‘ce*Bie ce nN
`
`a:3tePatep
`aSONISOIEE
`
`Fo
`
`IPR2018-00390
`
`}
`
`Page lof88
`
`I-MAK 1012.
`
`e
`
`a
`
`» ot oe
`
`” Be
`ll
`
`!
`"
`
`IPR2018-00390
`
`Page 1 of 88
`
`I-MAK 1012
`
`

`

`• L-.J b the Pharmaceutical Press
`I Society of Great Britain
`t'
`Publlsneu y
`R al Pharmaceu ICO
`Publications division of the oy
`1 Lambeth High Street, Londo~ S~b:J~~a~~lake, IL 60030-7820, USA
`1 00 South Atkinson Road, Suite
`,
`and the American Pharmaceutical Assh~iatti~n DC 20037-2985, USA
`NW Was mgo,
`A
`2215 Constitution venue
`,
`
`.
`. 1 p
`d Amencan
`© Pharmaceunca
`ress an
`(RP) is a trade mark of Pharmaceutical Press
`
`· n 2003
`·
`.
`Pharmaceuncal AssoclatlO
`
`First edition published 1986
`Second edition published 1994
`Third edition published 2000
`Fourth edition published 2003
`
`Text design by Barker Hilsdon, Lyme Regis
`Typeset by Bibliocraft Ltd, Dundee
`Printed in Great Britain by The Bath Press, Bath
`
`ISBN 0 85369 472 9 (UK)
`ISBN 1 58212 022 6 (USA)
`
`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.
`
`A catalogue record for this book is available from the British Library
`
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients.- 4th ed. I edited by Raymond C.
`Rowe, Paul J. Sheskey, Paul J. Weller.
`p.; em.
`Includes bibliographical references and index.
`ISBN.1~58212-022-6 (alk. paper) -ISBN 0-85369-472-9 (alk
`a er
`1. Exclp!ents-Handbooks, manuals, etc.
`· p p
`)
`[DNLM: 1. Excipiems-Handbooks. QV 735 H236 2003] I R
`C. II. Sheskey, Paul J.lll. Weller, Paul J.
`· owe, Raymond
`
`RS201.E87H36 2003
`615'.19--<lc21
`
`2003002641
`
`IPR2018-00390
`
`Page 2 of 88
`
`I-MAK 1012
`
`

