Handbook of
`
`PHARMACEUTICAL
`
`EXCIPIENTS
`
`Second Edition
`
`Edited by
`Ainley Wade and Paul J Weller
`
`American Pharmaceutical Association
`Washington
`
`Pharmaceutical Press
`ondon
`
`‘REBEL? fi?H&fi
`
`|nnoPharma Exhibit 10790001
`
`

`

`© 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, I Lambeth High
`Street, London, SE1 TJN, England.
`
`A catalogue record for this book is available from the British Library.
`
`Library of Congress Catalog Card Number: 9449492.
`
`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
`
`|nnoPharma Exhibit 1079.0002
`
`

`

`Alcohol
`
`1. Nonproprietary Names
`BF: Ethanol (96%)
`USP: Alcohol
`
`2. Synonyms
`Ethyl alcohoi; ethyl hydroxide; grain alcohol; methyl carbinol.
`
`3. Chemical Name and CAS Registry Number
`Ethanol [64~l7-5]
`
`4. Empirical Formula Molecular Weight
`C21-I60
`46.07
`
`5. Structural Formula
`
`C3H5OH
`
`6. Functional Category
`Antimicrobial preservative; disinfectant;
`solvent.
`
`skirt penetrantf
`
`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 pharmaceutical
`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 enhancersm and as disinfectants.
`
`Use
`
`Concentration ("/o Viv)
`
`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
`the term ‘ethanol’ used without other
`In the BP 1993,
`qualification refers to ethanol 2 99.5% vfv. 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.
`the term "dehydrated alcohol‘ refers to
`in the USP XXII,
`ethanol 2 99.5% v/v. The term ‘alcohol’, without other
`qualification refers to ethanol 94.9-96.0% v/v.
`the term
`In the Handbook of Pharmaceutical Excipienrs,
`‘alcohol’ is used for either ethanol 95% vfv or ethanol 96%
`vfv.
`Aicohol is a clear, colorless, mobile and volatile iiquid with a
`slight, characteristic odor and burning taste.
`See also Section 18.
`
`Alcohol
`
`7
`
`.9. Trharmacopeial Specifications
`Test
`BP 1993
`USP XXII
`Identification
`+
`+
`Specific gravity
`0.8038-0.8063
`0.812-0.816
`Acidity
`+
`+
`Clarity of solution
`+
`—
`Nonvolatile residue
`~<. 5 mgfl00 rnL
`s 1 mg,/40 ml.
`Water—insoluble
`--
`+
`
`substances
`Aldehydes
`Amy] alcohol, etc
`Benzene
`Fuse} oil constituents
`Acetone and
`propan-2-ol
`Methanol
`Rcducing substances
`Volatile impurities
`
`10 ppm
`
`—
`Q 2 ppm
`—
`—
`
`—
`+
`+
`
`‘
`
`+
`+
`—
`+
`+
`
`-l-
`—
`~_
`
`10. Typical Properties
`in aqueous
`is bactericidal
`Antimicrobial activity: ethanol
`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 the presence of
`nonionic surfactants and is ineffective against bacterial spores.
`Boiling point: 78.IS°C
`Flammability:
`readily flarnrnabie, burning with a blue,
`smokeless flame.
`Flash point: i4°C (closed cup)
`Solubility: miscible with chloroform, ether, glycerin and water
`(with rise of temperature and contraction of volume).
`Specific gravity: 0.8li9—0.8l39 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 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
`color clue to a reaction with residual amounts of aldehyde.
`Organic salts or acacia may be precipitated from aqueous
`solutions or dispersions. Ethanol solutions are also incon1pa—
`tible with aluminum containers and may interact with some
`drugs.
`
`13. Method of Manufacture
`
`is manufactured by the controlled enzymatic
`Ethanol
`fermentation of starch, sugar or other carbohydrates. A
`fermented liquid is produced containing about 15% ethanol;
`ethanol 95% vfv 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.
`
`|nnoPharma Exhibit 10790003
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`€
`

