Handbook of
`Pharmaceutical Excipients
`
`FO URTH EDITION
`
`Edited by
`
`Raymond C Rowe
`BPharm, PhD, DSc, FRPharmS, CChem, FRSC, CPhys, MlnstP
`
`Senior Principal Scientist
`
`AstraZeneca
`
`Macclesfield, UK
`
`Paul J Sheskey
`BSc, RPh
`
`Technical Service Leader
`
`Water Soluble Polymers R&D
`
`The Dow Chemical Company
`
`Midland
`
`Ml, USA
`
`Paul J Weller
`BSc, MSc, CChem, MRSC
`
`Publisher - Science and Practice
`
`Royal Pharmaceutical Society of Great Britain
`
`London, UK
`
`London • Chicago
`
`Pharmaceutical Press
`
`(RP)
`~ APhA
`
`American
`Pharmaceutical
`Association
`
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`

`

`Published by the Pharmaceutical Press
`Publications division of the Royal Pharmaceutical Society of Great Britain
`
`l Lambeth High Street, London SEl 7JN, UK
`l 00 South Atkinson Road , Suite 206, Grayslake, IL 60030-7820, USA
`
`and the American Pharmaceutical Association
`2215 Constitution Avenue NW, Washington, DC 20037-2985 , USA
`
`© Pharmaceutical Press and American Pharmaceutical Association 2003
`
`(RP) is a trade mark of Pharmaceutical Press
`
`First edition published 1986
`Second edition published 1994
`Third edition published 2000
`Fourth edition published 2003
`
`Text design by Barker Hilsdon, Lyme Regis
`Typeset by Bibliocraft Ltd, Dundee
`Printed in Great Britain by The Bath Press, Bath
`
`ISBN 0 85369 472 9 (UK)
`ISBN 1 58212 022 6 (USA)
`
`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, without the prior written permission
`of the copyright holder.
`The publisher makes no representation, express or implied,
`with regard to the accuracy of the information contained in
`this book and cannot accept any legal responsibility or
`liability for any errors or omissions that may be made.
`
`A catalogue record for this book is available from the British Library
`
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients.- 4th ed. / edited by Raymond C.
`Rowe, Paul J. Sheskey, Paul J. Weller.
`p. ;cm.
`Includes bibliographical references and index.
`ISBN 1-58212-022-6 (alk. paper) -ISBN 0-85369-472-9 (alk. paper)
`1. Excipients-Handbooks, manuals, etc.
`[DNLM: 1. Excipients-Handbooks. QV 735 H236 2003] I. Rowe, Raymond
`C. II. Sheskey, Paul J. III. Weller, Paul J.
`
`RS201.E87H36 2003
`615'.19-<lc21
`
`2003002641
`
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`

