.,,v,7
`
`
`
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`
`..‘_,- -
`,7.“
`.
`'. a~u....a
`‘
`.,w.,‘<,xQ.".'..\.
`
`
`EDITED B
`
`
`
`
`
`|PR2015-01099
`|PR2015-01097
`IPR2015-01100
`IPR2015-01105
`
`_
`
`Lupin EX1168
`Page 1
`
`IPR2015-01099
`IPR2015-01097
`IPR2015-01100
`IPR2015-01105
`
`Lupin EX1168
`Page 1
`
`

`
`
`
`PHARMACEUTECAL
`
`
`
`
`
`Third Edition
`
`Edited by
`
`Arthur H. Kibbe, Ph.D.
`Professor and Chair
`Department of Pharmaceutical Sciences
`Wilkes University School of Pharmacy
`Wilkes—Barre, Pennsylvania
`'
`
`Afim
`
`American Pllarmaceutical Association
`Washington, D.C.
`
` Phurrnucuulicul 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, L°”d°“ SE1 “N, UK
`www.pharmpress’.,comV
`/
`
`S
`
`© 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: 0~9l7330-96-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
`
`l. Excipients--Handbooks. QV 735 H236 2000]
`[DNLM:
`RS20l.E87 H36 2000
`61 5'.l9--dc2l
`
`A catalogue record for this book is available from the British Library.
`
`:
`
`99-044554
`
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval
`system, or transmitted in an
`y form or
`_
`er makes no re
`by any means, without the prior written permission of the copyright holder. The publish
`Presematlon, express or
`implied, with regard to the accuracy of the information
`contained in this book and cannot accept an
`Y legal responsibility or
`liability for any errors or omissions that may be made.
`
`Managing Editor: Melanie Segala
`Copyeditor:
`Paul Gottehrer
`Indexer:
`Lillian Rodberg
`Compositor:
`Roy Barnhill
`Cover Designer:
`Tim Kaage
`
`Page 3
`
`Page 3
`
`

`
`340 Methylparaben
`
`Methylparaben
`
`1. Nonproprietary Names
`
`BP: Methyl hydroxybenzoate
`JP: Methyl parahydroxybenzoate
`PhEur: Methylis parahydroxybenzoas
`USP: Methylparaben
`
`2. Synonyms
`
`E218; 4-hydroxybenzoic acid methyl ester; Methyl Chemosept;
`methyl p-hydroxybenzoate; Methyl Parasept; Nipagin M; Solbrol
`M; Tegosept M.
`
`3. Chemical Name and CAS Registry Number
`
`Methyl 4-hydroxybenzoate [99-76-3]
`
`4. Empirical Formula Molecular Weight
`
`c8H,,o3
`
`152.15
`
`5. Structural Formula
`
`ll
`
`OH
`
`6. Functional Category
`
`Antimicrobial preservative.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`
`Methylparaben is widely used as an antimicrobial preservative
`in cosmetics, food products, and pharmaceutical formulations.
`It may be used either alone,
`in combination with other para-
`bens, or with other antimicrobial agents. In cosmetics, meth-
`ylparaben is the most frequently used antimicrobial
`preservative”)
`
`The parabens are effective over a wide pH range and have a
`broad spectrum of antimicrobial activity although they are
`most effective against yeasts and molds. Antimicrobial activity
`increases as the chain length of the alkyl moiety isincreased;
`aqueous solubility however decreases. A mixture of parabens
`is thus frequently used to provide effective preservation. Pre-
`servative efficacy is also improved by the addition of 2—5%
`propylene glycol, or by using parabens in combination with
`other antimicrobial agents such as imidurea, see Section 10.
`
`Due to the poor solubility of the parabens, paraben salts, par-
`ticularly the sodium salt, are frequently used in formulations.
`However, this raises the pH of poorly buffered formulations.
`
`SEM: 1
`Excipiem: Methylparabcn
`Supplier: Bate Chemical Co Ltd
`Magnification: 600><
`
`Methylparaben (0.18%) together with propylparaben (0.02%)
`has been used for the preservation of various parenteral phar-
`maceutical formulations, see Section 14.
`
`
`
`
` Use Concentration (%)
`
`IM, IV, SC injections”)
`Inhalation solutions
`Intradermal injections
`Nasal solutions
`
`Ophthalmic preparations“‘)
`Oral solutions and suspensions
`Rectal preparations
`Topical preparations
`Vaginal preparations
`
`0‘) See Section 14.
