.
`
`.
`
`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
`
`~ .APhA
`
`American Pharmaceutical Association
`Washington, D.C.
`
`(RP)
`,.._,ieol ......
`London, United Kingdom
`
`FRESENIUS EXHIBIT 1022
`Page 1 of 24
`
`

`

`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
`1. Excipients--Handbooks, manuals, etc.
`Pharmaceutical Association.
`[DNLM: 1. Excipients--Handbooks. QV 735 H236 2000]
`RS201.E87 H36 2000
`615'.19--dc21
`
`I. Kibbe, Arthur H. II. American
`
`~-..
`
`A catalogue record for this book is available from the British Library.
`
`.,..
`
`\
`\
`
`I .
`
`99-044554
`
`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.
`
`Managing Editor:
`Copyeditor:
`Indexer:
`Compositor:
`Cover Designer:
`
`Melanie Segala
`Paul Gottehrer
`Lillian Rodberg
`Roy Barnhill
`Tim Kaage
`
`-
`
`FRESENIUS EXHIBIT 1022
`Page 2 of 24
`
`

`

`Preface
`
`Pharmaceutical do age form!> contain both active ingredient
`and inactive material called excipient . The behavior of the
`do age form i dependent on proce
`variable and the inter(cid:173)
`relation. hip between the variou excipients and their impact
`on the active ingredient. Suppliers of excipient have devel(cid:173)
`oped novel cxcipicnt mixtures and new phy i al form of ex(cid:173)
`cipients, which give them improved characteri tic . In addition.
`the international nature of the pharmaceutical indu . try and it
`upplier demands that formulators throughout the world have
`a much information as po sible about the chemical and phy. -
`ical nature of excipients and combination · of excipient.. For(cid:173)
`mulator are also concerned about the effect of the fini hed
`product on the patiem it i.
`intended to treat. Therefore, they
`are concerned about general and pccific toxic effect. of the
`excipients, allergic reaction
`to excipients, di ca c-. pccific in(cid:173)
`tolerance to cxcipicnt and interaction between the excipient
`and the active ingredient. In addition, formulators need to be
`aware of the potential environmental impact of the u e of ex(cid:173)
`cipient . La tly, the effect of regulatory change as ociated with
`harmonization i al o a concern of the profes ional formulator.
`The Handbook of Pharmaceutical Excipie111s is a joint publica(cid:173)
`tion of the American Pharmaceutical A ociation and the Royal
`Pharmaceutical Society of Great Britain. The Handbook of
`Pharmacewical Excipie111s, originally publi hed in 1986, wa.
`the first Engli h-language publication to comprehen ively and
`. y tematically de cribc the chemical and physical propertie of
`pharmaceutical cxcipient . The fir. t edition contained 145 mono(cid:173)
`graph. , and the econd contained 203. The present edition con(cid:173)
`tain. 210 monograph authored by experts in pharmaceutical
`formulation or excipient manufacture from around the world.
`Thi edition also contains the re uh of extensive laboratory
`in
`tc ting carried out over the la t two year
`in laboratorie
`Great Britain and the United
`tate . omc data developed by
`laboratory project are retained . It i clearly
`the fir t edition'
`noted as uch in the monographs. The new data generated for
`this edition should help the formulator in the election of ap(cid:173)
`propriate excipient for various do age forms. A major devel(cid:173)
`opment ince the publication of the la. t edition of the Handbook
`ha been the trend towards global pharmaceutical harmonization .
`To reHect thi., where appropriate, more detailed information on
`excipient u ed in Japan has been included in thi edition. Ad(cid:173)
`ditionally the indc ha been revi ed and expanded and the up(cid:173)
`plier ' directory ha been completely updated.
`in a y -
`The Handbook of Pharmaceutical Excipie11/s collect
`tematic and uniform manner e . ential data on the phy ical prop(cid:173)
`ertie of excipient uch as: boiling point, bulk and tap den ity,
