Handbook of
`
`PHARMACEUTICAL
`
`EXCIPIENTS
`
`Second Edition
`
`Edited by
`Ainley Wade and Paul J Weller
`
`American Pharmaceutical Association
`
`The Pharmaceutical Press
`London
`
`"Rnoabv avuafi
`
`InnoPharma Exhibit 1079.0001
`
`

`

`
`
`© 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
`
`InnoPharma Exhibit 1079.0002
`
`

`

`
`
`Alcohol
`
`7
`
`
`
`Alcohol
`
`1. Nonproprictary Names
`BF: Ethanol (96%)
`USP: Alcohol
`
`2. Synonyms
`Ethyl alcohol; ethyl hydroxide; grain alcohol; methyl carbinol.
`
`3. Chemical Name and CAS Registry Number
`Ethanol [6447-5]
`
`4. Empirical Formula Molecular Weight
`Czl-IGO
`46.07
`
`5. Structural Formula
`
`CZHSOH
`
`6. Functional Category
`Antimicrobial preservative; disinfectant; skin penetrantf
`solvent.
`
`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 preservativcf‘g) Topical ethanol solutions are
`also used as penetration enhancers“) and as disinfectants.
`
`Use
`
`Concentration (% vlv)
`
`Antimicrobial preservative
`Disinfectant
`Extracting solvent in galenical
`manufacture
`
`2 10
`60-90
`Up to 85
`
`Variable
`Solvent in film coating
`Variable
`Solvent in injectable solutions
`Variable
`Solvent in oral liquids
`
`Solvent in topical products 60-90
`
`8. Description
`the term ‘ethanol’ used without other
`In the BP 1993,
`qualification refers to ethanol 2 99.5% va. 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 9 99.5% viv. The term ‘alcohol’, without other
`qualification refers to ethanol 94.9-96.0‘34: v/v.
`the term
`In the Handbook of Pharmaceutical Excipients,
`‘alcohol’ is used for either ethanol 95% W or ethanol 96%
`va.
`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
`BP 1993
`USP XXII
`Identification
`+
`+
`Specific gravity
`0.8038—0.8063
`0312-0316
`Acidity
`+
`+
`Clarity of solution
`+
`—
`Nonvolatilc residue
`a 5 mgfloo mL
`$ 1 rug/40 mL
`Water—insoluble
`M
`+
`
`substances
`Aldehych
`Amy} alcohol, etc
`Benzene
`Fusel oil constituents
`Acetone and
`propan-Z-ol
`Methanol
`Rcducing substances
`Volatile impurities
`
`s 10 ppm
`—
`S 2 ppm
`—
`—
`
`—
`+
`+
`
`,
`
`+
`+
`—
`+
`+
`
`i-
`—
`~—
`
`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 saltsll Ethanol is inactivated in the presence of
`nonionic surfactants and is ineffective against bacterial spores.
`Boiling point: 78.15°C
`Flammability:
`readily flammable, 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: 0.8119—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 incompa—
`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% va 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.
`
`
`
`InnoPharma Exhibit 1079.0003
`
`

