`
`
`
`Handbook of
`
`PHARMACEUTICAL
`
`EXCIPIEN TS
`
`
`Third Edition
`
`Edired by
`
`Arthur H. Kibbe, Ph.D.
`Professor and Chair
`Deparlmenl of Pharmaceutical Sciences
`Wilkes Univershy School of Pharmacy
`Wilkes-Barre Pennsylvania
`
`@
`
`American Pharmaceutical Aswriaiinn
`Washington. D.C.
`
`London, United Kingdom
`
`MAIA Exhibit 1035
`
`MAIA V. BRACCO
`
`
`
`
`MAIA Exhibit 1035
`MAIA V. BRACCO
`IPR PETITION
`
`

`

`Published by the American Pharmaceutical Association
`2215'C0nstitution Avenue NW, Washington, DC 20037-2985, USA
`www.aphanet.org
`and the Pharmaceutical Press
`1 Lambeth High Street. London SE1 "MN. UK
`wwwpharmpresscom
`
`® 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—91i330-96-X (USA)
`
`Library or Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients I edited by Arthur H‘ Kibbc.—~3rd ed.
`p‘
`: cm.
`Includes bibliographical references and index.
`ISBN 0—9li330-96—X
`1. Excipients--Handbooks, manuals, etc.
`Pharmaceutical Association.
`[DNLM:
`l. Excipients--Handbooks, QV T35 H236 2000]
`RSZOIEST H36 2000
`615'.19--dc21
`
`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, wilhout the prior written permission of the copyright holder. The publisher makes no representation, express or
`implied, with regard to the accuracy of die information contained in this book and cannot accepl any lcgal responsibility or
`liabilily for any errors or omissions that may be made.
`
`Managing Editor: Melanie Segala
`Copyeditor:
`Paui Gottehrer
`Indexer:
`Lillian Rodberg
`Compositor:
`Roy Barnhill
`Cover Designer:
`Tim Kaage
`
`
`
`
`

`

`*—
`324 Marietta!
`
`Marmt'ml 325
`
`
`
`Mannitol
`
`l. Nonpruprletary Names
`BP: Mannitol
`JP: o-Mannite
`PhELir: Mannitolum
`USP: Mannitol
`
`2. Synonyms
`Cordycepic acid; E1421. D-mannitol: manna sugar: mannite:
`
`3. Chemical Name and CAS Registry Number
`o-Mannitol [69-65-81
`
`4. Empirical Formula Molecular Weight
`132.1?
`
`5. Structural Formula
`
`cope
`HO—fi'i—H
`HD—CI—l-l
`H—(II—UH
`H—(IZ—UH
`its“
`
`ti. Functional Category
`Sweetening agent: tablet and capsule diluent: tonieity agent:
`vehicle (hulking agent] for lyophilizetl preparations.
`
`1. Appllcatlom 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% wtw) in tablet formulations. where
`it is of particular value since it
`is not hygroscopic and may
`thus be used with moisture-sensitive active ingredients.
`Mannitot may he used in direct-compression tablet applica-
`tions."'5l for which the granular and sprayvdried forms are
`available. or in wet granulations.“’ Granulations containing
`maunitol have the advantage of being dried easily. Specific
`tablcl applications include antacid preparations. glyceryl trin-
`itrate tablets. and vitamin preparations. Mannitol is commonly
`used as an excipient
`in the manufacture of chewable tablet
`formulations because of its negative heat of solution. sweet-
`ness. and ‘mouth feel’IW
`In lyophilizcd preparations. rnannitol (20-90% wtw} has been
`included as a carrier to produce a stiff. homogeneous cake
`
`that improves the appearance of the lyophilized plug in a vi-
`al.“"123 A pyrogen-free form is available specifically for I
`5
`
`
`
`
`Mannitol has also been used to prevent thickening in aqueous
`antacid suspensions of aluminum hydroxide t4 7% wlv).
`[I
`has been suggested as a plasticizer in soft-gelatin capsules.
`as a component of susrained-rclease tnhlet formulations.“31
`and is used in food applications as a bulking agent.
`Therapeutically. mannitol administered purenterally is used as
`an osmotic diuretic. as a diagnostic agent for kidney function.
`as an adjunct
`in the treatment of acute renal failure and as
`an agent to reduce intraeranittl pressure. treat cerebral edema.
`and reduce intraocular pressurc. Given orally. mannitul
`is not
`absorbed significantly from the GI tract. hut in large doses it
`can cause osmotic diarrhea. see Section 14.
`
`8. Description
`Mannitol is u-mannitot. It is a hexahydrie alcohol related to
`mannuse and is isomeric with sorhitol.
`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
`othorhornhic needles when crystallized from alcohol.
`
`9. Pharmacopeial Specifications
`
`
` TB! JP PhEttr USP
`
`
`Identification
`+
`+
`+
`Characters
`+
`+
`—
`Solution appearance +
`+
`—
`Melting range
`res—159°C
`lbfi-lTOT
`ind—169°C
`Specific rotation
`+131“ to +145“ +23‘ to +25“ +13?“ to “as;
`Acidity
`+
`+
`+
`Loss on drying
`s 0.30%
`s 0.5%
`s 0.3%
`Chloride
`S 0.00???