`

`Preface
`
`PHARMACEUTICAL DOSAGE FORMS contain both pharma(cid:173)
`cologically active compounds and excipients added to aid the
`formulation and manufacture of the subsequent dosage form
`for administration to patients. Indeed, the properties of the final
`dosage form (i.e. its bioavailability and stability) are, for the
`most part, highly dependent on the excipients chosen, their
`concentration and interaction with both the active compound
`and each other. o longer can excipients be regarded simply as
`inert or inactive ingredients, and a detailed knowledge not only
`of the physical and chemical properties but also of the safety,
`handling and regulatory status of these materials is essential for
`formulators throughout the world. In addition, the growth of
`novel forms of delivery has resulted in an increase in the number
`of the excipients being used and suppliers of excipients have
`developed novel excipient mixtures and new physical forms to
`improve their properties. The Handbook of Pharmaceutical
`Excipients has been conceived as a systematic, comprehensive
`resource of information on all of these topics.
`The first edition of the Handbook was published in 1986
`and contained 145 monographs. This was followed by the
`second edition in 1994 containing 203 monographs and the
`third edition in 2000 containing 210 monographs. Since the
`release of the third edition two CD-ROM editions have also
`been released: Pharmaceutical Excipients 2000 included the
`third edition, and Pharmaceutical
`same material as
`the
`Excipients 2001, which included 20 new monographs.
`This new printed edition with its companion CD-ROM
`contains 250 monographs authored by experts in pharmaceu(cid:173)
`tical formulation or excipient manufacture from around the
`world. All the monographs have been reviewed and revised in
`the light of current knowledge. There has been a greater
`emphasis on including published data from primary sources
`although some data from laboratory projects included in
`previous editions have been retained where relevant. Varia(cid:173)
`tions in test methodology can have significant effects on the
`data generated (especially in the case of the compactability of
`an excipient}, and thus cause confusion. As a consequence, the
`editors have been more selective in including data relating to the
`physical properties of an excipient. However, comparative data
`that show differences between either source or batch of a
`specific excipient ·have been retained as this was considered
`relevant to the behavior of a material in practice. The Suppliers
`Directory (Appendix I) has also been completely updated with
`many more international suppliers included.
`In a systematic and uniform manner, the Handbook of
`Pharmaceutical Excipients collects essential data on the physi(cid:173)
`cal properties of excipients such as: boiling point, bulk and tap
`density, compression characteristics, hygroscopicity, flow(cid:173)
`ability, melting point, moisture content, moisture-absorption
`isotherms, particle size distribution, rheology, specific surface
`area, and solubility. Scanning electron microphotographs
`(SEMs) are also included for many of the excipients. The
`Handbook contains information from various international
`sources and personal observation and comments
`from
`monograph authors, steering committee members, and the
`editors.
`
`All of the monographs in the Handbook are thoroughly
`cross-referenced and indexed so that excipients may be identi(cid:173)
`fied by either a chemical, a nonproprietary, or a trade name.
`Most monographs list related substances to help the formulator
`to develop a list of possible materials for use in a new dosage
`form or product. Related substances are not directly substitu(cid:173)
`table for each other but, in general, they are excipients that have
`been used for similar purposes in various dosage forms.
`The Handbook of Pharmaceutical Excipients is a compre(cid:173)
`hensive, uniform guide to the uses, properties, and safety of
`pharmaceutical excipients, and is an essential reference source
`for those involved in the development, production, control, or
`regulation of pharmaceutical preparations. Since many phar(cid:173)
`maceutical excipients are also used in other applications, the
`Handbook of Pharmaceutical Excipients will also be of value to
`persons with an interest in the formulation or production of
`confectionery, cosmetics, and food products.
`
`Arrangement
`The information consists of monographs that are divided into
`22 sections to enable the reader to find the information of
`interest easily. Although it was originally intended that each
`monograph contain only information about a single excipient, it
`rapidly became clear that some substances or groups of sub(cid:173)
`stances should be discussed together. This gave rise to such
`monographs as 'Coloring Agents' and 'Hydrocarbons'. In addi(cid:173)
`tion, some materials have more than one monograph depending
`on the physical characteristics of the material, e.g. Starch versus
`Pregelatinized Starch. Regardless of the complexity of the
`monograph they are all divided into 22 sections as follows:
`
`1 Nonproprietary Names
`2 Synonyms
`3 Chemical Name and CAS Registry umber
`4 Empirical Formula and Molecular Weight
`5 Structural Formula
`6 Functional Category
`7 Applications in Pharmaceutical Formulation or Technology
`8 Description
`9 Pharmacopeial Specifications
`10 Typical Properties
`11 Stability and Storage Conditions
`12 Incompatibilities
`13 Method of Manufacture
`14 Safety
`15 Handling Precautions
`16 Regulatory Status
`17 Related Substances
`18 Comments
`19 Specific References
`20 General References
`21 Authors
`22 Date of Revision
`
`Descriptions of the sections appear below with information
`from an example monograph if needed.
`
`XVII
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`

