Handbook of
`PHARMACEUTICAL
`EXCIPIENTS
`
`

`
`/
`
`/Handbook of
`PHARMACEUTICAL
`EX CIPIENTS /7/ '
`
`__ _______ ,-i
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`,;7
`
`y
`
`Second Edition
`
`Edited by
`Ainley Wade and Paul J Weller
`
`American Pharmaceutical Association
`Washington
`
`1994
`
`The Pharmaceutical Press
`London
`
`8980
`
`18.6
`
`

`
`© Copyright 1986, 1994 by the American Pharmaceutical Association, 2215 Constitution Avenue NW, Washington,
`DC 20037-2985, USA, and The Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain, 1 Lambeth High
`Street, London, SEl 7JN, England.
`
`A catalogue record for this book is available from the British Library.
`
`Library of Congress Catalog Card Number: 94-79492.
`
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`International Standard Book Number (ISBN) in the UK: 0 85369 305 6
`International Standard Book Number (lS13N) in the USA: 091730668
`
`No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
`including photocopy, recording, or any information storage or retrieval system, without prior written permission from
`the joint publishers.
`
`Typeset in Great Britain by Alden Multimedia, Northampton.
`Printed and bound in Great Britain by
`
`

`
`Lecithin
`
`1. Nonproprietary Names
`USPNF: Lecithin
`See also Section 4.
`
`2. Synonyms
`E322; egg lecithin; Epikuron; Espholip; LSC; mixed soybean
`phosphatides; ovolecithin; Ovothin; soybean lecithin; soybean
`phospholipids; vegetable lecithin.
`
`3. Chemical Name and CAS Registry Number
`Lecithin [8002-43-5]
`The chemical nomenclature and CAS registry numbering of
`lecithin is complex. The commercially available lecithin, used
`in cosmetics, pharmaceuticals and food products, although a
`complex mixture of phospholipids and other materials, may be
`referred to in some literature sources as 1,2-diacyl-sn-glycero-
`3-phosphocholine (trivial chemical name, phosphatidylcho(cid:173)
`line). This material is the principal constituent of egg lecithin
`and has the same CAS registry number. The name lecithin and
`the CAS registry number above are thus used to refer to both
`lecithin and phosphatidylcholine in some literature sources.
`See also Section 4.
`
`4. Empirical Formula Molecular Weight
`The USPNF XVII describes lecithin as a complex mixture of
`acetone-insoluble phosphatides, which consist chiefly of
`phosphatidylcholine, phosphatidylethanolamine, phosphati(cid:173)
`dylserine and phosphatidylinositol, combined with various
`amounts of other substances such as triglycerides, fatty acids
`and carbohydrates as separated from a crude vegetable oil
`source.
`The composition of lecithin and hence its physical properties
`varies enormously depending upon the source of the lecithin
`and the degree of purification. Egg lecithin, for example,
`contains 69% phosphatidylcholine and 24% phosphatidy(cid:173)
`lethanolamine, whilst soybean lecithin contains 21 % phospha(cid:173)
`tidyicholine, 22% phosphatidy1ethanolamine and 19%
`phosphatidylinositol, along with other components.(l)
`
`5. Structural Formula
`
`o
`
`,
`
`II ri-R
`I 7
`II o
`
`CH-O-C-R2
`
`CH2-O-P-OCH2CH2N+ (CH3)3
`
`a-phosphatidylcholine
`Where, R J and R2 are fatty acids which may be different or
`identical.
`
`Lecithin 267
`
`Lecithin is a complex mixture of materials, see Section 4. The
`structure above shows phosphatidylcholine, the principal
`component of egg lecithin, in its a-form. In the ,B-form the
`phosphorus containing group and the R2 group exchange
`positions.
`
`6. Functional Category
`Emollient; emulsifying agent; solubilizing agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Lecithins are used in a wide variety of pharmaceutical
`applications. They are also used in cosmetics(2) and food
`products.
`Lecithins are mainly used in pharmaceutical products as
`dispersing, emulsifying and stabilizing agents and are included
`in intramuscular and intravenous injections, parenteral
`nutrition formulations and topical products, such as creams
`and ointments.
`Lecithins are also used in suppository bases,P) to reduce the
`brittleness of suppositories and have been investigated for their
`absorption enhancing properties in an intranasal insulin
`formulation.(4) Lecithins are also commonly used as a
`component of enteral and parenteral nutrition formulations.
`Liposomes in which lecithin is included as a component of the
`bilayer have been used to encapsulate drug substances and
`their potential as novel delivery systems has been investi(cid:173)
`gated.(5)
`Therapeutically, lecithin and derivatives have been used as a
`pulmonary surfactant in the treatment of neonatal respiratory
`distress syndrome.
`
`Use
`Aerosol inhalation
`IM injection
`Oral suspensions
`
`Concentration (%)
`
`0.1
`0.3-2.3
`0.25-10.0
`
`8. Description
`Lecithins vary greatly in their physical form, from viscous
`semiliquids to powders, depending upon the free fatty acid
`content. They may also vary in color from brown to light
`yellow, depending upon whether they are bleached or
`unbleached.
`Lecithins have practically no odor. Those derived from
`vegetable sources have a bland or nut-like taste, similar to
`soybean oil.
`
`9. Pharmacopeial Specifications
`
`Test
`Water
`Arsenic
`Lead
`Heavy metals
`Acid value
`Hexane-insoluble matter
`Acetone-insoluble matter
`
`USPNF XVII (Suppl 6)
`
`:;:; 1.5%
`:;:; 3 ppm
`:;:; 0.001%
`~ 0.004%
`:;:; 36
`~ 0.3%
`;;;, 50.0%
`
`

