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`735
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`
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`
`
`
`lHandbook 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
`
`AC?
`
`American Pharmaceutical Association
`
`Washington, D.C.
`
`(RP)
`Apotex (1PR20’l‘63‘00‘4’00) EX. 1045 p. 001
`London, United Kingdom
`
`Apotex (IPR2019-00400) Ex. 1045 p. 001
`
`

`

`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 SE1 7JN, UK
`www.pharmpress.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 / edited by Arthur H. Kibbe.--3rd ed.
`p.
`; cm.
`Includes bibliographical references and index.
`ISBN 0-917330—96—X
`l. Excipients--Handbooks, manuals, etc.
`Pharmaceutical Association.
`
`I. Kibbe, Arthur H. II. American
`
`[DNLMz 1. Excipients--Handbooks. QV 735 H236 2000]
`RS201.E87 H36 2000
`615'.19--dc21
`
`A catalogue record for this book is available from the British Library.
`
`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: Melanie Segala
`Copyeditor:
`Paul Gottehrer
`Indexer:
`Lillian Rodberg
`Compositor:
`Roy Bamhill
`Cover Designer:
`Tim Kaage
`
`Apotex (11311201900400) EX. 1045 p. 002
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`
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`

`

`
`
`Contents
`
`v
`
`Contents
`
`Committees
`Contributors
`Additions to the Third Edition
`Related Substances
`Preface
`Acknowledgments
`Notice to Readers
`
`Selected Bibliography
`Abbreviations
`Units of Measurement
`
`Monographs
`Acacia
`Acesulfame Potassium
`Albumin
`{Alcohol
`Alginic Acid
`Aliphatic Polyesters
`Alpha Tocopherol
`Ascorbic Acid
`Ascorbyl Palmitate
`Aspartame
`Bentonite
`Benzalkonium Chloride
`Benzethonium Chloride
`Benzoic Acid
`
`Benzyl Alcohol
`Benzyl Benzoate
`Bronopol
`Butylated Hydroxyanisole
`Butylated Hydroxytoluene
`B utylparab en
`/Calcium Carbonate
`
`Calcium Phosphate, Dibasic Anhydrous
`Calcium Phosphate, Dibasic Dihydrate
`Calcium Phosphate, Tribasic
`Calcium Stearate
`Calcium Sulfate
`Canola Oil
`Carbomer
`Carbon Dioxide
`
`\r
`
`Carboxymethylcellulose Calcium
`Carboxymethylcellulose Sodium
`V'Carrageenan
`Castor Oil, Hydrogenated
`Cellulose Acetate
`Cellulose Acetate Phthalatc
`Cellulose, Microcrystalline
`Cellulose, Powdered
`Cellulose, Silicified Microcrystalline
`Cetostearyl Alcohol
`Cetrimide
`
`Cetyl Alcohol
`Chlorhexidine
`Chlorobutanol
`Chlorocresol
`Chlorodifluoroethane (HCFC)
`Chlorofiuorocarbons (CFC)
`
`vii
`ix
`xii
`xiii
`xv
`xvii
`xviii
`xviii
`xix
`xx
`
`Cholesterol
`
`Citric Acid Monohydrate
`Colloidal Silicon Dioxide
`
`Coloring Agents
`\/ Corn Oil
`Cottonseed Oil
`Cresol
`Croscarmellose Sodium
`Crospovidone
`Cyclodextrins
`Dextrates
`Dextrin
`V/Dextrose
`Dibutyl Sebacate
`Diethanolamine
`Diethyl Phthalate
`Difluoroethane (HFC)
`Dimethyl Ether
`Docusate Sodium
`Edetic Acid
`
`Ethylcellulose
`Ethyl Maltol
`Ethyl Oleate
`Ethylparaben
`Ethyl Vanillin
`., Fructose
`Fumaric Acid
`
`L/(G'elatin
`V Glucose, Liquid
`1.. 'Glycerin
`Glyceryl Monooleate
`Glyceryl Monostearate
`Glyceryl Palmitostearate
`Glycofurol
`Guar Gum
`
`Heptafluoropropane (HFC)
`Hydrocarbons (HC)
`Hydrochloric Acid
`Hydroxyethyl Cellulose
`HydroxyprOpyl Cellulose
`Hydroxypropyl Cellulose, Low-substituted
`"Hydroxypropyl Methylcellulose
`Hydroxypropyl Methylcellulose Phthalate
`Imidurea
`
`Isopropyl Alcohol
`Isopropyl Myristate
`Isopropyl Palmitate
`Kaolin
`‘ "Lactic Acid
`Lactitol
`V”Lactose
`Lanolin
`Lanolin Alcohols
`Lanolin, Hydrous
`Lecithin
`
`Magnesium Aluminum Silicate
`Magnesium Carbonate
`Magnesium Oxide
`Magnesium Stearate
`Magnesium Trisilicate
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`99
`102
`107
`110
`112
`114
`117
`121
`126
`129
`132
`134
`
`138
`140
`143
`146
`154
`156
`158
`160
`163
`165
`169
`172
`175
`178
`180
`1 82
`184
`186
`188
`191
`195
`201
`203
`205
`208
`210
`213
`215
`218
`220
`223
`225
`228
`230
`232
`234
`236
`238
`240
`244
`249
`252
`256
`261
`263
`265
`267
`269
`272
`274
`276
`286
`288
`290
`292
`295
`299
`303
`305
`309
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`

