- -
`
`Handbook of
`Pharmaceutical Excipients
`
`FOURTH EDITION
`
`Edited by
`
`Raymond C Rowe
`BPharm, PhD, DSc, FRPharmS, CChem, FRSC, CPhys, MlnstP
`
`Senior Principal Scientist
`
`AstraZeneca
`
`Macclesfield, UK
`
`Paul J Sheskey
`BSc, RPh
`
`Technical Service Leader
`Water Soluble Polymers R&D
`
`The Dow Chemical Company
`
`Midland
`
`Ml, USA
`
`Paul J Weller
`BSc, MSc, CChem, MRSC
`
`Publisher - Science and Practice
`
`Royal Pharmaceutical Society of Great Britain
`
`London, UK
`
`(P.P)
`
`Pharmaceutical Press
`
`London • Chicago
`
`American
`Pharmaceutical
`Association
`
`AQUESTIVE EXHIBIT 1031 page 0001
`
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`-
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`

`

`Published by the Pharmaceutical Press
`Publications division of the Royal Pharmaceutical Society of Great Britain
`
`1 Lambeth High Street, London SE 1 7JN, UK
`100 South Atkinson Rood, Suite 206, Grayslake, IL 60030-7820, USA
`
`and the American Pharmaceutical Association
`2215 Constitution Avenue NW, Washington, DC 20037-29B5, USA
`
`Pha rmaceutical Press and American Pharmaceutical A sociation 2003
`
`(RP) i a trade mark of Pharmaceutical Press
`
`First edition publi hed 1986
`econd edition published 1994
`Third edition published 2000
`Fourth edition published 2003
`
`Text design by Barker Hilsdon, Lyme Regis
`Type et by Bibliocraft Ltd, Dundee
`Printed in Great Britain by The Bath Press, Bath
`
`ISBN O 85369 472 9 (UK)
`ISB 1 58212 022 6 (USA)
`
`II right re erved. o part of this publication may be
`reproduced, stored in a retrieval y rem, or tra nsmitted in any
`form or by any means, without the prior written permission
`of the copyright holder.
`The publisher makes no representation, expre s or implied,
`with rega rd to the a curacy of the information contained in
`this book and cannot accept any legal responsibility or
`liability for any errors or omission that may be made.
`
`A catalogue record fo r this book is available from the British Library
`
`Library of Congrc Cataloging-in-Publication Data
`Handbook of pharmaceutical excipients.-4th ed. / edited by Raymond
`Rowe, Paul J. Sheskey, Paul J. Weller.
`p. ;cm.
`Include bibliographical references and index.
`ISB 1-58212-022-6 (alk. paper) -ISB 0-85369-472-9 {alk. paper)
`1. Excipients-Handbooks, manua ls, etc.
`[D LM: 1. Excipients-Handbooks. QV 735 H2 6 2003] I. Rowe, Raymond
`C. II. Sheskey, Paul J. Ill. Weller, Paul J.
`
`RS201.E87H36 2003
`615'.19-dc21
`
`2003002641
`
`AQUESTIVE EXHIBIT 1031 page 0002
`
`

