Handbook of
`PHARMACEUTICAL
`EXCIPIENTS
`
`Second Edition
`
`Edited by
`Ainley Wade and Paul J Weller
`
`American Pharmaceutical Association
`Washington
`
`1994
`
`The Pharmaceutical Press
`London
`
`LUYE1008
`IPR of Patent No. 6,667,061
`
`

`
`© 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, SE1 7JN, England.
`
`A catalogue record for this book is available from the British Library.
`
`Library of Congress Catalog Card Number: 94-79492.
`
`International Standard Book Number (ISBN) in the UK: 0 85369 305 6
`International Standard Book Number (ISBN) in the USA: 0 91730 66 8
`
`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
`
`LUYE1008
`IPR of Patent No. 6,667,061
`
`

`
`used to absorb wound exudate or transepidermal water and
`sweat.
`Carboxymethylcellulose sodium is also used in cosmetics,
`toiletries(6) and food products.
`
`Use
`Emulsifying agent
`Gel-forming agent
`Injections
`Oral solutions
`Tablet binder
`
`Concentration (%)
`0.25-1.0
`4.0-6.0
`0.05-0.75
`0.1-1.0
`1.0-6.0
`
`8. Description
`Carboxymethylcellulose sodium occurs as a white to almost
`white colored, odorless, granular powder. See also Section 19.
`
`9. Pharmacopeia! Specifications
`
`Test
`
`Identification
`pH (1% wfv solution)
`Appearance of solution
`Viscosity
`Loss on drying
`Heavy metals
`Chloride
`Sodium glycolate
`Sulfated ash
`Assay (of sodium)
`
`PhEur 1986
`
`+
`6.0-8.0
`+
`+
`~ 10.0%
`~ 20 ppm
`~ 0.25%
`~ 0.4%
`20.0-33.3%
`~?.5-10.8%
`
`USP XXII
`(Suppl8)
`+
`6.5-8.5
`
`+
`~ 10.0%
`~ 0.004%
`
`6.5-9.5%
`
`SEM:l
`Excipient: Carboxymethylcellulose sodium
`Manufacturer: Buckeye Cellulose Corp
`Lot No.: 9247 AP
`Magnification: 120x
`Voltage: 10 kV
`
`78 Carboxymethylcellulose Sodium
`
`Carboxymethylcellulose
`Sodium
`
`1. Nonproprietary Names
`BP: Carmellose sodium
`PhEur: Carboxymethylcellulosum natricum
`USP: Carboxymethylcellulose sodium
`
`2. Synonyms
`Akucell; Blanose; Cekol; . cellulose gum; CMC sodium;
`Courlose; E466; Nymcel; SCMC; sodium carboxymethylcellu-
`lose; sodium cellulose glycolate; sodium CMC; Tylose CB.
`
`3. Chemical Name and CAS Registry Number
`Cellulose, carboxymethyl ether, sodium salt [9004-32-4]
`
`4. Empirical Formula Molecular Weight
`The USP XXII describes carboxymethylcellulose sodium as
`the sodium salt of a polycarboxymethyl ether . of cellulose.
`Typical molecular weight is 90 000-700 000.
`
`5. Structural Formula
`
`CH,OCH,COON•
`
`OH
`
`0
`
`H
`
`0
`
`OH
`
`Structure shown with a degree of substitution (DS) of 1.0.
`
`6. Functional Category
`Coating agent; tablet and capsule disintegrant; tablet binder;
`stabilizing agent; suspending agent; viscosity-increasing agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Carboxymethylcellulose sodium is widely used in oral and
`topical pharmaceutical formulations primarily for its viscosity-
`increasing properties. Viscous aqueous solutions are used to
`suspend powders intended for either topical application or oral
`and parenteral administration. (l) Carboxymethylcellulose
`sodium may also be used as a tablet binder and disinte-
`grant,C2-4) and to stabilize emulsions.(S)
`Higher concentrations, usually 4-6%, of the medium viscosity
`grade is used to produce gels which can be used as the base for
`applications and pastes; glycerin is often included in such gels
`to prevent drying out. Carboxymethylcellulose sodium is
`additionally one of the main ingredients of self adhesive
`ostomy, wound care and dermatological patches where it is
`
`LUYE1008
`IPR of Patent No. 6,667,061
`
`

`
`SEM:2
`Excipient: Carboxymethylcellulose sodium
`Manufacturer: Buckeye Cellulose Corp
`Lot No.: 9247 AP
`Magnification: 600x
`Voltage: 10 kV
`
`SEM:4
`Excipient: Carboxymethylcellulose sodium
`Manufacturer: Hercules Ltd
`Lot No.: 21 A-1 (44390)
`Magnification: 600x
`Voltage: 20 kV
`
`Carboxymethylcellulose Sodium 79
`
`SEM:3
`Excipient: Carboxymethylcellulose sodium
`Manufacturer: Hercules Ltd
`Lot No.: 21 A-1 (44390)
`Magnification: 120x
`Voltage: 20 kV
`
`10. Typical Properties
`Density (bulk): 0.75 gjcm3
`Dissociation constant: pKa = 4.30
`Melting point: browns at approximately 227°C, chars at
`approximately 252°C.
