Not to be taken
`from the room.
`
`For, Not to be taken
`referenc•
`
`from the room.
`
`1
`
`AMN1014
`
`

`

`Handbook of
`Ph rmaceutical
`
`SIXTH EDITION
`
`• •
`c1p1ents
`
`Edited by
`Raymond C Rowe BPharm, PhD, DSC, FRPharmS, FRSC, CPhys, MlnstP
`Chief Scientist
`/ntelligensys Ltd, Stokesley, North Yorkshire, UK
`
`Paul J Sheskey BSc, RPh
`Application Development leader
`The Dow Chemical Company, Midland, Mt USA
`
`Marian E Quinn BSc, MSc
`Development Editor
`Royal Pharmaceutical Society of Great Britain, London, UK
`
`APhA
`
`London • Chicago
`
`2
`
`

`

`Published by the Pharmaceutical Press
`An imprint of RPS Publishing
`
`1 Lambeth High Street, London SE1 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
`
`(RP) is a trade mark of RPS Publishing
`
`RPS Publishing is the publishing organisation of the 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 85369 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 catalogue record for this book is available from the British Library
`
`3
`
`

`

`6 Wan LSC, Lai WE Factors affecting drug release from drug-coated
`granules prepared by fluidized-bed coating. Int J Pharm 1991; 72: 163-
`174.
`7 Wojdak H eta/. The influence of selected properties on the stability of
`pharmaceutical emulsions. Pharmazie 1991; 46: 120-125.
`8 Dalal PS, Narurkar MM. In vitro and in vivo evaluation of sustained
`release suspensions of ibuprofen. Int] Pharm 1991; 73: 157-162.
`9 El Gawad A et a/. Formulation and stability of saluzide eye drops.
`Pharm Ind 1987; 49: 751-754.
`10 Huikari A, Karlsson A. Viscosity stability of methylcellulose solutions
`at different pH and temperature. Acta Pharm Fenn 1989; 98(4): 231-
`238.
`11 Huikari A. Effect of heat sterilization on the viscosity of methylcellulose
`solutions. Acta Pharm Fenn 1986; 95(1): 9-17.
`12 Huikari A eta/. Effect of heat sterilization on the molecular weight of
`methylcellulose determined using high pressure gel filtration chromato(cid:173)
`graphy and viscometry. Acta Pharm Fenn 1986; 95(3): 105-111.
`13 Anonymous. Final report on the safety assessment of hydroxyethylcel(cid:173)
`lulose,
`hydroxypropylcellulose, methylcellulose,
`hydroxypropyl
`methylcellulose and cellulose gum. JAm Coli Toxico/1986; 5(3): 1-60.
`14 FAO/WHO. Evaluation of certain food additives and contaminants.
`Thirty-fifth report of the joint FAO/WHO expert committee on food
`additives. World Health Organ Tech Rep Ser 1990: No. 789.
`15 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials, 11th
`edn. New York: Wiley, 2004; 2408.
`16 Mitchell K eta/. Influence of drugs on the properties of gels and swelling
`characteristics of matrices containing methylcellulose or hydroxypro(cid:173)
`pylmethylcellulose. Int] Pharm 1993; 100(1-3): 165-173.
`17 Huikari A, Kristoffersson E. Rheological properties of methylcellulose
