`
`
`
`
`Handbook of
`
`PHARMACEUTICAL
`
`EXCIPIEN TS
`
`Third Edition
`
`Edited by
`Arthur H. Kibbe, Ph.D.
`Professor and Chair
`Department of Pharmaceutical Sciences
`Wilkes University School of Pharmacy
`Wilkes—Barre, Pennsylvania
`
`‘
`
`i
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`3
`E
`E
`E
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`Q
`American Pharmaceutical Association
`
`AH‘IA
`
`Washington, DC.
`
`i
`E
`
`l
`
`3E
`
`(RP)
`
`Fhurmuceulical Press
`
`London, United Kingdom
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`?
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`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, DC 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.
`; cm.
`Includes bibliographical references and index.
`ISBN 0—917330—96—X
`1. Excipients—-Handbooks, manuals, etc.
`Pharmaceutical Association.
`[DNLM: l. Excipients--Handbooks. QV 735 H236 2000]
`RS201.E87 H36 2000
`615'.19-—dc21
`
`I. Kibbe, Arthur H. II. American
`
`99-044554
`
`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
`ot accept any legal responsibility or
`implied, with regard to the accuracy of the information contained in this book and canu
`liability for any errors or omissions that may be made.
`
`Managing Editor: Melanie Segala
`Copy/editor:
`Paul Gottehrer
`Indexer:
`Lillian Rodberg
`Compositor:
`Roy Barnhill "
`Cover Designer:
`Tiru Kaage
`
`AQUESTIVE EXHIBIT 1026
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`Alcohol
`
`7
`
`
`
`Alcohol
`
`I 1. Nonproprietary Names
`BP: Ethanol (96%)
`JP: Ethanol
`PhEur: Ethanolum (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 Molecular Weight
`
`CZHSO
`
`46.07
`
`5. Structural Formula
`
`H H
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`6. Functional Category
`
`Heavy metals
`
`Antimicrobial preservative; disinfectant; skin penetrant; sol»
`vent.
`
`In the USP, the term ‘dehydrated alcohol” refers to ethanol 2
`99.5% v/‘v. The term ‘alcohol’, without other qualification re-
`fers to ethanol 94.9-96.0% v/v.
`
`In the in, ethanol (alcohol) contains 95.1-95.6% v/v (by spe-
`cific gravity) of C2H60 at 15°C.
`
`In the Handbook of Pharmaceutical Excipients, the term ‘alr
`cohol-’ is used for either ethanol 95% v/v or ethanol 96% v/v.
`
`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
`+
`+
`+
`
`0812-0816
`0814-0816 08051708124
`+
`+
`+
`7
`+
`+
`+
`S 2.5 rag/100 mL S 1 mg/40 mL
`—
`7
`+
`
`Specific gravity
`Acidity
`Clarity of solution
`Nonvolatile residue
`Water-insoluble
`substances
`Aldehydes
`Amyl alcohol, etc.
`Absorbance
`Fusel oil constituents
`
`+
`—
`7
`+
`
`—
`7
`+
`—
`
`7
`7
`7
`+
`
`+
`+
`7
`—
`
`+
`+
`—
`7
`
`Acetone and propan-Z-ol 7
`Methanol
`7-
`Reducing substances
`+
`Organic volatile
`+
`impurities
`Chloride
`
`7
`7
`+
`S 1.2 ppm 7 7
`
`
`
`‘
`
`10. Typical Properties
`Antimicrobial activity: ethanol is bactericidal in aqueous mix7
`tures at concentrations between 60-95% vlv; the optimum
`concentration is generally considered to be 70% vlv. 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 blue, 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: 08119-08139 at 20”C
`
`the above typical properties are for alcohol (ethanol
`Note:
`95% or 96% v/v). See Section 18 for typical properties of
`dehydrated alcohol.
`
`1.
`
`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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`page 0003
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`Extracting solvent in galenical manufacture
`
`__ Solvent in film coating
`
`_-
`-_ Solvent in inject-able solutions
`
`' Solvent in oral liquids
`
`'
`Solvent in topical products
`
`
`8. Description
`In the BP, the term ‘ethanol’ used without other qualification
`
`Erefers to ethanol containing > 99. 5% vlv of C2H60 The term
`
`_ alcohol’ without other qualification, refers to ethanol
`'96 0-96. 6% v/v. Where other strengths are intended, the term
`
`n‘alcohol or ‘ethanol’ is used, followed by the statement of
`
`_. the strength_
`
`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 preservativeflle Topical ethanol solutions
`are also used as penetration enhancersm and as disinfectants.
`
`
`
`
`Use Concentration (% v/v)
`
`
`
`Antimicrobial preservative
`Disinfectant
`
`2 l 0
`60-90
`
`Up to 85
`Variable
`Variable
`Variable
`60-90
`
`
`
`