`

`
`
`
`
`3 Alcohol
`
`Ethanol is rapidly absorbed from the gastrointestinal tract and
`vapor may be abscrbed zhrrmgh the lungs. Ethanol
`is
`metabolized mainly in th: liver ta aoetaldehyde; which is
`further oxidized tcr acetate.
`Ethanol is a central nervous system depressant and ingestion
`of low to moderate: quantities can lead to symptoms Qf
`intoxication including muscle incoordination, visual impair»
`mom, slurrad speeczli, etc. Ingestion of higher cencemrations
`may cause clepreasicm of medullary action, lethargy, amnesia,
`hypothermia, hypoglycemia, stupor, coma, respiratory depres-
`sion and cardiovascular collapsa. The lethal human blood-
`aleohal concentratian is generally estimated to be 400-500 mg,’
`100 311..
`intoxicatiim are usually
`Although symptams of ethanol
`encountered fcsllx;-wing deliberate consumption emf‘ ethanol
`conlaiuing beveragss, many pharmaceutical products contain
`ethanol as a solvent which,
`if ingested in sufficiently large
`quantities, may cause adverse symptoms of intaxication.
`Parenteral products containing up to 50% of alcohol (ethanol
`935% or %‘i»’» vgv) have: been farmulated. Howaver, such
`concentrations can produce pain an intramuscular injection
`and laws: concentrations such as 5-10% Viv are preferred.
`Subcutaneous injection of alcohol (ethanol 95% v/V) similarly
`causes considerable pain follcrwed by anesthesia. If injections
`are made close to nerves, neuritis and nerve degeneration gnay
`occur. ‘ibis effect is useé lherapeutically to cause; anesthesia in
`cages cxf severe pain although the practice of using alcohol in
`panic blocks is controversial. Doses. of 1 ml. of absolute
`alcohol haw: been used for this purpose.(‘”
`Preparations containing greater than 50% ‘«’/V alcczhol may
`cause skin irritation when applied topicafly.
`
`LD;-,;, (guinea gig, IF}: 3.41 gjlcgm
`LD5o (guinea pig, IV); 2.3 gfkg
`LD;,o (guinea pig, oral): 5.56 gfkg
`1,1359 (hamster, ZIP): 5.0’? g/kg
`LDSQ (mouse, 11’): £1.93 gjkg
`LD5,; (mouse, IV): 1.9? gfkg
`L333; (mouse, aural}: 15 gjkg
`1.1359 (mnuse, SC}: 8.29 g/kg
`LD50 (rabbit, IP}: 0.96 gfkg
`LD5o (rabbit, IV): 2.3’! g/kg
`Lflgg (rabbit, oral): 6.3 glkg
`LD39 (rat, IP): 335 ggl-cg
`LD5¢, (rat, IV): 1.44 gfkg
`LD50 (rat, oral): ‘W6 gfkg
`
`‘I5. Handling Precautions
`Cfmerve normal precautions appropriate ta the circumstances
`and quantity of material handled. Ethanol and aqueous
`ethanol sclmzicsns shauld be handled in a wellwezntilated
`environment. In the UK, the long-term 3-hour TWA exposure
`limit For ethanol is 1900 mg/m3 (1000 ppm).“9 Ethanel may be
`irritant to the eyes and mucous membranes and eye pmtection
`and gleves are therefore recccmmanded. Ethane} is flammable
`and should be heated with care. Fixed sterage tanks should be
`clactrizally gmunded to avaid ignition from clezctmstatic
`discharges, when ethanol is transferred.
`
`16. Regulatory Status
`Included in the FDA inactive Ingredients Guidc {clental
`preparations, inhalations, IM and W injecti-ans, nasal and
`ophthalmic preparaticans, oral capsules, solutions, suspensions,
`syrups and tablets, rectal, topical and transdermal prepara-
`
`included in ncnparenteral and parenteral medicines
`tions).
`licensed in the UK.
`
`17. Pharmacopeias
`Aust, Br, Chin, (32, Egypt, Fr, Ger, Hung, Ind, It, Jpn, Mex,
`Neth, Nerd, Rom, Rug, Swiss, ‘Turk, US and Yug. Also in BP
`Vet.
`
`18. Related Substances
`
`Dehydrated alcohul; denatured alcuholg dilute alcohol;
`Isopropjii Alcohol.
`
`Dehydrated alctihol
`Synonyms: absolute alcohol; ethanol.
`/iuioignition zemperafurez 365°C
`Bailing paint: 785°C
`Explosive limits: 3.5-19.0% vjv in air
`Flask pa-Em: 12°C (closed cup)
`Hygrcweapicity: absorbs water rapidly fram the air.
`llfeifirzg paint: ~ 112°C
`Regfmcrive index: at?” = 1.36I
`Specegfic gravity; {l.7904—D.7935 at 20°C
`Surface tension: 22.75 mN/rn at 20°C (ethanoifvapor)
`Vapm’ densixy (relative): 1.59 (air = 1)
`Vapor pressure: 5.8 Pa at 20°C
`Viscasézy {dynamic}: 1.22 mPa 3 (1.22 GP) at 20°C
`Comments: dehydrated alcclml is ethanol 2: 99.5% Viv. See
`Section 8.
`
`Iiaenatured alcuhal
`Synonyms: industrial methylatad spirit; surgical spirit.
`Commenzs: denatured aloehol is alccshol, fer external use only,
`that has been rendered unfit far human censumption by that
`addition Inf a. denaturing agent such as methanol or methyl
`isobuzyl ketona.
`‘
`Dilute aleohul
`Synonyms: dilute ethanol.
`Specific gravfryr
`
`Sgrengtli of alcohol
`(“fix VIY)
`9f}
`80
`70
`fill
`50
`45
`25
`20
`
`Specific gravity a! 20°C
`
`0. 82893.33 E9
`E}.8S9“9~*3,8621
`£18368-{l.8883
`0l9103~0.9£ I4
`0.9314-0.9326
`0.9407-0.94! 7
`9.9594-<0.9'3'U3
`(}l9?48v-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) ccmlaining 90,
`80, T9, 60;. 50, 45, 25 and 20% ufv respectively cf ethanol.
`
`19. Comments
`
`Pessession and use (if non~den.sLtured alcohols are usually
`subject to class control by excise authorities.
`
`2!}. Specific References
`l. Cbiori CO, Ghebashy AA. A potcntiating effect of EDTA on thx:
`bactericidal activity of lower t3Onc:er1t£a£iO:‘1$ af‘ ethanol. Int J
`Pliarmaceutics I983; 17: 121428.
`
`|nnoPharma Exhibit 1079.0004
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`

