...
`
`Handbook of
`PHARMACEUTICAL
`EXCIPIENTS
`
`Second Edition
`
`Edited by
`Ainley Wade and Paul J Weller
`
`American Pharmaceutical Association
`Washington
`
`The Pharmaceutical Press
`London
`
`--·--· 1994 --
`-
`RD02b 7 97489
`
`-(cid:173)
`
`MYLAN PHARMS. INC. EXHIBIT 1023 PAGE 1
`
`

`
`© Copyright 1986, 1994 by the American Pharmaceutical Association, 2215 Constitution Avenue NW, Washington,
`DC 20037-2985, USA, and The Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain, 1 Lambeth High
`Street, London, SEl 7JN, England.
`
`A catalogue record for this book is available from the British Library.
`
`Library of Congress Catalog Card Number: 94-79492.
`
`International Standard Book Number (ISBN) in the UK: 0 85369 305 6
`International Standard Book Number (ISBN) in the USA: 0 91730 66 8
`
`No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
`including photocopy, recording, or any information storage or retrieval system, without prior written permission from
`the joint publishers.
`
`Typeset in Great Britain by Alden Multimedia, Northampton.
`Printed and bound in Great Britain by
`
`MYLAN PHARMS. INC. EXHIBIT 1023 PAGE 2
`
`

`
`Alcohol
`
`1. Nonproprietary Names
`BP: Ethanol (96%)
`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
`C2H60
`
`Molecular Weight
`46.07
`
`S. Structural Formula
`C2HsOH
`
`6. Functional Category
`Antimicrobial preservative; disinfectant; skin penetrant;
`solvent.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Ethanol and aqueous ethanol solutions of various concentra(cid:173)
`tions (see Sections 8 and 18) are widely used in pharmaceutical
`formulations and cosmetics. Although ethanol is primarily
`used as a solvent it is also employed in solutions as an
`antimicrobial preservative.<1
`2> Topical ethanol solutions are
`•
`also used as penetration enhancers<3> and as disinfectants.
`
`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 to 85
`
`Variable
`Variable
`Variable
`60-90
`
`8. Description
`In the BP 1993, the term 'ethanol' used without other
`qualification refers to ethanol ~ 99.5% v/v. 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.
`In the USP XXII, the term 'dehydrated alcohol' refers to
`ethanol ;;;;. 99.5% v/v. The term 'alcohol', without other
`qualification refers to ethanol 94.9-96.0% v/v.
`In the Handbook of Pharmaceutical Excipients, the term
`'alcohol' 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
`
`Identification
`Specific gravity
`Acidity
`Clarity of solution
`Nonvolatile residue
`Water-insoluble
`substances
`Aldehydes
`Amyl alcohol, etc
`Benzene
`Fusel oil constituents
`Acetone and
`propan-2-ol
`Methanol
`Reducing substances
`Volatile impurities
`
`BP 1993
`+
`0.8038-0.8063
`+
`+
`~ 5 mg/100 mL
`
`~IO ppm
`
`~ 2 ppm
`
`+
`+
`
`Alcohol 7
`
`USPXXII
`+
`0.812-0.816
`+
`
`:;; I mg/40 mL
`+
`
`+
`+
`
`+
`+
`
`+
`
`10. Typical Properties
`Antimicrobial activity: ethanol is bactericidal in aqueous
`mixtures at concentrations between 60-95% v/v; the optimum
`concentration is generally considered to be 70% v/v.
`Antimicrobial activity is enhanced in the presence of edetic
`acid or edetate salts.<!) Ethanol is inactivated in t he presence of
`nonionic surfactants and is ineffective against bacterial spores.
`Boiling point: 78. I 5°C
`Flammability: readily flammable, burning with a blue,
`smokeless 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 18 for typical properties of
`dehydrated alcohol.
`
`11. Stability and Storage Conditions
`Aqueous ethanol solutions may be sterilized by autoclaving or
`by filfration 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
`color due to a reaction with residual amounts of aldehyde.
`Organic salts or acacia may be precipitated from aqueous
`solutions or dispersions. Ethanol solutions are also incompa(cid:173)
`tible with aluminum containers and may interact with some
`drugs.
`
`13. Method of Manufacture
`Ethanol is manufactured by the con trolled enzymatic
`fermentation 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 aqueous ethanol solutions are widely used in a
`variety of pharmaceutical formulations and cosmetics. Ethanol
`is also consumed in alcoholic beverages.