`

`xv111
`
`Preface
`
`Section l, Nonproprietary Names, lists the exc1p1ent names
`used in the current British Pharmacopoeia, European Pharma(cid:173)
`copeia, Japanese Pharmacopeia, and the United States Pharma(cid:173)
`copeia/National Formulary.
`
`Section 2, Synonyms, lists other names for the exc1p1ent,
`including trade names used by suppliers (shown in italics).
`The inclusion of one supplier's trade name and the absence of
`others should in no way be interpreted as an endorsement of
`one supplier's product over the other. The large number of
`suppliers internationally makes it impossible to include all the
`trade names.
`
`Section 3, Chemical Name and CAS Registry Number, indicates
`the unique Chemical Abstract Services number for an excipiem
`along with the chemical name, e.g., Acacia [9000-01-5].
`
`Sections 4 and 5, Empirical Formula and Molecular Weight and
`Structural Formula, are self-explanatory. Many excipients are
`not pure chemical substances, in which case their composition
`is described either here or in Section 8.
`
`Section 6, Functional Category, lists the function(s) that an
`excipient is generally thought to perform, e.g., diluent, emulsi(cid:173)
`fying agent, etc.
`
`in Pharmaceutical Formulation or
`Section 7, Applications
`Technology, describes the various applications of the excipient.
`
`Section 8, Description, includes details of the physical appear(cid:173)
`ance of the excipient, e.g., white or yellow flakes, etc.
`
`Section 9, Pharmacopeial Specifications, briefly presents the
`compendia! standards for the excipient. Information included
`is obtained from the British Pharmacopoeia (BP), European
`Pharmacopeia (PhEur), Japanese Pharmacopeia (JP), and the
`United States Pharmacopeia/National Formulary
`(USP/
`USPNF). Information from the JP, USP and USPNF are
`included if the substance is in those compendia. Information
`from the PhEur is also included. If the excipient is not in the
`PhEur but is included in the BP, information is included from
`the BP. Pharmacopeias are continually updated with most now
`being produced as annual editions. However, although efforts
`were made to include up-to-date information at the time of
`publication of the Handbook, the reader is advised to consult
`the most current pharmacopeias or supplements.
`
`Section 10, Typical Properties, describes the physical properties
`of the excipient which are not shown in Section 9. All data are
`for measurements made at 20°C unless otherwise indicated.
`Where the solubility of the excipient is described in words, the
`following terms describe the solubility ranges:
`Very soluble
`1 part in less than 1
`1 part in 1-10
`Freely soluble
`Soluble
`1 part in 10-30
`Sparingly soluble
`1 part in 30-100
`Slightly soluble
`1 part in 100-1000
`Very slightly soluble
`1 part in 1000-10 000
`1 part in more than 10 000
`Practically insoluble
`or insoluble
`Where practical, data typical of the excipient or comparative
`data representative of different grades or sources of a material
`are included, the data being obtained from either the primary
`or the manufacturers' literature. In previous editions of the
`
`Handbook a laboratory project was undertaken to determine
`data for a variety of excipients and in some instances this data
`has been retained. For a description of the specific methods used
`to generate the data readers should consult the appropriate
`previous edition(s) of the Handbook.
`
`Section 11 , Stability and Storage Conditions, describes the
`conditions under which the bulk material as received from the
`supplier should be stored. In addition some monographs report
`on storage and stability of the dosage forms that contain the
`excipient.
`
`Section 12, Incompatibilities, describes the reported incompat(cid:173)
`ibilities for the excipient either with other excipients or with
`active ingredients. If an incompatibility is not listed it does not
`mean it does not occur but simply that it has not been reported
`or is not well known . Every formulation should be tested for
`incompatibilities prior to use in a commercial product.
`
`Section 13, Method of Manufacture, describes the common
`methods of manufacture and additional processes that are
`used to give the excipient its physical characteristics. In some
`cases the possibility of impurities will be indicated in the
`method of manufacture.
`
`Section 14, Safety, describes briefly the types of formulations in
`which the excipient has been used and presents relevant data
`concerning possible hazards and adverse reactions that have
`been reported. Relevant animal toxicity data are also shown.
`
`Section 15, Handling Precautions, indicates possible hazards
`associated with handling the excipient and makes recommen(cid:173)
`dations for suitable containment and protection methods. A
`familiarity with current good laboratory practice (GLP) and
`current good manufacturing practice (GMP) and standard
`chemical handling procedures is assumed.
`
`Section 16, Regulatory Status, describes the accepted uses in
`foods and licensed pharmaceuticals where known. However,
`the status of excipiems varies from one nation to another, and
`appropriate regulatory bodies should be consulted for guidance.
`
`Section 17, Related Substances, lists excipients similar to the
`excipient discussed in the monograph.
`
`Section 18, Comments, includes additional information and
`observations relevant to the excipient. Where appropriate, the
`different grades of the excipient available are discussed. Com(cid:173)
`ments are the opinion of the listed author(s) unless referenced or
`indicated otherwise.
`
`Section 19, Specific References, is a list of references cited within
`the monograph.
`
`Section 20, General References, lists references which have
`general information about this type of excipient or the types
`of dosage forms made with these excipients.
`
`Section 21, Authors, lists the current authors of the monograph
`in alphabetical order. Authors of previous versions of the
`monograph are shown in previous printed editions of the text.
`
`Section 22, Date of Revision, indicates the date on which
`changes were last made to the text of the monograph.
`
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`

