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Essential Chemistry for
FORMULATORS
OF SEMISOLID
AND LIQUID
DOSAGES

Authors

VITTHAL S. KULKARNI, Ph.D.

Scientific Advisor, Research and Development, DPT
Laboratories, Ltd., San Antonio, TX, USA

CHARLES SHAW, Ph.D.

Scientific Advisor, Research and Development, DPT
Laboratories, Ltd., San Antonio, TX, USA

Amsterdam • Boston • Heidelberg • London

New York • Oxford • Paris • San Diego
San Francisco • Singapore • Sydney • Tokyo
Academic Press is an imprint of Elsevier
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, UK
525 B Street, Suite 1800, San Diego, CA 92101-4495, USA
225 Wyman Street, Waltham, MA 02451, USA
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK
Copyright © 2016 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any
means, electronic or mechanical, including photocopying, recording, or any information
storage and retrieval system, without permission in writing from the publisher. Details on
how to seek permission, further information about the Publisher’s permissions policies and
our arrangements with organizations such as the Copyright Clearance Center and the
Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright
by the Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and
experience broaden our understanding, changes in research methods, professional practices,
or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described
herein. In using such information or methods they should be mindful of their own safety
and the safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or
editors, assume any liability for any injury and/or damage to persons or property as a
matter of products liability, negligence or otherwise, or from any use or operation of any
methods, products, instructions, or ideas contained in the material herein.
ISBN: 978-0-12-801024-2
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
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PREFACE

The focus of this book is the formulation, product development, testing,

and stability of semisolid and liquid dosage forms. Formulations of this type
are important throughout the industry, and are an essential vehicle for deliv-
ering pharmaceuticals safely and effectively to their intended target. Under-
standing the chemistry of surfactants and surface phenomena is key to
successfully formulating complex multicomponent formulations.
The formulation of semisolid dosages requires mixing several ingre-
dients to produce a uniform, homogeneous, stable product that can be
filled into suitable containers for the end user. This is also applicable to
some liquid formulations that are multicomponent systems. The mixing
of various ingredients that may be mutually immiscible liquids contain-
ing partially soluble or insoluble materials to form a uniform, stable
system requires a thorough knowledge of chemistry. The required
knowledge of physical, organic, and analytical chemistry that is essential
for pharmaceutical formulation development is well documented in
various books and research publications. The purpose of this book is not
to give fundamental details of the chemistry, but to draw attention to the
chemical principles underlying the formulation development of com-
plex mixtures. As some of the medications will be delivered through
specialized devices, a basic knowledge of engineering and, to a certain
extent, physics is also beneficial. Furthermore, an important aspect for
any chemist or pharmacist involved in pharmaceutical drug product
development is an awareness of the regulatory agency’s requirements,
generally known as the “Chemistry, Manufacturing, and Controls” part
of a drug product regulatory filing. In this book we have focused on
surfactants, thickeners, surface chemistry, drug delivery systems, methods
used for characterization, and regulatory aspects of testing drug
products.
We hope that this book will be helpful to scientists involved in the drug
product development of semisolid and liquid dosage forms, and that it will
give newcomers to this field a broad perspective of the chemistry involved
in formulating and testing drug products.
The process of writing and reviewing chapters was very time-consuming
and took many hours of personal time away from our families. We are

ix
x Preface

thankful to our colleagues and friends who assisted us at various stages. We

remain indebted to our wives Anuradha and Karen, and our family members
who supported us throughout the long process.

Vitthal S. Kulkarni and Charles Shaw

September 2015
CHAPTER 1

Introduction

Every year, several new drug products based on either new drug substances
or generics of existing drug products are approved and enter the market. In
2014, approximately 95 Abbreviated New Drug Applications (ANDAs, i.e.,
generic) and 106 New Drug Applications (NDAs) were approved by the
Center for Drug Evaluation and Research (CDER), a division of the US
Food and Drug Administration (FDA). This demonstrates that Research
and Development within the pharmaceutical industry is a very competi-
tive field. Achieving success in drug formulation development requires a
combined knowledge of chemistry, chemical and process engineering, and
the regulations. Drug product development activities include aspects of
preformulation/formulation development (including compatibility of the
API with formulation excipients, and the compatibility of the ingredients
and finished formulation with the manufacturing process, process parts,
and container-closure system), as well as aspects of manufacturing and sta-
bility testing.
Due to concerns relating to toxicity and possible side effects, very
few drug substances can be directly administered to the body. Additionally,
the amount of the drug substance administered (i.e., the maximum daily
dose) is often in milligram or microgram quantities. As a result, it is nec-
essary to mix the drug with other nondrug (inactive) ingredients in such
a way that the drugs can be safely delivered to their target within the
body.
The US FDA definitions for active ingredient, drug, and drug products are:
• Active Ingredient: any component that provides pharmacological activ-
ity or other direct effect in the diagnosis, cure, mitigation, treatment, or
prevention of disease or affects the structure or any function of the body
of man or animal.
• Drug:
• A substance recognized by an official pharmacopeia or formulary.
• A substance intended for use in diagnosis, cure, mitigation, treatment,
or prevention of disease.

Essential Chemistry for Formulators of Semisolid and Liquid Dosages © 2016 Elsevier Inc.
http://dx.doi.org/10.1016/B978-0-12-801024-2.00001-7 All rights reserved. 1
2 Essential Chemistry for Formulators of Semisolid and Liquid Dosages

•  substance (other than food) intended to affect the structure or any

A
function of the body.
• A substance intended for use as a component of medicine but not a
device or a component, part, or accessory of a device.
  Biological products are included within this definition and are generally
covered by the same laws and regulations, but differences exist regarding
their manufacturing process.
• Drug Product: a finished dosage form that contains an active drug ingre-
dient, generally, but not necessarily, in association with other active or
inactive ingredients.
As an example, a tablet of Ibuprofen of 200 mg strength may actually
weigh 500 mg, indicating that to deliver 200 mg of the drug substance,
300 mg of inactive ingredients are added to help safely deliver the drug
to its destination. The added inactive ingredients might also help to keep
the drug stable for a finite period. Therefore, converting a drug substance
into a safe and effective drug product is equally as important as inventing
the drug itself. This process of making drug products by combining the
drug substance (the API) and the necessary inactive ingredients (the
excipients) is called the formulation process. When formulating a drug
product, the goal is to make a safe and effective product that has an
acceptable shelf life, which can be easily administered (to promote patient
compliance).
Pharmaceutical formulations are mixtures of the pharmaceutically active
ingredient and selected inactive ingredients. Solution formulations that are
used for injectable dosage forms generally have fewer inactive ingredients—
such as water, cosolvents, buffering agents, and pH-adjusting agents. As a
result, they are much simpler to formulate compared to some of the semi-
solid formulations used for topical administration. The inactive ingredients
used in semisolid formulations may include water, oil, surfactants, emulsifi-
ers, stabilizers, chelators, preservatives, and pH-adjusting agents. These types
of formulations tend to be complex due to interactions between the various
ingredients and consequently require considerable development efforts
during the formulation process. Furthermore, when formulating a generic
version of an existing marketed product, reverse engineering of the refer-
ence drug product is often ­challenging for semisolids.
For all types of formulations, product development efforts require put-
ting together all of the ingredients, testing their mutual compatibility (e.g.,
the drug substance with the inactive ingredients, and between one inactive
ingredient and another), the solubility of the API in the formulation
 Introduction 3

