Handbook of Handbook of
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`PHARMACEUTICAL PHARMACEUTICAL
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`EXCIPIENTS EXCIPIENTS
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`NOVARTIS EXHIBIT 2006
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`/ > / >
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`/Handbook of /Handbook of
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`PHARMACEUTICAL PHARMACEUTICAL
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`EXCIPIENTS 7 / ' EXCIPIENTS 7 / '
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`---------,-;,-' ---------,-;,-'
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`e;7 e;7
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`Second Edition Second Edition
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`Edited by Edited by
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`Ainley Wade and Paul J Weller Ainley Wade and Paul J Weller
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`American Pharmaceutical Association American Pharmaceutical Association
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`Washington Washington
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`
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`1994 1994
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`The Pharmaceutical Press The Pharmaceutical Press
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`London London
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`8980 8980
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`18.6 18.6
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`NOVARTIS EXHIBIT 2006
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`© Copyright 1986, 1994 by the American Pharmaceutical Association, 2215 Constitution Avenue NW, Washington, © Copyright 1986, 1994 by the American Pharmaceutical Association, 2215 Constitution Avenue NW, Washington,
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`DC 20037-2985, USA, and The Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain, 1 Lambeth High DC 20037-2985, USA, and The Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain, 1 Lambeth High
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`Street, London, SEl 7JN, England. Street, London, SEl 7JN, England.
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`A catalogue record for this book is available from the British Library. A catalogue record for this book is available from the British Library.
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`Library of Congress Catalog Card Number: 94-79492. Library of Congress Catalog Card Number: 94-79492.
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`I I
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`I I
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`, \ n , \ n
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`1-+ <,.t;1 1-+ <,.t;1
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`} "--' } "--'
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`{ {
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`International Standard Book Number (ISBN) in the UK: 0 85369 305 6 International Standard Book Number (ISBN) in the UK: 0 85369 305 6
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`International Standard Book Number (lS13N) in the USA: 091730668 International Standard Book Number (lS13N) in the USA: 091730668
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`No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
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`including photocopy, recording, or any information storage or retrieval system, without prior written permission from including photocopy, recording, or any information storage or retrieval system, without prior written permission from
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`Typeset in Great Britain by Alden Multimedia, Northampton. Typeset in Great Britain by Alden Multimedia, Northampton.
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`Printed and bound in Great Britain by Printed and bound in Great Britain by
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`NOVARTIS EXHIBIT 2006
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`Polyoxyethylene Castor Polyoxyethylene Castor
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`Oil Derivatives Oil Derivatives
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`1. Nonproprietary Names 1. Nonproprietary Names
`
`Polyoxyethylene castor oil derivatives are a series of materials Polyoxyethylene castor oil derivatives are a series of materials
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`obtained by reacting varying amounts of ethylene oxide with obtained by reacting varying amounts of ethylene oxide with
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`either castor oil or hydrogenated castor oil. Several different either castor oil or hydrogenated castor oil. Several different
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`types of material are commercially available the best known types of material are commercially available the best known
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`being the Cremophors (BASF Corporation). Of these, two being the Cremophors (BASF Corporation). Of these, two
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`castor oil derivatives are listed in the USPNF XVII. castor oil derivatives are listed in the USPNF XVII.
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`USPNF: Polyoxyl 35 castor oil USPNF: Polyoxyl 35 castor oil
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`USPNF: Polyoxyl 40 hydrogenated castor oil USPNF: Polyoxyl 40 hydrogenated castor oil
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`See also Sections 2, 3, 4 and 17. See also Sections 2, 3, 4 and 17.
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`2. Synonyms 2. Synonyms
`
`Synonyms applicable to polyoxyethylene castor oil derivatives Synonyms applicable to polyoxyethylene castor oil derivatives
`
`are shown below. Table I shows synonyms for specific are shown below. Table I shows synonyms for specific
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`materials. materials.
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`Arlatone; Cremothon; Mapeg; Marlowet; Simulsol. Arlatone; Cremothon; Mapeg; Marlowet; Simulsol.
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`3. Chemical Name and CAS Registry Number 3. Chemical Name and CAS Registry Number
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`Polyethoxylated castor oil [61791-12-6] Polyethoxylated castor oil [61791-12-6]
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`4. Empirical Formula Molecular Weight 4. Empirical Formula Molecular Weight
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`Polyoxyethylene castor oil derivatives are complex mixtures of Polyoxyethylene castor oil derivatives are complex mixtures of
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`various hydrophobic and hydrophilic components. various hydrophobic and hydrophilic components.