`solutions: general flow properties and effects of added substances. Acta
`Pharm Penn 1985; 94(4): 143-154.
`18 Csempesz F, Puskas I. Controlling the physical stability of liposomal
`colloids. Tadros TF, ed. Colloid Stability and Application in Pharmacy.
`Weinheim, Germany: Wiley-VCH, 2007; 79-89.
`19 Food Chemicals Codex, 6th edn. Bethesda, MD: United States
`Pharmacopeia, 2008; 618.
`
`Methylparaben
`
`441
`
`20 General References
`Doelker E. Cellulose derivatives. Adv Polym Sci 1993; 107: 199-265.
`Dow Chemical Company. Material safety data sheet: Methocel A4M, 2004.
`European Directorate for
`the Quality of Medicines and Healthcare
`(EDQM). European Pharmacopoeia - State Of Work Of International
`Harmonisation. Pharmeuropa 2009; 21(1): 142-143. http://www.edq(cid:173)
`m.eu/site/-614.html (accessed 3 February 2009).
`Hladon T et a/. Physicochemical interactions of drugs with excipients in
`suspensions. Acta Pol Pharm 1986; 43(5): 471-480.
`Li], Mei X. Applications of cellulose and cellulose derivatives in immediate
`release solid dosage.ACS Symposium Series, 934Polysaccharides for
`Drug Delivery and Pharmaceutical Applications. 2006; 19-55.
`Mitchell K et a/. Influence of substitution type on the performance of
`methylcellulose and hydroxypropylmethylcellulose in gels and matrices.
`Int J Pharm 1993; 100(1-3): 143-154.
`Oxford University. Material safety data sheet: Methyl Cellulose, 2006.
`http://msds.chem.ox.ac.uk/ME.methyl_cellulose.html (accessed 3 Febru(cid:173)
`ary 2009).
`Rowe RC. The molecular weight of methyl cellulose used in pharmaceutical
`formulation. Int] Pharm 1982; 11: 175-179.
`Tapia Villanueva C, Sapag Hagar J. Methylcellulose: its pharmaceutical
`applications. Acta Farm Bonaerense 1995; 14(Jan-Mar): 41-47.
`Wan LS, Prasad KP. Influence of quantity of granulating liquid on water
`uptake and disintegration of tablets with methylcellulose. Pharm I11d
`1989; 51(1): 105-109.
`Wan LS, Prasad KP. Studies on the swelling of composite disintegrant(cid:173)
`methylcellulose films. Drug Dev Ind Pharm1990; 16(2): 191-200.
`
`21 Authors
`LV Allen Jr, PE Luner.
`
`22 Date of Revision
`3 February 2009.
`
`Methylparaben
`
`Nonproprietary Names
`BP: Methyl Hydroxybenzoate
`JP: Methyl Parahydroxybenzoate
`PhEur: Methyl Parahydroxybenzoate
`USP-NF: Methylparaben
`
`5
`
`Structural Formula
`0
`
`2
`Synonyms
`Aseptoform M; CoSept M; E218; 4-hydroxybenzoic acid methyl
`ester; metagin; Methyl Chemosept; methylis parahydroxybenzoas;
`methyl p-hydroxybenzoate; Methyl Parasept; Nipagin M; Solbrol
`M; Tegosept M; Uniphen P-23.
`
`3 Chemical Name and CAS Registry Number
`Methyl-4-hydroxybenzoate [99-76-3]
`
`Empirical Formula and Molecular Weight
`4
`C8H 80 3
`152.15
`
`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; see
`Table I. It may be used either alone or in combination with other
`
`4
`
`

