Controlled Drug Release Of Oral Dosage Forms 1st Edition

Visit the link below to download the full version of this book:

https://medipdf.com/product/controlled-drug-release-of-oral-dosage-forms-1st-edi
tion/

Click Download Now

First published in 1993 by
Ellis Horwood Limited
Market Cross House, Cooper Street,
Chichester, West Sussex, PO19 IEB, England
A division of
Simon & Schuster International Group

0 Ellis Horwood Limited, 1993

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or
transmitted, in any form, or by any means, electronic, mechanical, photocopying, recording or
otherwise, without prior permission, in writing, from the publisher

Printed and bound in Great Britain

by Bookcraft, Midsomer Norton

British Library Cataloguing in F’ublication Data

A catalogue record for this book is available from the British Library

ISBN O-13-1749564

Library of Congress Cataloging-in-Publication Dam

Available from the publisher
Table of contents

PREFACE . . . . . . . . . . . . . . . . . 0. . . . . . . . . . . . m. . . . . . . . . . . . m. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
. ..
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . m. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XIII

1 THE DIFFUSION EQUATIONS AND BASIC CONSIDERATIONS ............... 1

1.1 Introduction.. ................................................................................ 1
1 .I .I Process of diffusion.. ....................................................... 2
1 .I .2 Diffusion of a substance through a polymer.. ...................... 2
Polymer in the rubbery state (Case I). ................................ 2
Polymer in the glassy state (Case II). ................................. 3
Absorption of liquid in Case Ill.. ........................................ 3
1 .l .3 Steady and non-steady conditions.. ................................... 3
1 .I .4 Initial conditions.. ............................................................ 4
1 .I .5 Boundary conditions.. ...................................................... 4
1 .I .6 Volume of the surrounding atmosphere and partition factor . . 5
i.2 Equations of diffusion for various shapes .......................................... 6
1.2.1 Equations of diffusion for a thin sheet.. .............................. 6
1.2.2 Equations of diffusion for a rectangular parallelepiped .......... 7
Isotropic materials.. ......................................................... 7
Anisotropic materials.. ..................................................... 8
1.2.3 Cylinder of infinite and finite length.. ................................. 9
Cylinder of infinite length.. ............................................... 9
Cylinder of finite length.. .................................................. 9
1.2.4 Radial diffusion in a sphere.. ............................................. 10
1.3 Methods of solution when the diffusivity is constant.. ....................... 10
1.3.1 Kinds of solution ............................................................. 10
1 .3.2 Method of separation of variables.. .................................... 11
1.3.3 Method for the Laplace transform.. .................................... 15
1 .3.4 Method of reflection and superposition.. ............................ 17
Plane source ................................................................... 17
Reflection at a boundary.. ................................................ 19
Extended initial distribution of the substance.. .................... 19

2 MATHEMATICAL TREATMENT OF DIFFUSION IN A PLANE SHEET ......... 21

2.1 Introduction.. ................................................................................ 21
ii Table of contents

2.2 Non-steady state with a high coefficient of matter transfer on the

surface and an infinite volume of the surrounding.. ............................ 22
2.2.1 Uniform initial distribution in the sheet.. ............................. 22
2.2.2 Initial distribution f(x) in the sheet of thickness L.. .............. 31
Two different media.. ...................................................... 31
The two media are identical.. ............................................ 32
2.2.3 Non-steady state with a membrane with a uniform initial
distribution and surface concentration different.. ................. 34
2.3 Non-steady state with a finite coefficient of matter transfer on the
surface.. ....................................................................................... 37
2.4 Non-steady state diffusion in a stirred solution of limited volume ......... 40
2.4.1 Absorption of diffusing substance by the sheet.. ................. 41
2.4.2 Desorption of diffusing substance from the sheet in the
solution .......................................................................... 43
2.5 Steady-state with a membrane.. ...................................................... 45
2.5.1 High value of the coefficient of matter transfer on the
surf ace ........................................................................... 45
2.5.2 Case of finite value of the coefficient of matter transfer ....... 46
2.5.3 Composite membrane ...................................................... 47
2.5.4 Membrane separating gases or vapour.. ............................. 48