`

`
`
`
`
`3 Alcohnl
`
`Ethanol is rapidly abserbed from the gastrointestinal tract and
`vapor may he ahsnrhed zhrnngh 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 :0 moderate quantities can lead to symptoms of
`intoxication including muscle inwardinarien, visual impair»
`ment, slurred speech, etc. Ingestion of higher cancentrations
`may cause deprensinn of medullary aerial-l, lethargy, amnesia,
`hypothermia, hypoglycemia, stupnr, coma, respiratory depres—
`sion and cardiovascular collapse. The lethal human blood—
`alcohnl mncentratinn is generally estimated to be 400-500 mg!
`100 mL.
`intoxicatinn are usually
`Although symptnms of ethanol
`encountered fallnwing deliberate censumption nf‘ ethanol
`committing beverages, many pharmaceutical products contain
`ethanol as a solvent which,
`if ingested in sufficiently large
`quantities, may cause adverse symptoms of intnxicatinn.
`Parenteral products containing up to 50% of alcohol (ethanol
`995% or 96% vie) have been femulated. However, such
`concentrations can produce pain are intramuscular injection
`and lnwer concentratiens such as 540% vg‘v are preferred.
`Subcutaneous. injection of alcohnl (ethanol 95% WV) similarly
`(33.11863 considerable pain follawed by anesthesia. If injections
`are made close to nerves, neuritis and nerve degeneration pay
`occur. Ellis effect is user} rherapentically to cause anesthesia in
`canes {If severe pain although the mantle: of using alcohol in
`nerve blocks is controversial. Doses of 1 ml. nf absolute
`alcohol have been used for this purpose“)
`Preparations containing greater than 50% v/v almhol may
`eause skin irritatinn when applied inpically.
`
`LDsg {guinea pig. 1?): 3.41 gjligm
`1.1350 (guinea pig, IV); 2.3 gjkg
`1.13350 (guinea pig, oral): 5.56 glkg
`LDso (hamster. 1P): 5.0”? g/kg
`LDSO (mouse. 11’): 033 g,’kg
`1335,; (mouse. IV): 1.9? gfkg
`LDm (mouse, nral}: 1.5 gjkg
`LDsg (mnuse, SC}: 8.29 gfkg
`LDsfl (rabbit, 1P}: 0.96 gfkg
`LD50 (rabbit, IV): 2.3”! g/kg
`LDsg (rabbit, oral): 6.3 glkg
`LDSC, (rat, IP}: 3535 glkg
`LDgg (rat, m; 1.44 gfkg
`1.3350 (rat, oral): 7.05 gfkg
`
`'15. Handling Precautions
`Qbser've normal precautionr appropriate In the circumstances
`and quantity of material handledl Ethanol and aqueeus
`ethanol seluliens shnuld he handled in a well-ventilated
`environment. In the UK, the long-term 3«hot1r TWA exposure
`limit For ethanol is 1900 mg/m3 (1000 ppm).<53 Ethanol may be
`irritant to the eyes and mucous membranes and eye preteetion
`and glnves are therefore recemmended. Erhannl is flammable
`and Shmfld be heated with care. Fixed storage tanks Shoulcl be
`electrieally grnunded to amid ignition from electmslatic
`discharges, when ethanol is transferred.
`
`16. Regulatnry Status
`Included in the FBA inactive Ingredients Guide {éental
`pragmatism, inhalations. 1M and W injectiens. nasal and
`ophthalmic preparatiens, oral capsules, solutions, suspensione,
`syrups and tablets, rectal, topieal and transder'mal preparan
`
`included in ncnperenteral and parenteral medicines
`nous).
`licensed in the UK.
`
`17. Pharmacopeias
`Aust, Br, Chin, C2, Egypt, Fr, Ger, Hung, Ind, It, Jpn, Mex,
`Nell}, Nerd, Rom, Run. Swiss. "Turk, US anti Yug. Also in B?
`Vet.
`
`18. Related Substances
`
`Dehydrated alcohol; denatured alcnhol; dilute alcohol;
`Isopropyl Alcohol.
`
`Dehydrated alwhol
`Synonyms: absolute alcohol; ethanol.
`Autoignition :emperamre: 365°C
`Boiling point: 785°C
`Expiflsive limits: 3.5-19.ll% We in air
`Flask prism: 12°C (closed cup)
`Hygroreepieiry: absorbs were: rapidly fmm the air.
`Making pant; —— 112‘“:
`Refmcnive index: n32“ = 1.3m
`Specyic gravity; 0.7904—D.7935 at 20°C
`Surface tension: 22.75 mN/m at 20°C (eihanoig'vapor)
`Vapnr «family (relative): 1.59 (air = l)
`Vaper pressrrre: 5.8 Pa at 20°C
`Viscesézy {dynamic}: 1.22 mPa 3 (1.22 GP) at 20°C
`Comments: dehydrated nlcehol is ethanol 3: 99.5% W. See
`Section 8.
`
`Benamred aleuhal
`Synonyms: industrial methylated spirit; surgical spirit.
`Commeezsz denatured aloehol is alcnhnl, fer external use only,
`that has been rendered unfit fer human ennnumption by the
`addition Bf a denaturing agent such as methanol or methyl
`isobuzyl ketone.
`Dilute nleohnl
`Synonyms: dilute ethannl.
`Specific gravity:
`
`Snength of alcohol
`(“113 Viv)
`9f}
`80
`l0
`fill
`50
`45
`25
`20
`
`Specific gravity :1! 29°C
`
`
`0. 82893.83 E9
`0.859%33621
`(18868-38883
`0.9103~0.9l I4
`03314-09326
`03407-0944 7
`8.95944097303
`9338419759
`
`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) cnnlaining 90.
`80. 1'9, 6’0. 50, 45, 2S and 20% We respectively nf ethanol.
`
`19. Comments
`
`Passession and use nf non~denaturecl alcohols are usually
`subject to clnse control by excise authorities.
`
`20. Specific References
`l. Chiori CO, Ghebashy AA. A potentialing effect of EDTA on the
`bactericidal activity of Iowa: concentrations 0f ethanol, Int J
`Pharmaceutics 1983; 17: 121428.
`
`
`
`InnoPharma Exhibit 1079.0004
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`

