QV
`BS
`H236
`BLOO
`
`
`
`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
`
`S
`
`American Pharmaceutical Association
`Washington, D.C.
`
`(PP)
`
`Pharmaceutical Press
`
`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 SE] 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.
`; em.
`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--de21
`
`I. Kibbe, Arthur H. II. American
`
`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:
`Pau! Gottehrer
`Indexer:
`Lillian Rodberg
`Compositor:
`Roy Barnhill
`Cover Designer:
`Tim Kaage
`
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`

`

`
`
`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
`Butylparaben
`\Calcium Carbonate
`Calcium Phosphate, Dibasic Anhydrous
`Calcium Phosphate, Dibasic Dihydrate
`Calcium Phosphate, Tribasic
`Calcium Stearate
`Calcium Sulfate
`\; Canola Oil
`Carbomer
`Carbon Dioxide
`Carboxymethylcellulose Calcium
`Carboxymethylcellulose Sodium
`\/Carrageenan
`Castor Oil, Hydrogenated
`Cellulose Acetate
`Cellulose Acetate Phthalate
`Cellulose, Microcrystalline
`Cellulose, Powdered
`Cellulose, Silicified Microcrystalline
`Cetostearyl Alcohol
`Cetrimide
`Cetyl Alcohol
`Chlorhexidine
`Chlorobutanol
`Chlorocresol
`Chlorodifluoroethane (HCFC)
`Chlorofluorocarbons (CFC)
`
`vii
`ix
`xli
`xiii
`XV
`xvii
`XVili
`XViii
`X1X
`XX
`
`77
`79
`83
`85
`87
`91
`94
`96
`99
`102
`107
`110
`112
`114
`117
`121
`126
`129
`132
`134
`
`Cholesterol
`Citric Acid Monohydrate
`Colloidal Silicon Dioxide
`Coloring Agents
`y Corn Oil
`Cottonseed Oil
`Cresol
`Croscarmellose Sodium
`Crospovidone
`Cyclodextrins
`Dextrates
`Dextrin
`Dextrose
`Dibutyl Sebacate
`Diethanolamine
`Diethyl Phthalate
`Difiuoroethane (HFC)
`Dimethyl Ether
`Docusate Sodium
`Edetic Acid
`Ethylcellulose
`Ethyl Maltol
`Ethyl! Oleate
`Ethylparaben
`Ethyl Vanillin
`~ Fructose
`Fumaric Acid
`\-Gelatin
`\Glucose, Liquid
`\-Glycerin
`Glyceryl Monooleate
`Glyceryl Monostearate
`Glyceryl Palmitostearate
`Glycofurol
`Guar Gum
`Heptafluoropropane (HFC)
`Hydrocarbons (HC)
`Hydrochloric Acid
`Hydroxyethyl Cellulose
`Hydroxypropy! Cellulose
`Hydroxypropyl Cellulose, Low-substituted
`vy Hydroxypropyl Methylcellulose
`Hydroxypropy! Methylcellulose Phthalate
`Imidurea
`Isopropyl Alcohol
`Isopropyl Myristate
`Isopropyl Palmitate
`Kaolin
`“Lactic Acid
`Lactitol
`“Lactose
`Lanolin
`Lanolin Alcohols
`Lanolin, Hydrous
`Lecithin
`Magnesium Aluminum Silicate
`Magnesium Carbonate
`Magnesium Oxide
`Magnesium Stearate
`Magnesium Trisilicate
`
`Contents
`
`y
`
`138
`
`299
`303
`305
`309
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`

`vi Contents
`
`468
`Sodium Ascorbate
`311
`Malic Acid
`471
`Sodium Benzoate
`313
`Maltitol
`474
`Sodium Bicarbonate
`315
`Maltitol Solution
`478
`Sodium Chloride
`317
`‘, Maltodextrin
`482
`Sodium Citrate Dihydrate
`320
`, Maltol
`485
`_ Sodium Cyclamate
`322
`~j Maltose
`487
`| Sodium Lauryl Sulfate
`324
`Mannitol
`490
`Sodium Metabisulfite
`329
`Medium Chain Triglycerides
`493
`Sodium Phosphate, Dibasic
`332
`Meglumine
`496
`Sodium Phosphate, Monobasic
`334
`Menthol
`498
`Sodium Propionate
`336
`Methylcellulose
`501
`Sodium Starch Glycolate
`340
`Methylparaben
`505
`Sodium Stearyl Fumarate
`345
`VY Mineral Oil
`508
`\ Sorbie Acid
`347
`Mineral Oil, Light
`511
`Sorbitan Esters (Sorbitan Fatty Acid Esters)
`349
`Mineral Oil and Lanolin Alcohols
`515
`Sorbitol
`350
`Monoethanolamine
`519
`Soybean Oil
`352
`- Nitrogen
`
`
`Nitrous Oxide 354=\y Starch 522
`Oleic Acid
`356
`VStarch, Pregelatinized
`528
`Paraffin
`358
`‘Starch, Sterilizable Maize
`531
`\y Peanut Oil
`360
`Stearic Acid
`534
`Petrolatum
`362
`Stearyl Alcohol
