Pharmaceutical Excipients
`
`FOURTH EDITION
`
`Edited by
`
`Raymond C Rowe
`BPharm, PhD, DSc, FRPharmS, CChem, FRSC, CPhys, MlnstP
`
`Senior Principal Scientist
`
`AstraZeneca
`
`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
`
`(P.P)
`
`London • Chicago Pharmaceutical Press
`
`American
`Pharmaceutical
`Association
`
`

`
` Published by the Pharmac~utical Press
`Publications division of the Royal Pharmaceutical Society of Great Britain
`
`1 Lambeth High Street, London SE] 7JN, UK
`100 South Atkinson Road, Suite 206, Grayslake, IL 60030-7820, USA
`
`and the American Pharmaceutical Association
`2215 Constitution Avenue NW, Washington, DC 20037-2985, USA
`
`© Pharmaceutical Press and American Pharmaceutical Association 2003
`
`(RP) is a trade mark of Pharmaceutical Press
`
`First edition published 1986
`Second edition published 1994
`Third edition published 2000
`Fourth 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 O 85369 472 9 (UK)
`ISBN 1 58212 022 6 (USA)
`
`AU rights reserved. No part of this publication may be
`reproduced, stored iri 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
`
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients.- 4th ed. I edited by Raymond C.
`Rowe, Paul J. Sheskey, Paul J. Weller.
`p. ;cm.
`Includes bibliographical references and index.
`ISBN 1-58212-022-6 (alk. paper) -ISBN 0-85369-472-9 (alk. paper)
`1. Excipients-Handbooks, manuals, etc.
`[DNLM: 1. Excipients-Handbooks. QV 735 H236 2003] I. Rowe, Raymond
`C. II. Sheskey, Paul J. III. Weller, Paul J.
`
`RS201.E87H36 2003
`615'.19-<lc21
`
`2003002641
`
`Page 2
`
`

`
`Polyoxy~ ylene Alkyl Ethers
`
`1 Nonproprietary Names
`The polyoxyethylene alkyl ethers are a series of polyoxyethy(cid:173)
`lene glycol ethers of n-alcohols (lauryl, myristyl, cetyl, and
`stearyl alcohol). Of the large number of different materials
`commercially available, two types are listed in the USPNF 20,
`one type in the JP 2001, and four types in the PhEur 2002.
`
`BP:
`
`Macrogol cetostearyl ether
`Macrogol lauryl ether
`Macrogol oleyl ether
`Macrogol stearyl ether
`Lauromacrogol
`JP:
`PhEur: Macrogoli aether cetostearylicus
`Macrogoli aether laurilicum
`Macrogoli aether oleicum
`Macrogoli aether stearylicus
`USPNF: Polyoxyl 20 cetostearyl ether
`Polyoxyl 10 oleyl ether
`Polyoxyethylene alkyl ethers are employed extensively in
`cosmetics, where the CTFA names laureth-N, myreth-N,
`ceteth-N, and steareth-N are commonly used. In this nomen(cid:173)
`clature, N is the number of ethylene oxide groups, e.g.,
`steareth-20.
`See also Sections 2-5.
`
`2 Synonyms
`Polyoxyethylene alkyl ethers are nonionic surfactants pro(cid:173)
`duced by the polyethoxylation of linear fatty alcohols. Pro(cid:173)
`ducts tend to be mixtures of polymers of slightly varying
`molecular weights and the numbers used to describe polymer
`lengths are average values.
`Two systems of nomenclature are used to describe these
`materials. The number '10' in the name Texofor A10 refers to
`the approximate polymer length in oxyethylene units (i.e., y,
`see Section 5). The number '1000' in the name 'cetomac'rogol
`1000' refers to the average molecular weight of the polymer
`chain.
`
`Table I:
`
`Synonyms of selected polyoxyethylene alkyl ethers.
`
`Name
`
`Synonym
`
`Synonyms applicable to polyoxyethylene alkyl ethers are
`shown below.
`'
`Brij; Cremophor A; Cyclogol 1000; Empilan KB; Empilan
`KM; Ethylan C; macrogol ethers; Marlowet; Plurafac; Proco!;
`·
`Texofor A; Volpa.
`Table I shows synonyms for specific materials.
`
`3 Chemical Name and CAS Registry Number
`Polyethylene glycol monocetyl ether [9004-95-9]
`Polyethyltme glycol monolauryl ether [9002-92-0]
`Polyethylene glycol monooleyl ether [9004-98-2]
`Polyethylene glycol monostearyl ether [9005-00-9]
`
`4 Empirical Formula
`See Sections 1, 2, and 5.
`
`Molecular Weight
`
`5 Structural Formula
`CH3(CH2)x(OCH2CH2)yOH
`In the formula, (x + 1) is the number of carbon atoms in the
`alkyl chain, typically:
`12 lauryl (dodecyl)
`14 myristyl (tetradecyl)
`16 cetyl (hexadecyl)
`18 stearyl (octadecyl)
`and y is the number of ethylene oxide groups in the hydrophilic
`chain, typically 10-60.
`The polyoxyethylene alkyl ethers tend to be mixtures of
`polymers of slightly varying molecular weights, and the num(cid:173)
`bers quoted are average values. In cetomacrogol 1000, for
`example, xis 15 or 17, and y is 20-24.
`
`6 Functional Category
`Emulsifying agent; solubilizing agent; wetting agent.