`ion characteristic , hygroscopicity, tlowability, melting
`compre
`point, moi ture content, moisture-absorption isotherms, particle
`ize di tribution, rheology, pecific surface area, and olubility.
`Scanning electron microphotographs (SEMs) are also included
`for many of the excipient . The Handbook contains information
`from variou
`international . ources, but also includes laboratory
`data determined specifically for the Handbook and personal ob-
`tcering
`ervation and comment from the monograph author,
`committee member , and the editor. lL also contains information
`on the afe u e and potential toxicity of the material .
`All of the monographs in the Ha11dbook are thoroughly cro -
`referenced and indexed so that excipient may be identified
`by either a chemical, nonproprietary, or trade name. Most
`
`Preface xv
`
`Ii t related ub tance( ) to help the formulator
`monograph
`develop a Ii L of po sible material
`for u e in a new do age
`form or product Related ub tance are not di rectly ub ti(cid:173)
`tutablc for each other but are excipient
`that have been u ed
`for
`imilar purpo e
`in variou do age form .
`The Handbook of Pharmaceutical Excipie111s i a comprehen-
`ive, uniform guide to the u e , properties, and afety of phar(cid:173)
`maceutical excipients and is an es ential reference ource fo r
`tho e involved in the development, production, control or reg(cid:173)
`ince many pharma(cid:173)
`ulation of pharma eutical preparation .
`ceutical excipient are al o used in other applications, the
`Handbook of Pharmaceutical Excipients will al o be of va lue
`formulation or production
`to per on with an intere ·t in th
`of confectionery, co metic, and food product .
`
`Arrangement
`of monograph that are djvided into 22
`The Handbook con i
`ection · to make it ea y for the reader to go directly to the
`information of intere l. Although it wa originally intended that
`each monograph contain only information abou t a
`ingle excip(cid:173)
`ient, it rapidly became clear that some substance or group of
`sub tances must be di cu ed together. Thi gave ri e to uch
`monograph as ·Coloring Agent ' and 'Hydrocarbon .' In addi(cid:173)
`tion, ome material have more than one monograph depending
`on the phy ical characteri tic of the material due mai nly to it
`i the variou
`tarch mono(cid:173)
`preparation. A good example of thi
`graphs, particularly
`tarch v . Pregelatinized Starch. Regardle
`of the complexity of the monograph they are all divided in 22
`ection as follow :
`
`ame
`
`I. onproprietary
`2. ynonym
`umber
`3. Chemical Name and CAS Regi try
`4. Empirical Formula and Molecular Weight
`5. Structural Formula
`6. Functional Category
`7. Application
`in Pharmaceutical Formulation or Technology
`8. De cription
`9. Pharmacopeial Specifications
`I 0. Typical Propertie
`11. Stability and
`torage Condition
`I 2. fncompatibilitie
`13. Method of Manufacture
`14. afety
`15. Handling Precaution
`16. Regulatory Statu
`17. Pharmacopeia
`18. Related Substance
`19. Comments
`20. Specific Reference
`21. General References
`22. Authors
`
`To make it ea y for the fir t Lime u er, de cription of the
`ection appear below with information from an example
`monograph if needeC:.
`ection I. Nonproprietary ame , Ii t
`the excipient name
`u ed in the current Briti h Pharmacopoeia, European Pharma(cid:173)
`copeia, Japane e Pharmacopeia, and the United State Phar(cid:173)
`the appropriate
`macopeia. For nonpharmacopeial excipient
`or r
`i
`indicated.
`approved name, e.g., USA
`ection 2. ynonym , Ii t other name for the excipient, in(cid:173)
`cluding trade name used by supplier ; trade names are listed
`in italics. The inclusion of one supplier's trade name and the
`absence of other
`hould in no way be interpreted as an
`
`FRESENIUS EXHIBIT 1022
`Page 3 of 24
`
`

