060000000^9135
`
`Handbook of
`Pharmaceutical Excipients
`Sixth edition
`
`Edited by
`
`. *
`
`EXHIBIT
`
`Apotex (IPR2019-00400) Ex. 1047 p. 001
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`

`

`Handbook of
`Pharmaceutical Excipients
`
`SIXTH EDITION
`
`Edited by
`Raymond C Rowe BPharm, PhD, DSC, FRPharmS, FRSC, CPhys; MlnstP
`Chief Scientist
`Intelligensys Ltd, Stokesley, North Yorkshire, UK
`
`Paul J Sheskey bsc, rph
`Application Development Leader
`The Dow Chemical Company, Midland, Ml, USA
`
`Marian E Quinn bsc, msc
`Development Editor
`Royal Pharmaceutical Society of Great Britain, London, UK
`
`Katten
`
`Katten Machin Rosenman llp
`MAY 0 9 2018
`
`LIBRARY CHARLOTTE
`
`_____
`
`APhA
`
`London . Chicogo Pharmaceutical Press
`
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`

`

`Published by the Pharmaceutical Press
`An imprint of RPS Publishing
`
`1 Lambeth High Slreet, London SEI 7JN, UK
`100 South Atkinson Road, Suite 200, Grayslake, IL 60030-7820, USA
`
`and the American Pharmacists Association
`2215 Constitution Avenue, NW, Washington, DC 20037-2985, USA
`
`© Pharmaceutical Press and American Pharmacists Association 2009
`
`pp is a trade mark of RPS Publishing
`
`RPS Publishing is the publishing organisation of rhe Royal Pharmaceutical Society of Great Britain
`
`First published 1986
`Second edition published 1994
`Third edition published 2000
`Fourth edition published 2003
`Fifth edition published 2006
`Sixth edition published 2009
`
`Typeset by Data Standards Ltd, Frome, Somerset
`Printed in Italy by L.E.G.O. S.p.A,
`
`ISBN 978 0 35369 792 3 (UK)
`ISBN 978 1 58212 135 2 (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 dialogue record for this book is available from the British Library
`
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`