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`In polyoxyl 35 castor oil (Cremophor EL) the hydrophobic In polyoxyl 35 castor oil (Cremophor EL) the hydrophobic
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`constituents comprise about 83% of the total mixture, the constituents comprise about 83% of the total mixture, the
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`main component being glycerol polyethylene glycol ricinoleate. main component being glycerol polyethylene glycol ricinoleate.
`
`Other hydrophobic constituents include fatty acid esters of Other hydrophobic constituents include fatty acid esters of
`
`polyethylene glycol along with some unchanged castor oil. The polyethylene glycol along with some unchanged castor oil. The
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`hydrophilic part (17%) consists of polyethylene glycols and hydrophilic part (17%) consists of polyethylene glycols and
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`glycerol ethoxylates. glycerol ethoxylates.
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`In polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), In polyoxyl 40 hydrogenated castor oil (Cremophor RH 40),
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`approximately 75% of the components of the mixture are approximately 75% of the components of the mixture are
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`hydrophobic. These comprise mainly fatty acid esters of hydrophobic. These comprise mainly fatty acid esters of
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`glycerol polyethylene glycol and fatty acid esters of poly(cid:173)glycerol polyethylene glycol and fatty acid esters of poly(cid:173)
`
`ethylene glycol. The hydrophilic portion consists of polyethy(cid:173)ethylene glycol. The hydrophilic portion consists of polyethy(cid:173)
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`lene glycols and glycerol ethoxylates. lene glycols and glycerol ethoxylates.
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`
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`Polyoxyethylene Castor Oil Derivatives 371 Polyoxyethylene Castor Oil Derivatives 371
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`5. Structural Formula 5. Structural Formula
`
`See Section 4. See Section 4.
`
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`6. Functional Category 6. Functional Category
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`Emulsifying agent; solubilizing agent; wetting agent. Emulsifying agent; solubilizing agent; wetting agent.
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`7. Applications in Pharmaceutical Formulation or 7. Applications in Pharmaceutical Formulation or
`
`Technology Technology
`
`Polyoxyethylene castor oil derivatives are nonionic surfactants Polyoxyethylene castor oil derivatives are nonionic surfactants
`
`used in oral, topical and parenteral pharmaceutical formula(cid:173)used in oral, topical and parenteral pharmaceutical formula(cid:173)
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`tions. They are also used in cosmetics and animal feeds. tions. They are also used in cosmetics and animal feeds.
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`Polyoxyl 35 castor oil (Cremophor EL) is mainly used as an Polyoxyl 35 castor oil (Cremophor EL) is mainly used as an
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`emulsifing and solubilizing agent, and is particularly suitable emulsifing and solubilizing agent, and is particularly suitable
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`for the production of aqueous liquid preparations containing for the production of aqueous liquid preparations containing
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`volatile oils, fat-soluble vitamins and other hydrophobic volatile oils, fat-soluble vitamins and other hydrophobic
`
`substancesY·2) In 1 mL of a 25% v/v aqueous polyoxyl 35 substancesY·2) In 1 mL of a 25% v/v aqueous polyoxyl 35
`
`castor oil (Cremophor EL) solution it is possible to castor oil (Cremophor EL) solution it is possible to
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`incorporate: approximately 10 mg of vitamin A palmitate; incorporate: approximately 10 mg of vitamin A palmitate;
`
`approximately 10 mg of vitamin D; approximately 120 mg of approximately 10 mg of vitamin D; approximately 120 mg of
`
`vitamin E acetate; or approximately 120 mg of vitamin K I . vitamin E acetate; or approximately 120 mg of vitamin K I .
`
`To solubilize fat-soluble vitamins, the active ingredient or To solubilize fat-soluble vitamins, the active ingredient or
`
`ingredients should first be dissolved in polyoxyl 35 castor oil ingredients should first be dissolved in polyoxyl 35 castor oil
`
`(Cremophor EL). Water should then be added very slowly with (Cremophor EL). Water should then be added very slowly with
`
`vigorous stirring. As the water is added, the viscosity increases, vigorous stirring. As the water is added, the viscosity increases,
`
`reaching a maximum at a water content of approximately 40% reaching a maximum at a water content of approximately 40%
`
`vivo Solubilization can be facilitated by heating to approxi(cid:173)vivo Solubilization can be facilitated by heating to approxi(cid:173)
`
`mately 60°C for a short time and in some cases by adding mately 60°C for a short time and in some cases by adding
`
`polyethylene glycol and/or propylene glycol. In oral formula(cid:173)polyethylene glycol and/or propylene glycol. In oral formula(cid:173)
`
`tions the taste ofpolyoxyl35 castor oil (Cremophor EL) can be tions the taste ofpolyoxyl35 castor oil (Cremophor EL) can be
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`masked by a banana flavor. masked by a banana flavor.