`
`Cetomacrogol 1 000
`Polyoxyl 20 cetostearyl ether
`Polyoxyl 2 cetyl ether
`Polyoxyl 1 0 cetyl ether
`Polyoxyl 20 cetyl ether
`Polyoxyl 4 lauryl ether
`Polyoxyl 9 lauryl ether
`Polyoxyl 23 lauryl ether
`Polyoxyl 2 oleyl ether
`Polyoxyl 1 0 oleyl ether
`Polyoxyl 20 oleyl ether
`Polyoxyl 2 stearyl ether
`Polyoxyl 1 0 stearyl ether
`Polyoxyl 20 stearyl ether
`Polyoxyl 1 00 stearyl ether
`
`Polyethylene glycol 1000; macrocetyl ether; polyoxyethylene glycol 1000; monocetyl ether
`Atlas G-377 3
`Brii 52; ceteth-2; Lipocol C-2; Proco/ CA-2
`Brii 56; ceteth-1 O; Lipocol C-7 O; Proco/ CA- 7 0
`Brii 58; ceteth-20; Lipocol C-20.
`Brii 30; laureth-4; Lipocol L-4; Proco/ LA-4; Tego Alkanol L4
`Laureth 9; Lauromacrogol 400; polidocanol
`Brii 35; laureth-23; Lipocol L-23; Proco/ LA-23; Ritox 35; Tego Alkanol L23 P
`Brii 92; Brii 93; oleth-2; Lipocol 0-2; Proco/ OA-2
`Brii 96; Brii 97; oleth-1 0; polyethylene glycol monooleyl ether; Lipocol 0- 7 O; Proco/ OA- 70; Vo/po 7 0
`Brii 98; Brii 99; Lipocol 0-20; oleth-20; Proco/ OA-26; Vo/po 20
`Brii 72; Lipocol S-2; Proco/ SA-2; steareth-2; Tego Alkanol 52; Vo/po S-2
`Brii 7 6; Upocol 5- 7 O; Proco/ SA- 70; steareth-1 O; Tego Alkanol S 70; Vo/po 5- 7 0
`Brii 78; Lipocol S-20; Proco/ SA-20; steareth-20; Tego A/kanol 520 P; Vo/po S-20
`Brii 700; steareth-100
`
`469
`
`Page 3
`
`

`
`470
`
`Polyoxyethylene Alkyl Ethers
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Polyoxyethylene alkyl ethers are nonionic surfactants widely
`used in topical pharmaceutical formulations and cosmetics,
`primarily as emulsifying agents for water-in-oil and oil-in(cid:173)
`water emulsions.
`Polyoxyethylene alkyl ethers are als0 used in other applica(cid:173)
`tions such as solubilizing agents for essential oils, perfumery
`chemicals, vitamin oils, and drugs of low-water solubility;
`gelling and foaming agents (e.g., Brij 72 gives a quick-break(cid:173)
`ing foam, while Brij 97 (and others) gives clear gels at 15-20%
`concentration); antidusting agents for powders; wetting and
`dispersing agents for coarse-particle liquid dispersions; and
`detergents, especially in shampoos and similar cosmetic clean(cid:173)
`ing preparations.
`
`8 Description
`Polyoxyethylene alkyl ethers vary considerably in their physi(cid:173)
`cal appearance from liquids, to pastes, to solid waxy sub(cid:173)
`stances. They are colorless, white or cream-colored materials
`with a slight odor.
`
`9 Pharmacopeial Specifications
`See Table II.
`
`10 Typical Properties
`See Tables III and IV.
`
`Stability and Storage Conditions
`11
`Polyoxyethylene alkyl ethers are chemically stable in strongly
`acidic or alkaline conditions. The presence of strong electro(cid:173)
`lytes may, however, adversely affect the physical stability of
`emulsions containing polyoxyethylene alkyl ethers.
`On storage, polyoxyethylene alkyl ethers can undergo
`autoxidation, resulting in the formation of peroxides with an
`increase in acidity. Many. commercially available grades are
`thus supplied with added antioxidants. Typically, a mixture of
`0.01 % butylated hydroxyanisole and 0.005% citric acid is
`used for this purpose.
`Polyoxyethylene alkyl ethers should be stored in an airtight
`container, in a cool, dry place.
`
`Incompatibilities
`12
`Discoloration or precipitation may occur with iodides, mer(cid:173)
`cury salts, phenolic substances, salicylates, sulfonamides, and
`tannins. Polyoxyethylene alkyl ethers are also incompatible
`with benzocaine and oxidizable drugsY)
`The antimicrobial efficacy of some phenolic preservatives,
`such as the parabens, is reduced owing to hydrogen bonding.
`Cloud points are similarly depressed by phenols owing to
`hydrogen bonding between ether oxygen atoms and phenolic
`hydroxyl groups. Salts, other than nitrates, iodides, and
`thiocyanates (which cause an increase) can also depress cloud
`pointsY)
`
`Table II:
`
`Pharmacopeial specifications for polyoxyethylene alkyl ethers.
