Handbook of
`Pharmaceutical Excipients
`
`FIFTH EDITION
`
`Edited by
`
`Raymond C Rowe
`
`BPharm, PhD, DSc, FRPhormS, CChem,
`
`FRSC, CPhys, MinstP
`
`Chief Scientist
`
`Intelligensys Ltd
`
`Billingham, UK
`
`Paul J Sheskey
`
`BSc, RPh
`
`Technical Services Leader
`
`The Dow Chemical Company
`
`Midland
`
`MI, USA
`
`Sian C Owen
`
`BSc, MA
`
`Development Editor
`
`Royal Pharmaceutical Society of Great Britain
`
`London, UK
`
`APhA
`
`(PP
`
`Pharmaceutical Press
`
`London • Chicago (cid:9)
`
`Mylan Ex 1008, Page 1
`
`

`

`Published by the Pharmaceutical Press
`Publications division of the Royal Pharmaceutical Society of Great Britain
`
`1 Lambeth High Street, London SEI 7JN, UK
`100 South Atkinson Road, Suite 206, Grayslake, IL 60030-7820, USA
`
`and the American Pharmacists Association
`2215 Constitution Avenue, NW, Washington, DC 20037-2985, USA
`
`Pharmaceutical Press and American Pharmacists Association 2006
`
`(PP is a trademark of Pharmaceutical Press
`
`First published 1986
`Second edition published 1994
`Third edition published 2000
`Fourth edition published 2003
`Fifth edition published 2006
`
`Printed in Great Britain by Butler &,- Tanner, From; Somerset
`Typeset by Data Standards Ltd. Frame, Somerset
`
`ISBN 0 85369 618 7 (UK)
`ISBN 1 58212 058 7 (USA)
`
`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 informadon contained in
`this book and cannot accept any legal responsibility or
`liability for any errors or omissions that may be made.
`
`A catalogue record for this book is available from the British Library
`
`Library of Congress Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients.-5th ed. edited by Raymond C.
`Rowe. Paul J. Sheskey, Sian C. Owen.
`P. ; cm.
`Includes bibliographical references and index.
`ISBN 1-58212-058-7 (USA) — ISBN 0-85369-618-7 (UK)
`1. Excipients—Handbooks, manuals, etc.
`)DNLM: 1. Excipients—Handbooks. 2. Technology, Pharmaceutical—Handbooks.
`QV 735 H236 200611. Rowe, Raymond C. II. Sheskey, Paul J. III. Owen, Sian C.
`IV. American Pharmacists Association.
`
`RS201.E871-136 2006
`615'.19—dc22.
`
`2005028523
`
`Mylan Ex 1008, Page 2
`
`

`

`Mannitol
`
`I (cid:9) Nonproprietary Names
`BP: Mannitol
`JP: D-Mannitol
`PhEur: Mannitolum
`USP: Mannitol
`
`2 Synonyms
`Corclycepic acid; C*PharmMannidex; E421; manna sugar;
`D-mannite; marmite; Mannogem; Pearlitol.
`
`3 (cid:9) Chemical Name and CAS Registry Number
`D-Mannitol [69-65-8]
`
`4 (cid:9) Empirical Formula and Molecular Weight
`
`C6H1406 (cid:9)
`
`182.17
`
`5 (cid:9) Structural Formula
`
`HO (cid:9)
`
`HO (cid:9)
`
`H
`
`H
`
`CH2OH
`
`
`
`
`
`OH
`
`OH
`
`CH2OH
`
`6 (cid:9) Functional Category
`Diluent; diluent for lyphilized preparations; sweetening agent;
`tablet and capsule diluent; tonicity agent.
`
`7 (cid:9) 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% w/w) in tablet formulations, where it
`is of particular value since it is not hygroscopic and may thus he
`used with moisture-sensitive active ingredients.I1'2'
`Mannitol may be used in direct-compression tablet applica-
`tions,°' for which the granular and spray-dried forms are
`available, or in wet granulations.(8' Granulations containing
`mannitol have the advantage of being dried easily. Specific
`tablet applications include antacid preparations, glyceryl
`trinitrate 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,
`sweetness, and 'mouth feeP!9'1°1
`
`•
`
`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
`vial.(11--m A pyrogen-free form is available specifically for this
`use.
`Mannitol has also been used to prevent thickening in
`aqueous antacid suspensions of aluminum hydroxide (<7%
`w/v). It has been suggested as a plasticizer in soft-gelatin
`capsules, as a component of sustained-release tablet,formula-
`tions„(-" and as a carrier in dry powder inhalers.'22-2' It is also
`used as a diluent in rapidly dispersing oral dosage forms.'
`It 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 of acute 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 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. Manni-
`tol shows polymorphismY26)
`
`9 (cid:9) Pharmacopeia! Specifications
`See Table I.
`
`SEM: 1
`Excipient: Mannitol
`Manufacturer: Merck
`Magnification: 50 x
`Voltage: .3.5 kV
`
`00005558. . (cid:9)
`
`00 pm. (cid:9)
`
`MERCK R E
`
`Mylan Ex 1008, Page 3
`
`

