`
`
`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
`
`©APhA
`American Pharmaceutical Association
`
`Washington, D.C.
`
`Pharmaceutical Press
`
`London, United Kingdom
`
`|
`|
`
`|
`
`
`
`AQUESTIVE EXHIBIT 1026
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`AQUESTIVE EXHIBIT 1026 page 0001
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`
`Published by the American Pharmaceutical Association
`2215 Constitution Avenue NW, Washington, DE 20037-2985, USA
`www.aphanet.org
`and the Pharmaceutical Press
`1 Lambeth High Street, London SE1 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.
`; om.
`Includes bibliographical references and index.
`ISBN 0-917330-96-X
`1. Excipients--Handhooks, manuals, etc.
`JI. Kibbe, Arthur H.II. American
`Pharmaceutical Association.
`[DNLM:1. Excipients--Handbooks. QV 735 H236 2000]
`615',19--de21
`RS201.E87 H36 2000
`A catalogue record for this book is available from the British Library.
`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 thig book and cannot accept any legal responsibility ot
`liability for any errors or omissions that may be made.
`
`99-044554
`
`Managing Editor: Melanie Segala
`Copyeditor:
`Paul Gettehrer
`Indexer:
`Lillian Rodberg
`Compositor:
`Roy Barnhill -
`Cover Designer:
`Tim Kaage
`
`AQUESTIVE EXHIBIT 1026
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`
`
`Alcohol
`
`7
`
` Alcohol
`
`‘1. Nonproprietary Names
`BP: Ethanol (96%)
`JP: Ethanol
`PhEur: Ethanolum (96 per centum}
`USP: Alcohol
`
`2, Synonyms
`Ethyl alcohol; ethy! hydroxide; grain alcohol; methyl] carbinol.
`
`3, Chemical Name and CAS Registry Number
`
`Ethanol [64-17-5]
`
`4, Empirical Formula
`
`C,H,O
`
`Molecular Weight
`46.07
`
`5, Structural Formula
`
`In the USP, the term ‘dehydrated alcohol’ refers to ethanol 2
`99.5% viy. The term ‘alcohol’, without other qualification re-
`fers to ethanol 94,9-96.0% viv.
`In the JP, ethanol (alcohol) contains 95.1-95.6% v/v (by spe-
`cific gravity) of C,HgO at 15°C.
`In the Handbook of Pharmaceutical Excipients, the term ‘al-
`cohol’ is used for either ethanol 95% v/v or ethanol 96% viv.
`Alcohol is a clear, colorless, mobile, and volatile liquid with
`a slight, characteristic odor and burning taste.
`See also Section 18.
`
`9, Pharmacopeial Specifications
`
` Test JP PhEur USP
`
`
`
`Identification
`+
`+
`+
`Specific gravity
`0.814-0.816 0.8051-0,.8124
`0.812-0.816
`Acidity
`+
`+
`+
`Clarity of solution
`+
`+
`_—
`Nonvolatile residue
`+
`<2.5 mg/100 mL <1 mg/40 mL
`Water-insoluble
`—_—
`—
`+
`substances
`Aldehydes
`Amyl alcohol, ete.
`Absorbance
`Fusel oil constituents
`
`+
`—
`—
`+
`
`_—
`_
`+
`—_—
`
`.
`
`+
`+
`—_
`_
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Extracting solvent in galenical manufacture
`. Solventin film coating
`
`=. Solventin injectable solutions
`
`* Solvent in oral liquids
`
`“2 Solvent in topical products
`
`
`. 8. Description
`
`
`In the BP, the term ‘ethanol’ used without other qualification
`tefers to ethanol containing > 99.5% wv of C,H,O. The term
`
`alcohol’, without other qualification, refers to ethanol
`96.0-96.6% v/v. Where other strengths are intended, the term
`
`‘alcohol’ or ‘ethanol’ is used, followed by the statement of
`the: strength.
`
`6. Functional Category
`Antimicrobial preservative; disinfectant; skin penetrant; sol-
`vent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Ethanol and aqueous ethanol solutions of various concentra-
`tions (see Sections 8 and 18) are widely used in pharmaceu-
`tical formulations and cosmetics. Although ethanol
`is
`primarily used as a solvent it is also employed in solutions
`as an antimicrobial preservative.) Topical ethanol solutions
`are also used as penetration enhancers) and as disinfectants.
`
`
`
`
`Use Concentration (% v/v)
`
`Antimicrobial preservative
`Disinfectant
`
`210
`60-90
`
`Up to 85
`Variable
`Variable
`Variable
`60-90
`
`
`
`Acetone and propan-2-ol_ —
`Methanol!
