·Handbook of
`Pharmaceutical Excipients
`
`FOURTH EDITION
`
`Edited by
`
`Raymond C Rowe
`BPharm, PhD, DSc, FRPhormS, CChem, FRSC, CPhys, MlnstP
`
`Senior Principal Scientist
`
`AstroZeneco
`
`Macclesfield, UK
`
`Paul J Sheskey
`BSc, RPh
`
`Technical Service Leader
`
`Water Soluble Polymers R&D
`
`The Dow Chemical Company
`
`Midland
`
`Ml, USA
`
`Paul J Weller
`BSc, MSc, CChem, MRSC
`
`Publisher -Science and Practice
`
`Royal Pharmaceutical Society of Great Britain
`
`London, UK
`
`(RP)
`
`London • Chicago Pharmaceutical Press
`
`American
`Pharmaceutical
`Association
`
`Par Pharm., Inc.
`Exhibit 1021
`Page 001
`
`

`

`Published by the Pharmaceutical Press
`Publications division of the Royal Pharmaceutical Society of Great Britain
`
`1 Lambeth High Street, London SE 1 7JN, UK
`1 00 South Atkinson Road, Suite 206, Grayslake, IL 60030-7B20, USA
`
`and the American Pharmaceutical Association
`2215 Constitution Avenue NW, Washington, DC 20037-2985, USA
`
`© Pha rmace utica l Press an d Ameri ca n Pharmace utica l Association 2003
`
`(RP) is a trade mark o f Pharmaceuti cal Press
`
`First edition published 1986
`Second edition published 1994
`Third edition published 2000
`Fomth 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 1 582 12 022 6 (USA)
`
`All ri ghts reserved. No part of this publica tion may be
`reproduced, stored in a retri eva l system, or transmitted in any
`form or by any means, without the prior written permission
`of the copy right ho lder.
`The publisher makes no representation, express or implied,
`with rega rd to the accuracy of the informati on conta ined in
`this book a nd ca nnot accept a ny lega l respo nsibility or
`liab ility for a ny erro rs or o missions that may be made.
`
`A catalogue record fo r this book is ava ilable from the British Library
`
`Library of Congress Cataloging-in-Publication Data
`H andbook of pha rm aceut ica l excipients.- 4th eel. I ed ited by Ray mond C.
`Rowe, Paul j. Sheskey, Pa ul j. \'\feller.
`p.; cm.
`Includes bibliogra phica l references and index .
`ISBN 1-58212-022-6 (a lk. paper) - ISBN 0-85369-472-9 (a lk . paper)
`1. Excipients-Handbooks, manuals, etc.
`[DNLM: 1. Excipients-Handbooks. QV 735 H23o 2003] I. Rowe, Raymond
`C. 11. Sheskey, Paul J. III. Weller, Paul J.
`
`RS20 1.E87H36 2003
`615'. 19-<lc21
`
`2003002641
`
`Par Pharm., Inc.
`Exhibit 1021
`Page 002
`
`