`S 50 ppm
`5 0.007%
`Sulltuc
`S 0.0M-
`S [m ppm
`S 0.0m
`Arsenic
`S l.3 ppm
`—
`S l ppm
`Lead
`—
`S 0.5 ppm
`—
`Nickel
`+
`S 1 ppm
`-—
`Heuvy metals
`5 5 ppm
`—
`—
`Reducing sugars
`+
`+
`+
`Sulfuted ash
`5 (MM:
`5 fl. [1-
`—
`Sorbitol
`—
`s 2.0%
`—
`Bacterial :ndotortins
`—
`+“‘
`—
`
`its-101.5%:s 98.0%Assay 96-1015‘h
`
`
`
`"' Ttst applied only if the mannitol is to be used in die manufacture of
`palmlflt‘llill dosage forms.
`
`10. Typical Propertlu
`1 and 2.!"1
`Compresst'billry: see Figs.
`Density (bulk): 0.430 glcm’m for powder: 0.? gtcmm" for
`granules.
`Density {tapped}: 0.734 glcillw” for powder: 0.3 gtcm’l‘” f‘"
`granules
`Density (true): 1.514 gtcm‘"ll
`Dissertation constant; pK. = 13.5 at IS°C
`_
`Flash point: > ISOT
`Flatt-ability: powder is cohesive. granules are free flowing-
`Heat of combustion: “5.5? thg {3960 calt'g}
`Heat of solution: 420.9 Itg (-28.9 ealtg} at 25°C
`Melting point: lfifi-lfiBT
`Moisture content: see Fig. 3.01
`
`SEM: I
`Ereipiient; Memorial
`Manufacturer: Merck
`Mzartifiottl'mn: 50K
`Vallagc: 3.5 kV
`
`SEM: 3
`F—xrintettt: Mauuitol ptmtdcr
`Manufacturer. SPI Polyrvlt. Inc
`Int Nu: 314063
`Magmhearimt: Imx
`
`'
`
`
`
`SEM: 2
`Eacipiertt: Mntrttilot
`
`Mmtufactumr: Merck
`Magnification 500x
`when: 3.: tv
`
`SEM: 4
`incipient: Mamillnl. granular
`Manufaclurer SP1 Panels. Inc
`Lot No: ZOE-tl-‘ll
`Magnification: Ioox
`
`
`
`
`
`Oa'ntolart'ry: a 5.0m wtv aqueous solution is iso-osrnotie with
`serum.
`
`Particle size distribution: maximum of 0.1% greater than 500
`l-ll'D and minimum of 90% greater than 200 got in size for
`Pearlitpt 300 DC; maximum of 20% greater that: 500 pm
`and rrunimum of 35% greater than 100 ttrrt
`in size for
`Feminist-400 DC: maximum of 0.5% greater than 84! um
`it"! t'nlturnum of 90% greater than 150 pm in size for
`earlrtal' 500 DC. Average particle diameter is 250 ].Im for
`Eating! 300 DC. 360 pm for Peortt'tal 4'00 DC and
`llm for Fearlt'tdt 500 OCH" See Fig. 4-."J
`_'R¢froctt've index: num = I333
`
`Solubility: see table below.
`Solvent
`Solubility at 20°C
`Allal'ts
`Soluble
`Ethanol {95%)
`I
`in 83
`Falter
`Practically insoluble
`Glycerin
`l
`in l3
`Pmpan-I-ol
`l
`in 100
`Water
`|
`in 5.5
`
`Specific surface area: 0.31-0.39 mlt’g‘m
`W Handbook of Phamoceuticol Erefipietlfl. First Editian
`'31 Results or laboratory project for third edition.
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`__'__—_—_.
`
`- /
`
`__._L_J,,_I_—I—-|—|—L—l-—
`00102030405050709090100
`Cowmreaabnlomelml
`
`
`
`12
`
`10
`
`
`
`Moratu'recontain{'56}
`
`sh
`
`a:m M
`
`or
`233343 5257
`Flela’dvetmnidlwl‘lél
`
`75100
`
`rng. 1: Cowman:- character-Mics or ennui-r manniml
`(Moi. Raquela ml-
`0 ‘. Peat-{ital FG
`Cl : Peariiml MG
`A : Pmrlt'ral 662
`Tablet diameter: 20 mm
`Lubricant: magnesium stem 0.7% whv for Familial MG and
`Pearlitol 662. magnesium steamte 1% wlw' for Peat-lira! F6
`
`Fig. 3: Surgeon-desorption Isotllmn for mannitnL
`O : sorprion equilibrium moisture
`l : desorption equilibrium moisture
`
`as
`
`'
`33
`
`3.1
`
`2.9
`
`2.7
`
`“
`
`_-—E
`
`
`
`Tabletbreakingthicknesslrnm}
`
`
`
`
`
`Weight
`
`musizaWe}
`
`Median size = Bel-H11
`
`°o36912151a21242r30
`Compression farce {RN}
`
`Fig.2:Compt-mioncitmcterlaflesafgranuiarmamltol.
`Mean tablet weight: 500 mg
`Minimum compressional force for compaction: 7.35 kN
`Compressional force resulting in capping: M5 ItN
`
`a
`
`4n
`
`100
`so
`Particle alarnmar tum}
`
`160
`
`20“
`
`Pig. 4: Pardde she distribution or mannitnl powder-
`
`11. Stability and Storage Conditions
`Mannilu] is stable in the dry state and in aqueous solutions.
