be as¬
equipment maintenance must be stored and han¬ sured by appropriate means.
dled in a safe, sanitary, and orderly manner, with
12. Suitable expiration dating of drug products must
adequate measures taken to prevent mixups and
be instituted, especially for those liable to deterio¬
cross-contamination affecting drugs and drug
ration, so that the drug meets appropriate stand¬
products. They must be withheld from use until
ards of identity, strength, quality, and purity at
they have been identified, sampled, apd tested for
the time of use.
conformance with established specifications and
are released by a materials approval unit. 13. Complaint files must be maintained, carrying rec¬
ords of all written and oral complaints regarding
5. Master production and control records for each
each product, and an investigation of each com¬
drug product and each batch size of drug product
plaint must be made and recorded in writing.
shall be prepared, dated, and signed or initialed by
a competent and responsible individual, and shall
be independently checked, reconciled, dated,
signed, or initialed by a second competent and Food and Drug Administration
responsible individual to assume uniformity from
batch to batch.
(FDA)
6. Production and control procedures shall include
The enforcement of the Federal Food, Drug
all reasonable precautions to assure that the drugs and Cosmetic Act is the responsibility of the
produced have the safety, identity, strength, qual¬ Food and Drug Administration, which is a part
ity, and purity they are purported to possess, in¬ of the Department of Health and Human Ser¬
cluding but not limited to double checking of se¬ vices. The agency is administered by a Commis¬
lection; weighing and measuring of components; sioner, a Deputy Commissioner, and six Associ¬
the addition of ingredients during the process; ate Commissioners. It is broken down, at the
proper identification of all containers, lines, and headquarters level, into five Centers, namely,
equipment; adequate cleaning facilities to prevent
Foods (which includes cosmetics), Drugs, De¬
contamination and mix ups; appropriate precau¬
vices, Radiological Health, and Veterinary Drugs
tions to minimize microbiological and other con¬
tamination of the drug or the cross-contamination (which includes veterinary devices).
of any other drugs; adequate in-process checking FDA maintains a headquarters building in the
of weights, measures, and counts at appropriate District of Columbia, but its main headquarters
intervals, and the taking and maintaining of rep¬ activities are at 5600 Fishers Lane, Rockville,
resentative samples in process. MD 20852. There are ten regions and 17 district
7. Product containers and their components must be offices located throughout the United States.
tested and found to be suitable for their intended These local offices have the prime responsibility
use and should not be reactive, additive, or ab¬ for the day-to-day monitoring of manufacturers
sorptive so as to affect the safety, identity, of products falling within their jurisdiction. New
strength, quality, or purity of the drug or its com¬ drug applications, food additive petitions, prod¬
ponents. uct and plant registration, and the like are han¬
8. Packaging and labeling operations shall be ade¬ dled centrally. Inspectors generally work out of
quately controlled to assure that only those drug the various district offices, and they, together

870 • The Theory and Practice of Industrial Pharmacy

with their own local laboratory facilities and in that district. The monition is an in rem pro¬
under the direction of a director, are the prime ceeding, that is, it is a proceeding against the
contact with manufacturers to ensure that prod¬ articles to be seized for condemnation. Since the
ucts meet regulatory standards. articles themselves are the defendant in the
Inspections may be made without warning case, the owner, usually the manufacturer, if he
during reasonable business hours and may en¬ wishes to resist the seizure, becomes an “inter-
compass the buildings in which drugs are man¬ venor,” that is, alleging ownership, he files a
ufactured or in which raw materials or bulk claim for the goods and thus becomes the liti¬
drugs are held, including vehicles in which such gant. Under the law, seizure can be made in only
drugs are held or are being transported. Sec¬ one district of one quantity of the product un¬
tion 704 of the Act gives wide latitude to the less: (1) the Commissioner of Food and Drugs
scope of inquiry, which may be made into all finds that the goods represent a significant haz¬
areas of plant administration, from houseclean¬ ard to health, or (2) he finds that the drug is
ing to the qualifications of those responsible, for claimed to be a new drug, in which case multiple
production and quality control, as well as pro¬ seizures may take place. Drugs seized can be
duction records, formulas, assays, and all destroyed if there is no intervenor or if interven¬
quality-control documents kept in the regular tion is not successful. After intervention, the
course of business. drugs can, under proper safeguards, be released
Following the adoption of the 1962 Amend¬ back to the intervenor for relabeling to bring
ments, all plants manufacturing pharmaceutical them in compliance with the Act, or they can be
products were required to be registered. The returned to the manufacturer under bond for
requirement also included a mandate that FDA reworking if that will cure the misfeasance.
inspect each such establishment at least once 2. Injunction.38 An injunction is a legal
every two years. Such inspections cannot be re¬ term describing a court-directed prohibition
fused if made at a reasonable hour and if the against a person, firm, or corporation doing a
inspector shows proper credentials and presents particular act. Generally, in the case of indus¬
a formal “Notice of Inspection.” At the conclu¬ trial pharmacy, it can be against the production
sion of an inspection, an inspector may take of a drug not in compliance with GMP or the
samples, for which he is required to give a re¬ selling or shipping of such drug in interstate
ceipt,36 and if requested, to provide for payment commerce, or against certain advertising or pro¬
for the articles taken. In addition, if the inspec¬ motion found to be violative of the Act. The issu¬
tion warrants it, a report of deficiencies noted by ance of an injunction is not a function of the
the inspector is written out and delivered to the FDA. FDA must go to court and prove to a Fed¬
person in charge of the establishment. These eral District Judge that there is a violation of the
reports can form the basis for regulatory action law sufficient to cause him to invoke the ex¬
should they be serious enough or if, on a subse¬ traordinary remedy of injunction. The burden of
quent inspection, the deficiencies have not been proof is on FDA, and because of the extraordi¬
satisfactorily corrected. nary nature of the remedy, it is a heavy burden.
Injunction is a regulatory tool rarely used.
3. Criminal Prosecution.39 Criminal
action may be taken against persons, corpora¬
FDA Enforcement Powers tions, or responsible officers. A penalty of $1,000
Inasmuch as the Federal Food, Drug and Cos¬ or one year in jail for an unintentional first of¬
metic Act is a criminal statute, FDA activities fense may be exacted, or $10,000 and three
are discussed in terms of enforcement. If neces¬ years if the offense was committed with intent to
sary, legal action can be taken against any party defraud or mislead, or by a previous offender.
violating the Act. Such action can take one of the The latter form of action is relatively rare, and
"following forms. would normally involve a wanton disregard of
1. Seizure.37 Whenever FDA believes that a the law.
drug product that has traveled in interstate com¬ Prior to the institution of criminal proceed¬
merce, or is being held for shipment into inter¬ ings, however, Section 305 of the Act provides
state commerce, is in some way violative of the for an informal hearing procedure whereby the
Act, a so-called monition or complaint against manufacturer may present to an FDA hearing
the articles themselves is drawn up and pre¬ officer explanations for and circumstances be¬
sented to the United States Attorney in the Dis¬ hind the activities cited.40 The hearing officer
trict where the goods are located. He then pro¬ may receive documentary as well as oral evi¬
ceeds to make this case ex -parte (without an dence, after which he prepares a report, uni¬
adversary present) before a Federal Judge sitting formly dictated in the presence of the respond-

DRUG REGULATORY AFFAIRS • 871

ent. He asks the respondent to agree that the scription drugs. The reason for this agreement,
facts so stated are those presented by him, and of course, is to avoid unnecessary duplication of
in addition, gives the respondent a chance to enforcement procedures. The agencies have a
add explanatory matter to the report. The hear¬ close working relationship, with the FTC relying
ing report, with the hearing officer’s recommen¬ in large measure on FDA for its scientific exper¬
dation, is then forwarded to the compliance tise.
branch in Washington for final disposition. This Since the industrial pharmacist is generally
informal hearing procedure is important, both involved with FDA inspections, it might be in¬
for the manufacturer and for the FDA. It affords teresting to note in passing that the federal stat¬
the manufacturer a hearing at a level higher utes relating to crimes and criminal procedure
than that of the inspector, and it gives the FDA a make it a crime to forcibly assault, resist, oppose,
chance to reevaluate its regulatory thinking in impede, intimidate, or interfere with an FDA
the light of such explanation. Thus, the proce¬ inspector during the performance of his official
dure avoids unnecessary litigation and acts as a duties. Any such offense carries with it a fine of
buffer against precipitous action, either by the not more than $5,000 or imprisonment for not
regulating authority or by the regulated indus¬ more than 3 years, or both. If any of the afore¬
try. mentioned acts entails the use of a dangerous
weapon, the fine may be as high as $10,000 and
the imprisonment up to 10 years, or both.
Other Federal Laws Affecting the The Color Additives Amendments of 1960,
which are a part of the Federal Food, Drug and
Industry Cosmetic Act, specify that no product is to con¬
There are other laws with which the industrial tain any unsafe color additive. An unsafe color
pharmacist should be familiar. Perhaps the most additive is defined in Section 706(a) 21 USC 376
important is the Fair Packaging and Labeling of the Act as a drug ingredient that has been
Act, which is administered by both the Food and added for purposes of color only, but not in con¬
Drug Administration and the Federal Trade formity with a regulation issued under the Act,
Commission (FTC). The Fair Packaging and or not from a batch certified in accordance with
Labeling Act is designed primarily to protect the proper regulation, or not otherwise exempt from
consumer by requiring a prominent display of regulation by FDA.
statements of net contents and ingredients on The Post Office Department prohibits ship¬
the principal display panel of consumer packag¬ ments of poisons, explosives, or injurious or
ing. The law has certain specific requirements fraudulent materials through the mails and has
concerning the placement and size of this infor¬ jurisdiction over drugs falling within this defini¬
mation. Violation of the provisions of this Act tion. Violations are subject to seizure and fine.
might lead to seizure by FDA or-to a cease and The Alcohol Tax Division of the Internal Rev¬
desist order from the FTC. enue Service has jurisdiction over the use of al¬
Often the product development chemist is cohol in the formulation of drugs. Specially de¬
involved in helping to create advertising claims natured alcohol may be purchased for industrial
and copy. To do this, he should understand the use at a fully taxed price. After manufacture of
regulatory agency concerned with these matters. the drug, using such denatured alcohol, the
The FTC (Federal Trade Commission), operat¬ manufacturer may file a claim showing that it
ing under the Federal Trade Commission Act, has been used in the manufacture of a product
has jurisdiction over the advertising and promo¬ unfit for beverage purposes. This qualifies the
tion of all consumer products including drugs manufacturer for a recovery of most of the tax,
and cosmetics. This authority extends to all ad¬ known as a tax “drawback.”
vertising media and is concerned with deceptive Should the industrial pharmacist be involved
advertising practices and with promotion that is in the manufacture of narcotics or other con¬
deemed to be false and misleading. Since there trolled substances, such manufacture is within
is some overlap between the jurisdictions of the the ambit of the Controlled Substances Act and
FTC and the FDA, there has been an agreement regulations thereunder. The Drug Enforcement
between these agencies to the effect that, in Agency (DEA) maintains a quota system for the
general, the FTC would monitor advertising of manufacture of controlled substances and gen¬
OTC drugs and cosmetic products insofar as erally monitors this production by the use of es¬
false and misleading claims might be concerned, tablished yield ratios. Periodic inspection by
whereas the FDA would have responsibility for agents of the DEA are made for the purposes of
drug labeling and all advertising relating to pre¬ verifying accountability and security against

872 • The Theory and Practice of Industrial Pharmacy

loss. Regulations are not only concerned with is not unusual for such laws to exist in large
manufacture of controlled substances, but also municipalities as well as at the state and federal
with provisions against the diversion of these levels. These laws generally deal with misbrand¬
drugs. ing and adulteration, false advertising, and the
If a hearing becomes necessary under any maintenance of sanitary conditions. In order to
provision of the Federal Food, Drug and Cos¬ sort out the proper jurisdiction under which a
metic Act or the Controlled Substances Act, it is particular manufacturing operation is con¬
conducted under the provisions of the Adminis¬ ducted, a body of law known as “preemption”
trative Procedure Act, unless a specific hearing has evolved.
procedure is set forth in the principal Act.41 Rec¬ The doctrine of preemption means that when
ords, letters, memoranda, and other documents a greater and a lesser authority (i.e., a state and
pertaining to particular drugs and/or to matters municipality or the federal government and the
pertinent to a hearing may be requested under state) both regulate a particular activity such as
the provisions of the Freedom of Information the production of pharmaceutical products, and
Act. The FDA generally allows inspection of all find they are in conflict, the highest authority is
such documents except (1) internal memoranda most often deemed to have preempted the regu¬
relating to the regulatory aspects of the adminis¬ latory field, and the law of the higher authority
tration; (2) INDs or NDAs and the material con¬ prevails.
tained therein withdrawn or otherwise expired As with all general rules, the doctrine of pre¬
NDAs or INDs lie in a gray area, with the FDA emption has subrules. For example, if an opera¬
leaning toward disclosure, but with the over¬ tion is strictly an intrastate one, and there is no
whelming sentiment of the industry being that interstate commerce involved, the federal law
these should remain confidential; and (3) mate¬ cannot attach. Similarly, if there is an overriding
rials marked confidential upon submission on “local” concern, as for example a more stringent
request of the FDA by a regulated company. control of the holding or transportation of nar¬
Such material will remain confidential unless cotics for legitimate local reasons, then the more
called for by a third party, at which time the stringent local rule would apply.
party claiming confidentiality must prove to the Lest it be thought that a strictly intrastate
satisfaction of the FDA that the material is in¬ business, if it embraces the practice of industrial
deed confidential; the test is generally whether pharmacy, might be conducted only under state
or not the release of such material will place the law, the courts have increasingly taken the view
person, firm, or corporation submitting it at a that the federal law is applicable on a very broad
competitive disadvantage. scale. For example, it has been held that if any
Finally, there are several other acts that are component used in the manufacture of a drug
too specialized for discussion here, but that may has at any time been shipped in interstate com¬
also be of interest to the industrial pharmacist. merce, federal jurisdiction attaches. Since most
Their titles are fairly indicative of the subject components in a drug have been purchased and
matter of the contents: shipped from an out-of-state supplier, one can
readily understand that an almost universal fed¬
Animal Welfare Act eral jurisdiction applies to the regulation of drug
Caustic Poison Act products.
Controlled Substances Act
There is a uniform state Food, Drug and Cos¬
Controlled Substances Import and Export Act
metic Bill, which is patterned largely after the
Drag Abuse Office and Treatment Act
Hazardous Substances Act federal statute, and which has been endorsed by
Insecticide, Fungicide and Rodenticide Act (Eco¬ the Executive Committee of the Association of
nomic Poisons Act) Food and Drug Officials of the United States. It
Poison Prevention Packaging Act of 1970 has been adopted in many states, and with cer¬
Vims Serum and Toxin Act of 1944 tain modifications, those states dealing with the
manufacture of drugs, even if they themselves
do not use the uniform statute, lean heavily on
State and Local Regulations federal law and definitions. The District of Co¬
The right of any governmental authority to lumbia is, of course, regulated by the federal Act.
pass laws for the protection of its citizens is an Most states provide purity, labeling, and pack¬
inherent one. This right is called the “police aging requirements that are applicable to a
power,” and it is the basis upon which laws reg¬ “drug,” and these are defined most frequently in
ulating drugs and drug products, and their man¬ language identical or similar to that of the fed¬
ufacture, distribution, and sale are predicated. It eral Act. All but 17 states prohibit the marketing

