`
`LHandbook of
`
`PHARMACEUTICAL
`
`EX CIPIEN TS
`
`
`
`Third Edition
`
`Edited by
`
`Arthur H. Kibbe, Ph.D.
`Professor and Chair
`
`Department of Pharmaceutical Sciences
`Wilkes University School of Pharmacy
`Wilkes-Barre, Pennsylvania
`
`@
`
`American Pharmaceutical Association
`
`Washington. D.C.
`
`(RP)
`
`Pharmumlicu] Pru-
`
`London, United Kingdom
`
`Apotex, Inc. (IPR2019-00400), EX. 1006, p. 001
`
`Apotex, Inc. (IPR2019-00400), Ex. 1006, p. 001
`
`

`

`Published by the American Pharmaceutical Association
`2215 Constitution Avenue NW, Washington. DC 20037-2985. USA
`wwwaphanetorg
`and the Pharmaceutical Press
`
`1 Lambeth High Street, London SE1 TJN. 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—85369-3SI—l (UK)
`ISBN: 0—917330-96-X [USA]
`
`Library of Congress Cataloging-in-Publicalion 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
`
`l. ExcipientSuHandbooks. manuals. etc.
`Pharmaceutical Association.
`[DNLM: 1. Excipients——Handbooks. QV 735 H236 2000]
`RSZOIEB? H36 2000
`615'.l9--dc21
`
`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:
`Paul Gottehrer
`Indexer:
`Lillian Rodberg
`Compositor:
`Roy Barnhill
`Cover Designer:
`Tim Kaage
`
`
`
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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
`.
`Albumln
`:‘Alcohol
`.
`.
`.
`Algimc Acad
`.
`.
`Aliphatic Polyesters
`Alpha Tocopherol
`orh1e Acud
`Asc
`.
`.
`.
`‘
`Ascorbyl Palmitate
`A
`spartame
`entorute
`B
`_
`.
`_
`_
`Benzalkonlum Chloride
`Benzethonium Chloride
`.
`.
`Benzom And
`
`Benz)" “001101
`Benzyl Benzoate
`_
`3“)um
`Butylated Hydroxyamsole
`Butylated Hydroxyloluene
`Bmylparaben
`\,»’Calcium Carbonate
`Calcium Phosphate. Dibasic Anhydrous
`Calctum Phosphate. Dibasu: D1hydrate
`Calcium Phosphate. Tribasic
`Calctum Stearate
`Calcwm §ulfate
`\' Canola 0"
`.
`Carbomer‘
`_
`Carbon DIOdeB
`Carboxymethylcellulose Calcmm
`Carboxymethylcellulose Sodium
`V’Carrageenan
`Castor 011. Hydrogenated
`Cellulose Acetate
`Cellulose Acetate Phthalate
`Cellulose, Microcryslalline
`Cellulose. Powdered
`Cellulose, Silieified Mierocryslalline
`Cetostearyi Alcohol
`Celrimide
`Cetyl Alcohol
`Chlorhexidine
`Chlorobutanol
`Chloroeresol
`Chlorodifluoroethane {HCFC}
`Chlorofluorocarbons (CFC)
`
`‘
`
`vii
`ix
`xii
`xiii
`xv
`xvii
`xviii
`xviii
`xix
`xx
`
`I
`3
`5
`7
`10
`l3
`l8
`21
`25
`2?
`30
`
`33
`36
`38
`
`4‘
`44
`46
`49
`51
`53
`56
`60
`63
`68
`70
`73
`77
`79
`33
`85
`87
`91
`94
`96
`99
`102
`197
`110
`112
`114
`117
`121
`126
`129
`132
`134
`
`Cholesterol
`Citric Acid Monohydrate
`Colloidal Silicon Dioxide
`Coloring Agents
`v“ Corn 011
`130110355911 Oil
`Crcsol
`Croscarmellose Sodium
`Crospowdone
`Cyclodextrms
`Dextrales
`Dextrin
`V/Dextrose
`leutyl Sebacate
`Diethanolamine
`.
`[Methyl Phthalate
`.
`Difluoroethane (HFC)
`Dimethyl Ether
`.
`Docusale Sodmm
`.
`.
`Edetlc Actd
`
`Ethylcellulose
`Ethyl Maltol
`Ethyl Oleate
`.