`

`xvi Preface
`
`endor ement of one supplier' product over the other. The
`large number of upplier
`internationally make
`it impo
`ible
`to include all the trade name .
`Registry umbel'. indi(cid:173)
`Section 3, Chemica.l ame and C
`cate
`the unique Chemical Ab. tract Service number for an ex(cid:173)
`cipient along with th chemical name, e.g., Acacia [9000-01 -5 ].
`Section 4 and 5, Empirical Formula and Molecular Weight
`and Structural Formula, are elf-explanatory. Many excipi(cid:173)
`ent are not pure chemical ub tance , in which ca e their
`ection 8.
`compo ition i de cribed either here or in
`ection 6, Functional Category, Ii t
`the function( ) that an
`excipicnt i generally thought to perform, e.g. , diluent, emul (cid:173)
`ifying agent, etc.
`Section 7, Applications in Pharmaceutical Formulation or
`Technology, de cribe
`the variou application. of the excipient.
`, De cription
`include detail of the phy ical ap(cid:173)
`e tion
`pearance of the excipient, e.g., white or yellow flakes, etc.
`Section 9, Pharmacopeial pecifications briefly pre ent
`the
`compendia!
`tandard
`for the excipient. Information included i
`obtained from the Briti h Pharmacopoeia (BP), European Phar(cid:173)
`macopeia (PhEur), Japane e Pharmacopeia (JP), and the United
`State Pharmacopeia/ ational Formulary (U P). [nformation
`from the JP and U P are included if the ub tance i
`in tho e
`compendia. Information from the PhEur i al o included. If the
`excipient i not in the PhEur but i included in the BP. information
`in luded from the BP. The pharmacopeia are continually up(cid:173)
`i
`dated and revi ion or supplement are published. It was neces-
`ary to select a point in time and u e that a our reference when
`ection. Therefore
`selecting the information to be included in tbi
`the information i from the following volume :
`BP - 1998 Edition
`JP - Thirteenth Edition 1996
`upplements to 1999
`PhEur - Third Edition plu
`USP - USP 24 F 19 2000 Edition
`Since the USP and F were combined into a
`ingle reference
`many year ago it wa
`felt that a
`ingle abbreviation would
`be ufficient. Therefore throughout the Handbook whenever
`to thi combined text.
`the USP abbreviation i u ed it refer
`ection 10, Typical Propertie , de cribe
`the phy ical prop(cid:173)
`ertie of the excipient which are not hown in Section 9. All
`data are for mea urement made at 20°C unle
`otherwi e
`indicated. Where the olubility of the excipient i de cribed
`in word , the following term de cribe the olubility ranges:
`
`Very oluble
`Freely oluble
`Soluble
`Sparingly oluble
`Slightly soluble
`Very
`lightly oluble
`Practically in oluble
`or in oluble
`
`than
`part in les
`part in l - 10
`part in 10-30
`part in 30-100
`part in I 00-1000
`part in l 000- 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 ·upport of the third edition are clearly
`that were u ed to collect that
`uch. The method
`marked a
`data are included in Appendix II: HPE Laboratory Meth(cid:173)
`od . Data from the HPE Laboratory Project performed for the
`fir t edition are either replaced by the new data or referenced
`as such in each monograph. The reader i referred to the ear(cid:173)
`lier edition of thi book for the methods used .
`
`torage Conditions describe the con(cid:173)
`Section 11 , Stability and
`ditions under which the bulk material a received from the up(cid:173)
`plier hould be
