`
`Handbook of
`PHARMACEUTICAL
`EXCIPIENTS
`
`
`
`Third Edition
`
`Edited by
`Arthur H. Kibbe, Ph.D.
`Professor and Chair
`Department of Pharmaceutical Sciences
`Wilkes University School of Pharmacy
`Wilkes-Barre, Pennsylvania
`
`S
`
`American Pharmaceutical Association
`
`London, United Kingdom
`
`|
`
`MAIA Exhibit 1035
`
`MAIA V. BRACCO
`
`IPRPETITION
`
`
`
`
`MAIA Exhibit 1035
`MAIA V. BRACCO
`IPR PETITION
`
`

`

`Published by the American Pharmaceutical Association
`2215: Constitution Avenue NW, Washington, DC 20037-2985, USA
`www.aphanet.org
`and the Pharmaceutical Press
`1 Lambeth High Street, London SE] 7JN, UK
`www.pharmpress.com
`
`“
`
`© 1986, 1994, 2000 American Pharmaceutical Association and Pharmaceutical Press
`First edition 1986
`Second edition 1994
`Third. edition 2000
`
`Printed in the United States of America
`
`ISBN: 0-85369-381-1 (UK)
`ISBN: 0-917330-96-X (USA)
`
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients / edited by Arthur H. Kibbe.--3rd ed.
`p.
`; cm.
`Includes bibliographical references and index.
`ISBN 0-917330-96-X
`1, Excipients--Handbooks, manuals, etc.
`Pharmaceutical Association.
`[DNLM: 1. Excipients--Handbooks. QV 735 H236 2000]
`RS201.E87 H36 2000
`615'.19--de21
`
`I. Kibbe, Arthur H. II. American
`
`A catalogue record for this book is available from the British Library.
`
`99-044554
`
`All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or
`by any means, without the prior written permission of the copyright holder. The publisher makes no representation, express or
`implied, with regard to the accuracy of the information contained in this book and cannot accept any legal responsibility or
`liability for any errors or omissions that may be made.
`
`Managing Editor: Melanie Segala
`Copyeditor:
`Paul Gottehrer
`Indexer:
`Lillian Rodberg
`Compositor:
`Roy Barnhill
`Cover Designer:
`Tim Kaage
`
`
`
`
`

`

`—————————————
`324 Mannitol
`
`
`Mannitol
`
`1, Nonproprietary Names
`BP: Mannitol
`JP: p-Mannite
`PhEur: Mannitolum
`USP: Mannitol
`
`2. Synonyms
`Cordycepic acid; E421; p-mannitol; manna sugar; mannite;
`
`3. Chemical Name and CAS Registry Number
`p-Mannito! [69-65-8)
`
`4, Empirical Formula Molecular Weight
`182.17
`
`5, Structural Formula
`
`CH,OH
`o—-o—H
`oe ee
`4—¢—OH
`H—¢—oH
`tx,oH
`
`6. Functional Category
`Sweetening agent; tablet and capsule diluent; tonicity agent:
`vehicle (bulking agent) for lyophilized preparations.
`
`7, Applications in Pharmaceutical Formulation or
`Technology
`is widely used in pharmaceutical formulations and
`food products. In pharmaceutical preparations it is primarily
`used as a diluent (10-90% w/w) 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," for which the granular and spray-dried forms are
`available, or in wet granulations."© Granulations containing
`mannitol have the advantage of being dried easily. Specific
`tablet applications include antacid preparations, glyceryl trin-
`itrate tablets, and vitamin preparations, Mannitolis commonly
`used as an excipient
`in the manufacture of chewable tablet
`formulations because of its negative heat of solution, sweet-
`ness, and ‘mouth feel’.!7*
`In lyophilized preparations, mannitol (20-90% w/w) has been
`included as a carrier to produce a stiff, homogeneous cake
`
`that improves the appearance of the lyophilized plug in a vi-
`al!) 4 pyrogen-free form is available specifically for this
`
`Mannitol has also been used to prevent thickening in aqueous
`antacid suspensions of aluminum hydroxide (< 79%w/v).
`It
`has been suggested as a plasticizer in soft-gelatin capsules,
`as a component of sustained-release tablet formulations,''*)
`and is used in food applications as a bulking agent.
`Therapeutically, mannitol administered parenterally is used as
`an osmotic diuretic, as a diagnostic agent for kidney function,
`as an adjunct
`in the treatment ofacute renal failure and as
`an agent to reduce intracranial pressure, treat cerebral edema,
`and reduce intraocular pressure. Given orally, mannitol
`is not
`absorbed significantly from the GI tract, but in large doses it
`can cause osmotic diarrhea, see Section 14,
`
`8. Description
`Mannitol is p-mannitol: It is a hexahydric aleohol 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.