`
`MYLAN PHARMS. INC. EXHIBIT 1023 PAGE 3
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`

`
`,:.
`
`r
`
`' v ;: ..
`
`8 Alcohol
`
`Ethanol is rapidly absorbed from the gastrointestinal tract and
`vapor may be absorbed through the lungs. Ethanol is
`metabolized 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
`intoxication including muscle 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, respiratory depres(cid:173)
`sion and cardiovascular collapse. The lethal human blood(cid:173)
`alcohol concentration is generally estimated to be 400-500 mg/
`100 mL.
`Although symptoms of ethanol intoxication are usually
`encountered following deliberate consumption of ethanol
`containing 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
`concentrations can produce pain on intramuscular injection
`and lower concentrations such as 5-10% v/v are preferred.
`Subcutaneous 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.<4l
`Preparations containing greater than 50% v/v alcohol may
`cause skin irritation when applied topically.
`
`LD50 (guinea pig, IP): 3.41 g/kg<5>
`LD50 (guinea pig, IV): 2.3 g/kg
`LDso (guinea pig, oral): 5.56 g/kg
`LDso (hamster, IP): 5.07 g/kg
`LD50 (mouse, IP): 0.93 g/kg
`LD50 (mouse, IV): 1.97 g/ kg
`LD50 (mouse, oral): 7 .5 g/kg
`LD50 (mouse, SC): 8.29 gjkg
`LDso (rabbit, IP): 0.96 g/kg
`LD50 (rabbit, IV): 2.37 g/kg
`LDso (rabbit, oral): 6.3 g/kg
`LD50 (rat, IP): 3.75 g/kg
`LD50 (rat, IV): 1.44 g/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
`ethanol solutions should be handled in a well-ventilated
`environment. In the UK, the long-term 8-hour TWA exposure
`limit for ethanol is 1900 mg/m3 (1000 ppm).<6l 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
`discharges, when ethanol is transferred.
`
`:t
`
`16. Regulatory Status
`Included in the FDA Inactive Ingredients Guide (dental
`preparations, inhalations, IM and IV injections, nasal and
`ophthalmic preparations, oral capsules, solutions, suspensions,
`syrups and tablets, rectal, topical and transdermal prepara-
`
`tions). Included in nonparenteral and parenteral medicines
`licensed in the UK.
`
`17. Pharmacopeias
`Aust, Br, Chin, Cz, Egypt, Fr, Ger, Hung, Ind, It, Jpn, Mex,
`Neth, Nord, Rom, Rus, Swiss, Turk, US and Yug. Also in BP
`Vet.
`
`18. Related Substances
`Dehydrated alcohol; denatured alcohol; dilute alcohol;
`Isopropyl Alcohol.
`Dehydrated alcohol
`Synonyms: absolute alcohol; ethanol.
`Autoignition temperature: 365°C
`Boiling point: 78.5°C
`Explosive limits: 3.5-19.0% v/v in air
`Flash point: 12°C (closed cup)
`Hygroscopicity: absorbs wa ter rapidly from the air.
`Melting point: - l l2°C
`20 = 1.361
`Refractive index: n0
`Specific gravity: 0. 7904-0. 7935 at 20°C
`Surface tension: 22.75 mN/m at 20°C (ethanol/vapor)
`Vapor density (relative): l.59 (air = 1)
`Vapor pressure: 5.8 Pa at 20°C
`Viscosity (dynamic): l.22 mPa s (1.22 cP) at 20°C
`Comments: dehydrated alcohol is ethanol ~ 99.5% v/v. 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.
`Specific gravity:
`
`Strength of alcohol
`(o/o v/v)
`
`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
`0.9103-0.91 14
`0.9314-0.9326
`0.9407-0.9417
`0.9694-0.9703
`0.9748-0.9759
`
`Comments: the term 'dilute alcohol' refers to a mixture of
`ethanol and water of stated concentration. The BP 1993 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 non-denatured alcohols are usually
`subject to close control by excise authorities.
`
`20. Specific References
`I. 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.
`
`MYLAN PHARMS. INC. EXHIBIT 1023 PAGE 4
`
`

`
`2. Karabit MS, Juneskans OT, Lundgren P. The determination of
`antimicrobial characteristics of some pharmaceutical compounds
`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 /3-estradiol in hairless mouse skin. Phann Res
`1991; 8: 865-872.