`

`Acknowledgments
`
`A Handbook containing so much detail could not be produced
`without the help of a large number of pharmaceutical scientists
`based world-wide. The voluntary support of nearly 100 authors
`has been acknowledged as in previous editions, but the current
`editors would like to thank them all personally for their
`contribution to the Handbook. Grateful thanks also go to the
`members of the International Steering Committee who advised
`the editors and publishers on all aspects of the Handbook.
`Steering Committee members also diligently reviewed all of the
`monographs before their publication. Many authors and Steer(cid:173)
`ing Committee members have been involved in previous edi(cid:173)
`tions of the Handbook. For others, this was their first edition
`although not, we hope, their last. Thanks are also extended to
`
`excipient manufacturers and suppliers who provided helpful
`information on their products.
`Thanks are also gratefully extended to the editorial staff of
`the Pharmaceutical Press and American Pharmaceutical Asso(cid:173)
`ciation who were involved in the production of the Handbook:
`Tamsin Cousins, Laurent Galichet, Julian Graubart, Linda
`Horrell, Sian Owen, John Wilson and Louise Wykes. The
`diligent copy-editing and challenging questions asked by Len
`Cegielka helped the authors and editors, we hope, to express
`their thoughts clearly, concisely, and accurately.
`Raymond C Rowe, Paul J Sheskey and Paul J Weller
`February 2003
`
`Notice to Readers
`
`The Handbook of Pharmaceutical Excipients, 4th edition, is a
`reference work containing a compilation of information on the
`uses and properties of pharmaceutical excipients, and the
`reader is assumed to possess the necessary knowledge to
`interpret the information that the Handbook contains. The
`Handbook has no official status and there is no intent, implied
`or otherwise, that any of the information presented should
`constitute standards for the substances. The inclusion of an
`excipient in the Handbook, or a description of its use in a
`particular application, is not intended as an endorsement of that
`excipient or application. Similarly, reports of incompatibilities
`or adverse reactions to an excipient, in a particular application,
`may not necessarily prevent its use in other applications.
`Formulators should perform suitable experimental studies to
`satisfy themselves and regulatory bodies that a formulation is
`efficacious and safe to use.
`While considerable efforts were made to ensure the accuracy
`of the information presented in the Handbook, neither the
`publishers nor the compilers can accept liability for any errors
`or omissions. In particular, the inclusion of a supplier within the
`
`Suppliers Directory is not intended as an endorsement of that
`supplier or its products and, similarly, the unintentional omis(cid:173)
`sion of a supplier or product from the directory is not intended
`to reflect adversely on that supplier or its product.
`Although diligent effort was made to use as recent compen(cid:173)
`dia! information as possible, compendia are frequently revised
`and the reader is urged to consult current compendia, or
`supplements, for up-to-date information, particularly as efforts
`are currently in progress to harmonize standards for excipients.
`Data presented for a particular excipient may not be repre(cid:173)
`sentative of other batches or samples.
`Relevant data and constructive criticism are welcome and
`may be used to assist in the preparation of any future editions of
`the Handbook. The reader is asked to send any comments to
`the Editor, Handbook of Pharmaceutical Excipients, Royal
`Pharmaceutical Society of Great Britain, 1 Lambeth High
`Street, London SEl 7JN, UK, or Editor, Handbook of Pharma(cid:173)
`ceutical Excipients, American Pharmaceutical Association,
`2215 Constitution Avenue, NW, Washington, DC 20037-
`2985, USA.
`
`XIX
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`