`
`9, Pharmacopeial Specifications
`
`
` ‘Test JP PhEor USP
`
`
`Identification
`+
`+
`+
`Characters
`+
`+
`—
`Solution appearance +
`+
`—
`Melting range
`166-169°C
`165-170°C
`164- 169°C
`Specific rotation
`4137° to 4145° 423° to 425° +137° to +14
`Acidity
`+
`+
`+
`Loss on drying
`£0,30%
`S0.5%
`20.3%
`Chloride
`Ss O.007T%
`= 30 ppm
`Ss 0.007%
`Sulfate
`£0.01%
`S10 ppm
`5 0.01%
`Arsenic
`= 13 ppm
`=
`= 1 ppm
`Lead
`a
`5.0.5 ppm
`—
`Nickel
`+
`= 1 ppm
`_
`Heavy metals
`= 5 ppm
`-
`—
`Reducing sugars
`+
`+
`+
`Sulfated ash
`S$ 0.10%
`S0.1%
`_—
`Sorbitol
`-
`= 2.0%
`_
`Bacterial endotoxins
`—
`+0)
`-
`
`Assay %6-101.5% <= 98.0% 98-101.5%
`
`
`) Test applied only if the mannitol is to be used in the manufacture of
`parenternal dosage form.
`
`10. Typical Properties
`1 and 2,9)
`Compressibility: see Figs.
`Density (bulk): 0.430 g/cm**) for powder; 0.7 giem?) for
`granules.
`Density (tapped): 0.734 g/em*) for powder; 0.8 giem3!) for
`granules
`Density (true): 1.514 g/cm”
`Dissociation constant: pK, = 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 Ig (-28.9 cal/g) at 25°C
`Melting point: 166-168°C
`Moisture content: see Fig. 3.™
`
`
`
`
`
`
`SEM: 1
`Excipient: Mannitol
`Manufacturer: Merck
`Magnification; 50s
`
`Mannitol 325
`
`=
`
`SEM: 3
`Excipient: Mannitol powder
`Manufacturer: SPI Polyols, Inc
`Lot No: 3140G8
`Magnification: [hx
`
`Voltage: 3.5 kV
`
`
`
`SEM: 2
`Excipient: Mannitol
`
`Manufacturer: Merck
`Magnification: Sx
`Voltage: 3.5 kV
`
`SEM: 4
`Excipient: Mannitol granular
`Manufacturer: SPI Polyols, Inc
`Lot No: 2034P8.
`Magnification: 100s
`
`
`
`
`
`
`
`Osmotarity: a 5.07% w/v aqueous solution is iso-osmotic with
`serum,
`
`Particle size distribution: maximum of0.15% greater than 500
`tim and minimum of 90% greater than 200 tm in size for
`Pearlitol 300 DC; maximum of 20% greater than 500 um
`and minimum of 85% greater than 100 [imin size for
`Pearlitol 400 DC, maximum of 0.5% greater than 841 1m
`Pe an of 90% greater than 150 jm in size for
`Paik 400 DC, Average particle diameter is 250 jim for
`sm ttol 300 pe, 360 gm for Pearlitol 400 DC and
`Hm for Pearlitel 500 DC.\'4) See Fig, 4.1%
`Refractive index: fp” = 1,333
`
`Solubility: see table below,
`Solvent
`Solubility at 20°C
`Alkalis
`Soluble
`Ethanol (95%)
`Lin 83
`Ether
`Practically insoluble
`Glycerin
`Lin 18
`Propan-2-ol
`Lin 100
`Water
`Lin 3.5
`
`Specific surface area: 0.37-0.39 mg
`' Handbook of Pharmaceutical Excipients, First Edition.
`® Results of laboratory project for third edition.
`
`
`
`
`

`

`
`
`
`
`t
`70 @0
`90 100
`60
`50
`40
`30
`Compression force (kN)
`
`i¢ h
`
`yo
`
`20
`
`Fig. 1: Compression characteristics of granular mannitol
`(Pearlitol, Roquette Freres).
`©): Pearlitol FG
`O: Pearlitol MG
`A: Pearlitol GG2
`Tablet diameter: 20 mm
`Lubricant: magnesium stearate 0.7% wiw for Pearlitol MG and
`Pearlitol GG2, magnesium stearate 1% w/w for Pearlitol FG
`
`‘oe
`
`35
`
`E
`"8
`3
`a1 8
`i
`“|
`> i
`a7
`
`6
`
`21
`18
`15
`12
`9
`Compression force (KN)
`
`24
`
`27
`
`30
`
`Fig. 2: 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
`
`
`
` oe
`
`
`234693°0«C«dsi‘icz CCH «100
`Relative humidity (%)
`
`Fig. 3: Sorption-desorption isotherm for mannitol.