`Moisture content: typically, contains less than 10% of water.
`However, carboxymethylcellulose sodium is hygroscopic and
`absorbs significant amounts of water at temperatures up to
`3rC at relative humidities of about 80%. See also HPE Data
`and Section 11.
`Solubility: practically insoluble in acetone, ethanol, ether and
`toluene. Easily dispersed in water at all temperatures, forming
`clear, colloidal solutions. The aqueous solubility varies with
`the degree of substitution (DS). See Section 19.
`Viscosity: various grades of carboxymethylcellulose sodium
`are commercially available which have differing aqueous
`viscosities; aqueous 1% wjv solutions with viscosities of
`5-4000 mPa s (5-4000 cP) may be obtained.- An increase in
`concentration results in an increase in aqueous solution
`viscosity.(6) Viscosities of various grades of carboxymethyl-
`cellulose sodium are shown in Table I. See also Section 11.
`
`Table I: Viscosity of aqueous carboxymethylcellulose sodium solutions at
`25°C.
`
`Low viscosity
`Medium viscosity
`High viscosity
`
`Concentration
`(% wfv)
`4
`2
`1
`
`Viscosity
`·(mPa s)
`50-200
`400-800
`1500-3000
`
`LUYE1008
`IPR of Patent No. 6,667,061
`
`

`
`80 Carboxymethylcellulose Sodium
`
`HPE Laboratory Project Data
`Method
`Results
`Lab#
`MC-10
`8.5%
`Moisture content
`10
`5
`6.5%
`Moisture content
`MC-7
`See Fig. 1.
`EMC-1
`10
`Moisture content
`Supplier: Hercules Ltd (Lot #76493).
`
`50
`
`40
`
`0 0
`1.0
`C\1
`rti
`~ 30
`::3
`t) ·a
`E
`E ::3
`;g
`'5
`0' w
`-::!!.
`0
`
`20
`
`10
`
`b v
`I
`K
`A
`!....... w
`I-/ ~
`v ~
`(v ~
`
`""""""
`
`A
`
`0
`
`10
`
`20
`
`70
`60
`50
`40
`30
`% Relative- humidity
`
`80
`
`90 1 00
`
`Fig. 1: Equilibrium moisture content of carboxymethylcellulose
`sodium.
`·
`
`11. Stability and Storage Conditions
`Carboxymethylcellulose sodium is a stable, though hygro-
`scopic material. Under high humidity conditions carboxy-
`methylcellulose sodium can absorb a large quantity(> 50%)
`of water. In tablets, this has been associated with a decrease in
`tablet hardness and an increase in disintegration time.(?)
`Aqueous solutions are stable between pH 2-10; below pH 2
`precipitation can occur while above pH 10 solution viscosity
`rapidly decreases. Generally, solutions exhibit maximum
`viscosity and stability at pH 7-9.
`Carboxymethylcellulose sodium may be sterilized in the dry
`state by maintaining it at a temperature of 160°C for 1 hour.
`However, this process results in a significant decrease in
`viscosity and some deterioration in the properties of solutions
`prepared from the sterilized material.
`Aqueous solutions may similarly be sterilized by heating
`although this also results in some reduction in viscosity. After
`autoclaving, viscosity is reduced by about 25% although this
`reduction is less marked than for solutions prepared from
`material sterilized in the dry state. The extent of the reduction
`is dependent on the molecular weight and degree of
`sub~titution; higher molecular weight grades generally under-
`go a greater percentage reduction in viscosity. Sterilization of
`solutions by gamma irradiation also results in a reduction in
`viscosity.
`Aqueous solutions stored for prolonged periods should
`contain an antimicrobial preservative.<8)
`
`The bulk material should be stored in a well-closed container
`in a cool, dry, place.
`
`12. Incompatibilities
`Carboxymethylcellulose sodium is incompatible with strongly
`acidic solutions and· with the soluble salts of iron and some
`other metals, such as aluminum, mercury and zinc; it is also
`incompatible with xanthan gum. Precipitation can occur at
`pH < 2 and when mixed with ethanol (95%).
`Carboxymethylcellulose sodium also forms complex coacer-
`vates with gelatin and pectin. It additionally forms a complex
`with collagen and is capable of precipitating certain positively
`charged proteins.
`
`13. Method of Manufacture
`Alkali cellulose is prepared by steeping cellulose obtained from
`wood pulp or cotton fibres in sodium hydroxide solution. The
`alkali cellulose is then reacted with sodium monochloroacetate
`to produce carboxymethylcellulose sodium. Sodium chloride
`and sodium glycolate are obtained as by-products of this
`etherification.