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`Polyoxyl35 castor oil (Cremophor EL) has also been used as a Polyoxyl35 castor oil (Cremophor EL) has also been used as a
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`solvent in proprietary injections of diazepam, propanidid and solvent in proprietary injections of diazepam, propanidid and
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`alfaxalone with alfadolone acetate, see Section 14. Polyoxyl 35 alfaxalone with alfadolone acetate, see Section 14. Polyoxyl 35
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`castor oil (Cremophor EL) is also used in the production of castor oil (Cremophor EL) is also used in the production of
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`glycerin suppositories. glycerin suppositories.
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`In veterinary practice, polyoxyl 35 castor oil (Cremophor EL) In veterinary practice, polyoxyl 35 castor oil (Cremophor EL)
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`can be used to emulsify cod liver oil, and oils and fats can be used to emulsify cod liver oil, and oils and fats
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`incorporated into animal feeding stuffs. incorporated into animal feeding stuffs.
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`In cosmetics, polyoxyl 35 castor oil (Cremophor EL) is mainly In cosmetics, polyoxyl 35 castor oil (Cremophor EL) is mainly
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`used as a solubilizing agent for perfume bases and volatile oils used as a solubilizing agent for perfume bases and volatile oils
`
`in vehicles containing 30-50% v/v alcohol (ethanol or propan-in vehicles containing 30-50% v/v alcohol (ethanol or propan-
`
`2-01). In hand lotions it can be used to replace castor oil. 2-01). In hand lotions it can be used to replace castor oil.
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`Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) may Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) may
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`be used in preference to polyoxyl35 castor oil (Cremophor EL) be used in preference to polyoxyl35 castor oil (Cremophor EL)
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`in oral formulations since it is almost tasteless. In aqueous in oral formulations since it is almost tasteless. In aqueous
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`
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`Table I: Synonyms of selected polyoxyethylene castor oil derivatives. Table I: Synonyms of selected polyoxyethylene castor oil derivatives.
`
`
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`Name Name
`
`
`Polyoxyl S castor oil Polyoxyl S castor oil
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`Polyoxyl 9 castor oil Polyoxyl 9 castor oil
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`Polyoxyl IS castor oil Polyoxyl IS castor oil
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`
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`Polyoxyl 3S castor oil Polyoxyl 3S castor oil
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`
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`Polyoxyl 40 castor oil Polyoxyl 40 castor oil
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`
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`Polyoxyl 40 hydrogenated castor oil Polyoxyl 40 hydrogenated castor oil
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`
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`Polyoxyl 60 hydrogenated castor oil Polyoxyl 60 hydrogenated castor oil
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`
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`Synonym Synonym
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`Acconon CA-5; PEG-S castor oil; polyoxyethylene S castor oil. Acconon CA-5; PEG-S castor oil; polyoxyethylene S castor oil.
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`Acconon CA-9; castor oil POE-9; PEG-9 castor oil; polyoxyethylene 9 castor oil; Protachem CA-9. Acconon CA-9; castor oil POE-9; PEG-9 castor oil; polyoxyethylene 9 castor oil; Protachem CA-9.
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`Acconon CA-15; castor oil POE-IS; PEG-IS castor oil; polyoxyethylene IS castor oil; Protachem Acconon CA-15; castor oil POE-IS; PEG-IS castor oil; polyoxyethylene IS castor oil; Protachem
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`CA-15. CA-15.
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`Cremophor EL; Etocas 35; glycerol polyethyleneglycol ricinoleate; polyethoxylated castor oil; Cremophor EL; Etocas 35; glycerol polyethyleneglycol ricinoleate; polyethoxylated castor oil;
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`polyoxyethylene 3S castor oil. polyoxyethylene 3S castor oil.
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`Castor oil POE-40; Croduret 40; Nonionic GR-40; PEG-40 castor oil; polyoxyethylene 40 castor oil; Castor oil POE-40; Croduret 40; Nonionic GR-40; PEG-40 castor oil; polyoxyethylene 40 castor oil;
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`Protachem CA-40. Protachem CA-40.
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`Cremophor RH 40; glycerol polyethyleneglycol oxystearate; hydrogenated castor oil POE-40; PEG-40 Cremophor RH 40; glycerol polyethyleneglycol oxystearate; hydrogenated castor oil POE-40; PEG-40
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`hydrogenated castor oil; polyethoxylated hydrogenated castor oil; polyoxyethylene 40 hydrogenated hydrogenated castor oil; polyethoxylated hydrogenated castor oil; polyoxyethylene 40 hydrogenated
`
`castor oil; Nonionic GRH-40; Protachem CAH-40. castor oil; Nonionic GRH-40; Protachem CAH-40.