`Solutions may be Slerilized by filtration or by autoeiaving and
`if necessary may be antoelaved repeatedly with no adverse
`physical or chemical effects.”“ 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 built material should be stored in a well—closed container
`in a cool. dry. place.
`
`12. Inmmpatibilities
`None reported in the dry state. Mannitol solutions. 209l- wlv
`or stronger. may he salted out by potassium or sodium chlo-
`ride.""'} Precipitation has been reported to occur when a 25%
`win mannilol solution \vas allowed to contact plastic.""1 50-
`dium cephapirirt at 2 mga’mL and 30 mgirnl. is incompatible
`with 20% wiv aqueous mannilol 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 oxidalive degradation of a
`peptide in a Iyophilized formationdm Mannitol was found to
`reduce the ornl biovailability ol' cimetidine compared to su—
`cussed-193
`
`13. Method of Manufacture
`
`Mannitol may be extracted from the dried sap of manna and
`other nalura] sources by means of hot alcohol or other selec-
`tive solvents. It is commercially produced by the catalytic or
`electrolytic reduction of monosaccbarides sucl! as mannose
`and glucose,
`
`.asst-"ona-
`
`14. Safety
`Mannilol
`is a naturally occurring sugar alcohol found in an—
`imals and plants: it
`is present in small quantities in almost
`all vegetables, When consumed orally in large quantities. lax—
`nliVe effects may occur!“ If used in foods as a hodying agent
`and daily ingeslion of over 20g is foreseeable.
`lite producl
`label should bear the statement 'excessive consumption may
`have a laxative effoct'. After intravenous injection, mannitol
`is not metabolized to an}‘ appreciable extent and is minimally
`reabsorbed by Ihc renal
`tubule. about 30% of a dose being
`excreted in the urine in 3 hour-5.9"
`A number of adverse reactions to mannitol have been reported
`Primarily following the therapEutie use of 20% wlv aqueous
`i11l.t‘a\«'enolls infusionsml The quantity of Inannitol used as an
`elicipient
`is considerably less than that used therapeutically
`aml is consequently associated with a lower incidence of ad-
`Vlet‘se reactions. Hewever. allergic. hypersensitive-Iype reac—
`uons may occur when mannitol
`is used as an exeipienl.
`tin acceptable daily intake or rnannitol has not been specified
`hi“ lhe WHO since the amount consumed as a sweetening
`“E6111 was not considered lo represent a hazard to healthfm
`LB,“ (mouse. IP):
`l4 gfkglz‘l
`LD” (mouse. IV): 7.4? gfltg
`“3m (mouse, oral): 22 glitg
`LDsn (rat. 1V): 9.69 gflrg
`-__ LDso (fat. oral): I15 grit:
`
`'
`
`Manm'l'al' 327
`
`'
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Maunitol may be irritant to
`the eyes; eye protection is reeommendod.
`
`16. Regulatory Status
`ERAS listed. Accepted for use as a food additive in Europe.
`Included in the FDA Inactive ingredients Guide ([P, 1M. 1V.
`and SC injections. infusions. bueeal. oral and sub-lingual tab-
`lets and capsules). Included in nonparenleral and parenteral
`medicines licensed in the UK.
`
`11'. Pharmacopeias
`China. Eur. Int. Jpn. Pol. and US.
`18. Related Substances
`Sorbi'tol.
`
`19. Comments
`Mnnnitol is an isomer of sorbitot. the dilTerence between the
`two polyols occurring in the planar orienlation of the OH
`group on the second carbon atom. Each isomer is character-
`ized by its own individual set of properties, the most impor-
`tant difference being the response to moisture. Sorbilol
`is
`hygroscopic while mannitol resists moisture sorptiort. even at
`high relative Ilumidilies.
`Granular ntartnitol news well and imparts improved llow prop-
`erties to other materials. However. it usually cannot be used
`with concentralions of other materials exceeding 25% by
`weighl. Recommended levels ol‘iubricartt are 1% why calcium
`stearate or
`l—Z‘Rn
`\ll'N magnesium slearale. Suitable binders
`for preparing granulations of powdered n'tartnilol are gelatin,
`methylceliuiose 400. starch paste. povidone. and sorbilol.
`Usually. 3-6 times as much magnesium slearate or I.5-3 times
`as much calcium stearate is needed for lubrication of mannitol
`granulations than is needed for other exeipicnts.
`Mannitol has been reported to sublime at 130°C!“
`
`20. Specific References
`l. Kanig JL. Properties ol' fused manuitttl in compressed tablets.
`J Phamr Sci 1964: 53: 188492.
`2. Ward DR. Lalhrop LB, Lynch Ml. Dissolution and compat-
`ibility considerations for the use of mannitol in solid dosage
`forms. J Phone Sci 1969: 58:
`l464-l46‘l'.
`3. Ghancrn AH. Salt! FM. Abdel-Ghany 5. Mechanical and
`physical properties of sulfamelhoxazok-manu'tlol solid dis-
`persion in tablet form. 21cm ”mm Faun I936: 95: lé‘l-l‘l'l.
`4. Dehurd B, Lci'cbvre C. Guyot—Hermann AM. Hubert I.