`.
`Ethylparabcn
`Ethyl Vamllm
`\.. F
`t
`.
`rue 0.56
`Fumaric And
`.
`LIGelatm
`l/Glucose. Liquid
`‘1 Glycerin
`Glyceryl Monooleate
`Glyecryl Monoslearate
`Glyceryl Palmitostearate
`Glycofurol
`Guar Gum
`Heptafiuoropropane (HFC)
`Hydrocarbons (HC)
`Hydrochloric Acid
`Hydroxyethyl Cellulose
`Hydroxypropyl Cellulose
`Hydroxypropyl Cellulose, Low-substituted
`v'Hydroxypropyl Methylcellulose
`Hydroxypropyl Methylcellulose Phthalale
`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 Trisilieate
`
`133
`140
`143
`146
`154
`156
`158
`‘50
`163
`“55
`169
`172
`175
`178
`1 80
`182
`184
`186
`188
`191
`
`195
`201
`203
`205
`208
`310
`“
`213
`215
`213
`220
`223
`225
`228
`230
`232
`234
`235
`233
`240
`244
`249
`252
`256
`261
`263
`265
`267
`269
`272
`274
`276
`236
`283
`290
`292
`295
`299
`303
`305
`309
`
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`

`

`vi Contents
`
`Malic Acid
`Maltitol
`Maltitol Solution
`‘- Maltodexlrin
`
`.- Maltol
`“f Maltese
`Mannitol
`
`Medium Chain Triglycerides
`Meglumine
`Menthol
`
`Methylcellulose
`Mcthylparaben
`V Mineral Oil
`Mineral Oil. Light
`Mineral Oil and Lanolin Alcohols
`Monoethanolamine
`— Nitrogen
`Nitrous Oxide
`Oleic Acid
`Paraffin
`\‘ Peanut Oil
`Petrolatum
`Petrolatum and Latte-[in Alcohols
`Phenol
`
`Phonoxyethanol
`Phenylclhyl Alcohol
`Phenylrnercuric Acetate
`Phenylmcrcuric Borale
`Phenylmercuric Nitrate
`Polacrilin Potassium
`Poloxamer
`
`Polydextrose
`Polyethylene Glycol
`Polyethylene Oxide
`Polymethacrylates
`Polyoxyethylerte Aikyl Ethers
`Polyoxyethylene Castor Oil Derivatives
`Polyoxyethylene Sorbitan Fatty Acid Esters
`Polyoxycthylene Stearatcs
`Polyvinyl Alcohol
`PotaSSium Chloride
`Potassium Citrate
`Potassium Sorbate
`Povidorte
`
`Propylene Carbonate
`Propylene Glycol
`Propylene Glycol Alginatc
`Propyl Gallate
`Propylparaben
`Saccharin
`
`\ Saccharin Sodium
`2-Sesame Oil
`Shenac
`4‘ Sodium Alginale
`
`3]]
`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 Ascorbatc
`Sodium Benzoate
`Sodium Bicarbonate
`Sodium Chloride
`
`Sodium Citrate Dihydrate
`fl. Sodium Cyclamatc
`l" Sodium Lauryl Sulfate
`Sodium Metahisulfite
`
`Sodium Phosphate. Dihasic
`Sodium Phosphate, Monohasic
`Sodium Propionate
`Sodium Starch Glycolate
`Sodium Stearyi Fumarate
`\z Sorbic Acid
`Sorbitan Esters (Sorbitan Fatty Acid Esters)
`Sorbitol
`VSoybean Oil
`t; Starch
`\t-Starch, Pregelatinized
`l«Starch. Sterilizable Maize
`Stearic Acid
`
`Stearyl Alcohol
`Sucrose
`Sugar. Compressible
`Sugar. Confectioner‘s
`Vsugar Spheres
`wSuppository Bases, Hard Fat
`Lil'alc
`Tartaric Acid
`Tctrafluorocthanc [HFC)
`Thimerosal
`Titanium Dioxide
`Tragacanth
`Triacetin
`Triethanolamirte
`Triethyl Citrate
`Vanillin
`
`Vegetable Oil, Hydrogenated, Type 1
`Water
`Wax. Anionic Emolsifying
`Wax, Carnauba
`Wax, Cetyl Esters
`Wax. Microcrystallinc
`Wax, Nonionic Emulsifying
`Wax. White
`Wax, Yellow
`Xanthan Gum
`Xylitol
`Zein
`Zinc Stearate
`
`Appendix I: Suppliers’ Directory
`Appendix H: HPE Laboratory Methods
`index
`
`468
`471
`474
`478
`482
`485
`487
`490
`493
`496
`498
`501
`505
`508
`51 l
`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
`59}
`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 Wellcomc
`Ware. UK
`
`Roger Guest
`SmithKline Beecham Pharmaceuticals
`Crawlcy. 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 OL—cy-
`clodextrin and betadex is the pINN for B—cyclodextrin.