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`Cremophor RH 60; hydrogenated castor oil POE-60; PEG-60 hydrogenated castor oil; polyoxyethylene Cremophor RH 60; hydrogenated castor oil POE-60; PEG-60 hydrogenated castor oil; polyoxyethylene
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`60 hydrogenated castor oil; Protachem CAH-60. 60 hydrogenated castor oil; Protachem CAH-60.
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`372 Polyoxyethylene Castor Oil Derivatives 372 Polyoxyethylene Castor Oil Derivatives
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`alcoholic or completely aqueous solutions, polyoxyl 40 alcoholic or completely aqueous solutions, polyoxyl 40
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`hydrogenated castor oil (Cremophor RH 40) can be used to hydrogenated castor oil (Cremophor RH 40) can be used to
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`solubilize vitamins, essential oils and certain drugs. Using 1 solubilize vitamins, essential oils and certain drugs. Using 1
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`mL of a 25% v/v aqueous solution of polyoxyl 40 mL of a 25% v/v aqueous solution of polyoxyl 40
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`hydrogenated castor oil (Cremophor RH 40) it is possible to hydrogenated castor oil (Cremophor RH 40) it is possible to
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`solubilize: approximately 88 mg of vitamin A palmitate; solubilize: approximately 88 mg of vitamin A palmitate;
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`approximately 160 mg of vitamin A propionate. Other approximately 160 mg of vitamin A propionate. Other
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`materials which can be solubilized are: alfadolone; alfaxa(cid:173)materials which can be solubilized are: alfadolone; alfaxa(cid:173)
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`lone; hexachlorophane; hexetidine; methotrimeprazine; mico(cid:173)lone; hexachlorophane; hexetidine; methotrimeprazine; mico(cid:173)
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`nazole; propanidid; and thiopentone. nazole; propanidid; and thiopentone.
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`In aerosol vehicles which include water, the addition of In aerosol vehicles which include water, the addition of
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`polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) polyoxyl 40 hydrogenated castor oil (Cremophor RH 40)
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`improves the solubility of the propellant in the aqueous phase. improves the solubility of the propellant in the aqueous phase.
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`This enhancement applies both to dichlorodifluoromethane This enhancement applies both to dichlorodifluoromethane
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`and to propane/butane mixtures. and to propane/butane mixtures.
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`Foam formation in aqueous ethanol solutions containing Foam formation in aqueous ethanol solutions containing
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`polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) can polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) can
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`be suppressed by the a,ddition of small amounts of poly(cid:173)be suppressed by the a,ddition of small amounts of poly(cid:173)
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`propylene glycol 2000. propylene glycol 2000.
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`Polyoxyl40 hydrogenated castor oil (Cremophor RH 40) is also Polyoxyl40 hydrogenated castor oil (Cremophor RH 40) is also
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`used as an emulsifier of fatty acids and alcohols. used as an emulsifier of fatty acids and alcohols.
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`8. Description 8. Description
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`Polyoxyl35 castor oil (Cremophor EL) occurs as a pale yellow, Polyoxyl35 castor oil (Cremophor EL) occurs as a pale yellow,
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`viscous liquid, which is clear at temperatures above 26°C. It viscous liquid, which is clear at temperatures above 26°C. It
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`has a slight but characteristic odor and can be completely has a slight but characteristic odor and can be completely
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`liquefied by heating to 26°C. liquefied by heating to 26°C.
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`Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40)
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`occurs as a white, semisolid paste which liquefies at 30°C. It occurs as a white, semisolid paste which liquefies at 30°C. It
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`has a very faint characteristic odor and a slight taste in has a very faint characteristic odor and a slight taste in
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`aqueous solution. aqueous solution.
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`Polyoxyl 60 hydrogenated castor oil (Cremophor RH 60) Polyoxyl 60 hydrogenated castor oil (Cremophor RH 60)
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`occurs as a white paste at room temperature. It has little taste occurs as a white paste at room temperature. It has little taste
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`or odor in aqueous solution. or odor in aqueous solution.