`4. Lloyd JW. Use of anaesthesia: the anaesthetist and the pain clinic.
`Br Med J 1980; 281: 432-434.
`5. Sweet DV, editor. Registry of toxic effects of chemical substances.
`Cincinnati: US Department of Health, 1987.
`6. Health and Safety Executive. Occupational exposure limits 1993:
`EH40/93. London: HMSO, 1993.
`
`Alcohol 9
`
`21. General References
`Lund W, editor. The Pharmaceutical Codex: principles and practice of
`pharmaceutics, 12th edition. London: The Pharmaceutical 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.
`
`22. Authors
`UK: SJ Lewis.
`
`MYLAN PHARMS. INC. EXHIBIT 1023 PAGE 5
`
`

`
`Penzyl Alcohol
`~: r·
`
`; Nonproprietary Names
`~P: Benzyl alcohol
`~hEur: Alcohol benzylicus
`,IJSPNF: Benzyl alcohol
`"·. { _
`g~ Synonyms
`a-Hydroxytoluene; phenylcarbinol; phenylmethanol; o-tolue(cid:173)
`frlol.
`i·· ,.
`'3. Chemical Name and CAS Registry Number
`·Benzenemethanol [100-51-6]
`,.
`,4. Empirical Formula
`!CiHsO
`':s. Structural Formula
`
`Molecular Weight
`108.14
`
`0-CH,OH
`f6. Functional Category
`'·,Antimicrobial preservative; disinfectant; solvent.
`
`p. Applications in Pharmaceutical Formulation or·
`! Technology
`.: Benzyl alcohol is an antimicrobial preservative used in
`< cosmetics, foods and a wide range of pharmaceutical
`_; formulations,<1
`3> including oral and parenteral preparations,
`·
`· at concentrations up to 2.0% v/v. In cosmetics, concentrations
`i up to 3.0% v/v may be used as a preservative. Concentrations
`~- of 5% v/v or more are employed as a solubilizer, whilst a 10%
`{ v/v solution is used as a disinfectant.
`'i Benzyl alcohol 10% v/v solutions also have some local
`.i anesthetic properties which are exploited in some parenterals,
`'; cough products, ophthalmic solutions, ointments, and derma(cid:173)
`;, tological aerosol sprays.
`?, Although widely used as an antimicrobial preservative, benzyl
`alcohol, when administered to neonates, has been associated
`with some fatal adverse reactions. It is now recommended that
`parenteral products preserved with benzyl alcohol, or other
`~ antimicrobial preservatives, should not be used in newborn
`j:. infants if at all possible, see Section 14.
`
`8. Description
`~: A clear, colorless, oily liquid with a faint aromatic odor and a
`<: sharp, burning taste.
`
`;!i•
`
`~:
`
`9. Pharmacopeial Specifications
`
`Test
`
`~·-
`
`Identification
`Acidity
`?: Clarity of solution
`Specific gravity
`Distilling range
`
`PbEur 1990
`+
`+
`+
`1.043-1.049
`
`USPNFXVll
`+
`
`1.042-1.047
`202.5-206.S"C
`
`Benzyl Alcohol 35
`
`Continued
`
`Test
`
`Refractive index
`Residue on ignition
`Nonvolatile matter
`Chlorinated compounds
`Aldehyde
`Peroxide value
`Assay
`
`PhEur 1990
`
`1.538-1.541
`
`""0.05%
`..; 300 ppm
`""0.2%
`
`"" 5
`97.0-100.5%
`
`USPNFXVD
`
`1-539-1.541
`~ 0.005%
`
`+
`~ 0.2%
`
`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. Antimicrobial
`activity is reduced in the presence of nonionic surfactants, 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 Section 12.
`Reported minimum inhibitory concentrations (MICs) are
`shown in Table 1.<4l
`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 activity
`may be enhanced by heating. Benzyl alcohol 1 % v(v, at pH 5-
`6, has been claimed to be as effective as phenylmercuric nitrate
`0.002% w/v against Bacillus stearothermophilus at lOO"C for 30
`minutes.