`Reducing substances
`Organic volatile
`impurities
`Chloride
`
`+
`+
`
`Heavy metals
`
`_—
`_
`_—
`+
`
`+
`+
`_
`_—
`
`—
`—
`+
`s12ppm — —
`
`
`
`10. Typical Properties
`Antimicrobial activity: ethanol is bactericidal in aqueous mix-
`tures at concentrations between 60-95% v/v; the optimum
`concentration is generally considered to be 70% w/v. Anti-
`microbial activity is enhanced in the presence of edetic
`acid or edetate salts.“ Ethanol is inactivated in the pres-
`ence of nonionic surfactants and is ineffective against bac-
`terial spores.
`Boiling point: 78.15°C
`Flammability: readily flammable, burning with a bluc, smoke-
`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 aft 20°C
`Note:
`the above typical properties are for alcohol (ethanol
`95% or 96% viv). See Section 18 for typical properties of
`dehydrated alcohol.
`
`j
`
`11. Stability and Storage Conditions
`Aqueous ethanol solutions may be sterilized by autoclaving
`or by filtration and should be stored in airtight containers, in
`a cool place.
`
`12. Incompatibilities
`In acidic conditions, ethanol solutions may react vigorously
`with oxidizing materials. Mixtures with alkali may darken in
`
`AQUESTIVE EXHIBIT 1026
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`AQUESTIVE EXHIBIT 1026 page 0003
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`
`
`
`
`& Alcohol
`
`color due to a reaction with residual amounts of aldehyde.
`Organic salts or acacia may be precipitated from aqueous so-
`lutions or dispersions. Ethanol solutions are also incompatible
`with aluminum containers and may interact with some drugs.
`
`13. Method of Manufacture
`Ethanol is manufactured by the controlled enzymatic fermen-
`tation of starch, sugar, or other carbohydrates. A fermented
`liquid is produced containing about 15% ethanol; ethanol 95%
`viv is then obtained by fractional distillation. Ethanol may
`also be prepared by a number of synthetic methods.
`
`14. Safety
`Ethanol and aqueous ethanol solutions are widely used in a
`variety of pharmaceutical formulations and cosmetics. Ethanol
`is also consumed in alcoholic beverages.
`Ethanolis rapidly absorbed from the gastrointestinal tract and
`vapor may be absorbed through the lungs. Ethanol is metab-
`olized mainly in the liver to acetaldehyde, which is further
`oxidized to acetate.
`
`Ethanol] is a central nervous system depressant and ingestion
`of low to moderate quantities can lead to symptoms of intox-
`ication including muscle incoordination, visual
`impairment,
`slurred speech, etc. Ingestion of higher concentrations may
`cause depression of medullary action, lethargy, amnesia, hy-
`pothermia, hypoglycemia, stupor, coma, respiratory depression,
`and cardiovascular collapse. The lethal human blood-alcohol con-
`centration is generally estimated to be 400-500 mg/100 mL.
`Although symptoms of ethanol intoxication are usually en-
`countered following deliberate consumption of ethanol-con-
`taining beverages, many pharmaceutical products contain
`ethanol as a solvent which,
`if ingested in sufficiently large
`quantities, may cause adverse symptoms of intoxication.
`Parenteral products containing up to 50% of alcohol (ethanol
`95% or 96% viv) have been formulated. However, such con-
`centrations can produce pain on intramuscular injection and
`lower concentrations such as 5-10% v/v are preferred, Sub-
`cutaneous injection of alcohol (ethanol 95% v/v) similarly
`causes considerable 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.“
`Preparations containing greater than 50% v/v alcohol may
`cause skin irritation when applied topically.
`LDso (guinea pig, IP): 3.41 g/kg
`LDsy (guinea pig, FV): 2.3 g/kg
`LDs, (guinea pig, oral): 5.56 g/kg
`LDs59 (hamster, IP): 5.07 g/kg
`LD<9 (mouse, IP): 0.93 g/kg
`LDsq (mouse, IV): 1.97 gikg
`LD; (mouse, oral}: 7.5 g/kg
`LDs» (mouse, SC): 8.29 g/kg
`LD; (rabbit, IP}: 0.96 g/kg
`LDso (rabbit, IV): 2.37 g/kg
`LD, (rabbit, oral): 6.3 g/kg
`LDsp (rat, IP): 3.75 g/kg
`LDsy (rat, IV): 1.44 gfke
`LDs9 (rat, oral): 7.06 gékg
`
`15. Handling Precautions
`
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Ethanc! and aqueous ethanol
`solutions should be handled in a well-ventilated environment.
`In the UK, the long-term 8-hour TWA exposure limit for eth-
`anol is 1920 mg/m? (1000 ppm).Ethanol may be irritant to
`the eyes and mucous membranes and eye protection and
`gloves are therefore recommended. Ethanol is flammable and
`should be heated with care. Fixed storage tanks should be
`electrically grounded to avoid ignition from electrostatic dis-
`charges, when ethanol is transferred.
`
`16. Regulatory Status
`
`Included in the FDA Inactive Ingredients Guide (dental prep-
`arations,
`inhalations, IM and IV injections, nasal and oph-
`thalmic preparations, oral capsules, solutions, suspensions,
`syrups and tablets, rectal,
`topical, and transdermal prepara-
`tions). Included in nonparenteral and parenteral medicinesli-
`censed in the UK.