`
`Test
`
`JP 2001
`
`PhEur 2002
`
`PhEur 2002
`
`PhEur 2002
`(Suppl 4.1)
`
`PhEur 2002
`(Suppl 4.1)
`
`USPNF 20
`
`USPNF 20
`
`Lauro-macrogol Macrogol
`cetostearyl
`ether
`
`Macrogol stearyl Macrogol lauryl Macrogol oleyl Polyoxyl 20
`ether
`ether
`ether
`cetostearyl
`ether
`
`Polyoxyl 10 oleyl
`ether
`
`+
`+
`
`+
`,s;0.20%
`
`Identification
`Characters
`Water
`pH (10% solution)
`Alkalinity
`Acidity
`Residue on ignition
`Heavy metals
`Acid value
`Hydroxyl value
`Iodine value
`Saponification value
`Free polyethylene
`glycols
`Free ethylene oxide
`Dioxan
`Peroxide
`Average polymer
`length
`Organic volatile
`impurities
`Total ash
`
`+
`+
`,;;3.0%
`
`+
`+
`,;;3.0%
`
`+
`+
`,;;3.0%
`
`+
`+
`,;;3.0%
`
`+
`
`+
`
`+
`
`+
`
`< 1.0
`+
`<2.0
`,;;3.0
`
`,s;l.O
`+
`,;;2.0
`,;;3.0
`
`,s;l.O
`+
`<2.0
`,;;3.0
`
`<l ppm
`,s;lOppm
`
`<1 ppm
`,s;lOppm
`
`<1 ppm
`< lOppm
`
`<S;l.0
`+
`+
`,;;3.0
`
`<1 ppm
`< lOppm
`~10.0
`
`,s;0.2%
`
`,s;0.2%
`
`<0.2%
`
`+
`
`<1.0%
`4.5-7.5
`
`,s;0.4%
`,s;0.002%
`,s;0.5
`42-60
`
`,;;2.0
`<7.5%
`
`+
`
`,;;3.0%
`
`,s;0.4%
`,s;0.002%
`,s;l.O
`75-95
`23-40
`,;;3.0
`,;;7.5%
`
`,s;0.01%
`
`,s;0.01%
`
`17.2-25.0
`
`8.6-10.4
`
`+
`
`+
`
`Page 4
`
`

`
`Table Ill:
`Name
`
`Typical properties of selected commercially available grades of polyoxyethylene alkyl ethers.
`Physical form
`Acid value HLB value Hydroxyl value
`Iodine number Saponification Density
`(g/cm3
`value
`) at 20°c
`
`Water content Melting point or Cloud point (0 C) for
`(%)
`pour point (°C) 1 % aqueous solution
`
`Brij 30
`Brij 35
`Brij 52.
`Brij 56
`Brij 58
`Brij 72
`Brij 76
`Brij 78
`Brij 93
`Brij 97
`Brij 99
`Cremophor A6
`Cremophor A25
`Ethosperse 7 A4
`Ethosperse 7 A 7 2
`Ethosperse TDA6
`Ethosperse S 7 20
`Ethosperse G26
`Ethylan D252
`Ethylan 253
`Ethylan 254
`Ethylan 256
`Ethylan 257
`Ethylan 25 7 2
`Ethylan 2560
`Plurofac RA20
`Plurofac RA30
`Plurofac RA40
`Plurofac RA340
`Renex 30
`Renex 37
`Renex 36
`Texofor A7P
`Texofor AP
`Texofor A6
`Texofor A70
`Texofor A74
`Texofor A30
`Texofor A45
`Texofor A60
`Vo/po 70
`Vo/po 20
`Vo/po S-2
`Vo/po S-70
`Vo/po 5-720
`
`Liquid
`Solid
`Solid
`Solid
`Solid
`Solid
`Solid
`Solid
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`Liquid
`Liquid
`Liquid
`Liquid
`Liquid
`Solid
`Solid
`-
`-
`-
` -
`Cloudy liquid
`-
`-
`Solid
`-
`Solid
`Solid
`Solid
`Solid
`Solid
`Solid
`Hazy liquid
`Soft solid
`Soft solid
`Soft solid
`Waxy solid
`
`~2
`~5
`~1
`~1
`~1
`~1
`~1
`~1
`~1
`~1
`~l
`~1
`~1
`~2
`~2
`~1
`~0.5
`~2
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`~1
`~1
`~1
`-
`-
`-
`-
`-
`-
`-
`-
`<2
`<2
`<1
`<l
`<1
`
`9.7
`16.9
`5.3
`12.9
`15.7
`4.9
`12.4
`15.3
`4.9
`12.4
`15.3
`10-12
`15-17
`-
`-
`-
`-
`-
`5.6
`7.8
`9.8
`11.4
`12.2
`14.2
`18.6
`-
`-
`-
`-
`14.5
`15.4
`11.4
`16.2
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`145-165
`40--60
`160-180
`75-90
`45--60
`150-170
`75-90
`45--60
`160-180
`80-95
`50-65
`115-135
`35-45
`145-160
`72----82
`118-133
`385-430
`133-142
`-
`-
`-
`-
`-
`-
`-
`69-78
`85-95
`65-75
`73
`75----85
`60-74
`118-133
`-
`-
`-
`-
`-
`-
`-
`-
`79-91
`50-58
`150-170
`75-90
`45--60
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`~1
`~1
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`31-37
`18-25
`-
`-
`-
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`~3
`,.,;3
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`0.9965
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`~1.0
`""0.95
`~3.0
`""1.05
`-
`~ 1.0
`~3.0