`

`
`
`
`
`
`
`8 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%
`v/v is then obtained by fractional distillation. Ethanol may
`also be prepared by a number of synthetic methods.
`
`15. Handling Precautions
`
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Ethanol and aqueous ethanol
`solutions should be handled in a well-ventilated environment.
`In the UK, the longeterm 8-hour TWA exposure limit for eth-
`anol is 1920 mgi’m3 (1000 ppm).(6) 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.
`
`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.
`
`Ethanol is 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 ethanolecon—
`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% v/v) 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 l 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.
`
`LD50 (guinea pig, IP): 3.41 gfkgGJ
`LD50 (guinea pig, IV): 2.3 g/kg
`LD50 (guinea pig, oral): 5.56 g/kg
`LD50 (hamster, 1?): 5.07 g/kg
`LD50 (mouse, 1?): 0.93 g/kg
`LD50 (mouse, IV): 1.97 gfkg
`LDSG (mouse, oral): 7.5 g/kg
`LDSU (mouse, SC): 8.29 g/kg
`LD50 (rabbit, 1P): 0.96 g/kg
`LD50 (rabbit, IV): 2.37 g/kg
`LD50 (rabbit, oral): 6.3 g/kg
`LD50 (rat. IP): 3.75 g/kg
`LD50 (rat, IV): 1.44 gikg
`LD50 (rat, oral): 7.06 g/kg
`
`16. Regulatory Status
`
`Included in the FDA Inactive Ingredients Guide (dental prep—
`arations,
`inhalations, 1M and 1V injections, nasal and oph-
`thalmic preparations, oral capsules, solutions, suspensions,
`syrups and tablets, rectal,
`topical, and transdermal prepara-
`tions). Included in nonparenteral and parenteral medicines li—
`censed in the UK.
`
`1'7. Pharmacopeias
`
`China, Eur, Int, Jpn, Po], and US.
`
`18. Related Substances
`
`Déhydrated alcohol; denatured alcohol; dilute alcohol; isopro—.
`pyl alcohol.
`
`Dehydrated alcohol
`
`Synonyms: absolute alcohol; anhydrous ethanol; ethanol.
`Autoignition temperature: 365°C
`Boiling point: 785°C
`Explosive limits: 3.5-19.0% v/v in air
`Flash point: 12°C (closed cup)
`Hygroscopicity: absorbs water rapidly from the air.
`Melting point: ~112°C
`Refractive index: an = 1.361
`Spectfic gravity: 07904-07935 at 20°C
`Surface tension: 22.75 InN/m 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% V/V. See
`Section 8.
`
`Denatured alcohol
`
`Synonyms: industrial methylated spirit; surgical spirita
`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 page 0004
`AQUESTIVE EXHIBIT 1026
`page 0004
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`

`

`
`
`Alcohol 9
`
`Specific gravity:
`
`Specific gravity at 20°C
`Strength of alcohol
` (% WV)
`90
`0928903319
`30
`03599—09521
`70
`09360—08883
`60
`0910309114
`50
`0931409326
`45
`0940709417
`25
`0969409703
`
`20 0974809759
`
`Comments: the term ‘dilute alcohol’ refers to a mixture of ethanol
`and water of stated concentration. The BF 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. Int J Pharmaceutics 1989', 54:
`51—56.
`
`3. Lin P, Higuchi WI, Song W, Knrihara—Bergstrom T, Good WR.
`Quantitative evaluation of ethanol effects on diffusion and
`metabolism of B-estradiol in hairless mouse skin. Pharm Res
`199.1; 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-
`rice 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
`
`P] Weller.
`
`
`
`
`
`
`
`a
`
`
`
`AQUESTIVE EXHIBIT 1026
`
`AQUESTIVE EXHIBIT 1026 page 0005
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`page 0005
`
`