`

`Crospovidone
`
`Nonproprietary Names
`
`Table 1:
`
`Pharmacopeia! specifications for crospovidone.
`
`BP: Crospovidone
`PhEur: Crospovidonum
`USPNF: Crospovidone
`
`2 Synonyms
`Crosslinked povidone; E1202; Kollidon CL; Kollidon CL-M;
`Polyplasdone XL; Polyplasdone XL-10; polyvinylpolypyrroli(cid:173)
`done; PVPP; 1-vinyl-2-pyrrolidinone homopolymer.
`
`3 Chemical Name and CAS Registry Number
`1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8]
`
`Molecular Weight
`4 Empirical Formula
`>1 000 000
`(C6H 9N0) 11
`Crospovidone is a water-insoluble synthetic crosslinked
`homopolymer of N-vinyl-2-pyrrolidinone. An exact determi(cid:173)
`nation of the molecular weight has not been established
`because of the insolubility of the material.
`
`5 Structural Formula
`See Povidone.
`
`6 Functional Category
`Tablet disintegrant.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Crospovidone is a water-insoluble tablet disinregranr and
`dissolution agent used at 2-5% concentration in tablets pre(cid:173)
`pared by direct-compression or wet- and dry-granulation
`methods.0-4l It rapidly exhibits high capillary activity and
`pronounced hydration capacity, with little tendency to form
`gels. Studies suggest that the particle size of crospovidone
`strongly influences disintegration of analgesic tablets Y 1 Lar(cid:173)
`ger particles provide a faster disintegration than smaller
`particles. Crospovidone can also be used as a so lubility
`enhancer. With the technique of co-evaporation , crospovi (cid:173)
`done can be used to enhance the solubility of poorly soluble
`drugs . The drug is adsorbed on to crospovidone in the presence
`of a suitable solvent and the solvent is then evaporated. This
`technique results in faster dissolution rate.
`
`8 Description
`Crospovidone is a white to creamy-white, finely divided, free- ·
`flowing, practically tasteless, odorless or nearl y odorless,
`hygroscopic powder.
`
`9 Pharmacopeia! Specifications
`See Table I.
`
`184
`
`Test
`
`PhEur 2002
`
`USPNF 20 (Suppl 1)
`
`Identification
`Characters
`pH ( 1% suspension)
`Water
`Residue on ignition
`Water-soluble
`substances
`Peroxides
`Heavy metals
`Vi nylpyrrolidinone
`Loss on drying
`Nitrogen content
`(anhydrous basis)
`
`+
`+
`
`~0. 1 %
`~ 1.0%
`
`~ 400ppm
`~ 10ppm
`
`~5.0%
`11.0-12.8%
`
`+
`
`5.0-8.0
`~5. 0%
`~0.4%
`~ 1.5 %
`
`~0.00 1 %
`~0.1%
`
`11.0-12.8%
`
`1 0 Typical Properties
`Acidity/alkalinity: fH = 5.0-8.0 (1% w/v aqueous slurry)
`Density: 1.22 g/cm
`Density (bulk): see Table II.
`Density (tapped): see Table II.
`
`Table II:
`
`Density values of commercial grades of crospovidone.
`
`Commercial grade
`
`Density (bulk) g/cm3 Density (tapped) g/cm3
`
`Kollidon CL
`Kollidon CL-M
`Polyplasdone XL
`Polyp/as done XL-I 0
`
`0.3-0.4
`0.15-0.25
`0.213
`0.323
`
`0.4-0.5
`0 .3-0.5
`0.273
`0.461
`
`Moisture content: ma x imum moisture sorption is approxi(cid:173)
`mately 60%.
`Particle size distribution: less than 400 pm for Polyplasdone
`XL; less than 74 pm for Po/yplasdo11e XL-10. Approxi(cid:173)
`mately 50% greater than 50 pm and maximum of 3%
`greater than 250 ~tm in size for Kollidon CL. Minimum of
`90 % of particles are below 15 ~tm for Kollido11 CL-M.
`Solubility: practicall y insoluble in water and most common
`organic solve nts.
`Specific surface area: see Table III.
`
`Table Ill:
`done.
`
`Specific surface areas for commercial grades of crospovi-
`
`Commercial grade
`
`Surface area (m2 /g)
`
`.Kollidon CL
`Kollidon CL-M
`Polyplasdone XL
`Polyp/as done XL-I 0
`
`1.0
`. 3.0-6.0
`0.6-0.8
`1.2-1.4
`
`Par Pharm., Inc.
`Exhibit 1021
`Page 003
`
`