`
`Table I: Minimum inhibitory concentrations (MICs) of benzyl alcohol.<4>
`
`Microorganism
`
`MIC (µg/mL)
`
`Aspergillus niger
`Candida a/bicans
`Escherichia coli
`Pseudomonas aeruginosa
`Staphylococcus aureus
`
`5000
`2500
`2000
`2000
`25
`
`Autoignition temperature: 436.5°C
`Boiling point: 204.7°C
`Flammability: flammable. Limits in air 1.7-15.0% v/v.
`Flash point:
`l00.6°C (closed cup);
`l04.5°C (open cup).
`Freezing point: - l 5°C
`Melting point: -15.2°C
`Partition coefficients:
`Liquid paraffin: water = 0.2;
`Peanut oil:. water "' 1.3.
`Refractive index: no20 = 1.5404
`
`;
`-; .
`
`MYLAN PHARMS. INC. EXHIBIT 1023 PAGE 6
`
`

`
`36 Benzyl Alcohol
`
`Solubility:
`
`Solvent
`
`Chloroform
`Ethanol
`Ethanol (50%)
`Ether
`Fixed and volatile oils
`Water
`
`Solubility at 20°C
`Unless otherwise stated
`
`miscible in all proportions
`miscible in all proportions
`1 in 2.5
`miscible in all proportions
`miscible in all proportions
`I in 25 at 2s•c
`1 in 14 at 90°C
`
`Specific gravity: 1.0454 at 20°C
`Surface tension: 38.8 mN/m (38.8 dynes/cm)
`Vapor density (relative) : 3.72 (air = I)
`Vapor pressure:
`13.3 Pa (0.1 mmHg) at 30°C;
`1.769 kPa (13.3 mmHg) at 100°C.
`Viscosity (dynamic): 6 mPa s (6 cP) at 20°C
`
`11. Stability and Storage Conditions
`Benzyl alcohol oxidizes slowly in air to benzaldehyde and
`benzoic acid; it does not react with water. Aqueous solutions
`may be sterilized by filtration or autoclaving; some solutions
`may generate benzaldehyde during autoclaving.
`-.
`Benzyl alcohol may be stored in metal or glass containers
`although plastic containers should not be used. Exceptions to
`this include polypropylene containers or vessels coated with
`inert fluorinated polymers such as Teflon, see Section 12.
`Benzyl alcohol should be stored in an airtight container,
`protected from light, in a cool, dry, place.
`
`12. Incompatibilities
`Benzyl alcohol is incompatible with oxidizing agents and
`strong acids. It can also accelerate the autoxidation of fats.
`Although antimicrobial activity is reduced in the presence of
`nonionic surfactants, such as polysorbate 80, the reduction is
`less than is the case with hydroxybenzoate esters or quaternary
`ammonium compounds.
`Benzyl alcohol is compatible with methylcellulose and is only
`slowly sorbed by closures composed of natural rubber,
`Neoprene and butyl rubber closures, the resistance of which
`can be enhanced by coating with fluorinated polymers.<5>
`However, a 2% v/v aqueous solution in a polyethylene
`container, stored at 20°C, may lose up to 15% of its benzyl
`alcohol content in 13 weeks.<6> Losses to polyvinyl chloride and
`polypropylene containers under similar conditions are usually
`negligible.
`
`13. Method of Manufacture
`Benzyl alcohol is prepared commercially by the distillation of
`benzyl chloride with potassium or sodium carbonate. It may
`also be prepared by the Cannizzaro reaction of benzaldehyde
`and potassium hydroxide.
`
`14. Safety
`Benzyl alcohol is used in a wide variety of pharmaceutical
`formulations. It is metabolized to benzaldehyde and benzoic
`acid, with benzoic acid being further metabolized in the liver
`by conjugation with glycine to form hippuric acid which is
`excreted in the urine.
`Ingestion or inhalation of benzyl alcohol may cause headache,
`vertigo, nausea, vomiting and diarrhea. Overexposure may
`result in CNS depression and respiratory failure. However, the
`
`concentrations of benzyl alcohol normally employed as a
`preservative are not associated with such adverse effects.
`Reports of adverse reactions to benzyl alcohot<Ml used as an
`excipient include: neurotoxicity in patients administered be~!