`
`8. Description
`
`0065-0-25
`0035-0-07
`0.10
`0.033
`
`0.015—0-2
`0.015-0.2
`01-0-18
`0.02-0.3
`0.l-O.l8
`
`Methylparaben occurs as colorless crystals or a white crys-
`talline powder.
`It
`is odorless or almost odorless and has a
`slight burning taste.
`
`9. Pharmacopeial Specifications
`
`
`
` Test JP l’l1Elll‘ USP
`
`
`
`
`
`Identification
`Characters
`
`Melting range
`Acidity
`Loss on drying
`Residue on ignition
`Sulfated ash
`Chloride
`
`+
`+
`
`+
`+
`
`125-128°C
`—
`S 0.5%
`S O. 10%
`——
`S 0.035%
`
`1-5-128°C
`+
`-—
`—
`S 0.1%
`——
`
`+
`—
`
`125-128°C
`+
`S 0.5%
`S 0.05%
`-
`—
`
`—:—ef——Page-4j
`
`Page 4
`
`

`
`
`
`(Continuerl)
`Test
`
`Sulfate
`Heavy metals
`Readily carbonlzable
`substances
`
`Appearance of
`solution
`Related substances
`Assay (dried basis)
`
`JP
`
`I’hEur
`
`USP
`
`S 0.024% —
`S 20 ppm —
`+
`-——
`
`—
`
`+
`
`——
`—
`—
`
`+
`
`+
`2 99.0%
`
`—
`+
`99.0-100.5% 99.0~100.5%
`
`10. Typical Properties
`Antimicrobial activity: methylparaben 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 bacteria than against Gram-negative bacteria.
`
`Methylparaben is the least active of the parabens; antimi-
`crobial activity increases with increasing chain length of
`the alkyl moiety. Activity may be improved by using com-
`binations of parabens, since additive effects occur. There-
`fore, combinations of methyl, ethyl, propyl, and
`butylparaben are often used together. Activity has also been
`reported to be enhanced by the addition of other excipients
`such as: propylene glycol (2-5%);(3l phenylethyl alcoho1;(3)
`and edetie acid.(4l Activity may also be enhanced, due to
`synergistic effects, by using combinations of parabens with
`other antimicrobial preservatives such as imidureafsl
`
`The hydrolysis product, p-hydroxybenzoic acid, has prac-
`tically no antimicrobial activity.
`See also Section 12.
`
`Reported minimum inhibitory concentrations (MICS) for
`methylparaben are shown in Table 1.14)
`Density (true): 1.352 g/cm3‘“)
`Dissociation constant: pKa = 8.4 at 22°C
`Melting point: 125-128°C
`Partition coefficients: values for different vegetable oils vary con-
`siderably and are affected by the purity of the oil, see Table II.
`Solubility: see Table III
`
`1“) Results of laboratory project for third edition.
`
`11. Stability and Storage Conditions
`
`Aqueous solutions of methylparaben, at pH 3-6, may be ster-
`ilized by autoclaving at 120°C for 20 minutes, without de-
`compositionfgl Aqueous solutions at pH 3-6 are stable (less
`than 10% decomposition) for up to about 4 years at room
`temperature, while aqueous solutions at pH 8 or above are
`subject to rapid hydrolysis (10% or more after about 60 days
`storage at room temperature).(‘’)
`Predicted rate constants and half-lives at 25°C, for methylpa-
`raben dissolved in dilute hydrochloric acid solution at the ini-
`tial pH shown below:(9)
`
`Initial pl-I
`of solution
`1
`2
`3
`4
`
`Rate constant
`k :1: 61“) (hour'‘)
`(1.086 i 0.005) X l0‘4
`(1.16i0.12)>< l0‘5
`(6.1 i 1.5) X 10”
`(3.27 i 0.64) X l0‘7
`
`“" Indicates the standard error.
`
`Half-life
`t.,, i 01“) (day)
`266 i 13
`24-90i260
`47000 t 12000
`88000 i 17000
`
`Methylparaben 341
`
`Table I: Mininium inhibitory concentrations (MICs) of
`methylparaben in aqueous solution!”