`

`LSC, Lai WE Factors affecting drug release from drag-coated
`es prepared by fluidized-bed coating. Ini J Pharm 1991; 72:163-
`
`ik H el al. The influence of selected properties on the stability of
`iccuttcal emulsions. Phannaiie 1991; 46: 120-125.
`Niirtirkar MM i’> riir- and w evaluation of sustained
`■ t'cnsfons of ibuprofen, bit J Piiann 1991; 73: 157-162.
`»d A ct al. Formulation and stabilitv ot saluzidc eye drops,
`r bid 1987; 49: 751-754.
`iri A, Karlsson A. Viscosity stability of methylcellulose solutions
`event pH and temperature. Acta Pharm Fenn 1989; 98(4): 231-
`
`tri A. Effect of heat sterilization on the viscosity of methylcellulose
`mis. Acta Pharm Fenn 1986; 95(1): 9-17.
`tri A el al. Effect of heat sterilization on the molecular weight of
`-kellulose determined using high pressure gel filtration chromato-
`and viscometry. Acta Pharm Fenn 1986; 95(3): 105-111.
`.-s. Final report on the safety assessment of hydwxyethylcel
`tudroxypropykeUulose, methylceliulpse, hydro^yprbpyJ
`ic .-llulose and cellulose gum. / Aw Coll Toxicol 1986; 5(31: 1-60.
`'. -i'). Evaluation of certain food additives and contaminants.
`-report of the joint FAO/WHO expert committee on food
`r» WAirld Hcali’: Organ Tech Rep Ser 1990: No. 789.
`?.:. -d. Sax’s Dangerous Properties of Industrial Materials. 11th
`New York: Wiley, 2004; 2408.
`*ell K :-t al. Influence of drugs on the properties of gelsand swelling
`ctens- t>f matrices containing methylcellulose or hydroxypro-
`■ ■. . t ilokot' hit J Pharnt 1993; 10011—3i: 165-173.
`K A, Kristoffersson E. Rheological properties of mcthylcrllulose
`. s- general flow properties and effects of added substances. Acta
`Kfenn 1985; 94(4i: 143-154.
`pesz E Puskas I. Controlling the physical stability of liposomal
`ds. Tadros Th, ed. Colloid Stability and Application in Pharmacy.
`helm, Germany: Wiley-VCH, 2007; 79-89.
`I Chemicals Codex, 6th edn. Bethesda, MD: United States
`nacopeia, 2008; 618.
`
`Melhylpcraben 441
`
`20 General References
`Doelker E. Cellulose derivatives. Adv Polym Set 1993; 107: 199-265.
`Dow Chemical Company. Material safety data sheet: Methocel A4M, 2004.
`European Directontn. lor ihe Quality of Medicines and Healthcare
`1 DQMi. European Pharmacopoeia - State Of Work Of International
`Harinonisitrion. Phamienropa 2009: 21(1 fe 142-143. http:(Avww;cdq-
`m.eu/site/-614.html (accessed 3 February 2009).
`Hladon T et al. Physicochemical interactions of drugs with excipients in
`suspensions. Acta Pul Pharm 1986; 43(51: 471—480.
`Li J. Mei X. Applications of cellulose and cellulose derivatives in immediate
`release solid dosage.ACS Symposhrm Series, 934Fori'Succ/f.i.'«les for
`Drug Delivery and Pharmaceutical Appkcaiions, 2006; 19-55.
`Mitchell K et al. Influence of substitution type on the performance of
`methylcellulose and hydroxypropylmethvlcellulose in gels and matrices,
`for / Pharm 1993; 100.1-3): 143-154. '
`Oxford Univci-ity. Material safety data sheet: Methyl Cellulose, 2006.
`httpyfoi.s<.ls.chcm.ox.ac.uk/ME.methyl_cetlulose.html (accessed 3 Febru­
`ary 2009).
`Rowe RC. The molecular weight of methyl cellulose used in pharmaceutical
`formulation, bit J Pharml^Sh 11: 175-179.
`Tapia Villanueva 0. Sapag Hagar J. Methylcellulose: its pharmaceutical
`applications. Acta Fann B'htaetense 1995; 14(Jan-Mar): 41-47.
`Wan LS. Prasad KP. Influence of quantity of granulating liquid on water
`aptfikc and disintegration of tablets with methylcellulose. Pharm Ind
`1989; 51(1): 105-109.
`,
`Wan LS, Prasad KP. Studies on the swelling of composite disintegrant-
`methylcellulose films. Drug Dev Ind Pharm 1990; 16(2): 191-200.
`
`21 Authors
`LV Allen Jr, PE Luner.
`
`22 Date of Revision
`3 February 200.9.
`
`Methylparaben
`
`■^proprietary Names
`hyl Hydroxybenzoate
`tvl Parahydroxybenzoate
`Methyl Parahydroxybenzoate
`: Methylparaben
`
`5
`
`Structural Formula
`
`tnonyms
`s-.-r Al; CoSept M; E218; 4-hydroxybenzoic acid methyl
`Methyl Chemosept-, methvlis parahydroxyhenzoas;
`r r.vdroxybenzoate; Methyl Parasept-, Nipagin M; Solbrol
`isept M-, Uniphen P-23.
`
`hemical Name and CAS Registry Number
`4-hydroxybenzoate [99-76-3]
`
`mpirical Formula and Molecular Weight
`t 152.15
`
`OH
`
`6
`Functional Category
`Antimicrobial preservative.
`
`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`Methylparaben is widely used .is an antimicrobial preservative in
`cosmetics, food products, and pharmaceutical formulations; see
`Table I. It may be used either alone or in cOmbraatioti with other
`
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`