`Bouche R. Guyot JC. Study of different crystalline forms of
`mannitol: comparative behaviour under compression. Drug
`Dev ind Phorm IS‘S'J‘:
`l3: lSJS-l546.
`5. Molokhia AM. AI-Shora HI. Hammad AA. Aging of tablels
`prepared by direct compression of bases with different mois-
`ture content. Jill-us flew l'nri Filmer I98?; 13: 19334946.
`6. Mendes RW. Gall S. An CQ. Wet granulation: a comparison
`of Manni-Tab anrl mannitol. Drag Comer ind 1978-:
`l22(3l:
`36. 38. 40. M. Bil—SS.
`‘l'. Daoust RG. Lynch Ml. Mannitol in chewable tablets. Drug
`Cosme! l’l'td I963: 93(1): 26-28. 33. 92. 123-129.
`8. Herman J. Remon ll“. Aluminium-magnesium hydroxide lab-
`lets: effect of processing and coutpositiou of granulating
`solution on the granule propenies and in vitro antacid per—
`romance. Drug Dev had Phnmt I933: I4: I22I-I23‘i.
`
`
`
`
`
`
`

`

`—————
`
`328
`
`Mannitot
`
`10.
`
`ll.
`
`[2.
`
`13.
`
`14.
`15.
`
`lo.
`
`[7.
`
`18.
`
`Couriel B. Advances in lyophilization technology. Buil‘
`Par-enter Drug Assoc 1977; 31: 227-236.
`Williams NA. Lee Y. Polli GP. Jennings TA. The effects of
`cooling rale on solid phase transitions and associated vial
`breakage occurring in frozen mannitol solutions. J Parenter-
`Sci Technol l986; 40: 135-14].
`Stella VJ. Umprayn K. Waugh WN. Development of
`parenteral fonnulations of experimental cytotoxic agents. 1:
`rhizoxin (NSC-332598), Int J Pharmaceutics 1938; 43:
`[91—199.
`Williams NA, Dean T. Vial breakage by frozen mannitol solu-
`tions: correlation with thermal characterislics and effect of
`stereoisomerism. additives. and vial configuration. J' Pal-enter
`Sci Techno! 1991: 45: 94-100.
`Farah PV. 0h CK. Ritschel WA. Sustained release from Pre—
`cirol (glycerol palmito—stearale} matrix. Effect of rnannitol
`and hydroxypropyi methylcellolose on the release of theo-
`phyllinc. Drug Dev ind Pharm 1986:
`I2: 809-1327.
`Roquclle Fréres. Technical literature: Peariiroi. 1997,
`Murty BER. Kapoor JN. Properties of mannitol
`injection
`(25%) after repeated autoclavings. Am J Hosp Phone 1975'.
`32: 326—827.
`Jacobs .i. 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 1973: 35: 1337.
`Dubost DC. Kaufman M]. Zimmerman JA. Bogusky MJ.
`Coddington AB. Pitzenberger SM. Characterization of a solid
`state reaction produccl from a lycphilized formulation of a
`
`cyclic heptapepttde. A novel example of an excipient-induced
`oxidalion. Pharm Res 1996; 13; ISM—[314.
`19. Adkin DA. Davis SS. Sparrow RA, Huckle PD. Wilding IR.
`The effect of mannitol on the oral bioavailabilily of cimeti-
`dine. J Pharm Sci 1995: 84: 14054409.
`20. Flatulence. diarrhoea. and polyol sweeteners. Lancet 1983;
`ii: 1321.
`21. Porter GA. et al. Mannitol hemodilution-perfusion: the kinet—
`ics of rnannitol distribution and excretion during cardiopul-
`monary bypass. J Surg Res 1967; 7: 447—456.
`22. McNeil] IY. Hypersensitivity reaction to mannitol. Drug
`intei'i Ciin Pharm 1935; 19: 552-553.
`23. FAOIWHO, Evaluation of certain food additives and contam-
`inants: thirtieth report of the joint FACIIWHO expert com—
`mittee on food additives. Tech Rep Ser Wid' Hith Org 1987;
`No. 75].
`24. Sweet DV, editor, Registry or'i‘oxic Effects of Chemical Sub-
`stances. Cincinnati. US Department of Health. [987.
`25. Weast RC. editor. Handbook of Chemistry and Physics. 60th
`edition. Boca Raton. CRC Press Inc.. 1979: c—369.
`
`21. General References
`Czeisler JL. Perlnian KP. Diluents. 1n: Swarbriclr J. Boylan Jc.
`editors. Encycl'opedio of Pharmaceuticai Technoiogy. volume
`4. New York. Marcel Dekker. I988; 37—84.
`
`22. Authors
`
`NA Armstrong. GE Reier.
`
`
`
`
`
`
`

`

`————.
`
`518 Sal—blip!
`
`15. Handling Precautions
`May be 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
`GRAS listed. 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 and tablets. rectal. topical. and vaginal preparations).
`Included in parenteral and nonparenteral medicines licensed
`in the UK.
`
`17. Pharmacopeias
`China. Eur. Jpn. Pol. and US.
`
`13. Related Substances
`Mannitol: sorbitol solution 70%: nylitol.
`Sorhitol solution 70%
`Synonyms: sorbitol liquid; Sorbo.