`
`Microorganism
`
`MIC (pg/mL)
`
`Aerobacter aerogenes ATCC 8308
`Aspergillus aryzae
`Aspergillus niger ATCC 9642
`Aspergillus niger ATCC 10254
`Bacillus cereus var: mycoides ATCC 6462
`Bacillus subtilis ATCC 6633
`Camlicla albicans ATCC 10231
`Enterobacter cloacae ATCC 23355
`Escherichia coli ATCC 8739
`Escherichia coli ATCC 9637
`Klebsiella pneumoniae ATCC 8308
`Penicillimn chrysogenum ATCC 9480
`Penicilliunz digitatum ATCC 10030
`Proteus vulgaris ATCC 8427
`Proteus vulgaris ATCC 13315
`Pseudomonas aeruginosa ATCC 9027
`Pseudomonas aeruginosa ATCC 15442
`Pseudomonas stutzeri
`Rlzizopus nigrica/zs ATCC 6227A
`Succharomyces cerevisiae ATCC 9763
`Salmonella typhosa ATCC 6539
`Sarcina lutea
`Serratia marcescens ATCC 8100
`
`2000
`600
`1000
`1000
`2000
`2000
`2000
`1000
`1000
`1000
`1000
`500
`500
`2000
`1000
`4000
`4000
`2000
`500
`1000
`1000
`4000
`1000
`
`2000
`Staphylococcus aureus ATCC 6538P
`2000
`Staphylococcus epidermidis ATCC 12228
`250
`Trichoderma lignorum ATCC 8678
`
`Trichoclerma mentagrophytes 250
`
`Table II: Partition coefficients of methylparaben in vegetable oil
`and water.“-7)
`
`Solvent
`Partition coefficient
`011: water
`
`
`Almond oil
`Castor oil
`Corn oil
`
`7.5
`6.0
`4.1
`
`200
`Diethyl adipate
`18.0
`Isopropyl myristate
`7.0
`Lanolin
`0.1
`Mineral oil
`4.2
`Peanut 011
`Soybean oil 6.]
`
`
`
`Table III: Solubility of methylparaben in various solvents!”
`Solvent
`Solubility at 25°C
`Unless otherwise stated
`
`
`Ethanol
`Ethanol (95%)
`Ethanol (50%)
`Ether
`
`l
`1
`1
`1
`
`in 2
`in 3
`in 6
`in 10
`
`Glycerin
`Mineral oil
`Peanut oil
`Propylene glycol
`Water
`
`in 60
`1
`Practically insoluble
`1
`in 200
`1
`in 5
`1
`in 400
`1
`in 50 at 50°C
`1
`in 30 at 80°C
`'—§%
`
`Page 5
`
`

`
`342 Methylparaben
`
`The predicted amount of methylparaben remaining after au-
`toclaving is shown below for methylparaben dissolved in di-
`lute hydrochloric acid solution at the initial pH shown:(9)
`
`
`Predicted residual
`Rate constant
`Initial pH
`of solution
`k :1: 0'0’) (hour")
`amount after
`
`autoclaving (‘7a)
`
`84.77 i 0.46
`(4.96 ‘L 0.16) X 10"
`1
`98.51 t 0.12
`(4.49 i 0.37) X 10‘2
`2
`99.91 i 0.02
`(2.79 i- 0.57) X 10'3
`3
`
`4 99.95 i 0.01 (1.49 t 0.22) X 10‘3
`
`
`W Indicates the standard error.
`
`Methylparaben should be stored in a well-closed container in
`a cool, dry, place,
`
`12. Incompatibilities
`
`The antimicrobial activity of methylparaben and other parabens
`is considerably reduced in the presence of nonionic surfactants,
`such as polysorbate 80, as a result of micellization.(’°-1‘)
`
`However, propylene glycol (10%) has been shown to poten-
`tiate the antimicrobial activity of the parabens in the presence
`of nonionic surfactants and prevents the interaction between
`methylparaben and polysorbate 803”)
`Incompatibilities with other substances such as bentonite,(‘3)
`magnesium trisilicate,(”) talc,
`tragacanth,”-5) sodium algi-
`nate,“6) essential oils,(”) sorbitolflx) and atropine“) have
`been reported.
`
`Absorption of methylparaben by plastics has also been report-
`ed; the amount absorbed is dependent upon the type of plastic
`and the vehicle. It has been claimed that low- and high-density
`polyethylene bottles do not absorb methylparabenfzo)
`
`Methylparaben is discolored in the presence of iron and is
`subject to hydrolysis by weak alkalis and strong acids.