matrix, the chemical stability of each ingredient, and the physical stability
of the formulation as a whole. Developing stability-indicating test methods
is an inherent part of product development activities. The US Food and
Drug Administration (FDA) recommend using a Quality by Design
(QbD) approach when developing drug products, including generic prod-
ucts. When developing generics, three critical attributes are (1) the ingre-
dients are the same as in the reference-listed drug (RLD); (2) the
concentrations of the ingredients are the same as in the RLD; and (3) the
microstructure (arrangement of matter) within the generic is the same as
in the RLD.
Common types of dosage forms are solid, liquid, aerosol, suspension, and
semisolid. Solids are typically administered either orally, by inhalation (e.g.,
dry powder inhalers), or applied topically (e.g., powders). Liquids can be
injected, taken orally, applied topically, or administered via the nasal or pul-
monary route (in the form of a spray). Semisolids can be administered topi-
cally (e.g., creams, lotions, ointments, gels), transdermally, injected
subcutaneously (e.g., gels for subcutaneous administration), vaginally, or
anally (e.g., suppositories).
In recent years, several medications have appeared on the market in
which the drug product is delivered via a device in which the device is an
integral part of the medication. The term “Combination Products” is used
when the medication is composed of any combination of drug and a device.
Examples of combination products include pressurized metered-dose inhal-
ers, nebulizers, dry-powder inhalers, transdermal patches that deliver drugs
by iontophoresis or microneedle technology, and prefilled syringes. The
definition of a combination product includes:
• A product comprising two or more regulated components (i.e., drug/
device, biologic/device, drug/biologic, or drug/device/biologic) that
are physically, chemically, or otherwise combined or mixed and pro-
duced as a single entity.
• Two or more separate products packaged together in a single package or
as a unit and comprising drug and device products, device and biological
products, or biological and drug products.
• A drug, device, or biological product packaged separately that, according
to the investigational plan or proposed labeling, is intended for use only
with an approved individually specified drug, device, or biological prod-
uct in which both are required to achieve the intended use, indication,
or effect and in which upon approval of the proposed product the label-
ing of the approved product would need to be changed.
4 Essential Chemistry for Formulators of Semisolid and Liquid Dosages

• Any investigational drug, device, or biological product packaged sepa-

rately that according to its proposed labeling is for use only with another
individually specified investigational drug, device, or biological product in
which both are required to achieve the intended use, indication, or effect.
Inactive ingredients that act in the formulation as surfactants, emulsifiers,
thickeners, gelling agents, or stabilizers play critical roles in making stable
semisolid formulations. To successfully design and develop stable drug
products, it is critical to have a knowledge and understanding of surfactants
and surface chemistry. Formulation development is not complete until the
various ingredient compatibility aspects are studied and data are produced.
These compatibility aspects include API and excipients, solubility of the
API in the formulation matrix, and compatibility of the formulation with
the intended primary container-closure system. If more than one API is to
be incorporated in the formulation, the process becomes more complicated.
Establishing processing compatibility at all stages of the product develop-
ment life cycle is also a key aspect of formulation development—including
scale-up, full-scale manufacture, and the filling process. To assess the risks
and take appropriate measures to reduce them, the FDA recommends fol-
lowing a QbD approach for all stages of formulation and process develop-
ment. A detailed discussion surrounding QbD and stability testing is
provided in this book.
Chapters covering the rheology, particle size, microscopy, and miscella-
neous physical and chemical test methods for semisolid and liquid dosage
forms are included. Formulation topics such as the use of polymers, thickeners,
other excipients, and methods of manufacturing are also covered. A chapter is
also devoted to aerosol formulations, which is a rapidly growing area in terms
of new products.
Finally, no drug product can be placed into the market without approval
by regulatory agencies. Satisfying the regulatory requirements for new drug
products or generics is essential. A full chapter is devoted to a review of the
current regulatory landscape relating to semisolid and liquid dosage forms.
CHAPTER 2

Surfactants, Lipids, and Surface

Chemistry
Contents
2.1 I ntroduction 5
2.2 T ypes of Surfactants 6
2.2.1 Surfactant Micelles 6
2.2.2 Anionic Surfactants 7
2.2.3 Cationic Surfactants 8
2.2.4 Nonionic Surfactants 8
2.3 Natural Surfactants 8
2.3.1 Lipids 10
2.4 The Role of Surfactants in Pharmaceutical Formulations 12
2.4.1 Skin Penetration Enhancers 12
2.4.2 Emulsifying Agents 14
2.4.2.1 Hydrophile–Lipophile Balance (HLB) System 15
2.4.3 Aerosol Formulations 15
2.4.4 Surfactant Gels 15
2.5 Surface Chemistry for Pharmaceutical Formulations 16
2.5.1 Surface and Interfacial Tension 16
2.5.2 Contact Angle 17
2.6 Conclusion 18
References18

2.1 INTRODUCTION
This chapter presents an introduction to surface chemistry and surfactants
in pharmaceutical formulations. The choice and quantity of surfactants are
essential factors in the formation of stable and efficacious emulsions as
pharmaceutical dosage forms (including oral, topical, and injectable/infusible
dosage forms). Understanding the physical chemistry of surfactant mole-
cules in aqueous systems and at the air–water or liquid–liquid interface is
fundamental to designing drug delivery systems. Important parameters
include surface tension, contact angle, and critical micelle concentration.
Surfactants are “amphiphilic” molecules (or “amphiphiles”), containing both
hydrophilic and hydrophobic portions on the same molecule. They have been
termed “surface active agents” due to their activity at the air–water or water–oil
interfaces, reducing surface tension and improving miscibility. They are also

Essential Chemistry for Formulators of Semisolid and Liquid Dosages © 2016 Elsevier Inc.
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6 Essential Chemistry for Formulators of Semisolid and Liquid Dosages

Figure 2.1 Schematic representation of a surfactant molecule. The circle represents the
hydrophilic part of the molecule (also known as the head group or polar group), and the
long acyl chain represents the hydrophobic (lipophilic) part of the molecule.

considered as chemicals that form “new surfaces” (micelles, liposomes, etc.) in

the presence of water [1]. Surfactants are a class of chemicals that has ubiquitous
applications in industries; almost all industries need to use surfactants, including
engineering, food, petrochemical, pharmaceutical, and consumer products.