`Bibliography
`
`A selection of publications which contain useful information on pharmaceutical excipients is listed below:
`
`Ash M, Ash I. Handbook of Pharmaceutical Additives, 2nd
`edn. Endicott, NY: Synapse Information Resources, 2002.
`Aulton ME, ed. Pharmaceutics: the Science of Dosage Form
`Design, 2nd edn. Edinburgh: Churchill Livingstone, 2002.
`Banker GS, Rhodes CT, eds. Modern Pharmaceutics, 4th edn.
`New York: Marcel Dekker, 2002.
`British Pharmacopoeia 2002. London: The Stationery Office,
`2002.
`Bugay DE, Findlay WP. Pharmaceutical Excipients Character(cid:173)
`ization by IR, Raman, and NMR Spectroscopy. New York:
`Marcel Dekker, 1999.
`European Pharmacopoeia, 4th edn and supplements. Stras(cid:173)
`bourg: Council of Europe, 2002.
`Florence AT, Salole EG, eds. Formulation Factors in Adverse
`Reactions. London: Butterworth, 1990.
`Food and Drug Administration. Inactive Ingredient Guide.
`http://www.accessdata.fda.gov/scri pts/cder/i ig/i ndex.cfm
`(accessed 11 February 2003).
`Food Chemicals Codex, 4th edn. Washington, DC: National
`Academy Press, 1996.
`Gennaro AR, ed. Remington: the Science and Practice of
`Pharmacy, 20th edn. Baltimore: Lippincott Williams and
`Wilkins, 2000.
`Health and Safety Executive. EH40/2002: Occupational
`Exposure Limits 2002. Sudbury: Health and Safety
`Executive, 2001.
`Hoepfner E, Reng A, Schmidt PC, eds. Fiedler Encyclopedia of
`Excipients for Pharmaceuticals, Cosmetics and Related
`Areas. Aulendorf, Germany: Editio Cantor, 2002.
`
`Japan Pharmaceutical Excipients Council. Japanese Pharma(cid:173)
`ceutical Excipients 1993. Tokyo: Yakuji Nippo, 1994.
`Japanese Pharmacopeia, 14th edn. Tokyo, Japan, Yakuji
`Nippo, 2001.
`Kemper FH, Luepke N-P, Umbach W, eds. Blue List Cosmetic
`Ingredients. Aulendorf, Germany: Editio Cantor, 2000.
`Lewis RJ, ed. Sax's Dangerous Properties of Industrial
`Materials, 10th edn. New York: John Wiley, 2000.
`Lund W, ed. The Pharmaceutical Codex: Principles and
`Practice of Pharmaceutics, 12th edn. London: Pharmaceu(cid:173)
`tical Press, 1994.
`Smolinske SC. Handbook of Food, Drug and Cosmetic
`Excipients. Boca Raton, FL: CRC Press, 1992.
`Swarbrick J, Boylan JC, eds. Encyclopedia of Pharmaceu(cid:173)
`tical Technology, 2nd edn.
`ew York: Marcel Dekker,
`2002.
`Sweet DV, ed. Registry of Toxic Effects of Chemical
`Substances. Cincinnati: US Department of Health, 1987.
`Sweetman SC, ed. Martindale: the Complete Drug Reference,
`33rd edn. London: Pharmaceutical Press, 2002.
`The Merck Index: an Encyclopedia of Chemicals, Drugs, and
`Biologicals, 13th edn. Whitehouse Station, NJ: Merck,
`2001.
`United States Pharmacopeia 26 and National Formulary 21.
`Rockville, MD: United States Pharmacopeial Convention,
`2002.
`Weiner M, Bernstein IL. Adv erse Reactions to Drug
`Formulation Agents: a Handbook of Excipients. New York:
`Marcel Dekker, 1989.
`
`xx
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`