`
`14. Safety
`Carboxymethylcellulose sodium is used in oral, topical and
`some parenteral formulations. It is also widely used in
`cosmetics, toiletries and food products and is generally
`regarded as a nontoxic and nonirritant material. However,
`oral consumption of large amounts of carboxymethylcellulose
`sodium can have a laxative effect; therapeutically 4-10 g, in
`daily divided doses, of the medium and high viscosity grades of
`carboxymethylcellulose sodium have been used as bulk
`laxatives.
`The WHO has not specified an acceptable daily intake for
`carboxymethylcellulose sodium as a food additive since the
`levels necessary to achieve a desired effect were not considered
`to be a hazard to health. (9)
`·
`In animal studies, subcutaneous administration of carboxy-
`methylcellulose sodium has been found to cause inflammation
`and in some cases of repeated injection fibrosarcomas have
`been found at the injection site. (lOY
`Hypersensitivity and anaphylactic reactions have occurred in
`cattle and horses which have been. attributed to carboxy-
`methylcellulose sodium in parenteral formulations such as
`vaccines and penicillins.Cll,l2J
`LD50 (guinea pig, oral): 16 g/kg(l3)
`LD50 (mouse, oral): > 27 gjkg
`LD50 (rabbit, oral): > 27 gjkg
`LD50 (rat, oral): 27 g/kg
`
`15~ Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Carboxymethylcellulose
`sodium may be irritant to the eyes. Eye protection is
`recommended.
`
`16. Regulatory Status
`GRAS listed. Accepted as a food additive in Europe. Included
`in the FDA Inactive Ingredients Guide (dental preparations,
`inhalations, intra-articular, intrabursal, intradermal, intrale-
`sional, IM, intrasynovial and SC injections, oral capsules,
`drops, solutions, suspensions, syrups and tablets, topical and
`vaginal preparations). Included in nonparenteral medicines
`licensed in the UK.
`'
`' ··
`
`LUYE1008
`IPR of Patent No. 6,667,061
`
`

`
`17. Pharmacopeias
`Aust, Br, Braz, Cz, Egypt, Bur, Fr, Gr, Hung, Ind, It, Jpn,
`Mex, Neth, Nord, Rom, Swiss, US and Yug.
`
`18. Related Substances
`Carboxymethylcellulose Calcium; Carboxymethylcellulose so-
`dium 12; Croscarmellose Sodium.
`Carboxymethylcellulose sodium 12
`Pharmacopeias: USPNF.
`Comments: carboxymethylcellulose sodium 12 is the sodium
`salt of a polycarboxymethyl ether of cellulose. Its degree of
`substitution is between 1.15-1.45, corresponding to a sodium
`content, calculated on the dry basis, of 10.5-12.0%.
`
`19. Comments
`A number of grades of carboxymethylcellulose sodium are
`commercially available, the most frequently used grade having
`a degree of substitution (DS) of 0.7. The DS is defined as the
`average· number of hydroxyl groups substituted per anhydro-
`glucose unit and it is this which determines the aqueous
`solubility of the polymer.
`Grades are typically classified as being either low, medium or
`high viscosity. The degree of substitution and the maximum
`viscosity of an aqueous solution of stated concentration should
`be indicated on any carboxymethylcellulose sodium labelling.
`Carboxymethylcellulose sodium has been reported to give false
`positive results in the LAL test for eudotoxins.<14)
`
`20. Specific References
`1. Hussain MA, Aungst BJ, Maurin MB, Wu LS. Injectable
`suspensions for prolonged release nalbuphine. Drug Dev Ind
`Pharm 1991; 17: 67-76.
`2. Khan KA, Rhodes CT. Evaluation of different viscosity grades of
`sodium carboxymethylcellulose as tablet disintegrants. Pharm
`Acta Helv 1975; 50: 99-102.
`3. Shah NH, Lazarus JH, Sheth PR, Jarowski CI. Carboxymethyl-
`cellulose: effect of degree of polymerization and substitution on
`
`Carboxymethylcellulose Sodium 81
`
`tablet disintegration and dissolution. J Pharm Sci 1981; 70: 611-
`613.
`4. Singh J. Effect of sodium carboxymethylcelluloses on the
`disintegration, dissolution and bioavailability of lorazepam
`tablets. Drug Dev Ind Pharm 1992; 18: 375-383.
`5. Oza K.P, Frank SG. Microcrystalline cellulose stabilized emul-
`sions. J Disper Sci Technol1986; 7(5): 543-561.
`6. Mombellet H, Bale P. Sodium carboxymethylcellulose tooth-
`paste. Mfg Chern 1988; 59(11): 47, 49, 52.