3 MATHEMATICAL TREATMENT OF DIFFUSION IN AN ISOTROPIC

RECTANGULAR PARALLELEPIPED ....................................................... 49
3.1 Introduction.. ................................................................................ 49
3.2 Isotropic rectangular parallelepiped with a constant diffusivity ........... 50
3.2.1 Infinite coefficient of matter transfer on the surface.
Constant concentration on the surface.. ............................. 50
Use of trigonometrical series.. ........................................... 51
Use of error function.. ...................................................... 52
3.2.2 Finite coefficient of matter transfer on the surface.. ............ 55
3.3 Effect of the thickness of the sheet.. ............................................... 58

4 MATHEMATICAL TREATMENT OF RADIAL DIFFUSION IN A SPHERE..... 59

4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4.2 Solid sphere in non-steady state with constant diffusivity . . . . . . . . . . . . . . . . . . 60
4.2.1 Infinite coefficient of matter transfer on the surface . . . . . . . . . . . . 60
4.2.2 Finite coefficient of matter transfer on the surface . . . . . . . . . . . . . . 62
4.2.3 Diffusion between a sphere and a well-stirred surrounding
atmosphere of finite volume . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
4.3 Hollow sphere in non-steady state . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
4.4 Hollow sphere in steady state . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4.4.1 Hollow sphere with a constant concentration on each
surface.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
4.4.2 Hollow sphere with a constant concentration of the internal
surface and a finite coefficient of matter transfer on the
external surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

5 MATHEMATICAL TREATMENT OF DIFFUSION IN CYLINDERS . . . . . . . . . . . . . . . . 75

5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
5.2 Non-steady state with a solid cylinder of infinite length . . . . . . . . . . . . . . . . . . . . . . 77
5.2.1 Constant concentration on the surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
5.2.2 Finite coefficient of matter transfer on the surface . . . . . . . . . . . . . . 81
5.2.3 Solid cylinder in a well-stirred surrounding of finite volume... 86
 ...
Table of contents 111

5.3 Non-steady state with a solid cylinder of finite length.. ...................... 90

5.3.1 Constant concentration on the surface ............................... 90
5.3.2 Finite coefficient of matter transfer on each surface ............ 93
5.4 Non-steady state with a hollow cylinder of infinite length.. ................. 95
5.4.1 Surface concentration constant and equal on each surface ... 97
5.4.2 Constant concentrations on each surface.. ......................... 98
5.5 Steady state with a hollow cylinder of infinite length.. ....................... 99
5.5.1 Constant concentrations on each surface.. ......................... 99
5.5.2 Constant concentration on the internal surface and a finite
coefficient of matter transfer on the external surface .......... 101
5.5.3 Composite hollow cylinder ................................................ 101
5.6 Conclusions .................................................................................. 102

6 NUMERICAL ANALYSIS WITH ONE-DIMENSIONAL DIFFUSION

THROUGH A PLANE SHEET ................................................................ 105
6.1 Introduction.. ................................................................................. 105
6.2 Diffusion through a sheet with constant diffusivity.. .......................... 106
6.2.1 Infinite coefficient of matter transfer on the surface ............. 107
6.2.2 Finite coefficient of matter transfer on the surface .............. 110
6.3 Diffusion through a sheet with concentration-dependent diffusivity ..... 113
6.3.1 Infinite coefficient of matter transfer on the surface.. .......... 113
6.3.2 Finite coefficient of matter transfer on the surface.. ............. 114
6.4 Membrane separating two different media.. ...................................... 118
6.4.1 Infinite coefficient of matter transfer on each surface .......... 118
6.4.2 Finite coefficient of matter transfer on each surface ............. 119
6.5 Diffusion between two different sheets ........................................... 122
6.5.1 Constant diffusivities.. ..................................................... 122
6.5.2 Concentration-dependent diffusivities.. .............................. 125
6.6 Transfer with special conditions.. .................................................... 126
6.6.1 Programmation of temperature.. ........................................ 126
6.6.2 Programmation of the concentration in the surrounding ........ 127