`

`. Karabit MS, Juneskans OT, Lundgren P. The determination of
`antimicrobial characteristics of same pharmaceutical compounds
`in aqueous solutions. Int J Pharmaceutics 1939; 54: 51-56.
`. Liu P, Higuchi WI, Song W, Kurihara~Be:gstrom T, Good WR.
`Quantitative evaluation of ethanol effects on diffusion and
`metabolism of ,8-estradiol
`in hairless mouse skin. Pharm. Res
`1991; 8; 865-872.
`. Lloyd JW. Use of anaesthesia: the anaesthetist and the pain clinic.
`Br Med J 1980; 281: 432-434.
`. Sweet DV, editor. Registry of toxic effects of chemical substances.
`Cincinnati: US Department of Health, 1987.
`. Health and Safety Executive. Occupational exposure limits 1993:
`EI-I40g'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.
`Spiege! AJ, Noseworthy MN. Use of nonaqucous solvents in
`parenteral products. J Pharm Sci 1963; 52: 917~92'7.
`Wade A, editor. Pharmaceutical handbook, 19th edition. London: The
`Pharmaceutical Press, 1980: 227-230.
`
`22. Authors
`UK: S] Lewis.
`
`|nnoPharma Exhibit 1079.0005
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`893223;! Alcofsof 35
`
`Continued
`
`Trot
`
`Refractive index
`Residue an ignition.
`Noxwolatile matter
`Chlorinated compounds
`Aldehydé
`Peroxitie value
`Assay
`
`PhEur 1990
`
`l.S38—l.54l
`-
`£2 0.05%
`S, 300 ppm
`»-;< 0.2%
`é 5
`97.0-100.5%
`
`USPNF XVII
`
`1.539-1.541
`:33’, 0.005%
`«A
`+
`£ 02%
`-
`--
`
`10. Typical Properties
`Acidizgfiaikcrzinizyz aqueous solutions are neutral to litmus.
`Antimicmiziotl activity: benzyl alcohol is baotoriostatic: and is
`used as an antimicrobial preservative against Gram-positive
`bacteria, molds, fungi anti yeasts although it possssses only
`modest bactericidal properties. Optimum activity occurs at less
`than 131-} 5; little activity is shown above pH 8. Antimicrobial
`activity is rocluccd in the presence ofnonionic surfactants, such
`as polysorbate 80. Howevsr, 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 IP43’
`is moderately active against most
`Bacteria: bcnzyl alcohol
`Gram—p+z>siti\:e organisms (typical MICE are 3-5 mg/ELL),
`although some Gram-positive bacteria are very sensitive
`(MIC3 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. Bonzyl alcohol 1% Vflf, at pH 5-
`6, has been claimed to be as effective as phenylmerourio nitrate
`0.002% wfv against Bacillus sterzraxhermophifus at 100°C for 30
`minutes.
`
`Table 1: Minlrmxm inhibitory concentrations (MICs) of benzyl alcohol.”
`
`Microorganism
`
`MIC {,:zg{mL)
`
`Aspergilins zziger
`Candida albicans
`Escherichia coil‘
`Pseucforrzoncrsr aemginosa
`Szapfxyiococczxs duress
`
`5000
`2500
`2000
`2000
`25
`
`Autoignition zemperamre: 436.5“C
`Boiling point: 204-.7°C
`Fiammabifiryr flammable. Limits in air 1.?—l5.0°fa v,.’v.
`Pics}: polar:
`100.6°C (closed cup);
`10-=l.S°C (open cup}.
`Freezing paint: ~— 35°C
`Malling point: — 153°C
`Partition cogfficieotm
`Liquid paraffin: water = 0.2;
`Peanut oil: water —= 1.3.
`Refircrcrive fmfex: H928 = l.S404
`
`|nnoPharma Exhibit 1079.0006
`
`
`
`enzyl Alcohol
`
`
`L‘. Nonproprietary Names
`P: Eenzyl alcohol
`hEur: Alcohol benzylicus
`SPNF: Benzyl alcohol
`
`9? 3.
`
`Synonyms
`'-‘Hydroxyroluene; phenyloarbinol; phenylmethanol; o:—tolue-
`no}.
`
`
`
`A Chemical Name and CAS Registry Number
`fieozenemetlzaool {100«S1—6]
`4. Empirical Formula Molecular Weight
`;'G;l-I30
`103.14
`
`5. Structural Formula
`
` CH,0H
`
`
`
`6. Functional Category
`Antimicrobial proservative; disinfectant; solvent.
`
`
`
`7. Applications in Pharmaceutical Formulation or
`
`is an antimicrobial preservative used in
`Benzyl alcohol
`osmctics, foods and a. wide range of pharmaceutical
`ormulations,"‘33 including oral and parenteral preparations,
`gi aiconoentrations up to 2.0% vfv. In cosmetics, concentrations
`up to 3.0% xtfv may be used as a preservative. Concentrations
`of 5% vfv or more are employed as a solubilizer, whilst a 10%
`~ vfv solution is uaed as a disinfectant.
`: Bcnzyl alcohol 10% vfv solutions also have some local
`= anesthetic properties which are exploited in some paraoterals,
`cough products, ophthalmic solutions, oimmoots, and derma-
`tological aerosol sprays.
`.
`; Although widely used as an antinfiorobial preservative, benzyl
`A alcohol, when administered to neonates, has been associated
`with soma fatal aszlv-arse reactions. It is now rooommended that
`parenteral products preserved with benzyl alcohol, or other
`, antimicrobial preservatives, should not ho usod in newborn
`..'
`'1 infants if at all possible, see Section 14.
`
`
`
`8. Description
`A clear, colorless, oily liquid with a faint aromatic odor and a
`sharp, burning lasts.
`
`9. Phormacopeial Specifications
`Test
`Pl1Enr 1991]
`
`Identification
`Aciéity
`Clazity of solution
`Sperific gravity
`Distilling range
`
`+
`+
`+
`1.043-1.0-fl9
`—~
`
`USPNF XVII
`
`+
`--
`--
`l.O42~l.0%l":’
`202.5-206.5%
`
`
`
`