`

`442
`
`Methylparaben
`
`parabens or with other antimicrobial agents. In cosmetics,
`meth(:lparaben is the most frequently used antimicrobial preserva(cid:173)
`tive.< 1
`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 is increased, but aqueous
`solubility decreases; therefore a mixture of parabens is frequently
`used to provide effective preservation. Preservative efficacy is also
`improved by the addition of propylene glycol (2-5%), 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%)
`has been used for the preservation of various parenteral pharma(cid:173)
`ceutical formulations; see Section 14.
`
`Table 1: Uses of methylparobe~: .
`~~--~~-~--~~----~-----·
`Concentration (%)
`Use
`IM, IV, SC
`0.065-0.25
`Inhalation
`0.025-0.07
`Intradermal injections
`0. 1 0
`Nasal solutions
`0.033
`Ophthalmic preparationslol
`0.015-0.2
`Oral solutions and suspensions
`0.015-0.2
`Rectal ~reparations
`0.1-0.18
`Topica preparations
`0.02-0.3
`~c:gi_~~__P!_e:~_::~~~fl_~--------··----··--~~=-0. 1 8 ····----·--
`(a) See Section 14.
`
`Description
`8
`Methylparaben occurs as colorless crystals or a white crystalline
`powder. It is odorless or almost odorless and has a slight burning
`taste.
`SEM 1: Excipient: methylparaben; supplier: Bate Chemical Co. Ltd;
`magnification: 600 x.
`
`Pharmacopeia! Specifications
`9
`See Table II. See also Section 18.
`
`Table II:. Pharmacopelalsf>ecifk:ations for methylpbrob~n.
`
`JP XV
`Test
`- - - - - · - - - - - - - -
`+
`Identification
`Characters
`+
`Appearance of
`solution
`+
`Acidity
`Heavy metals
`~20ppm
`Impurities
`Melting range
`Related substances
`Sulfated ash
`Residue on ignition
`Assay (dried basis)
`
`+
`
`~0.1%
`98.0-102.0%
`
`PhEur 6.0
`+
`+
`+
`+
`+
`+
`~0.1%
`
`98.0-102.0%
`
`USP32-NF27
`+
`+
`+
`
`125-128oC
`+
`
`~0.1%
`98.0-102.0%
`
`1 0 Typical Properties
`Antimicrobial activity see Table III. Methylparaben exhibits
`antimicrobial activity of pH 4-8. Preservative efficacy decreases
`with increasing pH owing 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(cid:173)
`positive bacteria than against Gram-negative bacteria.
`Methylparaben is the least active of the parabens; antimicro(cid:173)
`bial activity increases with increasing chain length of the alkyl
`moiety. Activity may be improved by using combinations of
`parabens as synergistic effects occur. Therefore, combinations of
`methyl-, ethyl-, propyl-, and butylparaben are often used
`together. Activity has also been reported to be enhanced by the
`addition of other exci_Rients such as: pro~rlene glycol (2-5% );121
`phenylethyl alcohol;< 1 and edetic acid. 4 Activity may also be
`enhanced owing to synergistic effects by using combinations of
`parabens with other antimicrobial preservatives such as imi(cid:173)
`dureaY1
`The hydrolysis product p-hydroxy benzoic acid has practically
`no antimicrobial activity.
`See also Section 12.
`
`Tahle Ill: Minimum inhibitory concentrations (M\Cs) 'ofmethylpe~rbb~~'!
`in aqueoU$solution.141
`.h<'~
`.
`.
`.
`.
`. . .
`. .. ·
`. . •. .•.
`
`MIC (!lg/ml)
`Microorganism
`- - - - ·
`2000
`Aerobacter aerogenes ATCC 8308
`600
`Aspergillus oryzae
`Aspergillus niger ATCC 9642
`1000
`Aspergillus niger ATCC 1 0254
`1000
`Bacillus cereus var. mycoides ATCC 6462
`2000
`Bacillus subtilis ATCC 6633
`2000
`Candida albicans ATCC 1 0231
`2000
`Enterobacter cloacae ATCC 23355
`1000
`Escherichia coli ATCC 8739
`1000
`Escherichia coli ATCC 9637
`1000
`1000
`Klebsiella pneumoniae ATCC 8308
`Penicillium chrysogenum ATCC 9480
`500
`Penicillium digitotum ATCC 1 0030
`500
`Proteus vulgaris ATCC 8427
`2000
`Proteus vulgaris ATCC 13315
`1000
`4000
`Pseudomonas aeruginosa ATCC 9027
`4000
`Pseudomonas aeruginosa ATCC 15442
`Pseudomonas stutzeri
`2000
`Rhizopus nigricans ATCC 6227 A
`500
`Saccharomyces cerevisiae ATCC 97 63
`1000
`Salmonella typhosa ATCC 6539
`1000
`4000
`Sarcina lutea
`1000
`Serratia marcescens ATCC 81 00
`2000
`Staphylococcus aureus ATCC 6538P
`Staphylococcus epidermidis ATCC 12228
`2000
`250
`Trichoderma lignorum ATCC 8678
`250
`Trichoderma mentagrophytes
`-----------------------------
`
`5
`
`