7 NUMERICAL ANALYSIS WITH A RECTANGULAR PARALLELEPIPED,

AND A THREE-DIMENSIONAL TRANSFER.. .......................................... 129
7.1 Introduction.. ................................................................................ 129
7.2 Transfer through a rectangular parallelepiped with a constant
concentration on the surface.. ......................................................... 131
7.2.1 Constant diffusivity.. ........................................................ 132
7.2.2 Concentration-dependent diffusivity.. ................................. 135
7.3 Transfer through a rectangular parallelepiped with a finite coefficient
of matter transfer on the surface.. ................................................... 137
7.3.1 Constant diffusivity.. ........................................................ 137
7.3.2 Concentration-dependent diffusivities, and finite coefficient
of matter transfer on the surface.. ..................................... 142
7.4 Transfer with special conditions.. ..................................................... 146
7.4.1 Anisotropic material.. ....................................................... 146
7.4.2 Programmation of temperature.. ........................................ 146
7.4.3 Programmation of the concentration in the surrounding ........ 147

8 NUMERICAL ANALYSIS WITH A RADIAL TRANSPORT WITHIN A

SPHERE.. .......................................................................................... 149
8.1 Introduction.. . . . . . . . . . . . . . . . . . . . . . . . ,.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . 149
iv Table of contents

8.2 Radial diffusion through a sphere with constant diffusivity ..,.............. 150
8.2.1 Infinite coefficient of matter transfer on the surface . . . . . . . . . . . . 150
8.2.2 Finite coefficient of matter transfer on the surface . . . . . . . . . . . . . . 154
8.3 Radial diffusion through a sphere with concentration-dependent
diffusivity . . . . . . . . . . . . . . . . . . e. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
8.3.1 Infinite coefficient of matter transfer on the surface . . . . . . . . . . . . 156
8.3.2 Finite coefficient of matter transfer on the surface . . . . . . . . . . . . . . 157
8.4 Hollow sphere with constant concentration on the internal surface,
and constant diffusivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
8.4.1 Infinite coefficient of matter transfer on the external
surf ace.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . 160
8.4.2 Finite coefficient of matter transfer on the external surface.. 161
8.5 Hollow sphere with constant concentration on the internal surface,
and concentration-dependent diffusivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
8.5.1 Infinite coefficient of matter transfer on the external
surface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
8.5.2 Finite coefficient of matter transfer on the external surface.. 163
8.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ,...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164

9 NUMERICAL ANALYSIS WITH CYLINDERS.. ........................................ 167

9.1 Introduction.. ................................................................................ 168
9.2 Solid cylinder of infinite length.. ...................................................... 169
9.2.1 Constant diffusivity ......................................................... 173
9.2.2 Concentration-dependent diffusivity .................................. 176
9.3 Hollow cylinder of infinite length.. ................................................... 177
9.3.1 Constant diffusivity.. ....................................................... 177
9.3.2 Concentration-dependent diffusivity.. ................................ 179
9.4 Solid cylinder of finite length.. ......................................................... 181
9.4.1 Constant diffusivity.. ....................................................... 181
9.4.2 Concentration-dependent diffusivity.. ................................ 193
9.5 Conclusions .................................................................................. 196

10 DRUG DELIVERY FROM DOSAGE FORMS CONSISTING OF A DRUG

DISPERSED IN A NON-ERODIBLE POLYMER.. ....................................... 199
IO. 1 Introduction and definitions.. ........................................................... 199
10.1 .I Problems of the drug passing through the body.. ................. 199
10.1.2 Pharmacokinetics, pharmacodynamics and
biopharmaceutics.. .......................................................... 203
10.1 .3 Conventional dosage forms .............................................. 205
10.1 .4 Oral therapeutic systems.. ................................................ 206
IO. 1.5 Simple monolithic devices with a polymer matrix.. .............. 208
10.1.6 Processes with a double matter transfer.. ........................... 212
10.2 Drug-Eudragit sheet in gastric liquid.. ............................................... 215
10.2.1 Introduction.. .................................................................. 215
10.2.2 Theoretical aspects.. ........................................................ 216
10.2.3 Experimental.. ................................................................. 219
10.2.4 Results obtained with Eudragit as polymer matrix.. .............. 221
10.2.5 Conclusions with Eudragit as polymer matrix.. ..................... 224
10.3 Drug-Carbopol sheet in gastric liquid.. .............................................. 225
10.3.1 Introduction.. .................................................................. 225
10.3.2 Theoretical aspects .......................................................... 226
10.3.3 Experimental.. ................................................................. 226
10.3.4 Results with Drug-Carbopol devices.. ................................. 227
 Table of contents V