`

`. Karabit MS, Juneskans OT, Lundgren P. The determination of
`antimicrobial characteristics of some pharmaceutical compounds
`in aqueous solutions. Int J Fharmaceutics 1939; 54: 51-56.
`. Liu P, Higuchi WI, Song W, Kuriharafiezgstrom T, Good WR.
`Quantitative evaluation of ethanol effects on diffusion and
`metabolism of {3-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 [993:
`131-14083. 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: 9171927.
`Wade A, editor. Pharmaceutical handbook, 19th edition. London: The
`Pharmaceutical Ptess, 1980: 227-230.
`
`22. Authors
`UK: S] Lewis.
`
`
`
`InnoPharma Exhibit 1079.0005
`
`

`

`Bmzyf Alcalmi 35
`
` Continued
`
`Test
`
`Refractive index
`Residue on igniticn.
`Nonvolafila matter
`Chlorinatccl mmpcundc
`Aldehydc
`Permit}: value
`Array
`
`PhEur 1990
`
`1.5384541
`—~
`{1 0.05%
`g 3013 ppm
`s 3.2%
`ti”- 5
`gill-100.5%
`
`USPNF XVII
`
`1.539-1 .541
`g 0.005%
`«A
`+
`g {1.2%
`-—
`w-
`
`ill. Typical Properties
`Acidizyfm’kcrlinizy: aqueous solutions are neutral to litmus.
`Antimicmizial activity: benzyl alwth is bacteriostatic and is
`used as an antimicrobial preservative against Gram-pcsitire
`bacteria, molds, fungi anti yeasts althcugh it possesses 0111:;
`modest bactericidal properties. Optimum activity occurs at less
`than pH 5; little activity is shown above 13H 8. Antimicrobial
`activity is reduced in the presence ofnonicnic surfactants, such
`as polycarbate 80. Howcvcr, the rcducticn ln activity is less
`than is thc case with either hydroxybenzoatc esters or
`quaternary ammoninm compounds. The activity of benzyl
`almth may also be reduced by incompatibilities with same
`packaging materials, particularly polyethylene, see Section 12.
`Reported minimum inhibitory concentraticns (MICS) are
`shown in Table If“)
`Bacteria: benzyl alwth is mcderately active against most
`Gram—pcsitive organisms (typical MICE are-
`3—5
`tug/mm,
`althcugh some Gram-positive bacteria are very sensitive
`(MICE (1025-0135 mgf'mL). In general, benzyl alcohol is less
`active against Gram-negative organisms.
`Fungi: benzyl alcchel is effective against melds and yeasts,
`typical MICs are 3-5 mg/mL.
`Spams: benzyl alcohol is inactive against spores, but activity
`may be cnhanccd by heating. Benzyl alcohol 1% v/v, at pH 5-
`6, has been claimed to be as effective as phenylmcmuric nitrate
`0.802% wfv against Bacillus stearazhermaphifus at 100%: far 30
`minutes.
`
`Table 1: Minimum: inhibimry concentrations (MICs) of benzyl alcohol.”
`
`
`
` Microorganism MIC {ygImL}
`
`5000
`Aspergill‘m cigar
`2500
`Candida affirms
`2663
`Escherichia coil
`200E}
`Pseudamonar aemginosa
`
`Smphylawrws curate: 25
`
`Autaignition temperamre: 436.5%:
`Boiling paint: 204.7°C
`Fiammabr‘fz‘ry: flammable. Limits in air 1.745.024: vf’v.
`Hark grains:
`100.6%: (clcsed cup);
`104.S°C (open cup}.
`Freezing paint: ~15°C
`Melting pcfnr: —15,2°C
`Partition caejficimrm
`Liquid paraffin: water = 0.2;
`Peanut oil: water m 1.3.
`Reficrcrive index: now = 1.5404
`
`
`
`InnoPharma Exhibit 1079.0006
`
`
`
`enzyl Alcohol
`
`{c
`
`
`f. Nonpmprietary Names
`P: Benzyl alcchol
`hEur: Alcohol benzylicm
`SPNF: Benzyl alcchol
`
`___‘
`
`Syncnyms
`éflydrcxyrolucnc; phenylcarbinol; phenylmclhanol; can—{clue-
`ol.
`
`rn
`
`
`
`A Chemical Name and CAS Registry Number
`fieazcnemethanol {1%51—6]
`
`5. Structural Formula
`
`QWM
`
`6. Functional Category
`Antimicrcblal prcservaflvc; disinfectant; solvent.
`
`7. Applications in Pharmaceutical Formulation or
`
`4. Empirical Formula Molecular Weight
`Eflzflso
`103.14
`
`
`
`
`
`
`is an amimicrcbial preservative used in
`Benzyl alcohol
`csmctics. foods and a. wide range of pharmaceutical
`ormulations,“‘3} including oral and parenteral preparations,
`alconcentraticns up to 2.0% m. In cosmetics, ccnccntrations
`I? up to 3.0% vb; may be used as a preservative. Concentrations
`cf 5% m or more are employed as a solubilizer, whilst a 10%
`~ vlv solution is wed as a disinfectant.
`: BcHZyl alcohol 10% W solutions also have some local
`
`: anesthetic properties which are exploited in some parental-313,
`
`mug}: prcdtmts, ophthalmic sclutions, cimmmm, and dcrma»
`. tclcglcal acrcscl sprays.
`
`; Although widely used as an antimicrobial preservativa, benzyl
`‘ alcchol, when administered to neonates, has been asscciatcd
`with somc fatal aclversc rcactians. It is new rccommcnded that
`parenteral products preserved with benzyl almhul, or other
`, antimicrobial preservativcs. should not hr: uscd in newborn
`..’
`'1 infants if at all possible. see Section 14.
`
`
`
`:‘L 8. Description
`A clear, colorlcas, 0in liquid with a faint aromatic odor and a
`sharp, burning taste.
`
`9. Pharmacopeial Specificatinns
`Test
`PhEnr 199i]
`USPNF XVII
`
`ldemificaticn
`Adéity
`Clarity (If solution
`Specific gravity
`Distilling range
`
`+
`+
`+
`19434.0”
`fl
`
`+
`_.
`—-
`1.042armr
`202.5-2fi65‘C
`
`
`
`