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`
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`9. Pharmacopeial Specifications 9. Pharmacopeial Specifications
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`
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`Test Test
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`Identification Identification
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`Specific gravity Specific gravity
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`Congealing temperature Congealing temperature
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`Viscosity at 25°C Viscosity at 25°C
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`Water Water
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`Residue on ignition Residue on ignition
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`Heavy metals Heavy metals
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`Acid value Acid value
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`Hydroxyl value Hydroxyl value
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`Iodine value Iodine value
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`Saponification value Saponification value
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`USPNFXVII USPNFXVII
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`Polyoxyl35 Polyoxyl35
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`Polyoxyl40 Polyoxyl40
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`hydrogenated castor oil hydrogenated castor oil
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`castor oil castor oil
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`+ +
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`+ +
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`1.05-1.06 1.05-1.06
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`650-850 mPa s 650-850 mPa s
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`~ 3.0% ~ 3.0%
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`~ 0.3% ~ 0.3%
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`~ 0.001% ~ 0.001%
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`~ 2.0 ~ 2.0
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`65-80 65-80
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`25-35 25-35
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`60-75 60-75
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`
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`20-30°C 20-30°C
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`~ 3.0% ~ 3.0%
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`~ 0.3% ~ 0.3%
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`~ 0.001% ~ 0.001%
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`~ 2.0 ~ 2.0
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`60-80 60-80
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`~ 2.0 ~ 2.0
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`45-69 45-69
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`10. Typical Properties 10. Typical Properties
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`See Tables II, III and IV. See Tables II, III and IV.
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`Table n: Typical physical properties of selected commercially available polyoxyethylene castor oil derivatives. Table n: Typical physical properties of selected commercially available polyoxyethylene castor oil derivatives.
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`HLB HLB
`
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`Hydroxyl Hydroxyl
`Iodine Iodine
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`Saponification Water Saponification Water
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`Melting Melting
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`point rC) point rC)
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`value value
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`value value
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`value value
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`number number
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`content content
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`19-20 19-20
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`,., 30 ,., 30
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`Acid Acid
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`value value
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`.;:; 2.0 .;:; 2.0
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`.;:; 1.0 .;:; 1.0
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`12-14 12-14
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`14-16 14-16
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`65-78 65-78
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`60-80 60-80
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`28-32 28-32
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`.;:; I .;:; I
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`65-70 65-70
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`50-60 50-60
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`::::;;; 3% ::::;;; 3%
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`~ 2% ~ 2%
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`Solidification Solidification
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`point rC) point rC)
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`
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`21-23 21-23
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`Cloud point for a 1% Cloud point for a 1%
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`aqueous solution rC) aqueous solution rC)
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`72.5 72.5
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`95.6 95.6
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`
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`Name Name
`
`
`Polyoxyl 35 castor oil (Cremophor EL) Polyoxyl 35 castor oil (Cremophor EL)
`
`Polyoxyl 40 hydrogenated castor oil Polyoxyl 40 hydrogenated castor oil
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`(Cremophor RH 40) (Cremophor RH 40)
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`Polyoxyl 60 hydrogenated castor oil Polyoxyl 60 hydrogenated castor oil
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`(Cremophor RH 60) (Cremophor RH 60)
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`
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`.;:; 1.0 .;:; 1.0
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`
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`15-17 15-17
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`
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`50-70 50-70
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`
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`.;:; I .;:; I
`
`
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`40-50 40-50
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`
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`~ 2% ~ 2%
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`
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`,., 40 ,., 40
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`
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`Table ill: Typical physical properties of selected commercially available polyoxyethylene castor oil derivatives (continued). Table ill: Typical physical properties of selected commercially available polyoxyethylene castor oil derivatives (continued).
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`
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`Name Name
`
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`Density Density
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`g/cm3 g/cm3
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`
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`pH pH
`
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`Refractive Refractive
`
`index index
`
`at 20°C at 20°C
`
`
`Surface tension of Surface tension of
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`0.1% w/v aqueous 0.1% w/v aqueous
`
`solution (mN/m) solution (mN/m)
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`Critical micelle Critical micelle
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`Viscosity Viscosity
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`at 25°C (mPa s) concentration (%) at 25°C (mPa s) concentration (%)
`
`
`Polyoxyl 35 castor oil (Cremophor EL) Polyoxyl 35 castor oil (Cremophor EL)
`
`Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40)
`
`Polyoxyl 60 hydrogenated castor oil (Cremophor RH 60) Polyoxyl 60 hydrogenated castor oil (Cremophor RH 60)
`
`
`1.05-1.06 6-8 1.05-1.06 6-8
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`6-7 6-7
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`6-7 6-7
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`
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`~ 1.471 ~ 1.471
`40.9 40.9
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`1.453-1.457 43.0 1.453-1.457 43.0
`
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`650-800 650-800
`
`20-40a 20-40a
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`~ 0.009 ~ 0.009
`
`~ 0.039 ~ 0.039
`
`
`
`a. 30% w/v aqueous solution. a. 30% w/v aqueous solution.
`
`
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`Table IV: Solubility of selected commercially available polyoxyethylene castor oil derivatives. Table IV: Solubility of selected commercially available polyoxyethylene castor oil derivatives.