`# >: sorption equilibrium moisture
`Wi: desorption equilibrium moisture
`
`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.{'5) In solution, mannitol
`is not
`attacked by cold, dilute acids or alkalis, nor by atmospheric
`oxygen in the absence ofcatalysts. 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% wiv
`or stronger, may be salted out by potassium or sodium chlo-
`ride.'!®) Precipitation has been reported to occur when a 25%
`w/v mannitol solution was allowed to contact plastic.!'7) So-
`dium cephapirin at 2 mg/mL and 30 mg/mLis incompatible
`with 20%w/v aqueous mannitol solution. Mannitol is incom-
`patible with xylitol
`infusion and may form complexes with
`some metals (Fe, Al, Cu). Reducing sugar impurities in man-
`nitol have been implicated in the oxidative degradation of a
`peptide in a lyophilized formation.('*) Mannitol was found to
`reduce the oral biovailability of cimetidine compared to su-
`crose,(19)
`
`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 selec-
`tive solvents. It is commercially produced by the catalytic or
`electrolytic reduction of monosaccharides such as mannose
`and glucose,
`
`(%)
`
`
`
`Weightoversize
`
`Median size = 8Bum
`
`0
`
`40
`
`100
`80
`Particle diameter(um)
`
`160
`
`200
`
`Fig, 4: Particle size distribution of mannitol powder.
`
`pacndntinsy
`
`14. Safety
`Mannitol
`is a naturally occurring sugar alcohol found in an-
`imals and plants; it
`is present in small quantities in almost
`all vegetables. When consumedorally in large quantities, lax-
`ative effects may occur.!If used in foods as a bodying agent
`and daily ingestion of over 20g is foreseeable,
`the product
`label should bear the statement ‘excessive consumption may
`have a laxative effect’. After intravenous injection, mannitol
`is not metabolized to any appreciable extent and is minimally
`reabsorbed by the renal
`tubule, about 80% of a dose being
`excreted in the urine in 3 hours,'2!)
`A numberof adverse reactions to mannitol have been reported
`Primarily following the therapeutic use of 20% w/v aqueous
`intravenous infusions.2?) The quantity of mannitol used as an
`excipient
`is considerably less than that used therapeutically
`and is consequently associated with a lower incidence of ad-
`Verse reactions. However, allergic, hypersensitive-type reac-
`‘ons may occur when mannitol
`is used as an excipient.
`An acceptable daily intake of mannitol has not been specified
`by the WHO since the amount consumed @8 a sweetening
`‘gent was not considered to represent a hazard to health.(23)
`LDso (mouse, IP): 14 g/kg)
`LD.) (mouse, IV): 7.47 g/kg
`LDso (mouse, oral): 22 g/kg
`LDso (rat, TV): 9.69 g/kg
`b . LDso (rat, oral): 13.5 g/kg
`
`
`
`Mannitol 327
`
`-
`15, Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Mannitol may be irritant to
`the eyes; eye protection is recommended.
`
`16. Regulatory Status
`GRASlisted. Accepted for use as a food additive in Europe.
`Included in the FDA Inactive Ingredients Guide (IP, IM, IV,
`and SC injections, infusions, buccal, oral and sublingual tab-
`lets and capsules), Included in nonparenteral and parenteral
`medicines licensed in the UK.
`
`17. Pharmacopeias
`China, Eur, Int, Jpn, Pol, and US.
`18. Related Substances
`Sorbitol.
`
`19, Comments
`Mannitol is an isomer of sorbitol, the difference between the
`two polyols occurring in the planar orientation of the OH
`group on the second carbon atom. Each isomeris character-
`ized by its own individual set of properties, the most impor-
`tant difference being the response to moisture. Sorbitol
`is
`hygroscopic while mannitol resists moisture sorption, even at
`high relative humidities.
`Granular mannitol flows well and imparts improved flow prop-
`erties to other materials. However, it usually cannot be used
`with concentrations of other materials exceeding 25% by
`weight, Recommendedlevels of lubricant are 1% w/w calcium
`stearate or 1-2% w/w magnesium stearate. Suitable binders
`for preparing granulations of powdered mannitol are gelatin,
`methylcellulose 400, starch paste, povidone, and sorbitol.
`Usually, 3-6 times as much magnesium stearate or 1,5-3 times
`as much calcium stearate is needed for lubrication of mannitol
`granulations than is needed for other excipients.
`Mannitol has been reported to sublime at 130°C.2%
`
`20. Specific References
`1. Kanig JL. Properties of fused mannitol in compressed tablets.
`J Pharm Sct 1964; 53; 188-192.
`2. Ward DR, Lathrop LB, Lynch MJ. Dissolution and compat-
`ibility considerations for the use of mannitol in solid dosage
`forms. J Pharm Sei 1969; 58: 1464-1467.
`3. Ghanem AH, Sakr FM, Abdel-Ghany G. Mechanical and
`physical properties of sulfamethoxazole-mannitol solid dis-
`persion in tablet form. Acta Pharm Fenn 1986; 95: 167-172,
`4. Debord B, Lefebvre C, Guyot-Hermann AM, Hubert J,
`Bouché R, Guyot JC, Study of different crystalline forms of
`mannitol: comparative behaviour under compression. Drug
`Dev Ind Pharm 1987; 13: 1533-1546.
`5, Molokhia AM, Al-Shora HI, Hammad AA. Aging of tablets
`prepared by direct compression of bases with different mois-
`ture content, Drug Dev Ind Pharm 1987, 13: 1933-1946,
`6. Mendes RW, Goll 5, An CQ. Wet granulation: a comparison
`of Manni-Tab and mannitol. Drug Cosmet Ind 1978; 122(3):
`36, 38, 40, 44, 87-88.