2.2 TYPES OF SURFACTANTS
A schematic representation of a surfactant molecule is shown in Figure 2.1;
the hydrophilic (“water loving”) end of the surfactant molecule is referred
to as the “head group” or polar group, and the hydrophobic (“water hat-
ing”) portion is referred to as the “tail” (or lipophilic, oil-soluble end).
Depending on the charge of the polar group, surfactants are generally clas-
sified as cationic, anionic, nonionic, or zwitterionic (amphoteric) surfac-
tants. Surfactants can be water soluble or insoluble, natural or synthetic in
origin, and their chemical structures could be simple or large molecules or
polymeric. Surfactants that have polar groups at each end of a long acyl
chain are sometimes known as “bolaamphiphiles” [2].
When mixed in water, surfactants reduce the surface tension of the
water. As the concentration of the surfactant is increased, the surface tension
continues to drop. Above a certain concentration, the surfactant molecules
spontaneously form micelles. When these micelles start forming, further
additions of surfactant have no further effect on the surface tension of the
water. This concentration, at which the surface tension remains constant, is
called the Critical Micelle Concentration (CMC). A typical representation
of surface tension versus surfactant concentration is shown in Figure 2.2.

2.2.1 Surfactant Micelles
Micelles are self-assembled microstructures formed by surfactants in aqueous
systems. They can trap hydrophobic molecules in their hydrophobic core and
thereby act as wetting agents or solubilizing agents.This behavior enables them
to be effective cleansing agents. Depending on the structure of the surfactant
molecules, micelles of different shapes (including spherical, cylindrical, hexago-
nal, cubic lamellar, inverted cylindrical, and inverted spherical) can be formed.
 Surfactants, Lipids, and Surface Chemistry 7

Figure 2.2 A schematic representation of trend lines for surfactant physical properties
such as surface tension, conductivity, turbidity, and detergency as a function of surfac-
tant concentration. A change in trend is observed after Critical Micelle Concentration
(CMC) is reached. Adapted from Barnes, G. and Gentle, I., Interfacial Science An Introduc-
tion, Oxford University Press, 2005.

The size of a micelle is related to the number of monomers per micelle (com-
monly called the aggregation number) or the molecular weight of the micelle.
Factors affecting the formation of micelles include:
• Chain length of the surfactant molecule: molecules with longer chain
lengths are less soluble, and will form micelles at lower concentrations.
• The CMC of ionic surfactants is greatly affected by the presence of dis-
solved salts in the solution.The CMC is lowered as the concentration of
salts is increased [3,4] (see Table 2.1).
• When alcohol is added to the water, the CMC increases considerably. It
has been shown that, within a series of alcohols ranging from methanol
to butanol (at 10% concentration in water), there was no uniform trend
observed for the change in CMC for polysorbate 20 [5].
• Increase in temperature increases the CMC.
• If two or more surfactants are present in a solution, the surfactant with higher
CMC acts like an electrolyte, and the overall CMC of the mixture will
depend on the nature of the individual surfactants (i.e., ionic or nonionic).
2.2.2 Anionic Surfactants
Surfactants with a negative charge on the head group are called “anionic.”
Common examples are sodium salts of fatty acids and fatty sulfates, including
8 Essential Chemistry for Formulators of Semisolid and Liquid Dosages

Table 2.1 Change in critical micelle concentration (CMC) and aggregation number (N)
with salt concentration for ionic surfactants
CMC
Surfactant Medium (mM) N
Sodium dodecylsulfate Water 8.1 58
0.1 M NaCl 1.4 91
0.2 M NaCl 0.83 105
0.4 M NaCl 0.52 129
Dodecyltrimethylammonium Water 14.8 43
bromide 0.0175 M NaBr 10.4 71
0.05 M NaBr 7.0 76
0.1 M NaBr 4.65 78
Data from Ref. [3].

sodium lauryl sulfate.Typically, sodium, potassium, or ammonium salts of fatty

sulfonates with C8–C14 acyl chains tend to possess foaming and cleansing
properties, and are suitable for use in shampoo-type applications. Anionic sur-
factants also assist in the dissolution or absorption of drugs. Bile salts in the
stomach are anionic surfactants and play a critical role in food digestion [6,7].

2.2.3 Cationic Surfactants
Surfactants with a positive charge on their head group are called “cationic.”
Examples of cationic surfactants include long-chain quaternary ammonium
compounds (e.g., Dimethyldioctadecylammonium chloride). Some long-
chain quaternary surfactants show antimicrobial properties, and are used as
preservatives in pharmaceutical formulations.

2.2.4 Nonionic Surfactants
These do not ionize in the presence of water, and generally have a low
irritancy potential compared to ionic surfactants. The hydrophilic portion
of the nonionic surfactant molecule could be an alcohol, polyol derivative,
or esters of fatty molecules (waxes). Nonionic surfactants are widely used in
pharmaceutical formulations.
The structure of some of the synthetic surfactants are shown in Figure 2.3.

2.3 NATURAL SURFACTANTS
Surfactants are abundant in nature, and are present in both plants and
animals. Some proteins behave like surfactants and play critical roles in
various biological processes. An important group of protein surfactants
 Surfactants, Lipids, and Surface Chemistry 9

(a) Cl-
N+

CnH(2n+1) Na+
(b) O
O-
S
O
O

(c)
O H
HO
O a
O a b

(d) O

OCH2CH2 O R
W

O OCH2CH2 OH
X

HO H2CH2CO
Z OCH2CH2 OH
Y

Figure 2.3 (a) Benzalkonium chloride where n = C8 to C18. (b) Sodium lauryl sulfate
(sodium dodecyl sulfate). (c) Poloxamer (for Poloxamer 124, a = 12 and b = 20; Polox-
amer 188, a = 80 and b = 27; Poloxamer 237, a = 64 and b = 37; Poloxamer 338, a = 141
and b = 44; Poloxamer 407, a = 101 and b = 56). (d) Polysorbates (W + X + Y + Z = 20);
For Polysorbates 20, 40, 60, and 80, R = laurate, palmitate, stearate, and oleate,
respectively.

from a therapeutic point of view are “lung surfactants” (or “pulmonary

surfacants”) [8]. In humans, lung surfactants are composed of approximately
90% lipids (phospholipids, cholesterol, and other lipids) and four types of
pulmonary surfactant proteins (SP-A, SP-B, SP-C, and SP-D).The lung
surfactants facilitate gas exchange in the lungs and prevent them from
collapsing. The deficiency of lung surfactants can be caused by several
reasons, including: premature birth, lung injury, or genetic mutations that
inhibit surfactant production or function. Patients with lung surfactant
deficiency are in risk of respiratory failure (e.g., Respiratory Distress
Syndrome or Acute Respiratory Distress Syndrome) and the condition
needs to be treated using lung surfactant supplements. Examples of med-
ications include Survanta® and Surfaxin® (visit http://reference.medsca
pe.com/drugs/lung-surfactants for additional information). Other
examples of natural surfactants are bile salts [6,7,9].
10 Essential Chemistry for Formulators of Semisolid and Liquid Dosages