`tored. ln addition some monograph
`report on
`storage and stability of the do age form
`that contain the excip(cid:173)
`ient.
`Section 12, lncompatibilitie , describe
`the reported incompati(cid:173)
`bilitie for the excipient either with other excipient or with active
`ingredients. If an incompatibility i not listed it doe not mean it
`imply that it ha not been reported or is not
`does not occur but
`well known. Every formulation hould be tested for incompati(cid:173)
`bilities prior to u e in a commercial product.
`Section 13, Method of Manufacture, de cribe
`the common
`methods of manufacture and additional proce se that are used
`to give the excipient it physical characteri tic . In ome case
`the po sibility of impuritie will be indicated in the method
`of manufacture.
`ection 14, afety de cribe briefly the type of formulation
`in
`which the excipient has been u ed and pre en
`relevant data con(cid:173)
`cerning po
`ible hazard and adver e reaction
`that have been re(cid:173)
`ported. Relevant animal toxicity data are al o hown.
`ection I 5, Handling Precaution , indicate pos ible hazard
`a ociated with handling the excipient and make recommen(cid:173)
`dation
`for uitable containment and protective method . A
`familiarity with current good laboratory practice (GLP) and
`current good manufacturing practice (GMP) and
`tandard
`chemical handling procedure
`i a urned.
`Section 16, Regulatory Statu , describes the accepted uses
`ta(cid:173)
`in food and licensed pharmaceuticals where known . The
`tu of excipient varie
`from one nation to another, even in
`time of harmonization. Dependence on thi
`reference in
`thi
`place of checking with the regulatory body in the nation in
`which the product is to be sold i unwise.
`Section 17, Pharmacopeia
`the pharmacopeia in which
`Ii t
`the excipient i Ii ted . If the excipient i Ii ted in the European
`that are party to the PhEur
`Pharmacopeia (PhEur), countrie
`are not Ii ted ; only ·'Eur" is. The following countries are party
`to the PhEur: Au tria, Belgium, Bo nia-Herzegovina, Croatia,
`Cyprus, Czech Republic, Denmark, Finland, France, Germany,
`Greece, Iceland , Ireland, ltaly, Luxembourg, the
`etherland ,
`orway, Portugal ,
`Jovakia, Slovenia, Spain, Sweden, Swit(cid:173)
`zerland, Turkey. the United Kingdom of Great Britain and
`orthern Ireland, and the former Yugo lav Republic of Mace(cid:173)
`i
`donia. The information from the four major pharmacopeia
`Ii ted in ection 9.
`ection 18, Related ubstances, Ii ts the excipients similar
`to the excipient di cu ed in the monograph. The reader
`hould look at the monograph
`for the related substance for
`comparative information.
`Section 19, Comments, includes additional information and
`observation relevant to the excipient. Where appropriate, the
`different grades of the excipient available are di cu ed. Com(cid:173)
`ments are the opinion of the Ii ted author( ) unle
`referenced
`or indicated otherwi e.
`Section 20, Specific References, is a list of reference cited
`within the monograph .
`Section 2 I , General References, Ii c reference which have
`type of excipient or the types
`general information about thi
`of dosage forms made with these excipients.
`Section 22, Authors, list in alphabetical order the current author
`of the monograph. Authors of previou edition can be found in
`the earlier edi lion .
`
`FRESENIUS EXHIBIT 1022
`Page 4 of 24
`
`