`7. Daoust RG, Lynch MJ. Mannitol in chewable tablets. Drug
`Cosmer Ind 1963; 93(1): 26-28, 88, 92, 128-129.
`8. Herman J, Remon JP. Aluminium-magnesium hydroxide tab-
`lets: effect of processing and composition of granulating
`solution on the granule properties and in vitro antacid per-
`formance, Drug Dev Ind Pharm 1988; 14: 1221-1234,
`
`
`
`
`

`

`— 3
`
`28 Mannitol
`
`. Couriel B. Advances in lyophilization technology. Bull
`Parenter Drug Assoc 1977; 31: 227-236.
`. Williams NA, Lee Y, Polli GP, Jennings TA. The effects of
`cooling rate on solid phase transitions and associated vial
`breakage occurring in frozen mannitol solutions. J Parenter
`Sci Technol 1986; 40: 135-141.
`. Stella VJ, Umprayn K, Waugh WN. Development of
`parenteral formulations of experimental cytotoxic agents, I:
`rhizoxin (NSC-332598). Int J Pharmaceutics 1988; 43:
`191-199,
`. Williams NA, Dean T. Vial breakage by frozen mannitol solu-
`tions: correlation with thermal characteristics and effect of
`stereoisomerism, additives, and vial configuration. J Parenter
`Sci Technol 1991; 45; 94-100.
`. Parab PV, Oh CK,Ritschel WA. Sustained release from Pre-
`cirol (glycerol palmito-stearate) matrix. Effect of mannitol
`and hydroxypropyl methylcellulose on the release of theo-
`phylline. Drug Dev Ind Pharm 1986; 12: 1309-1327.
`. Roquette Fréres. Technical literature: Pearlitel, 1997.
`. Murty BSR, Kapoor JN. Properties of mannitol
`injection
`(25%) after repeated autoclavings. Am J Hosp Pharm 1975,
`32; 826-827.
`Jacobs J. Factors influencing drug stability in intravenous
`infusions. J Hosp Pharm 1969; 27: 341-347,
`. Epperson E. Mannitol crystallization in plastic containers
`[letter]. Am J Hosp Pharm 1978; 35; 1337.
`. Dubost DC, Kaufman MJ, Zimmerman JA, Bogusky MJ,
`Coddington AB, Pitzenberger SM. Characterization of a solid
`state reaction producct from a lyophilized formulation of a
`
`.
`
`20.
`
`21,
`
`22.
`
`23.
`
`cyclic heptapeptide. A novel example of an excipient-induced
`oxidation. Pharm Res 1996; 13; 1811-1814.
`. Adkin DA, Davis SS, Sparrow RA, Huckle PD, Wilding IR.
`The effect of mannitol on the oral bioavailability of cimeti-
`dine. J Pharm Sci 1995, 84: 1405-1409,
`Flatulence, diarrhoea, and polyol sweeteners. Lancet 1983;
`ii: 1321.
`Porter GA,et al. Mannitol hemodilution-perfusion: the kinet-
`ics of mannitol distribution and excretion during cardiopul-
`monary bypass. J Surg Res 1967; 7; 447-456.
`MeNeill TY. Hypersensitivity reaction to mannitol. Drug
`Intell Clin Pharm 1985; 19: 552-553.
`FAO/WHO, Evaluation of certain food additives and contam-
`inants: thirtieth report of the joint FAO/WHO expert com-
`mittee on food additives. Tech Rep Ser Wid Hlth Org 1987;
`No. 751.
`SweetDV,editor, Registry of Toxic Effects of Chemical Sub-
`stances. Cincinnati, US Department of Health, 1987.
`Weast RC, editor. Handbook of Chemistry and Physics, 60th
`edition, Boca Raton, CRC Press Inc., 1979; c-369.
`
`24.
`
`25.
`
`21.
`General References
`Czeisler IL, Perlman KP. Diluents. In: Swarbrick J, Boylan JC,
`editors. Encyclopedia of Pharmaceutical Technology, volume
`4, New York, Marcel Dekker, 1988; 37-84.
`
`22. Authors
`
`NA Armstrong, GE Reier.
`
`
`
`
`

`

`|
`
`518 Sorbitol
`
`15. Handling Precautions
`Maybe harmful if ingested in great quantities. May be irritant
`to the eyes. Observe normal precautions appropriate to the
`circumstances and quantity of material handled. Eye protec-
`tion, gloves, and a dust mask or respirator are recommended.
`
`16. Regulatory Status
`GRASlisted. Accepted for use as a food additive in Europe.
`Included in the FDA Inactive Ingredients Guide (intra-articu-
`lar and IM injections, oral capsules, solutions, suspensions,
`syrups andtablets, rectal, topical, and vaginal preparations).
`Included in parenteral and nonparenteral medicines licensed
`in the UK.
`
`17. Pharmacopeias
`China, Eur, Jpn, Pol, and US.
`
`18. Related Substances
`Mannitol; sorbitol solution 70%; xylitol.
`Sorbitol solution 70%
`Synonyms: sorbitol liquid; Serbo.
`Appearance: a clear, colorless and odorless viscous liquid.
