|PR2015-01099
`|PR2015-01097
`|PR2015-01100
`|PR2015-01105
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`Lupin EX1167
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`IPR2015-01099
`IPR2015-01097
`IPR2015-01100
`IPR2015-01105
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`Lupin EX1167
`Page 1
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`

`
`
`
`PHARMACEUTECAL
`EXCEPE
`
`
`
`
`
`Third Edition
`
`Edited by
`
`Arthur H. Kibbe, Ph.D.
`Professor and Chair
`Department of Pharmaceutical Sciences
`Wilkes University School of Pharmacy
`Wilkes—Barre, Pennsylvania
`4
`
`APIIA
`
`American Pharmaceutical Association
`Washington, D.C.
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`Pharmaceutical Press
`
`London, United Kingdom
`
`Page 2
`
`Page 2
`
`

`
`Published by the American Pharmaceutical Association
`2215 Constitution Avenue NW, Washington, DC 20037-2985, USA
`www.aphanet.org
`and the Pharmaceutical Press
`
`1 Lambeth High Street, London SE1 7JN, UK
`www.pharmpress’.,com\
`/
`
`© 1986, 1994;//2000}merican Pharmaceutical Association and Pharmaceutical Press
`
`First edition 1986/
`Second edition 1994
`Third edition 2000
`
`Printed in the United States of America
`
`ISBN: 0-85369-381-1 (UK)
`ISBN: 0-917330-96-X (USA)
`
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients / edited by Arthur H. Kibbe.--3rd ed.
`p.
`; cm.
`Includes bibliographical references and index.
`ISBN 0-917330-96-X
`
`l. Excipients--Handbooks, manuals, etc.
`Pharmaceutical Association.
`
`I. Kibbe, Arthur H. II. American
`
`[DNLM: 1. Excipients--Handbooks. QV 735 H236 2000]
`RS201.E87 H36 2000
`6l5'.l9--dc2l
`
`A catalogue record for this book is available from the British Library.
`
`99-04-4554
`
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in
`’
`an
`by any means, without the prior written permission of the copyright holder. The publisher makes no representation g/X
`implied, with regard to the accuracy of the information contained in this book and cannot accept any legal FQS ’ Sgilit
`liability for any errors or omissions that may be made.
`pon 1
`
`y
`
`31;
`or
`
`Managing Editor: Melanie Segala
`Copyeditor:
`Paul Gottehrer
`Indexer:
`Lillian Rodberg
`Compositor:
`Roy Barnhill
`Cover Designer:
`Tim Kaage
`
`Page 3
`
`Page 3
`
`

`
`
`
`Ethylparaben
`
`SEM: 1
`Excipient: Ethylparaben
`
`600><
`
`
`
`Er/'1ylparal)en 205
`
`1. Nonproprietary Names
`
`BP: Ethyl hydroxybenzoate
`JP: Ethyl parahydroxybenzoate
`PhEur: Ethylis parahydroxybenzoas
`USP: Ethylparaben
`
`2. Synonyms
`
`Ethyl 4-hydroxybenzoate [120-47-8]
`
`Cosepz E; E214; ethyl p-hydroxybenzoate; Ethyl parasept;
`4-hydroxybenzoic acid ethyl ester; Nipagin A; Preserval E;
`Solbrol A; ’I'egosept E; Unisept E.
`
`3. Chemical Name and CAS Registry Number
`
`4. Empirical Formula Molecular Weight
`
`C9H10O3
`
`166.18
`
`5. Structural Formula
`
`O
`ll
`C-*OCH2CH3
`
`SEIVI: 2
`Excipicnt: Ethylparaben
`Magnification: 3000><
`
`OH
`
`6. Functional Category
`
`Antimicrobial preservative.
`
`the sixth most frequently used preserv_ative.(” The parabens are effective over a wide pH range and have a
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`
`Ethylparabcn is widely used as an antimicrobial preservative
`in cosmetics, food products, and pharmaceutical formulations.
`It may be used either alone, in combination with other paraben
`esters, or with other antimicrobial agents. In cosmetics it is
`
`broad spectrum of antimicrobial activity although they are
`most effective against yeasts and molds, see Section 10.
`
`Due to the poor solubility of the parabens, paraben salts, par-
`ticularly the sodium salt, are frequently used. However, this
`may cause the pH of poorly buffered formulations to become
`more alkaline.
`L
`See Methylparaben for further information.
`
`8. Description
`
`Ethylparaben occurs as a wl1ite—colored, odorless or almost
`odorless, crystalline powder,
`
`Page 4
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`Page 4
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`