`

`

`

`

`

`

`

`Celphere (Asahi Kasei Co~porat_ion) is a pure spheronized
`Ystalline cellulose available m several different
`. 1
`pa rttc e
`nJia ocr
`. e ranges.
`SJl
`
`19
`
`2
`
`specific References
`E e'zian GM. Direct com pression of ta blets using mic
`1
`rocrysta .
`n
`. F
`h] Ph
`line cellulose [I~ re~c .
`arm Acta H elv 1972; 47: 321_363
`Lerk CF, Bolhu~s GK. Comparattve eva luation of excipienrs fo~
`dirrct compressi_on I. Pharm Week b/ 1973; 108: 469-481_
`f
`Lerk CF, Bolhms GK, de Boer AH. Com parative evalu r·
`II
`.
`f d.
`a IOn o
`excipients or
`Irect compresston
`. Pharm Weekbl 1974; 109:
`945-955.
`4 Lamberson RF, Raynor GE. T a bleting pro perties o f microcrystal(cid:173)
`line cellulose. Manu( Chern A erosol N ews 1976; 47(6) : 55-61.
`Lerk CF, Bol~ms GK, de Boer_ AH. Effect o f microcrystalline
`cellulose on hqmd penetranon m a nd disintegration of directly
`compressed tablets. j Pharm Sci 1979; 6 8: 205- 21 1.
`Chilamkurti RN, R~odes CT, Schwan z JB. Some studies o n
`compression properties of tablet matrices using a computerized
`instrumented press. Drug Dev Ind Pharm 1982; 8: 63--86.
`7 Wallace JW, Capo zzi JT, Sha ngraw RF. Perfo rma nce of
`pharmaceutical filler/binders as rei a ted to methods of powder
`characterization. Pha rm Techno/1 983; 7 (9): 94-104.
`Omray A, Omray P. Evaluation of mic rocryst alline cellulose as a
`glidant. Indian j Pharm Sci 1986; 48: 20-22.
`Celik M, Okutgen E. A feasibility study fo r the development of a
`prospective compaction functionality test and the establishment
`of a compaction d ata bank. Drug Dev Ind Pharm 1993; 19:
`2309-2334.
`10 Parker MD, York P, Rowe RC. Binder-substrate interactions in
`wet granulation 3: the effect of excipient source variation. Int j
`Pharm 1992; 80: 179- 190.
`II Callahan JC, Cleary GW, Elefant M, et a/. Equilibrium moisture
`content of pharmaceutical excipienrs. Drug Dev Ind Pharm
`1982; 8: 355-369.
`12 Cooper CB, Bai TR, Heyderman E, Co rrin B. Cellulose
`granulomas in the lungs of a cocaine sniffer. Br M ed j 1983;
`286: 2021-2022.
`13 Health and Safety Executive. EH40/2002: O ccupational Expo(cid:173)
`sure Limits 2002. Sudbury: Health and Safety Executive, 2002.
`14 Jam JK, Dixit VI<, Varma KC. Preparation of microcrystalline
`cellulose from cereal straw and irs evaluat ion as a ta blet
`excipient. Indian j Pharm Sci 1983; 45: 83--85.
`15 Singla AK, Sakhuja A, Malik A. Evaluation of microcrystalline
`cellulose prepared from absorbent cotton as a direct compression
`carrier. Drug Dev lnd Pharm 1988; 14: 1131-1136.
`.
`l6 Doelker E, Mordier D, lten H, Humbert-Droz P. Comparative
`tableting properties of sixteen microcrystalline celluloses. Drug
`Dev lnd Pharm 1987; 13: 1847-1875.
`17 Bassam F, York P, Rowe RC, Roberts RJ. Effect ~f particle s_ize
`and source on variability of Young's modulus of miCrocrystallme
`ce_llulose powders. j Pharm Pharmaco/1988; 40: 68P.
`.
`18 Dittgen M, Fricke S, Gerecke H. Microcrystalline cellulose m
`direct tabletting. Manu{ Chern 1993; 64(7): 17, 19, 21.
`
`Cellulose, Microcrystalline
`
`111
`
`21
`
`20
`
`19 Landin M Ma t.
`·
`1
`p 1
`'r mez- ac 1eco ~. Gomez-Amoz:~ J L eta/. Effect
`f
`'
`col unrry of origin on the properties of mi~rocrysralline
`0
`11
`ce u ?se. Tnt 1 Pharm 1993; 91: 123-13 1.
`L;ndm M, Martinez-Pacheco R G6mez-Amoza JL et a/. Effect
`0 . batch variation and source' of pulp on the ~ropcrnes of
`~Icrocrysta lline ce_llulose. Int j Pharm 1993; 9 1: 133-141.
`andin M, Marti nez-Pacheco R, Gomez-Amoza J L, et a/.
`Influence of microcrystalline cellulose source and hatch variation
`on tabletting behavior and ~tability of prednisone formulations.
`lnt J Pharm 1993; 91: 143-149.
`22 Podczeck F, Revesz P. Evaluation of the properties of micro-
`crystalhne and microfine cellulo~e powders. /nt 1 Pharm 1993;
`91: 183-193.
`23 Rowe RC, McKi llop AG, Bray D. The effect of batch and source
`variation on the crystallinity of microcryscalline cellulose. lnt j
`Pharm 1994; 101: 169-J 72.
`24 Hasegawa M . Direct compression: microcrystalline cellulose
`grade 12 versus classic grade I 02. Pharm Techno/ 2002; 26(5):
`50, 52, 54, 56, 58, 60.
`25 Kothari SH, Kumar Y, Banker GS. Comparative evaluations of
`powder and mechanical properties of low crystallinity cell uloses,
`microcrysta ll ine cell uloses, and powdered cell uloses. lnt J Pharm
`2002; 232: 69-SO.
`
`20 General References
`Asahi Kasei Corporation. Technical literature: Ceo/us KG micro(cid:173)
`crystalline cellulose, 2001.
`Asahi Kasei Corporation. Technical literature: Celphere microcrystal(cid:173)
`line cellulose spheres, 2001.
`DMV Pha rma. Techn ical literature: Pharmacel microcrystalline
`cellulose, 1998.
`Doelker E. Comparative compaction properties of various micro(cid:173)
`crystalline cellulose types and generic products. Drug Dev lnd
`Pharm 1993; 19: 2399-2471.
`FMC Biopolymer. Technical literature: Avice/ PH microcrystalline
`cellulose, 1998.
`International Specialty Products. Technical literature: Celex 101
`microcrystalline cellulose, 1997.
`Penwest Pharmaceuticals Co. Technical literature: Emcocel micro(cid:173)
`crystalline cellulose, 1997.
`Smolinske SC. Handbook of Food, Drug, and Cosmettc Excipients.
`Boca Raton, FL: CRC Press, 1992: 71-74.
`Staniforrh JN, Baichwal AR, Hart JP, Heng PWS. Effect of addition of
`water on the rheological and mechanical propenies of micro(cid:173)
`crystalline celluloses. Int J Pharm 1988; 41: 231-236.
`
`21 Author
`
`PJ Weller.
`
`22 Date of Revision
`
`26 N o vember 2002.
`
`IPR2018-00390
`
`Page 6 of 88
`
`I-MAK 1012
`
`

`

`

`

`

`

`114
`
`Cellulose, Powdered
`
`17 Related Substances
`Cellulose, miao.:rystalline.
`
`18 Comments
`The EINECS number for powdered cellulose is 232-674-9.
`
`19 Specific References
`Kod1ari SH, Kumar V, Banker GS. Comparative evaluations of
`powder and mechanical properties of low crystallinity celluloses,
`microcrystalline cell uloses, and powdered cell uloses. Tnt 1 Pharm
`2002; 232(1-2): 69-80.
`2 Lindner H, Kleinebudde P. Use of powdered cellulose for the
`production of pellets by extrusion sphcronization. 1 Pharm
`Pharmaco/ 1994; 46: 2-7.
`3 Callahan JC, Cleary GW, Elefanr M, eta/. Equilibrium moisture
`content of pharmaceutical excipients. Drug Dev Ind Pharm 1982;
`8: 355-369.
`4 Cooper CB, Bai TR, Heyderman E, Corrin B. Cellulose
`granulomas in the lungs of a cocaine sniffer. Br Med j 1983;
`286: 2021--2022.
`
`5 Health and Safety Executive. EH40!200l·
`Limits 2002. Sudbu.ry: Hralth and Safe · ~cc"P<~t1,,"<1
`ry .xecutlve, 2~~l,.,.....,
`See also Cellulose, microcrystalline.
`
`20 General References
`
`Allen LV. featured excipient: capsule and tahle
`Compouncf 2000; 4(4): 306-310, 324-325. t d,lucnli.J,,
`1
`Beida PM, .M1elck JB. The tabletting behavior
`I Ph"'
`wtch mixtures of cell uloses with lacroses E f cellaq~
`0
`· ur J Phar111 ~1')!.."11~~
`1996; 42(5): 325-330.
`''•P!~
`Smolinske SC. Handbook of Food, Dmg, and Co
`snret~e Q:11P!f>q
`Boca Raton, Fl: CRC Press, 1992: 7J_74.
`
`21 Author
`ME Aulton.
`
`22 Date of Revision
`21 October 2002.
`
`· - ---
`
`IPR2018-00390
`
`Page 9 of 88
`
`I-MAK 1012
`
`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`