`

`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; M etin
`<;elik, Pharmaceutical Technologies International; J. Bradley
`Dickerson, Schering-Plough; Anthony Fazzi, Wilkes Univer(cid:173)
`sity; Arlhur H. Kibbe, Wilkes University; Scott Ocheltree,
`Pharmacia & Upjohn; Garnet E. Peck. Purdue University; Lois
`Schofield, Glaxo Wellcome; Paul Sheskey, Dow Chemical;
`Bhogi 8. Sheth, University of Tennessee; and Kevin Silinskie,
`Wilkes University.
`
`Anthony Palmieri III
`June 1999
`
`Acknowledgments
`
`This edition of the Handbook of Pharmaceutical Excipienrs
`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 H PE Laboratory Project
`and the members of the two steering committees. The mem(cid:173)
`bers of the US and UK steering comminees 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-ediLOr of the second
`edition. His work on that edition and his advice on every
`aspect of this edition made my job much easier. ln addition,
`this edition had extensive laboratory work done by the HPE
`Laboratory Project headed by Anthony Palmieri III. Tt 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
`
`FRESENIUS EXHIBIT 1022
`Page 5 of 24
`
`

`

`xviii Notice to Readers
`
`Notice to Readers
`
`Selected Bibliography
`
`The Handbook of Pharmaceutical £.rcipie111s 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 10 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)
`Hects 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 10
`the Editor, Handbook of Pharmaceutical Excipicnts, Royal
`Pharmaceutical Society of Great Britain, I Lambeth High
`Street, London SEI 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. Modem Pharmaceutics, 2nd edi(cid:173)
`tion. New York, Marcel Dekker Inc., 1990.
`British Pharmacopoeia 1998. London. The S1ationery Office.
`1998.
`Budavari S, editor. The Merck l11dex: A11 Encyclopedia of Chem(cid:173)
`icals, Drugs, and Biologicals, 12th edition. Whitehouse Sta(cid:173)
`tion. NJ. Merck & Co., Inc., 1996.
`£11mpea11 Pharmacopoeia, 3rd edition and supplements. Stras(cid:173)
`bourg, Council of Europe, 1996.
`Florence AT, Salole EG, editors. Formulation Factors in Adverse
`Reactions. London, Bunerwonh & Co .. Ltd., 1990.
`Food and Drug Administration. Inactive Ingredient Guide. Wash(cid:173)
`ington. DC; FDA. 1996.
`Food Chemical.I Codex, 4th edition. Washington, DC, National
`Academy Press, 1996.
`Gennaro AR, editor. Reming1011: The Science and Practice of Phannucy,
`19th edition. Easton, PA. Mack Publishing Co., 1995.
`Health and Safety Executive. EH40/98: Occupational exposure
`limits, 1998. Sudbury, Health and Safety Executive, 1998.
`Japan Pharmaceutical Excipients Council. Japanese Pharmaceu(cid:173)
`tical £.rcipie111s 1993. Tokyo, Japan, Yakuji Nippo Ltd., 1994.
`Japan ese Pharmacopeia, 13th edition. Tokyo. Japan. Yakuji
`Nippo, Lid., 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 Plrarmaceutical Codex: Principles and Prac(cid:173)
`tice of Pharmaceutics, 12th edition. London, Pharmaceutical
`Press, 1994.
`Parfitt K, editor. Martindale: The Complete Drug Reference. 32nd
`edition. London, Pharmaceutical Press, 1999.
`Smolinske SC. Ha11dbook of Food, Drug a11d Cosmetic £xcipi(cid:173)
`e111s. Boca Raton. FL. CRC Press Inc.. 1992.
`Swarbrick J, Boylan J, editors. £11cycloptdia 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. 1987.
`United States Pharmacopeia 24 and National Formulary 19 and
`Supplements. Rockville, MD, United States Pharmacopeial
`Convention, Inc., 2000.
`Weiner M, Bernstein TL. Ad1•erse Reactio11s 10 Drug Formulatio11
`Agems: A Handbook of Excipients. New York, Marcel Dekker
`Inc., 1989.
`
`FRESENIUS EXHIBIT 1022
`Page 6 of 24
`
`