`

`SEM 1
`ExcifJient: Crospovidone (Polyplasdone XL- 10)
`lvJanufacturer: ISP Corp.
`Lot No. : S8 1031
`lvJagnificntion: 400 x
`Voltage: 10 kV
`
`11 Stability and Storage Conditions
`
`Since crospovidone is hygroscop ic, it should be stored in an
`airtight container in a cool, dry place.
`
`12
`
`Incompatibilities
`
`Crospovi done is compatible with most orga nic and inorgan ic
`pharmaceutical ingredients. \X7hen exposed to a high water
`level, crospovidone m ay form molec ular adducts with some
`materials; see Povidone.
`
`13 Method of Manufacture
`Acetylene and formaldehyde are reacted in the presence of a
`highly active catalyst to form butyned iol , which is hydroge(cid:173)
`nated to butanediol and then cyclodeh ydrogenated to fo rm
`butyrolactone. Pyrrolidone is produced by reacting butyrolac(cid:173)
`tone with ammonia. This is followed by a vinylation reaction
`in w hich pyrrolidone and acetylene are reacted under pressure.
`The monomer vinylpyrro lid one is then polymerized in solu(cid:173)
`tion, using a cata lyst. Cros povidone is prepared by a 'popcorn
`polymerization' process.
`
`14 Safety
`Crospovidone is used in oral pharmace utica l formulations and
`is generally regarded as a nontoxic and nonirritant material.
`Short-term animal toxicity studies have shown no adverse
`effects associated with crospovidone.(Gl However, owing to
`the lack of ava il able data , an acceptable daily intake in humans
`has not been specified by the WHO. (G)
`
`LDso (mouse, IP): 12 glkg
`
`Crospovidone
`
`185
`
`1 5 Handling Precautions
`Observe normal precautions appropriate to the circ umstances
`and quantity of material handled . EyP- protection, gloves, and a
`dust mask are recommended.
`
`16 Regulatory Status
`Accepted for use as a food additive in Europe. Included in the
`FDA Inactive Ingredients Guide (ora l capsules and tablets;
`topical, transderma l, and vaginal preparations). Included in
`nonparenteral medi cines licensed in the UK.
`
`17 Related Substances
`
`Povidone.
`
`18 Comments
`
`Crospovidone has been studied as a superdisintegra nt. T he
`a bili ty of the compou nd to swell has been exa mined directl y
`using scanning electron microscopy. (?) The impact of crospo(cid:173)
`vidone on percolation has also been examined. (S) The impact
`of crospovidone on dissolution of poorly soluble drugs in
`tablets has also been investigated.( 9 l
`
`19 Specific References
`Kornblum SS, Stoopak SB. A new tablet disintegrating agent:
`crosslinked polyvinylpyrrolidone. J Phar111 Sci 1973; 62: 43-49 .
`2 Rudnic EM, l a usier JM, Chilamkurti RN, Rhodes CT. Studies of
`the utility of c ross linked polyvinylpolypyrrolidine as a tablet
`disinregra nt. Dmg Dev Ind Phar111 1980; 6: 291-309.
`3 Gordon MS, Cho whan ZT. Effect of tablet solubility and
`hygroscopicity on disintegrant efficiency in direct compression
`tablets in terms of dissolution. J Pharm Sci 1987; 76: 907- 909 .
`4 Gordon MS, Rudraraju VS, Dani K, Chowhan ZT. Effect of the
`mode of su per disinregrant incorporation on dissoluti on in wet
`gra nul ated tablets. J Pharm Sci 1993; 82: 220-226 .
`5 Sch iermeier S, Schmidt PC. Fast dispersible ibuprofe n tablets. Eur
`j Phar111 Sci 2002; 15(3): 295- 305 .
`6 FAO/\VHO. Eva luation of certa in food additi ves and contami(cid:173)
`nants. Twenty-seventh report of the joi nt FAO/\XIHO expert
`commirtee on foo d additives. World Health Organ Tech Rep Ser
`1983; No. 696.
`7 Thibert R, Hancock BC. Direct visuali za tion of superdisinregrant
`hydration using environmental sca nning electron microscopy. J
`Pharm Sci 1996; 85: 1255-1258.
`8 Ca raba llo I, Fernandez-Arevalo M, Millan M, et al. Influence of
`disinregrant on the drug percolation threshold in tablets. Drug
`Dev Ind Pharm 1997; 23(7): 665-669 .
`9 Yen SY, Chen CR, lee MT, Chen LC. In vestigation of dissolution
`enhancement of ni fed ipine by deposition on superdisintegrants.
`Dmg Dev Ind Pharm 1997; 23(3) : 313-317.
`
`20 General References
`Barabas ES, Adeyeye CM. Crospovidone. In: Brittain HG, eel.
`Analytical Profiles of Dmg Substances and Excipients, vo l. 24.
`London: Academic Press, 1996: 87-163.
`BASF. Technical literature: Insoluble Kollidon grades, 1996.
`ISP. Technical literature: Polyplasdone crospovidone NF, 1999.
`Wa n LSC, Prasad KPP. Uptake of water by excipients in tablets. lnt J
`Pharm 1989; 50: 147-153.
`
`21 Authors
`
`X He, AH Kibbe.
`
`22 Date of Revision
`25 October 2002 .
`
`Par Pharm., Inc.
`Exhibit 1021
`Page 004
`
`

`

`Povidone
`
`Nonproprietary Names
`
`5 Structural Formula
`
`BP: Povidone
`JP: Povidone
`PhEur: Povidonum
`USP: Povidone
`
`2 Synonyms
`Plasdone;
`Kollidon;
`poly[1-(2-oxo-1-pyrro(cid:173)
`E1201;
`lidinyl)ethylene]; polyvidone; polyvinylpyrrolidone; PVP;
`1-vinyl-2- pyrrolidinone polymer.
`
`3 Chemical Name and CAS Registry Number
`
`1-Ethenyl-2-pyrrolidinone homopolymer [9003-39-8]
`
`Molecular Weight
`4 Empirical Formula
`(C6H9NO),
`2500-3 000 000
`The USP 25 describes povidone as a synthetic polymer
`consisting
`essentially of
`linear 1-vinyl-2-pyrrolidinone
`groups, the differing degree of polymerization of which results
`in polymers of various molecular weights. It is characterized by
`its viscosity in aqueous solution, relative to that of water,
`expressed as a K-va lue, ranging from 10 to 120. The K-value
`is calculated using Fikentscher's equation: ( I )
`75k' )+ /1
`log z = c J + l.Sk c
`(
`
`where z is the relative viscosity of the so lu tion of concentration
`c, k is the K-value x 10-3
`, and cis the concentration in% w/v.
`Alternatively, the K-value may be determined from the
`following equation:
`
`Clo
`
`-lH-CH2-
`
`n
`
`6 Functional Category
`Disintegrant; dissolution aid; suspending agent; tablet binder.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`
`Although povidone is used in a variety of pharmaceutical
`formulations, it is primarily used in so lid-dosage forms. In
`tableting, povidone solutions are used as binders in wet(cid:173)
`granulation processes. (2
`31 Povidone is also added to powder
`,
`blends in the dry form and granulated in situ by the addition of
`water, alcohol, or hydroalcoholic solutions. Povidone is used
`as a solubilizer in oral and parenteral formulation s and has
`been shown to enhance dissolution of poorly soluble drugs
`--6 1 Povidone solutions may also be
`from solid-dosage forms . (4
`used as coating agents.
`Povidone is additionally used as a suspending, stabilizing,
`or viscosity-increasing agent in a munber of topical and oral
`suspensions and solutions. The solubilit)' of a number of
`poorly soluble active drugs may be increased by mixing with
`povidone. See Table II.
`Special grades of pyrogen-free povidone are available and
`have been used in parenteral formulations; see Section 14.
`
`K-value
`
`300c log z ( c + l.5c log z )1 + 1.5
`V
`0. 15c + 0.003c'
`
`Table II:
`
`Uses of povidone.
`
`where z is the relative viscosity of the solution of concentration
`c, k is the K-value x 10-3
`, and cis the concentration in% w/v.
`Approximate molecular weights for different povidone
`grades are shown in Table I.
`
`Table 1:
`povidone.
`
`K-value
`
`12
`15
`17
`25
`30
`60
`90
`120
`
`Approximale molecular weighls for different grades of
`
`Approximate molecular weight
`
`2500
`8000
`10000
`30000
`50000
`400000
`1 000000
`3000000
`
`See also Section 8.
`
`508
`
`Use
`
`Concentration (%)
`
`Carrier lor drugs
`Dispersing agent
`Eye drops
`Suspending agent
`Tablet binder, tablet diluent, or coating agent
`
`10-25
`Up to 5
`2-10
`Up to 5
`0.5-5
`
`8 Description
`Povidone occurs as a fine, white to creamy-white colored,
`odorless or almost odorless, hygroscopic powder. Povidones
`with K-values equal to or lower than 30 are manufactured by
`spray-drying and occur as spheres. Povidone ·K-90 and higher
`K-value povidones are manufactured by drum drying and
`occur as plates.
`
`9 Pharmacopeia! Specifications
`See Table Ill.
`
`Par Pharm., Inc.
`Exhibit 1021
`Page 005
`
`