`1 >
`alcohol in intrathecal preparations;<10> hypersensitivity,<11
`•
`although relatively rare, and a fatal toxic syndrome in
`premature infants.(13- 15>
`The fatal toxic syndrome in low-birth-weight neonates, which
`includes symptoms of metabolic acidosis and respiratory
`depression, was attributed to the use of benzyl alcohol as a
`preservative in solutions used to flush umbilical catheters. As a
`result of this the FDA has recommended that benzyl alcohol
`should not be used in such flushing solutions and advised
`against the use of medicines containing preservatives in the
`17>
`newbom.<16
`•
`The WHO has set the estimated acceptable daily intake of the
`benzyl/benzoic moiety at up to 5 mg/kg body-weight daily.<18>
`LDso (mouse, IV): 0.32 g/kg<19>
`LD50 (mouse, oral): 1.58 g/kg
`LD50 (rabbit, oral): 1.04 g/kg
`LD50 (rabbit, skin): 2.0 g/kg
`LDso (rat, IP): 0.4 gfkg
`LD50 (rat, IV): 0.06 g/kg
`LD50 (rat, oral): 1.23 g/kg
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Benzyl alcohol (liquid and
`vapor) is irritant to the skin, eyes and mucous membranes. Eye
`protection, gloves and protective clothing are recommended.
`Benzyl alcohol should be handled in a well-ventilated
`environment; a self-contained breathing apparatus is recom(cid:173)
`mended in areas of poor ventilation. Benzyl alcohol is
`flammable.
`
`16. Regulatory Status
`Included in · the FDA Inactive Ingredients Guide (injections,
`oral capsules, solutions and tablets, topical and vaginal
`preparations). Included in parenteral and nonparenteral
`medicines licensed in the UK.
`
`17. Pharmacopeias
`Aust, Br, Egypt, Eur, Fr, Gr, Hung, Ind, It, Jpn, Mex, Neth,
`Nord, Port, Swiss and USPNF.
`
`18. Related Substances
`
`19. Comments
`
`20. Specific References
`I. Croshaw B. Preservatives for cosmetics and toiletries. J Soc
`Cosmet Chem 1977; 28: 3-16.
`2. Karabit MS, Juneskans OT, Lundgren P. Studies on the
`evaluation of preservative efficacy II: the determination of
`antimicrobial characteristics of benzyl alcohol. J Clin Hosp
`Phann 1986; 11: 281-289.
`3. Shah AK, Simons KJ, Briggs CJ. Physical, chemical, and
`bioavailability studies of parenteral diazepam formulations
`containing propylene glycol and polyethylene glycol 400. Drug
`Dev Ind Phann 1991; 17: 1635-1654.
`
`MYLAN PHARMS. INC. EXHIBIT 1023 PAGE 7
`
`r f ,.
`
`

`
`ts.
`.•
`
`} 10.
`
`Wallhausser KH. Benzyl alcohol. In: Kabara JJ, editor. Cosmetic
`and drug preservation principles and practice. New York: Marcel
`Dekker, 1984: 627-628.
`Royce A, Sykes G. Losses of bacteriostats from injections in
`rubber-closed containers. J Pharm Pharmacol 1957; 9: 814-823 .
`. 6. Roberts MS, Polack AE, Martin G, Blackbum HD. The storage
`of selected substances in aqueous solution in polyethylene
`i:
`containers: the effect of some physicochemical factors on the
`disappearance kinetics of the substances. Int J Pharmaceutics
`1979; 2: 295-306.
`Evens RP. Toxicity of intravenous benzyl alcohol [letter]. Drug
`Intell Clin Pharm 1975; 9: 154-155.
`Reynolds RD. Nebulizer bronchitis induced by bacteriostatic
`saline [letter]. JAMA 1990; 264: 35.
`·.:;. 9. Smolinske SC. Handbook of food, drug, and cosmetic excipients.
`3.
`Boca Raton, FL: CRC Press Inc, 1992: 47-54.
`Hahn AF, Feasby TE, Gilbert JJ. Paraparesis following
`intrathecal chemotherapy. Neurology 1983; 33: 1032-1038.
`Grant JA, Bilodeau PA, Guernsey BG, Gardner FH. Unsus(cid:173)
`pected benzyl alcohol hypersensitivity [letter]. N Engl J Med
`1982; 306: 108.
`Wilson JP, Solimando DA, Edwards MS. Parenteral benzyl
`alcohol-induced hypersensitivity reaction. Drug Intel! Clin Pharm
`1986; 20: 689-691.