`
`2. Synonyms
`
`Cyclodextrin: Cavitron; cyclic oligosaccharide; cycloamylose;
`cycloglucan; Encapsin; Rhodocap; Schardinger dextrin.
`
`ot—Cyclodextrin: alfadex; alpha-cycloamylose; alpha—cyclodex-
`trin; alpha-dextrin; cyclohexaamylose; cyclomaltohexose.
`
`[i—Cyelotlextrin: beta—cycloamylose; betttdes; heta-tiextrin; cy—
`cloheptaamylose; cycloheptaglucan; cyelomaltoheplose; Klep-
`rose.
`
`'y—Cycylodextrin: cyclooctaamylose; gamma cyclodextrin;
`Gamma W8.
`
`3. Chemical Name and CAS Registry Number
`
`OL-Cyclodextrin:
`B-Cyclodextrin:
`y—Cyclodextrin:
`
`[10016—20—3]
`[7585-39—9]
`[17465—86—0]
`
`4. Empirical Formula Molecular Weight
`
`ot—Cyclodextrin: C36H60030 972
`B—Cyclodextrin: C42H70035
`1135
`y—Cyclodextrin: C48H80040
`1297
`
`5. Structural Formula
`
` L'H21JR ‘
`
`[3- and y—cyclodextrins
`R’, R” = -H for ‘natural’ 0t—,
`R’, R” _ -CH3 for methyl cyclodextrins
`R’, R”
`-CHOHCH3 for hydroxyethyl cyclodextrins
`R’, R” = —CH2CHOHCH3 for 2—hydroxypropyl cyclodextrins
`Note: structure of B-cyclodextrin (7 glucose units) shown.
`
`Cyclodextrins
`
`165
`
`6. Functional Category
`
`Stabilizing agent; solubilizing agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`
`Cyclodextrins are crystalline. nonhygroscopic, cyclic 01i-
`gosaccharides derived from starch. Among the most common-
`ly used forms are 0t-,
`|3—, 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 hydroxyl 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.
`
`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.
`
`li~Cyelodextrin 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—
`ber of sources, and is able to form inclusion complexes with
`a number of molecules of pharmaceutical interest. However,
`fl—cyclodextrin should not he used in parenteral formulations
`since it is nephrotoxic. see Section I4. [ii-Cyclodextrin is con—
`sidered to he nontoxic when administered orally and has thus
`hecome primarily used in tablet and capsule formulations.
`B—C‘yclodexlrin derivatives tend to he nontoxic when usetl either
`orally or parenterally and the derivatives Z-ltydroxypropyl—li-cyelo—
`tlextrin and 3-hytlrosypropyl-[3-eyelodextrin are becoming of
`increasing importance in pharmaceutical
`l'orntulalioas.‘l'i’
`
`tit—Cyclodextrin is mainly used in parenteral formulations. al—
`though since it has the. smallest cavity of the cyclodextrins it
`can only form inelasion complexes with relatively few. small
`sized molecules.
`In contrast. y-eyelodestrin has the largest
`cavity and can he usetl to form inclusion complexes with large
`molecules. Current availability of y-cyelodextrin (Gamma W8)
`makes it an excellent choice because of its low toxicity and
`enhanced water solubility.
`
`1n oral tablet formulations [i-eyclotlextrin may he used in both
`wet granulation and direct compression processes. While the
`physical properties of B—eyelodextrin vary from manufacturer
`to n'ianul'aeturer. B-eyelodestriu tends to possess poor flow
`properties and requires a luhricunt, such as 0.1% wfw mag-
`nesium stearale. when it
`is directly compressed.”'-7l
`
`formulalions, cyclodextrins have. been used to
`'ln parenteral
`produce slahle and soluble preparations of drugs that would
`otherwise have been formulated using a nonauttenus solvent.