`
`17. Pharmacopeias
`
`China, Eur, Int, Jpn, Pol, and US.
`
`18. Related Substances
`
`Déhydrated alcohol; denatured alcohol; dilute alcohol; isopro-.
`pyl alcohol.
`
`Dehydrated alcohol
`Synonyms: absolute alcohol; anhydrous ethanol; ethanol.
`Autoignition temperature, 363°C
`Boiling point: 78.5°C
`Explosive limits. 3.5-19.0% viv in air
`Flash point: 12°C (closed cup)
`Hygroscopicity: absorbs water rapidly from the air.
`Melting point: -112°C
`Refractive index: np*° = 1.361
`Specific gravity: 0.7904-0.7935 at 20°C
`Surface tension: 22.75 mNfm at 20°C (ethanol/vapor)
`Vapor density (relative): 1.59 (air = 1)
`Vapor pressure: 5.8 Pa at 20°C
`Viscosity (dynamic): 1.22 mPa s (1.22 cP) at 20°C
`Comments: dehydrated alcohol
`is ethanol 2 99.5% viv. See
`Section 8.
`
`Denatured alcohol
`Synonyms: industrial methylated spirit; surgical spirit,
`Comments: denatured alcohol is alcohol, for external use only,
`that 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.
`
`
`
`
`
`AQUESTIVE EXHIBIT 1026
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`AQUESTIVE EXHIBIT 1026 page 0004
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`

`
`
`
`
`Alcohol 9
`
`Specific gravity:
`
`Strength of alcohol
`(% viv)
`
`Specific gravity at 20°C
`
`0.8289-0.8319
`90
`0,8599-0.8621
`80
`0.8860-0.8883
`70
`0.9103-0.9114
`60
`0.9314-0.9326
`50
`0.9407-0.9417
`45
`0.9694-0.9703
`25
`
`20 0.9748-0.9759
`
`Comments: the term ‘dilute alcohol’ refers to a mixture of ethanol
`and water of stated concentration. The BP lists eight strengths
`of dilute alcohol (dilute ethanol) containing 90, 80, 70, 60, 50,
`45, 25, and 20% v/v respectively of ethanol.
`
`19. Comments
`
`Possession and use of nondenatured alcohols are usually sub-
`ject to close control by excise authorities.
`
`2. Karabit MS, Juneskans OT, Lundgren P. The determination of
`antimicrobial characteristics of some pharmaceutical com-
`pounds in aqueous solutions. fat J Pharmaceutics 1989; 54:
`51-56.
`3, Liu P, Higuchi WI, Song W, Kurihara-Bergstrom T, Good WR.
`Quantitative evaluation of ethanol effects on diffusion and
`metabolism of B-estradiol in hairless mouse skin. Pharm Res
`1991; 8: 865-872.
`the anaesthetist and the pain
`4, Lloyd JW. Use of anaesthesia:
`clinic. Br Med J 1980; 281: 432-434.
`5. Sweet DV, editor. Registry of Toxic Effects of Chemical Sub-
`stances. Cincinnati, US Department of Health, 1987.
`6. Health and Safety Executive. Occupational exposure limits
`1998: EH40/98. Sudbury, Health and Safety Executive, 1998.
`
`21. General References
`
`Lund W,editor. The Pharmaceutical Codex: Principles and Prac-
`tice of Pharmaceutics, 12th edition. London, The Pharmaceu-
`tical Press, 1994; 694-695.
`Spiegel AJ, Noseworthy MN. Use of nonaqueous solvents in
`parenteral products. J Pharm Sei 1963; 52: 917-927,
`Wade A, editor. Pharmaceutical Handbook, 19th edition. London,
`The Pharmaceutical Press, 1980; 227-230.
`
`20. Specific References
`1. Chiori CO, Ghobashy AA. A potentiating effect of EDTA on
`the bactericidal activity of lower concentrations of ethanol.
`Int J Pharmaceutics 1983; 17: 121-128.
`
`22, Authors
`
`PY Weller.
`
`
`
`
`
`
`
`AQUESTIVE EXHIBIT 1026
`
`AQUESTIVE EXHIBIT 1026 page 0005
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`page 0005
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`

`
`
`
`Alcohal 9
`
`
`
`Specific gravity:
`
`Specific gravity at 20°C
`Strength of alcohol
` (% viv)
`90
`0.8289-0,8319
`80
`0.8599.6,8621
`70
`0,.8860-0,8883
`60
`0,9103-0,9114
`50
`0,9314-0,9326
`45
`0,.9407-0.9417
`25
`0.9694-0.9703
`
`20 0.9748-0.9759
`
`Comments: the term ‘dilute alcohol’ refers to a mixture of ethanol
`and water of stated concentration. The BP lists eight strengths
`of dilute alcohol (dilute ethanol) containing 90, 80, 70, 60, 50,
`45, 25, and 20% v/v respectively of ethanol.
