`Pharmaceutical Excipients
`
`FOURTH EDITION
`
`Edited by
`
`Raymond C Rowe
`BPhorm, PhD, DSc, FRPhormS, CChem, FRSC, CPhys, MlnstP
`
`Senior Principal Scientist
`
`AstroZeneco
`
`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 ond Practice
`
`Royal Phormoceuticol Society of Great Britain
`
`London, UK
`
`London • Chicago Pharmaceutical Press
`
`(RP)
`~ APhA
`
`American
`Pharmaceutical
`Association
`
`FRESENIUS EXHIBIT 1023
`Page 1 of 24
`
`
`
`Published by the Pharmaceutical Press
`Publications division of the Royal Pharmaceutical Society of Great Britain
`
`1 Lambeth High Street, London SEl 7JN, UK
`100 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 Bach Press, Bath
`
`ISBN O 85369 472 9 (UK)
`ISBN 1 58212 022 6 (USA)
`
`All rights reserved. No pare 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 che information contained in
`chis book and cannot accept any legal responsibility or
`liability for any errors or omissions chat may be made.
`
`A catalogue record for chis 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. n. Sheskey, Paul J. m. Weller, Paul j.
`
`RS201.E87H36 2003
`615' .19-dc21
`
`2003002641
`
`FRESENIUS EXHIBIT 1023
`Page 2 of 24
`
`
`
`Preface
`
`PHARMA C EUTICAL DO AGE FORMS contain both pharma(cid:173)
`cologically active compounds and excipient added to aid the
`formulation and manufa rure of the ub equent dosage form
`for admini tration ro patient . lndeed the properties of the final
`do age form (i.e. it bioavailability and
`tability) are, for the
`most part, highly dependent on the excipienr cho en, their
`concentration and interaction with both the active compound
`and each other. o longer can excipient be regarded imply a
`inert or ina rive ingredient , and a derailed knowledge nor only
`of the phy ical and chemical properties bur al o of the afety,
`handling and regulatory tatus of these materials is e sential for
`formularors throughout the world. In addition, rhe growth of
`novel form of delivery ha re ulted in an increa e in the number
`of rhe ex ipient being u ed and upplier of excipienr have
`developed novel excipient mixtures and new physical forms co
`improve their properties. The Handbook of Pharmaceutical
`Excipients ha been conceived a a y rematic, comprehen ive
`re ource of information on all of these topics.
`The first edition of the Handbook wa published in 1986
`and contained 145 monograph . This was followed by the
`econd edition in 1994 containing 203 monograph and the
`third edition in 2000 containing 2 LO monograph .
`ince the
`relea e of the third edition two D-ROM edition have al o
`been relea ed: Pharmaceutical Excipients 2000 included the
`third edition, and Pharmaceutical
`same material as
`the
`Excipients 2001, whi h included 20 new monograph .
`This new printed edition with its companion D-ROM
`contain 250 monograph authored by e pert in pharmaceu(cid:173)
`ti al formulation or excipient manufacture from around the
`world. All the monographs have been reviewed and revised in
`the light of current knowledge. There ha been a greater
`emphasis on including published data from primary source
`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 effect on the
`data generated (e pecially in the ca e of the compa rability of
`an excipienc), and thu cause confu ion. As a con equence, the
`editors have been more elective in including data relating to the
`phy ica l propertie of an excipienc. However comparative data
`that how 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 upplier
`Directory (Appendix l) has al o been completely updated with
`many more inrernational upplier included.
`ln a y tematic and uniform manner, rhe Handbook of
`Pharmaceutical Excipie11ts collects e encial dara on the phy i(cid:173)
`ca l properrie of excipienrs such as: boiling point, bulk and tap
`den icy, compression characterisrics, hygro copicity, flow(cid:173)
`abiliry, melting point, moisture content, moisrure-absorption
`isotherms, particle size distribution, rheology, specific surface
`area and olubiliry.
`arming electron microphotograph
`( EMs) are also included for many of the excipienrs. The
`Handbook contains information from variou
`international
`ource
`and per onal ob ervation and comment
`from
`monograph author ,
`teering committee members and the
`editors.
`
`in the Handbook are thoroughly
`All of the mon graph
`cross-referenced and indexed so that excipiencs may be identi(cid:173)
`fied by either a chemical, a nooproprictary, or a trade name.
`Most monograph list related ubstance to help the formulator
`to develop a Ii t of po
`ible material for u e in a new dosage
`form or product. Related sub ranees are not directly ubsticu(cid:173)
`table for each other but, in general, they are excipients tha t have
`been u ed for
`imilar purpo e in variou do age form .