`7. Khan KA, Rhodes CT. Water-sorption properties of tablet
`disintegrants. J Pharm Sci 1975; 64: 447-451.
`8. Banker G, Peck G, Williams E, Taylor D, Pirakitikulr P.
`Microbiological considerations of polymer solutions used in
`aqueous film coating. Drug Dev Ind Pharm 1982; 8: 41-51.
`9. FAOjWHO. Evaluation of certain food additives and contami-
`nants. Thirty-fifth report of the joint FAO/WHO expert
`committee on food additives. Tech Rep Ser Wld Hlth Org
`1990; No. 789.
`10. Teller MN, Brown GB. Carcinogenicity of carboxymethylcellu-
`lose in rats. Proc Am Assoc Cancer Res 1977; 18: 225.
`11. Schneider CH, de Week AL, Stuble E. Carboxymethylcellulose
`additives in penicillins and the elicidation of anaphylactic
`reactions. Experentia 1971; 27: 167-168.
`12. Aitken MM. Induction of hypersensitivity to carboxymethylcel-
`lulose in cattle. Res Vet Sci 1975; 19: 110-113.
`13. Sweet DV, editor. Registry of toxic effects of chemical
`substances. Cincinnati: US Department of Health, 1987.
`14. Tanaka S, Aketagawa J, Takahashi S, Shibata Y, Tsumuraya Y,
`Hashimoto Y. Activation of a limulus coagulation factor G by
`(1~3)-,8-D-glucans. Carbohydrate Res 1991; 218: 167-174.
`
`21. General References
`Doelker E. Cellulose derivatives. Adv Polymer Sci 1993; 107: 199-265.
`
`22. Authors
`UK: JE Fairbrother, DA Hollingsbee, PJ Weller.
`
`LUYE1008
`IPR of Patent No. 6,667,061
`
`

`
`Corn Oil
`
`1. Nonproprietary Names
`USPNF: Corn oil
`
`2. Synonyms
`Calchem IV0-108; Lipex 104; maize oil.
`
`3. Chemical Name and CAS Registry Number
`Corn oil [8001-30-7]
`
`4. Empirical Formula Molecular Weight
`Corn oil is composed of fatty acid esters with glycerol, known
`commonly as triglycerides. Typical corn oil produced in the
`US contains five major fatty acids: linoleic 58.9%; oleic 25.8%;
`palmitic 11.0%; stearic 1.7% and linolenic 1.1 %. Corn grown
`outside the US corn belt, including other countries, yields corn
`oil with lower linoleic, higher oleic and higher saturated fatty
`acid levels. Corn oil also contains small quantities of plant
`sterols.
`
`5. Structural Formula
`See Section 4.
`
`6. Functional Category
`Oleaginous vehicle; solvent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Corn oil is used primarily in pharmaceutical formulations as a
`solvent for intramuscular injections or as a vehicle for topical
`preparations. Emulsions containing up to 67% corn oil are
`also used as oral nutritional supplements, see also Section 19.
`Corn oil has a long history ~f use as an edible oil.
`.
`
`8. Description
`Clear, light yellow colored, oily liquid with a faint character-
`istic odor and slightly nutty, sweet taste resembling cooked
`sweet corn.
`
`9. Pharmacopeia! Specifications
`Test.
`USPNFXVll
`Specific gravity
`0.914-0.921
`Heavy metals
`~ 0.001%
`+
`Cottonseed oil
`+
`Fatty acid composition
`+
`Free fatty acids
`Iodine value
`102-130
`Saponification value
`187-193
`Unsaponifiable matter
`~ 1.5%
`
`10. Typical Properties
`Acid value: 2-6
`·
`Auto ignition temperature: 393 oc
`Density: see HPE Data.
`Flash point: 321 oc
`Hydroxyl value: 8-12
`
`Corn Oil 135
`
`Melting point: -18 to -10°C
`Refractive index:
`nn25 = 1.470-1.474;
`nn 40 = 1.464-1.468.
`Solubility: slightly soluble in ethanol (95%); miscible with
`benzene, chloroform, ether and hexane.
`Viscosity (dynamic): see HPE Data.
`
`Density
`
`HPE Laboratory Project Data
`Results
`Method
`Lab#
`0.918 gfcm3 (a)
`DE-5
`30
`0.915 g/cm3 (b)
`DE-5
`30
`38.83 mPa s (a)
`VIS-2
`30
`37.36 mPas (b)
`VIS-2
`30
`Supplier: a. Welch, Holme & Clark Co; b. Capital.
`
`Viscosity
`
`11. Stability and Storage Conditions
`Corn oil is stable when protected with nitrogen in tightly
`sealed bottles. On prolonged exposure to air it thickens and ·
`becomes rancid. Corn oil may be sterilized by dry heat,
`maintaining it at 150°C for one hour.(!)