`

`0.0
`
`m
`0
`>
`·c
`Q) u
`u
`c
`~
`X
`0
`0
`2244
`0
`~ -4.0 L-..L._...J...._...J....__J__I..--..l..--L.----l.---l-l...-.l..--'--...J...._...J -0.2
`1100 1300 1500 1700 1900 2100 2300 2500
`Wavelength/nm
`
`m
`0
`
`2367
`
`2453
`
`Figure 1: Near-infrared spectrum of methylparaben measured by
`reflecta nee.
`
`Density (true) 1.352 g/cm3
`Dissociation constant pK, = 8.4 at 22oC
`Melting point 125-128°C
`NIR spectra see Figure 1.
`Partition coefficients Values for different vegetable oils vary
`considerably and are affected by the purity of the oil; see Table
`IV.
`Solubility see Table V.
`
`Partition coefficient oil :water
`Solvent
`- : - - - : - . , . - - - - - - - - - - - - - - - - ·
`7.5
`Almond oil
`6.0
`Castor oil
`4.1
`Corn oil
`200
`Diethyl adipate
`18.0
`Isopropyl myristate
`7.0
`Lanolin
`0.1
`Mineral oil
`4.2
`Peanut oil
`6.1
`oil
`
`tfra.ble V: ;sol0bi1Hy 6f methy!IJC"lrabeD in various solvents. 14!
`Solvent
`at 25°C unless otherwise stated
`
`, ,
`
`"
`
`~·''''' , ' '
`
`Ethanol
`Ethanol (95%)
`Ethanol (50%)
`Ether
`Glycerin
`Mineral oil
`Peanut oil
`Propylene glycol
`Water
`
`1 in 2
`1 in 3
`1 in 6
`1 in 10
`1 in 60
`Practically insoluble
`1 in 200
`1 in 5
`1 in 400
`1 in 50 at 50°C
`1 in 30 at 80°C
`
`11 Stability and Storage Conditions
`Aqueous solutions of methylparaben at pH 3-6 may be sterilized b~
`autoclaving at 120oC for 20 minutes, without decomposition. 1 l
`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); see
`Tables VI and VII. 19l
`
`Methylparaben
`
`443
`
`Methylparaben should be stored in a well-closed container in a
`cool, dry place.
`
`Table.VI: Predicted rate constants and half-lives for- methylparaben
`dissolved in dilute hydrochloric acid solution"at2YC:
`
`Initial pH of
`solution
`1
`2
`3
`4
`
`Rate constant k ± a(a)
`(hour- 1)
`.086 ± 0.005) X
`.16 ± 0.12) X
`1 ± 1.5) X 1
`± o.64) x w-7
`
`(a) Indicates the standard error.
`
`Half-life f1h ± a(a) (day)
`
`266 ± 13
`2490±260
`47000 ± 12 000
`88000± 17000
`
`-
`
`-
`Table VII: Pre;dicted remaining amou_ntof methylparaben dissolved in
`__
`dilute hydrochloric acid solution, after autoclaving. _
`~-
`-~-------~~-
`Initial pH of
`solution
`1
`2
`3
`4
`
`(a) Indicates the standard error.
`
`Incompatibilities
`12
`The antimicrobial activity of methylparaben and other parabens is
`considerably reduced in the presence of nonionic surfactants, such
`11
`as polysorbate 80, as a result of micellizationY 0
`l However,
`•
`propylene glycol (10%) has been shown
`to potentiate the
`antimicrobial activity of the parabens in the presence of nonionic
`surfactants and prevents the interaction between methylparaben
`and polysorbate 80_11 2
`)
`Incompatibilities with other substances, such as bentonite, 113)
`magnesium trisilicate,114l talc, tragacanth,(lS) sodium alginate,116l
`9
`essential oils, (l?) sorbitol,0 8l and atropine, (1
`) have been reported. It
`also reacts with various sugars and related sugar alcohols.(2
`0l
`Absorption of methylparaben by plastics has also been reported;
`the amount absorbed is dependent upon the type of plastic and the
`vehicle. It has been claimed that low-density and high-density
`polyethylene bottles do not absorb methylparaben.tll)
`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 esterification of p-hydroxyben(cid:173)
`zoic acid with methanol.
`
`14 Safety
`Methylparaben and other parabens are widely used as antimicro(cid:173)
`bial preservatives in cosmetics and oral and topical pharmaceutical
`formulations. Although parabens have also been used as preserva(cid:173)
`tives in injections and ophthalmic preparations, they are now
`generally regarded as being unsuitable for these types of formula(cid:173)
`tions owing to the irritant potential of the parabens. These
`experiences may depend on immune responses to enzymatically
`formed metabolites of the parabens in the skin.
`Parabens are nonmutagenic, nonteratogenic, and noncarcino(cid:173)
`genic. Sensitization to the parabens is rare, and these compounds do
`not exhibit significant levels of photocontact sensitization or
`phototoxicity.
`Hypersensitivity reactions to parabens, generally of the delayed
`type and appearing as contact dermatitis, have been reported.
`However, given the widespread use of parabens as preservatives,
`such reactions are relatively uncommon; the classification of
`
`6
`
`