`537
`Petrolatum and Lanolin Alcohols
`365
`Sucrose
`539
`Phenol
`367
`Sugar, Compressible
`544
`Phenoxyethanol
`370
`Sugar, Confectioner’s
`546
`
`
`Phenylethyl Alcohol 372~~\Sugar Spheres 548
`
`
`Phenylmercuric Acetate 374~~~,Suppository Bases, Hard Fat 550
`Phenylmercuric Borate
`377
`ale
`S32
`Phenylmercuric Nitrate
`379
`Tartaric Acid
`558
`Polacrilin Potassium
`383
`Tetrafluoroethane (HFC)
`560
`Poloxamer
`386
`Thimerosal
`562
`Polydextrose
`389
`Titanium Dioxide
`565
`Polyethylene Glycol
`392
`Tragacanth
`568
`Polyethylene Oxide
`399
`Triacetin
`570
`Polymethacrylates
`401
`Triethanolamine
`572
`Polyoxyethylene Alkyl Ethers
`407
`Triethy! Citrate
`574
`Polyoxyethylene Castor Oil Derivatives
`412
`Vanillin
`576
`Polyoxyethylene Sorbitan Fatty Acid Esters
`416
`Vegetable Oil, Hydrogenated, Type I
`578
`Polyoxyethylene Stearates
`420
`Water
`580
`Polyvinyl! Alcohol
`424
`Wax, Anionic Emulsifying
`585
`Potassium Chloride
`426
`Wax, Carnauba
`587
`Potassium Citrate
`429
`Wax, Cetyl Esters
`589
`Potassium Sorbate
`431
`Wax, Microcrystalline
`591
`Povidone
`433
`Wax, Nonionic Emulsifying
`593
`Propylene Carbonate
`440
`Wax, White
`595
`Propylene Glycol
`442
`Wax, Yellow
`397
`Propylene Glycol Alginate
`445
`Xanthan Gum
`599
`Propyl Gallate
`447
`Xylitol
`602
`Propylparaben
`450
`Zein
`606
`Saccharin
`454
`Zinc Stearate
`608
`‘ Saccharin Sodium
`457
`‘,Sesame Oil
`460
`Shellac
`462
`s, Sodium Alginate
`465
`
`Appendix I: Suppliers’ Directory
`Appendix I]: HPE Laboratory Methods
`Index
`
`611
`641
`645
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`

`UKSteering Committee
`
`vii
`
`
`
`UKSteering
`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
`SmithKline 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
`
`Ainley Wade
`Bath, UK
`
`Paul J Weller
`Royal Pharmaceutical Society of Great Britain
`London, UK
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`

`Cyclodextrins
`
`
`
`
`1. Nonproprietary Names
`
`BP: Beta cyclodextrin
`PhEur: Betacyclodextrinun
`USP: Beta cyclodextrin
`Note: B-cyclodextrin is the only cyclodextrin to be currently
`described in a pharmacopeia. Alfadex is the rINN for a-cy-
`clodextrin and betadex is the pINN for B-cyclodextrin.
`
`2. Synonyms
`Cyclodextrin: Cavitron; cyclic oligosaccharide; cycloamylose;
`cycloglucan; Encapsin, Rhodocap, Schardinger dextrin.
`o-Cyclodextrin: alfadex; alpha-cycloamylose; alpha-cyclodex-
`trin; alpha-dextrin; cyclohexaamylose; cyclomaltohexose.
`B-Cyclodextrin: beta-cycloamylose; betadex; beta-dextrin; cy-
`cloheptaamylose; cycloheptagluean; cyclomaltoheptose; Klep-
`tose.
`
`y-Cycylodextrin: cyclooctaamylose; gamma cyclodextrin,
`Gamma Ws.
`
`Cyclodextrins
`
`165
`
`6. Functional Category
`
`Stabilizing agent; solubilizing agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`
`Cyclodextrins are crystalline, nonhygroscopic, cyclic oli-
`gosaccharides derived from starch. Among the most common-
`ly used forms are a-, B-, and y-cyclodextrin which have
`respectively 6, 7, and 8 glucose units, see Section 5. Substi-
`tuted cyclodextrin derivatives are also available, see Section
`18.
`
`In shape, cyclodextrins are ‘bucket-like’ or ‘cone-like’, toroid
`molecules. They thus have a rigid structure with a central
`cavity whose size varies according to the cyclodextrin type,
`see Section 8. Due to the arrangement of hydroxy] groups
`within the molecule the internal surface of the cavity is hy-
`drophobic while the outside of the torus is hydrophilic. This
`arrangement permits the cyclodextrin to accommodate a guest
`molecule within the cavity so forming an inclusion complex.