`l
`
`studies of gastric ~uice resistant co
`German]. Pharm~zze 1987; 42: 83?-8~111erlial Pr
`9 Neurath AR, Stnck N, Li YY D h
`l.
`'Para
`I
`"· ~I
`' e nath At-
`,,
`h
`phrha ate, a common p annaceutical
`.,
`1
`l and blocks the coreceptor bindin, ~~c1Pien1, i~ lu~
`,te on lhe aCJ,I~,.\
`glycoprotein gp120. BMC Infect D·g
`h AR S . k N
` 1 ~n .• ·
`2
`zs 001 1
`Ytru ''li
`10 Neurat
`,
`tnc
`, Jiang S, et a/
`; fll:
`· ~ntHity_ ·
`·~
`cellulose acetate phthalate: 'Ynerg
`induction of 'dead-end' gp4J six-h\IVtth Solubi ~,,,~~
`e IX btlndl~ ~tli1 ,.
`Dis 2002; 2(1 ): 6.
`11 Sakella~wu P, Rowe RC, White EF! T
`l( t ••.
`properties and glass transition temp · he ther1110~
`d
`~"'""'
`d . f"l
`.
`.
`eratures f
`o \olllt '·'•~.
`In 1 m coating. fnt 1 Phar
`envanves use
`12 Callahan }C, Cleary GW, Elefan_t M, eta/.~ 1985; 27, 1~}~
`content of pharmaceuncal exc1pient· D qu1hbnu"'
`,
`rug Dev l>d~~
`1982; 8: 355-369.
`'·
`'ff
`
`1,
`
`20 General References
`Doelker E. Cellulose derivatives. Adv Polym s ·
`FMC Biopolymer. Technical literature· Aqcz 93; 107: l~h
`19
`h h I
`l'D ..,
`uacoat
`.
`·
`acetate p t a ate aqueous dispersion 1996
`c , rei"'
`Obara S, Mcginty JW. Influence of proces ·.
`properties of free film s prepared fro~1ng vanables on,,
`dispersions by a spray technique. Int 1 Pbar ai~;ous ~oh~
`;n
`O'Connor RE, Berryman WH. Evaluation
`S; 116: 1-L
`ability: tablet swelling method and capillar/~i::1c !'hn lfll;.
`muhod.D~
`Dev lnd Pharm !992; 18:2123-21 33.
`Raffin F, Duru C, Jacob M, eta/. l'hysico-che~nical h
`.
`"'~
`f
`h ·
`·
`b"l"
`c aractenlan
`t e IOniC permea llry o an enteric coating poly
`1
`1995; 120(2): 205-214.
`er. Ill Jlfr-
`111
`Wyatt DM. Cellulose esters as direct compression matr
`JL
`Chern 1991; 62( 12): 20, 21, 23.
`Ices ... ""
`
`0
`
`21 Author
`RW Fengl.
`
`22 Date of Revision
`22 October 2002.
`
`122
`
`Cellulose Acelole Ph lholole
`
`re ermeable to certain
`.
`Cellulose acetate phthalate ftl~s a. ~de and ammonium
`ionic substances, such as potaSSI~m 10 ler subcoat should be
`chloride. [n such cases, an appropnate sea
`
`f latex particles rather
`.
`.
`.
`used.
`f
`A reconstituted collotdal d1sperswn_ 0
`llulose acetate
`rhan soh·enr solution coatmg matena 0 ce.
`ble pow-
`1
`.
`.1 bl Th"
`h ·r water-mso u
`IS w 1 e,
`phthalate IS also avat a e.
`b
`.
`ter
`"zed
`1
`f
`.
`f
`l"d su m1crome
`r·d
`·
`-
`A
`der 1s composed o so 1 or semlso 1
`.
`51
`Polvmer spheres With an average par 1
`d
`·
`10
`·
`t"cle SIZe 0
`0 2
`· 1-ltn.
`. h
`hi 1
`·
`typical coaring system made from t s atex P .
`.
`ow er IS a
`-
`30% soiJd-conrenr aqueous 1sper51on WI
`·
`"th a VISCOSity Ill t e
`.
`d"
`50-100 mPas range.
`
`19 Specific References
`Spitael J, Kinget R, Naessens K. Dissolution rare of cellulose
`acetate phthalate ~nd Bri:insred catalysis law. Pharm /nd 1980;
`42: 846..,';49.
`2 Takenaka li, Kawashima Y, Lin SY. Preparation of enteric(cid:173)
`coated microcapsules for tableting by spray-drying technique and
`in vitro simulation of drug release from the tablet in GJ tract.]
`Pharm Sci 1980: 69: 1388-1392.
`3 Takenaka H, Kawashima Y, Lin SY. Polymorphism of spray(cid:173)
`dried microencapsulated sulfamethoxazole with cellulose acetate
`phthalate and colloidal silica, montmorillonite, or talc. J Pharm
`Sci 1981; 70: 1256-1260.
`4 Stricker H, Kulke H. Rate of disintegration and passage of
`enteric-coated tablets in gastrointestinal tract [in German].
`Phamz lnd 1981; 43: 1018-1021.
`5 Maharaj l, Nairn JG, Campbell jB. Simple rapid method for the
`preparation of enteric-coated microspheres. j Pharm Sci 1984;
`73: 39-42.
`
`6 Berger .IW, Nairn JG. Some factors affecting the microencapsu(cid:173)
`lanon of pharmaceuticals with cellulose acetate phthalate. j
`Phamz Sci 1986; 75: 573-578.
`7 Lin SY, Kawashima Y. Drug release from tablets containing
`cellulose acetate phthalate as an additive or enteric-coating
`matenal. Pharm Res 1987; 4: 70-74.
`8 Thoma K, Hecken~uller H. Effect of film formers and
`
`P!astiCIU:rs on stab,iJty of resistance and disintegration beha(cid:173)
`VIOur. Parr 4: pharmaceutical-technological and analytical
`
`t
`
`IPR2018-00390
`
`Page 17 of 88
`
`I-MAK 1012
`
`