`

`
`
`
`Alcohol 9
`
`Specific gravity:
`__,,_.—...—.—n—w—
`
`Specific gravity at 20°C
`Strength of alcohol
` (% vlv)
`90
`03289-08319
`80
`08599—03621
`70
`03860—08883
`60
`09103-09114
`50
`(19314-09326
`45
`0.9407—D.9417
`25
`09694—09703
`
`20 09748-09759
`
`Comments: the term ‘dilute alcohol’ refers to a mixture of ethanol
`and water of stated concentration. The HP 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. Karahit 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. Lin 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: 865672.
`
`the anaesthetist and the pain
`4. Lloyd JW. Use of anaesthesia:
`clinic. Br Med J 1930‘, 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 A], Noseworthy MN. Use of nonaqueous solvents in
`parenteral products. J Pharm Sci 1963; 52: 917927.
`Wade A, editor. Pharmaceutical Handbook, 19th edition. London,
`The Pharmaceutical Press, 1980; 227-230.
`
`20. Specific References
`l. Chiori CO, Ghobashy AA. A potentiating effect of EDTA on
`the bactericidal activity of lower concentrations of ethanol.
`Int J Pharmaceutics 1983; 17: 121428.
`
`22. Authors
`
`P] Weller.
`
`
`
`
`
`
`
`fiawgfiiqu—m"
`
`mmsaw»
`
`
`AQUESTIVE EXHIBIT 1026 page 0006
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`AQUESTIVE EXHIBIT 1026
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`page 0006
`
`

`

`
`
`18 Alpha Tocopherol
`
`
`
`Alpha Tocopherol
`
`1. Nonproprietary Names
`
`BP: Alpha tocopherol
`JP: Tocopherol
`PhEur: ot—Tocopherolum
`USP: Vitamin E
`See also Sections 3, 9, and 18.
`
`2. Synonyms
`
`(i)—3,4—Dihydro—2,5,7,8atetramethylr2-(4,8,lZ-trimethyltridecyl)—
`2H—l—benzopyran-6rol; E307; synthetic alpha tocopherol; all-race
`ot-tocopherol; dl-ctitocopherol; 5,7,8-trimethyltocol.
`
`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~
`Be 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
`palmitatei”
`
`8. Description
`
`it is avail-
`Alpha tocopherol is a natural product. Therefore,
`able as either practically odorless, clear, colorless, yellow, yelr
`lowishahrown, or greenish-yellow colored viscous oil. See also
`Section 18.
`
`
`
`3. Chemical Name and CAS Registry Number
`
`9. Pharmacopcial Specifications
`
`(i)-(2RS,4’RS,S’RS)72,5,7,8—Tetramethyl—2-(4’,8’,12’—trimethy1—
`tridecy1)-6—chrornanol [l0191-41-O]
`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, dl-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
`
`C29H5002
`
`Molecular Weight
`43 0 . 72
`
`5. Structural Formula
`
`
`
`11,: 1s2 = R3 = CH3.
`Alpha tocopherol:
`R1: R3 : CH3; R2 = H.
`Beta tocopherol:
`Delta tocopherol:
`R1: CH3, R2 =R3 = H.
`Gamma tocopherol: R] :- RZ : CH3; 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
`
`Test
`
`JP
`
`PhEur
`
`USP
`
`+
`+
`+
`Identification
`+
`—
`—-
`Acidity
`—
`S 2
`-—-
`Acid value
`S 20 ppm —
`S 20 ppm
`Heavy metals
`S 0.1%
`—
`r
`Sulfated ash
`—w
`+
`Organic volatile impurities 7
`72.0-76%
`fl
`.Absorbance
`71 .0-76%
`Refractive index
`1503—1507 a
`#
`
`#
`0.9470955 #
`Specific gravity
`_
`Clarity and color of solution +
`——-
`
`Assay 96.0-‘102.0% 96.0—102.0% 96.0—102.0%W
`
`Note that the USP describes vitamin E as comprising d- or
`all-alpha tocopherol; d- or dI-alpha tocopheryl acetate; or d-
`or til-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
`difficult.
`
`10. Typical Properties
`Boiling point: 235°C
`Density (20°C): 0347—0951 glcrn3
`Flash point: 240°C
`Ignition point: 340°C
`Refractive index: ab20 = 1503—1507
`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 and silver salts. Oxidation products include
`tocopheroxide, tocopherquuinone, and tocopherylhydroquino—
`ne, as well as dimers and trimers. Tocopherol esters are more
`stable to oxidation than the free tocopherols but are in con-
`sequence less effective antioxidants. See also Section 18.
`Tocopherols should be stored under an inert gas, in an airtight
`container in a cool, dry, place and protected from light.
`
`AQUESTIVE EXHIBIT 1026 page 0007
`AQUESTIVE EXHIBIT 1026
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`