`

`_
`
`36 Benzyl Alcohal
`
`Solubility:
`
`fiolvent
`
`Chlorofcmn
`Bthatml
`Ethanol (50%)
`Ether
`Fixed and volatile oils
`Water
`
`Salnhflity at 29°C
`Unless atherwise stated
`
`miscible in all proportions
`miscible in all propurtions
`I in 2.5
`miscible in all pmporticns
`miscible in all proportions
`1 in 25 at 25°C
`1 in 14 at 90°C
`
`Specific gravity: 1.0454 at 20°C
`Smface tension: 33.8 mN,’m (38.8 clyuesicm)
`Vzapar derssizy (relative): 3.72 {air ='- 1}
`Vapur pressure:
`13.3 Pa {ill mmflg) at 30°C;
`1.7459 la:F’a (13.3 mmHg) at l00“C.
`Vismsity {dynamic}: 6 mPa s (6 GP) at 20°C
`
`11. Stability and Starage Cnusditians
`Benzyl alcohol oxidizas slowly in air to bezmlziehyde and
`benzcvic acid; it does not react with water. Aqueous seluticms
`may be sterilized by filtratian DI‘ autoclasving; same soluticns
`may generate benzaldahyde dming autaclawing.
`_,
`Benzyl alcohol may be stored in metal or glass containers
`although plastie containers should not be used. Exceptions to
`this include polypropylene containers 01‘ vessels mated with
`inert fluorinatestl pcslymers 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 alc-ahol
`is incompatible with oxidizing agents and
`strung acids. It can also ac:ce.le:rate the anwacldaticn of fats.
`Although antimicmhial activity is reduczed in the presence of
`nonionic: surfactants. such as palysmbate St}, the reduction is
`less than is the case with hydroxybenzoate: esters or quatemary
`ammonium mmpountia.
`Benzyl alcohol is compatible with methylcellulose and is only
`slowly sorbaed by closures cvbmposed of natural
`rubber,
`Naaprsne and butyl rubber clesures, the msistanca of which
`can be enhanced by coating with fluorinatad polymersffi}
`However, a 2% Viv aqueous solution in a polyethylene
`container, stored at 20"C, may Ease up to 15% cf ii-s benzyl
`alcohol content in 13 weeks“) Losses ta polyvinyl chloride and
`polypropylene contaiucrs undrsr similar conditions are usually
`negligible.
`
`13. Method of Manufactme
`
`Benzyl alcchol is prepared commercially by the distillation of
`benzyl chloride with potassium :3: sodium carbonate. It may
`also be prepared by the Canuizzam reaction of be11:«:aldehyde
`and potassium hyclmxide.
`
`14. Safety
`Benzyl alcehol is used in a wide variety of pharmaxseutical
`formulations. It is metabolized to benzaiclehyds and benzoic
`acid, with henzoic acid being further metabeliaed in the liver
`by mnjugation with glycine to form hippuric acid which is
`excrefced in the urine.
`Ingastion. or inhalation of bcznzyl alcolml may cause headache,
`vertigo, nausea, vomiting and diarrhea. Clverexposure may
`result in CNS depressian and respiratory failure. Hcewever, the
`
`,.....l«.a._r...........«',-r~e»¢~.~..;l<f»?i1-5,;,
`
`
`37y.
`5
`
`concentrations cat” benzyl alcohol normally employed as a
`preservative are net associated with such adverse effects.
`Reparts of adverse reactions to henzyl alcoholm” used as an
`excipient inclutle: neumtoxicity in patients administered benzgl
`alcahol in intrathacal pr«zparations;“°) hyperssansitlvitmm‘
`}
`although relative]
`rare, and a fatal
`toxic: syndrome:
`in
`premature infants. “S3
`The fatal toxic syndrome in low—birth-weight neonates, which
`includes symptoms of metabolic acidosis and regpiratory
`depression, was attributed to the use af benzyl alcmhol as a.
`preservative in solutians used ta flush umbilical cathetersl As a
`result: of this the FDA has recommended that benzyl alcohol
`shaulcl not be used in such flushing scslutlons and advised
`against the use crf medicines containing preservatives in the
`newborn.(’é*m
`1113 WHO has set the estimated acceptable daily intake of the
`benzylfbanzoic moiety at up to 5 mgglcg body—weight daily.”
`
`LD5g (mouse, IV): 0.32 gjkgw’
`LD34; (mange, Mal): 1.58 gjkg
`LD53 (rabbit, oral): 1.04 gfkg
`LDSO (rabbit, skin): 2.0 gjkg
`Llifigg (rat, 31?): 0.4 gjkg
`Ll);-.9 (rat, IV): 0.06 g/kg
`Llllsu (rat, aral): 1.23 gfkg
`
`15. Handling Precautions
`Observe normal precautions appropriate to the circumstances
`and quantity of material handled. Benzyl alcohol (liquid and
`vapor) is irritant la the skin, eyes and mucous membranes. Eye
`protection, gloves and protective clothing am recommended.
`Benzyl alcohcl should be handled in a wellwentilated
`envimnment; a selfasnsntained breathing apparatus is recom-
`mended in areas at‘ pear ventilation. Benzyl alwhal
`is
`flammablc.
`
`16. Regulatory Status
`Included in the FDA Inactive Ingredients Guide (injections,
`c:-ral capsules, solutions and tablets,
`topical and vaginal
`preparaticzns).
`Included in pareutaral and nonparenteral
`medicirzas licensed in the UK.
`
`17. Pharmacopeias
`Aust, Br, Egypt, Eur, Fr, Gr, Hung, Ind, It, Jpn, Mex, Neth,
`Nerd, Port, Swiss and USPNF.
`
`18. Related Substances
`
`19. Comments
`
`J’ Sm‘
`
`20. Specific References
`1. Cmshaw B. Preservatives for cosmetics and toiletries.
`Cflsinet Chem 1975?; 2.8: 3-16.
`2. Karabi: MS, Jnncskans QT, Lxmclgren P. Studies an the
`evaluatimx of preservative csfficacy II:
`the determination of
`antimicrobial clzaractcristics of bcnzyl alcohol. 3 Clin, Hosp
`Pharm 1986; 1]: 231-289.
`511311 AK, Simona KJ, Briggs Cl. Physical, chenfical, and
`bioavailability studies cal” parenteral diazepam fcrnnulaticrns
`containing prcpylem: glycol and polyethylene glycol 4&0. I:-rug
`Dev Ind Pharm 1991; 1?: E635-I654.
`
`3.
`
`
`
`|nnoPharma Exhibit 1079.000?
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`