`vi Contents
`
`Malic Acid
`Maltitol
`Maltitol Solution
`‘: Maltodextrin
`
`, Maltol
`‘2," Maltose
`Mannitol
`
`Medium Chain Triglycerides
`Meglumine
`Menthol
`
`Methylcellulose
`Methylparaben
`V Mineral Oil
`Mineral Oil, Light
`Mineral Oil and Lanolin Alcohols
`Monoethanolamine
`
`Nitrogen
`Nitrous Oxide
`Oleic Acid
`Paraffin
`
`\/ Peanut Oil
`Petrolatum
`Petrolatum and Lanolin Alcohols
`Phenol
`
`Phenoxyethanol
`Phenylethyl Alcohol
`Phenylmercuric Acetate
`Phenylmercuric Borate
`Phenylmercuric Nitrate
`Polacrilin Potassium
`Poloxamer
`
`Polydextrose
`Polyethylene Glycol
`Polyethylene Oxide
`Polymethacrylates
`Polyoxyethylene Alkyl Ethers
`Polyoxyethylene Castor Oil Derivatives
`Polyoxyethylene Sorbitan Fatty Acid Esters
`Polyoxycthylene Stearates
`Polyvinyl Alcohol
`Potassium Chloride
`Potassium Citrate
`Potassium Sorbate
`Povidone
`
`Propylene Carbonate
`Propylene Glycol
`Propylene Glycol Alginate
`Propyl Gallate
`Propylparaben
`Saccharin
`Saccharin Sodium
`:rSesame Oil
`Shellac
`
`\. Sodium Alginate
`
`311
`313
`315
`317
`
`320
`322
`324
`329
`332
`334
`336
`340
`345
`347
`
`349
`350
`352
`354
`356
`358
`360
`
`362
`365
`367
`370
`372
`374
`377
`379
`383
`386
`389
`392
`399
`401
`407
`412
`
`416
`420
`
`424
`426
`429
`431
`433
`440
`442
`445
`447
`450
`454
`457
`
`460
`462
`465
`
`Sodium Ascorbate
`Sodium Benzoate
`Sodium Bicarbonate
`Sodium Chloride
`
`Sodium Citrate Dihydrate
`_, Sodium Cyclamate
`V" Sodium Lauryl Sulfate
`Sodium Metabisulfite
`Sodium Phosphate, Dibasic
`Sodium Phosphate, Monobasic
`Sodium Propionate
`Sodium Starch Glycolate
`Sodium Stearyl Fumarate
`\/ Sorbic Acid
`
`Sorbitan Esters (Sorbitan Fatty Acid Esters)
`Sorbitol
`V’Soybean Oil
`\,vStarCh
`L‘Starch, Pregelatinized
`‘xStarch, Sterilizable Maize
`Stearic Acid
`
`Stearyl Alcohol
`Sucrose
`Sugar, Compressible
`Sugar, Confectioner's
`\/Sugar Spheres
`xlSuppository Bases, Hard Fat
`L/Talc
`Tartaric Acid
`Tetrafluoroethane (HFC)
`Thimerosal
`Titanium Dioxide
`Tragacanth
`Triacetin
`Triethanolamine
`Triethyl Citrate
`Vanillin
`
`Vegetable Oil, Hydrogenated, Type I
`Water
`
`Wax, Anionic Emulsifying
`Wax, Carnauba
`Wax, Cetyl Esters
`Wax, Microcrystalline
`Wax, Nonionic Emulsifying
`Wax, White
`Wax, Yellow
`Xanthan Gum
`Xylitol
`Zein
`Zinc Stearate
`
`Appendix I: Suppliers’ Directory
`Appendix II: HPE Laboratory Methods
`Index
`
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`468
`471
`474
`478
`482
`485
`487
`490
`493
`496
`498
`501
`505
`508
`511
`515
`519
`522
`528
`531
`534
`537
`539
`544
`546
`548
`550
`555
`558
`560
`562
`565
`568
`570
`572
`574
`576
`578
`580
`585
`587
`589
`591
`593
`595
`597
`599
`602
`606
`608
`
`611
`64]
`645
`
`
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`