`Cyclodextrins may thus be used to form inclusion complexes
`with a variety of drug molecules resulting primarily in im-
`provements to dissolution and bioavailability due to enhanced
`solubility and improved chemical and physical stability, see
`Section 19.
`
`
`
`3. Chemical Name and CASRegistry Number
`
`a-Cyclodextrin: [10016-20-3]
`B-Cyclodextrin: [7585-39-9]
`y-Cyclodextrin: [17465-86-0]
`
`Cyclodextrin inclusion complexes have also been used to
`mask the unpleasant taste of active materials and to convert
`a liquid substance into a solid material.
`f-Cyclodextrin is the most commonly used cyclodextrin al-
`though it is the least soluble, see Section 10. It is the least
`expensive cyclodextrin, is commercially available from a num-
`4. Empirical Formula Molecular Weight
`ber of sources, and is able to form inclusion complexes with
`a number of molecules of pharmaceutical interest. However,
`a-Cyclodextrin: C36H¢9039
`+972
`f-cyclodextrin should not be used in parenteral formulations
`B-Cyclodextrin: Cy,H79035
`$135
`since it is nephrotoxic, see Section 14. f-Cyclodextrin is con-
`y-Cyclodextrin: CygHgoO49+:1297
`sidered to be nontoxic when administered orally and hits thus
`become primarily used in tablet and capsule formulations.
`8-Cyclodextrin derivatives tend to be nontoxic when used either
`orally or parenterally and the derivatives 2-hydroxypropyl-f-cyclo-
`dextrin and 3-hydroxypropyl-B-cyclodextrin are becoming of
`increasing importance in pharmaceutical formulations.)
`o-Cyclodextrin is mainly used in parenteral formulations, al-
`though since it has the smallest cavity of the cyclodextrins it
`ean only form inclusion complexes with relatively few, small
`sized molecules.
`In contrast, y-cyclodextrin has the largest
`cavity and can be used to form inclusion complexes with large
`molecules, Current availability of y-cyclodextrin (Gamma W8)
`makes it an excellent choice because of its low toxicity and
`enhanced water solubility.
`In oral tablet formulations B-cyclodextrin may be usedin both
`wet granulation and direct compression processes, While the
`physical properties of [j-cyclodextrin vary from manufacturer
`to manufacturer, B-cyclodextrin tends to possess poor flow
`properties and requires a lubricant, such as 0.1% w/w mag:
`nesium stearate, whenit is directly compressed.”
`R’ R’”
`-H for ‘natural’ o-, B- and y-cyclodextrins
`;
`In parenteral
`formulations, cyclodextrins have been used to
`produce stable and soluble preparations of drugs that would
`R’, R” = -CH;, for methyl cyclodextrins
`R’, R”=-CHOHCH,;for hydroxyethyl cyclodextrins
`otherwise have been formulated using a nonaqueous solvent.
`R’, R” = -CH,CHOHCH; for 2-hydroxypropyl cyclodextrins
`Cyclodextrins have also been used in the formulation of so-
`lutions,®9 suppositories,“°' and cosmetics.
`Note: structure of B-cyclodextrin (7 glucose units) shown,
`
`5. Structural Formula
`
`
`
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`
`
`
`
`166 Cyclodextrins
`
`8. Description
`least
`Cyclodextrins are cyclic oligosaccharides containing at
`6 b-(+)-glucopyranose units attached by o& (134) glucoside
`bonds. The three natural cyclodextrins, of, B, and y, differ in
`their ring size andsolubility. They contain 6, 7, or & glucose
`units respectively,(!2)
`Cyclodextrins oceur as white, practically odorless, fine crys-
`talline powders, having a slightly sweet taste. Some cyclo-
`dextrin derivatives occur as amorphous powders.
`The PhEurlists a and y cyclodextrin as potential impurities
`in B-cyclodextrin,
`See also Table I,
`
`9. PharmacopeialSpecifications
`
` Test PhEur USP
`
`
`Characters
`+
`—
`Identification
`+
`+
`Color and clarity of solution
`+
`+
`+160 to +164°
`Specific rotation
`+160 to +164°
`Microbial limits
`+
`< 16.0%
`Water
`< 14.0%
`—
`Residue on ignition
`0.1%
`< 10 ppm
`Heavy metals
`<5 ppm
`—_—
`Reducing substances
`< 1.0%
`
`
`+Assay (anhydrous basis) 98.0-101.0%
`
`10. Typical Properties
`Conipressibility: 21-44% for B-cyclodextrin.
`Density (bulk):
`0.526 g/cm? for o-cyclodextrin;
`0.523 g/cm? for B-cyclodextrin;
`0.681 g/cmfor hydroxypropyl B-cyclodextrin;
`0.568 g/cm} for y-cyclodextrin.
`Density (tapped)®:
`0.685 g/cm? for o-cylodextrin;
`0.754 g/cm? for B-cyclodextrin;
`0.916 g/cm? g/cmfor hydroxypropyl B-cyclodextrin;
`0.684 g/cm? for y-cyclodextrin.