`

`I.
`
`12. Incompatibilities
`
`.
`
`.ToCopherols are incompatible with peroxides and metal ions,
`"especially iron, copper, and silver. Tocopherols may be ab—
`sorbed into plasticfizl
`
`I
`
`13, I Method of Manufacture
`: Naturally occurring tocopherois are obtained by the extraction
`or- molecular distillation of steam distillates of vegetable oils,
`'e.'g., alpha tocopherol occurs in concentrations of (Ll-0.3% in
`corn, rapeseed, soybean, sunflower, and wheat germ oils”)
`-. Beta and gamma tocopherol are usually found in natural
`sources along with alpha tocopherol. Racemic synthetic toco—
`pherois may be prepared by the condensation of the appro—
`priate methylated hydroquinone with racemic isophytoifl‘il
`
`'14. Safety
`
`-
`
`I
`
`I
`
`-
`
`-'
`
`'Tocopherols (vitamin E) occur in many food substances that
`.- are consumed as part of the normal diet. The daily nutritional
`requirement has not been clearly-defined but is estimated to
`'1' be'..3'-'2_0 mg. Absorption from the gastrointestinal tract is de
`”-Ipendent'upon normal pancreatic function and the presence of
`"'bile.:Tocopherols are widely distributed throughout the body
`I“ withsome ingested tocopherol metabolized in the liver; ex~
`" cre'tion' of metabolites is via the urine or bile. Individuals with
`r'vitamin E deficiency are usually treated by oral administration
`- of tocopherols although intramuscular and intravenous admin-
`istratiOn may sometimes be used.
`
`Tocopherols 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.
`
`I
`
`I
`
`_
`
`
`
`I'
`
`'- The use of tocopherols as antioxidants in pharmaceuticals and
`'food products is unlikely 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.
`i: 3
`I TheWHO has set an acceptable daily intake of tocopherol
`
`'
`-'.-_as_e'd' as-an antioxidant at 0.152 mg/kg bodyrweightfifil
`
`"
`
`_ 15...; Handling; Precautions
`___Ql_:is'erve.”normal:precautions appropriate to the circumstances
`and; quantity] of material handled. Gloves and eye protection
`'fare'recommended; -
`
`'
`
`'16. Regulatory Status
`
`GRAS listed. 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
`
`Bur, Jpn, and US.
`
`VNot-e that the nomenclature for tocopherols and tocophcrol
`derivatives is confusing and many pharmacopeias do not spec—
`lty clearly the isomer 01' form of the tocopherol.
`
`18. Related Substances
`
`d—Aipha tocophcrol: C29H5002
`Molecular weight: 430.72
`CAS number: [59—029]
`
`Alpha Tocopherol
`
`19
`
`(+)-(2R,4’R,8’R}-
`Synonyms: natural alpha tocopherol;
`2,5,7,8~tetramethyl-2-(4’,8',l2’-t1irnethyltridecyl)-6-chromanol;
`dictatocopherol; vitamin E.
`Appearance: a practically odorless, clear, yellow, or greenish“
`yellow colored viscous oil.
`Melting point: 2.5a3.5°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 i‘: the naturally occurring form of alpha {UGO-
`pherol.
`
`(3311-15203
`
`ell-Alpha tocopheryl acetate:
`Molecular weight: 472.73
`CAS number:
`[58—95—7]
`Synonyms:
`(+)-(2R,4’R,8’R)—2,5,7,8—tetramethy1-2-(4’,8’,12’-
`trimethyltridecyl)-6-cl3romanyl acetate; d-a-tocopheryl
`acetate; vitamin E.
`Appearance: a practically odorless, clear, yellow, or greenishw
`yellow colored viscous oil 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 [ot]D25: +0.25o (10% w/v solution in chloro—
`form)
`Comments: unstable to alkalis.
`
`til-Alpha toc0pheryl acetate: C31H5203
`Molecular weight: 472.73
`CAS number:
`[7695-91—2]
`Synonyms: (:)-3,4—dihydro-2,5,7,8-tetrainethyl-2—(4,8,lZ-trimethyl-
`tridecyl)72H~labenzopyran-é-ol acetate; (i)-(2RS,4’RS,8’RS)-
`2,5,7,8-tetramethy1727(4',8’,l 2’7trimethyltridecy1)767cbromanyl
`acetate; (i)-0t—tocopherol acetate; a~tocopheroli acetas; allrmcr
`or—toc0pheryl acetate; dl-ot—tocopheryl acetate; vitamin E.
`Appearance: a practically odorless, clear, yellow, or greenish-
`yellow viscous oil.
`Density: 0.953 gicm3
`Melting point: “27.50C
`Refractive index: nD30 : 14950-14972
`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 tocor
`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.
`
`l
`
`d-Alpha tocopheryl acid succinate: C33H5405
`Molecular weight: 530.8
`CAS number: [4345-03-3]
`Synonyms:
`(+)7txrtocopherol hydrogen succinate; d-ot-toco-
`pheryl acid succinate; vitamin E.
`Appearance: a practically odorless white powder.
`Melting point: 76-77OC
`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
`
`AQUESTIVE EXHIBIT 1026 page 0008
`
`page 0008
`
`
`
`
`
`
`
`
`
`
`