DRUG REGULATORY AFFAIRS • 873

of a new drug (which is defined in federal terms) particular application within the production pro¬
until a new drug application has been filed with cedure to accomplish its beneficial results.
FDA and has been approved. The drug labeling Trade secrets, on the other hand, are generally
requirements of each of the states, as governed those bits of knowledge or ingenuity that may
by their local laws, appear in Table 28-1. well be patentable, but for reasons best known to
the keeper of the secrets, are not imparted to the
general public. One explanation for the keeping
Intellectual and Industrial of a trade secret is that if it is exposed in a pa¬
tent, it can only be monopolized for a short pe¬
Property riod of years, generally 17, after which it can be
The term “intellectual and industrial prop¬ used by others with impunity. As long as the
erty” generally is understood to refer to patents, secret is kept a secret, its use can be exclusive
trademarks, and copyrights. There is often un¬ for an indefinite period. The law recognizes and
certainty, however, regarding the rights each of protects genuine trade secrets. Each of these
these embraces and the manner in which each subjects are discussed subsequently, with em¬
is obtained. There is also that nebulous some¬ phasis being placed on patents because they rep¬
thing called “know-how” and that further some¬ resent the most likely area of industrial property
thing called “trade secrets.” Perhaps most im¬ and intellectual protection for the industrial
portant for the industrial pharmacist is the pharmacist.
ability to recognize the rights, duties, and obliga¬
tions inherent in each of these concepts—as
applied to others as well as to himself. Patents
Briefly, a -patent is a statutory grant of monop¬
Nature of the Grant. In the United States,
oly for a period of years during which an inven¬ the protection of industrial property by patent
tor can exclude others from making, using, or
has its genesis in the Constitution, Article I,
selling his invention. The right is absolute as
Section 8, which states:
long as the validity of the patent is upheld. A
trademark, on the other hand, does not derive its The Congress shall have Power ... to promote the
value or indeed its validity from a statutory Progress of Science in useful Arts, by securing, for
grant. The right to the exclusive use of a trade¬ limited Times to Authors and Inventors the exclusive
mark is derived primarily from the common law Right to their respective Writings and Discoveries.
in that it must be properly used by the person
claiming ownership, and such use may be chal¬ This recognition, by those farsighted founders of
lenged by another even though there is a federal this country, of the essential means of promot¬
or state registration. Registration is merely a ing industrial advance has been the backbone of
procedural tool in that it serves as notice of use technologic and economic growth in the United
and claim of ownership. A copyright (often con¬ States since its inception. By rewarding the in¬
fused with a trademark) is a statutory grant ventive mind with a monopoly, others are
given to creators of artistic or literary works, so prompted to absorb the teaching and improve on
that they might enjoy the fruits of their intellec¬ it. A patent is a right granted by the United
tual labors for a period of years without fearing States Government to an inventor to exclude
plagiarism or other copying. others from making, using, and selling his in¬
Know-how is a term widely used to describe vention for a period of years (usually 17) in ex¬
the accumulated knowledge of a person, a group change for the benefits to be gained by disclos¬
of persons, or, in some instances, a corporate ing the invention to others and to have the
entity. It describes the general intelligence con¬ knowledge in the public domain following the
cerning either the manufacturing, or particular period of exclusive use.
steps in the manufacturing, of a product or prod¬ Most countries of the world have patent laws.
ucts and embraces the experience of years, They vary so widely in their requirements that it
largely empiric, that is generally claimed to im¬ would be impossible to enumerate the differ¬
part particular qualities of elegance or superior¬ ences in this chapter. It is useful to know, how¬
ity to the product manufactured in that manner. ever, that since the general rule in foreign coun¬
“Know-how,” if not patentable, is carefully hus¬ tries is to grant a patent to the first party filing
banded by the owner and usually passed on only for it, such filing should be done as rapidly as
to those who need to know in order to continue possible after the issuance of the United States
the production of the product. In general, it is Patent. Some measure of protection is afforded
knowledge that is common, but that involves a to the United States patent owner by an intema-

874 • The Theory and Practice of Industrial Pharmacy

 tionaJ Convention to which the United States Finally, in addition to being new, useful, and
belongs. The convention provides that a patent not obvious, the invention must not be barred by
application filed in a foreign country within one having been previously known, used, or sold
year of its first filing in a Convention country is publicly in the United States, or patented or de¬
given the earlier filing date. The following dis¬ scribed in a publication anywhere in the world
cussion relates only to United States Patent law. before the invention by the applicant, or more
Requirements. To be patentable, an inven¬ than one year prior to the filing of the applica¬
tion must be new, useful, and not obvious to one tion obtaining a patent.
skilled in the art to which the invention per¬ Since strong proof of the date of conception is
tains. To be new, the article must be novel, that the inventor’s best insurance for obtaining his
is, of a novelty requiring more than the use of patent, he should keep careful notes, preferably
journeymen skills in the field to which the in¬ in a bound notebook, giving a brief description of
vention applies. And newness alone does not the invention and the manner in which it is ex¬
support patentability. pected to work. This record should be dated by
The requirement that the development not be the inventor, and should be witnessed by at least
obvious is the main criterion for patentability. one other person who is able to understand the
An invention or development may not be obvi¬ invention. Often, in an interference or a litiga¬
ous for several reasons. The results obtained tion involving two or more claimants, this early
from the use of the development are unex¬ record can be controlling.
pected, that is, they are outside the general the¬ An interference is a procedural device used by
ory pertaining to the combination of the various the Patent Office and is declared when different
ingredients. This concept is also related to lack inventors have applied for the same invention.
of obviousness that might come about by way of Since uncorroborated testimony of the inventor
synthesization, with unexpected results arising as to the date of invention is not admissible, a
from the utilization of two or more known fea¬ failure to make early disclosure records as noted
tures in a combination resulting in something above can lead to the loss of valuable rights. The
greater than a mere sum of known effects. The attesting witness might have to give testimony
invention may relate to new compositions of at a later date, and therefore the fullest explana¬
matter as in the synthesis of a new chemical tion of the invention and the manner in which it
entity, which must not be an obvious variation of operates should be given to the witness, since he
the prior art compounds or compositions. The will later have to describe in detail that which
invention might also be a new approach to solv¬ was explained to him.
ing technical problems or even for the produc¬ Although it is not necessary to reduce an in¬
tion of a new plant strain. vention to practice, there must be in the applica¬
To be useful, the invention must be able to be tion enough detail to enable one skilled in the art
reduced to practice, and must perform in a pre¬ to practice it. Patent applications for pharma¬
dictable manner in accordance with the claims ceuticals generally are not filed until the utility
made for such performance in the Patent appli¬ of the pharmaceutical has been determined, and
cation. For other than pharmaceutical inven¬ this, in a sense, is “reduction to practice.”
tions, utility is rarely a problem. The United When an invention is made and sufficient
States Patent Office has taken an increasingly data gathered to prove it useful, the next step
stringent position with respect to utility data for should be a disclosure to a patent attorney, who
pharmaceuticals, particularly those intended for will then follow several prescribed steps to ob¬
the treatment of serious illness. The claims for tain the patent. He will usually want to do a
utility should be written clearly and concisely search of the prior art in an effort to determine
with as much detail as possible to prove that the novelty. Such a search is not required by the
product will perform in a uniform manner with a rules of the Patent Office, but a careful patent
- predictable result. Patent coverage can be ob¬ attorney will want the information so as not to
tained on compositions of matter, apparatuses, waste the time and money of his client or the
new processes of manufacture, new article of time of the patent examiner.
manufacture, and asexually reproduced plants. Once satisfied that the invention has all the
For the sake of completeness, it should be elements of patentability, the patent attorney
mentioned that design patents may be issued. draws up the application, the principal portions
These are generally for nonfunctional elements of which are the specification and the claims.
of an article of manufacture. The period of de¬ The specification is a detailed description of the
sign patent exclusivity is much shorter, running invention, including general and preferred ver¬
usually for a period of 7 years. sions, with necessary supporting data when ap-

DRUG REGULATORY AFFAIRS * 875

 877
DRUG REGULATORY AFFAIRS •
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plicable. A specification also may include draw¬ General Comments. Since the benefits de¬
ings, graphs, or any other aids to the rived from a patent are manifold, certain restric¬
understanding of the invention. If the prior art tions must be kept in mind both by the inventor
search has uncovered references, these may also and by those who would use the invention. A
be included in the specification, and distin¬ patent grants the right to exclude others from
guishing features of the invention for which pa¬ making, using, and selling the invention, but
tent is sought should be set forth. All of this is this right may be restricted if the patent is sub¬
designed to enable one skilled in the art to un¬ ordinate to another. For instance, a new chemi¬
derstand the invention and to employ it. cal entity that has been granted a patent may be
Perhaps the most critical part of the applica¬ taken by a second inventor and combined with
tion is the section containing claims, which ap¬ another compound to form a new and useful
pear as a series of numbered paragraphs setting compound, the properties of which were not
forth the scope of the patent protection sought. obvious to those skilled in the art. Thus, to prac¬
These claims are important because, when a tice the teaching of the second invention, one
patent is granted, the claims form the basis of would of necessity have to reward the original
exclusivity and determine whether another has inventor.
infringed on the issued patent. Beginning with Licensing is a system of rewarding the origi¬
the first of the numbered paragraphs, claims are nal inventor and to otherwise authorize the
presented in the order of the broadest protection practice of the invention by person^ other than
sought to the narrowest embodiment of the in¬ the inventor. The license grants the right to
vention. Since the claims determine infringe¬ make, to use, or to sell the invention, or any ap¬
ment, they should include all of the elements of propriate combination of these rights. A licensor
the invention, because no patent protection is is usually given periodic payments, called royal¬
accorded subject matter disclosed in the specifi¬ ties, for the term of the patent. Of course, it is
cation, only subject matter specifically claimed also possible, after negotiation, to purchase the
in the claims section. rights to a patent from the inventory by an out¬
Once all specifications and claims are written, right lump sum payment.
the necessary formal documents, including an Patent licensing is a delicate endeavor today,
oath by the inventor, are completed, an attorney since there have been decisions in the antitrust
is appointed, and the application is filed with the area which tend to restrict the types of license
Patent Office and receives an application num¬ that might be granted. For instance, it has been
ber and a filing date. It is thereafter examined by held in certain cases to be a violation of the anti¬
a patent examiner, who is generally a person trust laws to license an invention in only one
trained or skilled in the art relating to the inven¬ area of the marketplace and not in another—for
tion. Should questions arise in the mind of the example, to license the use of the invention in
examiner, he asks in writing for clarification or oral dosage forms to one licensee and in paren¬
limitation or other remedial steps. These are teral dosage forms to another licensee. Inatten¬
called Office Actions, to which responses by the tion to these important interdictions (which at
inventor are invited—indeed, are mandatory if this writing tend to become more and more re¬
the patent is to be issued. Following these ac¬ strictive) could lead to the imposition of fines,
tions, the application is allowed in all of its parts, both on the licensor and the licensee, or in more
in some of its parts, or in a restricted way, or it is aggravated cases, the loss of patent protection
finally rejected. There is an appeal procedure entirely.
from final rejection, but if it is not successful, Applications for patents in the United States
the application either becomes abandoned or are submitted in the name of the inventor, and
may be further appealed to the Patent Office he personally receives the grant of patent. In the
Board of Appeals, which is the final agency re¬ larger industrial centers, including pharmaceu¬
view. The Board is a tribunal of three highly tical manufacturers, it is common practice for
qualified Patent Office experts who pass on the the inventor to assign the patent application to
merits of the examiner’s and the applicant’s po¬ his employer in consideration of his continued
sitions. The decision of the Board may be ap¬ employment, that is, inasmuch as he was hired
pealed to the Court of Customs and Patent Ap¬ to do the research and was given the facilities to
peals or to any United States District Court do it by the employer, he is expected to make the
having jurisdiction. Elapsed time from applica¬ proper assignment. Usually, a contract covers
tion to allowance without an appeal is generally this right of the employer to receive and benefit
considered to be more than two years but less from the inventions of his employee. When no
than four. Appeals, of course, may make the such contract exists and the inventor balks at an
time span longer. assignment, a legal doctrine of “shop right” be-

878 • The Theory and Practice of Industrial Pharmacy

comes operative. This is a right that belongs to not by the fact of registration. The registration of
the employer, who has implicitly been given the a trademark may be accomplished either in a
right to use the invention because he supplied state having a trademark registration statute or
the necessary support for the inventor, and al¬ at the Federal level. To be registered in the
lows him to use the patent even though title United States Patent Office, the trademark must
remains in the name of the inventor. be used on goods that have actually travelled in
If there is more than one inventor, that is, if interstate commerce.
two or more individuals have contributed to the Thus, the application for a trademark must
conception and/or the reduction to practice of await the first use of that mark in interstate
the invention, each contributor is separately commerce, the date of which, along with the
named and becomes a “co-inventor.” The impor¬ date of its first use anywhere, must appear on
tant thing to remember about co-inventors is the application. The trademark must not be de¬
that each may separately exploit the patent, un¬ scriptive of the goods or any of its properties (al¬
less there is a contractual agreement among though it may be “suggestive”); it must not be so
them to act in concert. Therefore, one having an similar to prior registrations as to cause con¬
interest as a licensee in a patent for which there fusion as to the source of origin of the goods; it
are co-inventors, especially if that interest is must not be immoral or deceptive; and it must
exclusive, should either obtain a license from all not utilize the flag or insignia of the United
or have the noncontracting inventors agree on States or the portrait or likeness of any living
the licensing document to the exclusivity of the individual without that individual’s consent.
license granted. Trademark protection extends over a period of
An inventor can stop an infringement by ap¬ 20 years, and is renewable indefinitely as long as
plying to a Federal court for relief, which is gen¬ the trademark continues to be used by its owner.
erally available in two forms. One is injunction, Ownership of a trademark is transferable by as¬
that is, a judicially imposed restriction against signment, and the use thereof is able to be li¬
the infringer from continuing to make, use, or censed.
sell the invention; the other involves an award of A trademark represents good will. The consid¬
damages to the inventor for past infringement. erable value of such good will often cannot be
Since there can be no infringement prior to determined in units of absolute dollars. For in¬
the issuing of the patent, the inventor who stance, if by some quirk of massive misfortune,
wishes to exclude others even during the pen¬ all the Coca-Cola bottling plants in the United
dancy of his application can mark his product States should bum down today, there would be
with the phrases “Patent Pending” or “Patent no question that because of the extensive good
Applied For.” These phrases serve as warnings will in that trademark alone, the necessary fi¬
to putative infringers that they make, use, or sell nancing could be had to begin to rebuild the
the invention at their peril. Notices on goods plants tomorrow.
that bear patent numbers, of course, refer to al¬ A registered trademark may be infringed by
ready issued patents, and infringement after others who use the same mark or a similar mark
issue can result in damages generally based on on the same or similar goods or on goods that
the measure of sales lost by the patent holder. travel in the same channels of trade. The legal
Finally, it should not be overlooked that is¬ determination for an infringement is whether
sued patents in any particular field are a rich the second user of the mark confuses the buying
source of research data. Further, because coun¬ public regarding the originator of the goods on
tries foreign to the United States may issue pat¬ which the mark appears.
ents earlier than the U.S. Patent Office, foreign Since the axiom is that trademark rights are
inventions should be monitored, as they are gained only by proper use, it is possible to have
often the first indication of new technologic de¬ an infringement of an unregistered mark. An
velopments in the United States. action for such infringement is generally
couched in terms of the law of unfair competi¬
tion, of which the trademark laws have uni¬
formly been held to be a subdivision.
Trademarks A word trademark is a name; it is a special part
A trademark, unlike a patent, is not a statutory of the language having unusual characteristics.
grant of monopoly. A trademark is any word, It should always be used in conjunction with a
name, symbol, or device that a manufacturer or generic or descriptive term, for instance, Lib¬
trader places on his goods to distinguish them rium, brand of chlordiazepoxide. The use of a
from goods manufactured or sold by others. The descriptive or generic term preserves the func¬
validity of a trademark is tested by its proper use, tion of the trademark as a symbol pointing to the

DRUG REGULATORY AFFAIRS • 879

source of origii and not as a descriptive term for the jurisdictions in the United States today, both
the article itself. The trademark might be ren¬ law and equity relief can be sought in one court
dered invalid if it is not used at all or if it is used rather than in separate courts, which our com¬
improperly, that is, if it falls into the common mon law adopted from the ancient English prac¬
language to describe the article. Prime examples tice, but which has now been uniformly replaced
of trademarks that have been lost by such im¬ by the single jurisdiction system.
proper use are aspirin, cellophane, and escala¬ One possible grievance in an unfair competi¬
tor. Trademark owners jealously guard their tion action is interference with a contractual re¬
rights, and more popular trademarks become the lationship. Such interference could take the
subject of letters to publishers or printers to form of commercial disparagement, that is, dis¬
remind them that the trademark should always paragement of the name of a company or of its
be printed either in all-caps or at least in initial product; the hiring of an employee to gain in¬
caps, generally with quotation marks and never sight into the prior employer’s business prac¬
in the possessive. tices or customers; or some other inducement of
A claim to trademark rights is generally a breach of contract by one party to the detri¬
printed by the claimant on the goods and in ad¬ ment of another.
vertisements relating to the goods. Prior to Fed¬ The law of unfair competition also provides for
eral registration, the symbol “TM” is generally protection of know-how and trade secrets, which
used in conjunction with the mark. After regis¬ are as much a property right as a patent or a
tration, the symbol ® or the phrases “Trademark trademark. Although the theft or disclosure of
Registered,” “Trademark Registered in the these is actionable, anyone innocently receiving
United States Patent Office,” or “TM Reg. U.S. knowledge of a trade secret or know-how in the
Pat. Off.” are used. These notices serve, as with usual course of his business may practice such
patent notices, to tell would-be infringers that knowledge with' impunity. This points up the
they adopt this mark at their peril. Infringement peril of attempting to keep commercial secrets,
and unfair competition actions may be brought since their only protection lies in their freedom
in United States District Courts in the case of from theft. For this reason, when secret infor¬
Federally registered trademarks or in state mation is received or given, it is usually done on
courts on counts of unfair competition. Dam¬ the basis of a “confidential disclosure.” It should
ages are awarded against infringers based on an be given in writing, with the receiver acknowl¬
assessment of the damage that the infringement edging and promising to maintain its confiden¬
has caused to the goodwill of the trademark tiality.
owner. Finally, the law of unfair competition prevents
A trade name, for which registration also is the paJming-off of the goods of one trader as
permitted, is distinguishable from a trademark being those of another, as in false advertising
in that the trade name identifies the manufac¬ and in misleading statements made by sales per¬
turer or trader rather than the goods themselves. sonnel. Recent decisions have narrowed the
For instance, Schering-Plough Inc. is a trade scope of this type of protection in that elements
name identifying a manufacturer; Coricidin is of an article not protected by United States pat¬
that manufacturer’s well-known brand name for ents or trademark registrations may be copied
a product for the relief of the symptoms of colds. with impunity. Thus, nonfunctional features,
even though they are unique with the original
user and might serve to indicate origin, cannot
be held exclusively unless the originator can
Unfair Competition show that these nonfunctional features have
The law of unfair competition is almost as old gained “secondary meaning,” and are attributed
as the common law itself. Essentially, it is the in the minds of purchasers with the originator
effort of the law to referee in the marketplace only and with no one else. In other words, it
and to maintain fair and open competition serves to identify the goods as coming from a
among traders. It covers a vast array of commer¬ particular manufacturer or trader.
cial wrongs, some of which, e.g., the Patent and
Trademark laws, have been codified. Complaints
in the area of unfair competition generally seek
relief under the principles of both equity and Copyrights
law. That is, they seek specific performance or A copyright is a statutory grant of monopoly
specific nonperformance (injunction), which is for a period of years. Generally, it is for 27 years
an outgrowth of the ancient laws of equity, or renewable for another 27 years by the copyright
they seek money damages (law), or both. In all of owner or his heirs or assigns. After that, the