`The Handbook of Phan11aceutical Excipients i a ompre(cid:173)
`hensive, uniform guide to the uses, propertic , and safety of
`pharmaceutical excipients, and is an es ential reference source
`for tho e involved in the development, production, ontrol, or
`regulation of pharmaceutical preparation .
`ince many phar(cid:173)
`maceuti al excipient are al o u ed in other application
`the
`Handbook of Pharmaceutical Excipients will also be of va lue ro
`persons with an interest in the formulation or production of
`confectionery cosmetic , and food product .
`
`Arrangement
`The information con i t of monographs that are divided into
`22 ecrion
`to enable the reader to find the information of
`intere t ea ily. Although it wa originally intended thar each
`monograph contain only information about a single excipient, it
`rapidly became clear that ome ubstance or group of sub-
`ranee
`hou ld be discu sed rogecher. This gave rise to uch
`monograph a 'Coloring Agent 'and 'Hydrocarbon '. In addi(cid:173)
`tion, ome material have more than one monograph depending
`on the phy ical characteristics of the material, e.g.
`tarch versu
`Pregelatinized Starch. Regardless of the complexity of the
`monograph they are all divided into 22 section as follows :
`
`onproprietary ame
`1
`2 ynonym
`ame and CA Registry Number
`3
`hemical
`4 Empirical Formula and Molecular Weight
`5 Structural Formula
`6 Functional Category
`7 Applications in Pharmaceutical Formulation or Technology
`8 De cripnon
`9 Pharmacopeial Specification
`10 Typical Propertie
`11
`rability and Storage ondirions
`12 Incompatibilities
`13
`ethod of Manufacture
`14 Safety
`15 Handling Precautions
`16 Regulatory
`taru
`17 Related ub tan e
`18 Comment
`19 pecific References
`20 General References
`21 Author
`22 Date of Revision
`
`De criprions of the sections appear below with information
`from an example monograph if needed.
`
`XVII
`
`FRESENIUS EXHIBIT 1023
`Page 3 of 24
`
`
`
`xviii
`
`Preface
`
`Section 1, Nonproprietary Names, lists the excipient 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 excipient,
`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 produce over the ocher. The large number of
`suppliers internationally makes it impossible co include all the
`trade names.
`
`Section 3, Chemical Name and CAS Registry Number, indicates
`the unique Chemical Abstract Services number for an excipient
`along with the chemical name, e.g., Acacia 19000-01-SJ.
`
`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 funcrion(s) that an
`excipient is generally thought to perform, e.g., diluenr, emulsi(cid:173)
`fying agent, etc.
`
`in Pharmaceutical Formulation or
`Section 7, Applications
`Technology, describes the various applications of the excipienr.
`
`Section 8, Description, includes details of the physical appear(cid:173)
`ance of the excipienr, 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 UP), and the
`United Stares Pharmacopeia/Narional Formulary
`(USP/
`USPNF). fnformation 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 nor 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-ro-dare information ar the rime 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 excipienr which are not shown in Section 9. All data are
`for measurements made ac 20°C unless otherwise indicated.
`Where the solubility of rhe excipienr is described in words, rhe
`following terms describe the solubility ranges:
`Very soluble
`1 part in less than 1
`1 part in 1-10
`Freely soluble
`1 part in 10-30
`Soluble
`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 JO 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. ln 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
`ro 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 nor
`mean it does not occur but simply that it has not been reported
`or is nor well known. Every formulation should be rested for
`incompatibilities prior ro 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 dara 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 excipients varies from one nation ro 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 aurhor(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 rype of excipient or the rypes
`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.
`
`FRESENIUS EXHIBIT 1023
`Page 4 of 24
`
`
`
`Acknowledgments
`
`A Handbook conraining 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
`edicors would like co thank them all personally for their
`contribution to the Handbook. Grateful thanks also go to the
`members of the International Steering Committee who advised
`che edicors 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 co 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 b)' 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 co possess rhe necessary knowledge ro
`interpret the information that the Handbook contains. The
`Handbook has no official status and there is no intent, implied
`or otherwise, chat 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, reporrs 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 liabiliry 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)
`dial 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 excipiem 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.
`
`X I X
`
`FRESENIUS EXHIBIT 1023
`Page 5 of 24
`
`
`
`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. Phannaceutical 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. lnactive Ingredient Guide.
`http://www.accessdara.fda.gov/scripts/cder/iig/index.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 £, 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 Phannacopeia, 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 Jndustnal
`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
`£xcipients. Boca Raton, FL: CRC Press, 1992.