`Abbreviations
`
`Some units, terms, and symbols are not included in this list· as they are defined in the text. Common abbreviations have been
`omitted. The titles of journals are abbreviated according to the general style of the Index Medicus .
`
`~
`Ad
`ADI
`approx
`atm
`BAN
`bp
`BP
`BS
`BSI
`cal
`CAS
`CFC
`cm
`cm2
`cm3
`cmc
`CNS
`cP
`cSt
`CTFA
`D&C
`
`approximately.
`Addendum.
`acceptable daily intake.
`approximately.
`atmosphere.
`British Approved Name.
`boiling point.
`British Pharmacopoeia.
`British Standard (specification).
`British Standards Institution.
`calorie(s).
`Chemical Abstract Service.
`chlorofluorocarbon.
`centimeter(s).
`square centimeter(s).
`cubic centimeter(s).
`critical micelle concentration.
`central nervous system.
`centipoise(s).
`centistoke(s).
`Cosmetic, Toiletry, and Fragrance Association.
`designation applied in USA to dyes permitted for
`use in drugs and cosmetics.
`Department of Health (UK).
`DoH
`differential scanning calorimetry.
`DSC
`European Community.
`EC
`exemplit gratia, 'for example'.
`e.g.
`EINECS European Inventory of Existing Commercial Che-
`mica! Substances.
`et alii, 'and others'.
`European Union.
`Food and Agriculture Organization of the United
`Nations.
`Food and Agriculture Organization of the United
`Nations and the World Health Organization.
`Food Chemicals Codex.
`Food and Drug Administration of the USA.
`designation applied in USA to dyes permitted for
`use in foods, drugs, and cosmetics.
`Flat face beveled edge.
`gram(s).
`Good Manufacturing Practice.
`generally recognized as safe by the Food and Drug
`Administration of the USA.
`hydrocarbon.
`hydrochlorofluorocarbon.
`hydrofluorocarbon.
`human immunodeficiency virus.
`hydrophilic-lipophilic balance.
`Health and Safety Executive (UK).
`id est, 'that is'.
`intramuscular.
`
`INN
`IP
`ISO
`IU
`IV
`J
`JP
`kcal
`kg
`kJ
`kPa
`L
`LAL
`LCso
`
`LDso
`
`LdLo
`
`m
`m2
`m3
`M
`max
`MCA
`mg
`MIC
`mm
`mL
`mm
`mM
`mm2
`mm3
`mmHg
`mmol
`mN
`mo!
`mp
`mPa
`MPa
`µg
`µm
`N
`nm
`o/w
`o/w/o
`Pa
`pH
`
`PhEur
`pK.
`pph
`
`International Nonproprietary Name.
`intra peritoneal.
`International Organization for Standardization.
`International Units.
`intravenous.
`joule(s).
`Japanese Pharmacopeia.
`kilocalorie( s).
`kilogram(s).
`kilojoule(s).
`kilopascal(s).
`liter(s) .
`Limulus amoebocyte lysate.
`a concentration in air lethal to 50% of the specified
`animals on inhalation.
`a dose lethal to 50% of the specified animals or
`microorgamsms.
`lowest lethal dose for the specified anima ls or
`microorganisms.
`meter(s).
`square meter(s) .
`cubic meter(s).
`molar.
`maximum.
`Medicines Control Agency (UK).
`milligram(s).
`minimum inhibitory concentration.
`minute(s) or minimum.
`milliliter(s).
`millimeter(s).
`millimolar.
`square millimeter(s).
`cubic millimeter(s).
`millimeter(s) of mercury.
`millimole(s).
`millinewton ( s).
`mole(s).
`melting point.
`millipascal(s).
`megapascal(s) .
`microgram(s).
`micrometer(s).
`newton(s) or normal (concentration) .
`nanometer( s).
`oil-in-water.
`oil-in-water-in-oil.
`pascal(s).
`the negative logarithm of the hydrogen ion
`concentration.
`European Pharmacopeia.
`the negative logarithm of the dissociation constant.
`parts per hundred .
`
`XXI
`
`et al
`EU
`FAO
`
`FAO/
`WHO
`FCC
`FDA
`FD&C
`
`FFBE
`g
`GMP
`GRAS
`
`HC
`HCFC
`HFC
`HIV
`HLB
`HSE
`,.e.
`IM
`
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`