880 • The Theory and Practice of Industrial Pharmacy

 copyrighted material falls into the public domain because the purchase was not made by the per¬
and can be used by anyone. son injured (the privity doctrine), has largely
Copyright protection may be granted for works been abandoned. The implication of liability has
of art and literature, and a copyright carries with been so broadened that virtually anyone using
it, as does a patent, the right to exclude others the product and being hurt can, upon a showing
from reproducing the work of art or literature that the product was properly used (or at least
without compensation to the copyright owner. A not abused), be compensated for the injury.
copyright is obtained by the filing of an applica¬ The other concept is that of negligence, that
tion on which is stated the nature of the work; in is, the product or food was manufactured in
the case of published literature or music, a copy such a way that it contained a defect that should
is filed with the Library of Congress. For works have been eliminated or discovered by the man¬
of art, such as painting and sculpture, generally ufacturer. Thus, the article, when placed in the
a picture will suffice. The danger inherent in the hands of the consumer, carries with it an inher¬
publication of a copyrightable work lies in the ent danger even if properly used. The burden on
fact that rights gained through copyright might pharmaceutical manufacturers is especially
be lost if a proper copyright notice is not placed heavy, their product by its very nature being po¬
on the article before it is published or otherwise tentially dangerous; however, strict adherence
made public. Thus, a musical composition per¬ to current good manufacturing practices and
formed before an audience or a book dissemi¬ stringent quality control are the pharmaceutical
nated widely without a printed claim of copy¬ manufacturer’s best protection.
right almost invariably causes that work of art to
fall immediately into the public domain. Since it
is so easy to lose copyright rights, competent References
advice should be sought whenever a new work
1. 21 United States Code (USC) 301 et seq.
of art or literature is to be made available for 2. 21 USC 321 (g) (1).
public sale or use. The Copyright Office in the 3. 21 USC 321 (k).
Library of Congress supplies the forms neces¬ 4. 21 USC 321 (m).
sary for copyright application, but since applica¬ 5. 21 USC 321 (p).
tion is an after-the-fact event, advice concerning 6. 21 USC 321 (w), which was added by Section 102(e)
proper notice should be sought at an early stage of the Animal Drug Amendments of 1968, PL 90-399,
90th Congress, effective August 1, 1969.
in the development of the work of art or litera¬ 7. 21 USC 321 (x), which was added by Section 102(e)
ture. of the Animal Drug Amendments of 1968, ibid.
Copyright rights are commonly claimed by the 8. Constitution of the United States, Section 8, “The
use of the phrase: Copyright, year, name of the Congress shall have Power ... To regulate Com¬
copyright claimant. The symbol © might also be merce with foreign Nations, and among the several
used as: © year, name of claimant. states, and with the Indian tribes ...”
9. Insulin Amendment of 1941.
Antibiotic Amendments of 1945, 1947. 1949, and
1962.
Product Liability Prescription Drug (Durham-Humphrey) Amend¬
The manufacture of a product that is to be ment of 1951.
purchased for use or consumption carries with it Pesticides (Miller) Amendments of 1954.
the responsibility to make that product as free Procedural (Hale) Amendments of 1954 and 1956.
Food Additives Amendment of 1958.
from hazard as possible. The law of product lia¬
Color Additives Amendment of 1960.
bility is a common law concept. Broadly stated, it Drug (Kefauver-Harris) Amendments of 1962.
gives redress to a purchaser based on the con¬ Drug Abuse Control Amendments of 1965.
cept of breach of contract or of negligence, or Animal Drug Amendments of T 968.
some combination of the two. The breach of con- Controlled Substances Act of 1970.
- .tact, a legal fiction, holds that there is an im¬ Drug Listing Act of 1972.
Vitamins and Minerals Amendment of 1976.
plied warranty of merchantability of the goods Medical Device Amendment of 1976. (This “amend¬
for their intended use, that is, if used in the ment” is itself longer than the basic act.)
manner prescribed by the manufacturer or 10. Kefauver-Harris Amendments, Public Law (PL) 87-
seller, there will be no hazard inuring to the pur¬ 781, 87th Congress, October 10, 1962.
chaser or user. Increasingly, state laws are being 11. Section 102(c) of the Drug Amendments of 1962,
so broadened as to remove the need for a direct amending Section 505(d) (21 USC 355 (d)) of the
1938 Act.
relationship (as at the old common law) between 12. 21 Code of Federal Regulations (CFR) Part 312.
the purchaser and the seller. The anomalous sit¬ 13. 21 CFR 310(h).
uation, for instance, wherein a child hurt by a 14. 21 CFR 56.101-56.124 (1983 ed.).
product bought by a parent could not recover 15. IRBs must keep detailed records of their proceedings,

DRUG REGULATORY AFFAIRS • 881

 and if they refuse to make those records available to codeine, heroin, marijuana, morphine, opium, paral¬
the FDA, the agency may refuse to evaluate any IND dehyde, peyote, or sulfonmethane; or any chemical
data involving such an IRB. 21 CFR 56.115(c) (1983 derivative of such substance, which derivative of
ed.). such substance has been by the Secretary, after in¬
16. 21 CFR 314.1(f). vestigation, found to be, and by regulations desig¬
17. Section 201(w) (21 USC 321(w)) and Section 201(x) nated as, habit forming ...”
(21 USC 321(x)) respectively. 30. 21 CFR 131 and 130.102; recodified as 369 and
18. 21 CFR 433.1 (1983 ed.). This proposal was made on 310.201 respectively.
May 4, 1982 (47 FR 19954), and published in final 31. 21 CFR 201.56.
form on September 7, 1982 (47 FR 39155). 32. Section 510 of the Act (21 USC 360).
19. 21 CFR 429.40 (1983 ed.). 33. Section 501(a)(2) of the Act, 21 USC 351(a)(2).
20. This classification, which no longer exists, was 34. Current Good Manufacturing Practice Regulations
meant to provide for the situation in which a particu¬ appear at 21 CFR Parts 210 (general), 211 (finished
lar drug entity might be considered to be effective, pharmaceuticals), 229 (blood and allergenic prod¬
but its use must be restricted to certain dosage ranges ucts). Section 211.1 states:
or must not be in combination with other drugs, or (a) The criteria in §211.20-211.115, inclusive, shall
must be administered in some special way. Since the apply in determining whether the methods used in,
“but” was not a uniform consideration, however, or the facilities or controls used for, the manufacture,
these classifications were returned to the panels for processing, packing, or holding of a drug conform to
their determination of the effectiveness of the drug, or are operated or administered in conformity with
and if there were conditions on such effectiveness, current good manufacturing practice to assure that a
these were to be stated in proposed labeling. drug meets the requirements of the act as to safety,
21. American Public Health Association and National and has the identity and strength, and meets the
Council of Senior Citizens v. John G. Veneman, Act¬ quality and purity characteristics, which it puiports
ing Secretary of HEW, and Charles Edwards, Com¬ or is represented to possess, as required by Sec¬
missioner of FDA, 349 F. Supp. 1311, DC, 1972. tion 501(a)(2)(B) of the act.
22. Section of 107(c)(4) of Public Law 87-781, provided: (b) The regulations in this part permit the use of pre¬
In the case of any drug which, on the day, immedi¬ cision automatic mechanical or electronic equipment
ately preceding the enactment date, [October 10, in the production and control of drugs when adequate
1962] (A) was commercially used or sold in the inspection and checking procedures are used to as¬
United States, (B) was not a new drug as defined by sure proper performance.
Section 201(p) of the Basic Act as then in force and 35. Section 704 21 USC 374 of the Act gives FDA the
(C) was not covered by an effective application ynder right for purposes of enforcing the Act, upon the pres¬
Section 505 of that Act, the amendments to Sec¬ entation by the Inspector of appropriate credentials
tion 201(p) made by this Act under conditions pre¬ and a written notice to the owner, operator or agent in
scribed, recommended, or suggested in labeling with charge, the authority to enter at reasonable time, and
respect to such drug on that day. to inspect at reasonable times and within reasonable
limits and in a reasonable manner, any factory ware¬
23. Casper W. Weinberger, Secretary of Health, Educa¬
house or establishment in which drugs are manufac¬
tion & Welfare et al. v. Bentex Pharmaceuticals, Inc.,
tured, processed, packed, or held for introduction into
et al., 412 U.S. 645, 1973.
interstate commerce, or after such introduction, or to
24. USV Pharmaceutical Corporation v. Weinberger,
enter any vehicle being used to transport or haul
412 U.S. 655, 1973.
such drug in interstate commerce. This Section does
25. Casper W. Weinberger, Secretary of Health, Educa¬
not apply to pharmacies which operate under applica¬
tion & Welfare, et al. v. Hynson, Westcott & Dun¬
ble local laws and practitioners licensed by law to pre¬
ning, Incorporated, 412 U.S. 609, 1973.
scribe or administer drugs.
26. CIBA Corporation v. Weinberger, 412 U.S. 640,1973.
36. 21 CFR 1.106(b)(3).
27. United States v. Generix Drug Co., 103 S. Ct. 1298
37. Section 304 of the Act, 21 USC §334.
(1983).
38. Section 302 of the Act, 21 USC §332.
28. For example, for antacids, 21 CFR 331.1 et seq.
39. Section 303 of the Act, 21 USC §333.
(1983 ed.), and for antiflatulent products, 21 CFR
40. 21 USC 335.
332.1 et seq. (1983 ed.).
41. Section 701(c) of the Act (21 USC 371 (c)) and regu¬
29. "... alpha eucaine, barbituric acid, beta eucaine,
lations promulgated thereunder 21 CFR Part 12.
bromal, cannabis, carbromal, chloral, coca, cocaine,

882 • The Theory and Practice of Industrial Pharmacy

 Index

Page numbers in italics refer to illustrations; page numbers followed by a t refer to tables; page numbers followed
by an n refer to notes.

ABC concept of inventory management, 748, 748 selection of, 608

Abrasion test(s), 78 advantages of, 589
Absorption, 204-205, 205 components of, 589-597
factors affecting, 221-226 selection of, 606—608
percutaneous, 225, 536-539 containers for, 591-594, 731
See also Absorption profile(s); Bioavailability pressure limitations of, 600t
Absorption base(s), for semisohds, 545-547 quality control for, 615
Absorption profile(s), 204-205, 205 selection of, 607-608
in dosage form evaluation, 239, 240t stability testing of, 609-610
"Absorption window,” 233 dip tubes for, 595
Acacia, 327 quality control for, 613-614
Accela-Cota system, 347, 348, 351 dispersion, 603-604
capsule polishing with, 393 foam, 604-605
Accelerant(s), in topical drugs, 539 actuators for, 596, 598, 599
Acceptable quality level, 825-828, 826, 827 testing for stability of, 616-617
Accogel machine, 399 formulation of, 597-608
Accumulation, 205-208, 206, 207, 208 intranasal, formulation of, 605-606
Accuracy, 847-848 metered-dose actuators for, 596-597
Ac-Di-Sol, as disintegrant, 328 manufacture of, 610-613, 610, 611
Acetaminophen, ingredients for tablets, 344 net contents of, determination of, 616
quality assurance specifications for, 806t propellants for, 589-591, 590t, 592, 593
Acid value, of suppository bases, 569-575 identification of, in product testing, 616
Ackley capsule imprinter, 395 quality control for, 613
Acrylate polymer(s), in film coating, 366, 368 selection of, 606-607
Acrylic multipolymerfs), 715, 718t-719t, 720t-721t stability testing of, 609
Activation energy, 192, 765 quality control for, 613-615
Active oxygen value, 585 solution, 597-600
Actuators), for aerosols, 596-597, 596, 598, 599 spray patterns of, testing, 616, 616
quality control for, 613-614 suspension, 603-604
selection of, 608 for intranasal use, 606
Adhesion, 67 testing of, 615-618
Adhesive(s), for tablets, 3211, 327-328 for stability, 608-610
Adiabatic saturation temperature, 50 for toxicity, 617-618
Administrative Procedure Act, 873 two-phase, 597-600
Adrenocorticotropin (ACTH), preparation of suspension types of, 597-606
of, 488 vives for, 594-595, 594, 595
Adsorption, at solid-liquid interfaces, 119-121, 119 Aquasol, 600-603, 601, 602
base, 403-404, 405t discharge rate determination, 616
specific, surface charge and, 110 metering, 595, 595, 614, 616
Adulteration, 853 quality control for, 613-614
Adverse reaction(s), evaluation of, 854 selection of, 608
information on, on package inserts, 868 stability testing of, 610
Aeration, of semisolids, prevention of, 554-555 water-based, 600-603, 601, 602
of suspensions, prevention of, 42 with propellant and product separated, 607-608
treatment of, 704 Aggregating agent(s), suspensions with, examples of
See also Deaeration formulations, 495-496
Aerosol(s), 589-618 Aggregation, 114-116, 115, 116
actuators for, 596-597, 596, 598, 599 in suspension formulation, 481-484, 482, 483
quality control for, 613-614 of suspensions, measurement of, 484

883
 Agitation, in emulsion formation, foaming during, 512 Base adsorption, 403-404, 405t
timing and, 509 Batch production record, 830
in emulsion shelf life assessment, 529 Bentex case, 865
Air control. See Dust collection; Ventilation Bentonite, as auxiliary emulsifier, 518
Air jet(s), for fluid mixing, 7, 7 as disintegrant, 328
Air suspension, microencapsulation by, 419-420, 419t, Benzalkonium chloride, in suspensions, interaction
419 with other ingredients, 491
Alcohol, regulations on use of, 872 Benzocaine, increasing stability of, 775, 775t
Aluminum, aerosol containers of, 592-594, 600t, 607 BET nitrogen adsorption, 182
collapsible tubes of, 717 Beta-propiolactone, sterilization by, 635-636
drug stability and, 800 Bias, in statistics, 245-246
Aluminum cap(s), 671 Biliary clearance, 214-215, 215t
cleaning of, 665-666 Biliary excretion, 214-215
Aluminum hydroxide, in aggregated suspensions, 489 Biliary recycling, 215-216, 216
in antacid suspensions, 497-498 Binder(s), for tablets, 320, 3211, 327-328
Amide hydrolysis, 777-779, 778 force-displacement curves in selection of, 86, 86
Aminophyllinc tablet(s), ingredients for, 343 scale-up considerations with, 688-689
Amphiphilic compound(s), 502 Binding, of parabens, 465, 466, 468, 521, 522t, 552,
Ampul(s), filling of, 667 552t, 653
leaker test for, 673 to plasma proteins, drug elimination and, 208-209
sealing of, 671 effects of disease on, 220
Animal drug(s), new, 856-857, 862-863 Bingham plastic, 125, 126
Animal Drug Amendment (1968), 862-863 Binomial distribution, 258-260, 258t, 258
Animal feed, 857, 862-863 statistical tests of data with, 260-261
Animal test(s), 859 Binomial formula, 258-259
Antacid(s), chewable tablets, ingredients for, 343 Bioavailability, crossover studies of, 276-278
suspensions, 497-498 defined, 204
in vitro neutralization capacity of, 499-500, 499t in dosage form evaluation, 235-236, 237-239, 238,
Antiadherent(s), in tablets, 328 238t, 239t, 240t
Antibacterial agent(s), in sterile products, 642 of drugs in soft capsules, 410-411
Antibiotic(s), certification of, 863 of sustained release formulations, testing methods
testing of raw materials, 807, 808t for, 448-450, 449
Antifoam(s), in emulsion formation, 512 Biopharmaceutics, 197-242
Antioxidant(s), 783-784, 783t application of, in product development, 226-239
in emulsions, 522-523, 522t Biotransformation, 211-214. See also Metabolism
in polyethylene, 713 preclinical studies of, 227-229
in semisolid formulations, 554, 558t Bisulfite. See Sodium bisulfite
in sterile products, 642-644,' 644t “Black Box” regulation, 865
in suppositories, 585 Blendeifs). See Mixer(s)
in vegetable oils for semisolid formulations, 540-541 Blending. See Mixing
Antistatic additive(s), in polyethylene, 713 Blister pack, 726-727, 726, 727t
• Apocrine gland(s), 536 Blistering, of coated tablets, 371
Applicator(s), for aerosols. See Actuator(s) Bloom of gelatin, 400
Aquasol Valve, 600-603, 601, 602 Bloom on coated tablets, 371
Aquateric, 367-368 “Blooming,” of cocoa butter, 587
“Arching,” 314, 314 of glass, 712
Arrhenius equation, 192-193, 765-766, 766 Body-mix technique, 151
Asbestos, as filter aid, 151, 151t Bonding, cold, 73
Asbestos pad(s), sterile filtration with, 155-156 fusion, 73
Aseptic processing, 619, 633-634 Bond’s equation, 32
validation of, 622, 623 Bottle(s), sealing, for sterile products, 671
Aspartame, in liquid pharmaceuticals, 469, 469, 470t for tamper-resistance, 728, 728, 729-730
in tablets, 329 Bougies, 564
Aspirin, hydrolysis of, 773-774, 774t, 774 Boundary region(s). See Interface(s)
tablets, effervescent, 334-335, 344 Bowman’s capsule, 209
ingredients for, 344 Breach of contract, product liability and, 881
Atomization, in film coating of tablets, 360 Breaking test, for suppositories, 586-587, 587
Atomizer(s), for spray dryers, 61 Bridging, of film coat, 371
Attrition mill(s), 37t of particulate solids, 314, 314
Auditing, 815 Brittle fracture, 72
Autoanalyzer, 850 Brunauer, Emmett and Teller (BET) nitrogen
Autoclave(s), 625, 625 adsorption, 182
Autoxidation, 522, 780 Bubble pack, 728
Bubble point test, 157-158, 158, 159, 633
Bacterial Endotoxins Test, 675 Buffer(s), catalysis of degradation by, 768-769, 769
Bafflefs), in fluid mixing, 8 in sterile products, 644
Ball miil(s), 40-41 ionic strength calculations for solutions, 191
Barrier concept, sustained release formulations using, selection of, for liquid pharmaceuticals, 459-460,
443, 444-446, 445, 451-452 460