10.3.5 Conclusions with Drug-Carbopol devices.. ........................... 230

10.4 Effect of pH on drug release.. .......................................................... 231
10.4.1 Introduction ..................................................................... 231
10.4.2 Theoretical aspects.. ........................................................ 232
10.4.3 Experimental.. .................................................................. 233
10.4.4 Results with a Drug-Eudragit sheets.. ................................ 234
10.4.5 Conclusions.. ................................................................... 240
10.5 Spherical Drug-Eudragit beads in gastric liquid.. ................................. 242
10.5.1 Introduction.. ................................................................... 242
10.5.2 Theoretical aspects .......................................................... 242
10.5.3 Experimental.. .................................................................. 246
10.5.4 Results with Drug-Eudragit spheres.. .................................. 246
10.5.5 Conclusions.. ................................................................... 251

11 DRYING OF DOSAGE FORMS MADE OF A DRUG DISPERSED IN A

POLYMER MATRIX ............................................................................ 261
1 1 .I Introduction.. ................................................................................ 261
11.2 Drying dosage forms in a surrounding atmosphere of infinite volume . . 263
1 1 .2.1 Theoretical.. ................................................................... 263
1 1 .2.2 Experimental ................................................................... 267
11 .2.3 Results with a constant temperature.. ............................... 268
1 1.2.4 Effect of temperature.. ..................................................... 274
1 1 .3 Drying with a programmed temperature ......................................... 277
1 1 .3.1 Theoretical.. ................................................................... 279
1 1 .3.2 Experimental.. ................................................................. 280
1 1 .3.3 Results with a programmed temperature.. ......................... 280
11.4 Drying in a surrounding atmosphere of finite volume.. ........................ 286
1 1.4.1 Theoretical of drying in a surrounding atmosphere of finite
volume.. ......................................................................... 286
1 1 .4.2 Experimental.. ................................................................. 291
11 .4.3 Results.. ......................................................................... 291
1 1 .5 Drying with a controlled vapour pressure.. ........................................ 300
11.5.1 Theory of the process with controlled vapour pressure ........ 301
1 1 .5.2 Simulation of the process.. ............................................... 302
1 1 .6 Conclusions.. ................................................................................ 308

12 DRUG DELIVERY FROM DOSAGE FORMS CONSISTING OF A DRUG

DISPERSED IN AN ERODIBLE POLYMER.. ............................................. 313
12.1 Introduction.. ................................................................................ 313
12.2 Theoretical aspects ........................................................................ 314
1 2.2.1 Diffusional process.. ........................................................ 314
12.2.2 Polymer erosion is the driving force.. ................................. 317
1 2.3 Experiments.. ................................................................................ 318
1 2.4 Results.. ....................................................................................... 320
12.4.1 Results with the diffusion process.. ................................... 320
12.4.2 Results with the erosion process.. ..................................... 322
12.5 Conclusions.. ................................................................................ 327

13 DOSAGE FORMS MADE OF A CORE AND SHELL, WITH AN ERODIBLE

SHELL. CONSTANT RATE OF DELIVERY .............................................. 329
13.1 Introduction.. ................................................................................ 329
13.2 Theoretical aspects.. ...................................................................... 330
13.3 Experimental.. ............................................................................... 333
vi Table of contents

13.4 Results.. ....................................................................................... 334

13.4.1 Results with sodium salicycate.. ....................................... 334
13.4.2 Results with sulfanilamide.. .............................................. 338
13.5 Conclusions.. ................................................................................ 341