`Density (true):
`1.521 g/cm? for o-cylodextrin;
`1,378 g/cm} for hydroxypropyl B-cyclodextrin;
`1.471 g/cm? for y-cyclodextrin.
`Melting point:
`250-260°C for o-cyclodextrin;
`255-265°C for B-cyclodextrin;
`240-245°C for y-cyclodextrin.
`Moisture content:
`10.2% w/w for a-cyclodextrin;
`13-15% w/w for B-cyclodextrin;
`8-18% w/w for y-cyclodextrin.
`Particle size distribution:
`7-45 ttm for B-cyclodextrin.
`Solubility:
`o-cyclodextrin: soluble 1 in 7 parts of water at 20°C,
`1 in
`3 at 50°C,
`B-cyclodextrin; soluble 1
`in 200 parts of propylene glycol,
`|
`|
`in 50 of water at 20°C,
`in 20 at 50°C: practically insoluble
`in acetone, ethanol (95%), and methylene chloride,
`y-cyclodextrin: soluble 1
`in 4.4 parts of water at 20°C,
`in 2 at 45°C,
`
`1
`
`Specific rotation [ot] p?°:
`+150.5° for a-cyclodextrin;
`+162.0° for B-cyclodextrin;
`+177.4° for y-cyclodextrin.
`Surface tension:
`71 mN/m (71 dynes/em) for @-cyclodextrin at 250;
`71 mN/m (71 dynes/cm) for B-cyclodextrin at 25°C:
`71 mN/m (71 dynes/em) for y-cyclodextrin at 25°C.
`‘) Results of laboratory project for third edition,
`
`Table I: Physical characteristics of cyclodextrins,
`Characteristic
`Cyclodextrin
`a
`B
`Y
`
`Cavity diameter (A)
`4.7-5.3
`60-65
` 7.5-8.3
`Height of torus (A)
`7.9
`1.9
`1,9
`Diameter of periphery (A)
`14.6
`15.4
`17.5
`Approximate volumeof cavity (A3)
`174
`262
`472
`Approximate cavity volume
`256
`157
`104
`per mol cyclodextrin (mL)
`
`
`
`0.1 0.14per g cyclodextrin (mL) 0.20
`Note:
`1 nm = 10 A.
`
`11. Stability and Storage Conditions
`B-Cyclodextrin, and other cyclodextrins, are stable in the solid
`state if protected from high humidity.
`Cyclodextrins should be stored in a tightly sealed container,
`in a cool, dry, place.
`
`12. Incompatibilities
`The activity of some antimicrobial preservatives in aqueous
`solution can be reduced in the presence of hydroxypropyl-B-
`cyclodextrin, (3-15)
`
`13. Method of Manufacture
`Cyclodextrins are manufactured by the enzymatic degradation of
`starch using specialized bacteria, For example, B-cyclodextrin is pro-
`duced by the action of the enzyme cyclodextrin glucosyliransferase
`upon starch or a starch hydrolysate. An organic solvent is used to
`direct
`the reaction to produce: B-eyclodextrin and to prevent
`the
`growth of microorganisms during the enzymatic reaction, The in-
`soluble B-cyclodextrin organic solvent complex is separated from
`the noncyclic starch, and the organic solvent removed in vactio so
`that less than | ppm of solvent remains in the f-cyclodextrin. The
`B-cyclodextrin is then carbon treated and crystallized from water,
`dried, and collected,
`Hydroxyethy!-B-cyclodextrin is made by reacting B-cyclodex-
`trin with ethylene oxide, while hydroxypropyl-B-cyclodextrin
`is made by reacting J-cyclodextrin with propylene oxide.
`
`14. Safety
`Cyclodextrins are starch derivatives and are mainly usedin oral and
`parenteral pharmaceutical formulations, They are also used in cos-
`metics and food products and are generally regarded as essentially
`nontoxic and nonirritant materials, However, when parenterally ad-
`ministered, B-cyclodextrin is not metabolized but accumulates in the
`kidneys as insoluble cholesterol complexes, resulting in severe neph-
`rotoxicity.""® Other cyclodextrins, e.g., 2-hydroxypropyl-B-cyclo-
`dextrin, have been the subject afextensive toxicological studies and
`are not associated with nephrotoxicity and are reported to be safe
`for use in parenteral formulations.)
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`

`
`
`Cyclodextrins 167
`
`
`
`Cyelodextrin administered orally is metabolized by microflora in
`the colon forming the metabolites maltodextrin, maltose, and glu-
`cose, which are themselves further metabolized before being fi-
`nally excreted as carbon dioxide and water. Although a study
`published in 1957 suggested that orally administered cyclodex-
`trins were highly toxic,“” more recent animal toxicity studies in
`rats and dogs have shownthis not to be the case and cyclodextrins
`are now approved for use in food products andorally administered
`pharmaceuticals in a number of countries.