`Appearance: a clear. colorless and odorless viscous liquid.
`Phannacopeias: US.
`Comments: sorbitol solution is an aqueous solution of hydro-
`genated. partly hydrolyzed starch. For physical properties
`see Table I.
`
`Table 1: Physical properties of sorbitol in water solutions.
`Concentration
`Density
`Viscosity
`Refractive
`Freezing
`1% win)
`[glc'm3}
`{mPa 5)
`index
`point.
`
`at 25°C
`at. 25°C
`at 25°C
`(’0
`10
`1.034
`1.2
`1.343
`-1.1
`20
`1.073
`1.?
`1.365
`-3.8
`30
`1.114
`2.5
`1.333
`-8.0
`40
`1.155
`4.4
`1.400
`—]3.0
`50
`1.197
`9.1
`1.418
`—26.0
`60
`1.241]
`26.0
`1.43?
`—
`'11}
`1.293
`110.0
`1.453
`—
`80
`1.330
`900.0
`1.413
`—
`
`
`19. Comments
`
`Sorbitol may be substituted for sucrose to prepare 70—90%
`wiv syrups.
`Several different grades of sorbitol. with different polymor-
`phic fonn. particle size. and other physical characteristics are
`commercially available. e.g.. Neosorb (Roquette Fréres). Py—
`rogen—free grades are also available from some suppliers.
`
`211. 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 Phorrn 1932: 3:
`283-292.
`
`2. Bolton S. Atlun‘ R. Crystalline sorbitol tablets: effect of mix-
`ing time and lubricants on manufacturing. Drug Cosme: 1nd
`1984: 135(5): 44, 46. 4'1. 48. 50.
`3. DuRoss 1W. Modification of the crystalline structure of sor—
`bitol and its effects on tablcting characteristics. Pharmaceur
`Technol 1984: 8(9): 42—53.
`— an excipient
`instant
`4. Basedow AM. Moschl GA. Sorbitol
`with unique tableting properties. Drug Dev ind Pharm 1986;
`12: 2051—2089.
`5. Schmidt PC. Vortisch W. Influence of manufacturing method
`of fillers and binders on their tableting properties: compari-
`son of B commercially available sorbitols [in German].
`Piramt ind 1987; 49: 495-503.
`liquids.
`in pharmaceutical
`6. Daoust RG. Lynch Ml. Sorbitol
`Drug Cosme! ind 1962; 90(6): 689-691. 173. 7'16. 7‘17. 779.
`181—785.
`T. Sabatini GR. Gulesich JJ. Formulation of a stable and pal-
`atable oral suspension of procaine penicillin G. J Am Pharm
`Assoc (Pr-act Pizarro) 1956; 17: 806—308.
`8. Bandelin Fl. Tuschhoff IV. The stability of ascorbic acid in
`various liquid media. J Am Pitamt Assoc (Sci) 1955: 44'.
`241—244.
`9. Parikh ED. Lofgren W. A further stability study of an oral
`multivitamin liquid preparation. Drug Standards 1958; 26:
`56—61.
`10. Lindvall S. Andersson NSE. Studies on a new intramuscular
`haematinic, iron—sorbitol. Br J Pharmacoi 1961‘. I'l': 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.
`Iain NK. et a1. Sorbitol intolerance in adults. Am J' Gastro-
`ertteml 1935: 30: 678—681.
`I3. Brown AM. Masson E. ‘Hidden' sorbitol in proprietary med—
`icines — a cause for concern? Phat-in J 1991); 245: 211.
`14. Ayers CS. Abrams RA. Noncariogcnic sweeteners: sugar sub-
`stitutes for caries control. Demo! Hygiene 1987; 61: 162-167.
`15. Sweet DV. editor. Registry of Toxic Effects of Chemical Sub-
`stances. Cincinnati. US Department of Health. 193?.
`
`1?.
`
`21. General References
`Barr M. Kohl-i SR. Tice LF. The solubility of sorbitol in hydroal-
`coholic solutions. Am J Pharm 1957'. 129: 102-106.
`Blanchaf'd J. Fink WT. Duffy JP. Effect of sorbitol on interaction
`of phenolic preservatives with polysorhate 81]. J Phat-m Sci
`19’”: '66: 1470-1413.
`Burgess S. Sorbitol instant: a unique excipient. Mfg Chem 1983':
`58(6): 55. 57. 59.
`Collins J. Metabolic disease:
`time for fructose solutions to go.
`Lancer 1993: 341: 600.
`Rabinowitz MP. Reisberg P. Bodin .T‘l. GLC assay of sorbitol as
`cyclic ri—butylboronate. J’ Pharm Sci 1974; 63: 1601—1604.
`Roquetle Fréres. Technical literature: Neosorb-sorbito]. 1992.
`Shah DN. White 11.. Hern SL. Mechanism of interaction between
`polyols and aluminum hydroxide gel. J Pharm Sci 1981; 70:
`1101-1104.
`Zatz .lL. Lue R-Y. Flocculation of suspensions containing non-
`ionic surfactants by sorbitol. J Pitarm Sci 1987; 75: 157-1611
`
`22. Authors
`RA Nash.