`
`13. Method of Manufacture
`
`Methylparaben is prepared by the esteiification of p-hydroxybenzoic
`acid with methanol.
`
`14. Safety
`
`Methylparaben, and other parabens, are widely used as anti-
`microbial preservatives in cosmetics and oral and topical phar-
`maceutical formulations. Although parabens have also been
`used as preservatives in injections and ophthalmic prepara-
`tions they are now generally regarded as being unsuitable for
`these types of formulations due to the irritant potential of the
`parabens. These experiences may depend on immune respons-
`e:_to enzymatically formed metabolites of the parabens in the
`S
`III.
`
`Parabens arenonmutagenic, nonteratogenic, and noncarcino-
`genie. Sensitization to the parabens is rare, and these com-
`pounds do not exhibit significant
`levels of photocontact
`sensitization or phototoxicity.
`
`Hypersensitivity reactions to parabens, generally of the de-
`layed type, and appearing as contact dermatitis have been re-
`ported. However, given the widespread use of parabens as
`preservatives such reactions are relatively uncommon and the
`classification of parabens in some sources as high-rate sensi-
`tizers may thus be somewhat overstated.(3”
`
`Immediate hypersensitivity reactions following injection of
`preparations containing parabens have also been report-
`ed.m'24) Delayed-Contact dermatitis occurs more frequently
`when parabens are used topically, but has also been reported
`to occur after oral administration.(25‘27)
`
`Unexpectedly, preparations containing parabens may be used
`by patients who have reacted previously with Contact derma-
`titis, provided they are applied to another unaffected site. This
`has been termed the paraben paradoxfzg)
`
`Concern has been expressed over the use of methylparaben
`in infant parenteral products since bilirubin binding may be
`affected, which is potentially hazardous in hyperbilirubinaem-
`ic neonatesf”)
`
`Systemically no adverse effects to parabens have been report-
`ed. The WHO has set an estimated total acceptable daily in-
`take for methyl, ethyl, and propylparabens at up to 10 mg/kg
`body—weight.(3°’
`
`LD50 (dog, oral): 3.0 g/kgm’
`LD50 (mouse, IP): 0.96 g/kg
`LD50 (mouse, SC): 1.20 g/kg
`
`15. Handling Precautions
`
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Methylparaben may be ir-
`ritant to the skin, eyes, and mucous membranes and should
`be handled in a well-ventilated environment. Eye protection,
`gloves, and a dust mask or respirator are recommended.
`
`16. Regulatory Status
`
`Methylparaben and propylparaben are affirmed GRAS Direct
`Food Substances in the US at levels up to 0.1%. All esters
`except the benzyl ester are allowed for injection in Japan. In
`cosmetics,
`the EU and Brazil allow use of each paraben at
`0.4%, but the total of all parabens may not exceed 0.8%. The
`upper limit in Japan is 1.0%.
`
`Accepted for use as a food additive in Europe. Included in
`the FDA Inactive Ingredients Guide (IM, IV, and SC injec-
`tions, ophthalmic preparations, oral capsules,
`tablets, solu-
`tions and suspensions, otic, rectal,
`topical, and vaginal
`preparations). Included in medicines licensed in the UK.
`
`17. Pharmacopeias
`
`Eur, Int, Jpn, P01, and US.
`
`18. Related Substances
`
`Butylparaben; ethylparaben; methylparaben potassium; metli-
`ylparaben sodium; propylparaben.
`
`Methylparaben potassium: C3H7KO3
`Molecular weight: 190.25
`CAS number: [261l2-07-2]
`Synonyms: methyl 4—hydroxybenzoate potassium salt; potas-
`sium methyl hydroxybenzoate.
`Comments: methylparaben potassium may be used instead of
`methylparaben because of its greater aqueous solubility.
`
`Methylparaben sodium: C8H7NaO3
`Molecular weight: 174.14
`CAS number: [5026-62-0]
`Synonyms: E219; methyl 4-hydroxybenzoate sodium salt;
`sodium methyl hydroxybenzoate; soluble methyl hydroxy—
`benzoate.
`Page 6
`
`Page 6
`
`

`
`
`
`P/iarmacopeias: Eur and US.
`Appearance: a white odorless, or almost odorless, hygroscopic
`crystalline powder.
`Acidity/alkalinity: pH = 9.5-10.5 (0.1% aqueous solution).
`Solubility:
`1
`in 50 of ethanol (95%);
`1
`in 2 of water; practi-
`cally insoluble in fixed oils.