`Cyclodextrins are not irritant to the skin and eyes, or upon
`inhalation. There is also no evidence to suggest that cyclo-
`dextrins are mutagenic or teratogenic. A potential synergism
`of cyclodextrins with carcinogens has been reported.
`o-Cyclodextrin:
`LDsp (rat, IP): 1.0 g/kg@®
`LDso (rat, TV): 0.79 g/kg
`B-Cyclodextrin:
`LDso (mouse, IP): 0.33 g/kg®
`LDs9 (mouse, SC): 0.41 g/kg
`LDspo (rat, IP): 0.36 g/kg
`LDso (rat, IV): 1.0 g/kg
`LDgo (rat, oral): 18.8 g/kg
`LDsg (rat, SC): 3.7 g/kg
`y -Cyclodextrin:
`LDso(rat,IP): 4.6 g/kg
`LDso(rat,IV): 4.0 g/kg
`LD,9(rat,oral): 8.0 g/kg
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Cyclodextrins are fine or-
`ganic powders and should be handled in a well-ventilated en-
`vironment. Efforts should be made to limit the generation of
`dust which can be explosive.
`
`16. Regulatory Status
`Included in oral and rectal pharmaceutical formulations li-
`censed in Europe, Japan and the US.
`
`17. Pharmacopeias
`Eur and US.
`
`18. Related Substances
`
`Dimethyl-B-cyclodextrin
`Molecular weight: 1331
`Synonyms: DM-B-CD.
`Appearance: white crystalline powder.
`Cavity diameter: 6 A
`Melting point: 295-300°C
`Moisture content: < 1% w/w
`Solubility: soluble 1 in 135 parts of ethanol, and 1 in 1.75 of water
`at 25°C, Solubility decreases with increasing temperature.
`Surface tension: 62 mN/m (62 dynes/cm) at 25°C.
`Method of manufacture: dimethyl-B-cyclodextrin is prepared from
`B-cyclodextrin by the selective methylation of all C2 second-
`ary hydroxyl groups and all C6 primary hydroxyl groups (C3
`secondary hydroxyl groups remain unsubstituted).
`Comments: used in applications similar to B-cyclodextrin.@)
`
`2-Hydroxyethy!-B-cyclodextrin
`CAS number: [98513-20-3]
`Synonyms: 2-HE-B-CD.
`
`Appearance: white crystalline powder.
`Solubility: greater than 1
`in 2 parts of water at 25°C.
`Surface tension: 68-71 mN/m (68-71 dynes/cm) at 25°C.
`Comments: used in applications similar to B-cyclodextrin. The
`degree of substitution of hydroxyethyl groups can
`vary,(2:319)
`
`2-Hydroxypropy!-B-cyclodextrin
`CAS number: [128446-35-5]
`Synonyms: 2-HP-B-CD.
`Appearance: white crystalline powder.
`Solubility: greater than 1 in 2 parts of water at 25°C.
`Surface tension: 52-69 mN/m (52-69 dynes/cm) at 25°C.
`Comments: used in applications similar to B-cyclodextrin,
`however, since it is not nephrotoxic it has been suggested
`for use in parenteral formulations. The degree of substitu-
`tion of hydroxyethyl groups can vary.(>)
`
`3-Hydroxypropyl-f-cyclodextrin
`Synonyms: 3-HP-B-CD.
`Appearance: white crystalline powder.
`Solubility: greater than 1 in 2 parts of water at 25°C.
`Surface tension: 70-71 mN/m (70-71 dynes/em) at 25°C.
`Comments: used in applications similar to B-cyclodextrin,
`however, since it is not nephrotoxic it has been suggested
`for use in parenteral formulations. The degree of substitu-
`tion of hydroxyethyl groups can vary.?)
`
`Trimethyl-B-cyclodextrin
`Molecular weight: 1429
`Synonyms: TM-B-CD.
`Appearance: white crystalline powder.
`Cavity diameter: 4-7 A
`Melting point: 157°C
`Moisture content: < 1% w/w
`Solubility: soluble 1 in 3.2 parts of water at 25°C. Solubility
`decreases with increasing temperature.
`Surface tension: 56 mN/m (56 dynes/cm) at 25°C
`Method of manufacture:
`trimethyl-B-cyclodextrin is prepared
`from B-cyclodextrin by the complete methylation ofall C2
`and C3 secondary hydroxy! groups along with all C6 pri-
`mary hydroxyl groups.
`Comments: used in applications similar to B-cyclodextrin.?)
`
`19. Comments
`
`In addition to their use in pharmaceutical formulation, cyclodex-
`trins have also been investigated for use in various industrial ap-
`plications. Analytically, cyclodextrin polymers are used in
`chromatographic separations, particularly of chiral materials.
`
`5
`20. Specific References
`1. Brewster ME, Simpkins JW, Hora MS, Stern WC, Bodor N.