`

`the term 'alcohol' or 'ethanol' is used, followed by the state(cid:173)
`ment of the strength.
`In the PhEur 2002, anhydrous ethanol contains not les
`than 99.5% v/v of 2H 60 at 20°C. The term ethanol (96%) is
`used to describe the material containing water and 95.1-
`96.9% v/v of C2H 60 at 20°C.
`P 25, the term 'dehydrated alcohol' refers to
`In the
`ethanol ;;i:99.5 % v/v. The term 'alcohol' without other quali(cid:173)
`fication refer to ethanol 94.9-96.0% v/v.
`In the JP 2001, ethanol (alcohol) contain 95.1- 95.6% v/v
`(by spccifi gravity) of C2H 60 at 15° .
`In the Handbook of Pharmaceutical Excipients, the term
`'alcohol' i used for either ethanol 95 % v/v or ethanol 96 %
`v/v.
`Alcohol is a clear, colorle s, mobile, and volatile liquid with
`a slight, characteri tic odor and burning taste.
`See also Section 17.
`
`9 Pharmacopeial Specifications
`See Ta ble 11.
`
`Table II:
`
`Pharmacopeial specifications for alcohol.
`
`Test
`
`JP 2001
`
`PhEur 2002
`
`USP 25
`
`+
`
`+
`
`+
`
`+
`
`+
`+
`
`+
`
`+
`
`+
`
`Alcohol
`
`1 Nonproprietary Names
`BP: Ethanol (96%)
`JP: Ethanol
`PhEur: "rhanolum (96 per centum)
`USP: Alcohol
`
`2 Synonyms
`Ethyl alcohol; ethyl hydroxide; grain alcohol; methyl carbinol.
`
`3 Chemical Name and CAS Registry Number
`Ethanol [64-17-5]
`
`4 Empirical Formula
`
`C2H6O
`
`Molecular Weight
`46.07
`
`5 Structural Formula
`
`6 FunctionalCategory
`Antimicrohial preservative; disinfectant; kin penetrant; sol(cid:173)
`vent.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Ethanol and aqueous ethanol olutions of various concentra(cid:173)
`tions (see Section 8 and 17) are widely used in pharmaceutical
`formulations and cosmetics; see Table I. Although ethanol is
`primarily used as a solvent, it i also employed in solutions a
`an antimicrobial preservative.< 1
`21 Topical ethanol solution
`•
`are al o u ed a penetration enhancers13 > and a disinfectant .
`
`Tobie I: Uses of alcohol.
`
`Use
`
`Concentration(% v/v)
`
`Antimicrobial preservative
`Disinfectant
`Extracting solvent in galenical
`manufacture
`Solvent in film coating
`Solvent in injectable solutions
`Solvent in oral liquids
`Solvent in topical products
`
`~ 10
`60-90
`Up lo 85
`
`Variable
`Voriable
`Variable
`60-90
`
`+
`+
`+
`Identification
`Specific gravity 0.814--0.816 0.8051--0.81 24 0.812--0.816
`+
`+
`+
`Acidity
`+
`Clarity of solution +
`:oa;: 2 .5 mg/1 00ml ,a; I mg/ 40 mL
`~ 1 mg/40ml
`Nonvolatile
`residue
`Water-insoluble
`substances
`Aldehydes
`Amyl a lcohol,
`etc.
`Absorbonce
`Fuse! oil
`constituents
`Acetone and
`propan-2-ol
`Methanol
`Reducing
`substances
`Organic volatile
`impurities
`Chloride
`Heavy metals
`Assay
`
`+
`:oa;:1.2ppm
`95.1-95.6% 95 .1-96.9%
`
`92.3-93 .8% by
`weight
`94.9-96.0% by
`volume
`
`8 Description
`In the BP 2001, the term 'ethanol' used without other qualifi(cid:173)
`cation refers to ethanol containing ;;i: 99.5 % v/v of C2H6O,
`to
`The term 'alcohol', without other qualification, refer
`ethanol 95.1-96.9% v/v. Where other strengths are intended,
`
`10 Typical Properties
`Antimicrobial activity: ethanol is ba tericidal in aqueous
`mixture at concentrations between 60% and 95% v/v;
`the optimum concentration is generally considered to be
`
`AQUESTIVE EXHIBIT 1031 page 0003
`
`13
`
`