`-
`-
`~3.0
`-
`~l.O
`-
`~3.0
`~3.0
`-
`-
`~1.0
`-
`~3.0
`~3.0
`-
`0.896-0.906 at 60°( ~1.0
`1.020-1.028 at 60°( ~1.0
`0.95
`~0.5
`1.10
`~1.0
`0.98
`~ 1.0
`1.16
`~1.0
`1.12at38°C
`~0.5
`0.903
`~0.5
`0.930
`~0.5
`0.948
`~3.0
`0.972
`~0.5
`0.974 at40°C
`~0.5
`1.001
`~0.5
`~0.5
`-
`~0.1
`4
`0.976
`~0.1
`0.978
`~0.2
`0.977
`-
`1.0
`~3.0
`1.0
`~3.0
`1.0
`~ 1.0
`-
`1 .025 at 60°(
`0.875
`-
`0.140
`-
`-
`0.970
`0.995
`-
`1.035
`-
`1.055
`-
`1.065
`-
`-
`<l.0
`<1.0
`-
`< 1.0
`-
`<3.0
`-
`-
`<3.0
`
`33
`33
`31
`38
`43
`38
`38
`10
`16
`33
`41-43
`44-46
`
`5
`3
`5
`15
`21
`29
`45
`
`--6
`-27
`-23
`14
`16
`-
`40
`31
`26
`30
`35
`43
`47
`48
`-
`-
`
`-
`-
`
`Insoluble
`Insoluble
`lnsoiuble
`43
`49
`92
`>100
`
`-
`18.4
`99
`<32
`>100
`Insoluble
`Insoluble
`75
`100
`>100
`>100
`>100
`>55
`>100
`
`-
`-
`
`u
`0
`-<"
`0
`X
`'<
`CD
`3'-
`".S...
`CD
`::,
`CD
`)>
`7'"""
`'<
`m
`3'-
`CD
`;:;;
`
`.r:,.
`"I
`
`Page 5
`
`

`
`.ll,.
`.......
`"-)
`
`v
`0
`-<""
`0
`X -<
`~
`::y-
`-<
`CD
`:::,
`CD
`)>
`;,-:-
`-<
`-
`m
`::y-
`CD
`~
`u,
`
`Table IV: Typical properties of selected commercially available grades of polyoxyethylene alkyl ethers.
`
`Name
`
`Critical micelle
`concentration (%)
`
`Surface tension of aqueous solution Dynamic viscosity at 25°C
`at 20°C (mN/m)
`or pour point (mPa s)
`
`Refractive index at 60°C
`
`Solubility
`
`Brii 30
`Brii 35
`Brii 52
`Brii 56
`Brii 58
`Brii 72
`Brii 76
`Brii 78
`Brii 93
`Br;; 97
`Brii 99
`Cremophor A6
`Cremophor A25
`Ethosperse 7 A4
`Ethosperse 7 A 7 2
`Ethosperse TDA6
`Ethosperse S 7 20
`Ethosperse G26
`Ethylan D252
`Ethylan 253
`Ethylan 254
`Ethylan 256
`Ethylan 257
`Ethylan 25 7 2
`Ethylan 2560
`Plurafac RA20
`Plurafac RA30
`Plurafac RA40
`Plurafac RA340
`Renex 30
`Renex 37
`Renex 36
`Texofor ATP
`Texofor AP
`Texofor A6
`Texofor A70
`Texofor A74
`Texofor A30
`Texofor A45
`Texofor A60
`
`-
`0.013
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`0.006
`-
`-
`0.004
`-
`0.003
`0.004
`0.003
`
`(0.05%)
`
`(0.1%)
`
`(0.2%)
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`42.9
`-
`-
`36.5
`36.9
`46.0
`47.5
`48.3
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`30.7
`28.6
`30.3
`30.5
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`30
`-
`-
`-
`-
`-
`-
`-
`30
`100
`-
`-
`-
`30
`1000
`80
`460
`150 at 38°C
`-
`-
`-
`-
`-
`-
`-
`
`-
`-
`-
`42.3
`-
`-
`36.7
`36.6
`46.0
`47.0
`48.3
`
`60
`130
`80
`-
`-
`-
`-
`-
`-
`-
`-
`
`S ~ Soluble; I - Insoluble; D ~ Dispersible; SH~ Soluble on heating.
`Suppliers: ICI Surfactants (BriJJ.
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`1.4420-1.4424
`1 .4512-1.4520
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`Ethanol
`s
`s
`s
`s
`s
`s
`s
`s
`s
`s
`s
`s
`s
`s
`s
`s
`s
`s
`-
`-
`-
`-
`-
`-
`-
`
`s
`s
`s
`s
`s
`s
`s
`s
`s
`s
`s
`
`Fixed oils Propylene glycol Water
`s
`s
`s
`I
`s
`I
`I
`I
`I
`I
`s
`I
`s
`I
`I
`I
`s
`s
`I
`I
`s
`I
`I
`-
`-
`I
`s
`-
`SH
`-
`I
`-
`I
`-
`-
`I
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`I
`s
`I
`I
`s
`I
`I
`I
`I
`s
`s
`s
`s
`s
`s
`D
`s
`s
`I
`I
`I
`s
`s
`s
`s
`
`I
`I
`I
`-
`-
`-
`-
`-
`-
`-
`-
`
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`-
`
`s
`s
`D
`s
`I
`I
`s
`s
`s
`s
`s
`
`Page 6
`
`

`
`13 Method of Manufacture
`Polyoxyethylene alkyl ethers are prepared by the condensation
`of linear fatty alcohols with ethylene oxide. The reaction is
`controlled so that the required ether is formed with the
`polyethylene glycol of the desired molecular weight.