`Brown WJ, et al. Fatal benzyl alcohol poisoning in a neonatal
`intensive care unit (letter]. Lancet I 982; i: 1250.
`i·: x 14.
`Gershanik J, et al. The gasping syndrome and benzyl alcohol
`poisoning. N Engl J Med 1982; 307: 1384-1388.
`~ 15. McCloskey SE, Gershanik JJ, Lertora JJL, White L, George WJ.
`Toxicity of benzyl alcohol in adult and neonatal mice. J Pharm
`Sci 1986; 75: 702-705.
`
`·. 12.
`
`~-
`
`\:: 13.
`
`Benzyl Alcohol 37
`
`16. Benzyl alcohol may be toxic to newborns. FDA Drug Bull 1982;
`12: 10-11.
`17. Belson JJ. Benzyl alcohol questionnaire. Am J Hosp Pharm 1982;
`39: 1850,1852.
`18. FAO/WHO. Evaluation of certain food additives: twenty-third
`report of the joint F AO/WHO expert committee on food
`additives. Tech Rep Ser Wld Hlth Org 1980; No. 648.
`19. Sweet DV, editor. Registry of toxic effects of chemical
`substances. Cincinnati: US Department of Health, 1987.
`
`21. General References
`Akers MJ. Considerations in selecting antimicrobial preservative
`agents for parenteral product development. Phannaceut Technol
`1984; 8(5): 36-40,43,44,46.
`Bloomfield SF. Control of microbial contamination part 2: current
`problems in preservation. Br J Pharm Pract 1986; 8: 72,74-76,78,80.
`Carter DV, Charlton PT, Fenton AH, Housley JR, Lessel B. The
`preparation and the antibacterial and antifungal properties of some
`substituted benzyl alcohols. J Pharm Phannacol 1958; lO(Suppl):
`149T-159T.
`Harrison SM, Barry BW, Dugard PH. Benzyl alcohol vapour diffusion
`through human skin: dependence on thermodynamic activity in the
`vehicle. J Pharm Pharmacol 1982; 34(Suppl): 36P.
`Russell AD, Jenkins J, Harrison IH. The inclusion of antimicrobial
`agents in pharmaceutical products. Adv Appl Microbiol 1967; 9: 1-
`38.
`
`22. Authors
`UK: PJ Weller.
`USA: EL Brunson.
`
`, ·
`'·
`,::·. t
`
`~,:
`
`:,: ..
`
`MYLAN PHARMS. INC. EXHIBIT 1023 PAGE 8
`
`

`
`·rr- -"· r
`
`38 Benzyl Benzoate
`
`Benzyl Benzoate
`
`1. Nonproprietary Names
`BP: Benzyl benzoate
`USP: Benzyl benzoate
`
`2. Synonyms
`Benzoic acid benzyl ester; benzylbenzenecarboxylate; benzyl
`phenylformate.
`
`3. Chemical Name and CAS Registry Number
`Benzoic acid phenylmethyl ester [120-51-4)
`
`4. Empirical Formula
`C1~1202
`
`Molecular Weight
`212.24
`
`5. Structural Formula
`
`0
`
`II V 0V
`
`6. Functional Category
`Plasticizer; solubilizing agent; solvent; therapeutic agent.
`
`7. Applications in Pharmaceutical Fonnulation or
`Technology
`Benzyl benzoate is used as a solubilizing agent and nonaqu(cid:173)
`eous solvent in intramuscular injections at concentrations
`between 0.01-46.0% v/v.<1> It is also used as a solvent and
`plasticizer for cellulose and nitrocellulose. However, the most
`widespread pharmaceutical use of benzyl benzoate is as a
`topical therapeutic agent in the treatment of scabies. Benzyl ·
`benzoate is also used therapeutically as a parasiticide in
`veterinary medicine.<2>
`Other applications of benzyl benzoate include its use as a
`solvent and fixative for flavors and perfumes in cosmetics and
`food products.
`
`8. Description
`Benzyl benzoate is a clear, colorless, oily liquid with a slightly
`aromatic odor. It produces a sharp, burning sensation on the
`tongue. At temperatures below l 7°C it exists as clear, colorless
`crystals.