`

`Table Ill:
`
`Pharmacopeia! specifications for povidone.
`
`Test
`
`JP 2001
`
`PhEur 2002 USP 25
`(Suppl4.3)
`
`+
`+
`
`3.0-5.0
`4.0-7.0
`+
`+
`~ 5.0%
`~ 0.1%
`
`+
`
`3.0-7.0
`
`~ 5 . 0%
`~ 0.1%
`~ 10ppm
`~ 0.05 %
`~ 1 ppm
`~ 0 .2%
`
`+
`
`~5. 0%
`~0 .1 %
`
`ldentif.ication
`Characters
`pH
`K ~ 30
`3.0-5.0
`K> 30
`4.0-7.0
`Appearance of solution +
`Viscosity
`Water
`Residue on ignition
`Lead
`~ 500 ppmlaJ ~ 500 ppmlaJ
`Aldehydes
`Hydrazine
`~ 1 ppm
`~ 1 ppm
`Vi nylpyrrol id i none
`~ 1 0 ppm
`~ 1 0 ppm
`~ 400 ppmibJ ~ 400 ppmlbJ
`Peroxides
`K-value
`10- 120
`25-90
`90.0-108.0% 85.0-115.0% 85.0-115.0%
`~ 15
`>15
`90.0-108.0% 90.0-108 0% 90.0-108.0%
`~ 1 0 ppm
`~ 1 0 ppm
`Heavy metals
`Assay {nitrogen content) 11.5-12.8% 11.5-12.8% 11.5-12.8%
`
`loJ Expressed as acetaldehyde.
`
`lbl Expressed as hydrogen peroxide.
`
`1 0 Typical Properties
`Acidity/alkalinity: pH = 3.0-7.0 (5% w/v aqueous solution).
`Density (bulk): 0.29-0.39 g/cm 3 for Plasdone.
`Density (tapped): 0.39-0.54 g/cm3 for Plasdone.
`Density (true): 1.180 g/cm 3
`Flowability:
`20 g/s for povi~ne K -15
`16 g/s for povidone K-29/3 2
`Melting point: softens at 150 C.
`Moisture content: povidone is very hygroscopic, significant
`amounts of moi sture being absorbed at low relative humid (cid:173)
`ities. See Figures 1 and 2.
`
`50,--------------------------------.
`
`u 40
`'1n
`N
`0
`~
`.2 30
`"' ·a
`E
`E
`::J
`~ 20
`·:;
`CT w
`
`10
`
`0 o
`
`Figure 1:
`
`Relative humidity (%)
`Sorption-desorption isotherm of povidone K-15 (P/asdone
`K-15).
`
`w 100
`
`Povidone
`
`509
`
`u 40
`'1n
`N
`0
`~
`.2 30
`- ~
`0
`E
`E
`::J
`~ 20
`·:;
`CT
`w
`
`10
`
`0
`
`0
`
`Figure 2:
`
`1 0
`
`20 30 40 50 60 70 80 90 1 00
`Relative humidity (%)
`Sorption-desorption isotherm of povidone K-29 /32
`(Piasdone K-29/32).
`
`Particle size distribution:
`5% >200 ~tm
`Kollido!l25/30: 90% >50 ~tm, 50% >100 Jlm
`1
`Kollidon 90: 90% >200 ~tm, 95% >250 ~un 1 1
`Solubility:
`freely soluble
`in acids, chloroform, ethanol,
`ketones, methanol, and water; practically inso luble in
`ether, hydrocarbons, and mineral oil. In water, the concen(cid:173)
`tration of a solution is limited only by the viscosity of the
`resulting solution, which is a function of the K-value.
`Viscosity (dynamic): the viscosity of aqueous povidone solu(cid:173)
`tions depends on both the concentration and the molecul<:r
`weight of the polymer employed. See Tables IV and V. (7)
`
`Table IV: Dynamic viscosity of 10% w/v aqueous povidone
`(Kollidon) solutions at 20' C.I7t
`
`Grade
`
`K-11/14
`K-16/18
`K-24/27
`K-28/32
`K-85/95
`
`Dynamic viscosity (mPa s)
`
`1.3-2.3
`1.5-3 .5
`3.5-5.5
`5 .5-B .5
`300-700
`
`Dynamic viscosity of 5% w/v povidone (Kollidon) solutions
`Table V:
`in ethanol and propan-2-ol at 25"C.i71
`
`Grade
`
`K-12PF
`K-17PF
`K-25
`K-30
`K-90
`
`Dynamic viscosity (mPa s)
`
`Ethanol
`
`Propan-2-ol
`
`1.4
`1.9
`2.7
`3.4
`53.0
`
`2.7
`3.1
`4.7
`5.8
`90.0
`
`Par Pharm., Inc.
`Exhibit 1021
`Page 006
`
`