`
`14 Safety
`Polyoxyethylene alkyl ethers are used as nonionic surfactants
`in a variety of topical pharmaceutical formulations and cos(cid:173)
`metics. The polyoxyethylene alkyl ethers form a series of
`materials with varying physical properties and manufac(cid:173)
`turers' literature should be consulted for information on the
`applications and safety of specific materials.
`Although generally regarded as essentially nontoxic and
`nonirritant materials, some polyoxyethylene alkyl ethers,
`particularly when used in high concentration (>20%), appear
`to have a greater irritant potential than others.
`Animal toxicity studies suggest that polyoxyethylene alkyl
`ethers have a similar oral toxicity to other surfactants and can
`be regarded as being moderately toxic. In rats, the oral LD5o
`values range from about 2-4 g/kg body-weight.
`
`Polyoxyl 10 oleyl ether
`LD50 (rat, oral): 2.7g/kg
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Eye pro_tection and gloves
`are recommended.
`
`Polyoxyethylene Alkyl Ethers
`
`473
`
`17 Related Substances
`Nonionic emulsifying wax.
`
`18 Comments
`Many other polyoxyethylene ethers, such as diethers and
`polyethers, are commercially available and are also used as
`surfactants. In addition to their surfactant properties, the series
`of polyoxyethylene ethers with lauryl side chains, e.g., non(cid:173)
`oxynol 10, are also widely used as spermicides.
`
`19 Specific References
`1 Azaz E, Donbrow M, Hamburger R. Incompatibility of non-ionic
`surfactants with oxidizable drugs. Phann J 1973; 211: 15.
`2 McDonald C, Richardson C. The effect of added salts on
`solubilization by a non-ionic surfactant. J Phann Pharmacol
`1981; 33: 38-39.
`
`.
`
`20 General References
`Ammar HO, Khali RM. Solubilization of certain analgesics by
`Cetomacrogol 1000. Egypt J Phann Sci 1996; 37: 261-271.
`Elworthy PH, Guthrie WG. Adsorption of non-ionic surfactants at the
`griseofulvin-solution interface. J Pharm Pharmacol 1970;
`22(Suppl.): 114S-120S.
`Guveli D, Davis SS, Kayes JB. Viscometric studies on surface agent
`solutions and the examination of hydrophobic interactions.
`J Phann Pharmacol 1974; 26(Suppl.): 127P-128P.
`Walters KA, Dugard PH, Florence AT. Non-ionic surfactants and
`gastric mucosa! transport of paraquat. J Phann Pharmacol 1981;
`33: 207-213.
`
`21 Author
`CD Yu.
`
`16 Regulatory Status
`Included in nonparenteral medicines licensed in the USA and
`UK.
`
`22 Date of Revision
`1 November 2002.
`
`Page 7
`
`

`
`Polyo~e ylene Castor
`
`ii Derivatives
`
`1 Noni:>roprietary Names
`BP:
`Polyoxyl castor oil
`Hydrogenated polyoxyl castor oil
`PhEur: Macrogolglyceroli ricinoleas
`Macrogolglyceroli hydroxystearas
`USPNF: Polyoxyl 35 castor oil
`Polyoxyl 40 hydrogenated castor oil
`Polyoxyethylene castor oil derivatives are a series of materials
`obtained by, reacting varying amounts of ethylene oxide with
`either castor oil or hydrogenated castor oil. Several different
`types of material are commercially available, the best-known
`being the Cremophor series (BASF Corp.). Of these, two castor
`oil derivatives are listed in the PhEur 2002 and USPNF 20.
`See also Sections 2-4.
`
`2 Synonyms
`Synonyms applicable to polyoxyethylene castor oil derivatives
`are shown below. See Table I for information on specific
`materials.
`Arlatone; Cremothon; Mapeg; Marlowet; Simulsol.
`
`Synonyms of selected polyoxyethylene castor oil derivatives.
`
`Table I:
`
`Name
`
`Polyoxyl 5 castor oil
`
`Polyoxyl 9 castor oil
`
`Polyoxyl 15 castor oil
`
`Polyoxyl 35 castor oil
`
`Polyoxyl 40 castor oil
`
`Polyoxyl 40
`hydrogenated
`castor oil
`
`Polyoxyl 60
`hydrogenated
`castor oil
`
`474
`
`Synonym
`
`Acconon CA-5; PEG-5 castor oil;
`polyoxyethylene 5 castor oil.
`Acconon CA-9; castor oil POE-9; PEG-9
`castor oil; polyoxyethylene 9 castor oil;
`Protachem CA-9.
`Acconon CA-15; castor oil POE-15; PEG-15
`castor oil; polyoxyethylene 15 castor oil;
`Protachem CA-15.
`Cremophor EL; Cremophor ELP; Etocas 35;
`glycerol polyethyleneglycol ricinoleate;
`polyethoxylated castor oil;
`polyoxyethylene 35 castor oil.
`Castor oil POE-40; Croduret 40; Eumulgin
`RO; Nonionic GR-40; PEG-40 castor oil;
`polyoxyethylene 40 castor oil; Protachem
`CA-40.