`
`206 Ethylparaben
`
`9. Pharmacopeial Specifications
`
`
`
` Test JP PhEur USP
`
`Identification
`+
`+
`+
`Characters
`+
`+
`—
`Appearance of solution
`—
`+
`—
`Melting range
`116-118°C 115-118°C
`115-118°C
`Acidity
`——
`+
`+
`Loss on drying
`s 05%
`——
`S 0.5%
`Residue on ignition
`S 0.1%
`—
`S 0.05%
`Sulfated ash
`—
`5 0.1%
`—
`Chloride
`g 0.035% ——
`——
`Sulfate
`5 0.024% —
`—
`Heavy metals
`5 20 ppm —
`——
`Readily carbonizable
`+
`——
`——
`substances
`—
`+
`+
`Related substances
`+
`-—
`Organic volatile impurities —
`
`Assay (dried basis) 99.0-101.0% 99.0-100.5% 2 99.0%
`
`
`10. Typical Properties
`Antimicrobial activity: ethylparaben exhibits antimicrobial
`activity between pH 4-8. Preservative efficacy decreases
`with increasing pH due to the formation of the phenolate
`anion. Parabens are more active against yeasts and molds
`than against bacteria. They are also more active against
`Gram-positive than against Gram-negative bacteria.
`
`The activity of the parabens increases with increasing
`chain length of the alkyl moiety; solubility however
`decreases. Activity may be improved by using combina-
`tions of parabens since additive effects occur. Ethylparaben
`is thus commonly used with methyl and propylparaben in
`oral and topical formulations. (Such mixtures are commer-
`cially avajlable, e.g., Nipasept (Nipa Laboratories Inc.)). Activity
`has also been reported to be improved by the addition of other
`excipients, see Methylparaben for further information.
`
`Reported minimum inhibitory concentrations (MICs) for
`ethylparaben are shown in Table 1.91
`
`Boiling point: 297-298°C With decomposition
`Melting point: 115-118°C
`Partition coefficients: values for different vegetable oils vary
`considerably and are affected by the purity of the oil, see
`Table II.
`Solubility: see Table III.
`
`11. Stability and Storage Conditions
`
`Aqueous ethylparaben solutions at pH 3-6 can be sterilized
`by autoclaving without decomposition“) At pH 3-6 aqueous
`solutions are stable (less than 10% decomposition) for up to
`about 4 years at room temperature while solutions at pH 8 or
`above are subject to rapid hydrolysis (10% or more after about
`60 days at room temperature).(5’
`Ethylparaben should be stored in a well—c1osed container in
`a cool, dry, place.
`
`12. Incompatibilities
`
`The antimicrobial properties of ethylparaben are considerably re-
`duced in the presence of nonionic surfactants as a result of mi-
`cellization.‘-63 Absorption of ethylparaben by plastics has not been
`reported and appears probable given the behavior of other para-
`bens. Ethylparaben is coabsorbed on silica in the presence of
`
`Table 1: Minimum inhibitory concentrations (MICs) for
`ethylparaben in aqueous solution!”
`Microorganism
`MIC (V-8/ml-)
`
`1200
`Acrobacter aerogenes ATCC 8308
`500
`Aspergillus niger ATCC 9642
`400
`Aspergillur niger ATCC 10254
`1000
`Bacillus cereus var. mycoides ATCC 6462
`1000
`Bacillus subtilis ATCC 6633
`500
`Candida albicans ATCC 10231
`1000
`Enterobacter cloacae ATCC 23355
`1000
`Escherichia coli ATCC 8739
`1000
`Escherichia coli ATCC 9637
`500
`Klcbsiella pneumoniac ATCC 8308
`250
`Peuicillium chrysogenum ATCC 9480
`250
`Penicillium digitatum ATCC 10030
`500
`Proteus vulgaris ATCC 13315
`> 2000
`Pseudomonas aeruginosa ATCC 9027
`> 2000
`Pseudomonas aeruginosa ATCC 15442
`1000
`Pseudomonas stutzeri
`250
`Rhizopus nigricans ATCC 6227A
`500
`Saccharomyces cerevisiae ATCC 9763
`1000
`Salmonella typhosa ATCC 6539
`1000
`Serratia marcescens ATCC 8100
`1000
`Staphylococcus aureus ATCC 6538P
`1000
`Staphylococcus epidermidis ATCC 12228
`
`Trichophyton mentagrophytes 125
`
`Table II: Partition coefficients for ethylparaben in vegetable oil and
`water!”
`
`Solvent
`Partition coefficient
`Oil: water
`
`
`14-0
`Corn oil
`0.13
`Mineral oil
`16.1
`Peanut oil
`Soybean oil 18.8
`
`
`
`Table III: Solubility of ethylparaben in various solvents!”
`Solvent
`Solubility at 25°C
`Unless otherwise stated
`
`
`Acetone
`Ethanol
`Ethanol (95%)
`Ether
`
`Glycerin
`Methanol
`Mineral oil
`Peanut oil
`
`Freely soluble
`l
`in 1.4
`1
`in 2
`1
`in 3.5
`
`1
`l
`1
`1
`
`in 200
`in 0.9
`in 4000
`in 100
`
`Propylene glycol
`Water
`
`in 4
`1
`in 1250 at 15°C
`1
`in 910
`1
`1
`in 120 at 80°C_
`
`Page 5
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`Page 5
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`