`

`510
`
`Povidone
`
`SEM: 1
`ExcifJieut: Povidone K-15 (Piasdoue K-15)
`Mauufacturer: ISP
`Lot No .: 82A- l
`Maguificatiou : 60 x
`Voltage: 5 kV
`
`SEM: 3
`Excipieut: Povidone K-26/28 (Piasdoue K-26/28)
`!vlauufacturer: ISP
`Lot No.: 82A-2
`Maguificatiou: 60 x
`Voltage: 5 kV
`
`~~~~*
`
`SEM: 2
`Excipieut: Povidone K-15 (Piasdoue K-15)
`Mauufacturer: ISP
`Lot No.: 82A-1
`Maguificatiou: 600 x
`Voltage: 5 kV
`
`SEM: 4
`Excipieut: Povidone K-26/28 (Piasdoue K-26128)
`Mauufacturer: ISP
`Lot No.: 82A-2
`!vlaguificatiou: 600 x
`Voltage: 10 kV
`
`Par Pharm., Inc.
`Exhibit 1021
`Page 007
`
`

`

`SEM: 5
`Excipie11t: Povidone K-30 (Piasdo11e K-30)
`Ma1111(acturer: ISP
`Lot No.: 82A-4
`Mag11i(ication: 60 x
`
`SEM: 7
`Excipie11t: Povidone K-29/32 (Piasdo11e K-29132)
`Mallu(acturer: ISP
`Lot No.: 82A-3
`lvlag11i(icatio11: 60 x
`Voltage: 5 kV
`
`Pov id o ne
`
`511
`
`SEM: 8
`Excipie11t: Povidone K-29/32 (Piasdo11e I<-29132)
`lvla1111(acturer: !SP
`Lot No.: 82A-3
`Mag11i(icatio11: 600 x
`Voltage: 10 kV
`
`SEM: 6
`Excipie11t: Povidone K-30 (Piasdo11e K-30)
`Mallu(acturer: !SP
`Lot No. : 82A-4
`Mag11i(icatio11: 600 x
`Voltage: 10 kV
`......---
`
`....,.
`
`11 Stability and Storage Conditions
`Povidone darkens to some extenr on heating at 150°C, with
`a reduction in aqueous solubility. lt is stable to a short cycle
`of hea t exposure around 110-130°C; stea m sterilization of
`an aqueous solution does not alter its properties. Aqueous
`
`Par Pharm., Inc.
`Exhibit 1021
`Page 008
`
`