2.3.1 Lipids
Lipids are a subset of a large domain of natural surfactants and are
extremely important in pharmaceutical formulations as excipients. The word
“lipid” (or “lipide” in French) implies organic compounds originating
from animal or plant grease/fat. Typically, lipids are water insoluble and
their natural physical state is oily or waxy. Included under the general
category of “lipids” are simple long-chain fatty acids, fatty alcohols, esters,
amines, plant- or animal-derived oils (triglycerides), phospholipids (also
known as lecithin), and cholesterols. There are several other lipid classes
within the general group of “phospholipids.” Although lipids of natural
origin are water insoluble, they can be synthesized to meet specific head
group or acyl chain requirements for commercial applications. The
chemical structures of some lipids are shown in Figure 2.4. The critical
micelle concentration (CMC) of lipids is typically very low and as the
chain length of the lipids increase, the CMC decreases considerably.
Table 2.2 shows that phospholipids with acyl chains of more than nine
carbon atoms have a CMC of the order of 10−3 mM or less. Conse-
quently, for all practical purposes, phospholipids with long fatty acyl
chains do not form micelles when suspended in water. At very low con-
centrations they form monomolecular films at the air–water interface.
When in excess, they self-assemble into bilayers that are the building
blocks of cell membranes.
Lipids play a very significant role in pharmaceutical formulations of
parenteral, topical, transdermal, and oral dosage forms [10]. The lipids not
only form drug delivery systems for both water-soluble and water-insoluble
drugs, they also enhance drug penetration through the skin and drug
absorption through intestinal mucosal membranes for oral dosages. Lipid
analysis of human skin has been extensively investigated, and it is well estab-
lished that a variety of lipids including fatty acids, phospholipids, ceramides,
and many other types are present [11,12]. Topical or transdermal formula-
tions containing lipids are considered to be well tolerated/less irritating to
human skin [13,14].
Lipid-based formulations (LBS) of oral dosages, in particular liquid
formulations in soft-gel capsules, have shown improved efficacy by
enhancing the bioavailability of the drug. Digestion and dispersion are
critical factors that affect the performance of oral dosages of lipid-based
formulations. This is because during intestinal processing, physicochemi-
cal properties may change and impact performance by causing drug
 Surfactants, Lipids, and Surface Chemistry 11

2 2
1
2 3 2
2
2

E 2

1+

2+

2+

Figure 2.4 (a) Structure of dipalmitoyl phosphatidyl choline (DPPC), a typical phospholipid.
(From Kulkarni VS, Liposomes in personal care products. Delivery system handbook for personal
care and cosmetic products. In: Meyer R. Rosen, editor. Technology, applications and formula-
tions; in print 2005). (b) A type of sphingo lipid known as ceramide; several different types of
ceramides (variations in N-acyl chain length) are present in stratum corneum of human skin.

Table 2.2 Critical micelle concentrations for lecithins with

increasing acyl chain lengths
Lipids CMC (mM)
Dibutanoyl lecithn 80
Dihexanoyl lecithin 14.6
Dioctanoyl lecithin 0.265
Dinonanoyllecithin 2.87 × 10−3
Dipalmitoyl phosphatidyl choline 2 × 10−8
Compiled from Refs [31].

precipitation before the drug is absorbed. In order to aid formulation

development and assess which factors affect performance, standardized in
vitro methods have been developed along with a system for classifying
LBS formulations [15–17]. This classification is based on formulation
components and their dependence on digestion to facilitate dispersion.
12 Essential Chemistry for Formulators of Semisolid and Liquid Dosages

Five categories have been proposed; Type-I: drug mixed in triglyceride or

glyceride formulations; Type-II: formulations additionally having lipo-
philic surfactants; Type-IIIA: fine emulsion–self-emulsifying formulations
with hydrophilic surfactants and cosolvents; Type-IIIB: those that form
microemulsions with surfactants and cosolvents; and Type-IV: formula-
tions composed of surfactants and cosolvents.
Some of the lipid-based oral drugs in the marketplace are listed in Table 2.3
along with the surfactants or lipids used in their formulations.

2.4 THE ROLE OF SURFACTANTS IN PHARMACEUTICAL

FORMULATIONS
Surfactants, by the virtue of their intrinsic property of reducing the surface
tension of water and being amphiphilic in nature, have found various roles
in pharmaceutical formulations and have been used in all dosage forms.
Some of the surfactants used in different dosage forms as listed in FDA’s
(U.S. Food Drug Administration) “Inactive Ingredient Guide” (IIG) data-
base are shown in Table 2.4.

2.4.1 Skin Penetration Enhancers

The primary function of the skin is to protect the internal organs from
external invasion by forming a strong barrier between the outside envi-
ronment and the body. However, for topical dosage formulations such as
transdermals, penetration of the drug into the skin is essential. Therefore,
transdermal/topical formulations need to act against the natural func-
tion of the skin [18]. Although the skin acts as a barrier, it is not com-
pletely impermeable. Chemical penetration enhancers and certain
surfactants can be incorporated into topical/transdermal formulations
to help facilitate penetration of the drug into the skin [19]. Fatty acids
(e.g., oleic acid), fatty alcohols (e.g., myristyl or oleoyl alcohols), fatty
esters (e.g., isopropyl myristate), lipids, anionic and nonionic surfactants
are commonly used as chemical penetration enhancers. Although the
use of surfactants can enhance penetration of the drug into the skin,
they increase the risk of skin irritation. Consequently, skin irritation
potential becomes a critical factor to be considered when formulating
products for use on compromised skin. Formulations targeted for muco-
sal membranes (such as nasal, buccal cavity, vaginal, or suppositories)
generally use nonionic surfactants as they are less irritating than ionic
surfactants.
 Surfactants, Lipids, and Surface Chemistry 13