`Corn oil should be stored in an airtight, light-resistant
`container in a cool, dry, place.
`
`12. Incompatibilities
`
`13. Method of Manufacture
`Refined corn oil is obtained from the germ or embryo of Zea
`mays Linne (Fam. Gramineae) which contains nearly 50% of
`the fixed oil, compared with 3.0-6.5% in the whole kernel. The
`oil is obtained from the embryo by expression and/or solvent
`extraction. The crude oil is then refined to remove free fatty
`acids, phospholipids and impurities. It is bleached with solid
`adsorbents to lighten its color, dewaxed by chilling (which
`removes any solid waxy components) and deodorized at high
`temperature, under vacuum, to produce a bland, odorless,
`edible product.
`
`14. Safety
`Based upon its extensive history of food usage corn oil is
`generally regarded as a nontoxic and nonirritant material.
`
`15. llandling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Spillages of this material are
`very slippery and should be covered with an inert absorbent
`material prior to disposal.
`
`16. Regulatory Status
`Included in the FDA Inactive Ingredients Guide (IM
`injections, oral capsules, suspensions, tablets and topical
`emulsions).
`
`17. Pharmacopeias
`Cz, Egypt, Fr, Jpn, Mex and USPNF.
`
`18. Related Substances
`Canola Oil; Cottonseed Oil; Peanut Oil; Sesame Oil; Soybean
`Oil.
`
`LUYE1008
`IPR of Patent No. 6,667,061
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`

`
`136 Corn Oil
`
`19. Comments
`Corn oil contains a high content of unsaturated acids and has
`been used to replace fats and oils containing a high content of
`saturated acids in the diets of patients with hypercholester-
`olemia.
`
`20. Specific References
`1. Pasquale D, Jaconia D, Eisman P, Lachman L. A study of
`sterilizing conditions for injectable oils. Bull Parenter Drug Assoc
`1964; 18(3): 1-11.
`
`21. General References
`Mann JI, Carter R, Eaton P. Re-heating corn oil does not saturate its
`double bonds [letter]. Lancet 1977; ii: 401.
`Strecker LR, Maza A, Winnie GF. Corn oil- composition, processing
`and utilization. In: Erickson DR, editor. World conference
`proceedings. Edible fats and oils processing: basic principles and
`modern practices. American Oil Chemist's Society, 1990: 309-323.
`Watson SA, Ramstead PE, editors. Corn chemistry and technology.
`St. Paul: American Association of Cereal Chemists Inc, 1987: 53-
`78.
`
`22. Authors
`USA: KD Brenner.
`
`LUYE1008
`IPR of Patent No. 6,667,061
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`

`
`Cottonseed Oil
`
`1. Nonproprietary Names
`USPNF: Cottonseed oil
`
`2. Synonyms
`Calchem IV0-109; cotton oil; Lipex 109; refined cottonseed
`oil.
`
`3. Chemical Name and CAS Registry Number
`Cottonseed oil [8001-29-4]
`
`4. Empirical Formula Molecular Weight
`A typical analysis of refined cottonseed oil indicates the
`composition of the acids, present as glycerides, to be: linoleic
`acid 39.3%; oleic acid 33.1 %; palmitic acid 19.L%; stearic acid
`1.9%; arachidic acid 0.6% and myristic acid 0.3%. Also
`present are small quantities of phospholipid, phytosterols and
`pigments. The toxic polyphenolic pigment gossypol is present
`in raw cottonseed and in the oil cake remaining after
`expression of oil; it is not found in refined oil.
`
`5. Structural Formula
`See Section 4.
`
`6. Functional Category
`Oleaginous vehicle; solvent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Cottonseed oil is used in pharmaceutical formulations
`primarily as a solvent for intramuscular injections. Although
`it has been used in intravenous emulsions as a fat source in
`parenteral nutrition regilnens its use for this purpose has been
`superseded by soybean oil emulsions, see Section 14 ..
`
`8. Description
`Pale yellow or bright golden yellow colored·, clear oily liquid. It
`is odorless, or nearly so, with a bland, nutty taste. At
`temperatures below l0°C, particles of solid fat may separate
`from the oil and at about -5 to ooc the oil becomes solid or
`nearly so. If it solidifies, the oil should be remelted and
`thoroughly mixed before use.
`
`9. Pharmacopeia! Specifications
`
`Test
`Identification
`Specific gravity
`Heavy metals
`Trichloroethylene
`Solidification range of fatty acids
`Free fatty acids
`Iodine value
`Saponification value
`
`10. Typical Properties
`Autoignition temperature: 344°C
`
`USPNFXVII
`+
`0.915-0.921
`~ 0.001%
`+
`31-35°C
`+
`109-120
`190-198
`
`Cottonseed Oil 137
`
`Density: see HPE Data.
