`
`Handbook of
`
`- .
`
`PHARMACEUTICAL
`
`EXCIPIENTS
`
`Third Edition
`
`Edited by
`
`Arthur H. Kibbe, Ph.D.
`
`Professor and Chair
`
`
`Department of Pharmaceutical Sciences
`
`Wilkes University School of Pharmacy
`
`Wilkes-Barre, Pennsylvania
`
`American Pharmaceutical Association
`
`
`Washington, D.C.
`
`(RP)
`
`Pharmaooullcal ,._
`
`
`
`London, United Kingdom
`
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`

`

`Published by the American Pharmaceutical Association
`
`
`
`
`
`2215 Constitution Avenue NW, Washington, DC 20037-2985, USA
`www.aphanet.org
`
`and the Pharmaceutical Press
`
`
`1 Lambeth High Street, London SEl 7JN, UK
`www.phannpress.com
`
`
`
`
`
`
`
`
`
`© 1986, 1994, 2000 American Pharmaceutical Association and Pharmaceutical Press
`
`First edition 1986
`
`
`Second edition 1994
`
`Third edition 2000
`
`
`
`Printed in the United States of America
`
`
`
`
`
`ISBN: 0-85369-381-1 (UK)
`
`
`ISBN: 0-917330-96-X (USA)
`
`Library of Congress Cataloging-in-Publication Data
`
`
`
`
`
`
`Handbook of pharmaceutical excipients i edited by Arthur H. Kibbe.--3rd ed.
`p.; cm.
`Includes bibliographical references and index.
`
`
`
`ISBN 0-917330-96-X
`
`
`
`
`Arthur H. II. American1.Excipients--Handbooks, manuals, etc. I. Kibbe,
`
`Pharmaceutical Association.
`
`[DNLM: 1. Excipients--Handbooks. QV 735 H236 2000]
`
`RS201.E87 H36 2000
`615'.19--dc21
`
`.,..
`
`\
`\
`
`I
`.
`
`99-044554
`
`
`
`A catalogue record for this book is available from the British Library.
`
`
`
`�-..
`in any form or system, or transmitted stored in a retrieval may be reproduced, All rights reserved. No part of this publication
`
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`
`
`
`
`
`
`
`
`
`
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`
`
`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.
`
`
`Melanie Segala
`
`Managing Editor:
`Paul Gottehrer
`Copyeditor:
`
`Lillian Rodberg
`Indexer:
`Roy Barnhill
`Compositor:
`Tim Kaage
`Cover Designer:
`
`-
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`

`

`Preface
`
`Pharmaceutical dosage forms contain both active ingredients
`and inactive materials called excipients. The behavior of the
`dosage form is dependent on process variables and the inter(cid:173)
`relationship between the various excipients and their impact
`on the active ingredient. Suppliers of excipient have devel(cid:173)
`oped novel excipient mixtures and new physical forms of ex(cid:173)
`cipients, which give them improved characteristics. In addition,
`the international nature of the pharmaceutical industry and its
`suppliers demands that formulators throughout the world have
`as much information as possible about the chemical and phys(cid:173)
`ical nature of excipients and combinations of excipients. For(cid:173)
`mulators are also concerned about the effect of the finished
`product on the patient it is intended to treat. Therefore, they
`are concerned about general and specific toxic effects of the
`excipients, allergic reactions to excipients, disease-specific in(cid:173)
`tolerance to excipients and interactions between the excipient
`and the active ingredient. In addition, formulators need to be
`aware of the potential environmental impact of the use of ex(cid:173)
`cipients. Lastly, the effect of regulatory change associated with
`harmonization is also a concern of the professional formulator.
`The Handbook of Pharmaceutical Excipients is a joint publica(cid:173)
`tion of the American Pharmaceutical Association and the Royal
`Pharmaceutical Society of Great Britain. The Handbook of
`Pharmaceutical Excipients, originally published in 1986, was
`the first English-language publication to comprehensively and
`systematically describe the chemical and physical properties of
`pharmaceutical excipients. The first edition contained 145 mono(cid:173)
`graphs, and the second contained 203. The present edition con(cid:173)
`tains 210 monographs authored by experts in pharmaceutical
`formulation or excipient manufacture from around the world.