14 DOSAGE FORMS MADE OF CORE AND SHELL, WITH A NON-ERODIBLE

POLYMER.. ....................................................................................... 345
14.1 Introduction.. ................................................................................ 345
14.2 Theoretical.. .................................................................................. 346
14.3 Experimental.. ............................................................................... 352
14.4 Results.. ....................................................................................... 352
14.4.1 Data.. ............................................................................ 353
14.4.2 Validity of the model.. ...................................................... 354
14.4.3 Effect of parameters.. ...................................................... 354
14.4.4 Profiles of concentration.. ................................................ 357
14.5 Conclusions.. ................................................................................. 358

15 CONTROLLED RATE OF DELIVERY WHEN THE SOLUBILITY OF THE

DRUG IS LOW, BY USING A SWELLING POLYMER.. .............................. 363
15.1 Introduction.. ................................................................................ 363
15.2 Dosage form with a polymer matrix and a swelling polymer.. .............. 364
1 5.2.1 Theoretical.. ................................................................... 364
15.2.2 Experimental.. ................................................................. 365
15.2.3 Results.. ......................................................................... 366
15.3 Dosage forms with gelucire and a swelling polymer.. ......................... 373
1 5.3.1 Theoretical.. ................................................................... 373
15.3.2 Experimental.. ................................................................. 373
15.3.3 Results and discussion.. .................................................... 376
15.4 Dosage form with a core (swelling Polymer-Drug-Eudragit) and an
erodible polymer.. .......................................................................... 380
15.4.1 Theoretical.. ................................................................... 380
15.4.2 Experimental.. ................................................................. 382
15.4.3 Results.. ......................................................................... 383
15.5 Conclusions .................................................................................. 390

16 DOSAGE FORMS WITH A DRUG ATTACHED TO A POLYMER

DISPERSED IN A NON-ERODIBLE POLYMER MATRIX ............................ 393
16.1 Introduction.. ................................................................................ 393
16.2 Theoretical.. .................................................................................. 394
16.3 Experimental.. ............................................................................... 395
16.4 Results.. ....................................................................................... 397
16.5 Conclusions .................................................................................. 404

INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..~........................................................... 409

 PREFACE

Therapeutic systemsrepresent a new route for drug administration: as the drug is

delivered continuously at a controlled rate over a predeterminedperiod of time, uniform
and constantblood level is achieved,smaller amount of drug is neededreducing the side
effects, and the therapy is improved. Various people beyond the patient are concerned
with this therapy,physicians andpharmacistsin various areasof specialization,of course,
but also bio-engineersand even workers in chemicalengineering.Various oral therapeutic
systemsconsist of a polymer matrix through which the drug is dispersed,and thus good
knowledge of the matter transfers through the polymer is necessarywhen they are in
contact with the gastric or the intestine liquid.These matter transfers being controlled by
transient diffusion, the mathematical treatment of diffusion must be known when it is
feasible in simple casesand especiallyfor constantdiffusivity. Morever, in complex cases
and when the diffusivity is concentration-dependent, numerical methods with finite
differences must be used instead of the mathematical treatment. Finally, in order to
accustom the users with these ways of calculation, various mathematical or numerical
models are built andtestedin the study of different oral dosageforms. Thus a new way of
working is developed, coupling the experiments with the models of the process, these
experimentsbeing performed in so called in-vitro tests which simulate the conditions in
the body asmuch aspossible.
The “drug”, by using this term in the senseof a biologically active substance,is a
chemical compound administered to the patient’s organism, with which it develops a
reciprocal interaction for therapeuticpurposes.Generally, for many reasons,the drug is
not used in the pure state.The supply form of presentationof the drug, or dosageform, is
the completemedication.Conventionaldosageforms consistof the drug, the active agent,
 .
VIII Preface

and auxiliary substancesbiologically inert, the excipients. The role of excipients is