`

`444 Methylparaben
`
`in some sources as high-rate sensitizers may be
`parabens
`overstated. '22
`)
`Immediate hypersensitivity reactions following injection of
`preparations containing parabens have also been reported.'23
`25
`-
`l
`Delayed-contact dermatitis occurs more frequently when parabens
`are used topically, but has also been reported to occur after oral
`28
`administration. '26
`-
`)
`Unexpectedly, preparations containing parabens may be used by
`patients who have reacted previously with contact dermatitis
`provided they are applied to another, unaffected, site. This has
`been termed the para ben paradox. '29l
`Concern has been expressed over the use of methylparaben in
`infant parenteral products because bilirubin binding may be
`affected, which is potentially hazardous in hyperbilirubinemic
`neonates. '30
`)
`The WHO has set an estimated total acceptable daily intake for
`methyl-, ethyl-, and propylparabens at up to 10 mg/kg body(cid:173)
`weight. 131 )
`LD 50 (dog, oral): 3.0 g/kg!32
`LD5o (mouse, IP): 0.96 g/kg
`LD5o (mouse, SC): 1.20 g/kg
`
`l
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantity of material handled. Methylparaben may be irritant 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 USA 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 Database (IM, IV, and SC injections;
`inhalation preparations; ophthalmic preparations; oral capsules,
`tablets, solutions and suspensions; otic, rectal, topical, and vaginal
`preparations). Included in medicines licensed in the UK. Included in
`the Canadian List of Acceptable Non-medicinal Ingredients.
`
`17 Related Substances
`Butylparaben; ethylparaben; methylparaben potassium; methylpar(cid:173)
`aben sodium; propylparaben.
`Methylparaben potassium
`Empirical formula CsH7K03
`Molecular weight 190.25
`CAS number
`[26112-07-2]
`Synonyms Methyl 4-hydroxybenzoate potassium salt; potassium
`methyl hydroxybenzoate.
`Comments Methylparaben potassium may be used instead of
`methylparaben because of its greater aqueous solubility.
`Methylparaben sodium
`Empirical fonnula C8H 7Na03
`Molecular weight 17 4.14
`CAS number
`[5026-62-0]
`Synonyms E219; methyl4-hydroxybenzoate sodium salt; sodium
`methyl hydroxybenzoate; soluble methyl hydroxybenzoate.
`Appearance A white, odorless or almost odorless, hygroscopic
`crystalline powder.
`Acidity/alkalinity pH= 9.5-10.5 (0.1% w/v aqueous solution)
`Solubility 1 in 50 of ethanol (95%); 1 in 2 of water; practically
`insoluble in fixed oils.
`
`Comments Methylparaben sodium may be used
`instead of
`methylparaben because of its greater aqueous solubility. How(cid:173)
`ever, it may cause the pH of a formulation to become more
`alkaline.
`
`18 Comments
`Methylparaben is one of the materials that have been selected for
`harmonization by the Pharmacopeia! Discussion Group. For further
`information see the General Information Chapter <1196> in the
`USP32-NF27, the General Chapter 5.8 in PhEur 6.0, along with the