`This edition also contains the results of extensive laboratory
`testing carried out over the last two years in laboratories in
`Great Britain and the United States. Some data developed by
`the first edition's laboratory project are retained. It is clearly
`noted as such in the monographs. The new data generated for
`this edition hould help the formulator in the selection of ap(cid:173)
`propriate excipient
`for various dosage forms. A major devel(cid:173)
`opment since the publication of the last edition of the Handbook
`has been the trend towards global pharmaceutical harmonization.
`To reflect this, where appropriate, more detailed information on
`excipients used in Japan has been included in this edition. Ad(cid:173)
`ditionally the index has been revised and expanded and the sup(cid:173)
`plier ' directory has been completely updated.
`The Handbook of Pharmaceutical Excipients collects in a sys(cid:173)
`tematic and uniform manner essential data on the physical prop(cid:173)
`erties of excipients such as: boiling point, bulk and tap density,
`compression characteristics, hygroscopicity, flowability, 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, but also includes laboratory
`data determined specifically for the Handbook and personal ob(cid:173)
`servation and comments from the monograph author, steering
`committee members, and the editor. It also contains information
`on the safe use and potential toxicity of the materials .
`All of the monographs in the Handbook are thoroughly cross(cid:173)
`referenced and indexed so that excipients may be identified
`by either a chemical , nonproprietary, or trade name. Most
`
`Preface xv
`
`monographs list related substance(s) to help the formulator
`develop a list of possible materials for use in a new dosage
`form or product. Related substances are not directly substi(cid:173)
`tutable for each other but are excipients that have been used
`for similar purposes in various dosage forms.
`The Handbook of Pharmaceutical Excipients is a comprehen(cid:173)
`sive, uniform guide to the uses, properties, and safety of phar(cid:173)
`maceutical excipients and is an essential reference source for
`those involved in the development, production, control or reg(cid:173)
`ulation of pharmaceutical preparations. Since many pharma(cid:173)
`ceutical 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, cosmetic, and food products.
`
`Arrangement
`The Handbook consists of monographs that are divided into 22
`sections to make it easy for the reader to go directly to the
`information of interest. Although it was originally intended that
`each monograph contain only information about a single excip(cid:173)
`ient, it rapidly became clear that some substances or groups of
`substances must 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 due mainly to its
`preparation. A good example of this is the various starch mono(cid:173)
`graphs, particularly Starch vs. Pregelatinized Starch. Regardless
`of the complexity of the monograph they are all divided in 22
`sections as follows:
`
`I. Nonproprietary Names
`2. Synonyms
`3. Chemical Name and CAS Registry Number
`4. Empirical Formula and Molecular Weight
`5. Structural Formula
`6. Functional Category
`7. Applications in Pharmaceutical Formulation or Technology
`8. Description
`9. Pharmacopeial Specifications
`I 0. Typical Properties
`11. Stability and Storage Conditions
`12. Incompatibilities
`13. Method of Manufacture
`14. Safety
`15. Handling Precautions
`16. Regulatory Status
`17 . Pharmacopei as
`18. Related Substances
`19. Comments
`20. Specific References
`21. General References
`22. Authors
`
`To make it easy for the first time user, descriptions of the
`sections appear below with information from an example
`monograph if needed.
`Section 1, Nonproprietary Names, Ii ts the excipient names
`used in the current British Pharmacopoeia, European Pharma(cid:173)
`copeia, Japanese Pharmacopeia, and the United States Phar(cid:173)
`macopeia. For nonpharmacopeial excipients the appropriate
`approved name, e.g., USAN or INN is indicated.
`Section 2, Synonyms, lists other names for the excipient, in(cid:173)
`cluding trade names used by suppliers; trade names are listed
`in italics. The inclusion of one supplier's trade name and the
`absence of others should in no way be interpreted as an
`
`3
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`

`

`xvi Preface
`
`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, indi(cid:173)
`cates the unique Chemical Ab tract Services number for an ex(cid:173)
`cipient 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 excipi(cid:173)
`ents 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, emul(cid:173)
`sifying agent, etc.
`Section 7, Applications in Pharmaceutical Formulation or
`Technology, describes the various applications of the excipient.