essentially of binding the drug, filling the dosageform in order to ensurethe consistency
and volume necessaryfor the patient use.When in contactwith the gastric liquid, the drug
is releasedfrom the dosageform used for the administration. Two factors determine the
releaseof the drug: the solubility and the rate of dissolution. When the drug is released
from the dosageform, it must pass through several barriers, before reaching the site of
action. The driving force responsible for the transport of the drug through these
membranes is the concentration gradient across the membrane, the process being
controlled by diffusion. The amount of unchangeddrug that is absorbedby the organism
in a certain time and that arrives at the target site through the circulatory system, or
bioavailability, dependson the dosageform, and thus may be alteredby this dosageform.
The drug conveyed by the bloodstream, leaving the intravascular compartment is
distributed between extracellular and intracellular compartment where it can reach the
receptorsfor drugs lying in the tissues.Finally the drug is eliminated either by chemical
alteration of the molecule with formation of metabolites or by excretion via various
organs. The time required for elimination of half the plasma content of the drug by
metabolism or excretion, the biological half-time, is of high interest for the dosage
regimen prescribed by the physician. An exact dosage regimen is of high importance
when the concentrationof the drug must be maintained constantin the tissuesover a long
period of time. Morever, the concentrationof the drug must be kept between the median
lethal dose(causing the deathsof 50% of experimental animals) and the median effective
dose (effective in 50% of cases).The therapeutic index, equal to the ratio of these above
concentrationsdefinesthe safetymargin.
All conventional dosageforms made of a drug dispersedin excipients, releasethe
drug according to the following pattern. The drug is very rapidly dissolved from the
dosagefonn and quickly builds up to a maximum high concentration, which then falls
exponentially with tune becauseof the first order absorption.The result is an undulating
concentrationof the drug in the stomachor intestine, as well as in the blood and tissues,
where high concentrations with overdosages alternate with low concentrations and
underdosages.The limitations of conventional dosageforms made of drug and excipients
appearthen since they causeproblems in maintaining therapeutic drug levels over only
brief durationsof tune :

(i) The fluctuating drug levels with conventional dosageforms lead to an insufficient
efficacy of therapy provoking an excessiveuse of the drug.
 Preface ix

(ii) Overdosage appearing after dissolution of the drug may be responsible for a high
frequencyof side effects,leading to iatrogenicdamage.
(iii) High frequency of administration of conventional dosage forms is limited by the
reliability of the patient andthe patient compliance(omission,wrong frequency)
(iv) A potent drug may largely lose its therapeuticefficacy through improper formulation,
and thus a pharmacologicallyactive substanceis not necessarilyan effective drug.

Oral dosage systems able to release the drug at a constant rate for a given time
period are thus of mterest.The result is then a constantuniform concentrationof drug in
blood and tissuesover a given period of time, with the following advantages:
(i) Significant smaller amountsof drug are generally prescribedwith a therapeuticsystem
of drug delivery.
(ii) The reduced amount of drug administered reduces the problems of side effects,
improving the safety of therapy.
(iii) The patient compliance is usually better with these types of dosage forms, as the
frequencyof administration is considerablylower.

Simple oral dosageforms capableof controlling the releaseof the drug are often and
easily obtained with monolithic devices where the drug is dispersedin a biocompatible
polymer. This polymer which cau be either biodegradableor non degradable,plays the
role of a polymer matrix. Not only the polymer brings the consistency to the dosage
form, but also it controls the releaseof the drug. The processis generally as follows: the
liquid (gastric liquid or intestineliquid) entersthe polymer, dissolvesthe drug and enables
the drug to leave out the dosageform through the liquid located in the dosageform. The
matter transfers for the liquid and for the drug are controlled by transient diffusion, with
concentration-dependent diffusivities, the diffusivity of the drug depending on the
concentrationof the liquid in the dosageform. The releaseof the drug being controlled by
transient diffusion, exhibits a rather high rate at the beginning of the process which
decreaseswith time in an exponentialway. Thesedosageforms arevery simple to prepare
and rather inexpensive, but the processof releaseis controlled by diffusion, and the rate
of releaseis far from being constant.

The drug delivery from the dosageform is studied by using in-vitro tests,thesein-
vitro testsbeing built up in such a way that they simulate as much aspossible the story in
the stomach or intestine of the patient. These in-vitro tests are very useful for many
X Preface

reasons,and the most obvious are only given :

(i) The conditions of the in-vitro test are very well defined and standardized,enabling
comparisonsbetweenvarious results.
(ii) They are easyto perform, and the effect of eachparametercan be analysedseparately.
(iii) In contrastwith the in-vitro test, the in-vivo test is far more complex, asthis latter is
subjectto a variety of influencesthat differ greatly amongindividuals.