884 • Index
Bulk characterization, in preformulation research, 176- Cellulose acetate phthalate, in film coating, 367-368
184 Central limit theorem, 249
Bulk density, 71, 183, 183, 316 Centrality, measures of, 250
Bulk transport, in fluid mixing, 3-4 Centrifugation, in emulsion shelf life assessment, 528-
Burden, 759 529
Centrifuge(s), filtering, 166
Caking, in suspensions, 484 Ceresin, 540
Calcium sulfate, as tablet diluent, 326 Cetyl alcohol, in semisolids, 541
Calorimetry, differential scanning, solid CF granulator, 342, 342
characterization by, 179-180, 179, 180 Chamber product, 61
Cap(s), breakable, 730 Charge. See Surface charge
crown, 721 Chelating agent(s), in preventing oxidation, 784
lug, 721 in sterile products, 652-653
threaded screw, 720-721 Chemical weigh sheet, 685
See also Aluminum cap(s); Closure(s) Chemical weighing, dust collection specifications for,
Capillary-rise method, 108-109 739, 740
Cap-locking, 468 facilities for, 739-741, 740
Capping of tablets, 88-89, 88, 311-312, 701 Chilsonator roller-compactor, 319-320, 319, 698, 698
Capsule(s), 374-429. See also Microencapsulation Chi-square test(s) of significance, 261-262, 261t
disadvantages of, 294 Chlorpromazine, degradation of 785
hard, 374-398 ingredients for tablets, 344-345
filhng capacity of, 386t Chocolate-coated tablet(s), 332
fitting equipment for, 377-384 Chromatographic method(s), automated, 850-851
instrumentation of, 95-97, 96, 97 in stability testing, 789, 849, 849t
fitting operations for, 386-398 CIP system, 664
control procedures in, 392, 831 Clarification, 147, 471, 667. See also Filtration
scale-up considerations with, 702-703 filter media for, 148
special techniques, 395-398 Clarity test, 472
finishing of, 393-395 for sterile products, 673-674
formulations for, 389-392 Class 100 clean room, 660-661
handling and storage of empties, 376-377, 386- Clay(s), as auxiliary emulsifiers, 518
389, 703 as disintegrants, 328
humidity and, 703 in formulation of dispersed suspensions, 490
liquid and semisolid filling for, 397-398 Cleaning, of semisolid manufacturing equipment, 562-
materials used in, 374-375 563
method of production of, 375-377, 376 of sterile products processing equipment, 664, 666
scale-up considerations with, 687-696, 702-703 Clearance, 199-201. See also Renal clearance
in-process quality control for, 392, 831 biliary, 214-215, 215t
soft gelatin, 398-412 hepatic, 200, 212-214, 213
advantages of, 410-412 Clindamycin, degradation of 777, 777
bioavailability of drugs in, 410-411 Closure(s), 720-723. See also Cap(s); Rubber chosure(s)
for use as suppositories, 580 liners for, 720t, 722, 722t
manufacture of, 398-399, 406-408 pilferproof, 721-722
nature of contents of, 401-406 roll-on, 721-722
nature of shell of 3Q9-401, 400t, 401t non-reusable, 722
packaging of, 409-410 Clothing, for aseptic processing personnel, 661
pharmaceutical applications of, 398 Coacervation-phase separation, microencapsulation by,
physical stability of, 405-406, 408-409, 408 419t, 420-425, 425
sizes and shapes of, 399, 402 incompatible polymer method, 422-423, 422
sustained release, 442, 451-452 nonsolvent method, 423, 423
Carbidopa, combination therapy with levodopa, 229, polymer-polymer interaction method, 424, 424
234 salt method, 423-424, 423
levodopa bioavailability and, 229, 230t temperature change method, 422, 422
Carbon, as filter aid, 151, 1511 Coagulation, in colloidal system, 112-113
Carboxyl vinyl polymeris), as auxiliary emulsifiers, 518 Coagule(s), 483, 483
Carboxymethylcellulose, for viscosity control of liquid Coalescence, of emulsions, 527
pharmaceuticals, 470 Coater(s), fluidized-bed, 350-351, 352, 360-361
Camauba wax, in sustained release matrix tablets, 454 Coating, of suppositories, 579
Carton(s), sealed, 731 of tablets. See Tablet coating
Cartridge(s), sealing, 671 of tinplated aerosol containers, 607
Cascade impactor, for determining particle size of silicone, of glass, 491
aerosols, 617, 617 See also Microencapsulation
Case hardening, 52 Coating efficiency, 353-354
Casson plot, 129-130, 129, 130 Cocoa butter, 575-576
Castor oil, hydrogenated, in sustained release matrix “blooming” of, 587
tablets, 454 substitutes for, 576-577
Cellophane, for film wrapping, 724 Coextruded resin(s), 715
Cellulose, as filter aid, 150-151, 1511 Cohesion, 66-67
microcrystalline, as tablet diluent, 327 Cold bonding, 73

index *885
Cold cream, 545-546 Confidence interval(s), 255-256
Cold filling of aerosols, 612, 613 for binomial data, 259-260
apparatus for, 610, 611 Confidential disclosure, 880
Cold welding, 73 Confounding, 269
Colloid(s), hydrophilic, as emulsifiers, 518-519, 518t Congealing. See Spray congealing
protective, in formulation of aggregated suspensions, Conoweld system, for welding aerosol containers, 592
489 Consolidation of powders, 66, 73-75, 74
See also Emulsion(s); Suspension(s) Constant-level filling, 476-477, 477
Colloid mill(s), 42, 42 Consumer acceptance testing, 265-269
in cream production, 706, 707 Contact angle, 117-119, 117, 118t, 118, 480
in emulsion formation, 511, 512 Containers), for aerosols, 591-594
Colloidal silica(s), as antiadherents, 328 pressure limitations of, 600t
Color, evaluation of, in liquids, 472 quality control for, 615
in tablets, 297 selection of, 607-608
of soft gelatin capsules, 401 stability testing of, 609-610
variation in, in coated tablets, 371 for sterile products, 644-651
in tablets, 297, 313 cleaning of, 664-666, 665, 666
See also Colorant(s) sealing of, 668, 670, 671
Color Additives Amendments (1960), 872 size limitations on, 649
Colorant(s), in film coating, 369-370 glass, 645-649, 646t-647t, 648t, 711-712
in liquids, 471 for aerosols, 594, 599-600, 600t, 607
in suspensions, 491 for sterile products, 645-649
in tablets, 321t, 328-329 for suspensions, 491
restrictions on use of, 809t plastic, 645, 646t-647t, 712-716, 718t-719t,
testing of, 809 720t-721t
Colorimetric analysis, 849 for sterile products, 645
Column flow-through apparatus, in vitro drug for suspensions, 491
availability measurement with, 447 specifications for, considerations, 814
Combination therapy, biopharmaceutic considerations official, 840, 84It
in development of, 233-234 See also Packaging; Tube(s), collapsible; particular
Comminution, distribution and limit of, 33-36, 33, 34, materials
35 Contract manufacture, 709
energy for, 31-32 Contraindications, on package inserts, 868
theory of, 29-31 Controlled release. See Sustained release formulation(s)
See also Milling Controlled Substances Act, 872-873
Compaction of powders, 66-99. See also Granulation, Convective mixing, of solids, 15
compression Conveyor dryer(s), 57
energy involved in, 85-86, 85t, 85, 86t, 86 horizontal vibrating, 59-60, 60
force distribution in, 79-80, 79 Copyright, 874, 880-881
force-volume relationships in, 81-83, 82, 83 Correlation(s), 282-283, 282
moisture content and, 75-76, 75 Correlation equation(s), in fluid mixing, 12-13
under high loads, 78-81 Corticosteroid(s), components of cream bases for, 556t-
Compaction profile(s), 84-85, 84 557t
Compendium(-a), official, 838-839, 839t Cosmetic(s), dictionary of ingredients in, 541
Competition, unfair, 879 Cosolvency, microemulsion vs., 507
Complaint(s), 854 Cosolvent(s), in liquid pharmaceutical formulation,
Complexation, solubility and, 464-465, 465, 466, 466 460-461, 460
sustained release formulations using, 440-442, 441, Cost controls, 755-759, 757t, 758t
450-451 Counterfeiting, 853
Compressed gas(es), as propellants for aerosols, 589, Cream(s), 534
606 as bases for corticosteroids, components of, 556t-
filling apparatus for, 610-611 557t
Compressibility, bulk, coefficient of, 115, 115, 116 as bases for semisolids, 547
percent, 184, 184t, 316 scale-up considerations with, 705-706
Compressibility index, 67, 77 Creaming, of emulsions, 526-527
Compression, 66, 72-73, 72. See also Tabletting Criminal prosecution, 871-872
direct, 318, 318t Critical micelle concentration, 106, 107, 462
scale-up considerations with, 697 Crossing time, 437
tablet formulas for, 344-345 Crossover design, bioavailability studies using, 276-
rheologic measurements and, 144 278
Compression coating, 330-331, 372 Crushing strength, of granules, 78
Compression granulation. See under Granulation of tablets, 87-88, 87
Compression molding, of suppositories, 580 Crystal(s), form of, drug absorption and, 222
Compression test, diametric, of tablet strength, 297 habit of, 176, 177
Compressive test(s) of granule strength, 78 in suspension formulation, 486
Computers), tablet manufacture control by, 342 internal structure of, 176-177, 177
Concentrate filler, for aerosols, 611 mechanism of growth of, in colloidal systems, 116—
Condensation method of emulsification, 508 117, 117t

886 • Index
 structure factors affecting suspension formulation, Dioctyl-phthalate test method, 738, 738
486-487 Diosna mixer/granulator, 322-323, 323
Crystal bridging, in suspensions, 484 Dip coating, 372
Crystallinity, consolidation of powders and, 73-74 Dip tube(s), for aerosols, 595
preformulation research on, 176-180, 177, 178, 178t, quality control for, 613-614
179, 180 Disc mill(s), 42
Curve stripping, 202 Disinfection, surface, 636, 659-660
Cutting mill(s), 37, 37t, 41-42 Disintegrant(s), in tablets, 32It, 328
Cyclone product, 61 Disintegration, tablet excipients and, 329, 330
Disintegration test, for enteric coated tablets, 331-332,
D value, 620-621, 620 367
in preservative efficacy testing, 553-554 for tablets, 301, 301
Dalton’s law, 591 Disperse system(s). See Emulsion(s); Suspension!$)
Deaeration, in soft capsule manufacture, 406 Dispersion method(s), of emulsification, heat and, 508-
See also Aeration 509
Debye length, 111 of suspension formation, 488
Decompression, in tabletting, 83-85, 84 Disposition, 197-204
Deficit plot, 199, 199 multicompartment model of, 204
Defoamer(s), in emulsion formation, 512 one-compartment model of, 198, 198
Deformation of solids, 71, 71, 72 two-compartment model of, 202-204, 202
elastic, 72, 72 Dissociation constant (pKa), determination of, in
plastic, 72-73, 72 preformulation research, 185-186, 185
Degradation, general acid-base catalysis of, 768-769, drug absorption and, 222
769 Dissolution, of soft capsules, 410
ionic strength and, 769-770, 769, 770 preformulation research on, 189, 189, 190, 190t
order of reaction and, 761-764 Dissolution testing, of suppositories, 587
pathways of, 772-786 of tablets, 301-303, 303
pH and, 764, 764, 765 Distribution, 202-204, 202, 204
temperature and, 765-768, 766, 767, 767t, 768 Dixon Criteria for Testing an Extreme Mean, 257, 257t
Degree(s) of freedom, 247 Dosage form(s), design of, 169-289
Demulsification, 529, 793-794, 793 evaluation of, in product development, 234-239, 236,
Density, of aerosols, measurement of, 616 237t, 238t, 238, 239t, 240t
of powders, 70-71 See also particular dosage forms
of tablet granules, 315-316 Dosage regimen(s), biopharmaceutic considerations in
preformulation measurements of, 183, 183 development of, 232-233, 232
Dental cone(s), 333-334 for sustained release formulations, 439-440, 440
Depot formulation(s), 654 Dosage replacement factor, in suppository formulation,
Dermis, 535, 536 585 " '
Desensitizing agent(s), in flavoring liquid Dosatorfs), on hard-shell capsule filling machines,
pharmaceuticals, 470 instrumentation of, 95-97, 96, 97
Desorption, 120-121 Dose dependence, in dosage form evaluation, 235, 236-
Device(s), for sterile products, 651 237, 236, 237t, 238
Dew point, 49 Dowicil 200, as preservative in semisolids, 553
Dextrose, as tablet diluent, 327 Driacoater system, 347, 348-349, 351
Diametric compression test of tablet strength, 297 Drop-weight method, 109
Diatomite, as filter aid, 150, 151t Drug(s), animal, new, 856-857, 862-863
Dielectric constant, solubility and, 461-462 certification of, 863
Differential scanning calorimetry, solid characterization defined, 856
by, 179-180, 179, 180 generic, approval of, 862, 866
Differential thermal analysis, solid characterization by, “me-too,” regulatory requirements for, 865-866
179-180 new, 858-863
Diffuse double-layer theory, 111, 111, 112t, 506-507, applications, 860-862
506 defined, 856
Diffusion, Fick’s law and, 5, 221 investigational, 859-860
molecular, in fluid mixing, 5 1938 p*)visions on, 857
solids mixing by, 15-16 over-the-counter, approval of, 861
Diffusion testing, 158-159 labeling requirements for, 867
Dilatant behavior, 125, 125, 127, 128 review of safety and efficacy of, 866-867
Diluent(s), for capsule formulations, 389-392 prescription, 858
fox tablets, 321t, 325-327 labeling requirements for, 867-868
Dimensionless group(s), 12 Drug complex(es). See Complexation
Dimethylacetamide (DMA), as accelerant in semisolids, Drug Efficacy Study Implementation Review, 863-866
539 Drug Enforcement Agency, 872-873
as cosolvent in liquid pharmaceuticals, 461 Drug Listing Act (1972), 868-869
Dimethylformamide (DMF), as accelerant in Drug Price Competition and Patent Term Restoration
semisolids, 539 Act (1984), 862
Dimethylsulfoxide (DMSO), as accelerant in Drug release test(s), in vivo response prediction from
semisolids, 539 in vitro data, 449