`

`450 (cid:9)
`
`Mannitol
`
`SEM: 2
`Excipient: Ma nnirol
`Manufacturer: Merck
`Magnification: 500 x
`Voltage: 3.5 kV
`
`SEM: 4
`Excipient: Mannitol granular
`Manufacturer: SPI Polyols Inc.
`Lot No: 2034F8
`Magnification:100x
`
`00005559
`
`0 oral (cid:9)
`
`MERCK REM Te
`
`SEM: 3
`Excipient: Mannitol powder
`Manufacturer: SPI Polyols Inc.
`Lot No: 3140G8
`Magnification: 100x
`
`10 (cid:9) Typical Properties
`Compressibility: see Figure 1.
`Density (bulk):
`0.430g/cm" for powder;
`0.7g/cm' for granules.
`Density (tapped):
`0.734 g/cm3 for powder;
`0.8 g/cm' for granules.
`Density (true): 1.514 g/cm3
`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 (3.96 kcal/g)
`Heat of solution: -120.9 J/g (-28.9 cal/g) at 25°C
`Melting point: 166-168'C
`
`Moisture content: see Figure 2.
`Osmolarity: a 5.07% w/v aqueous solution is isoosmoric with
`serum.
`Particle size distribution:
`Pearlitol 300 DC: maximum of 0.1% greater than 500 pm
`and minimum of 90% greater than 200 pm in size;
`Pearlitol 400 DC: maximum of 20% greater than 500 pm
`and minimum of 85% greater than 10011m in size;
`Pearlitol 500 DC: maximum of 0.5% greater than 841 gm
`and minimum of 90% greater than 150 pm in size.
`Average particle diameter is 250 pm for Pearlitol 300
`DC, 360 pm for Pearlitol 400 DC and 520 pm for Pearlitol
`500 DC.12' 3 See also Figure 3.
`
`Table I:
`
`Pharmacopeia[ specifications For mannitol.
`
`Test
`
`JP 2001 (cid:9)
`
`PhEur 2005 (cid:9)
`
`USP 28
`
`Identification
`Characters
`Solution
`appearance
`Melting range
`Specific rotation
`Conductivity
`Acidity
`Loss on drying
`Chloride
`Sulfate
`Arsenic
`Lead
`Nickel
`Heavy metals
`Reducing sugars
`Residue on ignition
`Related substances
`Bacterial endotoxins
`Microbial
`contamination
`Assay (dried basis)
`
`165-170°C
`166-169°C
`164-169'C
`+137' to +145' +23' to +25' +137' to +145'
`4204-cm-1
`
`40.3%
`40.007%
`40.01%
`,1 ppm
`
`40.3%
`40.007%
`-40.01%
`4. 1.3 ppm
`
`T
`45 ppm
`
`40.10%
`
`40.5%
`
`40.5 ppm
`41 ppm
`
`40.2%
`
`4 0. 1%
`44 fl.Vgi'31
`100/g
`
`98.0%
`
`98.0-102.0% 96.0-101.5%
`
`to Test applied only if the marmite! is to be used in the manufacture of porenierol dosage fcrms.
`
`Mylan Ex 1008, Page 4
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`(cid:9)
`