`

`
`
`
`,Lluaadsmwwgufiifi‘fl‘ffi:‘t“'
`
`
`l'y.
`f
`
`.M
`
`.36
`
`133112)}! Alcuhul
`
` Suitability:
`810!th
`Sululxflity at 29°C
`Unless atheer stated
`
`Chlorofmm
`Ethanul
`Ethanol (50%)
`Ether
`Fixed and volatile oils
`Water
`
`miscible in all propurtions
`miscible in all propurtiens
`I in 2.5
`miscible in all pmporticns
`miscible in all pmporliuns
`1 in 25 at 25°C
`1 in 14 at 90°C
`
`Specific gravity: 1.0454 at ZIP(3
`Surface tension: 33.8 mem (38.8 dyuesicm)
`Vapur mm}: (reiazéve): 3.72 {air = l}
`Vapor pressure:
`13.3 Pa {0.1 mmHg) at 30°C;
`1.7459 kl’a (13.3 mmHg) at 1003C.
`Viscusity (dynamic): 6 mPa s (6 GP) at 20°C
`
`11. Stability and Sturage Cundifians
`Benzyl alcohol oxidizus slowly in air to bemléehyde and
`benzuic acid; it does not react with water. Aqueous selutiuns
`may be sterilized by filtratiun ur autoclaving; same solutiuns
`may generate benzaldahyde Liming autoclauing.
`_’
`Benzyl alcohol may be slated in metal or glass containers
`althuugh plastiu containers should not be used. Exceptions to
`this include pulypropylene containers or vessels mated with
`inert marinated palymers such as Teflon, see Section 12.
`Beuzyl alouhul should be stared in an airtight container,
`pmtected from light, in a coal, dry, place.
`
`12. Incumpafibilities
`Beuzyl alcehol
`is inwmpatible with axidiziug agents and
`strong acids. It can also accelurate the anwxldation of fats.
`Although antimicmlfial activity is reduced in tha presence of
`noninnic: surfactants, such as palysuxbats 80, the reduction is
`less than is the case with hydroxybeuzoate esters or quaternary
`ammonium campuunfiu.
`Benzyl alcohol is campatible with methylcellulose and is only
`slowly sorbud by dogmas composed of natural
`rubber,
`Nuuprene and butyl rubber ulusurcs, the: rusistanca of which
`can be enhanced by coating with fluoriuatud polymersf”
`Hawuvar, a 2% m aqueous sulution in a polyethylene
`container, stared at 209C, may lose up to 15% Qf its benzyl
`alcohol content in 13 weeksfs) Losses ta polyvinyl chloride and
`palypropylene contaiuurs under similar conditions are usually
`negligible.
`
`13. Method of Manufactm‘e
`
`Benzyl alcuhol is prcpared commercially by the distillation of
`benzyl chloride with potassium in sodium carbonate. It may
`also be prepared by the Canal-mam reaction of bemaldehyde
`and potassium hyclmxide.
`
`14. Safety
`Benzyl alcuhol is used in a wide variety of pharmaueutiual
`formulations. It is metabulizcd tu benzalclehydu and benzoic
`acid, with henzoic acid being further metabolized in the liver
`by conjugation with glycine to form hippuric acid which is
`slimmed in the urine.
`Ingustlou or inhalation of benzyl alcohul may cause headache,
`vertigo, nausea“ vomiting and diarrhea. merexposma may