`Pharmacopeias: US.
`Comments: sorbitol solution is an aqueous solution of hydro-
`genated, partly hydrolyzed starch. For physical properties
`see Table I.
`
`2, Bolton S, Atluri R, Crystalline sorbitol tablets: effect of mix-
`ing time and lubricants on manufacturing. Drug Cosmet Ind
`1984; 135(5): 44, 46, 47, 48, 50.
`3. DuRoss JW. Modification of the crystalline structure of sor-
`bitol and its effects on tableting characteristics. Pharmaceut
`Technol 1984; 8(9): 42-53.
`- an excipient
`instant
`4, Basedow AM, Méschl GA. Sorbitol
`with unique tableting properties. Drug Dev Ind Pharm 1986;
`12: 2061-2089.
`5, Schmidt PC, Vortisch W. Influence of manufacturing method
`offillers and binders on their tableting properties: compari-
`son of 8 commercially available sorbitols [in German].
`Pharm Ind 1987, 49: 495-503.
`liquids.
`in pharmaceutical
`6. Daoust RG, Lynch MJ. Sorbitol
`Drug Cosmet Ind 1962; 90(6): 689-691, 773, 776, 777, 779,
`781-785.
`7. Sabatini GR, Gulesich JJ. Formulation of a stable and pal-
`atable oral suspension of procaine penicillin G. J Am Pharm
`Assoc (Pract Pharm) 1956; 17: 806-808,
`8. Bandelin FJ, Tuschhoff JV. The stability of ascorbic acid in
`various liquid media. J Am Pharm Assoc (Sci) 1955; 44:
`241-244.
`9, Parikh BD, Lofgren FV. A further stability study of an oral
`multivitamin liquid preparation. Drug Standards 1958, 26:
`56-61.
`10, Lindvall $, Andersson NSE. Studies on a new intramuscular
`haematinic, iron-sorbitol. Br J Pharmacal 1961; 17: 358-371.
`11. Bundgaard H. Drug allergy: chemical and pharmaceutical
`aspects.
`In: Florence AT, Salole EG, editors. Formulation
`Factors in Adverse Reactions. London: Wright, 1990, 23-55.
`12. Jain NK, et al, Sorbitol intolerance in adults. Am J Gastro-
`enteral 1985; 80: 678-681.
`13. Brown AM, MassonE.‘Hidden’ sorbitol in proprietary med-
`Table I: Physical properties of sorbitol in water solutions.
`icines - a cause for concern? Pharm J 1990; 245: 211.
`Concentration
`Density
`Viscosity
`Refractive
`Freezing
`14, Ayers CS, Abrams RA, Noncariogenic sweeteners: sugar sub-
`stitutes for caries control. Dental Hygiene 1987; 61: 162-167.
`
`
`(9 wiw) (g/cm?)=(mPa s) index point
`
`
`
`
`at 25°C at 25°C=at 25°C (°C) 15. Sweet DV,editor. Registry of Toxic Effects of Chemical Sub-
`
`stances. Cincinnati, US Department of Health, 1987.
`10
`1.034
`1.2
`1.348
`-1.1
`20
`1.073
`L.7
`1.365
`-3.8
`30
`1.114
`2.5
`1.383
`-8.0
`40
`1.155
`4.4
`1.400
`-13.0
`50
`1.197
`9.1
`1.418
`-26.0
`60
`1.240
`26.0
`1.437
`_
`70
`1,293
`110.0
`1.458
`_
`80
`1.330
`900.0
`1.478
`_
`
`
`19, Comments
`
`Sorbitol may be substituted for sucrose to prepare 70-90%
`wiv syrups.
`Several different grades of sorbitol, with different polymor-
`phic form, particle size, and other physical characteristics are
`commercially available, e.g., Neosorb (Roquette Fréres). Py-
`rogen-free grades are also available from some suppliers.
`
`20. Specific References
`1. Molokhia AM, Moustafa MA, Gouda MW.Effect of storage
`conditions on the hardness, disintegration and drug release
`from some tablet bases. Drug Dev Ind Pharm 1982, 8:
`283-292,
`
`21. General References
`Barr M, Kohn SR, Tice LF, Thesolubility of sorbitol in hydroal-
`coholic solutions. Am J Pharm 1957; 129: 102-106,
`Blanchard J, Fink WT, Duffy JP. Effect of sorbitol on interaction
`of phenolic preservatives with polysorbate 80. J Pharm Sei
`1977; 66: 1470-1473.
`Burgess S. Sorbitol instant: a unique excipient. Mfg Chem 1987;
`58(6): 55, 57, 59.
`Collins J. Metabolic disease:
`time for fructose solutions to go.
`Lancet 1993; 341: 600,
`Rabinowitz MP, Reisberg P, Bodin JI. GLC assay of sorbitol as
`cyclic n-butylboronate. J Pharm Sci 1974; 63: 1601-1604.
`Roquette Fréres. Technical literature: Neosorb-sorbitol, 1992.
`Shah DN, White JL, Hem SL. Mechanism ofinteraction between
`polyols and aluminum hydroxide gel. J Pharm Sci 1981; 70:
`1101-1104.