Table 2.3 Lipids and surfactants used in some drug products in the marketplace
Trade Therapeutic
names Drug use Lipids/surfactants
Agenerases Amprenavir HIV antiviral Tocopherol PEG succinate,
and PEG 400
Rocaltrols Calcitriol Calcium Medium-chain
regulator triglycerides
Sandim- Cyclosporin Immuno- Corn oil, and linoleoyl
mune suppressant macrogolglyceride
Neorals Cyclosporin A/I Immuno- Corn oil monodiglycer-
suppressant ides, and polyoxyl 40
hydrogenated castor oil
Gengrafs CyclosporinA/III Immuno- Polyoxyl 35 castor oil,
suppressant polysorbate 80, and
sorbitan monooleate
Accutanes Isotretinoin Anti-comedo- Hydrogenated soybean oil
genic flakes, hydrogenated
vegetable oils, and
soybean oil
Kaletras Lopinavir and HIV antiviral Oleic acid, and polyoxyl
ritonavir 35 castor oil
Norvirs Ritonavir HIV antiviral Oleic acid, and polyoxyl
35 castor oil
Lamprene Clofazamine Treatment of Rapeseed oil, soybean
leprosy lecithin, hydrogenated
soybean oil, and
partially hydrogenated
vegetable oils
Sustivas Efavirenz HIV antiviral Sodium lauryl sulfate, and
sodium starch glycolate
Lofibra Finofibrate Lipid-regulating Sodium lauryl sulfate
Restandol Testosteroneun- Hormone Castor oil, and propylene
decanoate replacement glycol laurate
therapy
Prometrium Progesterone Hyperplasia Peanut oil, and lecithin
Rapamune Sirolimus Immuno- Phosphatidylcholine, and
suppressant polysorbate 80
Vesanoid Tretinoin Acute promy- Hydrogenated soybean oil
elocytic flakes, hydrogenated
leukemia vegetable oils, and
soybean oil
Compiled from Refs [15,16].
14 Essential Chemistry for Formulators of Semisolid and Liquid Dosages

Table 2.4 Some of the surfactants listed in FDA’s Inactive ingredient guide with the
reported use in different dosage forms
Type of
surfactant Surfactant Dosage form
Anionics Ammonium lauryl sulfate Topical aerosol, emulsions
Sodium lauryl sulfate Topical creams, gels, oral
capsule, drops, tablets
Alkyl aryl sodium sulfonate Topical suspension
Sodium cholestryl sulfate IV (infusion), injection
suspensions
Catatonics Polyquaternium 10 Topical
Quaternium-15 and -52 Topical emulsion, aerosol
foams
Benzalkonium chloride Topical, nasal, ophthalmic,
injectables
Cetrimonium chloride Topical
Cetylpyridinium chloride Inhalation aerosol, capsules
Nonionics Polysorbate X (X = 20 or 40 Injection, IV infusion, nasal
or 60 or 65 or 80) sprays, ophthalmic
suspensions, topical creams
Sorbitan monolaurate (or Topical lotions, emulsions
sorbitan monostearate) ointments
Glyceryl oleate (monostearate Topical, oral
or dibehenate)
Glyceryl trioleate Injection suspensions
PEG 5 oleate Topical, vaginal
Poloxamers (e.g., 124, 188, 407) Oral, topical, I.V. injection,
subcutaneous, and
ophthalmic
Polyglyceryl-3-oleate Oral capsules
Zwitterionics Dioleoyl Injections, liposomal
glycerophosphocholines
Egg phospholipids Intravenous, injection
Lecithin (soy lecithin) Liposomal, injection, oral,
nasal, inhalation aerosol
Coco betaine Topical
Compiled from http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.

2.4.2 Emulsifying Agents
Oil and water are immiscible with each other because of the very high inter-
facial tension at the oil-water interface. In the presence of surfactants, how-
ever, this oil-water interfacial tension can be reduced to such an extent that
the two immiscible phases can be made miscible. Many topical/transdermal
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 Surfactants, Lipids, and Surface Chemistry 15

dosages are creams that are emulsions of oil and water phases. Other emulsion
dosage forms including injectables, nasal sprays, and ophthalmic drops are
available commercially. The selection of the surfactants to use and their con-
centration in the formulation are critical to making stable emulsions. A study
of the oil-water interfacial tension as a function of surfactant concentration
helps to determine the critical concentration of surfactant needed to achieve
emulsification.

2.4.2.1 Hydrophile–Lipophile Balance (HLB) System

Surfactants are used to produce emulsions of oil droplets dispersed in water
(oil-in-water) or water droplets dispersed in oil (water-in-oil). Conse-
quently, emulsions have a large technological application, including in phar-
maceutical dosages. An empirical but very useful numerical rating system
was introduced by Griffin and is known as the Hydrophile–Lipophile Bal-
ance or HLB number [20]. In general, highly water-soluble surfactants have
high HLB values and highly oil-soluble surfactants have low HLB values.
HLB number ranges based on the solubility or dispersability of the surfac-
tants are shown in Table 2.5.
Generally, surfactants with an HLB in the range of 4–6 are water-in-
oil emulsifiers and 8–18 are oil-in-water emulsifiers. HLB values can
also be determined experimentally as HLB = 20(1−S/A) in which
S = saponification number of the ester and A = acid value of recovered
acid.
HLB numbers for some common surfactants are shown in Table 2.6.

2.4.3 Aerosol Formulations
Surfactants have been used extensively in aerosol formulations. Surfactants
reduce the surface tension of water and thereby facilitate atomization of the
formulation. For nasal spray formulations, the formation of uniform plumes
depends not only on the device but also on the formulation.The use of surfac-
tants in nasal sprays is common to achieve the effective delivered dose (proper
droplet size and plume) [22].The use of surfactants in topical aerosols (wound
healing sprays or pain relief sprays) or foam formulations is also common.

2.4.4 Surfactant Gels
The formation of gels by small amphiphilic molecules (surfactants) is well docu-
mented [23–25]. Gel formation by surfactants is considered a process similar to
micellization rather than crystallization. Poloxamers™ are polymeric nonionic
surfactants of ethylene oxide and propylene oxide, and several varieties of Polox-
amers™ are listed in the FDA IIG database for use in pharmaceutical
16 Essential Chemistry for Formulators of Semisolid and Liquid Dosages

Table 2.5 Surfactant water solubility and HLB ranges

Water solubility HLB range
No dispersibility in water 1–4
Poor dispersion 3–6
Milky dispersion after vigorous 6–8
shaking
Stable milky dispersion 8–10
Translucent to clear dispersion 10–13
Clear solution 13+

Table 2.6 HLB values for some common surfactants

Surfactant HLB
Sorbitan tristearate 2.1
Sucrose distearate 3
Glyceryl monooleate 3.4
Glyceryl monostearate 3.8
Span 80 (sorbitan monooleate) 4.3
Glyceryl monolaurate 5.2
Sorbitan monopalmitate 6.7
Soy lecithin 8
Sorbitan monolaurate 8.6
Tween 81 10
Tween 80 15
Sodium stearoyl-2-lactylate 12
Sodium oleate 18
Ammonium lauryl sulfate 31
Some of the values are from Ref. [21].

formulations. Two of the Poloxamers™, Poloxamer 188 and Poloxamer 407,

exhibit thermo-sensitive properties—that is, they are soluble in water at low
temperature and gel at higher temperature.

2.5 SURFACE CHEMISTRY FOR PHARMACEUTICAL

FORMULATIONS
2.5.1 Surface and Interfacial Tension
Physical properties including surface tension, osmotic pressure, conduc-
tivity, and detergency will change (either increase or decrease) as the
concentration of surfactant increases. There are several methods,
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Dieppe, 4 f., 160.
Dieulafoy, quoted, 135.
Dives, 75.
Domesday, 66, 110, 172, 229.
Domfront, 63, 154, 172.
Dover, 166.
Downing, E., 208.
Drogo of Hauteville, 200–02.
Duana, 228 f.
Dudo of Saint Quentin, 27, 47, 180.
Durham, 188.