`
`
`
`
`

`

`4M Polyoxyethytm: Serbian: Furry-leis Esters
`
`
`
`Polyoxyethylene
`Sorbitan Fatty Acid
`
`1. Nonl'mln'lelary Names
`3?: Polysorbatea 20‘ 50, and SO
`IF: Polysorbale 80
`PhEut': Polysot‘batum 20. 60. and 310
`USP: Polysorbates 20. 40. 60. and 30
`
`Synonyms of selected pnlysorbntes :Lte shown below. see also
`
` momma Symon
`
`
`Amman PML 30: Samurai FOE-L: Cn'licl' i".
`memirise.‘ POE-SML: Duifnx 20: 5-132:
`Glycosperse t-Zfi': Hades PSMLZO: taut-esprit
`smrzo; lu'potrorb 1:29; liposorh L-ZOK:
`Montana): 20: Nissan Maintain Mini.- Noah:
`3::er 7-20; Sat-bat PHIL-20: Sages Till-29:
`sorbitan monododeeanoale: T—Maz 20 Flu:
`20K; poly(on-l .Z-ethanediylj derivatives;
`polyoxyediylene on laurate; Protamrb t-er:
`'llo'cert 2i].
`Critter ti: Hating PSML4: Fmasorh b5: il'lweil
`21‘.
`Grille: 2: E434: Citywxperse 5-20: Hadug MM.“-
`20: Lamstodt SMPAZU: Uposner-201hmzcst
`SMP-ZO: Montana: 45". Premonb P-ZO:
`sorbium monoliexndecanoatc'.
`polyinxy-l .2velhancdiyll derivatives; Smilax
`PEP-20: flit-zen 4‘0.
`Aunts WK: Atlasalnnomn PMS” Capt'nul P055:
`Critter 3: £37an 60K: Mammoth: 60K:
`Entire 6:25; 5435; Gimme: 5-20.
`Gimsperse S-ZEIFS; (Fixes-pews: S—IOFKG:
`Haring PSMS‘M Moduli SVS—lS.‘ Matted: SMS-
`20: Um 5-20: “posed; S—IQK; latices! 5M5—
`2&NiMTS—l0:Noqho-SarhaT-60Mmmnw6&
`Palms T60 K: potyoayetliylene 2U mom:
`sorbilan nioriooctadeonmm
`polflotty-lJ-cll'tanediyl) amino-s; Foxes-art: s-
`20. sgm PMS-2D: FMaz 60: T—Mnr GDKHS:
`Thu-n 60; Them-60K: mm VS.
`Cn'ltetji: Hating PSMSJ; Fmtnrorb S4; Tween
`6L
`AWulvPSIS-N: Ciilletjj: E436: (throwers: Mr
`20; Glycogen: 73-20 FEE: Simm- 33-20
`KFG:HDdag P9349. buttered: MEG:
`moms 13.2% towers mans; {comm-20;
`Mom 65; mtbitatt lriouadocanoate
`polyioxy-IJ-euiamdiyl) derivatives: mm
`573320: Samba: m-zo; FMaz 651: 3‘1»th 66:
`Mn- O'SK: mm 6515.
`
`
`{Continued}
`Polysorbate
`Polysorbale 80
`
`'
`
`Synonym
`altl'm E; Air-moron mo 29-, Connie! POE-D:
`Critic: 4: CritietSil: Dirk-mitts: POE-5M0:
`Diem-pane 80K: ”ll-051: 50: Outfit: 80K.-
`Emrilzfii'lo: Ell-33: Glycospersz 0-25". Hm:
`PSMUJO: Lipotton‘: 0‘20: Upcmrb 0-2EI'K:
`Manta-no: 80: polyoxyelhylene 20 cleats: (Z)-
`sotrb'llan mono-Q-nctadccenonte
`polyioxy-IJfitinnettlyJ] derimives:
`Pmrasoro 0-20: Ween 30.
`Critic: 4i: “stroll: 0-5: Hades P-WO-S'.
`norbitun mono-Q-Dcutdecenoue
`pnlykuy- l.2-ethanediyl) derivatives:
`Pmtasori: 0-5: Sat-box HMO-5: T-Mti: 8i:
`Timer: BL
`AttonrultPSi'U-M; Critic: d5: Gl'ycosperse T0-
`20: Hating PSTO-Zfl: 1!»!th STO‘ZG.‘
`Lipotorb- TOAZO: Mowinnux 85: sort-itch
`tr't-g-octadcc: noate polyioxy-l .Z-etlmnediylt
`derivatives: Pmmrarb I’D-20‘ Samba! PTO‘ZE'.‘
`Them 85.
`Cirillo: n.
`Polysorbnte 120
`
`
`Folysorbnte Bl
`
`Polysorbste 85
`
`3. Chemical Names and CAS Registry Numbers
`See Table l.
`
`'llabte 1: Chemical name and CAS Registry Number of selected
`polysarbales.
`
`Payout-bate
`Chemical nun!