`

`20 Alpha Tocopherol
`
`til-Alpha tocopheryl acid succinate: C33H5405
`Molecular weight: 530.8
`CAS number: [17407-3773]
`Synonyms: (i)—ot-tocopberol hydrogen succinate; dl-a—tocopherol
`succinate; a'le‘otetocopheryl acid succinate; vitamin E.
`Appearance: a practically odorless white crystalline powder.
`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.
`
`Beta tocopherol: C33H4802
`Molecular weight: 416.66
`CAS number: [14803-8]
`(i)—3,4—dihydro-2,5,S-trimethyl-
`Synonyms: cumotocopherol;
`2-(4,8,1 2bimethyltridecyl)-2H— 1 —benzopyran-6-ol; 5, 8-dimethy1—
`tocol; neotocopherol; dl—B—tocopherol; vitamin E; pexylotocor
`pherol.
`Appearance: a pale yellow colored viscous oil.
`Solubility: practically insoluble in water; freely soluble in ace—
`tone, chloroform, ethanol (95%), ether, and vegetable oils.
`Specific rotation [or]D?0: +6.37o
`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 atmospheric
`oxygen.
`
`Delta tocopherol: C27H4602
`Molecular weight: 402.64
`CAS number: [11971371]
`Synonyms: (i)73,4rdihydro-2,8-dimethyl—2—{4,8,12-trimethyl-
`tridecyl)~2HAl~benzopyran-6-ol; E309; 8—melhyltocol; dl—S-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: C28H4802
`Molecular weight: 416.66
`CAS number:
`[76l6—22—0]
`Synonyms:
`(i)—3,4-dihydro-2,7,S-trimethyla2e(4,8,lZ-trimethyl-
`tridecyl)-2H—l-benzopyranrofil; 7,87dimethyltocolg E308; ell—y—
`tocopheroi; vitamin E; orxylotocopherol.
`Appearance: a pale yellow colored viscous oil.
`Melting point: 730°C
`Solubility: practically insoluble in water; freely soluble in ace-
`tone, chloroform, ethanol (95%), ether, and vegetable oils.
`Specific rotation [ot]D20: —2.4° (in 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-
`iis; 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: «tocopherois excipient is described in the USP as
`a vegetable oil solution containing not less than 50.0% of
`total
`tocopherois, of which not less 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 mixtures 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 IC, editors. Encyclopedia of Pharmaceutical
`Technology, volume 1. New York, Marcel Dekker, 1988;
`4l5-450.
`I
`2. Aliwood MC. Compatibility and stability of TPN mixtures in
`big bags. J Clin Hosp Pharm 1984; 9: 181m198.
`3. Buck DF. Antioxidants.
`In: Smith I, editor. Food Additive
`User’s Handbook. Blackie, Glasgow, 1991; 1-46.
`In:
`4. Rudy BC, Senkowskj BZ. dl-Alpha—tocoph‘eryl acetate.
`Florey K, editor. Analytical Profiles of Drug Substances, vole
`Lune 3. New York, Academic Press, 1974; 111—126.
`5. FAOfWHO. Evaluation of certain food additives and contam-
`inants. Thirtieth report of the joint FAQ/WHO expert commie
`tee on food additives. Tech Rep Ser WldHlth 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; 99405.
`
`22. Authors
`JA Stead.
`
`AQUESTIVE EXHIBIT 1026
`
`AQUESTIVE EXHIBIT 1026 page 0009
`
`page 0009
`
`
`
`