`Comments: methylparaben sodium may be used instead of
`methylparaben because of its greater aqueous solubility.
`However, it may cause the pH of a formulation to become
`more alkaline.
`
`19. Comments
`
`In addition to the most commonly used paraben esters, efforts
`have been made to use some less-common esters, which are
`listed below.
`
`Name
`
`Benzylparaben
`Isobutylparaben
`Isopropylparaben
`
`CAS No.
`
`94- 1 8-8
`4247-02-3
`4191-73-5
`
`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.
`Prickett PS, Murray HL, Mercer NH. Potentiation of preser-
`vatives (parabens) in pharmaceutical formulations by low
`concentrations of propylene glycol. J Pharm Sci 1961; 50:
`316-320.
`
`ix)
`
`3. Richards RME, McBride RJ. Phenylethanol enhancement of
`preservatives used in ophthalmic preparations. J Pharm
`Pharmacol 1971; 23:
`l4lS-146S.
`
`4. Haag TE, Loncrini DF. Esters of para-hydroxybenzoic acid.
`In: Kabara JJ, editor. Cosmetic and Drug Preservation. New
`York, Marcel Dekker, 1984; 63-77.
`5. Rosen WE, Berke PA, Matzin T, Peterson AF. Preservation
`of cosmetic lotions with imidazolidinyl urea plus parabens.
`J Soc Cosmet Chem 1977; 28: 83-87.
`6. Hibbott HW, Monks J. Preservation of emulsions - p-hydrox-
`ybenzoic ester partition coefficient. J Soc Cosmet Chem
`1961; 12: 2-10.
`7. Wan LSC, Kurup TRR, Chan LW. Partition of preservatives
`in oil/water systems. Plzarm Acta Helv 1986; 61: 308-313.
`8. Aalto TR, Firman MC, Rigler NE. p-Hydroxybenzoic acid
`esters as preservatives I: uses, antibacterial and antifungal
`studies, properties and determination. J Am Pharm Assoc
`(Sci) 1953; 42: 449-457.
`9. Kamada A, Yata N, Kubo K, Arakawa M. Stability of
`p-hydroxybenzoic acid esters in acidic medium. Chem Pharm
`Bull 1973; 21: 2073-2076.
`10. 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
`Plwrm Soc Jpn 1956; 76: 939-943.
`1 1. Patel N, Kostenbauder HB. Interaction of preservatives with
`macromolecules I: binding of parahydroxybenzoic acid esters
`by polyoxyethylene 20 sorbitan monooleate (Tween 80). J
`Am Plmrm Assoc (Sci) 1958; 47: 289-293.
`12. Poprzan J, deNavarre MG. The interference of nonionic
`emulsifiers with preservatives VIII. J Soc Cosmet Client
`1959; 10: 81-87.
`
`Met/zylparaben 343
`
`13. Yousef RT, E1-Nakeeb MA, Salama S. Effect of some phar-
`maceutical materials on the bactericidal activities of preser-
`vatives. Can J Pharm Sci 1973; 8: 54-56.
`14. Allwood MC. The adsorption of esters of p-hydroxybenzoic
`acid by magnesium trisilicate. Int J Pharmaceutics 1982; 11:
`101-107.
`15. Eisman PC, Cooper J, Jaconia D. Influence of gum tragacanth
`on the bactericidal activity of preservatives. J Am Plmrm
`Assoc (Sci) 1957; 46: 144-147.
`16. Myburgh JA, McCarthy TI. The influence of suspending
`agents on preservative activity in aqueous solid/liquid dis-
`persions. Pharm Weekbl (Sci) 1980; 2: 143-148.
`17. Chemburkar PB, Joslin RS. Effect of flavoring oils on pre-
`servative concentrations in oral liquid dosage forms. J Pharm
`Sci 1975; 64: 414-417.
`18. Runesson B, Gustavii K. Stability of parabens in the presence
`of polyols. Acta Pharm Suec 1986; 23: 151-162.
`19. Decks T. Oral atropine sulfate mixtures. Plzurm J 1983; 230:
`481.
`20. Kakemi K, Sezaki H, Arakawa E, Kimura K, Ikeda K. Inter-
`actions of parabens and other pharmaceutical adjuvants with
`plastic containers. Chem Pharm Bull 1971; 19: 2523-2529.