index • 887
Drug standards), 833-837, 834t, 835t, 836t, 837t mixed, 505, 505
Dry-bulb temperature, 49 HLB value determination for, 516
Dry-bulb thermometer, 50, 50 in semisolids, 542
Dryer(s), classification of, 55, 56 Emulsion(s), 502-533
conveyor, 57 aerosols using, 604-605
flash, 62, 62 applications and utility of, 503-504
fluidized-bed. See Fluidized-bed dryer(s) basic chemical principles related to, 100-122
freeze, 63-64 clear. See Microemulsion(s)
horizontal vibrating conveyor, 59-60, 60 defined, 502
microwave, 64 external (continuous) phase of, 502
moving-bed, 55, 57-58 filling equipment for, 668
pan, 58 formulation of, 512-526
pneumatic, 55, 60-62 phase ratio in, 513
spray. See Spray dryer(s) practical examples, 523-526
static-bed, 55-57 internal (disperse, discontinuous) phase of, 502
tray, 55-57, 57 inversion of, 502, 509
truck, 55-57 lipid phase ingredients for, 513, 513t
tunnel, 57 micellar, 503
turbo-tray, 57-58, 58 multiple, 502-503
Drying, 47-65 formation of, 519
behavior of solids during, 52-55, 53 parenteral, 523, 655
definition of, 47 production aspects of, 512
flash, 62 safety of, 512
freeze. See Freeze drying scale-up considerations with, 704-705
in pilot plant operation, 690-692 semisohd, manufacture of, 555-560, 560, 561, 562
loss on, 52 shelf life assessment for, 527-532, 530
microwave, 64 sources of microbial contamination in, 520
purpose of, 47 stability of, 526-527
rate of, method of determining, 52n chemical, 512, 529
specialized methods of, 62-64 kinetic vs. thermodynamic, 100-101, 526
spray. See Spray drying physical, 529-531, 791-794, 792, 793, 794, 795
theory of, 50-52 symptoms of instability in, 526-527
unsaturated surface, 53 types of, 507, 508t
Durham-Humphrey Amendment (1951), 858 viscosity of, 519
Dust collection, 736-739, 738. See also Ventilation shelf life and, 529-531, 530
DVLO theory, 112-113 Encapsulation. See Capsule(s); Microencapsulation
Dye(s). See Colorant(s) End-folded wrapper(s), 724-725, 725
Enteric coating(s), 331-332, 366-368
Eccrine gland(s), 535, 536 Epidermis, 535-536, 535
Economic order quantity, 751-753, 752 Epinephrine, degradation of, 784, 784
Ejection force(s), in tabletting, 81 Epoxy resin, for aerosol container coating, 607
Electrolyte(s), particle aggregation and, 481-482, 482 Equilibrium moisture content, 54, 54
Electrometric method(s), 848 Equilibrium relative humidity, 54-55
Electron accelerator's), sterilization by, 629-630, 629 Equilibrium solubility, crystal growth and, 116-117,
Electrophoretic method, for emulsion shelf life 117t
assessment, 531 Equipment, calibration of, 813, 813t
for suspension stability evaluation, 494 for sterile products processing, cleaning of, 664, 666
Electrostatic charge. See Surface charge quality control procedures for, 812-813, 813t, 829-
Electrostatic coating, 372 .| 830
Elimination, 198-202 selection of, in pilot plant operation, 684
capacity limitations on, 216-218 See also particular types of equipment and under
defined, 197 particular dosage forms and processes
effects of disease on, 218-220 Error sum of squares, 273
factors affecting, 208-220 Erweka KEA dedusting and polishing machine, 394-
presystemic, 223-225 % ! 395, 395
Elimination rate constant, 198 ' Erweka tester, 298
Embedded matrix concept, sustained release Ester hydrolysis, 772-777
formulations using, 442-444, 443, 445, 452 prevention of, 774-777
Emulsifiable concentrate(s), 512 Estradiol, preparation of suspension of, 488
Emulsification, 508-510 Ethanol, in aerosols, reactions with aluminum
descriptive theory of, 504-508, 505, 506 containers, 607
low-energy, 510, 559-560, 562 in water-based aerosols, 600
mechanical equipment for, 510-512, 511 Ethylcellulose, as granulating agent, 328
spontaneous, 511-512 in film coating, 365
Emulsifierfs), auxiliary, 518-519 Ethylene oxide, sterilization with, 551, 551t, 634-635,
choice of, in emulsion formulation, 513 634t
defined, 502 Eutectic point, 64
in cocoa butter suppositories, 576 Excipient(s), for capsule formulations, 389-392
in semisolids, 541-543 for sterile products, 642-644, 642t-643t

888 • Index
 for tablets, 321t, 324-329, 330 disc, 164-165, 165t
future trends in, 336 for sterilization, 630-633, 631t, 632t
selection of, in preformulation research, 194 for ultrafiltration, 166-167
Expiration date(s), 760, 802, 852-853. See also Shelf precoat pressure, 160, 162
life prefQter use with, 153-154, 153, 154, 154t
Exponential smoothing, sales forecasting using, 750- pressure, 160 „
751 rotary-drum vacuum, 166
sand, 159
F distribution, 256-257, 256t, 256 selection of, 152-154
F0 value, 621-622 tray and frame, 159
Fabric(s), as filter media, 148-149 vacuum, 160
Faculties, 734-747 for cake filtration, 166
cost of, 735, 735t See also Filter medium(-a)
dust coUection and cross-contamination in, 736-739, Filter aid(s), 149-152, 150, 1511, 154-155
738. See also Ventilation Filter cloth, 148
materials, lighting and air-conditioning specifications Filter medium (-a), 148-149, 148t. See also Filter(s)
for, 736, 737t selection of, 152-153
quality control and, 829-830 Filter press, plate and frame, 160, 161
space allocation in, 735-736, 735t Filtration, 146-168. See also Filter(s); Ultrafiltration
Fair Packaging and Labeling Act, 872 cake, 166
Farmatic SNC capsule filling equipment, 379-380, 379 filter media for, 148
Fatty acid(s), in semisolids, 541 depth, 146
FDA. See Food and Drug Administration cartridge units for, 149
Federal Food, Drug and Cosmetic Act (1938), history effects of, on product, 471 .
of, 857-858 equipment and systems for, 159-165
Federal Trade Commission, 872 gaseous, flow rate formula for, 153
Felt(s), as filter media, 148 in suppository production, 708
Ferrous sulfate tablet(s), ingredients for, 343 laboratory equipment for, 165-166
Fick’s law, 5, 221 nonsterile, 154-155
Filling, of liquid containers, 476-477, 477 of suspensions, scale-up considerations in, 704
See also under Capsule(s) sterile, 155-157, 157, 630-633, 6311, 632t, 667
Filling equipment, for aerosols, 610, 610, 612-613 filter media for, 148
for sterile liquids, 667-668, 668 test methods for, 637
for sterile solids, 668-669, 669, 670 surface, 146
See also under Capsule(s) cartridge units for, 149
FUm(s) (interfacial), 107-108, 107, 108, 504-506, 505, temperature and, 152
506 theory of, 146-147
FUm(s) (tablet coating), cast, 363 time estimates for, 155, 155
application in microencapsulation, 415 Fin seal wrappers), 725-726, 725
enteric, 331-332, 366-368 First-order equation, sales forecasting using, 751
formula optimization for, 364 Fitch plot, 129-130, 129, 130
free, application in microencapsulation, 415 Fixed model, 272, 274-275
ideal attributes of, 364 Flame projection, testing of aerosols for, 615
nonenteric, 365-366 Flash dryer(s), 62, 62
sprayed, 363 Flash point, testing of aerosols for, 615
tensile strength testing of, 363 Flavorfs), in liquids, 470-471, 470t
water vapor permeability testing of, 363 stability of, 472
Film balance, 107-108, 107 in solubilized emulsions, 520
FUm coating, 359-362 in suspensions, 491
development of formulations for, 362-364 in tablets, 321t, 329
evaluation of tablets after, 363-364 testing of, 809
formula optimization in, 364 Flocculation, 113
materials used in, 364-370 in emulsions, 507, 527
quality defects in, 371-372 in suspensions, 482-483, 483
scale-up considerations with, 701-702 Floccule(s), 113, 482-483, 483
vacuum, 372 Flow point, 481
See also Ftlm(s) Flow rate(s) of powders, 67, 69, 183-184
Film pressure, 107-108 Fluid(s), flow characteristics of, 3
Film wrapper(s), 724-726, 725 flow patterns of, 6, 6
Filterfs), cartridge, 149, 160-164, 163, 164 mixing of, 3-13
cleaning of, timing, 155, 155 batch, 6-8
disc, 160, 162 continuous, 8-9, 8, 9
dust collection, 738-739, 738 equipment for, 6-13
edge, 163, 163 fundamentals of, 3-6
gravity, 159-160 time dependence of mechanisms in, 5-6, 6
gravity bag, 159 Newtonian, 123-124, 126
high efficiency particulate air (HEPA), 660, 738-739 non-Newtonian, 125
integrity testing of, 157-159, 633 Fluid jet(s), for fluid mixing, 7-8
membrane, cartridge, 160-163, 164 Fluid-energy mill(s), 37, 37t, 41

INDEX • 889
Fluidity, 124 “flint," 491
Fluidized-bed coater(s), 350-351, 352, 360-361 light transmission by, 797-798, 798, 798t
Fluidized-bed dryer(s), 55, 58-60, 59, 60 insoluble flake formation and, 796-797, 797t, 797
scale-up considerations with, 691-692 manufacture of, 711-712
Fluidized-bed granulator-dryer, 59, 59 soda-lime, 646t-647t, 712
Fluidized-bed spray gianulator(s), 339-340, 339 stability and, 796-798
Fluorocarbon(s), as aerosol propellants, 589-590, 590t, types and test limits for, 648t, 796t
592 Glatt coater, 349, 351
limitations on use of, 606, 607 Glidant(s), 79
Foam(s), aerosols dispensed as, 604-605 in tablets, 32It, 328
actuators for, 596, 598, 599 Glomerular filtration, 209
testing for stability, 616-617 Glomerular filtration rate, 209
Foam depressant(s), in emulsion formation, 512 Glomerulus, 209
Foaming, in emulsion formation, 512 Glucose, liquid, as granulating agent, 327
Food and Drug Administration (FDA), 870-874 in liquid pharmaceuticals, 469
enforcement powers of, 871-872 Glycerin, as suppository base, 577
packaging regulations of, 731-732 Glycerinated gelatin, as suppository base, 577, 583
stability testing requirements of, 760, 802 Glycerine, in semisolids, 544
Food, Drug and Cosmetic Act (1938), history of, 857- Good Manufacturing Practices (GMP), 733, 869-870
858 in pilot plant operation, 686
Food, Drug and Cosmetic Bill, state, 873 quality control and, 829-833
Force-displacement curve(s), 86, 86 Gral mixer/granulator, 323-324, 325
Form/fill/seal system, 728-729, 729 Granulation, 76-78, 317-324. See also Tablet
Forward flow test, 159 granulation(s)
Fragrance(s). See Perfume(s) compression, 318-320, 319
Freedom of Information Act, 873 scale-up considerations with, 698, 698
Freeze drying, 62-64, 63, 672-673 dry, 317-320, 318t
formulations for, 653 common tablet ingredients in formulas for, 344
Freeze-thaw cycling technique, for suspension stability scale-up considerations with, 697-698, 698
evaluation, 494 dust collection specifications for, 739
Freundlich equation, 120 facilities for, 741, 741
Friabilator, 88, 299, 299 scale-up considerations with, 687-690, 688, 689,
Friability, of granules, 316 690, 691, 692, 693
of tablets, 88, 299 stability during, preformulation research on, 194
Friction, effects of, in powder compaction, 79 wet, 76-77, 76, 77, 320-324
Friedman’s two-way analysis, 287-288 common tablet ingredients in formulas for, 343
Froude number, 12 scale-up considerations with, 687-688
Fusion bonding, 73 state-of-the-art processing, 338
Fusion process, for anhydrous ointment manufacture, Granulators), 322-324, 323, 324, 325, 341-342, 341,
555 342
Fusion welding, 73 fluid bed spray, 339-340, 339
oscillating, 693, 694
Gamma ray(s), sterilization by, 629-630 Granulator-dryer, fluidized-bed, 59, 59
Gas(es), inert, in sterile solutions, 653 Granule(s), density of, 315-316
Gaseous filtration flow rate formula, 153 encapsulated slow release, 451-452
Gastrointestinal tract, presystemic metabolism in, 223- properties of, affecting tabletting, 77, 87-88, 87
224 strength of, 77-78, 316
Gel(s), 534, 548 Gravimetric filling. 476
scale-up considerations with, 705-706 Gravimetric method for measuring humidity, 50
Gel strength of gelatin, 400 Gravity filler, for liquids, 668
Gelatin, as granulating agent, 327 Gravity nutzch, 159-160
for hard capsules, 374-375 Griffith theory of cracks and flaws, 30
manufacture of, 375 Grinding. See Milling
for soft capsules, 400-401, 400t, 40It Grossing syrup(s), 356
manufacture of, 406 Gum(s), as auxiliary emulsifiers, 518, 518t, 523
glycerinated, as suppository base, 577, 583
Gelsiccation. See Freeze drying Hair follicle(s), 535, 536
Germall II, in semisolids, 552-553 Hammer mill(s), 37t, 37, 38-40, 38, 39, 693-694, 695
Gibbs equation, 103-104 Hard butter, manufacture of, 576
Glass, 645-649, 646t-647t, 648t, 711-712. See also Hardness of tablets, 297-299
under Containers) variation in, 314
advantages of, 711 Hartnett capsule imprinting machine, 395, 397
alkali release by 796, 796t Heat, in emulsion formation, 508-509
amber, 649, 712 Heat of activation, 192, 765
light protection by, 797-798, 798, 798t Heat of solution, 187-188, 188
borosilicate, 646t-647t, 712 Heckel plot(s), 82-83, 83
chemical resistance of, 648, 712 Helical flight mixer(s), 17
colored, 712 Helipath, in emulsion shelf life assessment, 530, 531
composition of, 711 Helium pycnometer, 69-70, 70

890 • Index
Hepatic clearance, 200, 212-214, 213 Incomplete block design, 278
Hepatic dysfunction, drug elimination and, 220, 220t independence, in statistics, 245
Hepatic extraction ratio, 212-213, 213 Indomethacin, biliary clearance of, 214-215, 215t
Hi-Coater system, 347, 348, 351 lnhaler(s), metered-dose, 596-597
Hildebrand’s solubility parameter, 461 Injunction, 871
Histogram, data display using, 250, 250 Inspection(s), FDA, 869-871
HLB temperature. See Phase inversion temperature penalties for interfering with, 872
HLB value, 514-517, 515t, 516t Inspissation, 626-627
Hofliger and Karg capsule filling equipment, 380, 381, Institutional Review Board(s), 860
382, 383 Instrumentation, of hard-shell capsule filling machines,
Hofmeister series, 113, 482 95-97, 96, 97
Hole theory, 152 of tablet machines, 89-95, 94
Homogenizer(s), for emulsion formation, 510-511, 511, Insulin, certification of, 863
512 preparation of suspension of, 488
for semisolid manufacture, 560-561 Integrity testing, of filtration systems, 157-159, 633
rotor-stator. See Colloid mill(s) Interesterification, in suppository base manufacture,
Honey, in liquid pharmaceuticals, 469 576
Hopper flow rate(s), 317 Interface(s), in emulsions and suspensions, 100, 101
Humectant(s), in semisolids, 544 of powder with air, 66-67, 66
Humidity, 48-50 solid-liquid, adsorption at, 119-121, 119
absolute, 49 Interfacial film(s), 107-108, 107, 108, 504—506, 505,
encapsulation and, 703 506
measurement of, 50 Interfacial tension, in emulsions, 504
relative, 49 See also Surface tension
equilibrium, 54-55 Interference, in patent law, 875
saturation, 49 Interparticle force(s), between surfaces, 111-113, 112,
Humidity chart, 48-50, 48 113, 114, 507
Hydrate(s), 177-178, 177 Intestinal flora, drug absorption and, 223
Hydrocarbon(s), as aerosol propellants, 589, 590, 590t, Intrinsic reaction velocity, 212
593, 606-607 Inventory(-ies), 747
standards for glass containers, 599-600 ABC classification of, 748, 748
in semisolids, 540, 544 conversion of, to months of supply, 749, 749t
Hydrocarbon wax(es), in semisolids, 540 management of, 747-748
Hydrochlorothiazide, stability studies on, 779, 779 systems for, 753-755
Hydrocolloid(s), as emulsifiers, 518-519, 518t reporting and analysis of, 749, 749t
Hydrocortisone, degradation of, 785, 785 Inversion, of emulsions, 502, 509
Hydrogenation, in suppository base manufacture, 576 Iodine value, of suppository bases, 569, 575
Hydrolysis, drug degradation by, 772-779 Ion(s), potential determining, 110
Hydrophilic materials), 480, 481 lon-exchange resin(s), for purified water system, 473
increasing wettability by use of, 480 Ion-exchange resin complex(es), sustained release
Hydrophilic-Lipophilic Balance, 514-517, 515t, 516t formulations using, 450-451
Hydrophobic material(s), 480, 481. Ionic strength, drug degradation and, 769-770, 769,
Hydrotrophy, solubility and, 466 770
Hydroxyl value, of suppository bases, 569 Ionizing radiation(s), sterilization by, 629-630, 629
Hydroxymethylcellulose, in sustained release matrix Iron, in soft gelatin capsules, 400
tablets, 454 Irrigating solution(s), standards for, 639
Hydroxypropyl cellulose, as granulating agent, 327-328 Isoelectric point, 110
in film coating, 365 Isotonicity, in parenteral preparations, 644, 655
Hydroxypropyl methylcellulose, as granulating agent,
327 Jelly(-ies),'as bases, for semisolids, 548
in film coating, 365
in formulation of dispersed suspensions, 490 Kaolin, in suspensions, preservative interaction with,
Hydroxypropyl methylcellulose phthalate, in film 491
coating, 368 Kefauver-Harris Amendments (1962), 858-870
Hygrometerfs), 50 Kelvin element, 139, 139
Hygroscopicity, of suppositories, 583 Kelvin equation, 103
preformulation research on, 181-182 Kick’s equation, 31
Hynson, Westcott, & Dunning decision, 866 Kidney(s), physiology of, 209-211
Hypothesis, null, 251 Kneading mixer(s), 11, 11
Hypothesis testing, 251-255 Know-how, 874, 880
of binomial data, 260-261
Labeling, defined, 856
Identification marking(s), on hard capsules, 395, 397 equipment for, 745-746
on tablets, 296-297 of sterile products, 676
Identification system(s), 853 quality control of, 814
Identity, standards of, 833-834, 834t requirements for, 867-868
Immersion-sword system, 348, 350 state laws, 876t-877t
Immersion-tube system, 348, 350 Labor, costs of, 758-759, 758t
Impeller(s), for fluid mixing, 6-7, 7 Lactose, as tablet diluent, 326