`Swarbrick J, Boylan JC, eds. Encyclopedia of Phannaceu(cid:173)
`tical Technology, 2nd edn. New York: Marcel Dekker,
`2002.
`Sweet DV, ed. Registry of Toxic Effects of Chemical
`Substances. Cincinnati: US Department of Health, L987.
`Sweetman SC, ed. Martindale: the Complete Drug Reference,
`33rd edn. London: Pharmaceutical Press, 2002.
`The Merck lndex: 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
`
`FRESENIUS EXHIBIT 1023
`Page 6 of 24
`
`
`
`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
`cm 3
`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.
`DoH
`Department of Health (UK).
`DSC
`differential scanning calorimetry.
`EC
`European Community.
`exemplit gratia, 'for example'.
`e.g.
`EINECS European Inventory of Existing Commercial Che-
`mica! Substances.
`et a/ii, '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
`Ad.ministration 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
`m 3
`M
`max
`MCA
`mg
`MIC
`mm
`mL
`mm
`mM
`mm2
`mm3
`mmHg
`mmol
`mN
`mol
`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.
`kiJocalorie(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
`microorganisms.
`lowest lethal dose for the specified animals or
`microorganisms.
`meter(s).
`square meter(s).
`cubic meter(s).
`molar.
`maximum.
`Medicines Control Agency (UK).
`milligram(s).
`minimum inhibitory concenrration.
`minute(s) or minimum.
`milliliter(s).
`mil limeter(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
`concenrration.
`European Pharmacopeia.
`the negative logarithm of the dissociation constant.
`parts per hundred.
`
`XXI
`
`eta/
`EU
`FAO
`
`FAO/
`WHO
`FCC
`FDA
`FD&C
`
`FFBE
`g
`GMP
`GRAS
`
`HC
`HCFC
`HFC
`HIV
`HLB
`HSE
`i.e.
`IM
`
`FRESENIUS EXHIBIT 1023
`Page 7 of 24
`
`
`
`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 lnternational
`d'Unites (lnternariona1 System of Units).
`total parental nutrition.
`time weighted average.
`United Kingdom.
`
`US or
`USA
`USAN
`USP
`USPNF
`UV
`v/v
`v/w
`WHO
`w/o
`w/o/w
`w/v
`w/w
`
`United States of America.
`
`United States Adopted Name.
`The United States Pharmacopeia.
`The United States National Formulary.
`ultraviolet.
`volume in volume.
`volume in weight.
`World Health Organization.
`water-in-oil.
`water-in-oil-in-water.
`weight in volume.
`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. SJ units are used throughout the Handbook with,
`where appropriate, imperial units reported in parentheses.
`
`Area
`) = 6.4516 x 10-4 square meter (m2i
`1 square inch (in2
`1 square foot (fr2
`) = 9.29030 x 10-2 square meter (m )
`1 square yard (yd 2
`) = 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-s newton (N)
`
`•
`Length
`J angstrom (A) = 10-10 meter (m)
`1 inch (in) = 2.54 x 10-2 meter (m)
`1 foot (fr) = 3.048 x 10- 1 meter (m)
`1 yard (yd)= 9.144 x 10- 1 meter (m)
`
`Pressure
`1 atmosphere (arm) = 0.101325 megapascal (MPa)
`
`1 millimetre of mercury (mrnHg) = 133.322 pascals (Pa)
`1 pound per square inch (psi) = 6894. 76 pascals (Pa)
`
`Surface tension
`1 dyne per centimeter (dyne/cm) = 1 rnillinewton per meter
`(mN/m)
`
`Temperature
`Celsius (0 C) = (1.8 x •q + 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 (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 (fr3) = 2.83168 x 10-2 cubic 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)
`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
`)
`
`)
`
`FRESENIUS EXHIBIT 1023
`Page 8 of 24
`
`
`
`Glycerin
`
`1 Nonproprietary Names
`BP: Glycerol
`JP: Concemrared glycerin
`PhEur: Glycerolum
`USP: Glycerin
`
`2 Synonyms
`Croderol; £422; glycerine; Glycon G-10O; 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
`
`C3HsO3
`
`Molecular Weight
`92.09
`
`S Structural Formula
`
`6 FuncrionalCategory
`Antimicrobial preservative; emollienr; hmneccam; plasticizer;
`solvent; sweetening agent; ronicity 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 l.