`Section 8, Description, includes details of the physical ap(cid:173)
`pearance 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 Phar(cid:173)
`macopeia (PhEur), Japanese Pharmacopeia (JP), and the United
`States Pharmacopeia/National Formulary (USP). Information
`from the JP and USP are included if the sub tance 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. The pharmacopeias are continually up(cid:173)
`dated and revisions or supplements are published. It was neces(cid:173)
`sary to select a point in time and use that as our reference when
`selecting the information to be included in this section. Therefore
`the information is from the following volumes:
`BP - 1998 Edition
`JP - Thirteenth Edition 1996
`PhEur - Third Edition plus supplements to 1999
`USP - USP 24 NF 19 2000 Edition
`Since the USP and NF were combined into a single reference
`many years ago it was felt that a single abbreviation would
`be sufficient. Therefore throughout the Handbook whenever
`the USP abbreviation is used it refers to this combined text.
`Section I 0, Typical Properties, describes the physical prop(cid:173)
`erties 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
`Freely soluble
`Soluble
`Sparingly soluble
`Slightly soluble
`Very slightly soluble
`Practically insoluble
`or insoluble
`
`part in less than
`part in 1-10
`part in 10-30
`part in 30-100
`part in 100-1000
`part in 1000-10 000
`part in more than IO 000
`
`Experimental data were determined specifically for the Hand(cid:173)
`book and are included in this section. Data from the HPE
`Laboratory Project in support of the third edition are clearly
`marked as such. The methods that were used to collect that
`data are included in Appendix II: HPE Laboratory Meth(cid:173)
`ods. Data from the HPE Laboratory Project performed for the
`first edition are either replaced by the new data or referenced
`as such in each monograph. The reader is referred to the ear(cid:173)
`lier editions of this book for the methods used.
`
`Section 11 , Stability and Storage Conditions, describes the con(cid:173)
`ditions under which the bulk material as received from the sup(cid:173)
`plier should be stored. In addition some monographs report on
`storage and stability of the dosage forms that contain the excip(cid:173)
`ient.
`Section 12, Incompatibilities, describes the reported incompati(cid:173)
`bilities 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 incompati(cid:173)
`bilities prior to use in a commercial product.
`Section 13, Method of Manufacture, describes the common
`methods of manufacture and additional proce ses 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 con(cid:173)
`cerning possible hazards and adverse reactions that have been re(cid:173)
`ported. 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 protective 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 . The sta(cid:173)
`tus of excipients varies from one nation to another, even in
`this time of harmonization. Dependence on this reference in
`place of checking with the regulatory body in the nation in
`which the product is to be sold is unwise.
`Section 17, Pharmacopeias, lists the pharmacopeias in which
`the excipient is listed. If the excipient is listed in the European
`Pharmacopeia (PhEur), countries that are party to the PhEur
`are not listed; only "Eur" is. The following countries are party
`to the PhEur: Austria, Belgium, Bosnia-Herzegovina, Croatia,
`Cyprus, Czech Republic, Denmark, Finland, France, Germany,
`Greece, Iceland, Ireland, Italy, Luxembourg, the Netherlands,
`Norway, Portugal , Slovakia, Slovenia, Spain, Sweden, Swit(cid:173)
`zerland, Turkey, the United Kingdom of Great Britain and
`Northern Ireland, and the former Yugoslav Republic of Mace(cid:173)
`donia. The information from the four major pharmacopeias is
`listed in Section 9.
`Section 18, Related Substances, lists the excipients similar
`to the excipient discussed in the monograph. The reader
`should look at the monographs for the related substance for
`comparative information.
`Section 19, 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 20, Specific References, is a list of references cited
`within the monograph.
`Section 21, General References, lists references which have
`general information about this type of excipient or the types
`of dosage forms made with these excipients.
`Section 22, Authors, lists in alphabetical order the current authors
`of the monograph. Authors of previous editions can be found in
`the earlier editions.
`
`4
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`Acknowledgments xvii
`
`Appreciation is extended to the following researchers who
`gave freely of their time to provide data for the laboratory
`project of the Handbook: Gregory Amidon, Pharmacia & Up(cid:173)
`john; Catherine Barnhart, Wilkes University; Don C. Beer,
`Schering-Plough; Scott Bolesta, Wilkes University; Metia
`<;elik, Pharmaceutical Technologies International; J. Bradley
`Dickerson, Schering-Plough; Anthony Fazzi, Wilkes Univer(cid:173)
`sity; Arthur H. Kibbe, Wilkes University; Scott Ocheltree,
`Pharmacia & Upjohn; Garnet E. Peck, Purdue University; Lois
`Schofield, Glaxo Wellcome; Paul Sheskey, Dow Chemical;
`Bhogi B. Sheth, University of Tennessee; and Kevin Silinskie,
`Wilkes University.