`
`Ethylparaben 207
`
`ethoxylated phenols”) Yellow iron oxide, ultramarine blue, and
`aluminum silicate extensively absorb ethylparaben in simple aque-
`ous systems, thus reducing preservative ef1icacy.(8-9)
`Ethylparaben is discolored in the presence of iron and is sub-
`ject to hydrolysis by weak alkalis and strong acids.
`See also Methylparaben.
`
`Ethylparaben sodium: C9H9NaO3
`Molecular weight: 188.17
`CAS number: [35285-68-8]
`Synonyms: E215; ethyl 4-hydroxybenzoatc sodium salt;
`sodium ethyl hydroxybenzoate.
`
`19. Comments
`
`13. Method of Manufacture
`
`See Methylparaben for further information.
`
`Ethylparaben is prepared by the esterification of p-hydroxybenzoic
`acid with ethanol.
`
`14. Safety
`
`Ethylparaben, and other parabens, are widely used as antimi-
`crobial preservatives in cosmetics, food products, and oral and
`topical pharmaceutical formulations.
`
`Systemically no adverse effects to parabens have been report-
`ed although they have been associated with hypersensitivity
`reactions. The WHO has set an estimated total acceptable dai-
`ly intake for methyl, ethyl, and propylparabens at up to
`10 mg/kg body-weightflo)
`LD50 (mouse, IP): 0.52 g/kgi")
`LD50 (mouse, oral): 3.0 g/kg
`
`15. Handling Precautions
`
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Ethylparaben may be irritant
`to the skin, eyes, and mucous membranes and should be han-
`dled in a well ventilated environment. Eye protection, gloves,
`and a dust mask or respirator are recommended.
`
`16. Regulatory Status
`
`Accepted as a food additive in Europe. Included in the FDA
`Inactive Ingredients Guide (oral and topical preparations). In-
`cluded in nonparenteral medicines licensed in the UK.
`
`17. Pharmacopeias
`
`China, Eur, Int, Jpn, Po], and Us_
`
`18. Related Substances
`
`Butylparabcn; Cthylparaben potassium; ethylparaben sodium;
`methylparaben; propylparaben.
`
`Ethylparaben potassium: C9H9KO3
`Molecular weight: 204.28
`CAS number: [36547-19-9]
`Synonyms: ethyl 4-hydroxybenzoate potassium salt; potassium
`ethyl hydroxybenzoate.
`
`Ex)
`
`20. Specific References
`1. Decker RL, Wenninger JA. Frequency of preservative use in
`cosmetic formulas as disclosed to FDA - 1987. Cosme! Toilet
`1987; 102(12): 21-24.
`Haag TE, Loncrini DF. In: Kabara JJ, editor. Cosmetic and
`Drug Preservation. New York, Marcel Dekker, 1984; 63-77.
`3. Wan LSC, Kurup TRR, Chan LW. Partition of preservatives
`in oil/water systems. Pharm Acta Helv 1986; 61: 308-313.
`4. Aalto TR, Firman MC, Rigler NE. p-Hydroxybenzoic acid
`esters as preservatives 1: uses, antibacterial and antifungal
`studies, properties and determination. J Am Pharm Assoc
`(Sci) 1953; 42: 449-457.
`5. Kamada A, Yata N, Kubo K, Arakawa M. Stability of p-
`hydroxybenzoic acid esters in acidic medium. Chem Pharm
`Bull 1973; 21: 2073-2076.
`6. Aoki M, Kameta A, Yoshioka I, Matsuzaki T. Application of
`surface active agents to pharmaceutical preparations 1: effect
`of Tween 20 upon the antifungal activities of p-hydroxyben-
`zoic acid esters in solubilized preparations [in Japanese]. J
`Pharm Soc Jpn 1956; 76: 939-943.
`7. Daniels R, Ruppreeht I-1, Effect of coadsorption on sorption
`and release of surfactant paraben mixtures from silica dis-
`persions. Acta Pharm Technol 1985; 31: 236-242.
`8. Sakamoto T, Yanagi M, Fukushima S, Mitsui T. Effects of
`some cosmetic pigments on the bactericidal activities of pre-
`servatives. J Soc Cosmet Chem 1987; 38: 83-98.
`9. Allwood MC. The adsorption of esters of p-hydroxybenzoic
`acid by magnesium trisilicate. Int J Pharmaceutics 1982; 11:
`101-107.
`
`10. FAO/WHO. Toxicological evaluation of certain food addi-
`tives with a review of general principles and of specifica-
`tions. Seventeenth report of the FAO/WHO expert committee
`on food additives. Tech Rep Ser Wld Hlth Org 1974; No. 539.
`11. Sweet DV, editor. Registry of Toxic Effects of Chemical Sub-
`stances. Cincinnati, US Department of Health, 1987
`
`21. General References
`Golightly LK, Smolinske SS, Bennett ML, Sutherland EW,
`Rumack BH. Pharmaceutical excipients: adverse effects asso-
`ciated with inactive ingredients in drug products (part 1). Med
`Toxicol 1988; 3: 128-165,
`
`22. Author
`
`MM Rieger.
`
`
`
`Page 6
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`Page 6