`

`512
`
`Povidone
`
`solutio ns are susceptible to mold growth and conseq uentl y
`require th e add ition of suita ble preserva tives.
`Povidone ma y be stored under ordinary conditions without
`undergoing decomposition or degradation. However, since the
`powder is hygroscopic, it shou ld be stored in an airtight
`conta iner in a cool, dry place.
`
`Incompatibilities
`12
`Povidone is compatible in so lution with a wide range of
`inorganic sa lts, natural and synthetic resin s, and other chemi (cid:173)
`ca ls. It forms molecular adducts in solution with sulfathiazole,
`sod ium sa licylate, sa licylic acid , phenobarbital, tannin , and
`other compounds; see Section 18 . The efficacy of some
`preservatives, e.g., thimerosal, may be adversely affected by
`the form ation of complexes with povidone.
`
`13 Method of Manufacture
`
`Povidone is manufac tured by the Reppe process. Acetylene and
`formaldehyde are reacted in the presence of a highly active
`copper acetylide ca talyst to form butynediol, which is hydro(cid:173)
`genated to butanediol and then cyclodehydrogenated to form
`butyrolactone. Pyrrolidone is produced by reacting buryrolac(cid:173)
`tone with ammonia. T his is followed by a vinylation reaction
`in which pyrrolidone and acetylene are reacted under pressure.
`The monomer, vinylpyrrolidone, is t hen polymerized in the
`presence of a combination of ca talysts to produce povidone.
`
`14 Safety
`
`Povidone ha s been used in pharmaceutica l formu lations for
`many years, being first used in the 1940s as a plasma expander,
`a lthough it has now been superseded for this purpose by
`dextran. (B)
`Povidone is widely used as an excipient, particul arl y in oral
`ta blets and so lutions. When consumed ora lly, povidone ma y
`be regarded as essentially nontox ic since it is not absorbed
`from the gastrointestina l tract or mucous membranes.<B) Povi(cid:173)
`done additionally has no irritant effect on the skin and ca uses
`no sensitization.
`Reports of adverse reactions to povidone primarily concern
`the formation of subcuta neous granulomas at the inj ection site
`of intramuscular injections formulated with povidone.<9
`) Evi(cid:173)
`dence also exists that povidone may accumu late in the organs
`of the bod y fo llow ing intramuscular inj ecti on.< IO)
`A temporary acceptable daily intake for povidone has been
`set by the WHO at up to 25 m g/kg body-weighr. <ll )
`LD so (mouse, IP ): 12 g/kg< 12
`
`)
`
`15 Handling Precautions
`
`Observe normal precautions appropriate to the circumsta nces
`and quantity of material handled. Eye protection, gloves, and a
`dust m ask are recommended.
`
`16 Regulatory Status
`
`Accepted in Europe as a food additive. Included in the FDA
`Inactive Ingredients Guide (IM and IV injections; ophthalm ic
`preparations; ora! capsu les, drops, granules, suspensions, and
`tablets; sublingua l ta blets; topical and vaginal preparations).
`Included in nonparentera l med icines licensed in the UK.
`
`17 Related Substances
`Crospovidone.
`
`18 Comments
`The molecular adduct formation properties of povidone may
`be used advantageously in so lutions, slow-release solid-dosage
`forms, and parenteral formulations. Perhaps the best-known
`exa mple of povid one complex formation is povidone-iodine,
`which is used as a topica l disinfectant.
`For accurate standardi za tion of solutions, the water content
`of the solid povidone must be determin ed before use and taken
`into account for any calculations.
`
`4
`
`19 Specific References
`Fikcntscher H, Herrle K. Pol yvin ylpyrro lidone. Modem Plastics
`1945; 23(3): 157-161 , 2 12,2 14,2 16,218.
`2 Becker D, Ri gassi T , Bauer- Brandl A. Effectiveness of binders in
`wet granul at ion: comparison using model formulation s of
`di fferent tabletabilit)' · Dmg Dev l11d Pharm 1997; 23(8): 791-
`808 .
`3 Stubberud L, Arwidsson HG, Hjorrsberg V, Graffner C. Water(cid:173)
`solid interactions. Part 3. Effect of glass transition temperature,
`T~ and processing on tensi le strength of compacts of lactose an d
`lactose/polyv in yl pyrrolidone. Pharm Dev Tech11ol 1996; 1(2):
`195-204.
`Iwata M, Ueda H. Dissolution properties of glibencla mide in
`combinations with polyvinylpyrrolidone. Dmg Dev l11d Pharm
`1996; 22: 116 1-11 65.
`5 Lu WG, Z hang Y, Xiong QM, et a/. Development of nifed ipine
`(NE) pellets with a high bioava ilabi lity. Cbi11 Phar111 J Z ho11gguo
`Yao:we Zazhi 1995; 30(Nov Su ppl ): 24-26.
`6 Chowda ry KP, Ra mes h KV . Microencapsu la ti on of solid
`dispersions of nifedipine- novel approac h for controlling drug
`release . l11dia11 Dmgs 1995; 32(0ct): 4 77-483 .
`7 BASF Corporation. Technical literature: Soluble Kollido11 grades,
`soluble polyvill ylpyrrolidolle for the pharmaceutical i11dustry,
`1997.
`8 Wessel W, Schoog M, \XIinkler E. Polyvi nylpyrrolido ne (PVP), its
`diagnostic, therapeutic a nd technica l applica ti on and conse(cid:173)
`quences thereof. Arzlleimittelforsclmllg 1971; 21: 1468-1482.
`9 Hizawa K, Otsuka H , lnaba H, et a/. Subcutaneo us pse udosar(cid:173)
`comaro us polyvinylp)'ITOiiclone gra nul oma. A111 J Surg Pathol
`1984; 8: 393-398.
`10 Christensen M, Joha nsen P, Hau C. Storage of polyvin ylpyrro(cid:173)
`lidone (PVP) in tissues following long-term treatment with a PVP
`containing vasopressin preparation. Acta Med Scand 1978; 204 :
`295-298 .
`11 FAO/\'XIHO. Eva luation of certain fo od addi tives and conrami(cid:173)
`nants . Twenty-seventh report of the joi nt FAO/\VHO expert
`committee on food additi ves. \'(lo rld Health Organ Tec!J Rep Ser
`1983; No. 696.
`12 Lewis RJ, eel . Sax's Da11gerous Properties of lndustrial !vfaterials,
`lOth edn. New York: Wiley, 2000 : 30 15.
`
`20 General References
`Adeyeye CM, Barabas E. Povidone. In : Brittain I--!G, ed . Analytical
`Profiles of Drug Substances and Excipients; vol. 22. London:
`Academ ic Press, 1993 : 555-685 .
`Horn D, Ditter \XI. Chromatograp hic stud y o f in teractions between
`polyvin ylpyrrolidone and drugs. J Pharm Sci 1982; 71: 1021-
`1026 .
`I--!J, Bla ke MJ. Fluorescent pro be stud y of
`Hsiao CH , Rhodes
`sul fo namide binding to povidone. J Phar111 Sci 1977; 66: 1157-
`1159.
`ISP. Technica llitera tme: Plasdom povidone US P, 1999.
`
`Par Pharm., Inc.
`Exhibit 1021
`Page 009
`
`