`
`Anthony Palmieri III
`June 1999
`
`Acknowledgments
`
`This edition of the Handbook of Pharmaceutical Excipients
`is the result of the efforts of many individuals and corpora(cid:173)
`tions. The publication of the Handbook continues to depend
`on the support of hundreds of scientists throughout the world
`who act as authors or members of the HPE Laboratory Project
`and the members of the two steering committees. The mem(cid:173)
`bers of the US and UK steering committees reviewed all the
`monographs and contributed to their overall quality. Without
`the energetic and enthusiastic effort by these two steering
`committees this book would be impossible to produce. Spe(cid:173)
`cifically I would like to thank the chair of the UK steering
`committee Paul Weller from the Royal Pharmaceutical Society
`of Great Britain staff who was the co-editor of the second
`edition. His work on that edition and his advice on every
`aspect of this edition made my job much easier. In addition,
`this edition had extensive laboratory work done by the HPE
`Laboratory Project headed by Anthony Palmieri III. It is rare
`in life to find an individual such as Tony who is both a good
`and dear friend and an accomplished colleague. Many others have
`contributed to the project and their assistance is appreciated,
`especially Linda Svok of my staff and Julian Graubart from
`the American Pharmaceutical Association.
`
`Arthur H. Kibbe
`June 1999
`
`5
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`xviii Notice to Readers
`
`Notice to Readers
`
`Selected Bibliography
`
`The Handbook of Pharmaceutical Excipients is a reference
`work containing a compilation of information on the uses and
`properties of pharmaceutical excipients and the reader is as(cid:173)
`sumed to possess the necessary knowledge to interpret the
`information 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 stan(cid:173)
`dards for the substances. The inclusion of an excipient in the
`Handbook, or a description of its use in a particular applica(cid:173)
`tion, 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 them(cid:173)
`selves 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 pub(cid:173)
`lishers 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
`omission 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 compendia!
`information as possible, compendia are frequently revised and
`the reader is urged to consult current compendia, or supple(cid:173)
`ments, for up-to-date information, particularly as efforts are
`currently in progress to harmonize standards for excipients.
`
`The laboratory data presented for a particular excipient re(cid:173)
`flects only the results of testing a particular batch or sample
`and may not be representative 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 Phar(cid:173)
`maceutical Excipients, American Pharmaceutical Association,
`2215 Constitution Avenue, N.W., Washington, DC 20037-2985.
`
`A selection of publications which contain information on phar(cid:173)
`maceutical excipients is listed below:
`
`Banker GS , Rhodes CT, editors. Modern Pharmaceutics, 2nd edi(cid:173)
`tion. New York, Marcel Dekker Inc., 1990.
`British Pharmacopoeia 1998. London, The Stationery Office,
`1998.
`Budavari S, editor. The Merck Index: An Encyclopedia of Chem(cid:173)
`icals, Drugs, and Biologicals, 12th edition. Whitehouse Sta(cid:173)
`tion, NJ. Merck & Co., Inc. , 1996.
`European Pharmacopoeia, 3rd edition and supplements. Stras(cid:173)
`bourg, Council of Europe, 1996.
`Florence AT, Salole EG, editors. Formulation Factors in Adverse
`Reactions. London, Butterworth & Co., Ltd., 1990.
`Food and Drug Administration. Inactive Ingredient Guide. Wash(cid:173)
`ington, DC; FDA, 1996.
`Food Chemicals Codex, 4th edition. Washington, DC, National
`Academy Press, 1996.
`Gennaro AR, editor. Remington: The Science and Practice of Pharmacy,
`19th edition. Easton, PA, Mack Publishing Co., 1995.
`Health and Safety Executive. EH40/98: Occupational exposure
`limits, 1998. Sudbury, Health and Safety Executive, I 998.
`Japan Pharmaceutical Excipients Council. Japan ese Pharmaceu(cid:173)
`tical Excipients 1993. Tokyo, Japan, Yakuji Nippo Ltd., I 994.