`Flash point: 321 oc
`Freezing point: -5 to ooc
`Heat of combustion: 37.1 kJ/g
`40 = 1.4645-1.4655
`Refractive index: n0
`Solubility: slightly soluble in ethanol (95%); miscible with
`carbon disulfide, chloroform and hexane.
`Surface tension:
`35.4 mN/m (35.4 dynes/em) at 20°C;
`31.3 mN/m (31.3 dynes/em) at 80°C.
`Viscosity (dynamic): up to 70.4 mPa s (70.4 cP) at 20°C. See
`also HPE Data.
`
`HPE Laboratory Project Data
`Method
`Lab#
`Results
`0.916 gfcm3
`DE-5
`30
`Density
`VIS-2·
`39.19 mPa s
`30
`Viscosity
`Supplier: Welch, Home & Clark Co.
`
`11. Stability and Storage Conditions
`Cottonseed oil is stable if stored in a well-filled, airtight, light-
`resistant container in a cool, dry, place.
`
`12. Incompatibilities
`
`13. Method of Manufacture
`Cottonseed oil is the refined fixed oil obtained from the seed of
`cultivated plants of various varieties of Gossypium hirsutum
`Linne or of other species of Gossypium (Fam. Malvaceae). The
`seeds contain about 15% oil. The testae of the seeds are frrst
`separated and the kernels then exposed to powerful expression
`in a hydraulic press. The crude oil thus obtained has a bright
`red or blackish-red color and requires purification before it is
`suitable for food or pharmaceutical purposes.
`
`14. Safety
`Cottonseed oil emulsions have in the J:>ast been used in long-
`term intravenous nutrition regimens.0·2) However, a complex
`series of adverse reactions, called the 'overloading syndrome'<3)
`seen with chronic administration of cottonseed oil emulsions
`has led to the cessation in the use of this material for parenteral
`nutrition purposes. For such applications it has been replaced
`by soybean oil. <2•4-6)
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Spillages of this material are
`very slippery and should be covered with an inert absorbent
`material prior to disposaL
`
`16. Regulatory Status
`Included in the FDA Inactive Ingredients Guide (IM
`injections).
`
`17. Pharmacopeias
`Egypt, Mex and USPNF.
`
`18. Related Substances
`Canola Oil; Corn Oil; Hydrogenated Vegetable Oil, Type I;
`Peanut Oil; Sesame Oil; Soybean OiL
`
`LUYE1008
`IPR of Patent No. 6,667,061
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`

`
`138 Cottonseed Oil
`
`19. Comments
`
`20. Specific References
`1. Cole WH. Fat emulsion for intravenous use. JAMA 1958; 166:
`1042-1043.
`2. McNiff BL. Clinical use of 10% soybean oil emulsion. Am J Hasp
`Pharm 1977; 34: 1080-1086.
`3. Goulon M, Barois A, Grosbuis S, Schortgen G. Fat embolism after
`repeated perfusion oflipid emulsion. Nouv Presse Med 1974; 3: 13-
`18.
`
`4. Davis SS. Pharmaceutical aspects of intravenous fat emulsions. J
`Hosp Pharm 1974; 32: 149-160.
`5. Davis SS. Pharmaceutical aspects of intravenous fat emulsions. J
`Hosp Pharm 1974; 32: 165-171.
`6. Singh M, Ravin LJ. Parenteral emulsions as drug carrier systems. J
`Parenter Sci Technol 1986; 40: 34-41.
`
`21. General References
`
`22. Authors
`USA: MC McCaffrey-Manzo.
`
`LUYE1008
`IPR of Patent No. 6,667,061
`
`

`
`294 Mannitol
`
`Mannitol
`
`1. Nonproprietary Names
`BP: Mannitol
`PhEur: Mannitolum
`USP: Mannitol
`
`8. Description
`Mannitol is D-mannitol. It is a hexahydric alcohol related to
`mannose and is isomeric with sorbitol.
`Mannitol occurs as a white, odorless, crystalline powder, or
`free-flowing granules. It has a sweet taste, approximately as
`sweet as glucose and half as sweet as sucrose, and imparts a
`cooling sensation in the mouth. Microscopically, it appears as
`orthorhombic needles when crystallized from alcohol.
`
`2. Synonyms
`Cordycepic acid; E421; 1,2,3,4,5,6-hexanehexol; manita;
`manna sugar; mannite; Pear/ito!.
`
`SEM: 1
`Excipient: Mannitol
`Manufacturer: Triangle Import & Export Co
`Magnification: 120x
`
`3. Chemical Name and CAS Registry Number
`n-Mannitol [69-65-8]
`
`4. Empirical Formula
`C6H1406
`
`Molecular Weight
`182.17
`
`5. Structural Formula
`
`yHzOH
`HO-C-H
`I
`HO-C-H
`I H-C-OH
`I
`H-C-OH
`I
`CH20H
`
`6. Functional Category
`Sweetening agent; tablet and capsule diluent; tonicity agent;
`vehicle (bulking agent) for lyophilized preparations.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Mannitol is widely used in pharmaceutical formulations and
`food products. In pharmaceutical preparations it is primarily
`used as a diluent (10-90% wjw) in tablet formulations, where it
`is of particular value since it is not hygroscopic and may thus
`be used with moisture sensitive active ingredients.