`Cyclodextrins have also been used in the formulation of so—
`lutions,(8:9) suppt}sitories,(10'”) and cosmetics“)
`
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`

`

`
`
`
`
`Specific rotation [(x]D25:
`+150.5° for (x—cyclodextrin;
`+162.0° for B-cyclodextrin;
`+177.4° for y—cyclodextrin.
`Surface tension:
`
`71 mN/m (71 dynes/cm) for ot-cyclodextrin at 25°C;
`71 mN/m (71 dynes/cm) for [i-eyclodextrirr at 25°C;
`71 mN/m (71 dynes/cm) for y~cyclodextrin at 25°C.
`(a) Results of laboratory project for third edition.
`
`Table 1: Physical characteristics of cyclodextrins.
`
`Characteristic
`Cyclodextrin
`
`a
`B
`r
`
`Cavity diameter (A)
`Height of torus (A)
`Diameter of periphery (A)
`Approximate volume of cavity (A3)
`Approximate cavity volume
`256
`157
`104
`per mol cyclodextrin (mL)
`
`
`
`0.1 0.14per g cyclodextrin (mL) 0.20
`Note:
`1 nm 2 10 A.
`
`6.0—6.5
`7.9
`15.4
`262
`
`7.5-8.3
`7.9
`17.5
`472
`
`4.7—5.3
`7.9
`14.6
`174
`
`I 66 Cyclodextrins
`
`8. Description
`
`least
`Cyclodextrirrs are cyclic oligusacehnrides containing at
`6 tJ-{+)-glueopyranose trnits attached by or 1H4) glueosidc
`bonds. The three natural cyclodextrins, or.
`[3. and y. differ in
`their ring size and solubility. They contain a. 7. or it glucose
`units respectivelym‘
`
`Cyctodextrins occur as white. practically odorless, fine crys—
`talline powders. having a slightly sweet taste. Some cyclo-
`dextrin derivatives oecrrr as amorphous powders.
`The PhEur lists 0t and y cyclodextrin as potential impurities
`in B-cyclodextrin.
`See also Table I.
`
`9. Pharmacopeial Specifications
`
`
`
` Test PhEur USP
`
`Characters
`+
`—
`Identification
`+
`+
`Color and clarity of solution
`+
`+
`+160 to +164°
`Specific rotation
`+160 to +164°
`Microbial limits
`+
`
`S 14.0%
`S 16.0%
`Water
`S 0.1%
`—
`Residue on ignition
`S 5 ppm
`S 10 ppm
`Heavy metals
`S 1.0%
`—
`Reducing substances
`
`
`+Assay (anhydrous basis) 98.0—101.0%
`
`10. Typical Properties
`Conrpressibility: 21-44% for B—cyclodextrin.
`Density (bulkfla)
`
`0.526 g/cm3 for ot—cyclodextrin;
`0.523 g/cm3 for B-cyclodextrin;
`0.681 g/cm3 for liydt'osypropyl B—cyclodextrin;
`0.568 g/cm3 for yscyclodextrin.
`Density (tappedfi‘l):
`0.685 g/cm3 for ot-cylodextrin;
`0.754 g/cm3 for B—cyclodextrin;
`0.916 g/cm3 g/cm3 for hydroxypropyl B—cyclodextrin;
`0.684 g/cm3 for y—cyclodcxtrin.
`Density (true):(“)
`1.521 g/cm3 for (x—cylodextrin;
`1.378 g/cm3 for hydroxypropyl B—cyclodextrin;
`1.471 g/cm3 for y—cyclodextrin.
`Melting point:
`250—260°C for oc—cyclodextrin;
`255-265°C for B-cyclodextrin;
`240-245°C for y—cyclodextrin.
`Moisture content:
`
`10.2% w/w for 0t—cyclodextrin;
`13—15% w/w for B-cyclodextrin;
`8—18% w/w for y—cyclodextrin.
`Particle size distribution:
`7—45 run for B-cyclodextrin.
`Solubility:
`
`Ot-cyclodextrin: soluble 1 in 7 parts of water at 20°C,
`3 at 50°C.