Edrisi, 238–40.
Edward the Confessor, king, 73–75.
Eleanor of Aquitaine, queen, 89, 118, 120, 123, 184.
Emma, queen, 73.
Empire, Angevin, 85;
Eastern, 91, 94, 129, 197–99, 201 f., 206, 214–17, 222, 226–
31, 243;
German, 87;
Holy Roman, 64, 86, 244;
Norman, 85–113;
its destruction, 116–39.
England, Normandy compared with, 5 f.;
Northmen in, 32–34;
before the Normans, 101–03, 223;
Norman Conquest, 52, 72–83;
results, 22 f., 100–13, 145 f., 151 f.;
loss of Normandy, 139–44.
Enna, 209.
Eryx, 208.
Escorial, 178.
Ethelred, king, 73.
Etna, 209, 239.
Eudes Rigaud, archbishop of Rouen, 168 f., 183.
Eugene of Palermo, emir, 239 f.
Eure, 7.
Évreux, 184, 187.
Exchequer, 11, 103–08, 142, 229.
Exmes, 71.

Falaise, 10, 53, 59, 133, 139, 153.

Fécamp, 160, 164, 171, 178.
Feudalism, 60, 64, 93, 133, 136–38, 233;
Norman, 67–69, 82, 145, 149–57;
in southern Italy, 209, 223–31.
Finance, Anglo-Norman, 69–71, 103–08;
Sicilian, 225, 228 f., 232 f.
Flanders, 61, 75.
Flaubert, G., 4, 8, 12;
quoted, 5.
Fontevrault, 117.
France, Normandy as a part of, 6 f., 16, 18–24, 48;
feudal relations with Normandy, 63–66;
government compared with that of Normandy, 64, 69–71;
geographical unity, 124–26;
how it conquered and absorbed Normandy, 126–44;
Norman influence on, 23, 144.
France, Anatole, quoted, 178.
Franks, Normandy under, 16, 20 f., 26.
Frederick Barbarossa, emperor, 86 f., 128 f.
Frederick II, king of Sicily and emperor, 24, 215, 219–21, 240,
245 f.
Freeman, E. A., 83;
on William the Conqueror, 53–56;
on the Norman Conquest, 73, 83, 101, 145 f.;
on the battle of Hastings, 77;
on Norman castles, 151;
 on the abbeys of Caen, 188;
on Frederick II, 245.
Fulk Rechin, quoted, 62 f.

Gaeta, 197 f.
Gaimar, 184.
Gascony, 88–91, 100, 139, 161.
Gavrai, 172.
Genoa, 232.
Geoffrey, duke of Brittany, 120.
Geoffrey Malaterra, quoted, 13, 207.
Geoffrey Martel, count of Anjou, 61–63.
Geoffrey de Mowbray, bishop of Coutances, 10, 186 f.
Geoffrey Plantagenet, count of Anjou, 85, 89, 99, 112.
Geoffrey, illegitimate son of Henry II, 116.
George of Antioch, admiral, 226, 242.
Gilbert Crispin, abbot of Westminster, 175.
Giobair, Ibn, quoted, 243.
Giraldus Cambrensis, quoted, 117 f., 123.
Girgenti, 209.
Gisors, 132 f., 135 f.
Glanvill, 108.
Goethe, 219, 243.
Greek influences in southern Italy and Sicily, 198, 209, 219, 223,
225–31, 235, 237–46.
Green, J. R., quoted, 122.
Gregory VII Pope, 72, 165 f., 202, 204 f.
Grentemaisnil, 154.
Grimoud, 60.
Guernsey, 144 f.
Gummere, F. B., quoted, 41.
Guy of Amiens, 76.
Hamburg, 33.
Haro, 145.
Harold, king of England, 73–80.
Harold Fairhair, 28, 38.
Hastings, battle of, 75–80, 84, 151, 166, 202.
Hastings, Viking leader, 33.
Hauteville, house of, 2, 200–02, 207, 209, 213. See Robert
Guiscard, Roger.
Havre, Le, 4 f.
Henricus Aristippus, 239 f.
Henry I, king of England, 89, 94, 105 f., 133, 160, 162 f., 181,
184, 229.
Henry II, king of England, 49, 85, 133, 219;
empire, 86–90;
European position, 87, 90 f.;
character, 92–94, 114, 117 f.;
government, 93–113, 153, 227–30;
death, 116 f., 154;
sons, 118–23;
relations with Philip Augustus, 127 f.;
privileges to Rouen, 161–63.
Henry V, king of England, 142.
Henry VI, king of England, 143.
Henry the Young King, 119–21, 123, 127, 154–57.
Henry I, king of France, 62 f., 65.
Henry III, emperor, 201.
Henry IV, emperor, 205.
Henry VI, emperor, 220.
Henry the Lion, duke of Saxony, 90.
Historians, Norman, 47, 154, 180–84.
Hohenstaufen, in Sicily, 220 f.
Honorius II, Pope, 210.
Hugh Capet, 65.
Hugh of Amiens, archbishop of Rouen, 179.
Hugo, Victor, quoted, 144.
Humphrey of Hauteville, 200–02.

Iceland, 3, 12, 31, 43 f.

Ile-de-France, 7, 125.
Innocent III, Pope, 137.
Ireland, 22, 31, 33, 57, 85 f., 88, 90, 160, 162 f.
Italy, influence on Normandy, 175;
Normans in, 181 f., 192, 198–211, 218–49;
political condition ca. 1000, 196–98;
relation to Renaissance, 246.

James, Henry, quoted, 6.

Jersey, 144 f., 184.
Jerusalem, Normans at, 128, 130, 167, 193–95, 198 f., 212,
214.
Jews, in Sicily, 225, 242.
Joan of Arc, 10, 19, 143 f.
Jocelin of Brakelonde, 173.
John, king of England, 85 f., 116, 131 f., 154;
character, 122 f., 126 f.;
struggle with Philip Augustus, 136–39;
loss of Normandy, 139 f.
John VIII, Pope, 237.
John of Salisbury, 238.
John the Scribe, 232.
Jomvikings, 43 f.
Joppa, 130.
Jumièges, 9, 171, 187.
Jury, Anglo-Norman, 23, 109–13, 142, 146.
Justices, Anglo-Norman, 108;
Sicilian, 227 f.
Kensington rune-stone, 1.
Kent, 166 f.
Knights’ fees, 68, 78, 100, 145, 150, 229, 231.
Krak, 134.