`

`

`

`

`

`

`

`

`

`

`

`w
`~ co
`
`....-
`0
`n
`0 (J>
`
`<D
`
`-
`
`-
`
`-
`
`92
`
`100
`
`>97
`
`-
`
`>97
`
`::-atlo"?h"n~ ,
`
`- c
`
`> 9 7
`-
`
`-
`
`-
`
`>95
`
`-
`>98
`
`>85
`-
`
`lable IV:
`
`Particle size distribution of selected commercially available lactoses.
`
`Supplier/grade
`
`Typical particle size distribution (%)
`
`< 10JUTI
`
`< 32JUTI
`
`< 45JUTI
`
`< 63 JUTI
`
`< 75JUTI
`
`< 100 JUil < 150 JUil < 200Jifll < 250JUII < 315 JUil < 400JUII < 600JUII < 800Jifll
`
`Borculo Domo Ingredients
`Microfine
`Zeparo)aJ
`DMVPharma
`Pharmafose 50M
`Pharmatose 80M
`Pharmatose 90M
`Pharmatose 7 OOM
`Pharmatose 1 I OM
`Pharmatose 125M
`Pharmatose 150M
`Pharmatose 200M
`Pharmatose 325M
`Pharmatose 350M
`Pharmafose 450M
`Pharmafose DCL I I (b)
`Pharmafose DCL 7 5
`Pharmafose DCL 21 (c)
`Foremost Farms USA
`Regular 3 I OA
`Regular 3108
`Impalpable 3 7 2
`Impalpable 3 7 3
`Spray Process 3 1 sfbl
`Fast-Flo 3161bJ
`Hollandse Melksuikerfobriek
`HMS Lactose DT
`Meggle GmbH
`Capsulae 60
`Flowlac 1 o()lal
`GranuLac 70
`GranuLac 140
`GranuLac 200
`GranuLac 230
`PrismaLac 40
`SacheLac 80
`Sorbolac 400
`Spherolac I 00
`Tablettose 70\a)
`Tablettose a()lo\
`
`99.9
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`8
`-
`-
`-
`-
`-
`
`24
`29
`65
`83
`5
`6
`
`-
`
`-
`< 10
`-
`< 40
`45--75
`>90
`-
`-
`>90
`-
`-
`-
`
`-
`-
`-
`-
`-
`-
`-
`25
`45
`60
`-
`75
`95
`10
`-
`15
`
`30
`37
`77
`93
`10
`9
`
`-
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`-
`-
`-
`-
`6
`9
`15
`55
`-
`-
`78
`-
`99
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`-
`
`-
`-
`-
`-
`-
`>90
`-
`-
`-
`< 20
`< 6
`
`-
`10-20
`
`-
`-
`-
`-
`-
`-
`-
`83
`-
`-
`-
`-
`25
`-
`
`53
`66
`97
`99
`33
`32
`
`25
`
`-
`-
`-
`-
`-
`
`-
`-
`-
`-
`-
`-
`
`-
`-
`4~5 70-95
`-
`-
`-
`10
`21
`65
`-
`68
`40
`85
`97
`-
`75
`90
`92
`98
`100
`98
`-
`45
`-
`-
`-
`-
`99
`
`-
`100
`-
`60
`50
`
`73
`86
`
`-
`-
`
`-
`
`< 10
`25--40
`40--60
`>80
`>90
`
`-
`< 20
`-
`-
`-
`-
`
`57
`62
`
`60
`
`-
`-
`-
`
`-
`-
`-
`-
`-
`-
`
`-
`95-100
`
`-
`
`10
`-
`-
`-
`-
`-
`-
`-
`
`-
`
`-
`
`-
`
`-
`-
`
`-
`-
`
`-
`
`-
`>85
`-
`
`< 10
`-
`-
`>75
`40-75
`-
`
`-
`84
`-
`99.7
`-
`-
`-
`100
`
`100
`
`100
`
`85
`
`100
`100
`
`100
`100
`
`-
`
`40-70
`
`-
`
`-
`-
`
`-
`-
`
`-
`
`-
`99
`100
`
`100
`100
`100
`
`-
`
`-
`
`-
`
`-
`-
`
`-
`-
`
`IPR2018-00390
`
`Page 23 of 88
`
`I-MAK 1012
`
`

`

`

`

`

`

`

`

`·------
`
`332
`
`Lactose
`
`33 Luk CF, Andrae AC, de Bot'r AH, 1!/ a/. Alterations of a-lactose
`during differmrial scanning calorimetry (lertuj. j Pharm Sci
`198--4: 73: 856-857.
`
`Quc:sr lnrernarional Inc. (She£field Prod
`Tabletting characteristics of lactose, 19U~). Technical
`
`,.
`11
`..:rill4~
`
`20 General References
`DMV Ph.Jrm.a. Teo.:hnio.:al hrerarurc:: Phamu1tose, 1998.
`~remosr Farm~ USA. Technicallirerature: Foremost lactose, 1998.
`c:ggle GmbH. Technicallirerarurc:: LActose monoh)'drate, 1999.
`Pea:;;Ji/-actose: rhc: natural excipient. Manu(Chem 1986; 57(10):
`
`21 Authors
`AH Kibbe, P] Weller.
`
`22 Date of Revision
`26 November 2002.
`
`IPR2018-00390
`
`Page 27 of 88
`
`I-MAK 1012
`
`