`Cremophor RH 40; Eumulgin HRE 40;
`glycerol polyethyleneglycol oxystearate;
`hydrogenated castor oil POE-40; PEG-40
`hydrogenated castor oil; polyethoxylated
`hydrogenated castor oil; polyoxyethylene
`40 hydrogenated castor oil; Lipocol
`HC0-40; Lipocol LAV HCO 40; Nikko/
`HCO 40; Nonionic GRH-40; Protachem
`CAH-40.
`Eumulgin HRE 60; hydrogenated castor oil
`POE-60; PEG-60 hydrogenated castor
`oil; polyoxyethylene 60 hydrogenated
`castor oil; Lipocol HC0-60; Nikko/ HCO
`60; Protachem CAH-60.
`
`3 Chemical Name and CAS Registry Number
`Polyethoxylated castor oil [ 61791-12-6]
`
`· 4 Empirical Formula
`Molecular Weight
`Polyoxyethylene castor oil derivatives are complex mixtures of
`various hydrophobic and hydrophilic components.
`The PhEur 2002 states that polyoxyl castor oil contains
`mainly ricinoleyl glycerol ethoxylated with 30-50 molecules of
`ethylene oxide (nominal value). The PhEur 2002 also states
`that polyoxyl hydrogenated castor oil contains mainly tri(cid:173)
`hydroxystearyl glycerol ethoxylated with 7-60 molecules of
`ethylene oxide (nominal value).
`In polyoxyl 35 castor oil (Cremophor EL), the relatively
`hydrophobic constituents comprise about 83% of the total
`mixture, the main component being glycerol polyethylene
`glycol ricinoleate. Other hydrophobic constituents include
`fatty acid esters of polyethylene glycol along with some
`unchanged castor oil. The hydrophilic part ( 17%) consists of
`polyethylene glycols and glycerol ethoxylates. Cremophor
`ELP, a 'purified' grade of Cremophor EL is also a polyoxyl
`35 castor oil; it has a lower content of water, potassium, and
`free fatty acids and hence is claimed to have improved stability.
`In polyoxyl 40 hydrogenated castor oil ( Cremophor RH
`40), approximately 75% of the components of the mixture are
`hydrophobic. These comprise mainly fatty acid esters of
`glycerol polyethylene glycol and fatty acid esters of polyethy(cid:173)
`lene glycol. The hydrophilic portion consists of polyethylene
`glycols and glycerol ethoxylates.
`
`5 Structural Formula
`See Section 4.
`
`6 Functional Category
`Emulsifying agent; solubilizing agent; wetting agent.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Polyoxyethylene castor oil derivatives are nonionic surfactants
`used in oral, topical, and parenteral pharmaceutical formula(cid:173)
`tions. They are also used in cosmetics and animal feeds.
`Polyoxyl 35 castor oil ( Cremophor EL) is mainly used as an
`emulsifing and solubilizing agent, and is particularly suitable
`for the production of aqueous liquid preparations containing
`volatile oils, fat-soluble vitamins, and other hydrophobic
`substancesY·2
`) In 1 mL of a 25% v/v aqueous polyoxyl 35
`castor oil (Cremophor EL) solution it is possible to incorporate
`approximately 10 mg of vitamin A palmitate; approximately
`10 mg of vitamin D; approximately 120 mg of vitamin E
`acetate; or. approximately 120 mg of vitamin K1 .
`To solubilize fat-soluble vitamins, the active ingredient or
`ingredients should first be dissolved in polyoxyl 35 castor oil
`(Cremophor EL). Water should then be added very slowly with
`vigorous stirring. As the water is added, the viscosity increases,
`reaching a maximum at a water content of approximately 40%
`
`Page 8
`
`

`
`v/v. Solubilization can be facilitated by heating to approxi(cid:173)
`mately 60°C for a short time and in some cases by adding
`polyethylene glycol and/or propylene glycol. In oral formula(cid:173)
`tions, the taste of polyoxyl 35 castor oil (Cremophor EL) can
`be masked by a banana flavor.
`.
`Polyoxyl 35 castor oil (Cre,nophor EL) has also been used
`as a solvent in ptoprietary injections of diazepam, propanidid,
`and alfaxalone with alfadolone acetate; see Section 14. Poly(cid:173)
`oxyl 35 castor oil (Cremophor EL) is also used in the produc(cid:173)
`tion of glycerin suppositories.
`In veterinary practice, polyoxyl 35 castor oil (Cremophor
`EL) can be used to emulsify cod liver oil, and oils and fats
`incorporated into animal feeding stuffs.
`In cosmetics, polyoxyl 35 castor oil (Cremophor EL) is
`mainly used as a solubilizing agent for perfume bases and
`volatile oils in vehicles containing 30-50% v/v alcohol (etha(cid:173)
`nol or propan-2-ol). In hand lotions, it can be used to replace
`castor oil.
`·
`Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40)
`may be used
`in preference
`to polyoxyl 35 castor oil
`(Cremophor EL) in oral formulations since it is almost taste(cid:173)
`less. In aqueous alcoholic or completely aqueous solutions,
`polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) can
`be used to solubilize vitamins, essential oils, and certain drugs.