`ln topical pharmaceutical formulations and cosmetics,
`glycerin is used primarily for its humectam and emollient
`properties. In parenteral formulations, glycerin is used mainly
`as a solvent. (If
`In oral solutions, glycerin is used as a solvent, sweetening
`agent, antimicrobial preservative, and viscosity-increasin_ff
`agent. Ir is also used as a plasticizer and in film coatings.' 2•
`Glycerin is additionally used in topical formularions such as
`creams and emulsions.f4I
`Glycerin is used as a plasticizer of gelatin in the production
`of soft-gelatin capsules and gelatin suppositories.
`Glycerin is emplo~ed as a therapeutic agent in a variety of
`clinical applicarions, 51 and is also used as a food additive.
`
`Table I: Uses of glycerin.
`
`Use
`
`Antimicrobial preservative
`Emollient
`Humectont
`Ophthalmic formulations
`Plaslicizer in tablet film coo ting
`Solvent for parenteral formulations
`Sweetening agent in alcoholic elixirs
`
`Concentration 1%)
`
`< 20
`~ 30
`'s 30
`0.5"'3.0
`Variable
`~ 50
`~ 20
`
`8 Description
`Glycerin is a clear, colorless, odorless, viscous, hygroscopic
`liquid; it has a sweet raste, approximately 0.6 times as sweet as
`sucrose.
`
`9 Pharmacopeial Specification5
`See Table II. See also Section 18.
`
`Table II: Phormocopeial specifications for glycerin.
`
`Test
`
`JP 2001
`
`PhEur 2002
`
`USP 25
`
`+
`+
`+
`+
`~ 1.470
`
`+
`
`+
`
`+
`+
`+
`+
`1 . .470-1.475 -
`+
`+
`+
`
`+
`~ 0.001% ~ l0ppm
`~5ppm
`~ 5ppm
`~2.0%
`~ 0.01%
`
`+
`
`~ 0.001%
`~5ppm
`~ 5.0%
`~ 0.01%
`;;i,.J.249
`,;;; 0.002%
`
`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
`Sulfate
`~ 0.002%
`Ammonium
`+
`+
`Calcium
`Arsenic
`~2ppm
`Acrolein, glucose or other +
`reducing substances
`Fatty acids and esters
`Orgonic volatile
`impurities
`Readily corbonizoble
`substances
`Assay
`
`+
`
`+
`+
`
`+
`
`+
`
`;i,98.0% 98.0-101.0% 99.0-101 .0%
`
`257
`
`FRESENIUS EXHIBIT 1023
`Page 9 of 24
`
`
`
`258
`
`Glycerin
`
`10 Typical Properties
`Boiling point: 290 C (with decompo ition)
`Den ity:
`1.2656 g/cm 3 at 15 C
`l.2636g/cm' at 20·
`1.2620 g/cm" at 25 C
`Fla h point: 176' C (open cup)
`Freezing point: see Table III.
`Hygroscopicity: hygro copic.
`Melting point: 17.8
`0 molarity: a 2.6% v/v aqueou solution is i oo motic with
`erurn.
`Refractive indc :
`
`llw: 1.4758
`ll'r:O = 1.4746
`nrf = 1.4730
`Solubility: see Table TV.
`Specific gravity: see Table V.
`Im (63.4 dyne /cm) at 20 C.
`Surface ten ion: 63.4 m
`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 ( 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
`1 in 500
`1 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
`1.156
`
`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
`l.311
`2.095
`6.05
`10.96
`22.94
`111.0
`
`11 Stability and Storage Conditions
`Glycerin i hygroscopic. Pure glycerin i not prone to oxidation
`by the atmosphere under ordinary storage conditions but it
`decompo cs on heating, with the evolution of toxic acrolein.
`Mixtures of glycerin with water, ethanol, and propylene glycol
`are chemically table.
`Glycerin may cry tallize if cored at low temperature ; the
`crystals do not melt until warmed to 20°C.
`Glycerin should be stored in an airtight container, in a cool,
`dry place.
`
`12
`Incompatibilities
`Glycerin may explode if mixed with strong oxidizing agents
`such as chromium trioxide, potassium chlorate, or potassium
`permanganate. ln dilute solution, the reaction proceeds at a
`lower rate with everal oxidation product being formed.
`Black discoloration of glycerin occurs in the presence of
`light, or on contact with zinc oxide or ba ic bismuth nitrate.
`An iron contaminant in glycerin is responsible for the
`darkening in color of mixtures containing phenols, alicy(cid:173)
`late and tannin.
`Glycerin form a boric acid complex, glyceroboric acid that
`1 a tronger acid than boric acid.
`
`13 Method of Manufacture
`Glycerin is mainly obtained from oils and fats as a by-product