`

`.V
`
`:1
`:1
`
`-
`
`. Wallhausser KI-1. Benzyl alcohol. in: Kahara JJ, editor. Cosmetic
`_
`and drug preservation principles and practice. New York: Marcel
`Deklter, 1984: 627-628.
`. Royce A, Sykes G. Losses of bacteriostats from injections in
`rubber-closed containers. J Pharm Pharmacol 1957'; 9: 814-823.
`. Roberts MS, Polack AB, Martin G, Blacldaurn HI). The storage
`of selected substances in aqueous solution in polyethylene
`containers:
`the effect of some physicochernical factors on the
`disappearance kinetics of the substances. Int .1 Pharmaceutics
`1979; 2: 195-306.
`Evens RP. Toxicity of intravenous benzyl alcohol [letter]. Drug
`Intell Clin Pharm 1975; 9: 154-155.
`Reynolds RD. Ncbulizer bronchitis induced by bacteriostatic
`saline [letter]. JAMA 1990; 264: 35.
`. Smolinske SC. Handbook of food, drug, and cosmetic excipients.
`Boca Raton, FL: CRC Press Inc, 1992: 47-54.
`Hahn AF, Feasby TE, Gilbert JJ. Paraparcsis following
`intrathecal chemotherapy. Neurology 1983; 33: 1032-1038.
`Grant JA, Bilodeau PA, Guernsey BG, Gardner F1-I. Unsus-
`- pected bcnzyl alcohol hypersensitivity Better}. N Engl J Med
`1932; 306: 108.
`. Wilson JP, Solimando DA, Edwards MS. Parenteral benzyl
`alcohol-induced hypersensitivity reaction. Drug Intell Clin Pharm
`1985; 20: 689-691.
`Brown W], et al. Fatal benzyl alcohol poisoning in a neonatal
`intensive care unit {letter}. Lancet 1982; i: 1250.
`Gershanik J, et al. The gasping syndrome and benzyl alcohol
`poisoning. N Engl J Med 1982; 307: 1334-1388.
`McCloskey SE, Gershanilc JJ, Lertora 111., White L, George W].
`Toxicity of bcnzyl alcohol in adult and neonatal mice. J Pharm
`Sci i936; 75: 702-705.
`
`Benzyl Alcohol 37
`
`16. Benzyl alcohol may be toxic to newborns. FDA Drug Bull 1982;
`12: 10-11.
`
`17. Belson J1 . Benzyl alcohol questionnaire. Am J Hosp Pharm 1982;
`39: 1850,1852.
`18. FAOIWHO. Evaluation of certain food additives: twenty-third
`report of the joint FAOJWHO 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
`Alcers MJ. Considerations in selecting antimicrobial preservative
`agents for parenteral product development. Pharmaceut Techno]
`i934; 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: 72,74-76,7830.
`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 Pharmacol 1958; 10(Supp1):
`149T-139T.
`
`Harrison SM, Barry BW, Dugarcl PH. Benzyl alcohol vapour diffusion
`through human skin: dependence on thermodynamic activity in the
`vehicle. J Pharm Pharmacol 1982; 34(Supp1): 361?‘.
`Russell AD, Jenkins J, Harrison IH. The inclusion of antimicrobial
`agents in pharrnaceutical products. Adv Appl Microbiol 1967; 9: 1-
`38.
`
`22. Authors
`UK: PJ Weller.
`USA: EL Brunson.
`
`|nnoPharma Exhibit 1079.0008
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`