`
`9. Pharmacopeial Specifications
`
`Test
`Identification
`Specific gravity
`Congealing temperature
`Refractive index
`Aldehyde
`Acidity
`Sulfated ash
`Assay
`
`BP 1993
`+
`1.118-1.122
`"1: 11.o•c
`1.568-1. 570
`
`+
`:,;;; 0.1%
`99.0-100.5%
`
`USP XXII
`+
`1.116-1.120
`"1: 18.0°C
`1.568-1.570
`+
`+
`
`99.0-100.5%
`
`10. Typical Properties
`Autoignition temperature: 481 °C
`Boiling point: 323°C
`Flash point: 148°C
`Freezing point: l 7°C
`Melting point: 21 °C
`Refractive index: no21 = 1.5681
`Solubility: practically insoluble in glycerin and water; miscible
`with chloroform, ethanol (95%), ether and oils.
`Specific gravity: l.12
`Vapor density {relati"ve): 7.3 (air =
`
`l)
`
`11. Stability and Storage Conditions
`Benzyl benzoate is stable when stored in tight, well-filled, light(cid:173)
`resistant containers. Exposure to excessive heat should be
`avoided.
`
`12. Incompatibilities
`Benzyl benzoate is incompatible with alkalis and oxidizing
`agents.
`
`13. Method of Manufacture
`Benzyl benzoate is a constituent of Peru balsam and occurs
`naturally in certain plant species. Commercially, it is produced
`synthetically by the dry esterification of sodium benzoate and
`benzoyl chloride in the presence of triet~ylamine or by the
`reaction of sodium benzylate on benzaldehyde.
`
`14. Safety
`Benzyl benzoate is metabolized by rapid hydrolysis to benzoic
`acid and benzyl alcohol. Benzyl alcohol is then further
`metabolized to hippuric acid which is excreted in the urine.
`Benzyl benzoate is widely used as a 25% v/v topical
`application in the treatment of scabies and as an excipient in
`intramuscular injections and oral products. Adverse reactions
`to benzyl benzoate include skin irritation and hypersensitivity
`reactions. Oral ingestion may cause harmful stimulation of the
`CNS and convulsions.
`LDso (cat, oral): 2.24 g/kg(3-SJ
`LD50 (guinea pig, oral): LO g/kg
`LD5o (mouse, oral): 1.4 g/kg
`LD50 (rabbit, oral): 1.68 g/kg
`LD50 (rabbit, skin): 4.0 g/kg
`LD50 (rat, oral): 0.5 g/kg
`LD50 (rat, skin): 4.0 g/kg
`
`15. Handling Precautions
`Benzyl benzoate may be harmful if ingested and is irritating tc
`the skin, eyes and mucous membranes. Observe norma:
`precautions appropriate to the circumstances and quantity ol
`material handled. Eye protection, gloves and a respirator art
`recommended. It is recommended that benzyl benzoate bt
`handled in a fume cupboard. Benzyl benzoate is combustible
`
`16. Regulatory Status
`Included in the FDA Inactive Ingredients Guide (IM injectiom
`and oral capsules). Included, as an active ingredient, ir
`nonparenteral medicines licensed in the UK.
`
`17. Pharmacopeias
`Aust, Br, Braz, Cz, Egypt, Fr, Hung, Ind, Int, It, Jpn, Mex
`Neth, Nord, Swiss, Turk, US and Yug. Also in the BP Vet.
`
`MYLAN PHARMS. INC. EXHIBIT 1023 PAGE 9
`
`

`
`:*· 18. Related Substances
`
`W. Specific References
`L Spiegel AJ, Noseworthy MM. Use of nonaqueous solvents in
`parenteral products. J Phann Sci 1963; 52: 917-927.
`DebufY, editor. The veterinary fonnulary: handbook of medicines
`used in veterinary practice, 2nd edition. London: The Phannaceu(cid:173)
`tical Press, 1994: 152-153.
`Graham BE, Kuizenga MH. Toxicity studies on benzyl benzoate
`and related benzyl compounds. J Pharmacol Exp Ther 1945; 84:
`358-362.
`
`Benzyl Benzoate 39
`
`4. Draize JH, et al. Toxicological investigations of compounds
`proposed for use as insect repellents. J Phannacol Exp Ther
`1948; 93: 26-39.
`5. Sweet DV, editor. Registry of toxic effects of chemical substances.
`Cincinnati: US Department of Health, 1987.