`

`Abbreviations
`
`Some uni1s , 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.
`
`ame.
`
`= -
`approximately.
`Ad - Addendum.
`ADI -acceptable daily intake.
`approx -
`approximately.
`atm -
`atmosphere.
`Au t - Auslrian.
`BA
`- Brilish Approved
`Belg - Belgian.
`b.p. -
`boiling point.
`BP - British Pharmacopoeia.
`Br - Bri1ish.
`Braz -
`Bra1ilian.
`B
`- British Standard ( pecification}.
`BSJ -
`British
`tandard" In titulion.
`cal -
`calorie(s).
`CAS - Chemical Abstract Service.
`CFC -
`chlorofluorocarbon.
`cm -
`cenLimeter(s).
`cm 2 -
`square centimeter(s).
`cm 3 -
`cubic centimcter(s).
`cmc -
`critical micclle concentrnlion.
`C S -
`central nervous ystem.
`cP -
`cenlipoise(s).
`cSt -
`centi toke( ).
`CTFA - Cosmetic, Toiletry. and Fragrance A ociation.
`D&C -
`designation applied in USA to dyes permiLted for
`use in drug and cosmetici,.
`DoH - Department of Health (UK).
`DSC -
`differential scanning calorimetry.
`EC - European Community,
`exemplil gratia, 'for example'.
`e.g. -
`et. al. -
`et a/ii, 'and others·.
`EU -
`European Union.
`Eur - European.
`FAQ -
`Food and Agriculture Organization of the United atio ns.
`FA0/WH0 -
`Food and Agriculture Organization of the United
`ations and the World Health Organization.
`FCC -
`Food Chemical Codex
`FDA -
`Food and Drug Administration of the USA.
`FD&C -
`de ignation applied in USA to dyes permitted for
`use in foods. drugs. and cosmetics.
`FFBE -
`Flat !'ace beveled edge.
`Fr -
`French.
`g -
`gram(s).
`Ger - German.
`GMP - Good Manufacturing Practice.
`generally recognized as safe by the Food and Drug
`GRAS -
`Adminimation of the USA.
`HC -
`hydrocarbon.
`HCFC -
`hydroehlorofluorocarhon .
`HFC -
`hydrofluorocarbon.
`HIV -
`human immunodeficiency virus.
`HLB -
`b.ydrophilic-lipophilic balance.
`
`Abbreviations xix
`
`onproprietary Name,
`
`HSE - Health and Safety Executive (UK).
`id est, ' that is'.
`i.e. -
`lM -
`illlramuscular.
`Ind. -
`Indian.
`!N
`-
`InlcmaLional
`lnL -
`International.
`IP -
`intraperitoneal.
`ISO -
`International Organization for Standardization.
`It -
`Italian.
`IV -
`intrnvenous.
`J -
`joulc(s).
`JP -
`Japanese Pharmacopeia.
`Jpn -
`Japanese.
`kcal -
`kilocalorie( ).
`kg -
`kilograrn(s).
`kJ -
`kilojoule(s).
`kPa -
`kilopascal (s).
`L -
`liler(s).
`Limu/us amoebocyte lysate.
`LAL -
`LC50 -
`a concentration in air lethal to 50% of the specified
`animals on inhalation.
`a dose lethal to 50% of the specified animal or
`LD 50 -
`microorganisms.
`lowest lethal dose for the specif:ied animals or mi-
`LdLo -
`croorgani ms.
`m - meter(s),
`m 2 -
`square meter(s).