`
`19, Commenis
`
`Possession and use of nondenatured alcohols are usually sub-
`ject to close control by excise authorities.
`
`2. Karabit MS, Juneskans OT, Lundgren P. The determination of
`antimicrobial characteristics of some pharmaceutical com-
`pounds in aqueous solutions. int J Pharmaceutics 1989; 54:
`51-56.
`3. Liu P, Higuchi WI, Song W, Kurihara-Bergstrom T, Good WR.
`Quantitative evaluation of ethanol effects on diffusion and
`metabolism of f-estradiol in hairless mouse skin, Pharm Res
`1991: 8: 865-872.
`the anaesthetist and the pain
`4, Lloyd TW. Use of anaesthesia:
`clinic. Br Med J 1980; 281: 432-434,
`5. Sweet DV, editor. Registry of Toxic Effects of Chemical Sub-
`stances. Cincinnati, US Department of Health, 1987.
`6. Health and Safety Executive. Occupational exposure limits
`1998; EH40/98. Sudbury, Health and Safety Executive, 1998.
`
`2E. General References
`Lund W,editor. The Pharmaceutical Codex: Principles and Prac-
`tice of Pharmaceutics, 12th edition, London, The Pharmaceu-
`tical Press, 1994; 694-695.
`Spiegel AJ, Noseworthy MN. Use of nonaqueous solvents in
`parenteral products. J Pharm Sci 1963; 52: 917-927.
`Wade A, editor. Pharmaceutical Handbook, 19th edition. London,
`The Pharmaceutical Press, 1980; 227-230.
`
`20. Specific References
`1. Chiori CO, Ghobashy AA. A potentiating effect of EDTA on
`the bactericidal activity of lower concentrations of ethanol.
`Int J Pharmaceutics 1983; 17: 121-128.
`
`22, Authors
`
`PJ Weller.
`
`
`
`
`
`AQUESTIVE EXHIBIT 1026
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`
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`
`
`18 Alpha Tocopherol
`
`
`
`Alpha Tocopherol
`
`1. Nonproprietary Names
`BP: Alpha tocopherol
`JP: ‘Tocopherol
`PhEur: &-Tocopherolum
`USP: Vitamin E
`See also Sections 3, 9, and 18.
`
`2. Synonyms
`(+)-3,4-Dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-
`2H-1-benzopyran-6-ol; E307; synthetic alpha tocopheral; ali-rac-
`ci-tocopherol; di-c-tocopherol; 5,7,8-himethyltocol.
`
`3. Chemical Name and CAS Registry Number
`(+)-(2RS,4’RS,8’RS)-2,5,7,8-Tetramethyl-2-(4’,8”,12’-trimethyl-
`tridecyl)-6-chromanol [10191-41-0]
`Note that alpha tocopherol has three chiral centers giving rise
`to eight
`isomeric forms. The naturally occurring form is
`known as d-alpha tocopherol or (2R,4’R,8’R)-alpha-toco-
`pherol. The synthetic form, di-alpha tocopherol or simply al-
`pha tocopherol, occurs as a racemic mixture containing
`equimolar quantities of all the isomers.
`Similar considerations apply to beta, delta, and gamma toco-
`pherol and tocopherol esters.
`See Section 18 for further information.
`
`4, Empirical Formula
`CogH5q02
`
`Molecular Weight
`430.72
`
`5, Structural Formula
`
`
`
`R, = Rp = Ry = CH.
`Alpha tocopherol:
`R, = R, = CH; R, = H.
`Beta tocopherol:
`Ry = CH;; Ry = R, =H.
`Delia tocopherol:
`Gamma tocopherol: R,; = R2 = CH;; R3 = H.
`* Indicates chiral centers.
`
`6. Functional Category
`Antioxidant; therapeutic agent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Alpha tocopherol is primarily recognized as a source of vi-
`tamin E and the commercially available materials and speci-
`fications reflect
`this purpose. While alpha tocopherol also
`
`the beta, delta, and gamma
`exhibits antioxidant properties,
`tocopherols are considered to be more effective as antioxi-
`dants.
`Of widespread regulatory acceptability, tocopherols are of val-
`ue in oil- or fat-based pharmaceutical products and are nor-
`mally used in the concentration range of 0.001-0.05%. There
`is frequently an optimum concentration; thus the autoxidation
`of linoleic acid and methyl linolenate is reduced at low con-
`centrations of alpha tocopherol but accelerated by higher con-
`centrations. Antioxidant effectiveness can be increased by the
`addition of oil-soluble synergists such as lecithin and ascorbyl
`palmitate.‘
`
`8. Description
`it is avail-
`Atpha tocopherol is a natural product. Therefore,
`able as either practically odorless, clear, colorless, yellow, yel-
`lowish-brown, or greenish-yellow colored viscous oil, See also
`Section 18.