`CA5 number
`
`Poiysntbate 20
`Polyoayetliylcne 2|}
`[9005-64-5]
`mitan inooolnurale
`Folysorbate 2i
`Polyoxycfltyicnc {4)
`[9035-64-5]
`wrbitan monolnurale
`Folysorlaute 40
`Polymyethylcnc 20
`[WE-6617]
`sorbitnn monnpalmilalc
`Polysorbnte 60
`Pclyoxyethylene 20
`19005-618]
`sorbitan mtcarate
`Polysomatc 6]
`Polyoxyethylenc (4}
`{mi-éi-Sl
`EOrlJilJlJ! monastcaralc
`Polysorbote 65
`Folyoxyelhyiene 20
`[9005-11-41]
`sorbilsn trim-state
`Polysorbate ED
`Polyoxyelhylene 3.0
`[9005-65-61
`sorbilan nicnooleatc
`Polysorhatc SI
`Polyoxyelliylcne t5:
`l‘JODS-E-S-fi]
`sothitan monooleate
`Polyoxyetliylene 2|]
`mitan Irioleale-
`Poiyoxycthylene '20
`sorbltan monoisostearaie
`
`Folysorbate SS
`Folysorbnte IZO
`
`[9005-1‘04]
`[06794-583]
`
`4. Emplrlcal Formula Molecular Weifllt
`Approximate molecular weights for selected polysorhales all:
`shown in Table ll.
`
`
`
`Table I]: Empirical female and molecular weight or selected
`polymrbalest.
`
`
`
` Polymrbate Formula Molecular weight
`Polymbnte 20
`ammo“
`ms
`Polysotbate 2!
`(32,11me
`573
`Palysothall: 40
`cuttmoas
`1234
`Polysorbat: 60
`Cwueog‘
`l312
`Polysorhatc 6]
`£3,11qu
`60?
`Polysutbalc as
`cwumoz,
`tats
`Folysm‘bnt: so
`Cullmom
`1310
`Polywrbate SI
`Cpl-ho”
`i549
`Polysorbate as
`CIWHMDH
`mo
`
`CummingsPolysor'batc 120 1m
`
`
`5. Structural Formula
`
`'5'”;
`Hrlcoigigow
`utogn‘gxo‘cnHC —————?
`|
`HFOIC,H.0),H
`CHIOfC:H.O]‘0CR
`Poiyoxyisliylenc sorbitan monomer
`
`Cl—I
`3
`l
`’
`H$0(C2H‘0)*ll
`momenta?m: ___J’
`|
`scotcnotocs
`cttzoccztt‘oyom
`Poly-oxyalrylem sorbitan Iriester
`
`w + x i- y 1- z = 2!] (Polysorhalc 20. 4D. 60. 65, 30. and 85)
`w + x + y +2 = 5 (Polysorbale 81}
`w + x + y +2 = 4 (Polysorhate 2] and (II)
`R 2 fatty acid
`
`6. Functional Category
`Emulsifying agent: nonionic surfactant; solubilizing agent;
`wetting. dispersingtsuspertding agent,
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Folyoxyutllylenc sorbitan fatty acid esters (polysorbales) are
`a Series of partial fatty acid esters of sorbitol and its anhy-
`drides copolymcrlzed with approximately 20. 5. or 4 moles
`of ethylene oxide for each mole of sotbitol and its anhydridcs.
`The resulting prstL‘t is therefore a mixture of molecules of
`ical.
`varying sizes rall'tcr than a uniform mixture or a single chem-
`
`Polysorbates containing 20 units of oxyetliylene are hydro-
`philic nonionic surfactants which are used widely as emulsi-
`fying agents in the preparation of stable oiI-En—water
`le‘maceutical emulsions. They may also be used as solubi-
`
`Palyogetltylen: 50erth Fatty Acid Esters 4i?
`
`Iixing 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.
`ability of drug molecules that are substrates for p-glyeopro
`
`Polysmbates are also unduly used in cosmetics and food producer.
`
`
` Use Concentration [5%)
`Emulsil‘ying agent
`Used alone in oil-iu-water emulsions
`l-IS
`
`Used in combination with hydrophilie
`I- It)
`emu
`fiers in oil-in-wster emulsions
`Used to increase the water-holding
`I-ll)
`properties of ointmenls
`Solubilizing agent
`For poorly soluble active constituents
`in Iipopllillc bases
`Mills agent
`0.1-3
`For insoluble active constituents in
`lipophitic hoses
`
`
`1-10
`
`8. Description
`Polysorbates have a characteristic odor and a wann. somewhat
`bitter taste. Their colors and physical forms at 25°C are shown
`below in Table III. allliough it should be noted that the ab-
`solute intensity of the producLs may vary from batch to hatch
`and manufacturer to manufactures.
`
`
`Table III: Color and physical form nioeleclcd potysorhalm It 25°C.
`Polymrbate
`Color and form at 35°C
`
`Polymrbate 20
`Yellow oily liquid
`Polysnrbale 2]
`Yellow oily Liquid
`Polysm'hatc 40
`Yellow oily liquid
`Polysorhate so
`Yellow oily liquid
`Polywrbate 61
`Ton solid
`Pnlysorbate 65
`Ton solid
`Polysotbale 80
`Yellow oily liquid
`Polymrbntt: 81
`Amber liquid
`Polysorbaie 85
`Amber liquid
`
`Folysorbau: 120 Yellow liquid
`
`—
`-—
`—
`+
`
`9. Pbarmacopelal Specifications
`
`
` Teal IP PllEIr USP
`
`
`identification
`Polysorbate 20
`Polysorbaie 4001
`Polysorbste 60
`Polysotlme 80
`Saponificstioo value
`—
`PDlysot‘bill: an
`Polysorbate 4003 —
`Polysnrbele 61]
`—-
`Polysorhate 80
`4545
`llydroxyl value
`Polysorbate 20
`—
`Polysorbale 40"“ —
`Polysorbate 60
`—
`Polysotlaate 80
`-—
`
`+
`—
`+
`+
`
`Atom
`—
`4565
`45-55
`‘35-!08
`—
`ill-96
`55-80
`
`+
`+
`+
`+
`
`«to-so
`41-52
`45-55
`45-55
`9&106
`89-105
`“-96
`65-80
`
`
`
`
`

`

`
`
`__'__—_—_.