`
`
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`Name Name
`
`
`Solubility Solubility
`
`Chloroform Ethanol Chloroform Ethanol
`
`
`Castor Castor
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`oil oil
`
`
`Fatty Fatty
`
`acids acids
`
`
`Fatty Fatty
`
`alcohols alcohols
`
`
`Olive Olive
`
`oil oil
`
`
`
`Water Water
`
`
`Polyoxyl 35 castor oil (Cremophor EL) Polyoxyl 35 castor oil (Cremophor EL)
`
`Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40)
`
`Polyoxyl 60 hydrogenated castor oil (Cremophor RH 60) Polyoxyl 60 hydrogenated castor oil (Cremophor RH 60)
`
`
`S S
`
`S S
`
`S S
`
`
`S S
`
`S S
`
`
`S S
`
`S S
`
`Sa Sa
`
`
`S S
`
`S S
`
`S S
`
`
`S S
`
`S S
`
`S S
`
`
`S S
`
`S S
`
`S S
`
`
`S S
`
`S S
`
`S S
`
`
`Key S = Soluble Key S = Soluble
`
`a. Need to add 0.5-1.0% water to maintain a clear solution. a. Need to add 0.5-1.0% water to maintain a clear solution.
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`11. Stability and Storage Conditions 11. Stability and Storage Conditions
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`Polyoxyl 35 castor oil (Cremophor EL) forms stable solutions Polyoxyl 35 castor oil (Cremophor EL) forms stable solutions
`
`in many organic solvents such as chloroform, ethanol and in many organic solvents such as chloroform, ethanol and
`
`propan-2-01; it also forms clear, stable, aqueous solutions. propan-2-01; it also forms clear, stable, aqueous solutions.
`
`Polyoxyl 35 castor oil (Cremophor EL) is miscible with other Polyoxyl 35 castor oil (Cremophor EL) is miscible with other
`
`polyoxyethylene castor oil derivatives and on heating with polyoxyethylene castor oil derivatives and on heating with
`
`fatty acids, fatty alcohols and some animal and vegetable oils. fatty acids, fatty alcohols and some animal and vegetable oils.
`
`Solutions of polyoxyl 40 hydrogenated castor oil (Cremophor Solutions of polyoxyl 40 hydrogenated castor oil (Cremophor
`
`RH 40) in aqueous alcohols are also stable. RH 40) in aqueous alcohols are also stable.
`
`On heating an aqueous solution the solubility of polyoxyl 35 On heating an aqueous solution the solubility of polyoxyl 35
`
`castor oil (Cremophor EL) is reduced and the solution becomes castor oil (Cremophor EL) is reduced and the solution becomes
`
`turbid. Aqueous solutions ofpolyoxyl hydrogenated castor oil turbid. Aqueous solutions ofpolyoxyl hydrogenated castor oil
`
`(Cremophor RH grades) heated for prolonged periods may (Cremophor RH grades) heated for prolonged periods may
`
`separate into solid and liquid phases on cooling. However, the separate into solid and liquid phases on cooling. However, the
`
`product can be restored to its original form by homogeniza(cid:173)product can be restored to its original form by homogeniza(cid:173)
`
`tion. tion.
`
`Aqueous solutions of polyoxyl 35 castor oil (Cremophor EL) Aqueous solutions of polyoxyl 35 castor oil (Cremophor EL)
`
`are stable in the presence of low concentrations of electrolytes are stable in the presence of low concentrations of electrolytes
`
`such as acids or salts, with the exception of mercuric chloride, such as acids or salts, with the exception of mercuric chloride,
`
`see Section 12. see Section 12.
`
`Aqueous solutions of polyoxyl 35 castor oil (Cremophor EL) Aqueous solutions of polyoxyl 35 castor oil (Cremophor EL)
`
`can be sterilized by autoclaving for 20 minutes at 121°C. In this can be sterilized by autoclaving for 20 minutes at 121°C. In this
`
`process a product may acquire a deeper color although this has process a product may acquire a deeper color although this has
`
`no significance for product stability. Aqueous solutions of no significance for product stability. Aqueous solutions of
`
`polyoxyl hydrogenated castor oil (Cremophor RH) can polyoxyl hydrogenated castor oil (Cremophor RH) can
`
`similarly be sterilized by autoclaving at 121°C, but this may similarly be sterilized by autoclaving at 121°C, but this may
`
`cause a slight decrease in the pH value. cause a slight decrease in the pH value.
`
`Although the method of manufacture used for polyoxyethy(cid:173)Although the method of manufacture used for polyoxyethy(cid:173)
`
`lene castor oil derivatives ensures that they are near-sterile, lene castor oil derivatives ensures that they are near-sterile,
`
`microbial contamination can occur on storage. microbial contamination can occur on storage.