`xx11
`
`Units of Measurement
`
`ppm
`psia
`RDA
`rpm
`s
`SC
`SEM
`
`SI
`
`TPN
`TWA
`UK
`
`parts per million.
`pounds per square inch absolute.
`recommended dietary allowance (USA).
`revolutions per minute.
`second(s).
`subcutaneous.
`scanning electron microscopy or scanning electron
`microphotograph.
`Statutory Instrument or Systeme International
`d'Unites (International System of Units).
`total parental nutrition.
`time weighted average.
`United Kingdom.
`
`United States of America.
`
`US or
`USA
`USAN
`United States Adopted Name.
`USP
`The United States Pharmacopeia.
`USPNF
`The United States National Formulary.
`UV
`ultraviolet.
`v/v
`volume in volume.
`v/w
`volume in weight.
`WHO World Health Organization.
`w/o
`water-in-oil.
`w/o/w
`water-in-oil-in-water.
`w/v
`weight in volume.
`w/w
`weight in weight.
`
`Units of Measurement
`
`The information below shows Imperial to SI unit conversions
`for the units of measurement most commonly used in the
`Handbook. SI units are used throughout the Handbook with,
`where appropriate, imperial units reported in parentheses.
`
`Area
`) = 6.4516 x 10-4 square meter (m2J
`1 square inch (in2
`1 square foot (ft2
`) = 9.29030 x 10-2 square meter (m )
`1 square yard (yd2
`) = 8.36127 x 10-1 square meter (m2
`)
`
`Density
`1 pound per cubic foot (lb/ft3
`
`) = 16.0185 kilograms per cubic
`meter (kg/m3
`)
`
`Energy
`1 kilocalorie (kcal)= 4.1840 x 103 joules (J)
`
`Force
`1 dyne (dynes) = 1 x 10-5 newton (N)
`
`Length
`•
`1 angstrom (A) = 10-10 meter (m)
`1 inch (in) = 2.54 x 10-2 meter (m)
`1 foot (ft) = 3.048 x 10-1 meter (m)
`1 yard (yd)= 9.144 x 10-1 meter (m)
`
`Pressure
`1 atmosphere (atm) = 0.101325 megapascal (MPa)
`
`1 millimetre of mercury (mmHg) = 133.322 pascals (Pa)
`1 pound per square inch (psi) = 6894. 76 pascals (Pa)
`
`Surface tension
`1 dyne per centimeter (dyne/cm) = 1 millinewton per meter
`(m
`Im)
`
`Temperature
`Celsius {°C) = (1.8 x 0 C) + 32 Fahrenheit (°F)
`Fahrenheit (°F) = (0.556 x °F) -17.8 Celsius (0 C)
`
`Viscosity (dynamic)
`1 centipoise (cP) = 1 millipascal second (mPa s)
`1 poise (P) = 0.1 pascal second (Pas)
`
`Viscosity (kinematic)
`1 centistoke (cSt) = 1 square millimeter per second (mm2/s)
`
`Volume
`) = 1.63871 x 10-5 cubic meter (m3
`1 cubic inch (in3
`)
`1 cubic foot (ft3
`) = 2.83168 x 10-2 cubic meter (m3
`)
`) = 7.64555 x 10-1 cubic meter (m3
`1 cubic yard (yd3
`1 pint (UK) = 5.68261 x 10-4 cubic meter (m3
`)
`1 pint (US)= 4.73176 x 10-4 cubic meter (m3
`)
`1 gallon (UK) = 4.54609 x 10-3 cubic meter (m3
`)
`1 gallon (US)= 3.78541 x 10-3 cubic meter (m3
`)
`
`)
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1023, p. 8 of 24
`
`

`

`Glycerin
`
`1 Nonproprietary Names
`BP: Glycerol
`JP: Concentrated glycerin
`PhEur: Glycerolum
`USP: Glycerin
`
`2 Synonyms
`Croderol; E422; glycerine; Glycon G-100; Kemstrene; Optim;
`Pricerine; 1,2,3-propanetriol; trihydroxypropane glycerol.
`
`3 Chemical Name and CAS Registry Number
`Propane-1,2,3-triol [56-81-5]
`
`4 Empirical Formula
`
`Molecular Weight
`
`C3H 80 3
`
`92.09
`
`5 Structural Formula
`
`6 Functional Category
`Antimicrobial preservative; emollient; humectant; plasticizer;
`solvent; sweetening agent; tonicity agent.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Glycerin is used in a wide variety of pharmaceutical formula(cid:173)
`tions including oral, otic, ophthalmic, topical, and parenteral
`preparations; see Table I.
`In topical pharmaceutical formulations and cosmetics,
`glycerin is used primarily for its humectant and emollient
`properties. In parenteral formulations, glycerin is used mainly
`as a solvent.(1 1
`In oral solutions, glycerin is used as a solvent, sweetening
`agent, antimicrobial preservative, and viscosity-increasing
`agent. It is also used as a plasticizer and in film coatings. (Z,JJ
`Glycerin is additionaJly used in topical formulations such as
`creams and emulsions.<4
`)
`Glycerin is used as a plasticizer of gelatin in the production
`of soft-gelatin capsules and gelatin suppositories.
`Glycerin is emplo(5ed as a therapeutic agent in a variety of
`clinical applications, S) and is also used as a food additive.
`
`Table I: Uses of glycerin.
`
`Use
`
`Concentration (%)
`
`Antimicrobial preservative
`Emollient
`Humectant
`Ophthalmic formulations
`Plasticizer in tablet film coating
`Solvent for parenteral formulations
`Sweetening agent in alcoholic elixirs
`
`< 20
`,:;; 30
`,:;; 30
`0.5-J.0
`Variable
`,:;; 50
`,:;; 20
`
`8 Description
`Glycerin is a clear, colorless, odorless, viscous, hygroscopic
`liquid; it has a sweet taste, approximately 0.6 times as sweet as
`ucrose.
`
`9 Pharmacopeial Specifications
`See Table II. See also Section 18.
`
`Table II:
`
`Pharmacopeial specifications for glycerin.
`
`Test
`
`JP 2001
`
`PhEur 2002
`
`USP 25
`
`+
`+
`+
`+
`,:;; l.470
`
`,:;; 0.001%
`,:;; 5ppm
`
`Identification
`Characters
`Appearance of solution
`Acidity or alkalinity
`Refractive index
`Aldehydes
`Related substances
`Halogenated compounds
`limit of chlorinated
`compounds
`Sugars
`Chloride
`Heavy metals
`Water
`,:;; 0.01%
`Sulfated ash
`;, 1.258
`Specific gravity
`,:;; 0.002%
`Sulfate
`Ammonium
`+
`Calcium
`+
`,:;; 2ppm
`Arsenic
`Acrolein, glucose or other +
`reducing substances
`Fatty acids and esters
`Organic volatile
`impurities
`Readily carbonizable
`substances
`Assay
`
`+
`
`+
`
`;, 98.0%
`
`+
`+
`+
`+
`1.470-1.475
`+
`+
`+
`
`+
`
`+
`
`+
`
`+
`,:;; l0ppm
`,:;; 5ppm
`,:;; 2.0%
`,:;; 0.01%
`
`,:;; 0.001%
`,:;; 5ppm
`,:;; 5.0%
`,:;; 0.01%
`;, 1.249
`,:;; 0.002%
`
`+
`
`+
`+
`
`98 .0-101.0% 99.0-101.0%
`
`257
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1023, p. 9 of 24
`
`