`

`33 Benz}! Berzzaate
`
`Benzyl Benzoate
`
`1. Nonproprietary Names
`BF: Benzyl benzoate:
`USP: Benzyl lzenzcuata
`
`2. Synonyms
`Banzai: acid benzyl ester; benzylbenzenecarboxylate; benzyl
`plxenylformate.
`
`3. Chemical Name and CAS Registry Number
`Banzai»: acid phenylmethyl eswr [i20»Si-4}
`
`4. Empirical Formula
`CmH1202
`
`Molecular Weight
`111 2.221
`
`5. Structural Formula
`
`6. Fun-ztiazanal Categary
`Plasticizer; solubilizing agent; solvem; therapeutic agent.
`
`7. Applicatinns in Pharmaceutical Formulation or
`Tecimulogy
`Benzyl benz-zzate is used as a alolubilizing agent and nonaqw
`eous solvent
`in intramuscular injectians at eoncenu-ations
`between 0.0l—46.0% vjvf“ It is also used as a selves: and
`plasticizer for cellulose and nitrocellulose. However, the most
`widespread pharmaceutical use of benzyl benzoate is as 22
`topical therapeutic agent in the treatment of scabies. Eenzyl
`benznate is alas used therapeutically as a parasiticidc in
`veterinary medicinal”
`Other applications of henzyl benzoate irmluda its use as a
`solvent and fixative for flavors and perfumes in ccnsmetics and
`food products.
`
`8. Description
`Benzyl benzoate is a clear, ccllmrless, oily liquid with a slightly
`ammatic odor. It produces a sharp, burning sensation on the
`tongue. At temperatures below 17°C it exists as clear, colorlass
`crystals.
`
`9. Pharmacopeial Specifications
`Test
`BP I993
`Idxzntificatiml
`+
`Spzxzilic gravity
`L118-1.l22
`Cangealingg temperature
`,>, 17.{}“C
`Refractive index
`1.568-1.5%)
`Aldehyde
`-——
`Acidity
`+
`Sulfatved ash
`é 0.1%
`Assay
`99.0-100.5%
`
`USP XXII
`+
`1.11:3-1.120
`L?» 18.{l"C
`1.568-1.570
`4-
`+
`—~
`99.0~ICl0.5°/o
`
`10. Typical Properties
`Aataignitian temperature: 481°C
`Boiling point: 323°C
`Flash point: 148°C
`Freezing pains: 127°C
`Melting poim: 21°C
`Refractive index: H1331 = 1.5681
`Solubility: praciically insoluble in glycerin and water; miscible
`with chlomforrn, ethanol (95%), ether and ails.
`Specific gratify: 2.12
`Vapor density (relative): 7.3 {air = 1)
`
`11. Stability and Storage Conditions
`Benzyl benzoate is stable when starred in tight, wellfilled, light-
`resistant containers. Exposure to excessivz: heat should be
`avoided.
`
`12.. Incompatibilities
`Benzyl benzcaate is incompatible with adkalis and oxidizing
`agents.
`
`13. Method of Nlanufacture
`
`Bo.-mzyl benzeate is 3. ccxnstituent of Pram balsam and occurs
`naturally in certain plant species. Commercially, it is produced
`synthetically by the dry esterification of sodium benzoate and
`benzcryl chloride in the presence of trietlzrylaminc 0:‘ by the
`mastic-n of sodium bang}-late on izenzalclehyde.