index • 891
Lag time, 624, 626 Lymphatic system, drug shunting through, 226
Laminar flow, in fluid mixing, 4-5 Lyophilic material(s). See Hydrophilic materials)
Lamination, collapsible tubes of, 717-720 Lyophilization. See Freeze drying
tamper-resistant seals for, 730-731 Lyophobic material(s), 480, 481
Lamination of tablets, 88-89, 88, 311-312 Lyotropic series ("Hoftneister series), 113, 482
Langmuir equation, 119-120, 120
Lanolin derivative(s), wettability enhancement by, 480 Macofar SAS capsule filling equipment, 380-381, 384
Latin square design, 277 Macromelting range test, for suppositories, 586
Laxative tablet(s), chewable, ingredients for, 343 Magnesium stearate, as lubricant, 328
Leaching, from plastic containers, 716 Mannitol, as sweetener in tablets, 329
Lead, collapsible tubes of, 717 as tablet diluent, 327
Leak testing, of aerosols, 612, 615 Manufacturing procedure(s), preparation of, in pilot
Leaker test, for sterile products, 673 plant operation, 685-686
Least significant difference test, 272 Manufacturing Working Formula Procedures (MWFP),
Least squares line, 279 810-812
Levodopa, combination therapy with carbidopa, 229, Markem capsule imprinting machine, 395, 397
234 Master formula record, 830
presystemic metabolism of, 229, 229t, 230t, Materials, costs of, 756-758, 757t, 758t
Liability, 881 handling of, in pilot plant operation, 687, 699
Licensing, patent, 878 management of, 747-755
Light, containers protecting against, 712, 797-798, planning requirements for, 754-755
798, 798t raw, evaluation of, in pilot plant operation, 683-684
See also Ultraviolet light quality control of, 804-810, 805t, 806t, 812, 839,
Light scatter decay method, for determining particle 839t, 840t
size of aerosols, 617 Maxwell element, 139, 139
Lilly capsule filling equipment, 377-379, 377, 378 Mean, 247, 816
Limit of detection, 846 Mean absolute deviation, 751
Limulus amebocyte lysate test, 674-675, 844 Median, 250
Lincomycin, degradation of, 776-777 Melting range, for suppository bases, 569
Linear variable differential transformer, 92, 92 Melting range test, for suppositories, 586
Linearity, 846 Metabolic clearance, 201-202, 201
Lipophilicity, drug absorption and, 222-223 Metabolism, presystemic, 223-225
Liquefaction time test, for rectal suppositories, 586, sequential, 202
586 See also Biotransformation
Liquid(s), 457-478 Metal(s), collapsible tubes of, 716-717
advantages of, 457 tamper-resistant seals for, 730
appearance of, 471 drug stability and, 800
compounding procedure for, 475-476, 475t heavy, oxidation and, 780
disadvantages of, 293 See also particular metals
flavors in, 470-471, 470t Methyl hydroxyethylcellulose, in film coating, 365
formulation of, 457-473 Methylcellulose, as granulating agent, 327
solubility in, 457-466 for viscosity control of liquid pharmaceuticals, 470
in soft capsules, 402-403 in formulation of dispersed suspensions, 490
manufacture of, 473-477 Methyldopa, preclinical studies of metabolism of, 227-
equipment for, 474 229, 228t, 229t
facilities for, 743-745 Methylprednisolone, degradation of, 785, 785
raw materials for, 473 mG2 S.p.A. capsule filling equipment, 381-382, 385,
scale-up considerations with, 703 386
packaging of, 476-477, 477 Micellar catalysis, 512
preservation of, 466-468, 467t Micellar distribution coefficient, 519-520
stability of, 471-473 Micelle(s), 100, 101, 106-107, 106, 462
sterile, filling equipment for, 667-668, 668 Microbe(s), classification of, 549-550
subjective product characteristics of, 468-471 See also Microbial contamination
sweetening agents for, 468-469, 469, 470t Microbial challenge test, 633
viscosity control of, 470 Microbial contamination, of emulsions, 520-522
Littleford mixer(s), 322, 322, 323, 324, 691 of liquids, 466-468, 473, 474, 477
Liver, drug metabolism in, 212-214, 224 of semisolids, 549-554
Load cell(s), for weighing semisolid batches, 558, 559 testing for, 842-844, 842t, 8431, 844t
London force(s), 483 See also Preservative(s)
Loo-Riegelman absorption profile. See Absorption Microbial death kinetics, 553-554, 554, 620-622, 620,
profile(s) 621, 6211
Loss on drying, 52 Microdialvsis cell(s), in sustained release formulations,
Lozenge(s), 333 451-452
Lubricantis), in suppository manufacture, 584-585 Microemulsion(s), 503, 507-508, 519-520
in tabletting, 79, 80-81, 80, 811, 3211, 328, 701 micellar, 508
force-displacement curves in evaluation of, 86 spontaneous formation of, 512
Lubricant efficiency, coefficient of, 80 Microencapsulation, 412-429
Lung(s), presystemic metabolism in, 224-225 advantages of, 412-413, 413

892 • Index
 coating materials for, 415-416, 415, 416t Mixing, 3-20
core materials for, 414, 414t batch, of fluids, 6-8
equipment and processing for, 419 of solids, 17-18
fundamental considerations in, 414-419 continuous, of fluids, 8-9, 8, 9
methodology of, 419-428, 4191 of solids, 18
problems of, 413 convective, of solids, 15
release properties and, 417-419, 418 diffusive, of solids, 15-16
stability enhancement by, 416-417, 417 equipment for. See Mixer(s)
sustained-release formulations using, 417-419, 418 inadequate, tablet weight variation from, 314
Microflltration, 166 measures of degree of, 18-19
Microindentation test(s), 88 of fluids, 3-13
Micromelting range test, for suppository bases, 586 equipment for, 6-13
Micronizerfs), 37, 37t, 41 fundamentals of, 3-6
Microscopy, fine particle characterization using, 182- time dependence of mechanisms in, 5-6, 6
183 of solids, 13-19
particle size distribution measurement by, 26-27 equipment for, 17-19
solid characterization by, 178-179 fundamentals of, 13-17
Microsquashing, 72 power requirements for, 19
Microwave drying, 64 scale-up considerations with, 687, 695-696, 697
Mill(s), attrition, 37t segregation mechanisms in, 16-17, 19
ball, 40-41 surface charges in, 16
colloid. See Colloid mill(s) polyphase, equipment for, 10-11
cutting, 37, 37t, 41-42 shear, of solids, 15
disc, 42 Moisture content, 52
fluid-energy, 37, 37t, 41 critical, 53
hammer, 37t, 37, 38-40, 38, 39, 693-694, 695 equilibrium, 54, 54
pebble, 40 in powder compaction, 75-76, 75
revolving, 37t Molasses, in liquid pharmaceuticals, 469
rod, 40 Mold release agent(s), in suppository manufacture, 584-
roller, 11, 11, 37, 37t, 42 585
selection of, 43, 44t, 45t Molding of suppositories, in-package, 582
tube, 40 methods of, 580-581, 581
types of, 37-42, 37, 37t scale-up considerations with, 708-709
Milling, 21-46 Monadic test(s), 265-267, 266
closed-circuit, 38 Monosodium glutamate, in flavoring liquid
dry, 45 pharmaceuticals, 470
energy' use in, 30, 31 Monsanto hardness tester, 297
equipment for. See Mill(s) Mottling. See Color, variation in
factors influencing, 42-43 Moving-bed dryerfs), 55, 57-58
open-circuit, 38 Mulling mixer(s), 11
pharmaceutical applications of, 21-22 Multiorifice-centrifugal process, microencapsulation by,
rate of, 36-37 419t, 425-426, 425
scale-up considerations with, 692-695
techniques of, 43-45 Narcotics, regulations on, 872-873
wet, 45 Nauta mixer-processor, 340-341, 341
See also Comminution Negligence, product liability and, 881
Mineral oil, as lubricant, 328 Nephelometer, filtration effectiveness assessment with,
in semisolids, 540 154, 154
Minim per gram factor, 404, 405t Nephron(s), 209
Minimum threshold level, 471 Nemst equation, 780-781
Misbranding, 853 New drug(s). See under Drug(s)
Mixer(s), granulating, 321-324, 322, 323, 324, 325 New Drug Application(s), 860-862
scale-up considerations with, 687-688, 688, 689, Nitrile polymer(s), 715, 718t-719t
690, 691, 692 Nonisothermal kinetic method, 768
helical flight, 17 Normal curve, standard, 248, 248t
kneading, 11, 11 Normal distribution, 246-250, 246, 247, 248, 248t, 249,
mathematical analysis of operation of, 11-13 250, 816-817, 816, 817, 817t
mulling, 11 Noyes-Whitney equation, 189, 221
planetary, 689 Null hypothesis, 251
rheologic measurements and, 144 Nutzch, gravity, 159-160
ribbon blender, 17,18 Nylon, 714, 720-721t.
selection of, for fluid mixing, 10-13
for solids mixing, 18-19 Ointment(s), 534
sigma blade, 688 anhydrous, fusion process fox manufacture of, 555
tumbling, for solids, 17-18, 17 greaseless, bases for, 548
twin shell, 17, 690 ophthalmic, bases for, 548
Mixer-dryer processer, double-cone, 340, 340 scale-up considerations with, 705-706
Mixer-granulatorfs), See Mixer(s), granulating white, as semisolid base, 544

iNDEX • 893
Opaquant-extender(s), in film coating, 370 shape factors for, 14, 315
Operating characteristic curve(s), 263, 263, 826-828, size of. See Particle size
826, 827 See also Solid(s)
Ophthalmic ointment(s), bases for, 548 Particle counters), particle characterization using, 182
Ophthalmic preparation(s), formulation of, 653, 656 Particle size, drug absorption and, 221, 222
standards for, 639 in aerosols, determination of, 617, 617
Optimization, 295 in emulsions, 503
empiric models in, 283-285 in stability studies, 531
of coating formulas, 364 in suspensions, in stability studies, 494
Orange-peel effect, in coated tablets, 371 interparticle interactions and, in colloidal system,
Order point system, 753-754, 754t, 755 115-116, 115, 116
Osaka capsule filling equipment, 383, 387 measurement of, 22-29, 23t, 24, 25, 26
Osmotic pump, controlled release dosage form using, tabletting and, 313, 315, 692-693
455, 455 See also Milling
Ostwald ripening, 116-117, 484 Partition coefficient, 188-189
Outlier(s), detection of, 257, 257t Passivation, of stainless steel, 703
Oven(s), circulating hot air, for drying, scale-up Paste(s), 534, 548
considerations with, 690-691 scale-up considerations with, 705-706
forced convection, for sterilization, 624, 624 Pastille(s), 333
Over-the-counter drug(s). See under Drug(s) Patent(s), 874-879
Oxidation-reduction, 780-785, See also Autoxidation Pebble mill, 40
drugs degrading by, 781t Pellegrini pan, 348, 350
preventing, 783-785 Pendant drop method, 109, 109
Ozokerite, 540 Penetration, of emulsions, 503
Penetrometer(s), 138, 138
Package insert(s), 868 Perfume(s), in semisolids, 540, 558-559
Packaging, 711-732. See also Container(s); Tube(s), in solubilized emulsions, 520
collapsible; particular materials in suspensions, 491
facilities for, 745-746, 745 Perlite, as filter aid. 150, 151t
FDA regulations on, 731-732 Permeation, rates for liner facings, 722t
materials for, official specifications for, 840, 841t through plastic containers, 715-716, 799
quality control of, 814 Peroxide value, 585
of liquid pharmaceuticals, 476-477, 477 Perry Industries capsule filling equipment, 383-384,
of semisolids, 562 388
of sterile products, 675-676 Personnel, 733-734
of suppositories, 581-582 for pilot plant operation, 682
scale-up considerations, 708-709 for sterile products production, 661-663
of suspensions, 491 quality control and, 829
of tablets, dust collection specifications for, 739 training of, 734
quality assurance during, 815, 832 Pessary(-ies), 564
stability and, 795-802 Petrolatum, in semisolids, 540, 544
of liquids, 472-473 handling of, 555
tamper-resistant, 723-731 Pfizer tester, 298
Paddle(s), for fluid mixing, 7 pH, drug absorption from rectal suppositories and, 565-
Paired t test(s), 254-255 566, 566t, 567
Paired test(s), for consumer acceptance, 267, 268-269 drug degradation and, 191-192, 191t, 192, 764, 764,
Palmityl alcohol, in semisolids, 541 765
Pan dryer(s), 58 solubility and, 186-187, 187, 458-460, 459, 460
Paper(s), filter, for laboratory use, 165 pH of maximum stability, 192, 192, 764, 764, 765
kraft, as filter media, 149 Pharmacokinetics, 197-208
Parabenfs), binding of, 465, 466, 468, 521, 522t, 552, application of, in product development, 226-239
552t, 653 Pharmacopeia(s), 838-839, 839t
in emulsions, 520 Phase inversion temperature (PIT), 309
in liquids, 467 emulsion stability and, 517
in semisolids, 552-553 in emulsifier selection, 516
Paraffin wax, 540 Phase separation, in emulsions. See Demulsification
Parahydroxybenzoic acid esters. See Paraben(s) Phase separation-coacervation. See Coacervation-phase
Parenteral formulation(s), long-acting, 653-654 separation
See also Sterile product(s) Phenobarbital tablet(s), ingredients for, 343
Pareto curve, 748, 748 Phenol index, in emulsifier selection, 516
Parke-Davis capsule filling equipment, 377-379 Phenolic(s), closures of, 723
Particle(s), characterization of, in preformulation Photolysis, drug degradation by, 785, 785
research, 182-183 Picking, of tablets, 312-313, 371
flaws in, 30 Piezo-electric device(s), on multi-station presses, 93, 93
forces in mixing of, 14-15 on single-station presses, 91-92, 91, 92
fracture of, 30 Pilocarpine, degradation of, 779
under compression, 72 Pilot plant operation, 681-710
interaction of, in suspensions, 481-484, 482, 483 equipment selection in, 684