`

`N+,onnitol (cid:9)
`
`451
`
`and 30 mg/rill_ concentration is incompatible with 20% w/v
`aqueous mannitol solution. Mannitol is incompatible with
`xylitol infusion and may form complexes with. some metals
`such as aluminum, copper, and iron. Reducing sugar impurities
`in mannitol have been implicated in the oxidative degradation
`of a peptide in a lyophilized formation.('1) Mannitol was found
`to reduce the oral bioavailability of cimetidine compared to
`sucrose.'
`
`13 (cid:9) 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.
`
`12
`
`6
`
`4
`
`Moisure content (%)
`
`2
`
`Figure 2:
`
`33 (cid:9)
`
`67 (cid:9)
`57 (cid:9)
`52 (cid:9)
`43 (cid:9)
`Relative humidity (%)
`Sorption—desorption isotherm for mannitol.
`Sorption equilibrium moisture
`1E: Desorption equilibrium moisture
`
`75 (cid:9)
`
`IGO
`
`100
`
`80
`
`oa
`
`60
`
`0
`
`—,r7)
`,a5 40
`
`20
`
`Table H: (cid:9)
`
`Solubility of mannitol.
`
`Solvent
`
`Alkalis
`Ethanol (95%)
`Ether
`Glycerin
`Propa n-2-ol
`Water
`
`Solubility at 20-C
`
`Soluble
`1 in 83
`Practically insoluble
`1 in 18
`1 in 100
`1 in 5.5
`
`100
`
`90
`
`80 z
`_c 70
`as 0
`60
`
`cb
`Lai 50
`
`1-1)
`
`40
`
`30
`
`20
`
`10
`
`0
`0 10 20 30 40 50 60 70 80 90 100
`
`Figure 1: (cid:9)
`
`Compression force (kN)
`
`Compression characteristics of granular mannitol (Peorittof,
`Roquette Freres).
`Q: Pearlitol 300DC
`Pearlitoi 400DC
`Pearlitof 5000C
`Tablet diameter: 20rnm
`Lubricant: magnesium stearate 0.7% w/w for Pearfitoi
`4000C and Pearlitoi 500DC; magnesium stearate
`w/w for Pearlitol 300DC.
`
`Refractive index: ng) = 1.333
`Solubility: see Table
`Specific surface area: 0.37-0.39 m2/g
`
`11 (cid:9)
`
`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.l2s) In solution, mannitol is not
`attacked by cold, dilute acids or alkalis, nor by atmospheric
`oxygen in the absence of catalysts. Marmite] does not undergo
`Maillard reactions.
`The bulk material should be stored in a well-dosed
`container in a cool, dry place.
`
`12 Incompatibilities
`
`Mannitol solutions, 20% w/v or stronger, may be salted out by
`potassium chloride or sodium chleride.l29j Precipitation has
`been reported to occur when a 25% w/v mannitol solution was
`allowed to contact plasti.c.f.'31 Sodium cephapirin at 2 troghnL
`
`Figure 3:
`
`40 (cid:9)
`
`100 (cid:9)
`80 (cid:9)
`Particle diameter (urn)
`Particle size distribution of mannitol powder.
`
`160
`
`200
`
`Mylan Ex 1008, Page 5
`
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`452 (cid:9)
`
`iMcmnitol
`
`14 Safety
`
`Mannitol is a naturally occurring sugar alcohol found in
`animals and plants; it is present in small quantities in almost all
`vegetables. Laxative effects may occur if mannitol is consumed
`orally in large quantities.° If it is used in foods as a bodying
`agent and daily ingestion of over 20 g 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.'4)
`A number of adverse reactions to mannitol have been
`reported, primarily following the_therapeutic use of 20% %v/v
`aqueous intravenous infusions.'" The quantity of mannitol
`used as an excipient is considerably less than that used
`therapeutically and is consequently associated with a lower
`incidence of adverse reactions. However, allergic, hypersensi-
`tive-type reactions 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 as a
`sweetening agent was not considered to represent a hazard to
`
`LDso (mouse, IP): 14 glkg 37)
`LD50 (mouse, IV): 7.47 g/kg
`LD30 (mouse, oral): 22 g/kg
`LD50 (rat, IV): 9.69 g/kg
`LD50 (rat, oral): 13.5 g/kg
`
`15 (cid:9) 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 (cid:9) Regulatory Status
`
`GRAS listed, 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 tablets,
`powders and capsules; ophthalmic preparations; topical solu-
`tions). Included in nonparenteral and parenteral medicines
`licensed in the UK.
`
`17 (cid:9) Related Substances
`Sorbitol.
`
`18 Comments
`
`Mannitol is an isomer of sorbitoI, the difference between the
`two polyols occurring in the planar orientation of the OH
`group on the second carbon atom. Each isomer is characterized