`
`14. Safety
`Benzyl bets:-aatc is metabolized by rapid hycimlysis to lzezazoia
`acid and benzyl alcohol. Benzyl alcohol
`is then further
`metabolmecl to hlppuric acid which is excreted in the urine.
`Benzyl bczizoate is widely used as a 25% vfv topical
`application in the treatment of scabies and as an axnipien: in
`intramuscular injections and oral products. Adverse reactions
`to benzyl benzaaw include skin irritation and hypersensitivity
`reactions. Oral ingestion may cause harmful stimulation of the
`CNS and convulsions.
`
`LD53 (cat, oral): 2.24 g,/kg‘3'”
`L059 {guinea pig, oral}: 1.0 gfkg
`LD5fl (mouse. oral): 1.4 gfkg
`{.1359 (rabbit, oral): 1.68 g/kg
`LD5a (rabbit, Sl£i1'l)I
`g,/kg
`L135‘; (rat, oral): 0.5 gfkg
`Lflso (rat, skin): 4.0 gfkg
`
`15. Handling Precautions
`Benzyl benzoate may be harmful if ingestecl and is irritating 1::
`the skin, eyes and mucous membranes. Obsarve norma
`pracautions appropriate to the circumstances and quantity 0:
`material handled. Bye protection, gloves and a respirator are
`recommencied. It is recommended that henzyl benzoatc be
`handled in a fume cupboard. Benzyl benzoate is combultible
`
`16. Regulatory Status
`Included in the FDA Inactive Ingredients Guide (IM injection:
`and oral capsules}.
`Included, as an acztive ingredient,
`ll
`ncmpanmterai meadicines licenserd in the UK.
`
`17. Pharmacopeias
`Aust, Br, Braz, C2, Egypt, Fr, Hung, Ind, kit, It, Jpn, Mex
`Neill, Nerd, Swiss, Turk, US and Yug. Also in the BF Vet.
`
`|nnoPharma Exhibit 1079.0009
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`

`

`Benzyl Benzmzte 39
`
`investigations of compounds
`4. Draize JH, et al. Toxicological
`proposed for use as insect repellents. J Pharmacol Exp Ther
`i94S; 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 benzoatc in
`benzyl benzoate lotion NF. Am J Hosp Pharm 1976; 33: 665-666.
`Hassan MMA, Mossa JS. Benzyl benzoate. In: F-lorey K, editor.
`Analytical profiles of drug substances, volume 10. New York:
`Academic Press, 1981: 55-74.
`
`22. Authors
`USA: SA. Daskalakis.
`
`18. Related Substances
`
`19. Comments
`
`
`
`. Specific References
`1. Spiegel AJ, Noseworthy MM. Use of nonaqueous solvents in
`parenteral products. J Pharm Sci 1963; 52: 917-927.
`‘ 2. Debuf Y, editor. The veterinary formulary: handbook of medicines
`used in veterinary practice, 2nd edition. London: The Phannacew
`tioal Press, 1994: 152-153.
`. 3. Graham BE, Kuizenga Ml-I. Toxicity studies on benzyl benzoate
`and related benzyl compounds. J Pharmacol Exp Ther 1945; 84:
`358-362.
`
`rr-="~=‘~"3=«'.\‘eT-'.7.**rr=.*?.€'i?.?.‘.'.&~
`
`
`
`|nnoPharma Exhibit 10790010
`
`