`

`

`

`

`

`

`

`

`

`

`

`

`

`604
`
`Storch
`
`granulated formulations, about half the total starch content if
`included in the granulation mixture and the balance as ~ar~ 0n
`the final blend with the ~ri.ed granul.atton. Also stare ~lie h
`used as a disintegrant exhtblts type II tsotherms and has a g
`. .
`.
`( 10)
`spectftc surface for water sorptwn.
`. .
`.
`Starch has been investigated as an excJptent tn nov(fJ1 drudg
`1 ( 12, 13)
`'dontal
`an
`I (11)
`ora ,
`pen
`'
`deljvery systems or nasa ,
`f
`.
`'f' d 1'
`h
`(I S)
`or er stte-spect te e tvery systems.
`.
`. .
`Starch is also used in topical preparations; for examp.le, tt ts
`widely used in dusting powders for its absorbe~cy, and~~ used
`as a protective covering in ointment formulations apl?lied to
`the skin. Starch mucilage has also been applied to the skm as an
`emollient has formed the base of some enemas, and has been
`used in tl~e treatment of iodine poisoning.
`Therapeutically, rice starch-based solutions have been used
`in the prevention and treatment of dehydration due to acute
`diarrheal diseases.
`
`8 Description
`Starch occurs as an odorless and tasteless, fine, white-colored
`powder comprising very small spherical or ovoid granules
`whose size and shape are characteristic for each botanical
`variety.
`
`9 Pharmacopeia! Specifications
`See Table I.
`
`1 0 Typical Properties
`Acidity/alkalinity: pH = 5.5-6.5 for a 2% w/v aqueous
`dispersion of corn starch, at 25°C.
`Compressibility: see Figure 1.
`Density (bulk): 0.462 glcm3 for corn starch.
`Density (tapped): 0.658 glcm3 for corn starch.
`Density (true): 1.478 glcm3 for corn starch.
`Flowability: 10.8-11.7 gls for corn starcht 1 30% for corn
`starch (Carr compressibility index).<1 l Corn starch is
`cohesive and has poor flow characteristics.
`Gelatinization temperature: 73°C for corn starch; 72°C for
`potato starch; 63°C for wheat starch.
`Moisture content: all starches are hygroscopic and rapidly
`<17 1gr A
`b b
`h
`·
`·
`·
`.
`t
`a .sor a mosp enc mmsture.
`·
`pproxtmate equili-
`bnum motsture content values at 50% relative humidity
`are 11% for corn starch; 18% for potato starch· 14% for
`rice starch; and 13 % for wheat starch. Between,30% and
`80% relative humidity, c?rn starch is the least hygroscopic
`s~arch an~ potato starch 1s the most hygroscopic. Commer(cid:173)
`Cially avatlable grades of corn starch usually contain 10-
`14% water. See also Figures 2 and 3.
`Particle size distribution:
`Corn starch: 2- 32 lil11
`Potato starch: 10-1 00 ~m
`Rice starch: 2-20 ~m
`Tapioca starch: 5-35 ~
`Wheat starch: 2-45 ~m
`Me.dian diameter for corn starch is 17 ~m and for wheat t
`h
`IS 23 ~tm.
`s arc
`Solubility: practically insolu.ble in cold ethanol (95%) and in
`cold water. Starch swells mstantaneously m· w t b b
`a er y a out
`
`181 Polyvalent cations prod
`5-10% at 37°C.<2
`•
`·
`b
`uce
`1
`ff lllore
`swelling than monova ent tons, ut pH has littl
`e e ect
`Specific surface area:
`·
`0.41-D.43 m2/g for corn starch
`0.12 m2/g for potato starch
`0.27-D.31 m2/g for wheat starch
`Swelling temperature:
`65oC for corn starch
`64°C for potato starch
`55°C for wheat starch
`Viscosity (dynamic): 13.0mPas (13.0cP) for a 2% w/va
`que-
`ous dispersion of corn starch at 25°C.
`
`Table 1:
`
`Test
`
`Pharmacopeial specifications for starch.
`
`JP 2001
`
`PhEur 2002
`
`USPNF 20
`
`Identification
`Bota nic
`characteristics
`Microbial limits
`pH
`Corn starch
`Potato starch
`Tapioca
`Wheat starch
`Acidity
`loss on drying
`Corn starch
`Rice starch
`Potato starch
`Tapioca
`Wheat starch
`Residue on
`ignition
`Sulfated ash
`Corn starch
`Rice starch
`Potato starch
`Wheat starch
`Iron
`Corn starch
`Potato starch
`Tapioca starch
`Wheat starch
`Organic volatile
`impurities
`Oxidizing
`substances
`Corn starch
`Potato starch
`Tapioca starch
`W heat starch
`Sulfur dioxide
`Corn starch
`Potato starch
`W heat starch
`Total protein
`Corn starch
`Rice starch
`Potato starch
`W hea t starch
`Foreign matter
`
`+
`
`+
`+
`
`+
`
`5 .0--8.0
`
`5 .0--8.0
`+
`
`~ 15 .0%
`~ 15 . 0%
`~ 18 .0%
`
`~ 15 .0%
`~ 15 .0%
`~ 20 . 0%
`
`~ 15 .0%
`
`~ 15 .0%
`
`~ 0 . 5%
`~ 1 .0%
`~ 0 .5%
`~ 1 .0%
`
`~ 0.6%
`~ 1.0%
`~ 0. 6%
`~ 0.6%
`
`~ 10ppm
`
`~ 10ppm
`
`+
`
`+
`
`~ 50 ppm
`~ 50 ppm
`
`~ 0. 1 %
`~ 0.3%
`+
`
`+
`+
`
`+
`
`4.5-7.0
`5.0--8.0
`4 .5-7.0
`4.5-7.0
`
`~1 4.0%
`
`~1 4.0%
`~1 4 .0%
`~1 4 .0%
`~0.5%
`
`~ 0.002%
`~ 0.002%
`~ 0.002%
`~ 0.002%
`+
`
`~ 0.002%
`~ 0.002%
`~ 0.002%
`~ 0.002%
`
`.:0 OOB%
`~o:oos%
`~ o.oos%
`
`-=---------
`
`IPR2018-00390
`
`Page 34 of 88
`
`I-MAK 1012
`
`