`Zatz JL, Lue R-Y. Flocculation of suspensions containing non-
`ionic surfactants by sorbitol. J Pharm Sci 1987; 76: 157-160.
`
`22, Authors
`
`RA Nash.
`
`
`
`
`

`

`416 Polyoxyethylene Sorbitan Fatty Acid Esters
`
`
`Polyoxyethylene
`Sorbitan Fatty Acid
`
`1. Nonproprietary Names
`BP: Polysorbates 20, 60, and 80
`JP: Polysorbate 80
`PhEur: Polysorbatum 20, 60, and 80
`USP: Polysorbates 20, 40, 60, and 80
`
`Synonyms of selected polysorbates are shown below, see alse
`
`(Continued)
`Polysorbate
`Polysorbate 80
`
`*
`
`Polysorbate 81
`
`Polysorbate 85
`
`Synonym
`Atles E; Armotan PMO 20, Capmul POE-O;
` Crifler 4; Criller 50; Drewmulse POE-SMO;
`Drewpone 80K; Durfax 80; Durfax 80K;
`Emrite 6120; E433; Glycosperse 0-20, Hodag
`PSMO-20, Liposorb 0-20), Liposorh G-20K;
`Montanox 80; polyoxyethylene 20 oleate; (Z)-
`sorbitan mono-9-octadecenoate
`poly(oxy-1,2-ethanediyl) derivatives;
`Protasork 0-20; Tween 80.
`Crillet 41; Hetsorb O-5; Hodag PSMO-5:
`sorbitan mono-9-oetadecenoate
`poly(oxy-1,2-ethanediyl) derivatives;
`Protasorb 0-5; Sorbax PMO-5; T-Maz 81;
`Tween 81.
`AlkamulsPSTO-20; Crillet 43; Glycasperse TO-
`20; Hodag PSTO-20; Lonzest STO-20;
`Liposorh TO-20; Montanox 83; sorbitan
`tri-9-octadecenoate poly(oxy-1,2-ethanediyl)
`derivatives; Protasorh TO-20; Sorbax PTO-20;
`Tween 85,
`Erillet 6,
`Polysorbate 120
`
`
`3, Chemical Names and CAS Registry Numbers
`See Table 1.
`
`Polyoxyethylene Sorbitan Fatty Acid Esters 417
`
`lizing agents for a variety of substances including essential
`oils and oil-soluble vitamins, and as wetting agents in the
`formulation of oral and parenteral Suspensions, Recently they
`have been found to be useful in improving the oral bioavail-
`tein.
`sballty of drug molecules that are substrates for p-glycopro-
`Polysorbates are also widely used in cosmetics and food products.
`
`Use
`Concentration (%)
`Emulsifying agent
`Used alone in oil-in-water emulsions
`
`Used in combination with hydrophilic
`emulsifiers in oil-in-water emulsions
`Used to increase the water-holding
`properties of ointments
`Solubilizing agent
`For poorly soluble active constituents
`in lipophilic bases
`Wetting agent
`01-3
`For insoluble active constituents in
`lipophilic bases
`
`
`ah
`1-10
`
`1-10
`
`8. Description
`Polysorbates have a characteristic odor and a warm, somewhat
`bitter taste. Their colors and physical forms at 25°C are shown
`below in Table II, although it should be noted that the ab-
`solute intensity of the products may vary from batch to batch
`and manufacturer to manufacturer,
`
`
`
`Table I: Empirical formula and molecular weight of selected
`paolysorbates.
`
`
`Polysorbate
`Formula
`Molecular weight
`Polysorbate 20
`CygHy yap
`1128
`Polysorbate 21
`CopHe909
`523
`Polysorbate 40
`CoA Or,
`1284
`Polysorbate 60
`CeHyrea,
`1312
`Polysorbate 61
`CyH209
`607
`Polysorbate 65
`Chooayo
`1845
`Polysorbate 80
`Cyn,
`1310
`Polysorbate 81
`Cute),
`649
`Polysorbate 85
`Choo asOon
`1839
`Polysorbate 120
`CoHyp6Ore
`1312
`
`
`5. Structural Formula
`
`CH,
`HEO(C,H,O),H
`HOCH,OCH
`HE
`HCO(C,H,O),H
`CH,O(C,H,0),0CR
`Polyoxyethylene sorbitan monoester
`
`?
`
`CH,
`|
`|
`HCO(CH,O),H
`RCO(OCH,),OCHwe—__f
`|
`HCO(C,H,0},0CR
`CH,0(C,H,0),0CR
`Polyoxyethylene sorbitan triester
`
`6. Functional Category
`Emulsifying agent; nonionic surfactant: solubilizing agent;
`wetting, dispersing/suspending agent,
`
` Polysorbate Synonym
`
`Armotan PML 20; Capmul POE-L; Crillet 1;
`Drewmulse; POE-SML; Durfax 20; E432;
`Glycosperse L-20; Hodag PSML-20; Lamesorh
`SML-20; Liposorh 1-20; Liposorh L-20K;
`Montanox 20; Nissan Nonion LT-221; Norfox
`Sorbo T-20; Sorbax PML-20; Sorgen TW-20;
`sorbitan monododecanoate; T-Maz 20 T-Maz
`20K; poly(oxy-1,2-cthanediyl) derivatives;
`Table I: Chemical name and CAS Registry Numberof selected
`polyoxyethylene 20 laurate; Protasorb 1-20;
`paolysorbates,
`Table IT; Color and physical form of selected polysorbates at 25°C,
`Tween 20,
`
`Polysorbate
`‘Chemical name
`CAS number
` Polysorbate Color and form at 25°C
`
`Crillet 11; Hodag PSML-4; Protasorb t-5; Tween
`2i.