Lanfranc, 175–78.
Laon, school of, 107, 177.
Laplace, 4, 12.
La Rochelle, 161.
La Roncière, Bourel de, quoted, 49.
Lavisse, E., quoted, 143.
Law, Norman, 11, 20, 23, 48 f., 69, 82, 108–13, 145 f., 224;
Roman, 137, 175–77, 179, 230 f., 236;
canon, 137, 168, 175–77, 179, 230.
LeMans, 63, 88, 116 f., 125, 160, 172.
Leo IX, Pope, 203.
Lessay, 187.
Libraries, Norman, 177–81;
south-Italian and Sicilian, 236–40, 242, 246;
papal, 240.
Limerick, 37.
Lindisfarne, 33.
Lire, 178.
Loire, relation to Plantagenet empire, 125, 128, 139 f.
Lombards, 175, 188, 192, 196–99, 222 f., 238.
London, 81, 162 f.
Lorraine, schools of, 107, 167.
Louis VII, king of France, 89, 118 f., 127.
Louis X, king of France, 142.
Luchaire, A., quoted, 70.
Lugdunensis Secunda, 9, 21, 26.
Luna, 33.
Lusignan, 138.
Luther, 18.
Lyons, 125.

Magna Græcia, 197, 238.

Mahan, A. T., 30.
Maine, 7, 10, 57, 62 f., 85, 87, 136.
Maitland, F. W., quoted, 48, 110, 113.
Malta, 221.
Manfred, 221, 240.
Mantes, 58.
Margam, Annals of, 139.
Margat, 134.
Marmoutier, 171.
Matilda, abbess of Caen, 174.
Matilda, empress, 85, 89, 163.
Matilda, queen, 11, 61, 77, 186–88.
Maupassant, 4, 8, 12.
Mediterranean, Northmen in, 33;
Normans in, 192 ff.
Meles, 198 f.
Melfi, council of, 204.
Messina, 129 f., 208, 237;
Straits of, 207, 210, 232.
Michelet, quoted, 11, 195.
Mileto, 210.
Millet, 4, 12.
Monasteries, plundered by Northmen, 35, 164;
Norman, 81, 164 f., 171–75;
their lands, 157 f., 171 f.;
schools, 175–77;
libraries, 177–80;
as centres of historical writing, 180–83;
 relation to mediæval epic, 185;
their churches, 186–89;
south-Italian, 176, 181, 225, 235–37.
Monreale, 189, 241 f.
Mont-Saint-Michel, 10, 171;
peasants, 158;
property, 172;
buildings, 158, 173, 187, 189;
library, 173, 178.
See Robert of Torigni.
Monte Cassino, 178, 235–37.
Monte Gargano, 198, 216.
Montelius, O., quoted, 37.
Montfort, 133.
Montpellier, 177.
Mortemer, 65.
Mosaics, in Sicily, 241 ff.

Nantes, 33.
Naples, 197 f., 222, 246.
Napoleon, 76.
Néel of Saint-Sauveur, 59.
Neilos Doxopatrios, 238, 240.
Nicæa, 52, 58, 195, 212.
Niccola Pisano, 246.
Nicholas II, Pope, 204.
Nietzsche, 18, 55.
Normandy, millenary of, 1–4, 25 f.;
compared with England, 5 f.;
general features, 6–8;
Upper and Lower, 8–11;
inhabitants, 11–16;
periods in its history, 17–22;
general importance, 22–24;
 conquered by Northmen, 26–48;
how far Scandinavian, 48–51;
under William the Conqueror, 59–61, 66–72, 152 f.;
its archives, 66 f.;
relations with Anjou and Maine, 61–63;
with France, 63–65;
with England, 73–83;
centre of Plantagenet empire, 85–88;
influence on England, 100–13;
conquered by Philip Augustus, 131–41;
occupied by English in fifteenth century, 142–44;
final union with France, 17, 19, 144;
influence on France, 23, 141;
dialect, 49, 145, 224;
life of lords, 149–57;
of peasants, 157 f.;
of towns, 159–64;
church, 71 f., 81, 164–71;
monasteries, 171–75;
their schools, 175–77;
libraries, 177–80;
historians, 12, 47, 180–84;
vernacular literature, 184–86;
architecture, 186–89;
the ‘greater Normandy,’ 147, 182.
Normans, characteristics, 11–16, 192, 225, 247;
conquest of England, 52, 72–83, 223 f.;
in southern Italy and Sicily, 2–4, 13 f., 16, 22–24, 94, 150,
177, 181, 189, 192, 198–211, 218–49;
in Spain, 16, 181, 192, 195;
as pilgrims, 193–96, 198 f., 241;
on the Crusades, 2, 16, 91, 127–31, 182, 184, 211–17;
in Syria, 215 f.
See Normandy.
Northmen, 12, 16 f.;
invasion of Normandy, 26 ff.;
causes and course of migrations, 29–31;
 in Frankish empire, 31–35;
in England, 31–34;
their culture and organization, 35–44;
influence on Normandy, 48–51;
as Crusaders, 211.
Noto, 209.

Odo, bishop of Bayeux, 4, 57, 76, 166 f., 185 f., 212.
Ordericus Vitalis, his History, 154, 174, 178, 180–83;
quoted, 14, 176, 180, 199.
Orleans, schools of, 177.
Ouche, 181.

Palermo, Normans at, 189, 208, 210 f., 226, 231 f., 238 ff.;
churches, 230, 241 f.;
palace, 242–44.
Palestine, 128, 130 f., 134, 212–16.
Papacy, Normandy and the, 22, 72, 74, 79, 91, 136, 165, 168;
relations with southern Normans, 192, 200, 202–05, 210, 221,
238.
Paris, 33 f., 76, 96, 136–38, 140;
basin, 8, 125;
Parlement of, 141 f.;
university of, 177.
Paris, Gaston, quoted, 185.
Peasants, Norman, 157 f.
Peers, court of, 138 f.
Perche, 7.
Peter the Hermit, 211.
Petrarch, 246.
Pevensey, 75.
Philip Augustus, 19, 24, 95, 116, 122;
character, 126;
struggle with Plantagenets, 127–29, 131–39;
on the Third Crusade, 128–30;
 policy in Normandy, 142, 163.
Philip d’Harcourt, bishop of Bayeux, 167;
his library, 178–80.
Picardy, 7 f.
Pilgrims, Normans as, 193–96, 198 f., 241.
Pisa, 221, 232.
Plantagenets, origin of, 61, 85, 89. See Henry II, Richard, John.
Plateæ, 228.
Poitiers, 88, 160.
Poitou, 62, 75, 88, 90, 100, 128, 138 f.
Pontorson, 160.
Poole, R. L., 114;
quoted, 107.
Powicke, F. M., 147;
quoted, 139, 141, 153.
Prentout, H., 24, 51, 147.
Provence, 90.

Quevilly, 163.