`

`

`

`

`

`

`

`

`

`

`

`

`

`i RW, Rhodes CT, Schw~rtz ]~. Some studies on
`hw11ktll't
`erties of tablet matrtces usmg a computerized
`1 C ~pression props Drug Dev Ind Pharm 1982; 8: 63-86.
`o· . . A M .
`tal pres .
`~'()I"
`. strurnen . S Goidas P,
`tmttnou
`.
`otsture sorption and
`Mabnlatans h of some tableted direct compression excipienrs.
`l ~~~~le scre~991; 68: 51~0.
`.
`/nt J p/Jarn: B, Shiromam. PK~ Clatr JH. Scal~-up feasability in
`. rs· determmanon through stattsttcal procedures
`1-kandarao
`' h r nuxe
`·
`-
`·
`high-s e~ Jnd Pharm 2001; 27: _ 651~5 /.
`.
`.
`vr~rg De~ pK Clair J. Statts_ttcal companson of htgh-shear
`H Shitolll301 he~r granulation usmg a common formulation. Drug
`(ersus lo~~arrtl 2000; 26: 357-364.
`Dev lnd 1' hnicalliterature: Starch 1500. 1997.
`li Colorcon K~c Spring MS. The granulation of ternary mixtures:
`li Jaiyeoba £'rhe stability of the excipients.] Pharm Pharmacal
`the effect o
`fl
`I •RL: Particle behaviour storage and ow. Br Chem Eng
`980· 32· 1-5.
`17 Carr 5· 1541-1549.
`c Cleary GW, Elefant M, et al. Equilibrium moisture
`1970; 1 ·
`1
`li Callahan ·f' pharmaceutical excipients. Drug Dev Ind Pharm
`c(){ltent o
`!982- 8· 355-369.
`-
`.
`' ·DE Peck GE Kildsig DO. A companson of the mmsture
`19 Wurster
`..desorptio'n properties of corn starch USP, and
`essible starch Drug Dev bid Pharm 1982; 8:
`adsorclpuon
`direc y com pr
`·
`I E p
`·
`0 0
`343-354.
`Health and Safety Executive. EH40120 2:
`x o-
`ccupatiO:ra
`lD SJjTe Limits 2002. Sudbury: Health and Safety Execunve, 2002.
`
`Starch . Pregela tin ized
`
`61 1
`
`21 Seppic. Technical Literature: Sepistab ST200. 1997.
`
`20 General References
`Mo~~deero Perales MC, ~unoz-Ruiz. A, Velasco-Antequera MV, et
`· Comparative tabletmg and microstructural properties of a new
`Starch for dtrect compression. Drug Deu Jnd Pharm 1996· 22:
`689-695.
`'
`Rees, JH, Tsardaka KD. Some effects of moisture on the viscoelastic
`behavior of modified starch during powder compaction. Eur J
`Pharm Biopharm 1994; 40: 193-197.
`Raquette Freres. Technical literature: Lycatab PGS. 2001.
`Sanghvi PP, Collins CC, Shukla AJ. Evaluation of Preflo modified
`starches as new direct compression excipients 1: tabletting
`characteristics. Pharm Res 1993; 10: 1597-1603.
`
`21 Author
`G Rowley.
`
`22 Date of Revision
`13 June 2002.
`
`I
`I
`1 1
`)
`
`i
`l '
`
`~
`
`IPR2018-00390
`
`Page 41 of 88
`
`I-MAK 1012
`
`