894 • Index
 for emulsions, 704-705 Polymerization, microencapsulation by, 427-428
for liquid dosage forms, 703 sustained release capsules using, 452
for semisolids, 705-706 Polymorphism, preformulation studies of, 178, 178,
for solid dosage forms, 687-703 180-181, 181, 230-231
for suppositories, 706-709 suspension stability and, 487
for suspensions, 703-704 Polyol(s), in semisolids, 544
personnel requirements for, 682 Polyolefin(s), 645
preparation of master manufacturing procedures in, Polypropylene, 645, 713, 718t-719t, 720t-721t
685-686 for film wrapping, 724
process evaluation in, 684-685 Polystyrene, 714, 718t-719t, 720t-721t
quality assurance in, 686 Polyvinyl acetate phthalate, in film coating, 368
reporting responsibilities in, 681-682 Polyvinyl chloride (PVC), 713-714, 718t-719t, 720t-
space requirements for, 682-683 7211
Pipet method, for particle size distribution blister packs of, 727
measurement, 28-29, 28, 29t Polyvinylpyrrolidone, as granulating agent, 328
pKa. See Dissociation constant Porcelain candle(s), sterile filtration with, 155-156
Planetary mixer(s), 689 Porosity, 69
Plasma clearance, 200-201 applied force and, in tabletting, 81-83, 82, 83
Plasma half-life, 198, 198 Potencv, standards of, 836-837, 836t, 837t
approach to steady state and, 206, 206 Pouch(es), 728-729, 729
biliary recycling and, 215-216 Povidone, in film coating, 365-366
Plasma renal clearance rate. See Renal clearance Powder(s), angle of repose of, 67, 68, 317
Plastic(s), 645, 646t-647t, 712-716, 718t-719t, 720t- compression and consolidation of. See Compaction of
72It. See also under Container(s) powders
additives in, 645, 646t-647t, 712-713 effect of applied forces on, 71-76, 71
advantages of, 645, 712 electrostatic forces in, 16, 67
collapsible tubes of, 717 flow properties of, preformulation research on, 183—
tamper-resistant seals for, 730 184, 184t
drug-plastic considerations, 715-716, 798-800, 799, flow rates of, 67, 69, 183-184
800t free surface energy of, 66, 66
thermoplastic, 645, 646t-647t granulation of. See Granulation
for closures, 723 insoluble, in semisolids, 544
thermosetting, for closures, 723 interface of, with air, 66-67, 66
types of, 645, 646t-647t, 713-715, 718t-719t, 720t- mass-volume relationships of, 68-71
7211 volume of, measurement of, 69-70, 70
Plastic closure(s), 723 wetting of, 117-119, 117, 118, 118t, 480-481
Plastic component(s), for sterile products, cleaning of, See also Particle(s); Solidfs)
665-666 Powdered glass test, 648, 712
Plasticizer(s), in film coating, 368-369 Power, of statistical tests, 265
in gelatin in soft capsules, 400 Power Law Equation, 125-126
Plastoelasticity, 83 Power number, 12
Plate process for soft capsule manufacture, 398 Powr Flo system, 607
Plug flow, 127, 143, 143 Precautions, on package inserts, 868
Plug strength tester, 75 Precipitation method(s), of suspension formation, 487-
Pneumatic dryer(s), 55, 60-62 488
Pohlman liquid whistle, 511, 511 Precision, 846-847, 847t
Point of zero charge, 110, 110 Precoating technique, 151
Poiseuille’s equation, 131 Prednisolone, degradation of, 781-782, 781t, 782, 785,
Poisson ratio, 80, 84 785
Polishing, of coated tablets, 356, 356, 358 precipitation of, 487
facilities for, 743, 744 Preemption, 873
of solutions, 667 Prefiiter(s), 153-154, 153, 154, 154t
Polyacrylic acid, in formulation of dispersed Preformulation, 171-196, 172, 173, 176
suspensions, 490 biopharmaceutics in, 229-231
Polyamide. See Nylon bulk characterization in, 176-184
Polycarbonate, 714-715, 720t-721t molecular optimization in, 171-176
Polyethylene, 713, 718t-719t, 720t-721t reporting of findings, 194-195
collapsible tubes of, 717 Prescription drug(s). See under Drug(s)
Polyethylene glycol(s), as lubricant, 328 Preservative(s), for emulsions, 520-522, 521t, 522t
as suppository base, 577-578, 578t, 583-584 for liquids, 466-468, 467t
in film coating, 366 for semisolids, 549-554
in semisolids, 544, 547-548 testing of, 550, 550t, 553-554, 554
Polyethylene terephthalate (PET), 715 for suspensions, 491
Polyethylene-polypropylene, 645 inactivation of, 491. See also under Paraben(s)
Polymer!"s), acrylate, in film coating, 366, 368 solubilities of, 552, 553t
carboxyl vinyl, as auxiliary emulsifiers, 518 Press(es), See Tablet press(es)
in sustained release matrix tablets, 453-454, 453t Pressure filling of aerosols, 610, 610, 612-613
nitrile, 715, 718t-719t Pressure pump filler, for liquids, 668

index • 895
Preval system, 608, 609 first-order, 762-763, 762, 763
Privity doctrine, 881 opposing (reversible), 770-771
Probability distributions, 246-250, 246t, 246, 247, 248, order of, drug degradation and, 761-764
248t, 249, 250 pseudo-first-order, 763-764, 764
Probenecid, antibiotics with, 234 pseudo-zero-order, 761-762
renal transport and, 210 second-order, 771
Procainamide, sustained release formulation design, side, 771-772
433-437, 435t, 436 zero-order, 761-762, 761, 762
Prodrug(s), 172-175, 173, 176, 223 Reaction velocity constant, 763
in sustained release formulations, 441, 442 Recall(s), 854, 863
Product development, biopharmaceutics and Reciprocating die process for soft capsule manufacture,
pharmacokinetics in, 226-239 399
design variables in, 231-234 Reconciliation, of liquid product yield, 745
See also particular dosage forms of tablet yield, 742, 743
Product liability, 881 Reconstitution, 62
Production management, 733-759 Record(s), maintenance, storage and retrieval of, 853-
Promulgen(s), 543 854
Propellant(s), for aerosols, 589-591, 590t, 592, 593 product distribution, 853
identification of, in product testing, 616 quality control of, 830
quality control for, 613 Redispersibility, evaluation of, in suspension stability
selection of, 606-607 tests, 493
stability testing of, 609 Re-esterification, in suppository base manufacture, 576-
Propeller(s), for fluid mixing, 6-7 577
side-entering, 8 Reference standard(s), for quality control tests, 842,
Propiolactone, sterilization by, 635-636 845
Propylene glycol, in semisolids, 544 Registration of trademarks, 874, 879
Pseudoplastic behavior, 125, 125, 127, 127 Regression, in data analysis, 278-283
Psychrometer, sling, 50, 50 simple linear, 278-279
Psychrometric chart, 48-50, 48 weighting in, 282
Psychrometry, 47-50 Regulation(s), 856-882. See also Food and Drug
Pump(s), positive displacement, for semisolid product Administration
transfer, 706, 707 definitions relating to, 856-857
Purchase price variance report, 756, 757t state and local, 873-874
Purger, for aerosols, 611-612 Renal clearance, 199-200, 199, 200, 201
Purity, standards of, 834-836, 834t, 835t, 837t calculation of, 210-211
Pycnometer, helium, 69-70, 70 experimental techniques using, 211
Pyrogen(s), source and elimination of contamination Renal excretion, experimental techniques for study of,
with, 641 211
Pyrogen testing, 674-675, 675, 844-845 mechanisms of, 209-211
Renal impairment, drug elimination and, 219-220,
Qualification, 832 219, 219t
Quality, standards of, 834, 834t Renal tubule(s), 209
Quality control, 804-855. See also particular dosage carrier-mediated transport across, 210-211
forms and processes passive transport across, 209-210
charts for, 817-824, 819, 820, 821, 822, 823 Replacement factor, for suppositories, 585
costs of, 759 Repose angle, 67, 68, 317
in pilot plant operation, 686 Reservoir aerosol-type delivery system, 597
in-process, 810-814, 830-832 Return of goods, 854
of finished products, 814-815, 833-854 Reverse osmosis system, for preparing Water for
of raw materials, 804-810, 805t, 806t, 812, 839, Injection, 664
839t, 840t Revolving mill(s), 37t
statistical, 815-824 Reynolds number, 12
testing program and method for, 840-845 Rheology, 123-145
aging effects in, 130-131, 130
R value, 80 artifactual observations in, from plug flow or slippage
Rabbit pyrogen assay, 674, 675, 844 planes, 143
Racemization, drug degradation by, 786 definitions and fundamental concepts in, 123-126
Radiation(s), ionizing, sterilization by, 629-630, 629 graphic presentation of data in, 128-131
ultraviolet. See Ultraviolet light properties influencing behavior in, 126-128
Rancidity, 782 specialized pharmaceutical applications of, 140-144 .
of suppositories, 585 types of instruments used in, 131-139
Random model, 272, 274-275 Rheometer(s), extrusion, 133-134, 133
Randomized block(s), 273-274 Rheopexy, 127, 128
Range, 250, 816-817 Ribbon blender, 17,18
Raoult’s law, 591 Ring alteration, hydrolysis by, 779
“Rat-holding,” 314, 314 Ring-detachment method, 109-110
Reaction(s), complex, 770-772 Rinserfs), for new containers, 665, 665, 666
consecutive, 771 Rittinger’s equation, 31-32

896 • Index
Roche Friabilator, 88, 299, 299 batch weighing, load cells for, 558, 559
Rod mill(s), 40 cleaning of manufacturing equipment, 562-563
Roller compactor, 319-320, 319, 698, 698 cosmetic criteria for, 549
Roller mill(s), 11, 11, 37, 37t, 42 emulsified, manufacture of, 555-560, 560, 561, 562
Rotary die process for soft capsule manufacture, 399, homogenization of, 560-561
407, 407 industrial processing of, 554-563, 559, 560, 561
Rotary molding machine for suppositories, 580-581, in-process quality control for, 831
581 packaging of, 562
Rotating bottle method, for drug availability percutaneous absorption of, 536-539
measurement, 447 preservatives for, 549-554
Rotoclone, 738 preventing aeration of, 554-555
Rotor-stator homogenizer(s). See Colloid mill(s) preventing contamination of, 551-552
ROTOSORT capsule sorting machine, 394, 394 raw materials for, 539-544
ROTOWEIGH capsule weighing machine, 392, 393 scale-up considerations with, 705-706
Round-robin test(s), of consumer acceptance, 268 storage of, 561-562
Royalty(-ies), 878 vehicles for, 544-549
Rubber closure(s), 722-723 skin penetration and, 538-539
drug stability and, 801-802, 801, 801t Sensitivity, 846
for freeze-dried products, 672-673 Sepro container(s), 607, 608
for sterile products, 646t-647t, 649-651, 650 Sequential testfs), of consumer acceptance, 268
cleaning of, 665-666 Sessile drop method, 109
insertion of, 668, 670, 671 Shape factor(s), 14, 315
Ruggedness test(s), 848 Shear mixing, of solids, 15
Shear rate(s), 3
Saccharin, in liquid pharmaceuticals, 469 in pharmaceutical applications, 140-142, 141
in tablets, 329 in viscous flow, 123
Safety stock, 753, 754t Shear stress, in viscous flow, 123
Sales forecasting, 750-751 Shearing, in suspension formation, 491-492
Salicylamide, degradation of, 778, 778 Shelf life, computation of, 193, 194
Salicylic acid, disposition of, 216-218, 216, 217, 217t, of emulsions, assessment of, 527-532, 530
218, 219 See also Expiration date(s); Stability
Salt formation, drug modification by, 171-172, 174t, Shellac, seal coating of tablets with, 355-356
175t Shipping, facilities for, 746-747
Sampling, 824-828, 826, 827, 828t Post Office regulations on, 872
in hypothesis testing, 252 Shop right, 878-879
in-process, 813-814 Shrink banding, 728, 728
of bulk materials, 245 Shrink wrapper(s), 725, 726
plans for, 825-828, 827 Shunting, drug absorption and, 226
construction using binomial distribution, 263 SI unit(s), 98t
random, 244-245 Sieving, equipment fox, 694-695, 696
size determination, 263-265 particle size distribution measurement by, 27, 27t,
systematic, 245 28t
Sanitary inspection(s), 869 •Sigma blade mixer(s), 688
Sanitation, in quality control, 810, 8111 Sigma-minus plot, 199, 199
Saponification-value, 569, 575 Sign test, 262-263, 262t
Sartorius absorption and solubility simulator, drug Significance, statistical, 251-255
availability measurement with, 447 chi-square tests of, 261-262, 2611
Saturation humidity, 49 power of tests of, 265
Saturation temperature, adiabatic, 50 Silica(s), colloidal, as antiadherents, 328
Scale-up techniques. See Pilot plant operation Silica gel, in formulation of aggregated suspensions,
Schleuniger tablet hardness tester, 298, 298 489
Schuhmann equation, 33 Silicone coating, of glass, 491
Schulze-Hardy rule, 113, 481-482 Simplex lattice, 283-284, 283, 284t, 285t
Screen(s), for hammer mills, 38-39, 39 Skin, 535-536, 535
Sedimentation, particle size distribution measurement absorption through, 225, 536-539
by, 27-29, 28, 29t presystemic metabolism in, 225
Sedimentation rate(s), in suspension formulation, 484- systemic drug administration through, 225, 233
486 Slugging, 318-319
Sedimentation volume, measurement of, in suspension scale-up considerations with, 697-698
stability evaluation, 492-493 Smoothing constant, 751
Segregation, intensity of, 5 Soap, in aerosols, containers for, 607
mechanisms of, in solids mixing, 16-17 Sodium bisulfite, as antioxidant, 784
scale of, 5 toxicity of, 644
Seidenader capsule polishing machine, 395, 396 Sodium carboxymethylcellulose, in film coating, 366
Seizure, 871 in formulation of dispersed suspensions, 490
Selvae system, 608 Sodium metabisulfite, as antioxidant, 783-784
Semisolid(s), 534-563 Softening time test, for rectal suppositories, 586, 586
antioxidants in, 554, 558t Solid(s), amorphous, 176-177

index • 897
Solid(s), amorphous (Continued) of emulsions, 526-527
microscopic appearance of, 178 chemical, 512
analytic methods for characterization of, 178-180, kinetic, 526
178t of hard capsules, 392
classification of, based on drying behavior, 53-54 of liquid pharmaceuticals, 471-473
drying of, 52-55, 53 of soft gelatin capsules, 404-406, 408-410, 408
effect of applied forces on, 71, 71 of suppositories, testing of, 583
finely divided, as emulsifiers, 518 typical problems of, 587-588
in soft capsules, 403-406, 405t of suspension aerosols, 603-604
mixing of, 13-19 of suspensions, 794-795, 794, 795
batch, 17-18 crystal factors in, 486-487
continuous, 18 evaluation of, 492-495
equipment for, 17-19 kinetic vs. thermodynamic, 100-101
fundamentals of, 13-17 yield value and, 142-143, 142
sterile, filling equipment for, 668-669, 669, 670 of sustained release formulations, 448
stress-strain curve for, 29-30, 29 of tablets, 790-791, 790t, 790, 791t, 791
See also Particle(s); Pcrwder(s) of toxicology formulations, 190-191
Solid-fat index, 569, 569 packaging components and, 795-802
Solidification point, of suppository bases, 569 physical, 798-795
Solubility, drug absorption and, 221 preformulation analysis of, 190-194, 191t, 192, 193t
equilibrium, crystal growth and, 116-117, 117t testing, 760-803, 851-853, 852t
in liquid pharmaceutical formulation, 457-466 analytic methods fox, 848-849
of hard capsules, treatments affecting, 395-396 chemical, 786-788, 786t, 786, 787t
pH and, 186-187, 187, 458-460, 459, 460 FDA requirements for, 760, 802
preformulation studies of, 184-189, 229-230 fitting fines to data from, 279-282, 279t, 280
Solubility analysis technique, 464-465, 465 high pressure liquid chromatography in, 789, 849,
Solubilization, in liquid pharmaceutical formulation, 849t
462-464, 464 theoretic considerations in, 761-772
preformulation research on, 188, 188 thermal, statistical techniques in prediction of, 788-
Solubilizing agent(s), 463t 789, 788t, 789
Solution(s), aerosol systems using, 597-600 Stability-indicating method(s), 849
“regular,” 461 Stainless steel, 703
reverse micellar, 508 aerosol containers of, 594, 600t
sterile. See Sterile product(s) Standard deviation, 247, 816-817, 817t
See also Liquid(s) Starch, as disintegrant, 328
Solvate(s), 177-178, 177 as granulating agent, 327
Solvent(s), in film coating, 368 as tablet diluent, 326-327
safety considerations with, 354 Static-bed dryerfs), 55-57
in granulation, safety considerations with, 689-690 Statistical inventory control, 753-754, 754t, 755
Solvent evaporation, microencapsulation by, 419t, 427 Statistical significance. See Significance
Solvent extraction method(s), 848-849 Statistics, 243-289
Sorbitol, as tablet diluent, 327 descriptive, 244
in semisolids, 544 in quality control, 815-824
paraben binding and, 465, 466 inference and estimation using, 250-263
Sorption, by plastic containers, 716, 799-800, 800t introductory concepts in, 244-250
Soudronic system, for welding aerosol containers, 592 nonparametric, 285-288
Specific reaction rate, 763 Steady state, 206-208, 206, 207, 208
Specific surface, 21 Stearic acid, as lubricant, 328
Specifications, 833-840 in semisolids, 541
for new products, 837-838 Stearyl alcohol, in semisofids, 541
for well-established products, 838 Sterile product(s), 639-677
official, 838-840, 839t additives in, 652-653
Specificity, 845-846 compounding, 667
Spectrophotometric method(s), 849 development of, 639-656
Spore(s), resistance of, to sterilization processes, 619, devices for, 651
620t filling procedures for, 667-669, 668, 669, 670
Spray congealing, 62 filtration of, 667
microencapsulation by, 419t, 426, 427 formulation of, 652-656
Spray dryer(s), 60-61, 61 route of administration and, 639-640, 655-656
wet granulation using, 338-339 packaging of, 675-676
Spray drying, 61-62 production of, 656-673, 657
microencapsulation by, 419t, 426-427 automated, 669, 670, 671-672
Spread, measures of. See Range; Standard deviation environmental control in, 658-661, 662t-663t
Stability, drug absorption and, 223 facilities for, 657-663, 659
enhancement of, by microencapsulation, 416-417, personnel for, 661-663
417 processing, 663-673
of aerosols, 608-610 quality control for, 656, 673-675, 675, 831
of coated tablets, 370-371 sealing, 668, 670, 671