`result in CNS depression and respiratory failure‘ Huwaver, the
`
`concentrations at” benzyl alcohol normally employed as a
`preservative are nut msmiated with such adverse afflicts.
`Reparts of adverse reactions to henzyl alcohol‘7“9) used as an
`excipient inclutle: neurotoxicity in patients administered benzgl
`alcuhol in intrathacal praparatiansgm) hypermsitlvityfu‘ 3‘
`although relative]
`rare, and a fatal
`toxic: syndromes in
`premature infants. “53
`The fatal taxis syndrome in low—birth—weight neonatas, which
`includw symptoms of metabolic acidosis and respiratory
`depression, was attributed m the use uf benzyl alcuhol as a.
`preservative in solutians used t0 flush umbilical catheters; As a
`result 0f this the FDA has remmmendecl that benzyl alcohol
`shaulcl not be used in such flushing sulutions and advised
`against the use of medicines containing preservatives in the
`newbomfmm
`The WHO has set the estimated acceptable daily intake cf the
`benzylfbenzoic moiety at up to 5 mgg’kg body—weight daily“)
`
`LDSg (moms, IV): 0.32 gg‘kgw’
`£1330 {amusez oral): 1.58 g‘ikg
`LDSQ. (rabbit, ural): 1,04 gfkg
`LDso (rabbit, skin): 2.0 gfkg
`L:ch (rat, 3?): 0.4 gjkg
`Lug, (rat, IV): 0.06 g/kg
`£1359 (rat, ural}: 1.23 gfkg
`
`15. Handling Precautions
`Observe normal precautions appropriate la the circmnslauces
`and quantity of material handled‘ Benzyl alcohol (liquid and
`Eli-1130?) is irritant to: the skin, syus and mucous membranes. Eye
`protection, gluvcs and protective clothing are recommended.
`Benzyl alcohcl should be handled in a welloveutilated
`envimument; a self—cuntained breathing apparatus is recom
`mended in arsas of pear ventilatiun. Baggy] alcuhul
`is
`flammablc.
`
`16. Regulatory Status
`Included in the FDA Inactive Ingredients Guide (injections,
`aural capsules, solutions and tablets,
`topical and vaginal
`preparatiuns).
`Included in pareutural and nonparenteral
`medicinus licensed in the UK.
`
`17. Pharmacopeias
`A1131, Br, Egypt, Eur, Fr, Gr, Hung, Ind, It, Jpn, Mex, Nethy
`Nerd, Font, Swiss and USPNF.
`
`18. Related Substances
`
`19. Comments
`
`J' Sm.“
`
`20. Specific Referencus
`l. Cmshaw B. Preservatives for cosmetics and toiletxias.
`Cusmet Chum 19?7;281 3—16.
`2. Karabl: MS, Juncskans QT, Lundgren P. Studies an the
`evaluatiun of preservative ufficacy II:
`the determination of
`anthnicrobial charactmisfics of benzyl alcohol. 3 Clix: Hosp
`Pharm 1986; 1]: 231-289.
`3‘ Shah AK, Simons KJ, Briggs CJ. Physical, chemical, and
`bioavailability studies of parenteral diazepam fannulatiuus
`containing propylene glycol and polyethylene glyccl 400. Brag
`Dev Ind Pharm 1991; 1?: l635-[654.
`
`
`
`InnoPharma Exhibit 1079.0007
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`