`UK Steering Committee
`
`vii
`
`
`
`UK Steering
`Committee
`
`Colin G Cable
`Royal Pharmaceutical Society of Great Britain
`Edinburgh, UK
`
`M Jayne Lawrence
`King‘s College London
`London, UK
`
`Andy Dundon
`Glaxo Wellcome
`Ware, UK
`
`Roger Guest
`SmithKIine Beecham Pharmaceuticals
`
`Crawley, UK
`
`John E Hogan
`
`Pfizer Ltd
`Sandwich, UK
`
`J Mike Newton
`School of Pharmacy; University of London
`London, UK
`
`Ray C Rowe
`Astra Zeneca Pharmaceuticals
`Macclesfield, UK
`
`'
`Amley Wade
`Bath, UK
`
`Paul J Weller
`Royal Pharmaceutical Society of Great Britain
`London, UK
`
`Apotex (IPR2019-00400) EX. 1045 p. 005
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`

`

`Glycerin
`
`1 Nonproprietary Names
`BP: Glycerol
`JP: Concentrated glycerin
`PhEur: Glycerolum
`USP: Glycerin
`
`2 Synonyms
`Croderol; E422; glycerine; Glycon G-100; Kemstrene; Optim;
`Pricerine; 1,2,3-propanetriol; trihydroxypropane glycerol.
`
`3 Chemical Name and CAS Registry Number
`Propane-l,2,3-triol [56-81-5]
`
`4 Empirical Formula
`C3H8O3
`
`Molecular Weight
`92.09
`
`6 Functional Category
`Antimicrobial preservative; emollient; humectant; plasticizer;
`solvent; sweetening agent; tonicity agent.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Glycerin is used in a wide variety of pharmaceutical formula­
`tions including oral, otic, ophthalmic, topical, and parenteral
`preparations; see Table I.
`In topical pharmaceutical formulations and cosmetics,
`glycerin is used primarily for its humectant and emollient
`properties. In parenteral formulations, glycerin is used mainly
`as a solvent/1’
`In oral solutions, glycerin is used as a solvent, sweetening
`agent, antimicrobial preservative, and viscosity-increasing
`agent. It is also used as a plasticizer and in film coatings.*2’1'
`Glycerin is additionally used in topical formulations such as
`creams and emulsions/4’
`Glycerin is used as a plasticizer of gelatin in the production
`of soft-gelatin capsules and gelatin suppositories.
`Glycerin is employed as a therapeutic agent in a variety of
`clinical applications/5’ and is also used as a food additive.
`
`Use
`
`Concentration (%)
`
`Antimicrobial preservative
`Table I: Uses of glycerin.
`Emollient
`Humectant
`Ophthalmic formulations
`Plasticizer in tablet film coating
`Solvent for parenteral formulations
`Sweetening agent in alcoholic elixirs
`
`<20
`<30
`<30
`O.5A3.O
`Variable
`<50
`<20
`
`8 Description
`Glycerin is a clear, colorless, odorless, viscous, hygroscopic
`liquid; it has a sweet taste, approximately 0.6 times as sweet as
`sucrose.
`
`9 Pharmacopeia! Specifications
`See Table II. See also Section 18.
`
`Table II: Pharmacopeial specifications for glycerin.
`
`Test
`
`JP 2001
`
`PhEur 2002
`
`USP 25
`
`+
`+
`—
`+
`+
`+
`—
`+
`1.470-1.475 —
`—
`+
`—
`+
`—
`+
`—
`+
`
`+
`Identification
`Characters
`+
`Appearance of solution
`+
`+
`Acidity or alkalinity
`Refractive index
`< 1.470
`—
`Aldehydes
`—
`Related substances
`Halogenated compounds —
`—
`Limit of chlorinated
`compounds
`Sugars
`+
`—
`Chloride
`<0.001% <10 ppm
`Heavy metals
`<5 ppm
`<5 ppm
`—
`Water
`<2.0%
`Sulfated ash
`<0.01% <0.01%
`Specific gravity
`—
`>1.258
`<0.002% —
`Sulfate
`—
`+
`Ammonium
`—
`+
`Calcium
`—
`<2 ppm
`Arsenic
`—
`Acrolein, glucose or other +
`reducing substances
`Fatty acids and esters
`Organic volatile
`impurities
`Readily carbonizable
`substances
`Assay
`
`+
`—
`
`+
`
`+
`—
`
`—
`
`—
`<0.001%
`<5 ppm
`<5.0%
`<0.01%
`> 1.249
`<0.002%
`—
`—
`—
`—
`
`+
`+
`
`—
`
`257
`
`>98.0% 98.0-101.0% 99.0-101.0%
`
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`