`

`14
`
`Alcohol
`
`70% v/v. Antimicrobial activifr is enhanced in the presence
`of edetic acid or edetate salts. Cl Ethanol is inactivated in the
`presence of nonionic surfactants and is ineffective against
`bacterial spore .
`Boiling point: 78.15°C
`Flammability: readily flammable, burning with a blue, smoke(cid:173)
`less flame.
`Flash point: 14°C (closed cup )
`Solubility: miscible with chloroform, ether, glycerin, and water
`(with rise of temperature and contraction of volume).
`Specific gravity: 0.8119--0.8139 at 20°c
`Note: the above typical properties are for alcohol (ethanol
`95% or 96% v/v). See Section 17 for typical properties of
`dehydrated alcohol.
`
`11 Stability and Storage Conditions
`Aqueous ethanol solutions may be sterilized by autoclaving or
`by filtration and hould be stored in airtight containers, in a
`cool place.
`
`12
`Incompatibilities
`In acidic conditions, ethanol olution may react vigorously
`with oxidizing materials. Mixtures with alkali may darken in
`color owing to a reaction with residual amount of aldehyde.
`Organic salts or acacia may be precipitated from aqueous
`solutions or dispersions. Ethanol solutions are al o in ompa(cid:173)
`tible with aluminum containers and may interact with some
`drugs.
`
`13 Method of Manufacture
`Ethanol is manufactured by the controlled enzymatic ferm n(cid:173)
`tation of starch, sugar, or other carbohydrates. A fermented
`liquid is produced containing about 15% ethanol; ethanol
`95% v/v is then obtained by fractional distillation. Ethanol
`may also be prepared by a number of synthetic methods.
`
`14 Safety
`Ethanol and aqueou ethanol solutions are widely used in a
`variety of pharmaceutical formulations and cosmetics. It is also
`consumed in alcoholic beverages.
`Ethanol is rapidly absorbed from the gastrointestinal tract
`and the vapor may be absorbed through the lungs; it is
`metabolized, mainly in the liver, to acetaldehyde, which is
`further oxidized to acetate.
`Ethanol is a central nervous system depressant and inges(cid:173)
`tion of low to moderate quantities can lead to symptoms of
`intoxication including mu de incoordination, visual impair(cid:173)
`ment, slurred speech, etc. Ingestion of higher concentrations
`may cause depression of medullary action, lethargy, amnesia,
`hypothermia, hypoglycemia, stupor, coma, re pirato ry depres-
`ion, and cardiovascular collapse. The lethal human blood(cid:173)
`alcohol concentration is generally estimated to be 400-500 mg/
`l OOmL.
`Although symptoms of ethanol intoxication are usually
`encountered following deliberate consumption of ethanol(cid:173)
`containing beverages, many pharmaceutical products contain
`ethanol as a solvent, which, if ingested in sufficiently large
`quantities, may cause adverse symptom of intoxication. In the
`USA, the maximum quantity of alcohol included in OTC
`medicines is 10% v/v for products labeled for use by people
`of 12 years of age and older, 5% v/v for products intended for
`
`use by children aged 6-12 years of age, and 0.5% v/v for
`products for use by children under 6 years of age.141
`Parenteral products containing up to 50% of alcohol
`(ethanol 95 or 96% v/v) have been formulated. However,
`such concentrations can produce pain on intramuscular injec(cid:173)
`tion and lower concentrations such as 5-10% v/v are preferred.
`Subcutaneous injection of alcohol (ethanol 95% v/v) similarly
`causes considera ble pain followed by anesthesia. If injections
`are made close to nerves, neuritis and nerve degeneration may
`occur. This effect is used therapeutically to cause anesthesia in
`cases of severe pain, although the practice of using alcohol in
`nerve blocks is controversial. Doses of 1 mL of absolute
`alcohol have been used for this purpose.151
`Preparations containing more than 50% v/v alcohol may
`cause skin irritation when applied topically.
`LD o (mouse, IP): 0.93 g/kg16l
`LD50 (mouse, IV): 1.97g/kg
`LDso (mou e, oral): 3.45 g/kg
`LD50 (mouse, S ): 8.29 g/kg
`LD50 (rat, IP): 3.75g/kg
`LD5o (rat, IV): 1.44g/kg
`LD50 (rat, oral): 7.06 g/kg
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Ethanol and aqueous etha(cid:173)
`nol solutions should be handled in a well-ventilated environ(cid:173)
`ment. In the UK, the long-term 8-hour TWA exposure limit for
`ethanol i 1920mg/m3 (lO00 ppm).m Ethanol may be irritant
`to the eye and mucou membranes and eye protection and
`thanol is flammable and should be
`gloves are recommended.
`heated with care. Fixed storage tanks should be electrically
`grounded to avoid ignition from electrostatic discharges when
`ethanol is transferred.
`
`16 Regulatory Status
`Included in the FDA Inactive Ingredients Guide (dental pre(cid:173)
`parations; inhalations; IM and IV injections; nasal and
`ophthalmic preparations; oral capsules, solutions, suspen(cid:173)
`sions, syrups, and tablets; rectal, topical, and transdermal
`preparations). Included in nonparenteral and parenteral med(cid:173)
`icine licensed in the UK.
`
`17 Related Substances
`Dehydrated alcohol; denatured alcohol; dilute alcohol; i opro(cid:173)
`pyl alcohol.
`
`Dehydrated alcohol
`Synonyms: absolute alcohol; anhydrous ethanol; ethanol.
`Autoignition temperature: 365°C
`Boiling point: 78.SCC
`Explosive limits: 3.5-19.0% v/v in air
`Flash point: 12°C (closed cup)
`Melting point: -1 12°C
`Moisture content: absorbs water rapidly from the ai r.
`Refractive index: ni,0 = 1.361
`Specific gravity: 0.7904--0.7935 at 20°C
`Surface tension: 22. 75 mN/m at 20°C (ethanol/vapor)
`Vapor density (relative): 1.59 (a ir= 1)
`Vapor pressure: 5. 8 Pa at 20°C
`Viscosity (dynamic): 1.22 mPa s ( 1.22 cP) at 20°C
`
`AQUESTIVE EXHIBIT 1031 page 0004
`
`