`

`:1
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`:l
`
`.V
`
`Benzyl Alcohol 37
`
`16. Benzyl alcohol may be toxic to newborns. FDA Drug Bull 1982;
`12: 10-11.
`
`17. Belson J} . Benzyl alcohol questionnaire. Am J Heep Pharm 1982;
`39: 1850,1852.
`18. FAOIWHO. Evaluation of certain food additives: twenty—third
`report of the joint FAOXWHO 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): 3640,43,“,46.
`Bloomfield SF. Control of microbial contamination part 2: current
`problems in preservation. Br J Pharm Pract 1986; 8: 7234-7632330.
`Carter DV, Charlton PT, Fenton AH, Hensley JR, Lessel B. The
`preparation and the antibacterial and antifungal properties of some
`substituted benzyl alcohols. J Pharm Pharmacol 1958; 10(Suppl):
`149T—159T.
`
`Harrison SM, Barry BW, Dugard PH. Benzyl alcohol vapour diffusion
`through human skin: dependence on thermodynamic activity in the
`vehicle. J Pharrn Pharmacol 1982; 34(Supp1): 361?.
`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.
`
` '
`
`. Wallhausser KH. Benzyl alcohol. in: Kabara JJ, editor. Cosmetic
`I
`and drug preservation principles and practice. New York: Marcel
`Dekker, 1984: 627-628.
`. Royce A, Sykes Gr. Losses of bacteriostats from injections in
`rubber-closed containers. J Pharm Phannacol 1957'; 9: Elm-823.
`. Roberts MS, Polack AB, Martin G, Blackburn HD. 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 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.
`. Smolinslte SC. Handbook of food, drug, and cosmetic exeipients.
`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 PH. Unsuse
`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 Intell Clin Pharm
`1985; 20: 689-691.
`Brown W], et a1. 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, Gershanik JJ, Lertora 111., White L, George W].
`Toxicity of benzyl alcohol in adult and neonatal mice. J Pharm
`Sci 3986;751 702-705.
`
`InnoPharma Exhibit 1079.0008
`
`