`
`Polyoxyethylene castor oil derivatives should be stored in a Polyoxyethylene castor oil derivatives should be stored in a
`
`well-filled, airtight container, protected from light, in a cool, well-filled, airtight container, protected from light, in a cool,
`
`dry, place. dry, place.
`
`
`12. Incompatibilities 12. Incompatibilities
`
`In strongly acidic or alkaline solutions the ester components of In strongly acidic or alkaline solutions the ester components of
`
`polyoxyethylene hydrogenated castor oil (Cremophor REf) are polyoxyethylene hydrogenated castor oil (Cremophor REf) are
`
`liable to saponify. liable to saponify.
`
`In aqueous solution, polyoxyl35 castor oil (Cremophor EL) is In aqueous solution, polyoxyl35 castor oil (Cremophor EL) is
`
`stable towards most electrolytes in the concentrations stable towards most electrolytes in the concentrations
`
`normally employed. However, it is incompatible with normally employed. However, it is incompatible with
`
`mercuric chloride since precipitation occurs. mercuric chloride since precipitation occurs.
`
`Some organic substances may cause precipitation at certain Some organic substances may cause precipitation at certain
`
`concentrations, especially compounds containing phenolic concentrations, especially compounds containing phenolic
`
`hydroxyl groups, e.g. phenol, resorcinol and tannins. hydroxyl groups, e.g. phenol, resorcinol and tannins.
`
`Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) and Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) and
`
`polyoxyl 60 hydrogenated castor oil (Cremophor RH 60) are polyoxyl 60 hydrogenated castor oil (Cremophor RH 60) are
`
`largely unaffected by the salts that cause hardness in water. largely unaffected by the salts that cause hardness in water.
`
`
`13. Method of Manufacture 13. Method of Manufacture
`
`Polyoxyethylene castor oil derivatives are prepared by reacting Polyoxyethylene castor oil derivatives are prepared by reacting
`
`varying amounts of ethylene oxide with either castor oil or varying amounts of ethylene oxide with either castor oil or
`
`hydrogenated castor oil under controlled conditions. hydrogenated castor oil under controlled conditions.
`
`Polyoxyl 35 castor oil (Cremophor EL) is thus produced by Polyoxyl 35 castor oil (Cremophor EL) is thus produced by
`
`reacting 1 mole of castor oil with 35-40 moles of ethylene reacting 1 mole of castor oil with 35-40 moles of ethylene
`
`oxide. oxide.
`
`Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) is Polyoxyl 40 hydrogenated castor oil (Cremophor RH 40) is
`
`produced by reacting 1 mole of hydrogenated castor oil with produced by reacting 1 mole of hydrogenated castor oil with
`
`40-45 moles of ethylene oxide. Polyoxyl 60 hydrogenated 40-45 moles of ethylene oxide. Polyoxyl 60 hydrogenated
`
`castor oil (Cremophor RH 60) is similarly produced by reacting castor oil (Cremophor RH 60) is similarly produced by reacting
`
`1 mole of hydrogenated castor oil with 60 moles of ethylene 1 mole of hydrogenated castor oil with 60 moles of ethylene
`
`oxide. oxide.
`
`
`
`Polyoxyethylene Castor Oil Derivatives 373 Polyoxyethylene Castor Oil Derivatives 373
`
`
`14. Safety 14. Safety
`
`Polyoxyethylene castor oil derivatives are used in a variety of Polyoxyethylene castor oil derivatives are used in a variety of
`
`oral, topical and parenteral pharmaceutical formulations. oral, topical and parenteral pharmaceutical formulations.
`
`Acute and chronic toxicity tests in animals have shown Acute and chronic toxicity tests in animals have shown
`
`polyoxyethylene castor oil derivatives to be essentially polyoxyethylene castor oil derivatives to be essentially
`
`nontoxic and nonirritant materials, see Table V.(3.4) How(cid:173)nontoxic and nonirritant materials, see Table V.(3.4) How(cid:173)
`
`ever, several serious anaphylactic reactions have been observed ever, several serious anaphylactic reactions have been observed
`
`in humans and animals following parenteral, and more rarely, in humans and animals following parenteral, and more rarely,
`
`oral administration of formulations containing polyoxyethy(cid:173)oral administration of formulations containing polyoxyethy(cid:173)
`
`lene castor oil derivatives.(5-14) The precise mechanism of the lene castor oil derivatives.(5-14) The precise mechanism of the
`
`reaction is not known. reaction is not known.