`

`Comment: dehydrated alcohol is ethanol ;;;,,99.5% v/v. ee
`Section 8.
`
`Denatured alcohol
`Synonyms: industrial methylated spirit; surgical spirit.
`Comme.nts: denatured alcohol is alcohol intended for external
`use only. It has been rendered unfit for human consumption
`by the addition of a denaturing agent such as methanol or
`methyl isobutyl ketone.
`
`Dilute alcohol
`Synonyms: dilute ethanol.
`Specific gravity: see Table III.
`
`Table Ill: Specific gravity of alcohol.
`Strength of alcohol l°lo v /vi
`
`Specific gravity at 20°C
`
`90
`80
`70
`60
`50
`45
`25
`20
`
`0.8289-0.8319
`0.8599-0.8621
`0.8860-0.8883
`0.9103-0.9114
`0. 9314-0. 9326
`0.9407-0.9417
`0.9694-0.9703
`0.97 48-0.9759
`
`Comments: the term 'dilute alcohol' refers to a mixture of
`ethanol and water of tated concentration. The BP 2001
`lists eight strengths of dilute alcohol (dilute ethanol) con(cid:173)
`taining 90%, 80%, 70%, 60%, 50%, 45%, 25%, and 20%
`v/v re pectively of ethanol.
`
`Alcohol
`
`15
`
`The ErNE S number for alcohol i 200-578-6.
`
`19 Specific References
`1 Chiori CO, Ghobashy AA. A potentiating effect of EDTA on the
`bactericidal activity of lower concentration of ethanol. fot J
`Phann 1983; 17: 121-128.
`2 Karabit MS, Juneskans OT, Lundgren P. Studies on the evaluation
`of preservative efficacy. IV. The determination of antimicrobial
`characteristics of some pharmaceutical compounds in aqueous
`solutions. Int J Pharm 1989; S4: 51-56.
`3 Liu P, Higuchi WI, Song W, et al. Quantitative evaluation of
`ethanol effect on diffusion and metabol ism of 13-estradiol in
`hairle s mouse skin. Pham: Res 1991; 8(7): 865~72.
`Jass H . Regulatory review. Cosmet Toilet 1995; 110(5}: 21-22.
`4
`5 Lloyd JW. Use of anaesthesia: the anaesthetist and the pain clinic.
`Br Med J 1980; 281: 432-434.
`6 Lewis RJ, ed. Sax's Dangerous Properties of Industrial Materials,
`10th edn. New York: Wiley, 2000: 1637- 1638.
`7 Health and Safety Executive. EH40/2002: O ccupational Exposure
`Limits 2002. Sudbury: Health and Safety Executive, 2002.
`
`20 General References
`Lund W, ed. The Pham,aceutical Codex: Principles and Practice of
`Pharniaceutics, 12th edn. London: Pharmaceutical Press, 1994:
`69~95.
`oseworthy MN. Use of nonaqueous solvent
`Spiegel AJ,
`parenteral products. J Phann Sci 1963; S2: 917-927.
`Wade A, ed. Pharniaceutica/ Handbook, 19th edn. London: Pharma(cid:173)
`ceutical Press, 1980: 227-230.
`
`in
`
`21 Author
`SC Owen.
`
`18 Comments
`Possession and use of nondenatured alcohols are usually
`subject to close control by exci e authorities.
`
`22 Dote of Revision
`15 October 2002.
`
`AQUESTIVE EXHIBIT 1031 page 0005
`
`

`

`Al,pha Tocopherol
`
`1 Nonproprietary Names
`BP: Alpha cocopherol
`JP: Tocopherol
`PhEur: ix-Tocopherolum
`USP: Vitamin E
`See also Sections 3, 9, and 17.
`
`2 Synonyms
`( ± )-3,4-dihydro-2,5, 7,8-tetramethyl-2-
`Copherol F1300;
`( 4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-ol; E307; East(cid:173)
`man Vitamin E TPGS; ynthetic alpha cocopherol; all-rac-ix(cid:173)
`tocopherol; d/-ix-tocopherol; 5,7,8-trimethylto ol.
`
`3 Chemical Name and CAS Registry Number
`( ± )-(2RS,4'R ,8'RS)-2 5,7,8-Tetramcthyl-2-(4',8',12'-trimc(cid:173)
`thyltridecyl)-6-chromanol [10191-41-0]
`ote that alpha tocopherol ha three chiral centres, giving