`The potential use of cyclodextrins in parenteral formulations.
`J Parenter Sci Technol 1989, 43: 231-240.
`“t
`2. Duchéne D, Wouessidjewe D. Physicochemical characteris-
`tics and pharmaceutical uses of cyclodextrin derivatives, part
`L Pharmaceut Technol 1990; 14(6): 26, 28, 34.
`3. Duchéne D, Wouessidjewe D. Physicochemical characteris-
`tics and pharmaceutical uses of cyclodextrin derivatives, part
`Il. Pharmacéut Technol 1990; 14(8): 14, 22, 24, 26.
`4. Brewster ME, Hora MS, Simpkins JW, Bodor N. Use of
`2-hydroxypropyl-f-cyclodextrin as a solubilizing and stabilizing
`excipient for protein drugs. Pharm Res 1991; 8: 792-795,
`5. Choudhury S$, Nelson KF. Improvementof oral bioavailabil-
`ity of carbamazepine by inclusion in 2-hydroxypropyl-B-
`cyclodextrin. Int J Pharmaceutics 1992, 85; 175-180.
`
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`

`
`
`
`
`168 Cyclodextrins
`
`6. El Shaboury MH. Physica! properties and dissolution profiles
`of tablets directly compressed with B-cyclodextrin. Int J
`Pharmaceutics 1990; 63: 95-100,
`7. Shangraw RF, Pande GS, Gala P. Characterization of the
`tableting properties of §-cyclodextrin and the effects of pro-
`cessing variables on inclusion complex formation, compact-
`ibility and dissolution. Drue Dev Ind Pharm 1992;
`18:
`1831-1851.
`8. Prankerd RJ, Stone HW, Sloan KB, Perrin JH. Degradation
`of aspartame in acidic aqueous media and its stabilization
`by complexation with cyclodextrins or modified cyclodex-
`trins. Jnt J Pharmaceutics 1992; 88: 189-199,
`9. Palmieri GF, Wehrlé P, Stamm A. Inclusion of vitamin D2
`in f}-cyclodextrin, Evaluation of different complexation meth-
`ods. Drug Dev Ind Pharm 1993; 19: 875-885,
`10. Szente L, Apostol I, Szejtli J. Suppositories containing B-
`cyclodextrin complexes, part 1: stability studies. Pharmazie
`1984; 39: 697-699.
`11, Szente L, Apostol I, Gerloezy A, Szejtli J. Suppositories con-
`taining B-cyclodextrin complexes, part 2: dissolution and
`absorption studies. Pharmazie 1985; 40; 406-407.
`12. Amann M, Dressnandt G. Solving problems with cyclodex-
`trins in cosmetics. Cosmer Toilet 1993: 108(1 1): 90, 92-95,
`13. Loftsson T, Stefansdéttir O, Fridriksdéttir H, Gudmundsson
`©. Interactions between preservatives and 2-hydroxypropyl-
`f-cyclodextrin, Drug Dev Ind Pharm 1992; 18: 1477-1484.
`14, Lehner SJ, Miller BW, Seydel JK. Interactions between p-
`hydroxybenzoic acid esters and hydroxypropyl-f-cyclodex-
`trin and their antimicrobial effect against Candida albicans,
`Int J Pharmaceutics 1993: 93: 201-208.
`15. Lehner SJ, Miiller BW, Seydel JK. Effect of hydroxypropyl-
`B-cyclodextrin on the antimicrobial action of preservatives.
`/ Pharm Pharmacol 1994; 46; 186-191,
`16. Frank DW, Gray JE, Weaver RN. Cyclodextrin nephrosis in
`the rat. Am J Pathol 1976; 83: 367-382.
`17. French D, The Schardinger dextrins. Adv Carbohydrate Chem
`1957; 12: 189-260.
`18. Sweet DV,editor. Registry of Toxic Effects of Chemical Sub-
`stances, Cincinnati, US Department of Health, 1987
`19. Menard FA, Dedhiya MG, Rhodes CT. Potential pharmaceu-
`tical applications of a new beta cyclodextrin derivative. Drug
`Dev Ind Pharm 1988; 14: 1529-1547,
`
`21. General References
`Bekers O, Uijtendaal EV, Beijnen JH, Bult A, Underberg WJM,
`Cyclodextrins in the pharmaceutical
`field. Drug Dev Ind
`Pharm 1991; 17: 1503-1549,
`Bender ML, Komiyama M. Cyclodextrin Chemistry. New York:
`Springer-Verlag, 1978.
`Darrouzet H. Preparing cyclodextrin inclusion compounds. Mfg
`Chem 1993; 64(11): 33-34.
`Fenyvest E, Antal B, Zsadon B, Szejtli J. Cyclodextrin polymer, a new
`tablet disintegrating agent. Pharmazie 1984; 39: 473-475,
`Leroy-Lechat F, Wouessidjewe D, Andreux J-P, Puisieux F, Duchéne D,
`Evaluation of the cytotoxicity of cyclodextrins and hydroxypropy-
`lated derivatives. Int J Pharmaceutics 1994: 101: 97-103.