`

`Jager KF, Bauer KH. Pol)'mer blends from PVP as a means to optimize
`properties of fluidized bed granulates and tablets. Acta Pharm
`Tech11ol 1984; 30(1): 85-92.
`Plaizier-Vercammen JA, DeNeve RE. Interaction of povidone with
`aromatic compounds Ill: thermo'd)'namics of the binding equili bria
`and interaction forces in buffer sol uti ons at var)'ing pH values and
`var)'ing dielectric constant. J Pharm Sci 1982; 71 : 552-556.
`Robinson BY, Sullivan FM, Borzelleca JF, Schwartz SL. PVP: A
`Critica l Review of the Ki11etics a11d Toxicology of PolyviHylpyrro(cid:173)
`lidoHe (Povido11e). Chelsea, Ml: Lewis Publishers, 1990.
`Shefter E, Cheng I< C. Drug-pol)'vin)'lp)'rrolidone (PVP) dispersions. A
`differential scanning calorimetric stud)'. l11t] Pharm 1980; 6: 179-
`182.
`
`Pov id one
`
`513
`
`Smolinske SC. Ha11dboo.~ of Food, Dmg, and Cosmetic Excipie11ts.
`Boca Raton, FL: CRC Press, 1992: 303-305.
`
`21 Author
`AH Kibbe.
`
`22 Date of Revision
`30 October 2002 .
`
`Par Pharm., Inc.
`Exhibit 1021
`Page 010
`
`

`

`Starch
`
`Nonproprietary Names
`
`S Structural Formula
`
`Q~H,OH O t H q~H,OH O
`
`~ H
`
`~ H
`
`~
`
`H
`
`~
`
`H
`
`~
`
`H ~~H,OH O
`
`H
`
`~ H
`
`~
`
`H
`
`~
`
`n = 300 to 1000
`~
`
`Amylose
`
`Glucose
`unit
`
`cH,OH ~CH,OH
`OH
`H
`
`H
`
`H
`OH
`
`H
`
`H
`
`OH
`
`H
`
`OH
`
`ol
`
`-o
`
`q
`o
`- o vt-:'-J o
`o -~ H
`
`CH,OH qcH,
`0
`H
`0
`H
`H
`
`H
`
`H
`
`H
`
`OH
`
`o"
`
`"
`
`OH
`
`Segment or arnylopeclm molecule
`
`6 Functional Category
`Glidant; tablet and capsu le diluent; tablet and capsu le disin(cid:173)
`tegrant; tablet binder.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Starch is used as an excipient primarily in oral solid -dosage
`formulations where it is utili zed as a binder, diluent, and
`disintegrant.
`As a di luent, starch is used for the preparation of standar(cid:173)
`dized triturates of colorants or potent drugs to facilitate
`subsequent mixing or blending processes in manufacturing
`operations. Starch is also used in dr)'-filled cawule formula(cid:173)
`tions for volume adjustment of the fill matrix. ( )
`In tab let formulations, freshly prepared starch paste is used
`at a concentration of 5-25% w/w in tablet granu lations as a
`binder. Selection of the quantity required in a given S)'Stem is
`determined b)' optimi zation studies, using parameters such as
`granu le fr iability", tablet friability, hardness, disintegration
`rate, and drug dissolution rate.
`Starch is one of the most commonlr used tablet disinte(cid:173)
`grants at concentrations of 3-15% w/w. c -9
`) However, unmod(cid:173)
`ified starch does not compress well and tends to increase tablet
`friabilit)' and capping if used in high concentrations. In
`
`603
`
`JP:
`
`BP:
`
`Maize starch
`Potato starch
`Rice starch
`Tapioca starch
`Wheat starch
`Corn starch
`Pot a to starch
`Rice starch
`Wheat starch
`PhEur: Maydis amylum (maize starch)
`Solani amylum (potato starch)
`Oryzae amylum (rice starch)
`Tritici amylum (wheat starch)
`USPNF: Starch
`Note that the USPNF 20 describes starch, in a single mono(cid:173)
`graph, as being obtained from either the mature grain of corn,
`Zea mays, or of wheat, Tritic11111 aestiu11m, or from tubers of
`the potato, Solan11m t11berosllm, or of tapioca, Manihot
`11tilissima. The PhEur 2002 has individual monographs for
`each of these starches, except for tapioca starch, along with
`an additional monograph for rice starch, Oryza sativa. The
`BP 2001 similar!)' describes maize, potato, rice,
`tapioca
`(cassava), and wheat starch
`in
`individual monographs,
`tapioca starch being obtained from the rhizomes of Manihot
`11tilissima Pohl. The JP 2001 similar!)' describes corn (maize),
`rice, potato and wheat starch in separate monograph s. See also
`Section 18.
`
`2 Synonyms
`Amido; amidon; am il o; amy lum; Aytex P; Fl11(tex W; Instant
`P11re-Cote; M.elojel; Meritena; Paygel 55; Perfectamyl D6PH;
`P11re-Bind; Pure-Cote; P11re-Dent; Pure-Gel; P11re-Set; P11rity
`21; P11rity 826; Tab let White.
`See also Sections 1 and 18.
`
`3 Chemical Name and CAS Registry Number
`Starch [9005-25-8]
`
`4 Empirical Formula
`
`Molecular Weight
`50 000-160 000
`
`(CGH, oOs)"
`where 11 = 300-1000.
`Starch consists of am)'lose and amylopectin, two pol)'sac(cid:173)
`charides based on IX-glucose. See also Sections 5 and 17 .
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Par Pharm., Inc.
`Exhibit 1021
`Page 011
`
`