`

`

`

`

`

`

`

`\82
`
`(roscormellose Sodium
`
`a Description
`· h
`dorless white or greyls -
`Croscarmellose sodium occurs as an o
`'
`white powder.
`
`9 Phannacopeial Specifications
`See Table II.
`
`Tobie II: Phormocopeial specifications lor croscarmellose sodium.
`PhEur 2002
`USPNF 20
`
`Identification
`Characters
`pH (1 % w/v dispersion)
`loss on drying
`Heavy metals
`Sodium chloride and sodium
`glycolate
`Sulfated ash
`Degree of substirution
`Content of water-soluble material
`Settling volume
`Microbial contamination
`Organic volatile impurities
`
`+
`+
`5.0-7.0
`.;; 10.0%
`.;; 10ppm
`~ 0.5%
`
`14.0-28.0%
`0 .60--0.85
`.;; 10.0%
`+
`+
`
`+
`
`5.0-7.0
`~ 1 0.0%
`.;;0.001 %
`~ 0.5%
`
`0 .60--0.85
`1.0-10.0%
`+
`
`+
`
`10 Typical Properties
`Bonding index: 0.0456
`Brittle fracture index: 0.1 000
`Density (bulk): 0.529 gjcm3 for Ac-Di-SoPl
`Density (tapped): 0.819 glcm3 for Ac-Di-Sof7 l
`Density (true): 1.543 gjcm3 for Ac-Di-Sol(7l
`Particle size distribution:
`Ac-Di-Sol: not more than 2% retained on a #200 (73.7 1J.m)
`mesh and not more than 10% retained on a #325 (44.51!m)
`mesh
`Pharmacel XL: more than 90% less than 45).lill, and more
`than 98% less than 100 11m in size
`Solubility: insoluble in water, although croscarmellose sodium
`rapidly swells to 4-8 times its original volume on contact
`with water.
`Specific surface area: 0.81-0.83 m2./g
`
`11 Stability and Storage Conditions
`Cr?scarmellose sodium is a stable though hygroscopic ma(cid:173)
`tenal.
`A model tablet formulation prepared by direct com
`II
`-
`.
`. h
`pres-
`s~on~ ~1t croscarme ose sodt~m as a disintegrant, showed no
`stgmf1cant difference m drug dissolution after storage at 30oC
`for 14 months.19l
`Cr~sca~mellose sodium should be stored in a well- 1 d
`contamer m a cool, dry place.
`c ose
`
`12 Incompatibilities
`The effica~y of disintegranrs, such as croscarmello
`.
`se sodium,
`may be slightly reduced in tablet fotmul t'
`either the wet-granulation or direct-com a t~ns prepared by
`·
`· ·
`·
`· h
`pression Process th
`c
`at
`ontam ygroscop!C exctplents such as so b' 1 00)
`-~1 Ito:
`or with soluble salts of iron and so pan h Wtth strong acids
`Croscarmellose sodium is not com
`me ot er metals such as
`
`aluminum, mercury, and zinc.
`
`13 Method of Manufacture
`Alkali cellulose is prepared . by st~eping cellulose
`from wood pulp or cotta~ ftbers, m sodium hydr~ obta'neo
`. n The alkali cellulose ts then reacted with s d. Xide Sol
`b
`.
`b
`h I I
`u.
`tiO •
`0 IUnt
`chloroacetate to o tat_n ca_r oxymet Y ce lulose sodtu ntoniJ.
`the substitution reacnon ts completed and aU of thell'l. Aher
`sod,ullt
`hydroxide has been used, the excess sod1urn Ill
`acetate slowly hydrolyzes to glycolic acid. The glonorhloro.
`changes a few of the sodium car?oxymethyl group/~0t1C aCtd
`he fret
`acid and catalyzes the formation of cross links t
`croscarmellose sodium. T he croscarmellose sodiu~ Produce
`IS t~e~
`extracted with aqueous alcohol and any remainin
`chloride or sodium glycolate is removed. After pu;.fsodturn
`1 'Cat•on
`f
`·
`d.
`l
`croscarmel ose so 1um o punty greater than 99 .0
`,
`obtained.(4l The croscarmellose sodium may be Ill:!~~ 1s
`break rhe polymer fibers into shorter lengths anJ eh
`to
`.
`fl
`.
`~
`improve 1ts ow properties.
`
`14 Safety
`Croscarmellose sodium is mainly used as a disintegrant in 0 1
`pharmaceutical fo:mulations _a~d is genera_lly regarded as ~an
`essentially nontoXIC and nontrntant matenal. However, ora\
`consumption of large amounts of croscarm~llose sodium may
`have a laxanve effect, although the quantmes used in solid
`dosage formulations are unlikely to cause such problems.
`In the UK, croscarmellose sodium is accepted for use 10
`dietary supplements.
`The WHO has not specified an acceptable daily intake for
`the related substance carboxymethylcellulose sodium, used as
`a food additive, since the levels necessary to achieve a desired
`effect were not considered sufficient to be a hazard to
`health. (1
`4 l
`See also Carboxymethylcellulose sodium.
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstance~
`and quantity of material handled. Croscarmellose sodiUm mal
`be irritant to the eyes; eye protection is recommended.
`
`16 Regulatory Status
`Included in the FDA Inactive Ingredients Guide (oral capsdles
`tn
`and tablets). Included in nonparenteral medicines license
`the UK.
`
`17 Related Substances
`Carbo:J..-ymethylcellulose
`calcium;
`sodium.
`
`carboxymethylcellulose
`
`18 Comments
`~'
`Y~lca ly, the degree of substitution (DS) for cro
`l
`T '
`sodmm is 0.7.
`
`19 Specific References
`. h,rJ
`gents '" j,J
`.
`1 B
`.
`otz~lakts JE, Augsburger LL. Disintegranng Drug Vet'
`gelann capsules. Parr I : mechanism of acnon.
`(Ill
`30rlevel ',fl'
`Pharrn 1988; 14(1): 29-41.
`2 Dahl TC, Sue IT, YumA. The influence of dts,nr~rored 1P ~~­
`caps~!~ size on dissolution of hard gelatin capSU c:, 17(7): 1
`hunud1ty conditions Drttg Dev Tnd Pharm 199 '
`1016.
`.
`
`IPR2018-00390
`
`Page 45 of 88
`
`I-MAK 1012
`
`