`
`9. Pharmacopeial Specifications
`
`Test
`
`JP
`
`PhEor
`
`USP
`
`+
`—_—
`—_
`S20 ppm
`_
`
`+
`+
`Identification
`+
`_—
`Acidity
`_
`s2
`Acid value
`<20ppm —
`Heavy metals
`< 0.1%
`_—
`Sulfated ash
`_
`+
`Organic volatile impurities
`72.0-76%
` —
`71.0-76%
`.Absorbance
`1.503-1.507 —
`—
`Refractive index
`0,.947-0.955 —
`—
`Specific gravity
`Clarity and color of solution +
`_
`—_—
`
`Assay 96.G-102.0% 96.0-102.0% 96.0-102.0%op
`
`Note that the USP describes vitamin E as comprising d- or
`di-alpha tocopherol; d- or dl-alpha tocopheryl acetate; or d-
`or di-alpha tocopheryl acid succinate. However,
`the PhEur
`describes alpha tocopherol and alpha tocopheryl acetate in
`separate monographs.
`The diversity of the tocopherols described in the various phar-
`macopeial monographs makes a comparison of specifications
`difficule.
`
`10. Typical Properties
`Boiling point: 235°C
`Density (20°C): 0.947-0.951 g/em?
`Flash point: 240°C
`Ignition point: 340°C
`Refractive index: np?° = 1.503-1.507
`Solubility: practically insoluble in water; freely soluble in ace~
`tone, ethanol, ether, and vegetable oils.
`
`i
`11. Stability and Storage Conditions
`Tocopherols are slowly oxidized by atmospheric oxygen and
`rapidly by ferric andsilver salts. Oxidation products include
`tocopheroxide, tocopherylquinone, and tocopherylhydroquino-
`ne, as well as dimers and trimers. Tocopherol! esters are mote
`stable to oxidation than the free tocopherols but are in con-
`sequence less effective antioxidants. See also Section 18,
`Tocopherols should be stored underan inert gas, in an airtight
`container in a cool, dry, place and protected from light.
`
`AQUESTIVE EXHIBIT 1026 page 0007
`AQUESTIVE EXHIBIT 1026
`page 0007
`
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`

`

`12. Incompatibilities
`_...Tocopherols are incompatible with peroxides and metal ions,
`‘especially iron, copper, and silver. Tocopherols may be ab-
`~ garbed into plastic.)
`| 7. 13, | Method of Manufacture
`‘ Naturally occurring tocopherols are obtained by the extraction
`-- or molecular distillation of steam distillates of vegetable oils,
`“S-@.g., alpha tocopherol occurs in concentrations of 0.1-0.3% in
`corn,
`tapeseed, soybean, sunflower, and wheat germ oils.)
`“ Beta and gamma tocopherol are usually found in natural
`. sources along with alpha tocopherol. Racemic synthetic toco-
`oS pherols may be prepared by the condensation of the appro-
`priate methylated hydroquinone with racemic isophytoi.
`
`-
`
`14. Safety
`~ Tocopherols (vitamin E) occur in many food substances that
`-.- are consumed as part of the normal diet. The daily nutritional
`“;
`réquirement has not been clearly defined but is estimated to
`:-be.3:20 mg: Absorption from the gastrointestinal tract is de-
`~ pendent upon normal pancreatic function and the presence of
`“pile. Tocopherols are widely distributed throughout the body
`2 with some ingested tocopherol metabolized in the liver; ex-
`~eretion of metabolites is via the urine or bile. Individuals with
`“vitamin E deficiency are usually treated by oral administration
`< of tocopherols although intramuscular and intravenous admin-
`istration may sometimes be used.
`Tocopherels are well tolerated although excessive oral intake
`may cause headache, fatigue, weakness, digestive disturbance,
`and nausea. Prolonged and intensive skin contact may lead to
`erythema and contact dermatitis.
`“ . The use of tocopherols as antioxidants in pharmaceuticals and
`‘food products is unfikely to pose any hazard to human health
`since the daily intake from such uses is small compared to
`: . \ the intake of naturally occurring tocopherols in the diet,
`os The’ WHO: has set an acceptable daily intake of tocopherol
`: “Used as-an antioxidant at 0.15-2 mg/kg body-weight.©
`15. HandlingPrecautions
`“2: Observe normal: precautions appropriate to the circumstances
`oy and. quantity’ of material handled. Gloves and eye protection
`Voare: recommended: -
`
`(16. Regulatory Status
`GRASlisted, Accepted in Europe as a food additive. Included
`in the FDA Inactive Ingredients Guide (oral capsules, tablets,
`and topical preparations). Included in nonparenteral medicines
`licensed in the UK.
`
`
`
`17. Pharmacopeias
`Eur, Jpn, and US.