`

`604
`
`Starch
`
`granulated formulations, about half the total starch content is
`included in the granulation mixture and the balance as part of
`the final blend with the dried granulation. Also starch when
`used as a disintegrant exhibits type II isotherms and has a high
`specific surface for water sorption. <IOl
`Starch has been investigated as an excipient in novel drug
`13
`delivery systems for nasal,<'' ' oral,< 12
`' peridontal, <14l and
`•
`other site-specific delivery systems. <IS )
`Starch is also used in topical preparations; for example, it is
`widely used in dusting powders for its absorbency, and is used
`as a protective covering in ointment formulations applied to
`the skin. Starch mucilage has also been applied to the skin as an
`emollient, has formed the base of some enemas, and has been
`used in the 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 25oC.
`Compressibility: see Figure 1.
`Density (bulk): 0.462 g/cm 3 for corn starch.
`Density (tapped): 0.658 g/cm 3 for corn starch.
`Density (true): 1.4 78 g/cm 3 for corn starch.
`Flowability: 10.8-11.7g/s for corn starch ·<9l 30% for corn
`starch (Carr compressibility index). < I G) 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 h~groscopic and rapidly
`absorb atmospheric moisture. <17
`1 1 Approximate equili(cid:173)
`•
`brium moisture 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, corn starch is the least hygroscopic
`starch and potato starch is the most hygroscopic. Commer(cid:173)
`cially available grades of corn starch usually contain 10-
`14% water. See also Figures 2 and 3.
`Particle size distribution:
`Corn starch: 2-32 ~1m
`Potato starch: 10-100 ~un
`Rice starch: 2-20 ~1m
`Tapioca starch: 5-35 ~un
`Wheat starch: 2-45 ~1111
`Median diameter for corn starch is 17 ~1m and for wheat starch
`is 23 ~1111.
`Solubility: practically insoluble in cold ethanol (95 %) and in
`cold water. Starch swells instantaneously in water by about
`
`181 Pol yva lent ca tions produce more
`5-10% at 37 c.< 2
`•
`swelling than monovalent ions, but pi-I has little effect.
`Specific surface area:
`0.41-{).43 m2/g for corn starch
`O.J2m 2/g for potato starch
`0.27-D.31m 2/g for wheat starch
`Swelling temperature:
`65 C for corn starch
`64 C for potato starch
`55"C for wheat starch
`Viscosity (dynamic): 13 .0mPas (13.0cP) for a 2% w/v aque(cid:173)
`ous dispersion of corn starch at 25 C.
`
`Table 1:
`
`Pharmacopeia! specifications for starch .
`
`Test
`
`JP 2001
`
`PhEur 2002
`
`USPNF 20
`
`Identification
`Botanic
`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 storch
`Tapioca starch
`Wheat starch
`Sulfur dioxide
`Corn starch
`Potato starch
`Wheat starch
`Total protein
`Corn starch
`Rice starch
`Potato starch
`Wheat starch
`Foreign matter
`
`+
`+
`
`+
`
`4.5-7.0
`5.0-8.0
`4.5-7.0
`4.5-7.0
`
`~ 14.0%
`
`~ 14 . 0%
`~