`

`

`

`

`

`

`

`

`

`

`

`l7 Related Substances
`
`Crospovidone.
`
`18 Comments
`
`.d
`The molecular adduct forma tion properties of p
`done flla1
`be used advantageously in solutions, slow-releaseov
`I .
`SOJ -d
`p
`I f
`forms and parentera ormu at10ns. erhaps the be
`OSagt
`exam~le of povidone complex formation is povido st-knov.~
`ne;odult.
`w hich is used as a topical disinfectant.
`For accurate standardization of solutions, the war
`b d
`'d
`. db
`erconreill
`efore use a d
`of the solid povt one must e etermme
`n taket
`into accoun t for any calculations.
`
`1 1.
`
`4
`
`19 Specific References
`1 Fikentscher H, Herrle K. Polyvinylpyrrolidone. Modern PIJsr
`1945; 23(3): 157-161, 212, 214, 216,218.
`li!
`2 Becker D, Rigassi T , Bauer-Brand! A. Effectiveness of bmden
`wet granulation: comparison using model formulanons:
`different tabletability. Drug Dev lnd Pharm 1997; 23(81: -jJ.
`808.
`3 Stubberud L, Arwidsson HG, Hjorrsberg V, Graffner C. Water(cid:173)
`solid interactions. Part 3. Effect of glass transition temperJilJI(.
`Tg and processing on tensile strength of compacts of lal'tose.m.:
`lactose/polyvinyl pyrrolidone. Pharm Dev Techno/ 1996; I!
`195-204.
`Iwata M, Ueda H. Dissolution propertie of glibendamr.k rn
`combinations with polyvinylpyrrolidone. Dmg Del' Ind PhJr111
`1996; 22: 1161-1165.
`5 Lu WG, Zhang Y, Xiong QM, eta/. Development oi ruiedrp11
`(NE) pellets with a high bioavailability. Cbm Pbamz } Zhong_\'
`Yaoxue Zazhi 1995; 30(Nov Suppl): 24-26.
`.
`6 Chowdary KP, Ramesh KV. Microencapsulanon ot soM
`dispersions of nifedipine-novel approach for conrrolhng ~
`J•
`release. indian Drugs 1995; 32(0 ct): 477-483.
`7 BASF Corporation. Technical literature: Soluble Koiltdot~grJ '"
`soluble polyuinylpyrrolidone for tbe pharmacetttiCIII mdu;rn.
`p\'1' ~~
`1997.
`.
`8 Wessel W Schoog M Winkler E Polrvinylpyrrohdone I
`'
`.
`r . and con.-t-
`'
`,
`.
`_148!
`d!agnostic, therapeuric and technical app 1canon
`8
`quences thereof. Arzneimittelforsdnmg 1971; 21: 146
`do<Jf·
`9 Hizawa K, Otsuka H, Inaha H, eta/. Subcutaneou~pseuPJtr~
`comatous polyvinylpyrrolidone granuloma. Am 1 11rg
`1984; 8: 393-398.
`·!p11f~
`10 Christensen M, johansen p Hau C. Storage of pol}"''~t)ha.P11
`I'd
`·
`·
`'
`1enr WI
`1 one (PVP) m nssues followmg long-term tre~rn d 197g;2~·
`containing vasopressin preparation. Acta Med Scan
`d conr~
`295-298.
`. .
`11 FAOIWHO. Evaluation of certain food addmves ~0 e'~
`nanrs. Twenty-seventh reporr ot the joinr FAOI'I
`71 h RtP5<1
`committee on food additives. Wnrld Health Orga11 ec
`a/ MartriJI.'
`1983; No. 696.
`12 Lewis RJ, ed. Sax's Dangerous Properties of bzdustrl
`lOth edn. New York: Wiley, 2000: 3015.
`
`0
`
`20 General References
`. 131yn)
`. HG ed. At ~·
`.
`Ad
`eyeye CM, Barabas E. Povidone. In: Bnrtarn
`•1 12. Lon
`Profiles of Drug Substances and Excipients, vo · ~
`,(Ill
`racrions be;~;!'
`H Academic Press, 1993: 555--{)85.
`.
`orn D, . Dttter W. Chromatographic srudy of 1nr19g2; 71:
`polyvmylpyrrolidone and drugs. J Phamr Sc
`d~ ~
`1026.
`be stl1 •1;--
`Hs·
`prO
`6 I ,
`Iao CH, Rhodes Hj, Blake MJ. Fluorescen~ 1977; 6 :
`sulfonamide binding to povidone. ] Pharm Set
`1159. .
`999·
`ISP. Techntcalliterature: Plasdone povidone USP, 1
`
`512
`
`Povidone
`
`owth and consequently
`d
`solutions are susceptible. to mol sfrvatives
`require the addition of suttabl~ pre d . ary c~nditions without
`Povidone may be stored un er ord ~~ H owever since the
`.
`d
`· ·
`or degra anon.
`'
`.
`. h
`undergomg ecompos~no~ h
`ld be stored in an aung t
`powder is hygroscopic, It s o u
`container in a cool, dry place.
`
`Incompatibilities
`12
`· th a wide range of
`1 ·
`.
`.
`h
`h
`·
`Povidone is compatible 111 so unon WI
`d ot er c emt-
`·
`·
`h
`inorganic salts, natural and synt enc re~ms, ~n
`.
`le
`cals. It forms molecula.r adduct.s in solunon wtth sulfat~~az~nd
`sodium salicylate sahcyhc actd, phenobarbital, tannf '
`other compound~; see Section 18. The efficacy o
`some
`preservatives, e.g., thimerosal~ may ~e adversely affected by
`the formation of complexes wtth povtdone.
`
`13 Method of Manufacture
`Povidone is manufactured by the Reppe process. Acetylene and
`formaldehyde are reacted in the presence of a highl y active
`copper acetylide catalyst to fo rm butynediol, w hich is hydro(cid:173)
`genated to butanediol and then cyclodehydrogenated to form
`butyrolactone. Pyrrolidone is produced by reacting butyrolac(cid:173)
`tone with ammonia. This is followed by a vinylation reaction
`in which pyrrolidone and acetylene are reacted under pressure.
`The monomer, vinylpyrrolidone, is then polymerized in the
`presence of a combination of catalysts to produce povidone.
`
`14 Safety
`Povidone has been used in pharmaceutical formulations for
`many years, being first used in the 1940s as a plasma expander,
`although it has now been superseded for this purpose by
`dextran.<SJ
`Povidone is widely used as an excipient, particularly in oral
`