`442 Methylparaben
`
`parabens or with other antimicrobial agents. In cosmetics,
`methylparaben is tire most frequently used antimicrobial preserva­
`tive. (j|
`The parabens are effective over a wide pH range and have a
`broad spectrum of antimicrobial activity, although they arc most
`effective against yeasts and molds. Antimicrobial activity increases
`as the. chain length of the alkyl moiety is increased, but aqueous
`solubilitt decreases; therefore a mixture of parabens is frcqiienrly
`used to provide effective preservation. Preservative efficacy is also
`improved by the addition of propylene glycol
`or by using
`parabens in combination with other antimicrobial agents such as
`imidurea; see Section 10.
`Owing to the poor solubility of the parabens, paraben salts
`(particularly the sodium salt) are more frequently used in
`formulations. However, this raises the pH of poorly buffered
`formulations.
`Methylparaben (0.18%) together with propylparaben (0.02%i
`has been used for the preservation of various parenteral pharma­
`ceutical formulations; see Section 14.
`
`Table I: Uses of mefhylporaben.
`
`Use
`IM, IV, SC injections^
`Inhalation solutions
`Intradermal injections
`Nasal solutions
`Ophthalmic preparations^'
`Oral solutions and suspensions
`Rectal preparations
`Topical preparations
`Vaginal preparations
`
`(a) See Section 1 4.
`
`Concentrotion (%)
`0.065-0.25
`0.025-0.07
`0 10
`0.033
`0.015-0.2
`0.015-0 2
`0.1-0.18
`0.02-0.3
`0.1-0.18
`
`8 Description
`Methylparaben occurs as colorless crystals or a white crystalline
`powder. It is odorless or almost odorless and has a slight burning
`taste.
`
`Table II: Pharmacopeial specifications for methylparaben
`
`Test
`Identification
`Characters
`Appearance of
`solution
`Acidity
`Heavy metals
`Impurities
`Melting range
`Related substances
`Sulfated ash
`Residue on ignition
`Assay (dried basis)
`
`JPXV
`-4-
`—
`4-
`
`PhEur 6,0
`••1-
`
`USP32-NF27
`4-
`—
`+
`
`+
`<20 ppm
`—
`
`+
`-p
`-
`-
`-
`—
`125-128 C
`—
`-+
`+
`—
`<0.1%
`—
`—
`<0.1%
`<0.1%
`98.0-102.0% 98.0-102.0% 98 0-102
`
`10 Typical Properties
`Antimicrobial activity see Table III. Methylparaben ev*::'.:
`antimicrobial activity of pH 4-8. Preservative efficacy deer. '; ;..:
`with increasing pH owing to the formation of the phen-.- ;®
`anion. Parabens are more active against yeasts and molds s..’.
`against bacteria. They are also more active against GchM
`, ;
`positive bacteria than against Gram-negative bacteria.
`Methylparaben is the least active of the parabens; anruttc
`bial activity increases with increasing chain length of the afc
`moiety. Activity may be improved by using combinatic-:
`parabens as synergistic effects occur. Therefore, combinatic
`methyl-, ethyl-, propyl-, and butylparabcn are after
`together. Activity has also been reported to be enhanced
`addition of other excipients such as: propylene glycol (2-5
`phenylethyl alcohol;13’ and edetic acid.14’ Activity may =
`enhanced owing to synergistic effects by using combinac
`parabens with other antimicrobial preservatives such j
`durea.15’
`The hydrolysis product p-hydroxy benzoic acid has prac
`no antimicrobial activity.
`See also Section 12.
`
`I,.
`
`-.i:
`
`1; Excipient; methylparaben; supplier: Bate Chemical Co. Ltd;
`magnification: 600x.
`
`Table III: Minimum inhibitory concentrations (MICsj of rhef--/:::
`in aqueous solution.’^
`■^*'7
`
`Microorganism
`Aerobacler aerogenes ATCC 8308
`Aspergillus oryzae
`Aspergillus niger AlCC 9642
`Aspergillus nigef ATCC 10254
`Bacillus cereus vor. mycoides ATCC 6462
`Bacillus subtilis ATCC 6633
`Candida albicans ATCC 10231
`Enterobacler cloacae ATCC 23355
`Escherichia coli ATCC 8739
`Escherichia coli ATCC 9637
`Klebsiella pneumoniae ATCC 8308
`Penicil/ium chrysogenum ATCC 9480
`Penicillium digitatum ATCC 10030
`Proteus vulgaris ATCC 8427
`Proteus vulgaris ATCC 13315
`Pseudomonas aeruginosa AICC 902/
`Pseudomonas aeruginosa ATCC 15442
`Pseudomonas stutzeri
`Rhizopus r.igricans ATCC 6227A
`Saccharomrces cerevisiae AlUC 9/63
`Saimonelic iyohosa ATCC 6539
`Sarcina lulea
`Serrolia marcescens ATCC 8100
`Sfaahylococcus aureus ATCC 6538r
`Stopixyiococcus epiderrmdis ATCC 12228
`Tnchode-rma iignorum ATCC 8678
`Trichoderma menlogrpphytes
`
`9 Pharmacopeial Specifications
`See Table II. See also Section 18.
`
`‘•I
`
`S
`
`:3
`
`MIC (ag. «L
`2000
`600
`1000
`1000
`2000
`2000
`2000
`1000
`1OOC
`1000
`1000
`500
`500
`2000
`1 OOC
`4000
`4003
`2000
`500
`1003
`100"
`4003
`1003
`2003
`200v
`25C
`250
`
`: b
`
`-1
`?
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`