`'State of Work' document on the PhEur EDQM website, and also
`the General Information Chapter 8 in the JP XV.
`The BP 2009, Ph Eur 6.0 and USP32-NF27 also
`Methylparaben Sodium as a separate monograph.
`The EINECS number for methylparaben is 202-785-7. In
`addition to the most commonly used paraben esters, some other
`less-common esters have also been used; see Table VIII. A
`specification for methylparaben is contained in the Food Chemicals
`Codex (FCC).(33l
`The PubChem Compound ID (CID) for methylparaben is 7456.
`
`list
`
`Table VIII: CAS numbers of less common
`
`Name
`CAS Number
`94-1 8-8
`Benzylparaben
`4247-02-3
`lsobutylparaben
`~opr_c:>pyp_::r~~_::~------------~-~_!_:~~:~---------
`
`19 Specific References
`1 Decker RL, Wenninger JA. Frequency of preservative use in cosmetic
`formulas as disclosed to FDA-1987. Cosmet Toilet 1987; 102(12):
`21-24.
`2 Prickett PS et al. Potentiation of preservatives (parabens) in pharma(cid:173)
`ceutical formulations by low concentrations of propylene glycol. J
`Pharm Sci 1961; 50: 316-320.
`3 Richards RME, McBride RJ. Phenylethanol enhancement of preserva(cid:173)
`tives used in ophthalmic preparations. ]'Pharm Pharmaco/1971; 23:
`1415-1465.
`4 Haag TE, Loncrini DF. Esters of para-hydroxybenzoic acid. Kabara JJ,
`ed. Cosmetic and Drug Preservation. New York: Marcel Dekker, 1984;
`63-77.
`5 Rosen WE et a/. 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-hydroxybenzoic
`ester partition coefficient.] Soc Cosmet Chern 1961; 12: 2-10.
`7 Wan LSC eta!. Partition of preservatives in oil/water systems. Pharm
`Acta Helv 1986; 61: 308-313.
`8 Aalto TR et al. fJ-Hydroxybenzoic acid esters as preservatives I: uses,
`antibacterial and antifungal studies, properties and determination. JAm
`Pharm Assoc Sci 1953; 42: 449-457.
`9 Kamada A et al. Stability of p-hydroxybenzoic acid esters in acidic
`medium. Chern Pharm Bull1973; 21: 2073-2076.
`10 Aoki M et a/. [Application of surface active agents to pharmaceutical
`preparations I: effect of Tween 20 upon the antifungal activities of p(cid:173)
`hydroxybenzoic acid esters in solubilized preparations.] J Pharm Soc
`]pn 1956; 76: 939-943[in Japanese].
`11 Patel N, Kostenbauder HB. Interaction of preservatives with macro(cid:173)
`molecules I: binding of parahydroxybenzoic acid esters by polyox(cid:173)
`yethylene 20 sorbitan monooleate (Tween 80). JAm Pharm Assoc Sci
`1958; 47: 289-293.
`12 Poprzan J, deNavarre MG. The interference of nonionic emulsifiers
`with preservatives VIII. J Soc Cosmet Chem 1959; 10: 81-87.
`13 Youse£ RT et a!. Effect of some pharmaceutical materials on the
`bactericidal activities of preservatives. Can J Pharm Sci 1973; 8:54-56.
`14 Allwood MC. The adsorption of esters of p-hydroxybenzoic acid by
`magnesium trisilicate. Int J Pharm 1982; 11: 101-107.
`15 Eisman PC eta/. Influence of gum tragacanth on the bactericidal activity
`of preservatives. JAm Pharm Assoc Sci 1957; 46: 144-147.
`
`7
`
`