There are several objectives in this book devoted to the study of the process of
matter transfers in oral dosageforms with a polymer matrix able to control the releaseof
the drug. As the driving force for the matter transfers of the liquid and the drug through
the polymer is the gradient of concentration, the process is controlled by transient
diffusion. Some emphasisis thus placed upon the mathematicaltreatment of diffusion in
solids of various shapes,when the processis so simple that an analytical solution exists.
As very often the process of matter transfers is rather complex, it must be studied by
using numerical methodswith finite differences. Finally, various examplesare described
by consideringsimple oral dosageforms with either a non-erodibleor an erodible polymer
matrix, and with more complex systemsconsisting of a core and shell. These studiesare
made by using the method coupling experimentswith short tests and long real tests and
modelling of the process.
The book is divided in threeparts with sixteenchapters:
The first part presents an overview of the mathematical treatment of diffusion
through a polymer in the elastomeric state.Various shapesare consideredfor the solid :
thin plane sheets,rectangular parallelepiped, cylinders and spheres.In order to help the
reader’s understanding, some emphasis is placed upon the conditions in which the
mathematical treatment is feasible constant diffusivity, uniform initial concentration,
simple boundary conditions. For people wanting to improve their backgroundknowledge
of the mathematical treatment of diffusion, various examplesare describedin a didactic
way in the first five chapters.Specialconsiderationis given to the operationalconditions :
with a very high volume of the liquid in which the dosageform is immersed, or with a
finite volume of this liquid ; with a very high coefficient of matter transfer on the surface
leading to a constant concentration on the surface, or with a finite coefficient of matter
transfer on the surface.

- In chapter 1, general equations of diffusion are given for various shapesof the dosage
form. and basic considerationsare described.
 Preface xi

- In chapter 2, the mathematical treatment of diffusion is shown in various caseswith a

plane sheetand mono-directionaldiffusion.
- In chapter 3, the mathematical treatment of diffusion is given with a rectangular
parallelepipedand three-dimensionaldiffusion.
- In chapter4, radial diffusion through spheresis studied.
- In chapter 5, cylinders of infinite and finite lengths are consideredwith radial diffusion
in the first caseand radial andlongitudinal diffusion in the secondcase.
The secondpart is devotedto numerical treatmentof diffusion, in order to accustom
the readersto this new and powerful way of working. This method is very useful, as very
often no analytical solution can be obtained from the mathematicaltreatment,becauseof
the complexity of the process : double matter transfers of the liquid and drug,
concentration-dependent diffusivity. Explicit numericalmethodswith finite differencesare
developed, becauseof their easy use with microcomputers. Four chaptersenable one to
consider various shapes.
- In chapter 6, plane thin sheets are considered and classical examples of numerical
analysis are developedin the following simple cases: the diffusivity is either constantor
concentration-dependent,while various values of the coefficient of matter transfer on the
surfaceare given.
- In chapter 7, numerical analysis is developed with a rectangular parallelepiped and a
three-dimensionaltransfer.
- In chapter8, numerical analysisfor the radial transferthrough a sphereis presented.
- In chapter 9, the matter transfers, either radial with long cylinders or radial and
longitudinal with cylinders of finite length, are studied with the help of numerical
analysis.
The third part examines various approchesto industrial problems with practical
purposes. A new method coupling experiments and modelling of the process is widely
used.
Experimentsareusedfor the following reasons:
- to get deepknowledge of the process
- to obtain the values of parameters,such as the diffusivities by using short tests
- to test the validity of the models.
Modelling of the process is widely used, either with the mathematical treatment
when the problem is simple, or with the numerical treatmentwhen the processis complex.
Each of these different casesare discussedin chapters 10 to 16, working through
the difficulties encounteredwith experimentsand calculation.
xii Preface