`Pande GS, Shangraw RF. Characterization of B-cyclodextrin for direct
`compression tableting. Int J Pharmaceutics 1994; 101: 71-80.
`Pitha J, Szente L, Szejtli J. Molecular encapsulation by cyclo-
`dextrin and congeners. In: Bruck SD, editor. Controlled Drug
`Delivery, volume I. Boca Raton, FL, CRC Press, 1983.
`Shao Z, Krishinamoorthy R, Mitra AK, Cyclodextrins as nasal
`absorption promoters of insulin: mechanistic evaluations.
`Pharm Res 1992; 9: 1157-1163,
`Stoddard F, Zarycki R. Cyclodextrins. Boca Raton, FL, CRC
`Press, 1991.
`Strattan CE, 2-Hydroxypropyl-B-cyclodextrin, part II: safety and
`manufacturing issues. Pharmaceut Technol 1992; 16(2): 52,
`54, 56, 58,
`Szejtli J. Cyclodextrins in drug formulations: part I. Pharmaceut
`Technol Int 1991; 3(2): 15-18, 20-22.
`Szejtli J. Cyclodextrins in drug formulations: part II. Pharmaceut
`Technol Int 1991; 3(3): 16, 18, 20, 22, 24.
`Szejtli J. General overview of cyclodextrin. Chem Rev 1998; 98:
`1743-2076.
`Yamamoto M, Yoshida A, Hirayama F, Uekama K, Some physi-
`cochemical properties of branched B-cyclodextrins and their
`inclusion characteristics.
`Int J Pharmaceutics 1989; 49:
`163-171.
`
`22. Authors
`
`RA Nash.
`
`
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`

`
`
`SEM: 1
`Excipient; Methylparaben
`Supplier: Bate Chemical Co Ltd
`
`Magnification: 600%
`
`Methylparaben (0.18%) together with propylparaben (0.02%)
`has been used for the preservation of various parenteral phar-
`maceutical formulations, see Section 14.
`
`
`
` Use Concentration (%)
`
`IM, IV, SC injections
`Inhalation solutions
`Intradermal injections
`Nasal solutions
`Ophthalmic preparations
`Oral solutions and suspensions
`Rectal preparations
`Topical preparations
`Vaginal preparations
`
`{@) See Section 14.
`
`8. Description
`
`0.065-0.25
`0.025-0.07
`0.10
`0.033
`0.015-0.2
`0.015-0.2
`0.1-0.18
`0.02-0.3
`0.1-0.18
`
`Methylparaben occurs as colorless crystals or a white crys-
`talline powder.
`It
`is odorless or almost odorless and has a
`slight burning taste.
`
`
`
`
`
`340 Methylparaben Methylparab
`
`1. Nonproprietary Names
`
`BP: Methyl hydroxybenzoate
`JP: Methyl parahydroxybenzoate
`PhEur: Methylis parahydroxybenzoas
`USP: Methylparaben
`
`2. Synonyms
`
`E218; 4-hydroxybenzoic acid methyl ester; Methyl Chemosept;
`methyl p-hydroxybenzoate; Methyl Parasept; Nipagin M; Solbrol
`M; Tegosept M.
`
`3. Chemical Name and CAS Registry Number
`
`Methyl 4-hydroxybenzoate [99-76-3]
`
`4. Empirical Formula Molecular Weight
`
`C;H,0;
`
`152.15
`
`5. Structural Formula
`
`iC
`
`—OCH;
`
`OH
`
`6. Functional Category
`
`Antimicrobial preservative.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`
`Methylparaben is widely used as an antimicrobial preservative
`in cosmetics, food products, and pharmaceutical formulations.
`It may be used either alone, in combination with other para-
`bens, or with other antimicrobial agents. In cosmetics, meth-
`ylparaben is the most frequently used antimicrobial
`preservative.)
`
`9. Pharmacopeial Specifications
`
`The parabens are effective over a wide pH range and have a
`broad spectrum of antimicrobial activity although they are
`most effective against yeasts and molds. Antimicrobial activity
`increases as the chain length ofthe alkyl moiety is increased;
`+
`+
`Identification
`aqueous solubility however decreases. A mixture of parabens
`=
`a
`Characters
`is thus frequently used to provide effective preservation. Pre-
`servative efficacy is also improved by the addition of 2-5%
`
`
`Melting range 125-128°C=125-128°C 125-128°C
`propylene glycol, or by using parabens in combination with
`Acidity
`_-
`+
`o
`other antimicrobial agents such as imidurea, see Section 10.
`Loss on drying
`s 0.5%
`—
`= 0.5%
`Residue on ignition
`< 0.10%
`a=
`<$ 0,05%
`Due to the poor solubility of the parabens, paraben salts, par-
`Sulfated ash
`Sa
`0.1%
`_
`ticularly the sodium salt, are frequently used in formulations.