`
`1 in
`
`l
`in 200 parts of propylene glycol.
`B-cyciorlextrin: soluble |
`in 30 at 50°C; practically insoluble
`I
`in 50 ot‘ water at 20°C.
`in acetone, ethanol [95“). and methylene chloride.
`'y—cyclodcxtrin: soluble l
`in 4.4 parts of water at 20°C,
`in 2 at 45°C.
`
`I
`
`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.(13‘15)
`
`13. Method of Manufacture
`
`Cyclodextrins are manufactured by the enzymatic degradation of
`starch using specialized bacteria. For example. fl—cyclodcxlrin is pro-
`duced by the action of the enzyme cyclodextrin glucrrsyllransferase
`upon starch or a starch hydrolysate. An organic solvent is used to
`direct
`the reaction to produce fi—cyclodextrin and to prevent
`the
`growth of microorganisms during the enzymatic reaction. The in—
`soluble li~cyclodextrin orgiurie solvent complex is separated from
`the noncyciic starch. and the organic solvent removed in mean so
`that less than I ppm of solvent remains in the fl»cyclodcxtrin. The
`fl-cyclodexrrin is than carbon treated and crystallized from water.
`dried, and collected.
`
`Hydroxyc-thyl-ti-cyclodextria is made by reacting fi-cyclodex—
`trio with ethylene oxide, while hydroitypropy-l—fi—cyclodexlrin
`is made by reacting B-cyelodestrin with propylene oxide.
`
`14. Safety
`
`Cyclodcxuins are starch derivatives and are mainly used in oral and
`parenteral phannaccntical formulations. They Lee also used in cosv
`metics and food products and are generally regarded as essentially
`nontoxic and nonirritant materials. Horvcver, when parentenrlly ad—
`ministered. l3~cyclodextrin is not metabolized but accumulates in the
`kidneys as insoluble cholesterol complexes, resulting in severe neph—
`r‘ormticity.”m Other cyclr‘rdextrins. c.g.. Znhydrosypropylufl—cyclo-
`destrin. have been the subject of extensive toxicological studies and
`are not associated with nephrotosieity and are reported to be sale
`For use in parenteral formulations!”
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`
`
`Cyclodextrins
`
`I 67
`
`
`
`Cyclodextrin administered orally is metabolized by mieroflora 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,(17) more recent animal toxicity studies in
`rats and dogs have shown this not to be the case and cyclodextrins
`are now approved for use in food products and orally 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.
`ot-Cyclodextrin:
`LDSO (rat, IP): 1.0 g/kg‘ls)
`LD50 (rat, IV): 0.79 g/kg
`B-Cyclodextrin:
`LDSO (mouse, IP): 0.33 g/kg‘lg)
`LDso (mouse, SC): 0.41 g/kg
`LDSO (rat, IP): 0.36 g/kg
`LD50 (rat, IV): 1.0 g/kg
`LDSO (rat, oral): 18.8 g/kg
`LD50 (rat, SC): 3.7 g/kg
`Y -Cyclodextrin:
`LD50(rat,IP): 4.6 g/kg
`LD50(rat,IV): 4.0 g/kg
`LD50(rat,0ral): 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-fl-cyclodextrin
`Molecular weight: 1331
`Synonyms: DM-B-CD.
`Appearance: white crystalline powder.
`Cavity diameter: 6 A
`Melting point: 295-300°C
`Moisture content: S 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 methylution of all C2 second-
`ary hydroxyl groups and all C6 primary hydroxyl groups (C3
`secondary hydroxyl groups remain unsubstituted).
`Continents: used in applicalions similar to B-cyelodextrin.(2-3)
`
`2-Hydroxyethyl-fl-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.(2-3v19)
`
`2-Hydroxypropyl-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.(1'5)
`
`3-Hydroxypropyl-fl-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/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.(2-3)
`
`'ITimethyl-fl-cyclodextrin
`Molecular weight: 1429
`Synonyms: TM-B-CD.
`Appearance: white crystalline powder.
`Cavity iiimiieter: 4—7 A
`Melting point: 157°C
`Moisture content: S 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 mrmufirtrtm'e:
`trimethyl-B—eyelotlextrin is prepared
`from B‘eyelodcxtrin by the complete methylation of all C2
`and C3 secondary hydroxyl groups along with all C6 pri-
`mary hydroxyl groups.