`258 Glycerin
`
`10 Typical Properties
`Boiling point: 290°C (with decomposition)
`Density:
`1.2656g/cm3 at 15°C
`1.2636 g/cm3 at 20°C
`1.2620 g/cm3 at 25°C
`Flash point: 176°C (open cup)
`Freezing point: see Table III.
`Hygroscopicity: hygroscopic.
`Melting point: 17.8°C
`Osmolarity: a 2.6% v/v aqueous solution is isoosmotic with
`serum.
`Refractive index:
`= 1.4758
`= 1.4746
`nls = 1.4730
`Solubility: see Table IV.
`Specific gravity: see Table V.
`Surface tension: 63.4 mN/m (63.4dynes/cm) at 20°C.
`Vapor density (relative): 3.17 (air = 1)
`Viscosity (dynamic): see Table VI.
`
`Table III: 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 1 1
`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
`1.311
`2.095
`6.05
`10.96
`22.94
`111.0
`
`11 Stability and Storage Conditions
`Glycerin is hygroscopic. Pure glycerin is not prone to oxidation
`by the atmosphere under ordinary storage conditions but it
`decomposes on heating, with the evolution of toxic acrolein.
`Mixtures of glycerin with water, ethanol, and propylene glycol
`are chemically stable.
`Glycerin may crystallize if stored at low temperatures; the
`crystals do not melt until warmed to 20°C.
`Glycerin should be stored in an airtight container, in a cool,
`dry place.
`
`12
`Incompatibilities
`Glycerin may explode if mixed with strong oxidizing agents
`such as chromium trioxide, potassium chlorate, or potassium
`permanganate. In dilute solution, the reaction proceeds at a
`slower rate with several oxidation products being formed.
`Black discoloration of glycerin occurs in the presence of
`light, or on contact with zinc oxide or basic bismuth nitrate.
`An iron contaminant in glycerin is responsible for the
`darkening in color of mixtures containing phenols, salicy­
`lates, and tannin.
`Glycerin forms a boric acid complex, glyceroboric acid, that
`is a stronger acid than boric acid.
`
`13 Method of Manufacture
`Glycerin is mainly obtained from oils and fats as a by-product
`in the manufacture of soaps and fatty acids. It may also be
`obtained from natural sources by fermentation of, for exam­
`ple, sugar beet molasses in the presence of large quantities of
`sodium sulfite. Synthetically, glycerin may be prepared by the
`chlorination and saponification of propylene.
`
`14 Safety
`Glycerin occurs naturally in animal and vegetable fats and oils
`that are consumed as part of a normal diet. Glycerin is readily
`absorbed from the intestine and is either metabolized to carbon
`dioxide and glycogen or used in the synthesis of body fats.
`Glycerin is used in a wide variety of pharmaceutical
`formulations including oral, ophthalmic, parenteral, and topi­
`cal preparations. Adverse effects are mainly due to the dehy­
`drating properties of glycerin.(5>
`Oral doses are demulcent and mildly laxative in action.
`Large doses may produce headache, thirst, nausea, and hyper­
`glycemia. The therapeutic parenteral administration of very
`large glycerin doses, 70-80 g over 30-60 minutes in achilts to
`reduce cranial pressure, may induce hemolysis, hemoglobin­
`uria, and renal failure.<6) Slower administration has no deleter­
`ious effects.(7)
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`