`Propylparaben
`
`1 Nonproprietary Names
`BP: Propyl Hydroxybenzoate
`JP: Propyl Parahydroxybenzoate
`PhEur: Propyl Parahydroxybenzoate
`USP-NF: Propylparaben
`
`2 Synonyms
`.■\septc>fcr>r, P; CoSepi P; E216; 4-hydroxybenzoic acid propyl
`ester; Nipagin P; Nipasnl M; propagin; Propyl Aseptofarm-, propyl
`fcutex; Propyl ('bentdsepl; propylis pacahydrdxybertzoas; propyl p-
`hvdroxybenzoate; Propyl Parasept: Solbrol P: 7e.«ose/..'Uniphen
`P-23.
`
`3 Chemical Name and CAS Registry Number
`Propyl 4-hydroxybenzoatc [94-13-3]
`
`4 Empirical Formula and Molecular Weight
`C10H12O3
`180.20
`
`Structural Formula
`
`Table 1: Uses of propylparaben in pharmaceutical preparaSdru.
`
`Use
`IM, IV, SC injections
`Inhalation solutions
`Intradermal injections
`Nasal solutions
`Ophthalmic preparations
`Oral solutions and suspensions
`Rectal preparations
`Topical preparations
`Vaginal preparations
`
`Concentration (%,
`6.005-0.2
`0.015
`0.02-0.26
`0.017
`0.005-0 01
`0.01-0.02
`0.02-0.01
`0.01-0.6
`0.02-0.1
`
`8 Description
`Propylparaben occurs as a white, crystalline, odorless,
`powder.
`
`9 Pharmacopeial Specifications
`See Table II.
`
`Table II: Pharmacopeial specifications for propylparaben
`
`Test
`Identification
`Characters
`Melting range
`Acidity
`Loss on drying
`Residue on ignition
`Sulfated ash
`Appearance of solution
`Heavy metals
`Related substances
`Assay
`
`JPXV
`
`-L.
`
`PhEur 6.0
`+
`
`.i-1i -
`
`-
`+
`-
`—
`$0.1%
`
`—
`96.0-99.0c’C
`+
`-
`$0.1%
`—
`d-
`$20 ppm
`-4-
`98.0-102.0% 98.0-102.0% *3 1-
`
`_ —
`
`Functional Category
`Antimicrobial preservative.
`
`Applications in Pharmaceutical Formulation or
`Technology
`Propylparaben is widely used as an antimicrobial preservative in
`cosmetics, food products, and pharmaceutical formulations; see
`Table I.
`It may be used alone,, in combination with other paraben esters,
`or with other antimicrobial agents. It is one of the most frequently
`used preservatives in cosmetics. 1
`The parabens arc effective over a wide pH range and have a
`broad spectrum of antimicrobial activity, airhough they are most
`effective against yeasts and molds; see Section 10.
`Owing to the poor solubility of the parabens, the paraben salts,
`particularly the sodium salt, are frequently used in formulations.
`This. may cause the pH of poorly buffered formulations to become
`more alkaline.
`Propylparaben (0.02% w/v) together with methylparaben
`(0.18% w/v) has been used for the preservation of various
`parenteral pharmaceutical formulations; see Section 14.
`See Methylparaben for further information.
`
`10 Typical Properties
`Antimicrobial activity
`Propylparaben exhibits antimicrobial activity betwe=
`Preservative efficacy decreases with increasing pH
`the formation of the phenolate anion. ParabetS y.
`active against yeasts and molds than against b
`are also more active against Gram-positive rurr
`Grain-negative bacteria. The activity of tze
`increases with increasing chain length of the ckr
`however, solubility decreases.
`Activity may be improved by using combinations cc :-
`additive effects occur. Propylparaben has bees: . ;
`methylparaben in parenteral preparations, ac^ *•
`combination with other parabens in topim. «
`formulations. Activity has also been reported t: re tiSt
`by the addition of other excipients; see Methyl? . . . .
`Reported minimum inhibitory concentrations
`propylparaben are provided in Table HI.12'
`Boiling point 295CC
`Density (bulk) 0.426 g/cnr’
`Density (tapped) 0.706 g/cm3
`Densityitrue) 1.288 g/cmJ
`Dissociation constant pK’s = 8.4 at 22<’C
`Flash point 140°C
`
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