`
`
`Table V: LDso values of selected polyoxyethyleue castor oil Table V: LDso values of selected polyoxyethyleue castor oil
`
`derivatives.(3.4.1S) derivatives.(3.4.1S)
`
`
`
`Name Name
`
`
`Polyoxyl 35 castor oil Polyoxyl 35 castor oil
`
`(Cremophor EL) (Cremophor EL)
`
`
`Polyoxyl 40 hydrogenated Polyoxyl 40 hydrogenated
`
`castor oil (Cremophor RH 40) castor oil (Cremophor RH 40)
`
`
`Polyoxyl 60 hydrogenated Polyoxyl 60 hydrogenated
`
`castor oil (Cremophor RH 60) castor oil (Cremophor RH 60)
`
`
`Animal and Animal and
`
`route route
`
`Cat (oral) Cat (oral)
`
`Dog (IV) Dog (IV)
`
`Mouse (IV) Mouse (IV)
`
`Rabbit (oral) Rabbit (oral)
`
`Rat (oral) Rat (oral)
`
`Mouse (IP) Mouse (IP)
`
`Mouse (IV) Mouse (IV)
`
`Rat (oral) Rat (oral)
`
`Mouse (IP) Mouse (IP)
`
`Rat (oral) Rat (oral)
`
`
`LDso LDso
`
`g/kg body-weight g/kg body-weight
`
`> 10 > 10
`
`0.64 0.64
`
`2.5 2.5
`
`>10 >10
`
`> 6.4 > 6.4
`
`> 12.5 > 12.5
`
`> 12.0 > 12.0
`
`> 16.0 > 16.0
`
`> 12.5 > 12.5
`
`> 16.0 > 16.0
`
`
`15. Handling Precautions 15. Handling Precautions
`
`Observe normal precautions appropriate to the circumstances Observe normal precautions appropriate to the circumstances
`
`and quantity of material handled. Eye protection and gloves and quantity of material handled. Eye protection and gloves
`
`are recommended. are recommended.
`
`
`16. Regulatory Status 16. Regulatory Status
`
`Included in the FDA Inactive Ingredients Guide (IV Included in the FDA Inactive Ingredients Guide (IV
`
`injections). Inclued in parenteral medicines licensed in the UK. injections). Inclued in parenteral medicines licensed in the UK.
`
`
`
`17. Pharmacopeias 17. Pharmacopeias
`
`
`Name Name
`
`Polyoxyl 35 castor oil Polyoxyl 35 castor oil
`
`Polyoxyl 40 hydrogenated Polyoxyl 40 hydrogenated
`
`castor oil castor oil
`
`
`
`Pharmacopeia Pharmacopeia
`
`
`USPNF. USPNF.
`
`USPNF. USPNF.
`
`
`18. Related Substances 18. Related Substances
`
`Poloxyethylene Alkyl Ethers; Polyoxyethylene Stearates. Poloxyethylene Alkyl Ethers; Polyoxyethylene Stearates.
`
`Mixtures of different polyoxyethylene castor oil derivatives are Mixtures of different polyoxyethylene castor oil derivatives are
`
`commercially available. For example, Cremophor RH 410 is a commercially available. For example, Cremophor RH 410 is a
`
`mixture of 90% polyoxyl 40 hydrogenated castor oil mixture of 90% polyoxyl 40 hydrogenated castor oil
`
`(Cremophor RH 40) with 10% water, and Cremophor RH (Cremophor RH 40) with 10% water, and Cremophor RH
`
`455 is a mixture of 90% polyoxyl 40 hydrogenated castor oil 455 is a mixture of 90% polyoxyl 40 hydrogenated castor oil
`
`(Cremophor RH 40), 5% propylene glycol and 5% water. At (Cremophor RH 40), 5% propylene glycol and 5% water. At
`
`room temperature, Cremophor RH 410 and Cremophor 455 are room temperature, Cremophor RH 410 and Cremophor 455 are
`
`viscous, slightly opalescent liquids. viscous, slightly opalescent liquids.
`
`
`19. Comments 19. Comments
`
`Note that the trade name Cremophor (BASF Corporation) is Note that the trade name Cremophor (BASF Corporation) is
`
`also used for other polyoxyethylene derivatives, e.g. the also used for other polyoxyethylene derivatives, e.g. the
`
`Cremophor A series are polyoxyethylene alkyl ethers. Cremophor A series are polyoxyethylene alkyl ethers.
`
`NOVARTIS EXHIBIT 2006
`Par v. Novartis, IPR 2016-00075
`Page 6 of 7
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`374 Polyoxyethylene Castor Oil Derivatives 374 Polyoxyethylene Castor Oil Derivatives
`
`
`20. Specific References 20. Specific References
`
`1. Macek TJ. Preparation of parenteral dispersions. J Phann Sci 1. Macek TJ. Preparation of parenteral