`
`- /
`
`__._L_J,,_I_—I—-|—|—L—l-—
`00102030405050709090100
`Cowmreaabnlomelml
`
`
`
`12
`
`10
`
`
`
`Moratu'recontain{'56}
`
`sh
`
`a:m M
`
`or
`233343 5257
`Flela’dvetmnidlwl‘lél
`
`75100
`
`rng. 1: Cowman:- character-Mics or ennui-r manniml
`(Moi. Raquela ml-
`0 ‘. Peat-{ital FG
`Cl : Peariiml MG
`A : Pmrlt'ral 662
`Tablet diameter: 20 mm
`Lubricant: magnesium stem 0.7% whv for Familial MG and
`Pearlitol 662. magnesium steamte 1% wlw' for Peat-lira! F6
`
`Fig. 3: Surgeon-desorption Isotllmn for mannitnL
`O : sorprion equilibrium moisture
`l : desorption equilibrium moisture
`
`as
`
`'
`33
`
`3.1
`
`2.9
`
`2.7
`
`“
`
`_-—E
`
`
`
`Tabletbreakingthicknesslrnm}
`
`
`
`
`
`Weight
`
`musizaWe}
`
`Median size = Bel-H11
`
`°o36912151a21242r30
`Compression farce {RN}
`
`Fig.2:Compt-mioncitmcterlaflesafgranuiarmamltol.
`Mean tablet weight: 500 mg
`Minimum compressional force for compaction: 7.35 kN
`Compressional force resulting in capping: M5 ItN
`
`a
`
`4n
`
`100
`so
`Particle alarnmar tum}
`
`160
`
`20“
`
`Pig. 4: Pardde she distribution or mannitnl powder-
`
`11. Stability and Storage Conditions
`Mannilu] is stable in the dry state and in aqueous solutions.
`Solutions may be Slerilized by filtration or by autoeiaving and
`if necessary may be antoelaved repeatedly with no adverse
`physical or chemical effects.”“ 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 built material should be stored in a well—closed container
`in a cool. dry. place.
`
`12. Inmmpatibilities
`None reported in the dry state. Mannitol solutions. 209l- wlv
`or stronger. may he salted out by potassium or sodium chlo-
`ride.""'} Precipitation has been reported to occur when a 25%
`win mannilol solution \vas allowed to contact plastic.""1 50-
`dium cephapirirt at 2 mga’mL and 30 mgirnl. is incompatible
`with 20% wiv aqueous mannilol 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 oxidalive degradation of a
`peptide in a Iyophilized formationdm Mannitol was found to
`reduce the ornl biovailability ol' cimetidine compared to su—
`cussed-193
`
`13. Method of Manufacture
`
`Mannitol may be extracted from the dried sap of manna and
`other nalura] sources by means of hot alcohol or other selec-
`tive solvents. It is commercially produced by the catalytic or
`electrolytic reduction of monosaccbarides sucl! as mannose
`and glucose,
`
`.asst-"ona-
`
`14. Safety
`Mannilol
`is a naturally occurring sugar alcohol found in an—
`imals and plants: it
`is present in small quantities in almost
`all vegetables, When consumed orally in large quantities. lax—
`nliVe effects may occur!“ If used in foods as a hodying agent
`and daily ingeslion of over 20g is foreseeable.
`lite producl
`label should bear the statement 'excessive consumption may
`have a laxative effoct'. After intravenous injection, mannitol
`is not metabolized to an}‘ appreciable extent and is minimally
`reabsorbed by Ihc renal
`tubule. about 30% of a dose being
`excreted in the urine in 3 hour-5.9"
`A number of adverse reactions to mannitol have been reported
`Primarily following the therapEutie use of 20% wlv aqueous
`i11l.t‘a\«'enolls infusionsml The quantity of Inannitol used as an
`elicipient
`is considerably less than that used therapeutically
`aml is consequently associated with a lower incidence of ad-
`Vlet‘se reactions. Hewever. allergic. hypersensitive-Iype reac—
`uons may occur when mannitol
`is used as an exeipienl.
`tin acceptable daily intake or rnannitol has not been specified
`hi“ lhe WHO since the amount consumed as a sweetening
`“E6111 was not considered lo represent a hazard to healthfm
`LB,“ (mouse. IP):
`l4 gfkglz‘l
`LD” (mouse. IV): 7.4? gfltg
`“3m (mouse, oral): 22 glitg
`LDsn (rat. 1V): 9.69 gflrg
`-__ LDso (fat. oral): I15 grit:
`
`'
`
`Manm'l'al' 327
`
`'
`15. Handling Preca