US TheStandard-of@
`
`The Official Compendia of Standards
`
`AQUESTIVE EXHIBIT 1078 Page 0001
`
`

`

`2003
`
`7
`
`THE UNITED STATES PHARMACOPEIA
`USP 26
`
`NE 2 l
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Inc., meeting at Washington, D.C.,
`April 12-16, 2000. Prepared by the Council of Experts
`and published by the Board of Trustees
`
`Official from January 1, 2003
`
`The designation on the cover ofthis publication, “USP NF
`2003,”is for ease of identification only. The publication
`contains two separate compendia: The Pharmacopeiaof the
`United States Twenty-sixth Revision, and the National
`Formulary, Twenty-first Edition.
`
`UNITED STATES PHARMACOPEIAL CONVENTION,INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`AQUESTIVE EXHIBIT 1078 Page 0002
`AQUESTIVE EXHIBIT 1078 Page 0002
`
`

`

`NOTICE AND WARNING
`
`Concerning U.S. Patent or Trademark Rights
`
`The inclusion in the Pharmacopeia orin the National Formulary of a monographon any drugin respect
`to which patent or trademark rights may exist shall not be deemed, andis not intended as,a grant of, or
`authority to exercise, any right or privilege protected by such patent or trademark. All such rights and
`privileges are vested in the patent or trademark owner, and no other person may exercise the same with-
`out express permission, authority, or license secured from suchpatent or trademark owner.
`
`Concerning Use of USP or NF Text
`
`Attention is called to the fact that USP and NF text is fully copyrighted. Authors and others wishing to
`use portions of the text should request permission to do so from the Secretary of the USPC Board of
`Trustees.
`
`Copyright © 2002 The United States Pharmacopeial Convention, Inc.
`12601 Twinbrook Parkway, Rockville, MD 20852
`All rights reserved.
`ISSN 0195-7996
`ISBN 1-889788-13-9
`Printed in Canada by Webcom Limited, Toronto, Ontario
`
`AQUESTIVE EXHIBIT 1078 Page 0003
`AQUESTIVE EXHIBIT 1078 Page 0003
`
`