`
`Polysorbate 20
`Polyoxyethylene 20
`[9005-64-53]
`Polysorbate 20
`Yellow oily liquid
`sorbitan monolaurate
`Crillet 2; E434; Glycosperse 5-20; Hodag PSMP-
`Polysorbate 21
`Yellow oily liquid
`20; Lamesorb SMP-20; Liposorb P-20, Lonzest
`Polysorbate 21
`Polyoxyethylene (4)
`[90054-5]
`Polysorbate 40
`Yellow oily liquid
`SMP-20; Mantanox 40, Pratasorb P-20,
`sorbitan monolaurate
`Polysorbate 60
`Yellow oily liquid
`sorbitan monohexadecanoate;
`Polysorbate 61
`Tan solid
`Polysorbate 40
`Polyoxyethylene 20
`[9005-66-7]
`poly(oxy-1,2-ethanediyl) derivatives; Sorbax
`Polysorbate 65
`Tan solid
`sorbitan monopalmitate
`PMP-20; Tween 40.
`Polysorbate 60
`Polyoxyethylene 20
`[9005-67-8]
`Polysorbate 80
`Yellow oily liquid
`sorbitan monostearate
`W+x4y +z = 20 (Polysorbate 20, 40, 60, 65, 80, and 85)
`Atlas 70K; Atlas Armotan PMS 20; Capmul POE-S;
`Polysorbate 81
`Amber liquid
`W+X 4+ y +2 =5(Polysorbate 81)
`Crillet 3; Drewpone 60K; Durfax 60; Durfax 60K;
`Polysorbate 61
`Polyoxyethylene (4)
`(9005-67-8]
`Polysorbate 85
`Amber liquid
`sorbitun monostearate
`W+X + y +2 = 4 (Polysorbate 21 and 61)
`Emrite 6125; E435; Glycosperse 5-20;
`
`Polysorbate 120 Yellow liquid
`Glycosperse 5-20FG; Glycosperse S-20FKG;
`R=fatty acid
`Polysorbate 65
`Polyoxyethylene 20
`[9005-71-4]
`Hodag PSMS-20, Hodag SVS-18; Lamsorb SMS-
`sorbitan tristearate
`20; Liposorb 8-20, Liposorb S8-20K; Lonzest SMS-
`Polysorbate 80
`Polyoxyethylene 20
`(9005-65-6]
`20; Nikkel TS-10; NorfoxSorboT-60Montanox 60;
`9. Pharmacopeial Specifications
`sorbitan monooleate
`Polycon T 60K; polyoxyethylene 20 stearate:
`
`Polysorbate 31
`Polyoxyethylene (5)
`(9005-65-6]
`sorbitan monooctadecanoate
`sorbitan monooleate
` Test JP PhEur USP
`
`
`
`poly(oxy-1,2-ethanediyl) derivatives; Protasorb S-
`[9005-70-3]
`Polysorbate 85
`Polyoxyethylene 20
`Identification
`20, Sorbax PMS-20; T-Maz 60; T-Max 60KHS;
`sorbitan trioleate
`7. Applications in Pharmaceutical Formulation or
`Tween 60; Tween GOK: Tween 60 VS,
`+
`+
`—
`Polysorbate 20
`[66794-58-9]
`Polysorbate 120
`Polyoxyethylene 20
`Technology
`
`
`Crillet 31; Hodag PSMS-4; Protasorb 8-4; Tween Polysorbate 40%==— — +
`
`sorbitan monoisostearate
`ol.
`Polysorbate 60
`—
`+
`+
`Polyoxyethylene sorbitan fatty acid esters (polysorbates) are
`Polysorbate 80
`+
`+
`+
`Alkaruds PSTS-20; Criller 35; E436; Glycosperse TS-
`4 series of partial fatty acid esters of sorbitol and its anhy-
`Saponification value
`20, Glycosperse TS-20 FG; Glycosperse TS-20
`drides copolymerized with approximately 20, 5, or 4 moles
`40-50
`40-50
`KFG:Hodag PSTS-20; Lamesorh STS-20;
`Polysorbate 20
`of ethylene oxide for each mole of sorbitol and its anhydrides.