`Using 1 mL of a 25% v/v aqueous solution of polyoxyl 40
`hydrogenated castor oil (Cremophor RH 40), it is possible to
`solubilize approximately 88 mg of vitamin A palmitate, or
`approximately 160 mg of vitamin A propionate. Other materi(cid:173)
`als that can be solubilized are alfadolone, alfaxalone, hexa(cid:173)
`chlorophene, hexetidine,
`levomepromazine, miconazole,
`propanidid, and thiopental.
`In aerosol vehicles that include water, the addition of
`polyoxyl 40 hydrogenated castor oil (Cremophor RH 40)
`improves the solubility of the propellant in the aqueous
`phase. This enhancement applies both to dichlorodifluoro(cid:173)
`methane and to propane/butane mixtures.
`Foam formation in aqueous ethanol solutions containing
`polyoxyl 40 hydrogenated castor oil ( Cremophor RH 40) can
`be suppressed by the addition of small amounts of polypropy(cid:173)
`lene glycol 2000.
`
`Polyoxyethylene Castor Oil Derivatives
`
`475
`
`Polyoxyl 40 hydrogenated castor oil ( Cremophor RH 40) is
`also used as an emulsifier of fatty acids and alcohols.
`
`8 Description
`Polyoxyl 35 castor oil (Cremophor EL) occurs as a pale yellow,
`viscous liquid that is clear at temperatures above 26°C. It has a
`slight but characteristic odor and can be completely liquefied
`by heating to 26°C.
`Polyoxyl 40 hydrogenated castor oil ( Cremophor RH 40)
`occurs as a white, semisolid paste that liquefies at 30°C. It has a
`very faint characteristic odor and a slight taste in aqueous
`solution.
`Polyoxyl 60 hydrogenated castor oil (Cremophor RH 60)
`occurs as a white paste at room temperature. It has little taste
`or odor in aqueous solution.
`
`9 Pharmacopeial Specifications
`See Table IL
`
`10 Typical Properties
`See Tables III, IV, and V.
`
`Stability and Storage Conditions
`11
`Polyoxyl 35 castor oil (Cremophor EL and Cremophor ELP)
`forms stable solutions in many organic solvents such as chloro(cid:173)
`form, ethanol, and propan-2-ol; it also forms clear, stable,
`aqueous solutions. Polyoxyl 35 castor oil ( Cremophor EL and
`Cremophor ELP) is miscible with other polyoxyethylene
`castor oil derivatives and on heating with fatty acids, fatty
`alcohols, and some animal and vegetable oils. Solutions of
`polyoxyl 40 hydrogenated castor oil ( Cremophor RH 40) in
`aqueous alcohols are also stable.
`
`Table II: Pharmacopeial specifications for polyoxyethylene c~stor oil derivatives.
`
`Test
`
`PhEur 2002
`
`PhEur 2002
`
`USPNF 20
`
`USPNF 20
`
`Polyoxyl castor oil
`
`Polyoxyl hydrogenated
`castor oil
`
`Polyoxyl 35 castor oil
`
`Polyoxyl 40 hydrogenated
`castor oil
`
`Identification
`Characters
`Appearance of solution
`Alkalinity
`Specific gravity
`Congealing temperature
`Viscosity at 25°C
`Water
`Residue on ignition
`Heavy metals
`Acid value
`Hydroxyl value
`Iodine value
`Saponification value
`Dioxan
`Free ethylene oxide
`Organic volatile impurities
`
`+
`+
`+
`+
`R< 1.05
`
`500-800 mPa s
`:s::;3.0%
`:s::;0.3%
`:s::; lOppm
`:s::;2.0
`+
`25-35
`+
`:s::; lOppm
`:( 1 ppm
`
`+
`+
`+
`+
`
`:(3.0%
`:s::;0.3%
`:s::; lOppm
`:(2.0
`+
`:(5
`+
`:s::; lOppm
`:( 1 ppm
`
`+
`
`+
`
`1.05-1.06
`
`650-850 mPa s
`:s::;3.0%
`:s::;0.3%
`:(0.001 %
`:s::;2.0
`65-80
`25-35
`60-75
`
`16-26°C
`
`:s::;3.0%
`:(0.3%
`:s::;0.001%
`:(2.0
`60-80
`:s::;2.0
`45-69
`
`+
`
`+
`
`Page 9
`
`

`
`.i::,.
`'I
`0,.
`
`u
`
`0 -< 0
`
`(./>
`
`~
`
`X
`--<
`~
`::,-
`--<
`(1)
`:::,
`(1)
`(J
`0
`0
`0
`0
`(1)
`<
`0
`<
`(1)
`c.n
`
`Table Ill:
`
`Typical physical properties of selected commercially available polyoxyethylene castor oil derivatives.
`
`Name
`
`Acid value
`
`HLB value
`
`Hydroxyl value Iodine number Saponification Water content Melting point
`(OC)
`value
`
`Solidification
`point (0 C)
`
`Cloud point for a
`1% aqueous
`solution (0 C)
`
`Polyoxyl 35 castor oil (Cremophor EL)
`Poloxyl 35 castor oil, purified
`(Cremophor ELP)
`Polyoxyl 40 hydrogenated castor oil
`( Cremophor RH 40)
`Polyoxyl 60 hydrogenated castor oil
`
`,,;2.0
`,,;2.0
`
`,,; 1.0
`
`,,; 1.0
`
`12-14
`12-14
`
`14-16
`
`15-17
`
`65-78
`65-78
`
`60-80
`
`50-70
`
`28---32
`28---32
`
`,,;1
`
`,,;1
`
`65-70
`65-70
`
`50-60
`
`40-50
`
`,,;3%
`,,;0.5%
`
`,,;2%
`
`,,;2%
`
`19-20
`
`-
`
`~30
`
`~40
`
`21-23
`
`-
`
`72.5
`
`95.6
`
`-:
`
`Table IV:
`
`Name
`
`Typical physical properties of selected commercially available polyoxyethylene castor oil derivatives.