`Mannitol may be used in direct compression tablet applica-
`tions, (l-S) for which the granular form was especially
`developed, or wet granulations, (6) which may be readily
`dried. A lubricant, such as magnesium stearate 1-2% wjw
`should be used in direct compression processes, see also
`Section 19. Specific tablet applications include antacid
`formulations, glyceryl trinitrate tablets and vitamin prepara-
`tions.
`Mannitol is commonly used as an excipient in the manufacture
`of chewable tablet formulations ,because of its negative heat of
`solution, sweetness and 'mouth feel' p.s)
`In lyophilized preparations, mannitol (20.-90% wjw) has been
`included as a carrier to produce a stiff, homogeneous cake that
`improves the appearance of the lyophilized plug in a vial.C9-12)
`Mannitol has also been used to prevent thickening in aqueous
`antacid suspensions of aluminum hydroxide ( < 7% w/v). In
`addition, mannitol has been suggested as a plasticizer in soft
`gelatin capsules, as a component of sustained release tablet
`formulationsC13) and is used in food applications as a bulking
`agent.
`Therapeutically, supersaturated aqueous solutions ofmannitol
`(20-25% w/v) are widely used as osmotic diuretics.
`
`SEM:2'
`Excipient: Mannitol
`Manufacturer: Triangle Import & Export Co
`Magnification: 600x
`
`LUYE1008
`IPR of Patent No. 6,667,061
`
`

`
`9. Pharmacopeial Specifications
`Test·
`PhEur 1987
`
`USPXXTI
`(Suppl8)
`+
`165-169°C
`+ 137° to 145°
`+
`~ 0.3%
`~ 0.007%
`~ 0.01%
`~ 1 ppm
`+
`
`Identification
`+
`Melting range
`165-168°C
`Specific rotation *
`+23° to +24°
`Acidity
`+
`Loss on drying
`~ 0.5%
`Chloride
`~ 70 ppm
`Sulfate
`~ 120 ppm
`Arsenic
`~ 2ppm
`Reducing sugars
`+
`Sulfated ash
`~ 0.1%
`Assay
`96.0-101.5%
`98.0-102.0%
`*Note that the preparation and concentration of the mannitol solution
`used to measure the specific optical rotation is different in the PhEur
`1987 and USP XXII.
`,
`
`10. Typical Properties
`Compressibility: see HPE Data and Fig. 1.
`Density (bulk):
`0.66 gfcm3 for Pear/ito! FG;
`0. 72 gfcm3 for Pear/ito! MG;
`0.67 gfcm3 for Pear/ito! GG2.c14)
`See also HPE Data.
`Density (particle):) .48 g/cm3
`Density (tapped):
`0.76 gfcm3 for Pear/ito! FG;
`0.82 gfcm3 for Pear/ito! MG;
`0.78 gfcm3 for Pear/ito! GG2.C14)
`See also HPE Data.
`Dissociation constant: pKa = 13.5 at 18°C
`Flash point: > 150°C
`Flowability: powder is cohesive, granules are free flowing.
`Heat of combustion: 16.57 kJ/g (3960 cal/g)
`Heat of solution: -120.9 Jfg (-28.9 cal/g) at 25°C
`Melting point: 166-168°C
`Moisture content: see HPE Data and Fig. 2.
`Osmolarity: a 5.07% wfv aqueous solution is iso-osmotic with
`serum.
`Particle size distribution: maximum of 0.1% greater than 500
`Jlm and minimum of 90% greater than 200 Jlm in size for
`Pear/ito! FG; maximum of 20% greater than 500 Jlm and
`minimum of 85% greater than 100 Jlm in size for Pear/ito! MG;
`maximum of 0.5% greater than 841 Jlm and minimum of 90%
`greater than 150 Jlm in size for Pear/ito! GG2.c14) Average
`particle diameter is 250 Jlm for Pear/ito! FG, 360 Jlm for
`Pearlitol MG and 520 Jlm for Pear/ito! GG2.c14) See also HPE
`Data.