`Japanes e Pharmacopeia , 13th edition. Tokyo, Japan, Yakuji
`Nippo, Ltd., 1996.
`Lewis RJ, editor. Sax's Dangerous Properties of Industrial Mate(cid:173)
`rials, 9th edition. New York, Van Nostrand Reinhold, 1996.
`Lund W, editor. The Pharmaceutical Codex: Principles and Prac(cid:173)
`tice of Pharmaceutics, I 2th edition. London, Pharmaceutical
`Press, 1994.
`Parfitt K, editor. Martindale: The Complete Drug Reference, 32nd
`edition. London, Pharmaceutical Press, 1999.
`Smolinske SC. Handbook of Food, Drug and Cosmetic Excipi(cid:173)
`ents. Boca Raton, FL, CRC Press Inc., 1992.
`Swarbrick J, Boylan J, editors. Encyclopedia of Pharmaceutical
`Technology, volumes 1-8. New York, Marcel Dekker Inc.,
`1988-1999.
`Sweet DV, editor. Registry of Toxic Effects of Chemical Sub(cid:173)
`stances. Cincinnati, US Department of Health, I 987.
`United States Pharmacopeia 24 and National Formulary 19 and
`Supplements. Rockville, MD, United States Pharmacopeial
`Convention, Inc. , 2000.
`Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation
`Agents: A Handbook of Excipients. New York, Marcel Dekker
`Inc., 1989.
`
`6
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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.
`
`approximately.
`"' -
`Ad - Addendum.
`ADI -acceptable daily intake.
`approx -
`approximately.
`atm -
`atmosphere.
`Aust - Austrian.
`BAN - British Approved Name.
`Belg - Belgian.
`b.p. -
`boiling point.
`BP - British Pharmacopoeia.
`Br - British.
`Braz - Brazilian.
`BS - British Standard (specification).
`BSI - British Standards lrlstitution.
`cal -
`calorie(s).
`CAS - Chemical Abstract Service.
`CFC -
`chlorofluorocarbon.
`cm -
`centimeter(s).
`cm2 -
`square centimeter(s).
`cm 3 -
`cubic centimeter(s).
`cmc -
`critical micelle concentration.
`CNS -
`central nervous system.
`cP -
`centipoise(s).
`cSt -
`centistoke(s).
`CTFA - Cosmetic, Toiletry, and Fragrance Association.
`designation applied in USA to dyes permitted for
`D&C -
`use in drugs and cosmetics.
`DoH - Department of Health (UK).
`DSC -
`differential scanning calorimetry.
`EC - European Community.
`exemplit gratia, 'for example'.
`e.g. -
`et a/ii, 'and others'.
`et. al. -
`EU -
`European Union.
`Eur -
`European.
`FAO - Food and Agriculture Organization of the United Nations.
`Food and Agriculture Organization of the United
`FAO/WHO -
`Nations and the World Health Organization.
`FCC -
`Food Chemicals Codex
`Food and Drug Administration of the USA.
`FDA -
`designation applied in USA to dyes permitted for
`FD&C -
`use in foods, drugs, and cosmetics.
`FFBE -
`Flat face beveled edge.
`Fr -
`French.
`g -
`gram(s).
`Ger - German.
`GMP - Good Manufacturing Practice.
`generally recognized as safe by the Food and Drug
`GRAS -
`Administration of the USA.
`HC -
`hydrocarbon.
`HCFC -
`hydrochlorofluorocarbon.
`HFC -
`hydronuorocarbon.
`HIV -
`human immunodeficiency virus.
`HLB -
`hydrophilic-lipophilic balance.
`
`Abbreviations xix
`
`HSE - Health and Safety Executive (UK).
`id est, 'that is '.
`i.e. -
`IM -
`intramuscular.
`Ind. -
`Indian.
`INN -
`International Nonproprietary Name.
`Int -
`International.
`IP -
`intraperitoneal.
`ISO -
`International Organization for Standardization.
`It -
`Italian.
`IV -
`intravenous.
`joule(s).
`J -
`JP -
`Japanese Pharmacopeia.
`Jpn -
`Japanese.
`kcal -
`kilocalorie(s).
`kg -
`kilogram(s).
`kl -
`kilojoule(s).
`kPa -
`kilopascal(s).
`L -
`liter(s).
`limulus amoebocyte lysate.