`
`Density (g/cm3
`
`)
`
`pH
`
`Refractive index at 20°C
`
`Surface tension of 0. 1 %
`w/v aqueous solution
`(mN/m)
`
`Viscosity at 25°C (mPa s)
`·
`
`Critical micelle
`concentration (°lo)
`
`Polyoxyl 35 castor oil (Cremophor EL)
`Poloxyl 35 castor oil, purified (Cremophor ELP)
`Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40)
`Polyoxyl 60 hydrogenated castor oil
`
`1.05-1.06
`1.05-1.06
`
`1.471
`
`1.453-1.457
`
`6-8
`5-7
`6-7
`6-7
`
`40.9
`
`43.0
`
`650-800
`600-750
`20-4o(a)
`
`~0.009
`~0.009
`~0.039
`
`fol 30% w/v aqueous solution.
`
`Table V:
`
`Solubility of selected commercially available polyoxyethylene castor oil derivatives.
`
`Name
`
`Solubility
`
`Polyoxyl 35 castor oil (Cremophor EL)
`Poloxyl 35 castor oil, purified (Cremophor ELP)
`Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40)
`Polyoxyl 60 hydrogenated castor oil
`
`S = Soluble.
`!ol Ne~d to add 0.5-1.0% water to maintain a clear solution.
`
`Castor oil
`s
`s
`s
`s
`
`Chloroform
`s
`s
`s
`
`Ethanol
`s
`s
`s
`5(a)
`
`Fatty acids
`s
`s
`s
`s
`
`Fatty alcohols
`s
`s
`s
`s
`
`Olive oil
`s
`s
`s
`s
`
`Water
`s
`s
`s
`s
`
`Page 10
`
`

`
`On heating of an aqueous solution, the solubility of poly(cid:173)
`oxyl 35 castor oil (Cremophor EL and Cremophor ELF) is
`reduced and the solution becomes turbid. Aqueous solutions of
`polyoxyl hydrogenated castor oil (Cremophor RH grades)
`heated for prolonged periods may separate into solid and
`liquid phases on cooling. However, the product can be
`restored to its original form by homogenization.
`Aqueous solutions of polyoxyl 35 castor oil ( Cremophor
`EL and Cremophor ELF) are stable in the presence of low
`concentrations of electrolytes such as acids or salts, with the
`exception of mercuric chloride; see Section 12.
`Aqueous solutions of polyoxyl 35 castor oil (Cremophor
`EL and Cremophor ELF) can be sterilized by autoclaving for
`20 minutes at 121 °C. In this process, a product may acquire a
`deeper color but this has no significance for product stability.
`Aqueous solutions of polyoxyl hydrogenated castor oil (Cre(cid:173)
`) can similarly be sterilized by autoclaving at 121 °C, but this
`may cause a slight decrease in the pH value.
`Although the method of manufacture used for polyoxyethy(cid:173)
`lene castor oil derivatives ensures that they are near-sterile,
`microbial contamination can occur on storage.
`Polyoxyethylene castor oil derivatives should be stored in a
`well-filled, airtight container, protected from light, in a cool,
`dry place.
`
`Incompatibilities
`12
`In strongly acidic or alkaline solutions, the ester components of
`polyoxyethylene hydrogenated castor oil (Cremophor RH) are
`liable to saponify.
`In aqueous solution, polyoxyl 35 castor oil (Cremophor EL
`and Cremophor ELF) is stable toward most electrolytes in the
`concentrations normally employed. However, it is incompati(cid:173)
`ble with mercuric chloride since precipitation occurs.
`Some organic substances may cause precipitation at certain
`concentrations, especially compounds containing phenolic
`hydroxyl groups, e.g., phenol, resorcinol, and tannins.
`Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40)
`and polyoxyl 60 hydrogenated castor oil are largely unaffected
`by the salts that cause hardness in water.
`
`13 Method of Manufacture
`Polyoxyethylene castor oil derivatives are prepared by reacting
`varying amounts of ethylene oxide with either castor oil or
`hydrogenated castor oil under controlled conditions.
`Polyoxyl 35 castor oil (Cremophor EL) is produced in this
`way by reacting 1 mole of castor oil with 35-40 moles of
`ethylene oxide.
`Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) is
`produced by reacting 1 mole of hydrogenated castor oil with
`40-45 moles of ethylene oxide. Polyoxyl 60 hydrogenated
`castor oil is similarly produced by reacting 1 mole of hydro(cid:173)
`genated castor oil with 60 moles of ethylene oxide.
`
`14 Safety
`Polyoxyethylene castor oil derivatives are used in a variety of
`oral, topical, and parenteral pharmaceutical formulations.
`Acute and chronic toxicity tests in animals have shown
`polyoxyethylene castor oil derivatives to be essentially non(cid:173)
`4
`) However,
`toxic and nonirritant materials; see Table V