`
`268 Lecithin
`
`10. Typical Properties
`Density:
`0.97 g/cm3 for liquid lecithin;
`0.5 g/cm3 for powdered lecithin.
`Iodine number:
`95-100 for liquid lecithin;
`82-88 for powdered lecithin.
`Isoelectric point: ~ 3.5
`Saponification value: 196
`Solubility: lecithins are soluble in aliphatic and aromatic
`hydrocarbons, halogenated hydrocarbons, mineral oil and
`fatty acids. They are practically insoluble in cold vegetable and
`animal oils, polar solvents and water. When mixed with water
`however, lecithins hydrate to form emulsions.
`
`11. Stability and Storage Conditions
`Lecithins decompose at extreme pH. They are also hygroscopic
`and subject to microbial degradation. When heated, lecithins
`oxidize, darken and decompose. Temperatures of 160-180°C
`will cause degradation within 24 hours.
`Fluid, or waxy, lecithin grades should be stored at room
`temperature or above; temperatures below 10°C may cause
`separation.
`All lecithin grades should be stored in well-closed containers
`protected from light.
`
`12. Incompatibilities
`Incompatible with esterases due to hydrolysis.
`
`13. Method of Manufacture
`Lecithins are essential components of cell membranes and may
`thus in principle be obtained from a wide variety of living
`matter. In practice however, lecithins are usually obtained
`from vegetable products such as soybean, peanut, cottonseed,
`sunflower, rapeseed, corn or groundnut oil. Soybean lecithin is
`the most commercially important vegetable lecithin. Lecithin
`obtained from eggs is also commercially important and was
`the first lecithin to be discovered.
`Vegetable lecithins are obtained as a by-product in the
`vegetable oil refining process. Polar lipids are extracted with
`hexane and after removal of the solvent a crude vegetable oil
`obtained. Lecithin is then removed from the crude oil by water
`extraction. Following drying the lecithin may then be further
`purified.(I)
`With egg lecithin, a different manufacturing process must be
`used since the lecithin in egg yolks is more tightly bound to
`proteins than in vegetable sources. Egg lecithin is thus
`obtained by solvent extraction from liquid egg yolks using
`acetone or from freeze dried egg yolks using ethanol.(l)
`Synthetic lecithins may also be produced.
`
`14. Safety
`Lecithin is a component of cell membranes and is therefore
`consumed as a normal part of the diet. Although excessive
`consumption may be harmful, oral doses of up to 80 g daily
`have been used therapeutically in the treatment of tardive
`dyskinesia.(6) When used in topical formulations lecithin is
`generally regarded as a nonirritant and nonsensitizing
`material. (2)
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Lecithins may be irritant to
`the eyes; eye protection and gloves are recommended.
`
`t
`
`16. Regulatory Status
`GRAS listed. Accepted as a food additive in Europe. Included
`in the FDA Inactive Ingredients Guide (inhalations, 1M and
`IV injections, oral capsules, suspensions and tablets, rectal,
`topical and vaginal preparations). Included in nonparenteral
`and parenteral medicines licensed in the UK.
`
`17. Pharmacopeias
`Aust, Mex and USPNF.
`
`18. Related Substances
`
`19. Comments
`Lecithins contain a variety of unspecified materials and care
`should therefore be exercised in the use of unpurified lecithin
`in injectable or topical dosage forms as interaction with the
`active substance or other excipients may occur. Unpurified
`lecithins may also have a greater potential for irritancy in
`formulations.
`Supplier's literature should be consulted for information on
`the different grades of lecithin available and their applications
`in formulations.
`
`20. Specific References
`I. Schneider M. Achieving purer lecithin. Drug Cosmet Ind 1992;
`150(2): 54, 56, 62, 64, 66, 10 1-103.
`2. Lecithin: its composition, properties and use in cosmetic formula(cid:173)
`tions. Cosmet Perfum 1974; 89(7): 31-35.
`3. Novak E, et al. Evaluation of cefmetazole rectal suppository
`formulations. Drug Dev Ind Pharm 1991; 17: 373-389.
`4. Intranasal insulin formulation reported to be promising. Pharm J
`1991; 247: 17.
`5. Grit M, Zuidam NJ, Underberg WJM, Crommelin DJA.
`Hydrolysis of partially saturated egg phosphatidy1choline in
`aqueous liposome dispersions and the effect of cholesterol
`incorporation on hydrolysis kinetics. J Pharm Pharmacol 1993;
`45: 490-495.
`6. Growdon JR, et al. Lecithin can suppress tardive dyskinesia
`[letter). N Engl J Med 1978; 298: 1029-1030.
`
`21. General References
`Ansell GB, Hawthorne IN. Phospholipids. New York: Elsevier, 1964.
`Arias C, Rueda C. Comparative study of lipid systems from various
`sources by rotational viscometry and potentiometry. Drug Dev Ind
`Pharm 1992; 18: 1773-1786.
`Hanin I, Pepeu G, editors. Phospholipids: biochemical, pharmaceu(cid:173)
`tical and analytical considerations. New York: Plenum, 1990.
`
`22. Authors
`USA: W Han.