898 • Index
 solutes for, 642-644, 642t-643t, 644t multilayered, 579
solvent system for, 652 packaging of, 581-582
stability of, 656 scafe-up considerations, 708-709
standards for, 639 rectal, factors affecting drug absorption from, 565-
vehicles for, 640-641 568
Sterility test(s), 636-637 scale-up considerations with, 706-709
Sterilization, 619-638 stability of, testing, 583
by filtration. See Filtration, sterile typical problems of, 587-588
by ionizing radiation, 629-630, 629 storage of, 587
by ultraviolet light, 628-629, 628t testing of, 585-587
chemical processes of, 634-636 therapeutic uses of, 564-565
evaluation of, 636-637 types and shapes of, 564, 565, 579-580
gas, 634-636 weight and volume control of, 584, 585
lower temperature, 626-627 Suppository base(s), cocoa butter as. 575-576
nonthermal methods of, 628-633 history of,-564
physical processes of, 623-633 hydrophilic, 577-579
spores’ resistance to, 619, 620t ideal, 575
thermal methods of, 623-628 physicochemical characteristics of, affecting drug
dry heat, 624-625 absorption, 567-568
moist heat, 623t, 625-627 types of, 568-575, 570t-574t
validation of processes of, 619-623 typical, 577
Sterilizer(s), double-ended, 656, 657 vegetable oil, 569, 576-577
types of, 624 water-dispersible, 578-579
Stem layer, 111, 111 Surface(s), interparticle forces between, 111-113, 112,
Stickiness, measurement of, 143 113, 114, 507
Sticking, of tablets, 312-313, 371 See also Interface(s)
prevention of, 701 Surface active agent(s), 100, 101, 103-106, 104, 105,
Still(s), for preparing Water for Injection, 663-664 106
Stirrer(s), mechanical, for emulsion formation, 510, as accelerants in topically applied drugs, 539
512 drug absorption from rectal suppositories and, 567
Stock recovery(-ies), 863 effects of, on properties of system, 105-106, 106
Stock Turn Rate, 749 ester hydrolysis and, 775, 775t
Stokes equation, 28, 484-485 in emulsion formation, 504-507, 513-517, 514t,
creaming of emulsions and, 526-527 515t
Strain, 71, 71 in formulation of aggregated suspensions, 489
Strain gauge(s), on capsule machine dosator, 95, 97 in suppository bases, 578-579
on multi-station presses, 92-93, 92, 93, 94 in suspension aerosols, 604
on single-station presses, 90-91, 90, 91 in water-based aerosols, 600
Stratum comeum, 535-536 structural requirements of, 105
hydration of, skin penetration and, 538 wettability and, 480
Stress-shear rate curve(s), 128, 128 Surface charge, in emulsions and suspensions, 110-
Stress-strain curve, for solids, 29-30, 29 111, 110, 111
Strip package, 727-728, 728 in powder, 16, 67
Strong-Cobb tester, 298 Surface excess, 103-104, 104
Sublimation, 62-63, 63 Surface tension, effects of solutes on, 103-105, 104,
drying by. See Freeze drying 105
Subsidence, 483 measurement of, 102-103, 102, 108-110
Sucrose, as granulating agent, 327 molecular basis for, 101-103, 101, 102, 103t
as tablet diluent, 327 Surfactant(s). See Surface active agent(s)
in liquid pharmaceuticals, 468 Suspending agent(s), for soft capsule filling, 404, 405t
Sugar, preservative characteristics of, 467-468 in formulation of dispersed suspensions, 489-490
Sugar coating, 332, 355-359 scale-up considerations in use of, 703
formulations used in, 357t Suspension(s), 479-501
polishing in, 356, 356, 358 adjuvants in formulation of, 491
Sulfur treatment, of glass, 712 aerosols using, 603-604
Sulindac, biliary clearance of, 214-215, 214, 215t intranasal, 606
biliary recycling of, 215-216, 216 aggregated, formulation of, 489
Suppository(-ies), 564-588 antacid, 497-498
blood levels of drugs administered in, 568, 568 in vitro neutralization capacity of, 499-500, 499t
coated, 579 basic chemical principles related to, 100-122
compressed tablet, 579 biopharmaceutical considerations with, 498-500
dosage replacement factor for, 585 crystal habit in, 486
dose characteristics of, 564 crystal structure factors in formulation of, 486-487
formulation of, 582-585 dispersed (peptized), 113
manufacture of, 580-582, 581 formulation of, 489-490
molding of, in-package, 582 filling equipment for, 668
methods of, 580-581, 581 formation of, 487-488
scale-up considerations, 708-709 formulation of, 488-492

INDEX • 899
 J

Suspension(s), formulation of (Continued) multiple, 330-331

crystal structure factors in, 486-487 compression of. See Tabletting
illustrative examples, 495-500 delayed-action, 331-332
parenteral, 654-655
in soft capsules, 403-404, 405t
depot (implantation), 334
disadvantages of, 294
T
parenteral, bioavailability of, 500 disintegration of, 301, 301
formulation of, 654-655 dispensing', 335
particle interactions and behavior in. 481-484, 482, dissolution of, 301-303, 303
483 double impression on, 314
preparative techniques for, 491-492 drug content and release from, 299-303
scale-up considerations with, 703-704 effervescent, 334-335
sedimentation rates of, 484-486 enteric coated, 331-332, 366-368
X
stability of, 794-795, 794, 795 evaluation of, 296-303
crystal factors in, 486-487 excipients for, 321t, 324-329, 330
evaluation of, 492-495 future trends in, 336
kinetic vs. thermodynamic, 100-101 film-coated, 332-333. See also Film coating
yield value and, 142-143, 142 for oral ingestion, 329-333
theoretic considerations with, 479-487 for preparing solutions, 334-336
wetting and, 480-481 for use in oral cavity, 333-334
with high solids content, 497, 497t future trends in, 336-342
with low solids content, examples of formulations, gastric retention, 337
496-497, 496t general appearance of, 296-299
with wetting and aggregating agents, examples of hardness and friability of, 297-299
formulations, 495-496 devices for testing, 297-298, 298, 299, 299
Sustained release formulation(s), 430-456 hypodermic, 335
advantages of, 430-431 identification markings on, 296-297
controlled release technology for, 455-456, 455 in-process quality control for, 831
design of, 233, 431-433, 433, 434 international considerations in formulation of, 329
implementation of, 440-446 lamination of, 88-89, 88, 311-312
disadvantages of, 431 manufacture of, computer control of, 342
dosage form modification approaches to, 442-446 improvements, 337-342, 338t
drug availability measurement, in vitro, 446-448, See also particular processes r
447 matrix, for sustained release, 453-455, 453t
in vivo, 448-450, 449 mottling of, 297, 313
drug modification approaches to, 440-442, 441 of slow release granulations, 452
drugs unsuitable for, 431, 43It organoleptic properties of, 297
microencapsulation for, 417-419, 418 physical stability of, 790-791, 790t, 790, 7911, 791
multiple dosing with, 439-440, 440 picking and sticking of, 312-313
. practical formulation of, 450-455 potency uniformity of, 300-301
product evaluation and testing of, 446-450 properties of, 295-296 %
theory of, 431-440 affecting coating, 347-348
with first-order release approximation, 437-439, purity of, 301
437t, 438t, 438 repeat-action, 331
with zero-order release approximation, 433-437, 434t role of, in therapy, 293
Sweat gland(s), 535, 536 scale-up considerations with, 687-702
Sweetening agent(s), in liquids, 468-469, 469, 470t size and shape of, 296
in tablets, 32It, 329 strength of, 86-89
testing of, 809-810 sublingual, 333
Synchrowax(es), 540 sugar-coated, 332. See also Sugar coating
System-suitability test(s), 848 sustained release, 336-337, 442, 453-455, 453t
types and classes of, 329-336, 33It
t distribution, 250-251, 251 vaginal, 334
t test, 251-253, 252t weight variation in, 300, 300t, 309-311, 311, 313-
independent two-sample, 254 314
one-sided, 255 Tablet coating, 346-373
one-sided vs. two-sided, 252, 259 automation of, 354, 355
with paired samples, 254-255 dust collection specifications for, 739
Tablet(s), 293-345 equipment for, 348-352, 349, 350, 351, 352, 354
advantages of, 293-294 facilities for, 354, 742-743, 744
buccal, 333 future trends in, 336, 372
capping of, 88-89, 88, 311-312, 701 history of, 346
challenges in design, formulation and manufacture parameters of, 352-354
of, 295 principles of, 346-354
chewable, 333 processes of, 354-362
chocolate-coated, 332 quality control in, 370
coated, evaluation of, 363-364 scale-up considerations with, 701-702
manufacture of. See Tablet coating specialized, 372
compressed, 329-330 stability testing^n, 370-371 &

900 • Index
 tablet properties affecting, 347-348 Theophylline, blood levels from different dosage forms,
See also Film coating; Sugar coating 568, 568
Tablet crushing strength. See Hardness of tablets sustained-release, 336-337
Tablet granulation(s), 314-317 Thermal analysis, differential, solid characterization by,
basic characteristics of, 314-315 179-180
flow properties of, 316-317 Thermogravimetric analysis, solid characterization by,
tablet weight variation from problems with, 313- 179-180, 179
314, 314 Thermometers), dry-bulb, 50, 50
manufacture of. See Granulation wet-bulb, 50, 50
properties of, 315-317 Thiamine hydrochloride lablet(s), ingredients for, 344
slow release, 452 Thief, sampling using, 245
Tablet press(es), 303-306 Thixotropy, 127-128, 127, 480
capabilities of, 700t Tin, collapsible tubes of, 717
counters for, 742, 743 drug stability and, 800
eccentric, 79 Tinplate, aerosol containers of, 592, 600t, 607
facilities for, 741-742, 742 Titralyzer, 850
instrumentation of, 89-95 Titrimetric method(s), 848
signal processing with, 94, 94 Tolbutamide, disposition of, in hepatic disease, 220,
mechanized feeders for, 309, 310 220t
multi-station rotary, 303-304, 305, 306t, 307 Tonicity, of parenteral preparations, 644, 655
instrumentation of, 92-93, 92, 93, 94 Topo granulator, 341-342, 341
single-punch, 303, 304 Torque, 472-473, 722
instrumentation of, 90-92, 90, 91, 92 Toxicity test(s), 845
tooling for, 306-309, 308 Toxicology studies, preclinical, biopharmaceutic
problems related to, 312, 314 considerations in, 227
Tablet triturate(s), 335-336 stability in formulations for, 190-191
Tabletting, 303-314 Trade name, 879
decompression in, 83-85, 84 Trade secret(s), 874, 880
dust collection specifications for, 739 Trademark(s), 874, 879-880
ejection forces in, 81 Tragacanth, as granulating agent, 327
energy involved in, 85-86, 85t, 85, 86t, 86 Transformation(s), in statistics, 278
equipment for, auxiliary, 309-311 Transient derivative(s), 776
See also Tablet press(es) Tray dryer(s), 55-57, 57
facilities for, 741-742, 742 Triangle test(s), of consumer acceptance, 267-268
force-volume relationships in, 81-83, 82, 83 Troche(s), 333
in-process quality control of, 311 Truck dryer(s), 55-57
processing problems in, 311-314 Tube(s), collapsible, 716-720
rheologic measurements and, 144 metal, drug stability and, 800
scale-up considerations with, 699-701 tamper-resistant seals for, 730-731
Tackiness, measurement of, 143 Tube mill(s), 40
Talc, as lubricant, 328 Tukey’s multiple range method, 272-273
Tank(s), for liquid pharmaceutical manufacture, 474 Tumbling mixer(s)) 17-18, 17
Tape seal(s), 730 Tunnel dryer(s), 57
Taub’s rule, 119, 119 Turbine(s), for fluid mixing, 7, 7
Technicon Autoanalyzer, 850 Turbo-tray dryer(s), 57-58, 58
Temperature, adiabatic saturation, 50 Turbulent flow, in fluid mixing, 4
crystal growth and, 117 Turnover, 749
drug degradation and, 765-768, 766, 767, 767t, 768 Twin shell mixer(s), 17, 690
dry-bulb, 49 Tyler Standard Scale, 27, 27t
emulsion shelf life assessment and, 528 Tyndallization, 626-627
filtration efficiency and, 152
in semisolid production, scale-up considerations, 706
Ultrafiltration, membrane, 166-167, 167
in suppository manufacture, 708-709
membrane filters for, 149, 166-167
solubility and, in preformulation research, 187-188,
Ultrasonifier(s), in emulsion formation, 511, 511
188
Ultraviolet fight, sterilization using, 628-629, 628t
viscosity and, 152, 152t
surface disinfection using, 659-660
wet-bulb, 49-50
Unfair competition, 879
Test(s), biologic, 841-842, 842t, 843t
United States Standard Scale, 27, 27t
in quality control, 840-845
Urea, closures of, 723
automated continuous system for, 850-851
Urinary excretion, 198-199, 199
quality of analytic methods, 845-849
Urine, pH of, renal clearance of drugs and, 210
microbiologic, 842-844, 842t, 843t, 844t
automated, 851
of bulk product, 814-815 Vacuum crimper, for aerosols, 611-612
See also under Stability; particular test methods and Vacuum filling, 476-477, 477
parameters for sterile liquids, 668
Theobroma oil. See Cocoa butter Vacuum film coating, 372
Theo-Dur (sustained-release theophylline), 336-337 Validation, 832-833

INDEX • 901
Valve(s), for aerosols, 594-595, 594, 595 Volume of powders, 68-70, 69, 70
Aquasol, 600-603, 601, 602 Volumetric filling, 476
discharge rate determination, 616
metering, 595, 595, 614, 616 Wagner-Nelson method, 204
quality control for, 613-614 Warehousing, facilities for, 746
selection of, 608 Warning notice(s), for over-the-counter drugs, 867
stability testing of, 610 for prescription drugs, 868
Valve placer, for aerosols, 611 on package inserts, 868
van der Waals force(s), 483 Washbum equation, 119
Vanishing cream base(s), 547, 549t Water, in liquid pharmaceuticals, 473, 474
Vapor pressure, of aerosol propellants, 590-591, 590t, in suppositories, 583
592, 593 quality control of, 810
testing of aerosols for, 615-616 See also Water for Injection
Variance, 247 Water activity, 54-55
analysis of, 269-278 Water attack test, 648, 712
missing values and, 275-276 Water for Injection, preparation of, 663-664
nonparametric tests for, 287-288 quality testing of, 640-641
one-way,1269-272 storage and distribution of, 664
two-wajr, 273-274 Water number, 545, 546t
with multiple comparisons, 272-273 of suppository bases, 569
comparison of, 256-257, 256t, 256 “Weathering,” of glass, 712
Variation, assignable, 816 Weight undersize, 29
chance, 816 Weight variation, in hard capsules, testing for, 392
(coefficient of, 250 in tablets, 300, 300t, 309-311, 311, 313-314
Veegum HV, as disintegrant, 328 Weighted averaging, sales forecasting using, 750
Vegetable oil(s), in semisolids, 540-541 Weighting procedure, in regression analysis, 282
treatment of, to produce suppository bases, 576-577 Welding, cold, 73
Ventilation, in sterile products production, 660-661, fusion, 73
660 of aerosol containers, 592
quality assurance monitoring of, 810, 812t Wet point, 480-481
See also Dust collection Wet scrubbeifs), 738
Vericap 1200 capsule weighing machine, 392, 394 Wet-bulb temperature, 49-50
Versator, 704, 705 Wet-bulb thermometer, 50, 50
Vial(s), sealing, 671 Wetting, 117-119, 117, 118, 118t, 480-481
Viscoelastic flow, 123, 139, 139 Wetting agent(s), suspensions with, examples of
Viscoelastic slope, 83 formulations, 495-496
Viscometer(s), capillary (tube), 131-134, 132, 133 White ointment, as semisolid base, 544
cone and plate, 136-137, 136 Wilcoxon rank sum test, 286-287
Couette (rotational), 134-136, 134, 136 Wiley Act (1906), 857
density-dependent, 137-138 Wilhelmy plate method, 109
for emulsion shelf life assessment, 530, 531 Work index, in milling, 32
Ostwald, 131-133, 132 Wrapping material(s), for moist heat sterilization, 62
pressure, 133-134, 133 See also Packaging
Viscosity, 3 Wurster Air Suspension Apparatus, 419-420, 419
apparent, 125
coefficient of, 124 X-ray analysis, solid characterization by, 180, 180
kinematic, 124
of emulsions, 519 Yield point, in comminution, 29, 29
shelf life and, 529-531, 530 in compression of powders, 72
of gelatin, for soft capsules, 400 Yield value, 126
of liquid pharmaceuticals, control of, 470 determination of, 128-130, 129, 130
of suppositories, 584 suspension stability and, 142-143, 142
suitable, in pharmaceutical applications, 140-142 Young Laplace equation, 102
temperature and, 152, 152t
units of, 124 Z value, 621t, 621
Vitamin A, degradation of, 787-788, 787, 788 Zanasi Nigris capsule filling equipment, 384, 389, 39
Vitamin B] tablet(s), ingredients for, 344 391
Volume contraction, of suppositories, 584 Zein, seal coating of tablets with, 356

902 * Index
0,