`
`Polysorbate 40%==— — 41-52
`
`Liposorb TS-20; Liposorb TS-20K; Lanzet STS-20;
`The resulting product is therefore a mixture of molecules of
`Momanox 65, sorbitan trioctadecanoate
`Polysorbate 60
`-
`43-55
`45-55
`ical,
`varying sizes rather than a uniform mixture of a single chem-
`poly(oxy-1,2-ethanediyl) derivatives; Protasorb
`Polysorbate 80
`45-35
`45-55
`45-55
`4. Empirical Formula=Molecular Weight
`Hydroxyl value
`(STS-20, Sorbax PTS-20; T-Maz 65K; Tween 65;
`Approximate molecular weights for selected polysorbates are
`Tween 65K; Tween 65V8,
`Polysorbates containing 20 units of oxyethylene are hydro-
`Polysorbate 20
`—
`95-108
`96-108
`shown in Table II.
`Philic nonionic surfactants which are used widely as emulsi-
`Polysorbate 44) —
`-
`89-105
`fying agents in the preparation of stable oil-in-water
`Polysorbate 60
`_
`31-96,
`81-96
`Pharmaceutical emulsions. They may also be used as solubj-
`Polysorbate 80
`_
`65-80
`65-80
`
`
`
`
`

`

`
`
`
`
`t
`70 @0
`90 100
`60
`50
`40
`30
`Compression force (kN)
`
`i¢ h
`
`yo
`
`20
`
`Fig. 1: Compression characteristics of granular mannitol
`(Pearlitol, Roquette Freres).
`©): Pearlitol FG
`O: Pearlitol MG
`A: Pearlitol GG2
`Tablet diameter: 20 mm
`Lubricant: magnesium stearate 0.7% wiw for Pearlitol MG and
`Pearlitol GG2, magnesium stearate 1% w/w for Pearlitol FG
`
`‘oe
`
`35
`
`E
`"8
`3
`a1 8
`i
`“|
`> i
`a7
`
`6
`
`21
`18
`15
`12
`9
`Compression force (KN)
`
`24
`
`27
`
`30
`
`Fig. 2: 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
`
`
`
` oe
`
`
`234693°0«C«dsi‘icz CCH «100
`Relative humidity (%)
`
`Fig. 3: Sorption-desorption isotherm for mannitol.
`# >: sorption equilibrium moisture
`Wi: desorption equilibrium moisture
`
`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.{'5) In solution, mannitol
`is not
`attacked by cold, dilute acids or alkalis, nor by atmospheric
`oxygen in the absence ofcatalysts. 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% wiv
`or stronger, may be salted out by potassium or sodium chlo-
`ride.'!®) Precipitation has been reported to occur when a 25%
`w/v mannitol solution was allowed to contact plastic.!'7) So-
`dium cephapirin at 2 mg/mL and 30 mg/mLis incompatible
`with 20%w/v aqueous mannitol solution. Mannitol is incom-
`patible with xylitol
`infusion and may form complexes with
`some metals (Fe, Al, Cu). Reducing sugar impurities in man-
`nitol have been implicated in the oxidative degradation of a
`peptide in a lyophilized formation.('*) Mannitol was found to
`reduce the oral biovailability of cimetidine compared to su-
`crose,(19)
`
`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 selec-
`tive solvents. It is commercially produced by the catalytic or
`electrolytic reduction of monosaccharides such as mannose
`and glucose,
`
`(%)
`
`
`
`Weightoversize
`
`Median size = 8Bum
`
`0
`
`40
`
`100
`80
`Particle diameter(um)
`
`160
`
`200
`
`Fig, 4: Particle size distribution of mannitol powder.
`
`pacndntinsy
`
`14. Safety
`Mannitol
`is a naturally occurring sugar alcohol found in an-
`imals and plants; it
`is present in small quantities in almost
`all vegetables. When consumedorally in large quantities, lax-
`ative effects may occur.!If used in foods as a bodying agent
`and daily ingestion of over 20g is foreseeable,
`the product
`label should bear the statement ‘excessive consumption may
`have a laxative effect’. After intravenous injection, mannitol
`is not metabolized to any appreciable extent and is minimally
`reabsorbed by the renal
`tubule, about 80% of a dose being
`excreted in the urine in 3 hours,'2!)
`A numberof adverse reactions to mannitol have been reported
`Primarily following the therapeutic use of 20% w/v aqueous
`intravenous infusions.2?) The quantity of mannitol used as an
`excipient
`is considerably less than that used therapeutically
`and is consequently associated with a lower incidence of ad-
`Verse reactions. However, allergic, hypersensitive-type reac-
`‘ons may occur when mannitol
`is used as an excipient.
`An acceptable daily intake of mannitol has not been specified
`by the WHO since the amount consumed @8 a sweetening
`‘gent was not considered to represent a hazard to health.(23)
`LDso (mouse, IP): 14 g/kg)
`LD.) (mouse, IV): 7.47 g/kg
`LDso (mouse, oral): 22 g/kg
`LDso (rat, TV): 9.69 g/kg
`b . LDso (rat, oral): 13.5 g/kg
`
`
`
`Mannitol 327
`
`-
`15, Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Mannitol may be irritant to
`the eyes; eye protection is recommended.
`
`16. Regulatory Status
`GRASlisted. Accepted for use as a food additive in Europe.
`Included