`

`9. Pharmacopeial Specifications
`Test
`USPNF XVI}
`
`Melting range
`Heavy metals
`Free fatty acids
`I-lydroxyl value
`Iodine value
`Saponification value
`
`85-88°C
`g 0.001%
`4*
`154- E 62
`S, 5
`176-182
`
`10. Typical Properties
`Acid value: S 5
`Density (tapped): see HPE Data.
`Flash point: 316°C (open cup)
`Moisture content:
`s<._ 0.1%
`Particle size distribution: see HPE Data.
`Specific gravity: 1.023
`Solubility: insoluble in water; soluble in acetone and chloro-
`form.
`
`HPE Laboratory Project Data
`Method
`Lab #
`Results
`
`Bulk/tap density
`Castorwax
`
`ETD-6
`
`Casrorwax MP 70
`
`ETD-6
`
`Caslorwax MP 80
`
`BTD-6
`
`Density
`DE-1
`Castorwax
`Casrorwax. P 70 DE]
`Castorwax MP 80
`DE-1
`Particle size
`,
`PSD-4
`
`8
`
`3
`
`8
`
`7
`7
`7
`l7
`
`l2.5"/o
`Volume:
`Weight: 9.0%
`Volume: 12.5%
`Weight: 8.0%
`Volume: 12.0%
`Weight: 9.0%
`
`1.03 i 0.01 g/cm3
`1.07 1 0.02 g;cm3
`0.985 J; 0.006 g,‘cm3
`97.7% 2 1000 pm
`(for flakes)
`
`82 Hydrogenated Castor Oil
`
`Hydrogenated Castor
`Oil
`
`1. Nonproprietary Names
`USPNF: Hydrogenated castor oil
`
`2. Synonyms
`Casrorwax; Castorwax MP 70; Castorwax MP 80; Opczlwax;
`Sfrnuisof.
`
`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.
`C57O9H:_w
`939.50
`
`5. Structural Formula
`
`OH
`0
`1
`II
`cu,—o— C—(CH,‘)",—CH~—{Cl-i2j|,—Cl-1,
`
`C!”
`if
`CH1—O-— C—{CH3)m—CH—(CH,),—(‘.H,
`
`ll
`?H
`0
`CH2‘ O—C—lCH2):o—CH‘lCl‘l2ls'"CH)
`
`6. Functional Category
`Extended release agent; stiffening agent;
`lubricant.
`
`tablet and capsule
`
`Supplier: NL Industries Inc.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Hydrogenated castor oil is a hard, high melting point wax used
`in oral and topical pharmaceutical formulations.
`In topical formulations, hydrogenated castor oil
`provide stiffness to creams and emulsions.m
`is used to
`In orai
`formulations, hydrogenated eastor oil
`prepare sustained release tablet and capsule preparationsgefi)
`the hydrogenated castor oil may be used as a coat or to form a
`solid matrix. Hydrogenated castor oil is additionally used to
`lubricate the die walls of tablet presses;(””5) it is similarly used
`as a lubricant in food processing.
`Hydrogenated castor oil is also used in cosmetics.
`
`is used to
`
`11. Stability and Storage Conditions
`Hydrogenated castor oil is stable at temperatures up to 150°C.
`Clear, stable, chloroform solutions containing up to 15% wjv
`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
`is compatible with most natural
`Hydrogenated castor oil
`vegetable and animal waxes. No incompatibilities are reported
`in the literature.
`
`Use
`
`Concentration ("26)
`
`13. Method of Manufacture
`
`Coating agent (delayed release)
`Delayed release drug matrix
`Tablet die lubricant
`
`5-20
`5-10
`0.1-2
`
`8. Description
`Hydrogenated Castor oil occurs as a white colored powder or
`flakes.
`
`Hydrogenated castor oil is prepared by the hydrogenation of
`castor oil using a catalyst.
`
`14. Safety
`is used in oral and topical
`Hydrogenated castor oil
`pharmaceutical formulations where it
`is generally regarded
`as an essentially nontoxic and nonirritant material.
`
`|nnoPharma Exhibit 1079.0011
`
`

`

`I-_I}.