`

`258
`
`Glycerin
`
`10 Typical Properties
`Boiling point: 290°C (with decomposition)
`Density:
`l.2656g/cm3 at 15°C
`1.2636 g/cm3 at 20°c
`1.2620 g/cm3 at 25°C
`Flash point: 176°C (open cup)
`Freezing point: see Table III.
`Hygroscopicity: hygroscopic.
`Melting point: 17.8°C
`Osmolarity: a 2.6 % v/v aqueous solution is isoosmotic with
`serum.
`Refractive index:
`n~~ = 1.4758
`n5'
`= 1.4746
`5
`n0 = 1.4730
`Solubility: see Table IV.
`Specific gravity: see Table V.
`Surface tension: 63.4 mN/m (63.4 dynes/cm) at 20°C.
`Vapor density (relative): 3.17 (air= 1)
`Viscosity (dynamic): see Table VI.
`
`Table Ill:
`
`Freezing points of aqueous glycerin solutions.
`
`Concentration of aqueous
`glycerin solution (% w/w)
`
`Freezing point (0 C)
`
`10.0
`20.0
`30.0
`40.0
`50.0
`60.0
`66.7
`80.0
`90.0
`
`Table IV:
`
`Solubility of glycerin .
`
`Solvent
`
`Acetone
`Benzene
`Chloroform
`Ethanol (95%)
`Ether
`Ethyl acetate
`Methanol
`Oils
`Water
`
`-1.6
`-4.8
`-9.5
`-15.4
`-23
`-34.7
`-46.5
`-20.3
`-1.6
`
`Solubility at 20°c
`
`Slightly soluble
`Practically insoluble
`Practically insoluble
`Soluble
`l in 500
`l in 11
`Soluble
`Practically insoluble
`Soluble
`
`Table V: Specific gravity of glycerin.
`
`Concentration of aqueous
`glycerin solution (% w/w)
`
`Specific gravity at 20°C
`
`10
`20
`30
`40
`50
`60
`
`1.024
`1.049
`1.075
`1.101
`1.128
`l.156
`
`Table VI: Viscosity (dynamic) of aqueous glycerin solutions.
`
`Concentration of aqueous
`glycerin solution(% w/w)
`
`Viscosity at 20°C (mPa s)
`
`5
`10
`25
`50
`60
`70
`83
`
`1.143
`1.311
`2.095
`6.05
`10.96
`22 .94
`111 .0
`
`11 Stability and Storage Conditions
`Glycerin is hygroscopic. Pure glycerin is not prone to oxidation
`by the atmosphere under ordinary storage conditions but it
`decomposes on heating, with the evolution of toxic acrolein.
`Mixtures of glycerin with water, ethanol, and propylene glycol
`are chemically stable.
`Glycerin may crystallize if stored at low temperatures; the
`crystals do not melt until warmed to 20°C.
`Glycerin should be stored in an airtight container, in a cool,
`dry place.
`
`Incompatibilities
`12
`Glycerin may explode if mixed with strong oxidizing agents
`such as chromium trioxide, potassium chlorate, or potassium
`permanganate. In dilute solution, the reaction proceeds at a
`slowe