`Comments: used in applications similar to B-cyclodextrin.(2-3)
`
`19. Comments
`
`In addition to their use in pharmaceutical formulation, cyclodex-
`trins have also been investigated for use in various industrial ap-
`plications. Analylieally, cyclodextrin polymers are used in
`chromatographic separations, particularly of chiral materials.
`
`:
`20. Specific References
`l-lora MS, Stern WC, Bodor N.
`1. Brewster ME, Simpkins JW,
`The potential use of cyclodextrins in parenteral formulations.
`J Pmamtu‘ Sci Techno! [989: 43: 23l—24U.
`’.
`2. Duchéne D, Wouessidjewe D. Physicochemical characteris-
`tics and pharmaceutical uses of cyclodextrin derivatives, part
`I. Pharmrtr'cut T’eclmol 1990; 14(6): 26, 28, 34.
`3. Duchéne D, Wouessidjewe D. Physicochemical characteris-
`tics and pharmaceutical uses of eyelodextrin derivatives, part
`II. lermm‘em Technol 1990; Mtg]: 14, 22, 24, 26.
`4. Brewster ME, Hora MS, Simpkins JW, Bodor N. Use of
`2—hydroxypropyI—B-cyelodexlrin as :1 solubilizing and stabilizing
`excipient for protein drugs. Firm-iii Rm- 199k 8: 792—795.
`5. Chourlhury S, Nelson KF. Improvement of oral bioavailabil—
`ity of earbamazepine by inclusion in l-hydroxypropyI—fl—
`cyclodextrin. int .i Phommcrmirs 1992: 85: [75-130.
`
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`

`

`
`
`I68 Cyclodextrins
`
`6. E1 Shaboury MH. Physical properties and dissolution profiles
`of tablets directly compressed with B-eyclodestrin. Int J
`Pharmaceutics 1990: 63: 95401].
`7. Shangraw RF, Pande GS, Gala P. Characterization of the
`tableting properties of ticyclodextrin and the effects of pro-
`cessing variables on inclusion complex Formation, compact—
`ihility and dissolution. Drag Dev 1nd Phone 1992:
`IS:
`183l-l851.
`
`8. Prankerd R1. Stone HW. Sloan KB. Perrin JH. Degradation
`of aspartante in acidic aqueous media and its stabilization
`by complexation with cyclodextrins or modified cyclodex-
`lrins. in: J Pharmaceutics 1992'. 88: 189099.
`9. Palntieri GF. Wehrlé P. Stamm A.
`inclusion of vitamin D2
`in B—cyelodextn‘n. Evaluation of different contplexntion meth-
`ods. Drng Dev Ind Phorm 1993;
`I9: 875-885.
`10. Szcnte L, Apostol I, Szejtli J. Suppositories containing B-
`cyclodextrin complexes, part 1: stability studies. Phttrmnzie
`1984: 39: 697-699.
`
`11. Szente L. Apostol I. Gerioczy A. Szejtli J. Suppositories con-
`taining B—cyclodextrin complexes. part 2: dissolution and
`absorption studies. Pin-innate £985: 40: 406-401.
`l2. Amann M. Dressnandt G. Solving problems with cycledesv
`trins in cosmetics. Cot-met Toilet 1993:
`IOSU l): 9t}, 92-95.
`13. Lol'tsson T. Stefansdottir 0. Fridriksdottir H, Gudmundsson
`0. Interactions between preservatives and 2~hydroxypropyl-
`B—cyclodextrin. Drag Dev Ind Phone “992: 18: 1477—1484.
`[4. Lehner SJ. Muller BW. Seydel JK. [nteractions between {i—
`hydrosybenzoic acid esters and hydroxypropyl—B-cycledes-
`trio and their antimicrobial effect against Candide olht'cons.
`In! J Phortttnrfmttt'cs 1993; 93: 201-203.
`15. Lehner SJ. Muller BW. Seydel 1K. Effect of hydroxypropyl-
`B-cyclodestrin on the antimicrobiai action of preservatives.
`.J' Pharm Phnrmeco! 1994: 46:
`ISfi—I‘Jl.
`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
`[957: 12: 189—260.