`21. Weiner M, Bernstein IL. Adverse Reactions to Drug Formu-
`lation Agents: A Handbook of Excipients. New York, Marcel
`Dekker, 1989; 298-300.
`22. Aldrete JA, Johnson DA. Allergy to local anesthetics. JAMA
`1969; 207: 356-357.
`23. Latronica RJ, Goldberg AF, Wightman JR. Local anesthetic
`sensitivity: report of a case. Oral Surg 1969; 28: 439-441.
`24. Nagel JE, Fuscaldo JT, Fireman P. Paraben allergy. JAMA
`1977; 237: 1594-1595.
`25. Michiielsson G, Juhlin L. Urticaria induced by preservatives
`and dye additives in food and drugs. Br J Dermatol 1973;
`88: 525-532.
`26. Warin RP, Smith R]. Challenge test battery in chronic urti-
`caria. Br J Dermatol 1976; 94: 401-406.
`27. Kaminer Y, Apter A, Tyano S, Livni E, Wijsenbeek H.
`Delayed hypersensitivity reactions to orally administered
`methylparaben. Clin Pharm 1982; 1: 469-470.
`28. Fisher AA. Cortaid cream dermatitis and the paraben paradox
`[letter]. J Am Acad Dermatol 1982; 6: 116-117.
`29. Loria CJ, Escheverria P, Smith AL. Effect of antibiotic for-
`mulations in serum protein: bilirubin interaction of newborn
`infants. J Pediatr 1976; 89: 479-482.
`30. FAO/WHO. Toxicological evaluation of certain food addi-
`tives with a review of general principles and of specifica-
`tions. Seventeenth report of the joint FAO/WHO expert
`committee on food additives. Tech Rep Ser Wld Hlth Org
`1974; No. 539.
`31. Sweet DV, editor. Registry of Toxic Effects of Chemical Sub-
`stances. Cincinnati, US Department of Health, 1987.
`
`21. General References
`Bando H, et al. Effects of skin metabolism on percutaneous pen-
`etration of lipophilic drugs. J Pharm Sci 1997; 86: 759-761.
`Forster S, Buckton G, Beezer AE. The importance of chain length
`on the wettability and solubility of organic homologs. Int J
`Plmrmaceutics 1991; 72: 29-34.
`Golightly LK, Smolinske SS, Bennett ML, Sutherland EW,
`Rumack BH. Pharmaceutical excipicnts: adverse effects asso-
`ciated with inactive ingredients in drug products (part 1). Med
`Toxicol 1988; 3: 128-165.
`Grant DJW, Mehdizadeh M, Chow AH-L, Fairbrother IE. Non-
`linear van’t Hoff solubility-temperature plots and their phar-
`maceutical
`interpretation.
`lnt J Pharmaceutics 1984; 18;
`25-38.
`Jian L, Li Wan Po A. Ciliotoxicity of methyl- and pl'0pyl-p-
`hydroxybenzoates: a dose-response and surface-response
`study. J Pharm Pharmacol 1993; 45: 925-927.
`
`Page 7
`
`Page 7
`
`

`
`344 Ii/Iethylparaben
`
`Jones PS, Thigpen D, Morrison JL, Richardson AP.
`17-Hydroxybenzoic acid esters as preservatives III:
`the ph)/Si—
`ological disposition of p-hydroxybenzoic acid and its esters.
`J Am Pharm Assoc (Sci) 1956; 45: 268-273,
`Kostenbauder HB. Physical chemical aspects of preservative
`selection for pharmaceutical and cosmetic emulsions. Dev Ind
`Microbiol 1962; 1: 286-296.
`Marouchoc SR. Cosmetic preservation. Cosme! Technol 1980;
`200)‘ 3844-
`Matthews C, Davidson J, Bauer E, Morrison JL, Richardson AP.
`p-Hydroxybcnzoic acid esters as preservatives 11: acute and
`
`chronic toxicity in dogs, rats and mice. J Am Pharm Assoc
`(.565) 1956; 453 260-267.
`Sakamoto T. Yanagi M, Fukushima S, Mitsui T. Effects of some
`cosmetic pigments on the bactericidal activities of preserva-
`tives. J Soc Cosmet Chem 1987; 38: 83-98.
`Sokol H. Recent developments in the preservation of pharmaceu-
`ticals. Drug Standards 1952; 20: 89-106.
`
`22. Authors
`
`MM Rieger.
`
`Page 8
`
`Page 8