`Note that the nomenclature for tocopherols and tocopherol
`derivatives is confusing and many pharmacopeias do aot spec-
`ify clearly the isomer or form of the tocopherol.
`
`18. Related Substances
`
`d-Aipha tocopherol: C2H5,05
`Molecular weight: 430.72
`CAS number: (59-02-9]
`
`Alpha Tocopherol
`
`19
`
`(+)-(2R,4’'R,8’R}-
`Synonyms: natural alpha tocopherol;
`2,5,7,8-tetramethyl-2-(4’,8’,12’-trimethyltridecy})-6-chromancl;
`d-ca-tocopherol; vitamin E.
`Appearance: a practically odorless, clear, yellow, or greenish-
`yellow colored viscous oil.
`Melting point: 2.5-3.5°C
`Solubility: practically insoluble in water; soluble in ethanol
`(95%). Miscible with acetone, chloroform, ether, and veg-
`etable oils.
`
`Specific gravity: 0.95
`Comments: this ig the naturally occurring form of alpha toco-
`pherol.
`
`d-Alpha tocopheryl acetate: C;,H;.0;
`Melecular weight: 472.73
`CAS number: [38-95-7]
`Synonyms:
`(+)-(28,4’R,8'R)-2,5,7,8-tetramethyl-2-(4’,8’,12’-
`trimethyltridecyl)-6-chromanyl acetate; d-a-tocopheryl
`acetate: vitamin E.
`Appearance: a practically odorless, clear, yellow, or greenish-
`yellow colored viscous ofl which may solidify in the cold.
`Melting point: 28°C
`Solubility: practically insoluble in water; soluble in ethanol
`(95%). Miscible with acetone, chloroform, ‘ether, and veg-
`etable oils.
`Specific rotation [O]p*5: +0,.25° (10% w/y solution in chloro-
`form)
`Comments: unstable to alkalis.
`
`di-Alpha tocophery] acetate: C3,;H..0,
`Molecular weight: 472.73
`CAS number: [7695-91-2]|
`Synonyms: (x)-3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8, 12-trimethyl-
`tridecyl)-2A-1-benzopyran-6-ol acetate; (+)-(2R5,4’RS,8'RS)-
`2,5,7,8-tetramethyl-2-(4’,8”,12’-trimethyltridecyl)-6-chromanyl
`acetate; (+)-o+tocopherol acetate; o-tocopheroli acetas; all-rac-
`o-tocopheryl acetate; di-c-tocopheryl acetate; vitamin E.
`Appearance: a practically odortess, clear, yellow, or greenish-
`yellow viscous oil.
`Density: 0.953 g/cm?
`Melting point: -27,.5°C
`Refractive index: np*° = 1.4950-1.4972
`Solubility: practically insoluble in water; freely soluble in ace-
`tone, chloroform, ethanol, ether, and vegetable oils; soluble
`in ethanol (95%).
`Comments: unstable to alkali. However, unlike alpha toco-
`pherol,
`the acetate is much less susceptible to the effects
`of air, light, or ultraviolet light. Alpha tocopherol acetate
`concentrate, a powdered form of alpha tocopherol acetate,
`is described in the PhEur. The concentrate may be prepared
`by either dispersing alpha tocopherol acetate in a suitable
`carrier such as acacia or gelatin, or by adsorbing alpha
`tocopherol acetate on silicic acid.
`
`i
`
`d-Alpha tocophery! acid succinate: Cz,H5,05
`Molecular weight: 530.8
`CAS number: [4345-03-3]
`Synonyms:
`(+)-a-tocopherol hydrogen succinate; d-o-toco-
`pheryl acid succinate; vitamin E.
`Appearance: a practically odorless white powder.
`Melting point: 76-77°C
`Solubility: practically insoluble in water; slightly soluble in
`alkaline solutions; soluble in acetone, ethanol (95%), ether,
`and vegetable oils; very soluble in chloroform.
`Comments: unstable to alkalis.
`
`AQUESTIVE EXHIBIT 1026
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`AQUESTIVE EXHIBIT 1026 page 0008
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`

`20 Alpha Tocopherol
`
`di-Alpha tocopheryl acid succinate: C3;H5,05
`Molecular weight: 530.8
`CAS number: [17407-37-3]
`Synonyms: (4)-o-tocopherol hydrogen succinate, di-a-tocopherol
`succinate: di-c-tocopheryl acid succinate; vitamin E.
`Appearance: a practically odorless white crystalline powder.
`Solubility: practically insoluble in water, slightly soluble in
`alkaline solutions; soluble im acetone, ethanol (95%), ether,
`and vegetable oils; very soluble in chloroform.
`Comments: unstable to atkalis.
`
`Beta tocopherol: C,H,05
`Molecular weight: 416.66
`CAS number: [148-03-8]
`Synonyms: cumetocopherol; (+)-3,4-dihydro-2,5,8-trimethy]-
`2-(4,8,12-trimethyltridecyl)-2H-| -benzopyran-6-ol; 5,8-dimethyl-
`tocol; nectocopheral; di-B-tocopherol; vitamin E; p-xylotoco-
`pherol.