`
`18. Sweet DV, editor. Registry of Toxic Effects of Chemical Sub-
`stances. Cincinnati. {18 Department of Health. 1987
`19. Menard FA. Dedhiya MG. Rhodes CT. Potential pharmaceu-
`tical applications of a new beta cyclodextrin derivative. Drug
`Dev 1nd Pharm 1988: 14: 1529-1547.
`
`21. General References
`
`Bekers O, Uijtendaal EV. Beijnen JH, Bult A, Underherg WJM,
`Cyclodextrins in the pharmaceutical
`field. Drag Dev Ind
`Phorm l991: 17:
`[503—1549.
`
`Bender ML, Kontiyama M. Cyclodextrin Chemistry. New York:
`Springer-Veriag, 1978.
`Darrouzet H. Preparing cyclodextrin inclusion compounds. Mfg
`Chem 1993; 64(11): 3384.
`Fenyvest E, Antal B. Zsadon B. Szejtli J. Cyclodextrin polymer. a new
`tablet disintegrating agent. Pheromone |9841 39: 473-475.
`Leroy-Lechat F, Wonessidjewe D, Andreas J—P. Pnisieux F. Ducht‘nte D.
`Evaluation of the cytotoxicity of cyclodextrins and hydmxypropy-
`iated derivatives. {or J Phommcetttt‘cs I994: 10]: 97—103.
`Pande GS. Shangraw RF. Characterization of B-eyelodextrin for direct
`compression tnbleting. Int J Pharmaceutics 1994: 101: 71-80.
`Pitlia J. Szente L. Szejtli J. Molecular encapsulation by cyclo—
`dextrin and congeners. In: Bruck SD, editor. Conn-oiled Drug
`Dct’t‘uetw. volume I. Boca Raton. FL. CRC Press. 1983.
`Shae Z. Krishiuamoortlty R, Mitre AK. Cyclodextrins as nasal
`absorption promoters of insulin: mechanistic evaluations.
`Phnrin Res 1992; 9: 11574163.
`
`Stoddard F, Zarycki R. Cyclodextrins. Boca Raton, FL, CRC
`Press. 1991.
`
`Strattatt CE. 2—Hydroxypropyl-[fi—eyclodextrin, part II: safety and
`manufacturing issues. Pharmacetrt Technol 1992'. 16(2): 52,
`54. 56, 58.
`
`Szejtli J. Cyclodextrins in drug formulations: part I. Pharmaceut
`Techno! Int 1991; 3(2): 15-18, 20-22.
`Szejtli J. Cyclodextrins in drug formulations: part II. Pharmaceut
`Techno] Int 1991; 3(3): 16,
`IS. 20, 22, 24.
`Szejtli J. General overview of cyclodextrin. Chem Rev 1998; 98:
`1743-2076.
`
`Yamamoto M. Yoshidn A, Hiraytmta F, Ueltama K. Some physi-
`coehcmical properties of branched B-cyclodestrins and their
`inclusion characteristics.
`in: J Pharmaceutics 1989; 49:
`163-171.
`
`22. Authors
`
`RA Nash.
`
`
`
`
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`
`
`340 Methylpamben Methylparab
`
`l. Nonproprietary Names
`
`BP: Methyl hydroxybenzoate
`JP: Methyl parahydroxybenzoate
`PhEur: Methylis parahydroxybenzoas
`USP: Methylparahen
`
`2. Synonyms
`
`E213; 4-hydroxybcnzoic acid methyl ester; Methyl Chemosept:
`methyl p-hydroxybenzoatc; Methyl Parasept; Nipagr‘rt M; Sclbml
`M: Tegorepr M.
`
`3. Chemical Name and CAS Registry Number
`
`Methyl 4-hydroxybenzoate [99-76-3]
`
`4. Empirical Formula Molecular Weight
`
`C3H303
`
`152.15
`
`5. Structural Formula
`
`t?
`C-'0CH3
`
`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.‘U
`
`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 of the alkyl moiety is increased;
`aqueous solubility however decreases. A mixture of parabens
`is thus frequently used to provide effective preservation. Pre~
`servative efficacy is also improved by the addition of 2—596
`propylene glycol. or by using parabens in combination with
`other antimicrobial agents such as imidurca. see Section 10.
`
`Due to the poor solubility of the parahens. paraben salts. par-
`ticularly the sodium salt, are frequently used in formulations.