`LAL -
`LC 50 -
`a concentration in air lethal to 50% of the specified
`animals on inhalation.
`a dose lethal to 50% of the specified animals or
`LD50 -
`microorganisms.
`LdLo -
`lowest lethal dose for the specified animals or mi-
`croorganisms.
`m - meter(s).
`m2 -
`square meter(s).
`m3 -
`cubic meter(s).
`M - molar.
`max - maximum.
`MCA - Medicines Control Agency (UK).
`mg - milligram(s).
`MIC - minimum inhibitory concentration.
`min - minute(s) or minimum.
`mL - milliliter(s).
`mm - millimeter(s).
`mM - millimolar.
`mm2 -
`square millimeter(s).
`mm 3 -
`cubic millimeter(s).
`mmHg - millimeter(s) of mercury.
`mmol - millimole(s).
`mN - millinewton(s).
`mol - mole(s).
`m.p. - melting point.
`mPa - millipascal(s).
`MPa - megapascal(s).
`µg - microgram(s).
`µm - micrometer(s).
`newton(s) or normal (concentration).
`N -
`Neth - Netherlands.
`nm -
`nanometer(s).
`Nord - Nordic.
`o/w -
`oil-in-water.
`olw/o -
`oil-in-water-in-oil.
`Pa -
`pascal(s).
`the negative logarithm of the hydrogen ion concentra(cid:173)
`pH -
`tion.
`PhEur -
`pKa -
`
`European Pharmacopeia.
`the negative logarithm of the dissociation constant.
`
`7
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1022, p. 7 of 24
`
`

`

`xx Abbreviations and Units of Measurement
`
`Polish.
`Pol -
`Portuguese:
`Port -
`parts per hundred.
`pph -
`parts per million.
`ppm -
`pounds per square inch absolute.
`psia -
`recommended dietary allowance (USA).
`RDA -
`revolutions per minute.
`rpm -
`s -
`second(s).
`SC -
`subcutaneous.
`SEM -
`scanning electron microscopy or scanning electron
`microphotograph.
`Statutory Instrument or Systeme International d' Unites
`SI -
`(International System of Units) .
`TPN -
`total parental nutrition .
`
`time weighted average.
`TWA -
`UK - United Kingdom .
`US or USA - United States of America.
`USAN - United States Adopted Name.
`USP - The United States Pharmacopeia 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 parenthesis.
`
`Pressure
`I atmosphere (atm) = 0.10 I 325 megapascal (MPa)
`1 millimetre of mercury (mmHg) = 133.322 pascals (Pa)
`I pound per square inch (psi) = 6894.76 pascals (Pa)
`
`Area
`1 square inch (in2) = 6.4516 x 10-4 square meter (m2)
`1 square foot (ft2) = 9.29030 x 10-2 square meter (m2)
`I square yard (yd2) = 8.36127 x 10-1 square meter (m2)
`
`Density
`I 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)
`
`Surface tension
`1 dyne per centimeter (dyne/cm) = I millinewton per meter
`(mN/m)
`
`Temperature
`I degree Fahrenheit (°F) = 5/9 degree Celsius (0 C)
`
`Viscosity (dynamic)
`1 centipoise (cP) = 1 millipascal second (mPa s)
`1 poise (P) = 0.1 pascal second (Pa s)
`
`Viscosity (kinematic)
`1 centistoke (cSt) = 1 square millimeter per second (mm2/s)
`
`Volume
`1 cubic inch (in 3) = 1.63871 x 10-5 cubic meter (m3)
`1 cubic foot (ft3) = 2.83168 x 10-2 cuoic meter (m3)
`1 cubic yard (yd3) = 7.64555 x 10-1 cubic meter (m3)
`.1 pint (UK) = 5.68261 x 10-4 cubic meter (m3)
`l 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)
`
`8
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252, Ex. 1022, p. 8 of 24
`
`

`

`22U 0/ycenn
`
`Glycerin
`
`8.Description
`
`Glycerin is a clear, colorless, odorless, viscous, hygroscopic
`
`
`
`
`
`
`
`
`liquid; it has a sweet taste, approximately 0.6 times as sweet
`as sucrose.
`
`Identification +
`Characters +
`� 1.249
`
`Specific gravity 1.221-1.230
`2.Synonyms
`Color
`
`Appearance of solution
`Croderol; E422; glycerine; G/ycon G-100; Kemstrene; Pricerine;
`
`
`
`Acidity or alkalinity +
`
`
`
`1,2,3-propanetriol; trihydroxypropane glycerol.