`by its own individual set of properties, the most important
`difference being the response to moisture. Sorbitol is hygro-
`scopic, while mannitol resists moisture sorption, even at high
`relative humidities.
`Granular mannitol flows well and imparts improved flow
`properties to other materials. However, it usually cannot be
`used with concentrations of other materials exceeding 25% by
`weight. Recommended levels 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,
`methylceilulose 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.'38)
`A specification for mannitol is contained in the Food
`Chemicals Codex (FCC). The EINECS number for mannitol is
`200-711-8.
`
`19 (cid:9)
`
`Specific References
`
`1 Allen LV. Featured excipient: capsule and tablet diluents. bit J
`Pharm Compound 2000; 4(4): 306-310, 324-325.
`2 Yoshinari T, Forbes RT, York P, Kawashima Y. Improved
`compaction properties of mannitol after a moisture induced
`polymorphic transition. Int J Pharm 2003; 258(1-2): 121-131,
`3 Kanig, JL. Properties of fused mannitol in compressed tablets. J
`Pharm Sci 1964; 53: 188-192,
`4 Ward DR, Lathrop LB, Lynch MJ. Dissolution and compatibility
`considerations for the use of mannitol in solid dosage forms. J
`Pharm Sci 1969; 58: 1464-1467.
`Ghanern AH, Sakr FM, Abdel-Ghany G. Mechanical and physical
`properties of sulfamethoxazole-mannitol solid dispersion in tablet
`form. Acta Pharm Fenn 1986; 95: 167-172.
`6 Debord B, Lefebvre C, Guyot-Hermann AM, et al. Study of
`different crystalline forms of mannitol: comparative behaviour
`under compression. Drug Dev Ind Pharm 1987; 13: 1533-1546.
`7 Molokhia AM, Al-Shora HI, Hamrnad AA. Aging of tablets
`prepared by direct compression of bases with different moisture
`content. Drug Dee Ind Pharm 1987; 13: 1933-1946.
`8 Mendes RW, Gott S, An CQ. Wer granulation: a comparison of
`Manni-Tab and mannitol. Drug Cosnzet Ind 1978;122(3): 36, 38,
`40, 44, 87-88.
`9 Daousr RG, Lynch MJ. Mannitol in chewable tablets. Drug
`Cosnzet Ind 1963; 93(1): 26-28, 88, 92, 128-129.
`10 Herman J, Remon JP. Aluminium-magnesium hydroxide tablets:
`effect of processing and composition of granulating solution on the
`granule properties and in vitro antacid performance. Drug Dezi Ind
`Pharm 1988; 14: 1221-4234.
`I1 Couriel B. Advances in lyophilization technology. Bull Parenter
`Drug Assoc 1977; 31: 227-236.
`12 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.
`13 Stella VJ, Umprayn K, Waugh WN. Development of parenteral
`formulations of experimental cytotoxic agents I: rhizoxin (NSC-
`332598). int J Pharm 1988; 43: 191-199.
`14 Williams NA, Dean T. Vial breakage by frozen mannitol solutions:
`correlation with thermal characteristics and effect of stereoisomer-
`ism, additives, and vial configuration. J Parenter SciTechno11991;
`45: 94-100.
`15 Chan HK, Au-Yeung KL, Gonda I. Development of a mathema-
`tical model for the water distribution in freeze-dried solids. Pharm
`Res 1999; 16(5): 660-665.
`16 (cid:9) Pyne A, Surana R, Suryanarayanan R. Crystallization of mannitol
`below T.,' during freeze-drying in binary and ternary aqueous
`systems. Pharm Res 2002; 19: 901-908.
`17 Pyne A, Charrer)ee K, Suryanarayanan R. Solute crystallisation in
`mannitol-glycine systems. Implications on protein stabilisation in
`freeze-dried formulations. J Pharm Sci 2003; 92(11): 2272-2283.
`18 (cid:9) Cavatur RK, Vernuri NM, Pyne A, et al. Crystallization behavior
`of mannitol in frozen aqueous solutions. Pharm Res 2002; 19:
`894-900.
`19 lzursu K-I, Koiima S. Excipient crystallinity and its protein-
`structure-stabilizing effect during freeze-drying. J Pharm Pharrna-
`col 2002; 54: 1033-1039.
`20 Johnson RE, Kirchoff CF, Gand HE. mannitol-sucrose mixtures:
`versatile formulations for protein lyophilisation. J Pharm Sci 2002;
`91(4): 914-922.
`21 Parab PV, Oh CK, Ritschel WA. Sustained release from Precirol
`(glycerol palmito-stearate) matrix. Effect of mannitol and hydr-
`oxypropyl methyleellulose on the release of theophylline. Drug
`Dee Ind Pharm 1986; 12: 1309-1327.
`
`Mylan Ex 1008, Page 6
`
`