`
`= 0.035% —Chloride _
`
`
`However, this raises the pH of poorly buffered formulations.
`
`Test
`
`JP
`
`PhEur
`
`+
`
`USP
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`

`

`(Continued)
`
`Test
`Sulfate
`Heavy metals
`Readily carbonizable
`substances
`Appearance of
`solution
`Related substances
`Assay (dried basis)
`
`PhEur
`JP
`—_
`<= 0.024%
`20pm —
`+
`—e
`
`=
`
`+
`
`USP
`=
`=
`=
`
`+
`
`+
`> 99,0%
`
`—_
`+
`99,0-100.5% 99.0-100.5%
`
`10. Typical Properties
`Antimicrobial activity: methylparaben exhibits antimicrobial
`activity between pH 4-8. Preservative efficacy decreases
`with increasing pH due to the formation of the phenolate
`anion. Parabens are more active against yeasts and molds
`than against bacteria. They are also more active against Gram-
`positive bacteria than against Gram-negative bacteria.
`Methylparaben is the least active of the parabens; antimi-
`crobial activity increases with increasing chain length of
`the alkyl moiety. Activity may be improved by using com-
`binations of parabens, since additive effects occur. There-
`fore, combinations of methyl, ethyl, propyl, and
`butylparaben are often used together. Activity has also been
`reported to be enhanced bythe addition of other excipients
`such as: propylene glycol (2-5%);@) phenylethyl alcohol;®
`and edetic acid.) Activity may also be enhanced, due to
`synergistic effects, by using combinations of parabens with
`other antimicrobial preservatives such as imidurea.“)
`The hydrolysis product, p-hydroxybenzoic acid, has prac-
`tically no antimicrobial activity.
`See also Section 12.
`
`Reported minimum inhibitory concentrations (MICs) for
`methylparaben are shown in Table I.
`Density (true): 1.352 glem3@
`Dissociation constant: pK, = 8.4 at 22°C
`Melting point: 125-128°C
`Partition coefficients: values for different vegetable oils vary con-
`siderably and are affected by the purity of the oil, see Table II.
`Solubility: see Table III
`
`‘) Results of laboratory project for third edition.
`
`11. Stability and Storage Conditions
`Aqueoussolutions of methylparaben, at pH 3-6, may bester-
`ilized by autoclaving at 120°C for 20 minutes, without de-
`composition.) Aqueous solutions at pH 3-6 are stable (less
`than 10% decomposition) for up to about 4 years at room
`temperature, while aqueous solutions at pH 8 or above are
`subject to rapid hydrolysis (10% or more after about 60 days
`storage at room temperature).
`Predicted rate constants and half-lives at 25°C, for methylpa-
`raben dissolved in dilute hydrochloric acid solution at the ini-
`tial pH shown below:!?)
`
`Initial pH
`of solution
`
`Rate constant
`Half-life
`
`k £ o@ (hour)
`t,, to(day)
`
`266 + 13
`(1.086 + 0.005) x 104
`1
`2490 + 260
`(1.16 + 0.12) x 10-5
`2
`47000 + 12000
`(6.1 + 1.5) x 10°7
`3
`
`4 88000 + 17000 (3.27 + 0.64) x 10-7
`
`
`(®) Indicates the standard error.
`
`Methylparaben 341
`
`Table I: Minimum inhibitory concentrations (MICs) of
`methylparaben in aqueous solution.)
`
`Microorganism
`Aerobacter aerogenes ATCC 8308
`Aspergillus oryzae
`Aspergillus niger ATCC 9642
`Aspergillus niger ATCC 10254
`Bacillus cereus var. mycoides ATCC 6462
`Bacillus subtilis ATCC 6633
`Candida albicans ATCC 10231
`Enterobacter cloacae ATCC 23355
`Escherichia coli ATCC 8739
`Escherichia coli ATCC 9637
`Klebsiella pneumoniae ATCC 8308
`Penicillium chrysogenum ATCC 9480
`Penicillium digitatum ATCC 10030
`Proteus vulgaris ATCC 8427
`Proteus vulgaris ATCC 13315
`Pseudomonas aeruginosa ATCC 9027
`Pseudomonas aeruginosa ATCC 15442
`Pseudomonasstutzeri
`Rhizopus nigricans ATCC 6227A
`Saccharomyces cerevisiae ATCC 9763
`Salmonella typhosa ATCC 6539
`Sarcina lutea
`Serratia marcescens ATCC 8100
`Staphylococcus aureus ATCC 6538P
`Staphylococcus epidermidis ATCC 12228
`Trichoderma lignorum ATCC 8678
`Trichoderma mentagrophytes
`
`MIC (\tg/mL)
`2000
`600
`1000
`1000
`2000
`2000
`2000
`1000
`1000
`1000
`1000
`500
`500
`2000
`1000
`4