`1.470-1.475
`
`Refractive index 1.449-1.454
`s; 0.01%
`
`Residue on ignition 50.01%
`50.01%
`
`Sulfated ash
`s; 0.001%
`s; 0.001% s; IO ppm
`Chloride
`Ammonium
`Calcium
`s; 0.002%
`s; 0.002%
`Sulfate
`s; 1.5 ppm
`s; 2 ppm
`Arsenic
`s; 5 ppm
`s; 5 ppm S 5 ppm
`Heavy metals
`s; 0.003%
`
`
`Chlorinated compounds (as Cl)
`
`
`Organic volatile impurities
`Aldehydes
`
`
`Acrolein, glucose and other
`ubstances +
`reducing
`Fatty acids and esters +
`
`Readily carbonizable
`substances
`Sugar
`Water
`Assay
`
`
`
`9.Pharmacopeial Specifications
`
`Test
`
`JP
`
`USP
`PhEur
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`s; 2.0%
`s; 5.0%
`99-101%
`84%-87% 98-101%
`
`1.Nonproprietary Names
`
`
`BP: Glycerol
`
`JP: Concentrated Glycerin
`PhEur: Glycerolum
`USP: Glycerin
`
`3.Chemical Name and CAS Registry Number
`
`
`
`Propane-1,2,3-triol [56-81-5]
`
`
`4.Empirical Formula
`
`
`Molecular Weight
`
`C3H803
`
`92.09
`
`
`
`5.Structural Formula
`
`I
`H-C-OH
`I
`H-C-OH
`I
`H-C-OH
`I
`
`
`
`6.Functional Category
`
`Antimicrobial preservative; emollient; humectanl; plasticizer;
`
`
`10.Typical Properties
`
`
`
`
`solvent; sweetening agent; tonicity agent.
`Boiling point: 290°C (with decomposition)
`Density:
`
`1.2656 g/cm3 al 15°C;
`1.2636 g/cm3 at 20°C;
`Glycerin i used in a wide variety of pharmaceutical formulations
`
`
`I .2620 g/cm3 al 25°C.
`
`
`
`
`including oral, otic, ophthalmic, topical, and parenteral preparation .
`Flash point: 176°C (open cup)
`
`
`It is also used in cosmetics and as a food additive.
`
`Freezing point:
`
`
`
`
`In topical pharmaceutical formulations and cosmetics, glyc­
`
`
`
`erin is used primarily for it humeclanl and emollient prop­
`
`
`
`
`erties. In parenteral formulations glycerin is mainly used as
`Concentration of aqueous
`
`
`
`a solvent.f1> In oral solutions glycerin is used as a solvent.
`
`
`glycerin solution (% w/w)
`
`
`
`sweetening agent, antimicrobial pre ervative, and viscosity­
`IO
`
`
`
`
`increasing agent. Glycerin is also used as a plasticizer of gel­
`20
`
`
`
`
`atin in the production of soft-gelatin capsules and gelatin sup­
`30
`
`
`
`
`positories. Glycerin is additionally employed as a therapeutic
`40
`
`
`agent in a variety of clinical applications.
`50.
`60
`66.7
`
`80
`90
`
`7.Applications in Pharmaceutical Formulation or
`
`
`
`Technology
`
`Use
`
`Concentration (%)
`
`Freezing point
`
`(OC)
`
`-1.6
`-4.8
`-9.5
`-15.4
`-23
`-34.7
`-46.5
`-20.3
`-1.6
`
`>20
`Antimicrobial preservative
`Up to 30
`Emollient
`Humectant
`Up to 30
`
`Ophthalmic formulations
`0.5-3.0
`Variable
`
`
`Plasticizer in tablet film coating
`
`Sol vent for parenteral formulations
`Up to 50
`
`
`Sweetening agent in alcoholic elixirs
`Up to 20
`
`hygroscopic.
`Hygroscopicity:
`Melting point: 17.8°C
`
`Osmo/arity:
`erum.
`
`
`a 2.6% v/v aqueous solution
`
`iso-osmotic with
`
` PFIZER, INC. v. NOVO NORDISK A/S - IPR2020-01252,