`

`
`
`33 Benzyl Ben-mate
`
`
`
`Benzyl Benzoate
`
`1. Nonpmprietary Names
`BP: Benzyl benzsate
`USP: Benzyl benzeats
`
`2. Synonyms
`Banzai: acid benzyl ester; benzylbenzsnecarboxylate; benzyl
`phenylformats.
`
`3. Chemical Name and CAS Registry Number
`Banzai»: acid phenylmethyl ester [1213»SL4}
`
`4. Empirical Formula
`(3141311202
`
`Molecular Weight
`21 2.24
`
`5. Structural Formula
`
`6. Functianal Categary
`Plasticizer; solubflizing agent; solvent; therapeutic agent.
`
`7. Appficatinns in Pharmaceutical Fannulation or
`Technology
`Benzyl benzmte is used as a solubiliz'mg agent and nonaqu—
`eaus solvent
`in intramuscular injectisns at concentrations
`between 13.01—46.03?) WV.” It is also used as a when: and
`plasticizer for cellulose and nitrocellulose. However, the most
`Mdespread pharmaceutical use of benzyl benzoate is as a
`topical therapeutic agent in the treatment of scabies. Benzyl‘
`benzeats is alas used therapeutically as a parasiticidc in
`veterinary medicine?)
`Other applications (if henzyl benzoats include its use as a
`solvent and fixative for flavors and perfumes in cssmetics and
`food products.
`
`8. Description
`Bessy] benzeate is a clear. colerless, 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 3? I993 USP XXII
`
`
`Identificatisn
`+
`+
`Spmific gravity
`1.1184122
`Lilli—1.120
`Cangcaling lempsramre
`3 17.0%:
`2 18.0%?
`Refractive index
`1568-1570
`1.5684 .579
`Aldehyde
`-——
`+
`Acidity
`+
`+
`Sulfated ash
`g 0.1%
`—~
`
`Assay
`99.0-100.5%
`99.01055?»
`
`10. Typical Properties
`Axfaigniz‘iw imperatw‘e: 481°C
`Boiling point: 323°C
`Flash point: 148cc
`Freezng point: 127°C
`Melting poim: 21°C
`Refiaczz‘ve index: “1331 = 1.5681
`Soiubflity: praclically insoluble in glycarin and water; miscible
`with chlamfarm. ethanol (95%), ether and ails.
`Specific graviry: 2.12
`Vapor density (relative): 7.3 {air = 1)
`
`11. Stability and Storage Conditions
`Benzyi benzoate is stable when stared in tight, well—filled, light-
`resistant containsrs. Exposure to sxcessivs heat should be
`avoided.
`
`12. Incompatibilities
`Benzyl bemoan: is incompatible with smalls and oxidizing
`agents.
`
`13. Method of Manufacture
`
`Banzyi benzeate is a. mnstituent of Pram balsam and occurs
`naturally in certain plant species. Cnmmercially, it is prnduced
`synthetically by the dry esterifisation sf sodium benzoate and
`benzayl chloride in the presence of triethflaminr. 01‘ by the
`rcasticun of sedium bmzylste 0n benzalclehyde.
`
`14. Safety
`Benzyl bemoan is metabolized by rapid hytimlysis to moi:
`acid am benzyl alcohol. Benzyl alcohol
`is then further
`metabol'med to hippuric acid which is excreted in the urine.
`Benzyl
`1321;202:112
`is widely used as a 25% m topical
`application in the treatment 0!" scabies and as an animal}: in
`intramuscular injections and oral products. Adverse reactions
`to benzyl benznaw include skin irritation and hypersensitivity
`resciisns. Oral ingestirm may cause harmful stimulatiim of the
`CNS and convulsions.
`
`LDm (cat, oral): 2.24 g/kgw'”
`L059 {glfinea pig, aural): 1.0 gg'kg
`LDSQ. (mouse. oral): 1.4 gfkg
`L135.) (rabbit, oral): 1.68 g/lcg
`LDm (rabbit, skin): 4.0 gm
`L135.) (rat, oral): {1.5 gfkg
`LDso (rat, skin): 4.0 gfkg
`
`15. Handling Pracaufions
`Benzyl benzan may be harmful if ingestscl and is irritating tr
`the skin, eyes and mucous membranes. Obsarve norms
`prscsutions appropriate to the circumstances and quantity 0:
`material handled. Bye pretection, gloves and a mpirator an
`recommemied. It is recommended that benzyl benzoate b2
`handled in a fume sup-board. Benzyl benzoate is combustible
`
`16. Regulatory Status
`Included in the FDA Inactive Ingredients Guidc (1M injection:
`and oral capsules}.
`Included, as an active ingredient,
`it
`nonpamntsrai meadicims liesan in the UK.
`
`17. Pharmacopeias
`Aust, Br, Braz, Cs, Egypt, Fr, Hung, Ind, kit, It, Jpn, Mex
`Neill, Nerd, Swiss, Turk, US and Yug. Alss in the BF Vet.
`
`InnoPharma Exhibit 1079.0009
`
`