`ri e to eight i omeric forms. The naturally occurring form is
`known as d-alpha tocopherol or (2R,4'R,8'R)-alpha-toco(cid:173)
`pherol.
`he ynthetic form, di-alpha tocophcrol or
`imply
`alpha tocopherol, occurs a a racemic mixture containing
`equimolar quantities of all the isomers.
`Similar considerations apply to beta, delta, and gamma
`tocopherol and tocopherol esters.
`See ection 17 for further information.
`
`4 Empirical Formula
`C2 HsoO2
`
`Molecular Weight
`430.72
`
`5 Structura1I Formu'la
`
`Alpha tocopherol: R1 = R2 = R3 = H3
`Beta tocopherol: R1 = R3= H3 ; R2 = H
`Delta tocopherol: R1 = CH3i R2 = R3 = H
`Gamma tocopherol: R1 = R = CH3; R3 = H
`~ Indicates chiral centers.
`
`6 Functional Category
`Antioxidant; therapeutic agent.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Alpha tocopherol is primarily recognized a a ource of vitamin
`E, and the commercially available material and specifications
`reflect thi purpo e. While alpha tocopherol also exhibits
`
`antio idant properties, the beta, delta, and gamma tocopher(cid:173)
`ols are considered to be more effective as antioxidants.
`Alpha-tocopherol is a highly lipophilic compound, and is an
`e cellent solvent for many poorly soluble drugs.Cl) Of wide(cid:173)
`spread regulatory acceptability, tocopherols are of value in oil(cid:173)
`or fat-based pharmaceutical product and are normally used in
`the concentration range 0.001--0.05% v/v. There is frequently
`an optimum concentration; thus the autoxidation of linoleic
`acid and methyl linolenate is reduced at low concentration of
`alpha tocopherol, and is accelerated by higher concentrations.
`Antioxidant effectiveness can be increased by the addition of
`oil-soluble synergists such a lecithin and ascorbyl palmitate.c2>
`
`8 Description
`Alpha tocopherol is a natural product. Therefore, it is available
`either as a practically odorless, clear, colorle s, yellow, yellow(cid:173)
`ish-brown, or greenish-yellow viscous oil. See also Section 17.
`
`9 Pharmacopeial Specifications
`See Table I.
`
`Table I:
`
`Phormocopeial specifications for alpha tocopherol.
`
`Test
`
`JP 2001
`
`PhEur 2002
`
`USP 25
`
`Identification
`Acidity
`Acid value
`Optical rotation
`Heavy metals
`Sulfated ash
`Organic volatile
`impurities
`Absorbance
`Refractive index
`Specific gravity
`Clarity and color
`of solution
`Assay
`
`+
`
`+
`
`+
`
`~ 20ppm
`
`,.; 2
`to +0.01° +
`--0.01
`~ l 0ppm
`~ 0.1%
`
`+
`
`+
`
`+
`1.503-1 .507
`0. 947--0.955
`+
`
`96.0-l 02.0% 96.0-102.0%
`
`96.0-l 02.0%
`
`Note that the U P 25 describes vitamin E a comprising
`d- or di-alpha tocopherol, d- or di-alpha tocopheryl acetate, or
`d- or di-alpha tocopheryl acid succinatc. However, the PhEur
`2002 describes alpha rocopherol and alpha tocopheryl acetate
`in separate monographs.
`The diver ity of the tocopherols described in the variou
`pharmacopeial monographs makes the comparison of specifi(cid:173)
`cations more complicated; see Section 17.
`
`10 Typical Properties
`Boiling point: 235°C
`Den ity: 0.947--0.951 g/cm3
`Flash point: 240°C
`Ignition point: 340°C
`Refractive index: n5° = 1.503-1.507
`Solubility: practically insoluble in water- freely soluble m
`acetone, ethanol, ether, and vegetable oils.
`
`-
`
`-
`
`AQUESTIVE EXHIBIT 1031 page 0006
`
`2.7
`
`-
`
`- -
`
`- - -
`
`-
`
`