`Appearance: a pale yellow colored viscous oil.
`Solubility: practically insoluble in water; freely soluble in ace-
`tone, chloroform, ethancl (95%), ether, and vegetable oils.
`Specific rotation [ot]p,7°: +6.37°
`Comments:
`less active biologically than alpha tocopherol.
`Obtained along with alpha tocopherol and gamma toco-
`pherol from natural sources. Beta tocopherol is very stable
`to heat and alkalis and is slowly oxidized by atrnospheric
`oxygen.
`
`Delta tocopherol: C57H,,03
`Molecular weight: 402.64
`CAS number: [119-13-1]
`Synonyms: (+)-3,4-dihydro-2,8-dimethyl-2-(4,8, 12-trimethy]-
`tridecyl)-2H-1-benzopyran-6-o1; E309; 8-methyltocol; «i-3-toco-
`pherol; vitamin E.
`Appearance: a pale yellow colored viscous oil.
`Solubility: practically insoluble in water; freely soluble in ace-
`tone, chloroform, ethanol (95%), ether, and vegetable oils.
`Comments: occurs naturally as 30% of the tocopherol content
`of soybean oil. Delta tocopherol
`is said to be the most
`potent antioxidant of the tocopherols.
`
`Gamma tocopherol: Cy.H4,02
`Molecular. weight. 416.66
`CAS number: [7616-22-0)
`Synonyms:
`(+)-3,4-dihydro-2,7,8-trimethyl-2-(4,8, 12-trimethyl-
`tridecy!)-21-1-benzopyran-6-ol; 7,8-dimethyltocol; E308; di-y-
`tocopherol; vitamin E; o-xylotocopherol.
`Appearance: a pale yellow colored viscous oil.
`Melting paint: -30°C
`Solubility: practically insoluble in water; freely soluble in ace-
`tone, chloroform, ethanol (95%), ether, and vegetable oils.
`Specific rotation [a]p29; -2.4° Gn ethanol(95%))
`
`Comments: occurs in natural sources along with alpha and
`beta tocophero], Gamma tocopherol
`is biologically less
`active than alpha tocopherol. Very stable to heat and alka-
`lis; slowly oxidized by atmospheric oxygen and gradually
`darkens on exposure to light.
`
`Tocopherols excipient
`Synonyms: Embanox tocopherol.
`Appearance: a pale yellow colored viscous oil.
`Pharmacopeias: US.
`Comments: tocopherols excipient is described in the USP as
`a vegetable oil solution containing not less than 50.0% of
`total
`tocopherels, of which not fess than 80.0% consists
`of varying amounts of beta, delta, and gamma tocopherols.
`
`19. Comments
`
`Note that most commercially available tocopherols are used
`as sources of vitamin E rather than as antioxidants in phar-
`maceutical formulations.
`Various tuixtures of tocopherols, and mixtures of tocopherols
`with other excipients are commercially available and individ-
`ual manufacturers should be consulted for specific information
`on their products.
`©
`
`20. Specific References
`1. Johnson DM, Gu LC. Autoxidation and antioxidants, In: Swar-
`brick J, Boylan JC, editors. Encyclopedia af Pharmaceutical
`Technology, volume 1. New York, Marcel Dekker, 1988;
`415-450.
`,
`2. Aliwood MC. Compatibility and stability of TPN mixtures in
`big bags. / Clin Hosp Pharm 1984; 9: 181-198.
`3. Buck DF. Antioxidants.
`In: Smith J, editor. Foed Additive
`User’s Handbook. Blackie, Glasgow, 1991; 1-46.
`In:
`4, Rudy BC, Senkewski BZ. dl-Alpha-tocopheryl acetate.
`Florey K, editor. Analytical Profiles of Drug Substances, vol-
`ume 3. New York, Academic Press, 1974; 111-126.
`5. FAO/WHO. Evaluation of certain food additives and contam-
`inants. Thirtieth report of the joint FAO/WHO expert commit-
`tee on food additives. Tech Rep Ser Wid Hith Org 1987; No.
`751.
`
`21. General References
`US National Research Council Food and Nutrition Board. Rec-
`ommended dietary allowances, 10th edition. Washington DC,
`National Academy Press, 1989; 99-105.
`
`22. Authors
`JA Stead.
`
`AQUESTIVE EXHIBIT 1026
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`AQUESTIVE EXHIBIT 1026 page 0009
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`page 0009
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`

`
`
`enzyl Alcohol
`
`Empirical Formula
`
`Molecular Weight
`108.14
`
`Structural Formula
`
`HOH
`
`
`; Nonproprietary Names
`BP: Benzyl alcohol
`
`“JP: Benzyl alcohol
`
`-PhEur: Alcohol benzylicus
`
`‘USP: Benzyl alcohol
`: Synonyms
`
`_orHydrosytoluene phenylcarbinol; phenylmethanol; c-toluenol.