Rabelais, 169.
Racine, 11.
Ragnar Lodbrok, 42.
Ranulf, vicomte, 59.
Raven, Lay of the, 38.
Renaissance, of twelfth century, 235–40, 245 f.
Rhys, J., quoted, 49.
Richard the Lion-Hearted, king, 85, 95, 116, 153–55;
character, 120–22, 126, 129 f.;
Crusade, 127–31, 215;
struggle with Philip Augustus, 127–29, 131–36;
death, 136.
Richard of Aversa, 204.
Richard, abbot of Préaux, 180.
Richard, bishop of Bayeux, 177.
Richard Fitz-Neal, author of Dialogus, 104, 106.
Richard the Good, duke, 52, 73, 195.
Rigsmal, quoted, 38.
Robert Crispin, 195.
Robert Curthose, duke, 89, 96, 154, 212 f.
Robert the Devil, 52.
Robert Guiscard, 186, 200–08.
Robert the Magnificent, 52 f., 65, 195.
Robert of Selby, 229.
Robert of Torigni, 167, 172 f., 178, 180.
Roger I, the Great Count, 200, 202, 206–11, 225.
Roger II, king of Sicily, 24, 206, 210 f., 219–22, 225–34, 238–49.
Roger Borsa, duke of Apulia, 206 f., 213.
Roger of Toeni, 195.
Roland, Song of, 80, 184 f., 193.
Rollo, duke, 26–29, 42, 45 f., 184.
Romanesque, Norman, 12, 186–89.
Romans, Normandy under, 16, 20 f., 26;
southern Italy under, 197.
Rome, pilgrimages to, 194 f.;
Normans at, 205.
Rossano, 237.
Rouen, 1 f., 9 f., 21, 26, 46, 60, 73, 88, 95, 117, 133 f., 136, 139,
142, 144, 153, 172, 175, 178, 200;
described, 9, 162 f.;
churches, 2, 9, 12, 162 f., 169, 171, 187;
Établissements, 160–62;
commerce, 160, 162;
libraries, 178.
See Eudes Rigaud.
Round, J. H., 77, 83, 114.
Russia, 30.
Saga, Burnt Njal, 11;
of Harold Fairhair, 28;
of St. Olaf, 46.
Saint-Céneri, 154.
Saint-Évroul, 154, 171, 173, 176, 178, 181–83, 195, 206. See
Ordericus.
Saint-Lô, 10.
Saint-Pierre-sur-Dives, Abbot Haimo, 170.
Saint-Sauveur, convent, 169.
Saint-Sauveur-le-Vicomte, 59.
Saint-Valéry-sur-Somme, 75.
Saint-Wandrille, 9, 51, 171.
St. Alexis, Life of, 184.
St. Francis, quoted, 11.
St. Gall, Monk of, quoted, 31.
St. Ives, 175, 179.
St. James, 193.
St. Michael, 198. See Mont-Saint-Michel.
Saintonge, 63.
Saladin, 128.
Salerno, 198–200, 205, 222, 232;
university, 177, 238.
Salutati, 246.
Salzmann, L. F., quoted, 91, 109, 118.
Saracens, of Syria, 128–31, 192, 212–14;
of Sicily, 192, 196, 198 f., 208 f., 223, 225;
of Spain, 192, 195.
Savigny, Congregation of, 171, 174.
Savoy, 90.
Schools, Norman, 175–77.
Seine, 7–9;
relation to Plantagenet empire, 125, 134 f., 139 f.
Seville, 33.
Sheriff, Anglo-Norman, 103–05, 107.
‘Sicilian monarchy,’ 210.
Sicily, Normans in, 2–4, 13 f., 16, 22–24, 75, 127, 177, 181, 189,
192, 201 f., 204, 206–11;
Norman kingdom of, 94, 105, 150, 210 f., 216, 218–49.
Simon, count, 210.
Sorel, A., 4, 25;
quoted, 7.
Spain, 75, 181, 232;
schools of, 177, 180, 235;
Normans in, 192, 195, 211.
Spatz, Wilhelm, 77.
Springer, A., quoted, 239.
Stamfordbridge, 75.
State, beginnings of modern, 93, 233 f.
Stephen, king, 69, 89, 162, 167.
Stubbs, William, 114;
quoted, 92 f., 102, 121.
Syracuse, 209.

Tagliacozzo, 221.
Taillefer, 79 f.
Tancarville, 9, 155.
Tancred, Crusader, 2, 213–16.
Tancred of Lecce, king of Sicily, 220.
Taormina, 209.
Thibaud, count of Blois, 62.
Thierry, abbot of Saint-Évroul, 195.
Thomas Brown, 229.
Tiglath-Pileser, 17 f.
Tinchebrai, 89.
Touraine, 62, 88, 131, 136.
Tournaments, 154–57, 189.
Tours, 62, 88, 116, 125, 132, 160, 177.
Towns, Norman, 81, 159–64.
Translators, Sicilian, 238–40, 246.
Trouville, 4.
Turks, 130 f.
Turold, bishop of Bayeux, 185.

Urban II, Pope, 210 f.

Val-des-Dunes, 54, 59.

Valognes, 10, 59 f.
Varaville, 54, 65.
Vavassor, 150.
Venice, 206, 232.
Venosa, 206.
Verneuil, 132, 160.
Verson, Conte des vilains, 158.
Vexin, 7, 125, 134.
Vicomte, 69, 71, 103, 145.
Victor III, Pope, 236.
Vidal de la Blache, quoted, 7.
Vikings, see Northmen.
Vire, 10.
Vitalis, founder of Savigny, 174.
Voltaire, quoted, 86.

Wace, 76, 184;

quoted, 15.
Warfare, mediæval, 68 f., 77–79, 133–35, 152–54.
Westminster, 56, 95, 136.
William the Conqueror, 10, 14, 19, 163, 192;
descent, 52;
 character, 53–59, 83, 85, 188;
early years, 59 f.;
relations with Anjou and Maine, 61–63;
with France, 63–65;
Normandy under, 66–72, 106, 151 f.;
relations with the church, 71 f., 165, 186–88;
invasion of England, 73–75;
battle of Hastings, 76–80;
crowned king, 81;
death, 58, 117.
William Rufus, king of England, 89, 212.
William I, the Bad, king of Sicily, 219, 221, 239 f., 246.
William II, the Good, king of Sicily, 90, 219, 221, 230, 241.
William III, king of Sicily, 220.
William, duke of Apulia, 207, 210.
William of Arques, 65.
William of Conches, 177.
William, prince, son of Henry I, 89.
William of the Iron Arm, 200 f.
William of Jumièges, 180.
William Longsword, duke, 46, 49.
William of Malmesbury, quoted, 14.
William Marshal, 154–57.
Winchester, 56, 163.
Witan, 74, 102.
Writs, of Henry II, 98, 111 f.;
of Sicilian kings, 227.

Xerxes, size of his army, 78.

 Transcriber’s Notes
Punctuation, hyphenation, and spelling were made
consistent when a predominant preference was found in the
original book; otherwise they were not changed.
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collected, sequentially renumbered, and repositioned between
the end of the last chapter and the Index.
The index was not checked for proper alphabetization or
correct page references.
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