`

`28
`
`Alpha Tocopherol
`
`11 Stability and Storage Conditions
`Tocopherols arc oxidized slowly by atmospheric oxygen and
`rapidly by ferric and silver salts. Oxidation products include
`tocopheroxide, tocopherylquinone, and tocopherylhydroqui(cid:173)
`none, a well as dimers and trimers. Tocopherol esters arc
`more stable to oxidation than the free tocopherols but are in
`consequence less effective antioxidant . See also ection 17.
`Tocopherols should be stored under an inert gas, in an
`airtight container in a cool, dry place and protected from light.
`
`Incompatibilities
`12
`Tocopherols are incompatible with peroxides and metal ions,
`especially iron, copper, and silver. Tocopherols may be
`absorbed into plastic.<31
`
`13 Method of Manufacture
`Naturally occurring tocopherols are obtained by the extraction
`or molecular distillation of steam distillates of vegetable oils;
`for example, alpha tocopherol occurs in concentrations of 0.1-
`0.3 % in corn, rapeseed, soybean, sunflower, and wheat germ
`oils.<4
`> Beta and gamma tocopherol are usually found in
`natural ources along with alpha to opherol. Ra emic syn(cid:173)
`thetic tocopherols may be prepared by the condensation of
`the appropriate methylated hydroquinone with racemic
`isophytol. <SJ
`
`14 Safety
`Tocophcrols (vitamin E) occur in many food substances that
`are consumed a part of the normal diet. The daily nutritional
`requirement has not been clearly defined but i estimated to be
`3.0-20.0 mg. Ab orption from the gastrointestinal tract is
`dependent upon normal pancreati function and the presence
`of bile. Tocopherols are widely distributed throughout the
`body, with some ingested tocopherol metabolized in the
`liver; excretion of metabolites is via the urine or bile. Indivi(cid:173)
`duals with vitamin E deficiency are usually treated by oral
`administration of tocopherols, although intramuscular and
`intravenous administration may sometimes be used.
`Tocopherols are well tolerated, although excessive oral
`intake may cause headache, fatigue, weaknes , digestive dis(cid:173)
`turbance, and nausea. Prolonged and intensive kin contact
`may lead to erythema and contact dermatitis.
`The use of tocopherol as antioxidants in pharmaceuticals
`and food products is unlikely to pose any hazard to human
`health since the daily intake from such use is small compared
`to the intake of naturally occurring tocopherols in the diet.
`The WHO ha set an acceptable daily intake of toco~herol
`used as an antioxidant at 0.15-2.0 mg/kg body-weight. 1
`
`1 S Handling Precautions
`Observe normal precautions appropriate to the circumstance
`and quantity of material handled. Glove and eye protection
`are recommended.
`
`16 Regulatory Status
`GRAS Ji red. Accepted in Europe as a food additive. Included
`in the FDA Inactive Ingredients Guide (oral capsules, tablets,
`and topical preparations). Included in nonparenteral medicines
`licen ed in the UK.
`
`1 7 Related Substances
`d-Alpha tocopherol; d-alpha tocopheryl acetate; di-alpha
`tocopheryl acetate; d-alpha tocopheryl acid succinate; di(cid:173)
`alpha tocopheryl acid succinate; beta tocopherol; delta toco(cid:173)
`pherol; gamma tocopherol; rocopberols excipient.
`
`d·Alpha tocopherol
`mpirical formula: C29 TsoO2
`Molecular weight: 430.72
`CAS number: [59-02-9)
`( + )-(2R,4' R,8' R)-
`tocopherol;
`Synonyms: natural alpha
`2,5, 7,8-tetramethyl-2-( 4' ,8', 12' -trimethyltri decyl )-6-chro(cid:173)
`manol; d-:x-tocopherol; vitamin E.
`, clear, yellow, or greenish(cid:173)
`Appearance: a practically odorle
`yellow viscous oil.
`Melting point: 2.5-3.5°C
`Solubility: practically insoluble in water; soluble in ethanol
`(95%). Miscible with acetone, ch loroform, ether, and
`vegetable oils.
`Specific gravity: 0.95
`Comments: d-alpha tocopherol is the naturally occurring form
`of alpha tocopherol.
`
`d-Alpha tocopheryl acetate
`Empirical formula: C31Hs2O3
`Molecular weight: 4 72. 73
`CAS number: [58-95-7)
`( +)-(2R,4'R,8' R)-2,5,7 8-tetramethyl-2-(4' ,8', 12' -
`Synonyms:
`trimeth y l tridecyl)-6-ch romanyl acetate; d-cc-tocopheryl
`acetate; vitamin E.
`Appearance: a practically odorless, clear, yellow, or greenish(cid:173)
`yellow colored viscou oil that may solidify in the cold.
`Melting point: 28°C
`Solubility: practically insoluble in water· oluble in ethanol
`(95%). Miscible with acetone, chloroform, ether, and
`vegetable oils.
`Specific rotation [ct)ff: +0.25° (10% w/v solution in chloro(cid:173)
`form)
`Comments: unstable to alkalis.
`
`di-Alpha tocopheryl acetate
`m.pirical formula: C31Hs2O3
`Molecular weight: 472.73
`CAS number: [7695-91-2)
`( ± )-3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-
`Synonyms:
`acetate;
`trimethyltridecyl)-2H-1-benzopyran-6-ol
`( ± )-(2RS,4' RS,8' RS)-2,5, 7,8-tetramethyl -2-(4' ,8', 12' -tri(cid:173)
`methyltridecyl)-6-chromanyl acetate; ( ± )-ct-tocopherol
`acetate; o:-tocopheroli acetas; al/-rac- cc-tocopheryl acet(cid:173)
`ate; d!-cx-tocophcryl acetate; vitamin E.
`Appearance: a practically odorless, clear, yellow, or greenish-
`yellow viscous oil.
`Density: 0.953 g/cm3
`Melting point: -27.s°C
`Refractive index: ni0
`::: 1.4950-1.4972
`Solubility: practically insoluble in water; freely oluble in
`acetone, chloroform, ethanol, ether, and vegetable oils;
`soluble in ethanol (95%).
`Comments: unstable to alkali. However, unlike alpha toco(cid:173)
`pherol, the acetate is much le s susceptible to the effects of
`air, light, or ultraviolet Light. Alpha tocopherol acetate
`tocopherol
`concentrate, a powdered form of alpha
`acetate, is described in the PhEur 2002. The concentrate
`may be prepared by either di persing alpha tocopherol
`
`AQUESTIVE EXHIBIT 1031 page 0007
`
`