- Chapter 10 concentrateson the drug delivery from simple dosageforms consisting of a

drug dispersedin a non-erodible polymer. Two matter transfers are consideredwith the
liquid entering the polymer, dissolving the drug and enabling the drug to leave the dosage
form through the liquid located in the polymer. These two transfers are connectedwith
eachother, and the diffusivity of the drug dependson the liquid concentration.
- Chapter 11 shows the complexity of the process of drying of dosage forms with a
polymer matrix, the process being controlled not only by evaporation but also by
diffusion of the liquid through the polymer. Various examplesare describedand the effect
of factors such as the temperatureor programmation of temperature,the pressureof the
vapour in the surrounding atmosphere,is evaluated.
- Chapter 12 discussesthe problem of drug delivery from dosageforms made of a drug
dispersedin an erodible polyme matrix.
- Chapter 13 focuses on the interest of preparing dosage forms with constant rate of
delivery. Typical dosageforms are presentedwith a core containing the drug dispersedin
a polymer andwith an erodible shell surroundingthe core.
- Chapter 14 deals with dosageforms made of a core and shell, where the core contains
the drug dispersedin a non-erodiblepolymer and the shell is a non-erodiblepolymer. The
effect of the relative thicknessof the shell is of high interest.
- Chapter 15 is devoted to special dosageforms able to deliver the drug from the dosage
form when the drug is poorly soluble in the liquid. A swelling polymer is thus addedin
the erodible polymer matrix which helps the disintegration of the dosageform and thus
disseminationof the drug in the liquid. As somepolymers swell differently in gastric and
intestine liquid, they allow the dosageform to deliver the drug partly in the stomach and
intestine.
- Chapter 16 examines the problem of dosage forms where the drug is attached to a
polymer, this branchedpolymer being dispersedin a polymer matrix.
 ACKNOWLEDGEMENTS

A large part of this book covers various applications and industrial problems, as
many people working in industrial firms have influenced this work through industrial
contracts.I am glad to thank them for their interestingcooperation.

Many colleaguesand studentshave supportedmy efforts and brought contributions

worth noting.
Deep gratitude is extendedto my colleaguesM. Rollet who showedme round the
world of galenic pharmacy as well as J. Bardon and C. Chaumat. I am grateful for the
collaboration of my colleague J. L. Taverdet in the work concernedwith the preparation
and studies of dosageforms. I give my best thanks to my colleaguesJ. Bouzon for his
participation in numerical analysis and modelling of the process, and J. P. Montheard
who dealt with the polymerization problemsin chapter 16. I appreciatethe kind help of H.
Liu and J. Paulet.

My best appreciationis given to my students:

Y. Armand, D. Bidah, N. Chaffi, A. Droin, A. Eddine, N. Farah, M. Kolli, N.
Laghoueg, F. Magnard, P. Magron, Y. Malley, E.M. Ouriemchi, M. Saber, who did
their best for preparating their Theses.Many thanks to D. Berthet for his efficient help in
calculation and for his drawings, and to C. Cervantes, N. Fauvet, D. Ianna and M.
Novais Da Costafor their competenttyping of the manuscript.
1

The diffusion equations and basic

considerations

1 .I INTRODUCTION

1 .l.l PROCESS OF DIFFUSION

Generally diffusion is the process through which matter is transferred from one
place to another, resulting from random molecular motions. Of course, on the average, the
matter is transferred by diffusion from the region of higher to that of lower concentration
of the matter. The example of diffusion of a drop of dye in motionless water is a good
example.
Transfer of heat by conduction is also due to random molecular motions transferring
kinetic energy, and there is some analogy between these two processes of matter and heat
transfers. The mathematical equation of heat conduction was established by Fourier in
1822. A few decades later, Fick in 1855, recognizing this analogy, put diffusion on a
quantitative basis by adopting the same equation. In an isotropic substance the rate of
transfer of diffusing substancethrough unit area of a section is proportional to the gradient
of concentration measured normal to this section.

(1.1) F= -D K
. ax
where g is the gradient of concentration C of the substance along the x-axis of diffusion,
X

F is the rate of transfer per unit area of the section perpendicular to the x-axis,
and the coefficient D is called the diffusion coefficient of diffusivity.