`Glycerin may also be used orally in doses of 1.0-1.5g/kg
`body-weight to reduce intraocular pressure.
`When used as an excipient or food additive, glycerin is not
`usually associated with any adverse effects and is generally
`regarded as a nontoxic and nonirritant material.
`LD50 (guinea pig, oral): 7.75 g/kg<8)
`LD5o (mouse, IP): 8.98 g/kg
`LD50 (mouse, IV): 4.25 g/kg
`LD50 (mouse, oral): 4.1 g/kg
`LD50 (mouse, SC): 0.09 g/kg
`LD50 (rabbit, IV): 0.05 g/kg
`LD50 (rat, IP): 4.42 g/kg
`LD50 (rat, oral): 12.6 g/kg
`LD5o (rat, SC): 0.1 g/kg
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Eye protection and gloves
`are recommended. In the UK, the recommended long-term (8-
`hour TWA) exposure limit for glycerin mist is 10mg/m3.(9)
`Glycerin is combustible and may react explosively with strong
`oxidizing agents; see Section 12.
`
`16 Regulatory Status
`GRAS listed. Accepted as a food additive in Europe. Included
`in the FDA Inactive Ingredients Guide (inhalations; injections;
`nasal and ophthalmic preparations; oral capsules, solutions,
`suspensions and tablets; otic, rectal, topical, transdermal, and
`vaginal preparations). Included in nonparenteral and parent­
`eral medicines licensed in the UK.
`
`17 Related Substances
`
`Glycerin
`
`259
`
`19 Specific References
`1 Spiegel AJ, Noseworthy MM. Use of nonaqueous solvents in
`parenteral products. J Pharm Sci 1963; 52: 917-927.
`2 Kumar V, Kang J, Yang T. Preparation and characterization of
`spray-dried oxidized cellulose particles. Pharm Dev Technol 2001;
`6(3): 449^58.
`3 Palviainen P, Heinamaki J, Myllarinen P, et al. Corn starches as
`film formers in aqueous-based film coating. Pharm Dev Technol
`2001; 6(3): 353-361.
`4 Viegas TX, Van-Winkle LL, Lehman PA, et al. Evaluation of
`creams and ointments as suitable formulations for peldesine. Int J
`Pharm 2001; 219(1-2): 73-80.
`5 Sweetman SC, ed. Martindale: The Complete Drug Reference,
`33rd edn. London: Pharmaceutical Press, 2002: 1616-1617.
`6 Hagnevik K, Gordon E, Lins LE, et al. Glycerol-induced
`haemolysis with haemoglobinuria and acute renal failure. Lancet
`1974; i: 75-77.
`7 Welch KMA, Meyer JS, Okamoto S, et al. Glycerol-induced
`haemolysis. Report of three cases, [letter]. Lancet 1974; 1(7847):
`416-417.
`8 8, Lewis RJ, ed. Sax’s Dangerous Properties of Industrial
`Materials, 10th edn. New York: Wiley, 2000: 1874—1875.
`9 Health and Safety Executive. EH40/2002: Occupational Exposure
`Limits 2002. Sudbury: Health and Safety Executive, 2002.
`
`20 General References
`Grissom CB, Chagovetz AM, Wang Z. Use of viscosigens to stabilize
`vitamin Bj? solutions against photolysis. ] Pharm Sci 1993; 82(6):
`641-643.
`Jungermann E, Sonntag NOV, eds. Glycerine: A Key Cosmetic
`Ingredient. New York: Marcel Dekker, 1991.
`Smolinske SC. Handbook of Food, Drug, and Cosmetic Excipients.
`Boca Raton, FL: CRC Press, 1992: 199-204.
`Staples R, Misher A, Wardell J. Gastrointestinal irritant effect of
`glycerin as compared with sorbitol and propylene glycol in rats
`and dogs. J Pharm Sci 1967; 56: 398-400.
`
`18 Comments
`The EINECS number for glycerin is 200-289-5.
`Some pharmacopeias also contain specifications for diluted
`glycerin solutions. The JP 2001 contains a monograph for
`‘glycerin’ that contains 84-87% of propane-l,2,3-triol
`(CjHgOs). The PhEur 2002 contains a monograph for
`‘glycerol 85 per cent’ that contains 83.5-88.5% of propane-
`1,2,3-triol (CsHgOs).
`
`21 Author
`JC Price.
`
`22 Date of Revision
`8 October 2002.
`
`Apotex (IPR2019-00400) Ex. 1045 p. 008
`
`