`

`(cid:9) (cid:9) Dubost DC, Kaufman MJ, Zimmerman JA, et al. Characterization
`
`22 Tee SK, Marriott C. Zeng XM, Martin GP. Use of different sugars
`as fine and coarse carriers for aerosolised salbutamol sulphate. Int
`J Pharm 2000; 208: 111-123.
`23 Steckel H, Bolzen N. Alternative sugars as potential carriers for dry
`powder inhalers. Int J Pharm 2004; 270(1-21: 297-306.
`2 4 Lee KJ, Kang A. Delfino JJ, et al. Evaluation of critical formu-
`lation factors in the development of a rapidly dispersing capto-
`pril oral dosage form. Drug Den Ind Pharm 2003; 29(9;:
`967-979.
`25 Seager H. Drug development products and the Zydis fast
`dissolving dosage form.] Pharm Pharrnacol 1998; 50: 375-382.
`2 6 Bauer H, Herkert T, Bartels .M, et al. Investigations on
`polymorphism of mannitolisorbitol mixtures after spray drying
`using differential scanning calorimetry, x-ray diffraction and near
`infrared spectroscopy. Pharm Ind 2000; 62(3): 231-235.
`27 Roquette Freres. Technical literature: Pearlitol, 2004.
`28 Murry BSR, Kapoor JN. Properties of mannitol injection
`(25%) after repeated autoclavings. Am J Hosp Pharm 1975; 32:
`826-827.
`29 Jacobs J. Factors influencing drug stability in intravenous
`infusions.] Hasp Pharm 1969; 27: 341-347.
`30 Epperson E. Mannitol crystallization in plastic containers [letter].
`Am J Hosp Pharm 1978; 35: 1337.
`
`31
`
`of a solid state reaction product from a lyophilized formulation of
`a cyclic heptapeptide. A novel example of an excipient-induced
`oxidation. Pharm Res 1996; 13: 1811-1814.
`32 Adkin DA, Davis SS, Sparrow RA, et al. The effect of mannitol on
`the oral bioavailahility of cimetidine. J Pharm Sci 1995; 84: 1405--
`1409.
`33 Anonymous. Flatulence, diarrhoea, and polyol sweeteners. Lancet
`1983; ii: 1321.
`
`Mcnnitc,1 (cid:9)
`
`453
`
`34 Porter GA, Starr A, Kimsey J, Lenertz H. Mannitol hemodilution—
`perfusion: the kinetics of mannitol distribution and excretion
`during cardiopulmonary bypass. J Surg .Res 1967; 7: 447-456.
`35 (cid:9) McNeill 1Y. Hypersensitivity reaction to mannitol. Drug I ntell
`Pharm 1985; 19: 552-553.
`36 FAO/WHO. Evaluation of certain food additives and contami-
`nants. Thirtieth report of the joint FAO/WHO expert committee
`on food additives. World Health Organ Tech Rep Ser 1987; No.
`751.
`37 (cid:9) Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials,
`11th edn. New York: Wiley, 2004: 1944-1945.
`38 Weast RC. ed. Handbook of Chemistry and Physics, 60th edn.
`Boca Raton: CRC Press, 1979: c-369.
`
`20 General References
`Armstrong NA. Tablet manufacture. Diluents. In: Swarbrick J, Boylan
`JC, eds. Encyclopedia of Pharmaceutical Technology; 2nd edn, vol.
`3. New York: Marcel Dekker, 2002: 2713-2732.
`PikaI1v1j. Freeze drying. In: Swarbrick J, Boylan JC, eds. Encyclopedia
`of Pharmaceutical Technology, 2nd edn, vol. 2. New York: Marcel
`Dekker, 2002: 1299-1326.
`
`21 Authors
`
`NA Armstrong.
`
`22 (cid:9) Date of Revision
`
`16 August 2005.
`
`Mylan Ex 1008, Page 7
`
`