`

`acetate in a suitable carrier such as acacia or gelatin, or by
`adsorbing alpha tocopherol acetate on silicic acid.
`
`d-Alpha tocopheryl acid succinote
`Empirical formula: C33Hs4O5
`Molecular weight: 530.8
`CAS number: (4345-03-3]
`Synonyms: ( + )-cx-tocopherol hydrogen succinate; d-cx-toco-
`pheryl acid succinate; vitamin E.
`Appearance: a practically odorless white powder.
`Melting point: 76-77°C
`Solubility: practically in oluble in water; slightly soluble in
`alkaline solutions; soluble in acetone, ethanol (95%), ether,
`and vegetable oils; very soluble in chloroform.
`Comments: unstable to alkalis.
`
`di-Alpha tocopheryl acid succinafe
`Empirical formula: C33Hs4Os
`Molecular weight: 530.8
`CAS number: [17407-37-3]
`Synonyms: ( ± )-cx-tocopherol hydrogen succinate; d/-cx-toco(cid:173)
`pheryl acid succinate; d/-a:-tocopherol succinate; vitamin E.
`Appearance: a practically odorless, white crystalline powd~r.
`Solubility: practically in oluble in water; slightly soluble in
`alka line solutions; soluble in acetone, ethanol (95%), ether,
`and vegetable oils; very soluble in chloroform.
`Comments: unstable to alkalis.
`
`Beta tocopherol
`Empirical formula: C2sH4sO2
`Molecular weight: 416.66
`CAS number: (148-03-8]
`( ± )-3,4-dihydro-2,5,8-
`Synonym :
`cumotocopherol;
`trirnethyl-2-( 4,8, l2-trimethyltridecyl)-2H-1-P-benzopyran-
`6-ol; 5,8-dimethyltocol; neotocopherol; dl-P-tocopherol;
`vitamin E; p-xylotocopherol.
`Appearance: a pale yellow-colored viscous oil.
`Solubility: practically insoluble in water; freely oluble in
`acetone, chloroform, ethanol (95%), ether, and vegetable
`oils.
`Specific rotation [cxJr,0
`: +6.37°
`Comment : le
`active biologically than alpha tocopherol.
`Obtained along with alpha tocopherol and gamma toco(cid:173)
`pherol from natural sources. Beta tocopherol i very stable
`to hear and alkalis and is slowly oxidized by atmospheric
`oxygen.
`
`Delta tocopherol
`27~ 602
`Empirical formula:
`Molecular weight: 402.64
`CAS number: (119-13-1]
`( ± )-3,4-dihydro-2,8-dimethyl-2-(4,8,12-tri-
`Synonyms:
`merhyltridecyl)-2H-1-benzopyran-6-ol; E309; 8-methyl(cid:173)
`tocol; dl-6-tocopherol; vitamin E.
`Appearance: a pale yellow-colored viscou oil.
`Solubility: practically insoluble in water; freely soluble in
`acetone, chloroform, ethanol (95%), ether, and vegetable
`oil.
`Comments: occurs naturally as 30% of the tocopherol content
`of soybean oil. Delta tocopherol i said to be the most
`potent antioxidant of the tocopherols.
`
`Gamma tacopherol
`Empirical formula: C28H4sO2
`Molecular weight: 416.66
`CAS number: [7616-22-0]
`
`Alpha Tocopherol
`
`29
`
`( ± )-3,4-dihydro-2,7,8-trimethyl-2-(4,8,12-tri-
`Synonyms:
`methyltridecyl)-2H-1-benzopyran-6-ol; 7,8-dimethyltocol;
`E308; d/-y-tocopherol; vitamin E; o-xylococopherol.
`Appearance: a pale yellow-colored viscous oil.
`Melting point: -30°C
`Solubility: practically insoluble in water; freely soluble in
`acetone, chloroform, ethanol (95%), ether, and vegetable
`oils.
`Specific rotation [c:t.]r,0
`: - 2.4° (in ethanol (95%))
`Comments: occurs in natural ources along with alpha and
`beta rocopherol. Gamma tocopherol is biologically less
`a tive than alpha tocopherol. Very stable to heat and
`alkalis; slowly oxidized by atmospheric oxygen and gradu(cid:173)
`ally darkens on exposure to light.
`
`Tocoph.erols excipient
`Synonyms: Embanox tocopberol.
`Appearance: a pale yellow-colored viscous oil.
`Comments: tocopherols excipient i described in the USP F 20
`as a vegetable oil solution containing not less than 50.0% of
`total tocopherols, of which not less than 80.0% consist of
`varying amounts of beta, delta, and gamma tocopherols.
`
`18 Comments
`Note that most commercially available tocopherols are used as
`sources of vitamin E, rather than· as antioxidants in pharma(cid:173)
`ceutical formulation .
`Various mixture of tocopherols, and mixtures of rocopher(cid:173)
`,ols with other excipients, are commercially available and
`individual manufacturers should be consulted for specific
`information on their products.
`
`2
`
`19 Specific References
`ielsen PB, Miillertz, orling T, Kristen en HG. The effect of
`a -tocopherol on the in vitro solubilisation of lipophilic drugs. Int J
`Pbarm 2001; 222: 217-224.
`John on DM, Gu LC. Autoxidation and antioxidants. In:
`warbrick J, Boylan JC, eds. Encyclopedia of Pharmaceutical
`Technology, volume l.
`ew York: Marcel Dekker, 1988: 415-
`450.
`3 Allwood MC. Compatibility and stability of TPN mixtures in big
`bags. J Clin Hosp Pharn, 1984; 9: 181-198.
`4 Buck DF. Antioxidant . In: Smith J, ed. Food Additive User's
`Handbook. Glasgow: Blackie, 1991: 1-46.
`5 Rudy BC, Senkowski BZ. d/-Alpha-tocopheryl acetate. In: Florey
`K, ed. Analytical Profiles of Drug Substances, volume 3. New
`York: Academic Press, 1974: 111-126.
`6 FAO/WHO. Evaluation of certain food additive and contami(cid:173)
`nants. Thirtieth report of the joint FAO/WHO expert committee
`on food additives. World Health Organ Tech Rep Ser 1987; No.
`751.
`
`20 General References
`utrition Board. Recom(cid:173)
`US
`ational Research Council Food and
`mended Dietary Allowances, 10th edn. Washington DC:
`ational
`Academy Press, 1989: 99-105.
`
`21 Author
`SC Owen.
`
`22 Date of Revision
`29 July 2002.
`
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`AQUESTIVE EXHIBIT 1031 page 0008
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`