`m3 -
`cubic meter( ).
`M- molar.
`max - maximum .
`MCA - Medicine Control Agency (UK).
`mg - milligram(s).
`MIC - minimum inhibitory concentration.
`min - minute( ) or minimum.
`mL - mHliliter(s).
`mm - millimeter(s).
`mM - millimolar.
`mm2 -
`quare millimeter( ).
`cubic millimeter(s).
`1111113 -
`mmHg - millimeter(s) of mercury.
`mmol - millimole(s).
`- millinewton(s),
`m
`mol - mole(s).
`m.p. - melting point.
`111Pa - millipascal(s).
`MPa - megapascal(s).
`µ g - mierogram(s).
`µm - micrometer(s) .
`-
`newton( ) or normal (concentration).
`eth -
`etherlands.
`nm -
`nanometer(s).
`ordic.
`o rd -
`o/w -
`oil-in-water.
`o/w/o -
`oil-in-waler-in-oil.
`Pa -
`pa cal( ).
`the negative logarithm of Lbe hydrngen ion concentra(cid:173)
`pH -
`tio n.
`PhEur -
`pK0 -
`
`European Pharmacopeia.
`the negative logarithm of the dissociation constant.
`
`FRESENIUS EXHIBIT 1022
`Page 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
`microphotograpb.
`SI -
`Statutory Instrument or Systeme International d'Unites
`(International System of Units).
`TPN -
`total parental □ utrition.
`
`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
`
`Tbe information below shows Imperial lo 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) = 0.101325 megapascal (MPa)
`I millimetre of mercury (mmHg) = 133.322 pascals (Pa)
`I pound per square inch (psi) = 6894.76 pascals (Pa)
`
`Area
`I square inch (in2) = 6.4516 x 10·4 square meter (m2)
`I square foot (ft2) = 9.29030 x I 0·2 square meter (m"2)
`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
`l ki localorie (kcal) = 4. I 840 x 103 joules (J)
`
`Force
`I dyne (dynes) = I x 10·5 newton (N)
`
`Length
`I angstrom (A.) = 10·10 meter (m)
`I inch (in) = 2.54 x 10·2 meter (m)
`I foot (ft) = 3.048 x 10· 1 meter (m)
`I yard (yd)= 9.144 x 10·1 meter (m)
`
`Surf ace tension
`I dyne per centimeter (dyne/cm) = I millinewton per meter
`(mN/m)
`
`Temperature
`I degree Fahrenhei1 (°F) = 5/9 degree Celsius (°C)
`
`Viscosity (dynamic)
`I centipoise (cP} = I millipascal second (mPa s)
`I poise (P) = 0.1 pascal second (Pa s)
`
`Viscosity (kinematic)
`l centistoke (cSt) = l square millimeter per second (mm2/s)
`
`Volume
`I cubic inch (in3) = 1.63871 x J0·5 cubic meter (m3)
`I cubic foot (ft3) = 2.83168 x 10·2 cub·ic meter (m3)
`I cubic yard (yd3) = 7.64555 x 10· 1 cubic mecer (m3)
`I pint (UK) = 5.68261 x lo-4 cubic meter (m3)
`1 pint (US)= 4.73 176 x 104 cubic meter (m3)
`I gallon (UK) = 4.54609 x I 0·3 cubic meter (m3)
`l gallon (US) = 3.78541 x 10·3 cubic meter (m3)
`
`FRESENIUS EXHIBIT 1022
`Page 8 of 24
`
`