`

`
`
`,. Nonproprietary Names
`
`”13:13: Benzyl alcohol
`" JP: Benzyl alcohol
`
`I PhEur: Alcohol benzylicus
`USP: Benzyl alcohol
`
`
`2:
`. ail-lydroxytoluene; phenylcarbinol; phenylmethanol; ot—toluenol.
`
`
`
`Chemical Name and CAS Registry Number
`
`
`B'enzenemethanol [100-51-6]
`
`.
`
`Empirical Formula Molecular Weight
`
`
`
`- n30
`
`Structural Formula
`
`108.14
`
`HZOH
`
`Functional Category
`
`microbial preservative; disinfectant; solvent.
`
`
`
`
`
`
`'2'. Applications in Pharmaceutical Formulation 01‘
`'
`- Technology
`
`B'eriZyl alcohol is an antimicrobial preservative used in cos-
`_eti'cs, foods, and a wide range of pharmaceutical formula
`_.'t_ions,(1'3)
`including oral and parenteral preparations, at
`
`oncentrations up to 2.0% v/v. In cosmetics, concentrations
`
`_p-__to 3.0% Vlv may be used as a preservative. Concentrations
`_:.'5% v/v or more are employed as a solubilizer, while a
`0% viv solution is used as a disinfectant.
`
`
`B'e'na'yl alcohol 10% v/v solutions also have some local anes—
`
`' tic; properties which are exploited in some parenterals,
`ou‘gh products, ophthalmic solutions, ointments, and derma-
`
`
`OIogi'cal aerosol sprays.
`
`:_Ough widely used as an antimicrobial preservative, benzyl
`0_1i'ol,.when administered to neonates, has been associated
`th=:-some fatal adverse reactions. It is now recommended
`
`tparenteral products preserved with benzyl alcohol, or oth-
`antlmicrobial preservatives, should not be used in newborn
`
`
`Hf IltS.'if at all possible, see Section 14.
`
`
`
`
`D scription
`
`_
`'_af,'.coiorless, oily liquid with a faint aromatic odor and
`
`a sharp, = burning taste.
`
`
`
`Benzyi Alcohol 41
`
`9. Pharmacopeial Specifications
`
`Test
`Identification
`Characters
`
`Solubility
`Acidity
`Clarity of solution
`
`,1
`
`Specific gravity
`Distilling range
`Refractive index
`Residue on ignition
`Nonvolatile matter
`Chlorinated
`compounds
`Aldehyde
`Peroxide value
`
`Organic volatile
`impurities
`Assay
`
`JP
`+
`+
`
`——
`+
`—
`
`PhEur
`+
`+
`
`+
`+
`+
`
`USP
`+
`—
`
`7
`+
`7
`
`104371049
`1043-1053
`202.5-206.5°C 7
`l.538-l.54l
`1.5384541
`S 0.005%
`7
`7
`S 0.05%
`+
`S 300 ppm
`
`1042-10“
`202.5-206.5°C
`1539-1541
`5 0.005%
`S 0.05%
`S 0.03%
`
`+
`—
`
`7
`
`S 0.2%
`S 5
`
`7
`
`S 0.2%
`—
`
`+
`
`97.0—100.5%
`
`97.0-1005‘7’0
`
`2 98.0%
`
`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 incompatibilities with
`some packaging materials, particularly polyethylene, see Sec-
`tion 12. Reported minimum inhibitory concentrations (MICs)
`are shown in Table 114)
`
`Bacteria: benzyl alcohol is moderately active against most
`Gram-positive organisms (typical MICs are 3-5 mg/rnL),
`although some Gram-positive bacteria are very sensitive
`(MICs 0025-005 mg/mL). In general, benzyl alcohol is
`less active against Gramwnegative 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 phenylrn-
`ercuric nitrate 0.002% w/v against Bacillus stearotherma-
`philas 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% v/v. 3
`Flash point:
`‘
`100.6°C (closed cup);
`104.5°C (open cup).
`Freezing point: 45°C
`Melting point: -15.2°C
`
`AQUESTIVE EXHIBIT 1