`

`Benzyl Alcohol
`
`Nonproprietary Names
`
`BP: Benzyl alcohol
`JP: Benzyl alcohol
`lcohol benzylicus
`PhEur:
`USP F: : Benzyl alcohol
`
`9 Pharmacopeiol Specifications
`ee able I.
`
`Table I:
`
`Test
`
`Pharmacopeial specifications for benzyl olconol.
`
`JP 2001
`
`PnEur 2002
`
`USPNF 20
`
`+
`
`+
`
`+
`
`Identification
`Characters
`Solubility
`+
`Acidity
`Clarity of solution +
`Specific gravity
`1.043-1 .053
`202.5-206.5 C
`Distilling range
`1.538-1 .541
`Refractive index
`Residue on ignition ..; 0.005%
`Nonvolatile matter
`Chlorinated
`compounds
`Benzaldehyde
`Peroxide value
`Organic volatile
`impurities
`Assay
`
`;;;. 98 .0%
`
`+
`+
`+
`+
`
`+
`
`+
`
`I .043-1 .049
`
`1.042-1.047
`
`1 .538- 1.541
`
`..; 0.05%
`,s:; 300ppm
`
`1.539-1 .54 1
`..; 0.005%
`,.; 1 mg
`,.; 0 .03%
`
`,.; 0.2%
`,.; 5
`
`..; 0 .2%
`
`+
`
`97.0-100.5% 97.0- l 00.5'7o
`
`2 Synonyms
`ix-Hydroxytoluene; phenylcarbinol; phenylmethanol· cx-tolue(cid:173)
`nol.
`
`3 Chemical Name and CAS Registry Number
`Benzcnemethanol [ I 00-5 1-6]
`
`4 Empirical Formula
`
`-HsO
`
`Molecular Weight
`108.14
`
`5 Structural Formula
`
`0-CH,oo
`
`6 Functional Category
`Antimicrobial preservative; disinfectant; olvenr.
`
`7 Applications in Pharmaceutical Formulation
`or Technology
`Benzyl alcohol is an antimicrobial preservative used in cos(cid:173)
`metic I foods, and a wide range of pharma eutical formula(cid:173)
`including oral and parenteral preparation , at
`tions,' -4)
`concentration up to 2.0% v/v. In cosmetics, concentrations
`up to 3.0% v/v may be u cd as a preservative. Concentrations
`of 5% v/v or more are employed as a solubilizcr, while a 10%
`v/v olurion is used as a disinfectant.
`Benzyl alcohol 10% v/v solutions also have ome local
`anesthetic propertie , which are exploited in some parent(cid:173)
`eral , cough products, ophthalmic solution ointments, and
`dermatological aerosol sprays.
`Although widely used as an antimicrobial preservative,
`bcnzyl alcohol has been associated with some fatal adver e
`reactions when administered to neonates. It is now recom(cid:173)
`mended that parenteral products pre erved with benzyl alco(cid:173)
`hol, or other antimicrobial preservatives, should not be used in
`newborn infant if at all possible; see Section 14.
`
`10 Typical Properties
`Acidity/alkalinity: aqueous olutions are neutral to litmus.
`Antimicrobial activity: benzyl alcohol i bacterio tatic and is
`used as an antimicrobial preservative against Gram-positive
`bacteria, mold , fungi, and yeast , although it posse ses
`only mode t bactericidal properties. Optimum activity
`occur at pH below 5; little activity i hown above pH 8.
`Antimi robial activity is reduced in the presence of nonionic
`surfactants, such as polysorbate 80. However, the reduction
`in activity is less than i the case with either hydroxybenzo(cid:173)
`a te esters or quaternary ammonium compounds. The activ(cid:173)
`reduced by
`ity of benzyl alcohol may also be
`incompatibilities with some packaging materials, particu(cid:173)
`larly polyethylene; see Section 12.
`See Table lI for reported minimum inhibitory concentrations
`(MICs).
`
`Table II: Minimum inhibitory concentrations (MICs) of benzyl
`alcohol.141
`
`Microorganism
`
`MIC lµg/mll
`
`Aspergillus niger
`Candido olbicons
`Escherichia coli
`Pseudomonos oeruginoso
`Staphylococcus oureus
`
`5000
`2500
`2000
`2000
`25
`
`8 Description
`A clear, colorless, oily liquid with a faint aromatic odor and a
`harp, burning taste.
`
`Bacteria: benzyl alcohol is moderately active again t most
`(typical M ICs are 3-5 mg/mL),
`Gram-positive organism
`although some Gram-positive bacteria are very sensitive
`
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`53
`AQUESTIVE EXHIBIT 1031 page 0009
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`

`

`54
`
`Benzyl Alcohol
`
`(MI Cs 0.025--0.05 mg/mL). In general, benzyl alcohol is less
`active against Gram-negative organisms.
`Fungi: benzyl alcohol is effective against mold and yeasts;
`typical MI s are 3-5 mg/mL.