`
`
`. Chemical Name and CAS Registry Number
`
`Benzenemethanol [100-51-6]
`
`
`
`
`
`
`
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`
`
`
`Benzyl alcohol is an antimicrobial preservative used in cos-
`etics, foods, and a wide range of pharmaceutical formula-
`tions,[-?) including oral and parenteral preparations, at
`
`oncentrations up to 2.0% viv. In cosmetics, concentrations
`
`ip to 3.0% v/v may be used as a preservative. Concentrations
`f.3% viv or more are employed as a solubilizer, while a
`
`
`0% viv solution is used as a disinfectant.
`
`Benzyl alcohol 10% v/v solutions also have some local anes-
`ietic. properties which are exploited in some parenterals,
`
`ough products, ophthalmic solutions, ointments, and derma-
`ological aerosol sprays.
`
`hough widely used as an antimicrobial preservative, benzyl
`
`ohol, when administered to neonates, has been associated
`
`th:some fatal adverse reactions. It is now recommended
`f parenteral products preserved with benzyl alcohol, or oth-
`
`Antimicrobial preservatives, should not be used in newborn
`
`fantsif at all possible, see Section 14.
`Description
` ear, colorless, oily liquid with a faint aromatic odor and
`a sharp, burning taste.
`
`
`Functional Category
`microbial preservative; disinfectant; solvent.
`
`
`
`Benzyl Alcohol 41
`
`9, Pharmacopeial Specifications
`
`Test
`Identification
`Characters
`
`Solubility
`Acidity
`Clarity of solution
`Specific gravity
`Distilling range
`Refractive index
`Residue on ignition
`Nonvolatile matter
`Chlorinated
`compounds
`Aldehyde
`Peroxide value
`
`Organic volatile
`impurities
`Assay
`
`JP
`+
`+
`
`PhEur
`+
`+
`
`USP
`+
`—_—
`
`+
`—_
`+
`+
`+
`—
`1.043-1.049
`1.043-1.053
`202.5-206.5°C —
`1.538-1.541
`1,538-1,541
`<= 0.005%
`—
`—_—
`<= 0.03%
`+
`< 300 ppm
`
`—
`+
`—
`1,042-1.047
`202.5-206.5°C
`1.539-1.541
`= 0.005%
`= 0.05%
`S$ 0.03%
`
`+
`_—
`
`—_
`
`S$ 0.2%
`=5
`
`_—
`
`€ 0.2%
`_—
`
`+
`
`97.0-100.5%
`
` 97.0-100.5% 298.0%
`
`10. Typical Properties
`Acidity/alkalinity: aqueous solutions are neutral to litmus.
`Antimicrobial activity: benzyl alcohol
`is bacteriostatic and is
`used as an antimicrobial preservative against Gram-positive
`bacteria, molds, fungi, and yeasts although it possesses only
`modest bactericidal properties. Optimum activity occurs at
`less than pH 5; little activity is shown above pH 8. Antimi-
`crobial activity is reduced in the presence of nonionic sur-
`factants, such as polysorbate 80. However, the reduction in
`activity is less than is the case with either hydroxybenzoate
`esters or quaternary ammonium compounds. The activity of
`benzyl alcohol may also be reduced by incornpatibilities with
`some packaging materials, particularly polyethylene, see Sec-
`tion 12. Reported minimum inhibitory concentrations (MICs)
`are shown in Table I.
`Bacteria: benzyl alcohol is moderately active against most
`Gram-positive organisms (typical MICs are 3-5 mg/ml.),
`although some Gram-positive bacteria are very sensitive
`(MICs 0.025-0.05 mg/mL). In general, benzyl alcohol is
`less active against Gram-negative organisms.
`Fungi: benzyl alcohol is effective against molds and
`yeasts; typical MICs are 3-5 mg/mL.
`Spores: benzyl alcohol is inactive against spores, but activ-
`ity may be enhanced by heating. Benzyl alcohol 1% v/v,
`at pH 5-6, has been claimed to be as effective as phenylm-
`ercuric nitrate 0.002% w/v against Bacillus stearothermo-
`philus at 100°C for 30 minutes.
`Autoignition temperature: 436.5°C
`Boiling point: 204.7°C
`Flammability: flammable, Limits in air 1.7-15.0% wiv. 4
`Flash point:
`'
`100.6°C (closed cup);
`104.5°C (open cup).
`Freezing point: -15°C
`Melting point: -15.2°C
`
`AQUESTIVE EXHIBIT 1026
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`AQUESTIVE EXHIBIT 1026 page 0010
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`

`42 Benzyl Alcohol
`
`Table I: Minimum inhibitory concentrations (MICs)
`of benzyl alcohol.
`
`negligible. Benzyl alcohol can damage polystyrene syringes
`by ext