`

`16 Myburgh JA, McCarthy TJ. The influence of suspending agents on
`preservative activity in aqueous solid/liquid dispersions. Pharm Weekbl
`Sci 1980; 2: 143-148.
`17 Chemburkar PB, Joslin RS. Effect of flavoring oils on preservative
`concentrations in oral liquid dosage forms.] 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. Pharm J 1983; 230: 481.
`20 Ma M et al. Interaction of methylparaben preservative with selected
`sugars and sugar alcohols.] Pharm Sci 2002; 91(7): 1715-1723.
`21 Kakemi K et al. Interactions of parabens and other pharmaceutical
`adjuvants with plastic containers. Chem Pharm Bull1971; 19: 2523-
`2529.
`22 Weiner M, Bernstein IL. Adverse Reactions to Drug Formulation
`Agents: A Handbook of Excipients. New York: Marcel Dekker, 1989;
`298-300.
`23 Aldrete ]A, Johnson DA. Allergy to local anesthetics. JAm Med Assoc
`1969;207: 356-357.
`24 Latronica RJ et a/. Local anesthetic sensitivity: report of a case. Oral
`Surg 1969; 28: 439-441.
`25 Nagel JE et al. Paraben allergy.] Am Med Assoc 1977; 237: 1594-
`1595.
`26 Michaelsson G, Juhlin L. Urticaria induced by preservatives and dye
`additives in food and drugs. Br] Dermato/1973; 88: 525-532.
`27 Warin RP, Smith RJ. Challenge test battery in chronic urticaria. Br J
`Dermatol1976; 94: 401-406.
`28 Kaminer Y et al. Delayed hypersensitivity reaction to orally adminis(cid:173)
`tered methylparaben. Clin Pharm 1982; 1(5): 469-470.
`29 Fisher AA. Cortaid cream dermatitis and the 'paraben paradox' [letter].
`JAm Acad Dermato/1982; 6: 116-117.
`30 Loria C] et a/. Effect of antibiotic formulations in serum protein:
`bilirubin interaction of newborn infants. J Pediatr 1976; 89(3): 479-
`482.
`31 FAOIWHO. Toxicological evaluation of certain food additives with a
`review of general principles and of specifications. Seventeenth report of
`the joint FAO/WHO expert committee on food additives. World Health
`Organ Tech Rep Ser 1974: No. 539.
`32 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials, 11th
`edn. New York: Wiley, 2004; 2004.
`33 Food Chemicals Codex, 6th edn. Bethesda, MD: United States
`Pharmacopeia, 2008; 639.
`
`Mineral Oil
`
`445
`
`20 General References
`Banda H et a!. Effects of skin metabolism on percutaneous penetration of
`lipophilic drugs. J Pharm Sci 1997; 86(6): 759-761.
`European Directorate for the Quality of Medicines and Healthcare
`(EDQM). European Pharmacopoeia - State Of Work Of International
`Harmonisation. Pharmeuropa 2009; 21(1): 142-143. http://www.edq(cid:173)
`m.eu/site/-614.html (accessed 3 February 2009).
`Forster S et a!. The importance of chain length on the wettability and
`solubility of organic homologs. Int] Pharm 1991; 72: 29-34.
`Golightly LK eta!. Pharmaceutical excipients: adverse effects associated with
`inactive ingredients in drug products (part I). Med Toxicol1988; 3: 128-
`165.
`Grant DJW et al. Non-linear van't Hoff solubility-temperature plots and
`their pharmaceutical interpretation. Int J Pharm 1984; 18: 25-38.
`Jian L, Li Wan Po A. Ciliotoxicity of methyl- and propyl-p-hydroxybenzo(cid:173)
`ates: a dose-response and surface-response study. J Pharm Pharmacal
`1993; 45: 925-927.
`Jones PS et al. p-Hydroxybenzoic acid esters as preservatives Ill: the
`physiological disposition of p-hydroxybenzoic acid and its esters. J Am
`Pharm AssocSci 1956; 45: 268-273.
`Kostenbauder HB. Physical chemical aspects of preservative selection for
`pharmaceutical and cosmetic emulsions. Dev Ind Microbial 1962; 1:
`286-296.
`Marouchoc SR. Cosmetic preservation. Cosmet Techno/1980; 2(10): 38-
`44.
`Matthews C et a!. p-Hydroxybenzoic acid esters as preservatives II: acute
`and chronic toxicity in dogs, rats and mice.] Am Ph arm AssocSci 1956;
`45: 260-267.
`Sakamoto T et a!. Effects of some cosmetic pigments on the bactericidal
`activities of preservatives. J Soc Cosmet Chem 1987; 38: 83-98.
`Sokol H. Recent developments in the preservation of pharmaceuticals. Drug
`Standards 1952; 20: 89-106.
`
`21 Author
`S Haley.
`
`22 Date of Revision
`3 February 2009.
`
`Mineral Oil
`
`Nonproprietary Names
`BP: Liquid Paraffin
`JP: Liquid Paraffin
`PhEur: Paraffin, Liquid
`USP: Mineral Oil
`
`Empirical Formula and Molecular Weight
`4
`Mineral oil is a mixture of refined liquid saturated aliphatic (C14-
`C18) and cyclic hydrocarbons obtained from petroleum.
`
`Structural Formula
`5
`See Section 4.
`
`2
`Synonyms
`Avatech; Drakeol; heavy mineral oil; heavy liquid petrolatum;
`liquid petrolatum; paraffin oil; paraffinum liquidum; Sirius; white 7
`mineral oil.
`
`3 Chemical Name and CAS Registry Number
`Mineral oil [8012-95-1)
`
`Functional Category
`6
`Emollient; lubricant; oleaginous vehicle; solvent; vaccine adjuvant.
`
`Applications in Pharmaceutical Formulation or
`Technology
`Mineral oil is used primarily as an excipient in topical pharmaceu(cid:173)
`tical formulations, where its emollient properties are exploited as an
`ingredient in ointment bases; see Table I. It is additionally used in
`oil-in-water emulsions, (l-S) as a solvent, and as a lubricant in
`capsule and tablet formulations, and to a limited extent as a mold-
`
`8
`
`