`

`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 Pharmaceu—
`tical Press, 1994: 152—153.
`. 3. Graham BE, Kuizenga MH. Toxicity studies on benzyl benzoate
`and related benzyl compounds. J Pharmacol Exp Ther 1945; 84:
`358-362.
`
`
`
`
`
`-"7'31?““"“3‘933‘571‘THFEW‘573’2’2334
`
`
`
`
`
`Benzyl Benzaate 39
`
`investigations of compounds
`4. Draize Hi, 3: al. Toxicological
`proposed for use as insect repellents. J Pharmacol Exp The:
`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 benzoatc 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.
`
`
`
`InnoPharma Exhibit 1079.0010
`
`

`

`9. Pharmacopeial Specifications
`Test
`USPNF XVII
`
`Melting range
`Heavy metals
`Free fatty acids
`Hydroxyl value
`Iodine value
`Saponification value
`
`85-88°C
`g 0.001%
`4-
`154- i 62
`as 5
`176-182
`
`10. Typical Properties
`Acid value: S 5
`Density (tapped): see HPE Data.
`Flash point: 316°C (open cup)
`Moisture content: g 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
`
`Castorwox MP 70
`
`ETD—6
`
`Caseorwax MP 80
`
`ETD-6
`
`Density
`DIE-l
`Castorwax
`Castorwox . P 70 DE]
`Castarwax MP 80
`DE-l
`Particle size
`,
`PSD-4
`
`8
`
`8
`
`8
`
`7
`7
`7
`[7
`
`Volume: 12.5%
`Weight: 9.0%
`Volume: 12.5%
`Weight: 8.0%
`Volume: 12.0%
`Weight: 9.0%
`
`1.03 i 0.01 g/cm3
`1.07 i 0.02 gfcm3
`0.985 i 0.006 glcm3
`97.7% 3 1000 run
`(for flakes)
`
`82 Hydrogenated Castor Oil
`
`
`
`Hydrogenated Castor
`Oil
`
`1. Nonproprietary Names
`USPNF: Hydrogenated castor oil
`
`2. Synonyms
`Castorwax; Castorwax MP 70; Castorwax MP 80; Opalwax;
`Silomisot'.
`
`3. Chemical Name and CAS Registry Number
`Glyceryl—tri—( l 2—hydroxystearate) [8001-78—3]
`
`4. Empirical Formula Molecular Weight
`The USPNF XVII describes hydrogenated castor oil as the
`refined, bleached, hydrogenated, and deodorized caster oil,
`consisting mainly of the triglyceride of hydroxystearic acid.
`C5709Huo
`939.50
`
`5. Structural Formula
`
`I
`a"
`?
`Clix—O— C—(CHI‘lm—CH‘KHZL—CHa
`
`Ci)”
`ii
`CHI—O“ C—iCHzlm—CH—(CHzls—CHJ
`
`
`
`OH
`0
`l
`ll
`CHz— O—C—(CHE),U—CH—(Ctlzlswctt,
`
`6. Functional Category
`Extended release agent; stiffening agent;
`lubricant.
`
`tablet and capsule
`
`Supplier: NL Industries Inc.
`
`7. Applications in Pharmaceutical Formulation or
`Technology
`Hydrogenated caster oil is a hard, high melting point wax used
`in oral and topical pharmaceutical formulations.
`In topical formulations, hydrogenated caster oil
`provide stiffness to creams and emulsions“)
`is used to
`In erai
`formulations, hydrogenated castor oil
`prepare sustained release tablet and capsule preparations?”
`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;(4’5) it is similarly used
`as a lubricant in food processing.
`Hydrogenated castor oil is also used in cosmetics.
`
`is used to
`
`ll. 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 caster oil may be produced. Hydrogenated
`castor oil may also be dissolved at temperatures greater than
`90°C in polar solvonts 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 (%)
`
`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 caster 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 generatly regarded
`as an essentially nontoxic and nonirritant material.
`
`InnoPharma Exhibit 1079.0011
`
`
`
`

`

`Mute mat mxiciiy 51mm in 311911:ng haw 2;th may,
`Mémgeflaiefii £31381“ '3‘“
`*5
`2*
`f‘i‘fi‘lmely nmimtc mataria}.
`{rr‘siaiinn mm mm rmgbgts gimme that hyémgcmmd msmr m}
`cause-s mihfi. tmnszam “magnum m the {3%.
`1.13m {r311 mai}:
`1* 53,112
`
`15. Hmfling i’recaufims
`thzwe mama! prmmims appmpriam m m: airmtmmnmg
`and qua