`

`22U Ulycert11
`
`Glycerin
`
`onproprietary Names
`1.
`BP: Glycerol
`JP: Concentrated Glycerin
`Ph ur: Glycerolum
`USP: Glycerin
`
`2. Synonyms
`Croderol: E422: glycerine: G/yco11 G-100: Kemstre11e; Priceri11e;
`1.2,3-propanelriol; trihydro ypropanc glycerol.
`
`3. Chemical Name and CA Regi try umber
`Propane- 1.2,3-triol [56-8 J -5]
`
`4. Empirical Formula
`C3H 0 3
`
`Molecular Weight
`92.09
`
`5.
`
`tructural Formula
`
`H
`I
`H-C-OH
`I
`H-
`-OH
`I
`H-T-OH
`H
`
`6. Functional Category
`Antimicrobial pre. ervative: emollient: humectant: pla. ticizer;
`olvent: ·weetcning agent: tonicity agent.
`
`7. pplications in Pharmaceutical Formulation or
`Technology
`Glycerin i u. ed in a wide variety of pharmaceutical formulation~
`in luding oral, otic, ophthalmic, topical, and parcnteml preparations.
`It i also u d in co mctics and as a food additive.
`In topical pharmaceutical formulations and cosmcuc', glyc(cid:173)
`erin i u ed primarily for it humectant and emollient prop(cid:173)
`erties. In parenteral f rmulation glycerin i · mainly u ed a,
`a olvent.(I> In oral solutions glycerin is used as a ~olvent,
`weetening agent, antimicrobial pre ervative. and vi ·co ity(cid:173)
`increasing agent. Glycerin is also used a a pla ticizer of gel(cid:173)
`atin in the production of ·oft-gelatin capsule and gelatin . up(cid:173)
`po itorie . Glycerin i~ additionally employed a a therapeutic
`agent in a varie ty of clinical application·.
`
`se
`
`Concentration ( % )
`
`Antimicrobial preservative
`Emollient
`Humectant
`Ophthalmic formulation
`Plastici,er in tabkt film coating
`olvent for parenteral formulations
`weetening agent in alcoholic elixirs
`
`> 20
`Up to 30
`Up 10 30
`0.5-3.0
`Variable
`Up 10 50
`Up to 20
`
`8. D cription
`
`Glycerin i a clear, colorle s, odorle s, vi cou , hygroscopic
`liquid; it ha a sweet taste, approximately 0.6 time a weet
`as ucro!>e.
`
`9. Pharmacopeial pecifications
`
`Te t
`
`JP
`
`PhEur
`
`SP
`
`Identification
`Characters
`pecific gravity
`olor
`Appearance of olution
`Acidity or alkalinity
`Refractive index
`Residue on ignition
`Sulfated ash
`Chloride
`Ammonium
`Calcium
`ulfatc
`Ar enic
`I le.ivy metals
`Chlorinated compounds (as Cl)
`Organic vola1ile impurities
`Aldehydes
`1\crolein. glucose and other
`reducing . ub t:inccs
`Fatly acids and ester.
`Readily carbonizable
`substances
`ugars
`Water
`A say
`
`+
`+
`l.221 - 1.230
`+
`
`+
`
`+
`
`+
`1.449-1.454 1.470-1.475
`$ 0.01%
`
`$0.0 1%
`$ 10 ppm
`
`$ 5 ppm
`+
`
`+
`
`+
`+
`
`$ 0.001%
`+
`+
`$ 0.002%
`$ 2 ppm
`$ 5 ppm
`
`+
`+
`+
`
`+
`+
`;;: 1.249
`+
`
`+
`
`$ 0.01%
`
`s 0.OOl'l!c
`
`$ 0.002%
`$ 1.5 ppm
`$ 5 ppm
`$ 0.003%
`+
`
`+
`
`+
`$2.0%
`98-101 %
`
`$ 5.0%
`99-101%
`
`4%- 7o/c
`
`10. Typical Propertie
`Boiling point: 290°C (with de ompo ition)
`Den ity:
`1.2656 g/cm3 at I 5°C;
`1.2636 g/cm 3 at 20°C;
`1.2620 g/cm 3 at 25°C.
`Flash point: I 76°C (open cup)
`Free·i11g point:
`
`oncentration of aqueou
`glycerin ·olution (% w/w)
`
`Freezing point
`(OC)
`
`10
`20
`30
`40
`50.
`60
`66.7
`80
`90
`
`-1.6
`-4.8
`-9.5
`-15.4
`-23
`-34.7
`-46.5
`-20.3
`-1.6
`
`Hygro copicity: hygroscopic.
`Melling point: 17. °C
`0 molarity: a 2.6% v/v aqueou
`. erum.
`
`olution i
`
`i o-o motic with
`
`FRESENIUS EXHIBIT 1022
`Page 9 of 24
`
`

`

`Refractive index:
`n0 15 = 1.4758;
`n0 20 = 1.4746;
`n0 25 = 1.4730.
`Solubility:
`
`Solvent
`
`Acct ne
`BenLene
`Chloroform
`thanol (95~ )
`Ether
`thyl acetate
`Methanol
`Oils
`Water
`
`Specific gravity:
`
`olubilit at 20°c
`
`Slightly soluble
`Practically insoluble
`Practically in oluble
`Soluble
`I in 500
`I in 11
`Soluble
`Practically insoluble
`Soluble
`
`oncentration of aqueous
`glycerin olution (% w/w)
`
`pecific gravity
`at 20°c
`
`10
`20
`30
`40
`50
`60
`
`1.024
`1.049
`1.075
`I.IOI
`1. 128
`1. 156
`
`Surface tension:
`63.4 m Im (63.4 dyne. /cm) at 20°C.
`Vapor density (relarive): 3. I 7 (air = I)
`Viscosity (