`
`21. General References
`Gupta VD, Ho HW. Quantitative determination of benzyl benzoate in
`benzyl benzoate lotion NF. Am J Hosp Pharm 1976; 33: 665-666.
`Hassan MMA, Mossa JS. Benzyl benzoate. In: Florey K, editor.
`Analytical profiles of drug substances, volume 10. New York:
`Academic Press, 1981: 55-74.
`
`22. Authors
`USA: SA Daskalakis.
`
`MYLAN PHARMS. INC. EXHIBIT 1023 PAGE 10
`
`

`
`82 Hydrogenated Castor Oil
`
`Hydrogenated Castor
`Oil
`
`1. Nonproprietary Names
`USPNF: Hydrogenated castor oil
`
`2. Synonyms
`Castorwax; Castorwax MP 70; Castorwax MP 80; Opalwax;
`Simulsol.
`
`3. Chemical Name and CAS Registry Number
`Glyceryl-tri-(12-hydroxystearate) [8001-78-3]
`
`4. Empirical Formula Molecular Weight
`The USPNF XVII describes hydrogenated castor oil as the
`refined, bleached, hydrogenated, and deodorized castor oil,
`consisting mainly of the triglyceride of hydroxystearic acid.
`Cs109H110
`939.50
`
`5. Structural Formula
`
`OH
`0
`I
`II
`CH1-0- C-(CH1)rn-CH-(CH 2),- CH1
`
`I
`
`~
`
`r1-0-;-(CH1
`
`?H
`
`10- ; :-
`
`)
`
`(CH1),-CH1
`
`9. Pharmacopeial Specifications
`
`Test
`
`Melting range
`Heavy metals
`Free fa tty acids
`Hydroxyl value
`Iodine value
`Saponification value
`
`USPNF XVII
`
`85-88°C
`"'0.001%
`+
`154-162
`
`"' 5
`176- 182
`
`10. Typical Properties
`Acid value: ~ 5
`Density ( tapped) : see HPE Data.
`Flash point: 316°C (open cup)
`Moisture content:~ 0.1%
`Particle size distribution: see HPE Data.
`Specific gravity: 1.023
`Solubility: insoluble in water; soluble in acetone and chloro(cid:173)
`form.
`
`HPE Laboratory Project Data
`
`Method
`
`Lab #
`
`Results
`
`Bulk/tap density
`Castorwax
`
`BTD-6
`
`Castorwax MP 70
`
`BTD-6
`
`Caslorwax MP 80
`
`BTD-6
`
`Density
`DE-I
`Castonvax
`DE-1
`Castorwax MP 70
`Castorwax MP 80 DE-I
`Particle size
`PSD-4
`
`Supplier: NL Industries Inc.
`
`8
`
`8
`
`8
`
`7
`7
`7
`17
`
`Volume: 12.5%
`Weight: 9.0%
`Vo lume: 12.5%
`Weight: 8.0%
`Volume: 12.0%
`Weight: 9.0%
`
`1.03 ± 0.01 g/cm3
`1.07 ± 0.02 g/cm3
`0.985 ± 0.006 g/cm3
`97.7% ~ 1000 µm
`(for flakes)
`
`11. Stability and Storage Conditions
`Hydrogenated castor oil is stable at temperatures up to 150°C.
`Clear, stable, chloroform solutions containing up to 15% w/v
`of hydrogenated castor oil may be produced. Hydrogenated
`castor oil may also be dissolved at temperatures greater than
`90°C in polar solvents and mixtures of aromatic and polar
`solvents but the hydrogenated castor oil precipitates out on
`cooling below 90°C.
`Store in a well-closed container in a cool, dry, place.
`
`12. Incompatibilities
`Hydrogenated castor oil is compatible with most natural
`vegetable and animal waxes. No incompatibilities are reported
`in the literature.
`
`13. Method of Manufacture
`Hydrogenated castor oil is prepared by the hydrogenation of
`castor oil using a catalyst.
`
`14. Safety
`Hydrogenated castor oil is used in oral and topical
`pharmaceutical formulations where it is generally regarded
`as an essentially nontoxic and nonirritant material.
`
`CH 1- 0-C-(CH 1)"-CH-(CH1),-CH,
`
`6. Functional Category
`Extended release agent; stiffening agent; tablet and capsule
`lubricant.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Hydrogenated castor oil is