`However. this raises the pH of poorly buffered formulations.
`
`SEM: 1
`Excipicnt: Melhylparaben
`Supplier: Bale Chemical Co Ltd
`Magnification: 600x
`
`
`
`Methylparahen (0.18%) together with propylparaben (0.02%)
`has been used for the preservation of various parenteral phar-
`maceutical formulations. see Section 14.
`
`
`
` Use Concentration (%)
`
`1M. IV. SC injectionsi-‘J
`Inhalation solutions
`Intradcrmal injections
`Nasal solutions
`Ophthalmic preparations“)
`Oral solutions and suspensions
`Rectal preparations
`Topical preparations
`Vaginal preparations
`
`{‘1 See Section 14.
`
`8. Description
`
`0.065025
`0025-007
`0J0
`0.033
`0.01502
`0015-02
`0.|—0.18
`0.02—0.14
`0.1—0.18
`
`Mcthylparaben occurs as colorless crystals or a white crys-
`talline powder.
`It
`is odorless or almost odorless and has a
`slight burning taste.
`
`9. Pharmacopeial Specifications
`
`Test
`
`JP
`
`PhEor
`
`USP
`
`+
`+
`+
`identification
`—
`+
`+
`Characters
`I25—128°C
`l25-128°C
`125-123°C
`Melting range
`+
`+
`——-
`Acidity
`s 0.5%
`—
`S 0.5%
`Loss on drying
`S 0.05%
`-—
`S 0.l0%
`Residue on ignition
`--
`S 0.1%
`—
`Sulfated ash
`
`
`
`S 0.035% —Chloride —
`
`
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`

`(Continued)
`
`JP
`5 0.024%
`5 20 ppm
`+
`
`PhEur
`-—
`——
`—
`
`—
`
`+
`
`USP
`'—
`-
`—
`
`+
`
`Test
`Sulfate
`Heavy metals
`Readily carbonizable
`substances
`Appearance of
`solution
`Related substances
`+
`+
`—
`2 99.0%Assay (dried basis) 99.0-100.5% 99.0-100.5%
`
`
`
`
`
`'I‘ypical Properties
`10.
`Antimicrobial activity: methylparahen exhibits antimicrobial
`activity between pH 4-8. Preservativc 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.
`
`Mcthylparaben 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
`bulylparaben are often used together. Activity has also been
`reported to be enhanced by the addition of other excipients
`such as: propylene glycol (2690);“) phenyiethyl alcohol!”
`and edctic acidl‘” Activity may also be enhanced, due to
`synergistic effects. by using combinations of parabcns with
`other antimicrobial preservatives such as imidurealm
`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 LE4}
`Density (true): 1.352 glcmml
`.
`Dissociation constant: pK, = 8.4 at 22°C
`Melting point: 125-128°C
`Partition cocfiicients: values for different vegetable oils vary con-
`siderably and are affected by the purity of the oil. see Table II.
`Solubility: see Table III
`
`"3 Results of laboratory project for third edition.
`
`11. Stability and Storage Conditions
`
`Aqueous solutions of methylparabcn. at pH 3.6, may be ster-
`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 temperaturellm
`Predicted rate constants and half—lives at 25°C, for methylpa-
`raben dissolved in dilute hydrochloric acid solution at the ini-
`tial pH shown betowfi")
`
`Initial [111
`of solution
`
`Rate constant
`Half-life
`
`It :1: am (hour!)
`1-,, d: at" (dart
`
`266 :1: 13
`(1.086 a 0.005) x 104
`1
`24901260
`(1.16t0.12)x10'5
`2
`4?000 i 12000
`(6.] l: 1.5} x 107
`3
`
`4 88000 1 17000 (3.27 t 0.64) x Itr“
`
`
`m Indicates the standard error.
`
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`Methyipttraben 34.1
`
`Table 1: Minimum inhibitory concentrations (M [(35) of
`methylparaben in aqueous solution“)
`
` Microorganism MIC (1,113!le
`
`Aerobocrer oerogenes ATCC 3308
`2000
`Aspergillus oryzae
`600
`Aspetgt‘llus niger ATCC 9642
`1000
`Aspctzillns niger ATCC 10254
`1000
`Bacillus cerettr vat: mycot‘des ATCC 6462
`2000
`Bacillus subtiiis ATCC