`Refractive index: nn 20 = 1.333
`Solubility:
`
`Solvent
`Alkalis
`Ethanol (95%)
`Ether
`Glycerin
`Propan-2-ol
`Water
`
`Solubility at 20°C
`soluble
`1 in 83
`practically insoluble
`1 in 18
`1 in 100
`1 in 5.5
`
`Specific surface area: 0.60 m2/g
`
`Mannitol 295
`
`HPE Laboratory Project Data
`Method
`Lab#
`Results
`No flow (a)
`FL0-3
`24
`B: 0.381 gfcm3 (b)
`BTD-5
`6
`T: 0.599 gfcm3
`B: 0.429 g/cm3 (c)
`T: 0.679 gfcm3
`B: 0.420 gfcm3 (a)
`T: 0.633 gfcm3
`See Fig. 3. (c)
`0.277% (a)
`12.5 f.LID (a)
`See also Fig. 4.
`
`BTD-5
`
`BTD-5
`
`COM-3
`MC-29
`PSD-7
`
`6
`
`6
`
`20
`23
`24
`
`Average flow rate
`Bulk/tap density
`
`Compressibility
`Moisture content
`Particle size
`
`Solubility (a)
`Ethanol (95%) at 25°C SOL-6
`Ethanol (95%) ~t 37°C SOL-6
`Hexane at 25°C
`SOL-6
`Hexane at 37°C
`SOL-6
`Propylene glycol at 25°C SOL-6
`Propylene glycol at 37°C SOL-6
`Water at 25°C
`SOL-6
`Water at 37°C
`SOL-6
`Supplier:
`a. Pfizer Inc;
`b. George Lihe;
`c. Atlas Chemical Industries (UK) Ltd (Lot No.: 2022BO).
`
`23
`23
`23
`23
`23
`23
`23
`23
`
`0.0133 gfmL
`0.0139 gfmL
`< · Q.OOI gfmL
`< 0.001· g/mL
`0.100-0.200 g/mL
`0.100-0.200 gfmL
`0.1798 g/mL
`0.2234 gfmL
`
`11. Stability and Storage Conditions
`Mannitol is stable in the dry state and in aqueous solutions.
`Solutions may be sterilized by filtration or by autoclaving and
`if necessary may be autoclaved repeatedly with no adverse
`physical or chemical effects. (15) In solution, mannitol is not
`attacked by cold, dilute acids or alkalis, nor by atmospheric
`oxygen in the absence· of catalysts. Mannitol does not undergo
`Maillard reactions.
`The bulk material should be stored in a well-closed container
`in a cool, dry, place.
`
`12. Incompatibilities
`None reported in the dry state. Mannitol solutions, 20% w/v
`or stronger, may be salted out by potassium or sodium
`chloride.C16) Precipitation has been reported to occur when a
`25% wfv mannitol solution was allowed to contact plastic.C17)
`Sodium cephapirin at 2 mg/mL and 30 mg/mL is incompatible
`with 20% wfv aqueous mannitol solution. Mannitol is
`incompatible with xylitol infusion and may form complexes
`with some metals (Fe, AJ, Cu).
`
`13. Method of Manufacture
`Mannitol may be extracted from the dried sap of manna and
`other natural sources by means of hot alcohol or other
`selective solvents. It is commercially produced by the catalytic
`or electrolytic reduction of monosaccharides such as mannose
`and glucose.
`
`14. Safety
`Mannitol is a naturally occurring sugar alcohol found in
`animals and plants; it is present in small quantities in almost all
`vegetables. Only small amounts are absorbed from the
`gastrointestinal tract following oral consumption. When
`consumed orally in large quantities laxative effects may
`occur. c1s) If used in foods as a bodying agent and daily
`
`LUYE1008
`IPR of Patent No. 6,667,061
`
`

`
`296 Mannitol
`
`6
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`.....
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`.....
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
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`
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`
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`c:
`
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`
`1 0 20 30 40 50 60 70 80 90 100
`Compression force (kN)
`
`0
`
`3
`
`6
`
`21
`18
`15
`12
`9
`Compression force, KN
`
`24
`
`27
`
`2.7
`~ If
`30
`
`Fig. 1: Compression characteristics of granular mannitol
`(Pear/ito/, Roquette Freres).<14>
`0 Pear/ito! FG
`0 Pear/ito! MG
`b,. Pearlitol GG2
`Tablet diameter: 20 mm
`Lubricant: magnesium stearate 0.7% w/w for Pearlitol MG
`and Pearlitol GG2, magnesium stearate 1% wfw for Pear/ito!
`FG.
`
`Fig. 3: Compression characteristics of granular mannitol.
`Mean tablet weight: 500 mg
`Minimum compressional force for compaction: 7.35 kN
`Compressional force resulting in capping: 24.5 kN
`
`5.0
`
`4.0
`
`3.0
`
`2.0
`
`1.0
`
`Increase
`in weight
`(%)
`
`0
`
`0
`
`20
`
`100
`
`80
`
`60
`
`Q
`
`Weight
`oversize
`(%)
`
`40
`
`/
`.rv"
`n.
`Q ~ ~
`v-
`80
`60
`40
`
`A
`
`100
`
`Rel