`

`USP 26
`
`Official Monographs | Alcohol
`
`59
`
`H,C~
`
`oH
`
`[64-/7-5].
`
`disperse the specimenusing a vortexing mixer. Add 5.0 mL-ofasolu-
`Alcohol
`tion ofmethanolin water (45 in 50), insert the stoppersecurely, shake
`vigorously for 2 minutes, and centrifuge at 2500 rpm for 3 minutes.
`Removethe lower, aqueous alcoholphase, and transfer this test solu-
`tion to a stoppered vial. Apply separately 20 pL of the test solution
`and 20 pL ofaStandard solution ofUSP Aiclometasone Dipropionate
`RS in methanolcontaining about 0.25 mg per mL toasuitable thin-
`CHO 46.07
`layer chromatographic plate (see Chromatography (621)) coated
`Ethanol.
`with a 0.25-mm layer of chromatographic silica gel mixture, and
`Ethyl alcohol
`dry the applications with theaid of a stream of nitrogen. Position
`the plate in a saturated, unlined chromatographic chamber, and devel-
`op the chromatogramsin a solvent.system consisting of a mixture of
`chloroform and acetone(7: 1) until the solvent front has moved about
`three-fourths of the length of the plate. Removethe plate from the
`developing chamber, mark the solvent front, and allow the solvent
`to evaporate. Observe the plate under short-wavelength UVlight:
`the R, value ofthe principal spot obtained from thetest solution cor-
`respondsto that obtained from the Standard solution.
`Microbiallimits (61)—It meets the requirements of the tests for ab-
`sence .of Staphylococcus aureus and Pseudomonasaeruginosa.
`Minimum fill (755): meets the requirements.
`Assay—
`Methanol-water solution—Dilute 450 mL of methanol with water
`to 500 mL, and mix.
`0.05 M Monobasic potassium phosphate—Transfer 3.40 g of
`monobasic potassium phosphate to a 500-mL volumetric flask, add
`water to volume, and mix.
`__
`Mobile phase—Prepare a filtered and degassed mixture of metha-
`nol and 0.05 M Monobasic potassium phosphate (2 : 1).Make adjust-
`ments if necessary (see System Suitability under Chromatography
`( neat standard solution—Transfer about 30 mg of betametha-
`621)).
`‘
`sone dipropionate to a 200-mL volumetric flask, add Methanol-water
`solution to volume, and mix.
`;
`Standard preparation—Transferabout 20 mg of USP Alclometa-
`sone Dipropionate RS, accurately weighed, to a 200-mL volumetric
`flask, add Methanol-water solution to volume, and mix. Transfer 5.0
`mL ofthis solution to a small stoppered flask, add 5.0 mL ofInternal
`standard solution, and mix to obtain a Standardpreparation having a
`known concentration ofabout 0.05 mg ofUSP Alclometasone Dipro-
`pionate RS per mL.
`ue
`Assay preporation—Transfer an accurately weighed quantity of
`Ointment, equivalentto about 0.5 mg of alclometasone dipropionate,
`to a 50-mL centrifuge tube, add 10 mL of 2,2,4-trimethylpentane, in-
`sert a stopper securely into the tube, and disperse the specimen using
`a vortexing mixer. Add 5.0 mL ofInternal standard solution and 5.0
`mL of Methanol-water solution, insert the stopper securely, shake
`vigorously for 2 minutes, and centrifuge at 2500 rpm for 3 minutes.
`Remove the lower, aqueous alcohol phase, and transfer this Assay
`preparation to a stoppered vial.
`‘
`Chromatographic system (see Chromatography (621)}—Theliq-
`uid chromatograph is equipped with a 254-nm detector and a 4-mm
`x 30-cm column that contains packing L1. The flow rate is about 1.2
`mL per minute. Chromatograph the Standardpreparation, and record
`the peak. responses as directed under Procedure: the resolution, R,
`between the analyte and internal standard peaks is not less than
`3.0, and the relative standard deviation for replicate injections is
`not more than 2%.
`Procedure—Separately inject equal volumes (about 20 pL) of the
`Standard preparation and the Assay preparation into the chromato-
`graph, record the chromatograms, and measure the responses for the
`major peaks. The relative retention times are about 0:7 for alclome-
`tasone dipropionate and 1.0 for betamethasone ‘dipropionate. Calcu-
`late the quantity, in mg, of C,,H,,ClO, in the portion of Ointment
`taken by the formula:
`
`» Alcohol contains not less than 92.3 percent and not
`more than 93.8 percent, by weight, corresponding to
`not less than 94.9 percent and not more than 96.0 per-
`cent, by volume, at 15.56°, of C,H,OH.
`
`Packaging and storage—Preserve in tight containers, remote from
`fire.
`Identification—
`A: Mix 5 drops in a small beaker with 1 mL of potassium per-
`manganate solution (1 in 100) and 5 drops of 2 N sulfuric acid, and
`cover the beaker immediately with a filter paper moistened with a
`solution recently prepared by dissolving 0.1 g of sodium nitroferri-
`cyanide and 0.25 g of piperazine in 5 mL of water:
`an intense blue
`color is produced onthe filter paper, the color becoming paler after a
`few minutes.
`B:
`To 5 mL ofa solution (1 in 10) add 1 mL of 1.0 N sodium
`hydroxide, then slowly (over a period of 3 minutes) add 2 mL of
`0.1 N iodine:
`the odor of iodoform develops, and a yellow precipi-
`tate is formed within 30 minutes.
`Specific gravity (841):
`between 0.812 and 0.816 at 15.56°, indicat-
`ing between 92.3% and 93.8%, by weight, or between 94.9%and
`96.0%, by volume, of C,H,OH.
`:
`Acidity—To 50 mL,in a glass-stopperedflask, add 50 mL ofrecently
`boiled water. Addphenolphthalein TS, andtitrate with 0.020 N so-
`dium hydroxide to a pink color that persists for 30 seconds:
`not
`more than 0.90 mL of 0.020 N sodium hydroxideis required for neu-
`tralization.
`Limit of nonvolatile resid@ue—Evaporate 40 mL in a tared dish on a
`water bath, and dry at 105° for 1 hour: ‘the weight of the residue
`does not exceed | mg.
`Water-insoluble substances—Dilute it with an equal volume of
`water:
`the mixtureis clear and remains clear for 30 minutes after
`cooling to 10°.
`Aldehydes and other foreign organic substances—Place 20 mL in
`a glass-stoppered cylinderthat has been thoroughly cleaned with hy~
`drochloric acid, then rinsed with water andfinally with the Alcohol-to
`be tested. Cool the contents to approximately 15°, and add, by means
`ofa carefully cleaned pipet, 0.10 mL of 0.10 N potassium permanga-
`nate, notingaccurately the time of addition. Mix at once by inverting
`the stoppered cylinder, and allowit to stand at 15° for 5 minutes:
`the
`pink: color doesnot entirely disappear.
`Amyl alcohol and nonvolatile, carbonizable substances—Allow
`25 mL to. evaporate spontaneously from a porcelain dish, carefully
`protected from dust, until the surface of the dish is barely moist:
`no
`red or brown color is produced immediately upon the addition ofa
`few drops of sulfuric acid.
`Limit of acetone and isopropyl alcohol—To1.0 mL add 1.0 mL of
`water, 1.0 mL of a saturated solution of dibasic sodium phosphate,
`and 3.0 mL ofa saturated solution of potassium permanganate. Warm
`the mixture to 45° to 50°, and allow to stand until the permanganate
`color is discharged. Add 3.0 mL of 2.5 N sodium hydroxide, andfil-
`ter, without washing, through a sintered-glassfilter. Prepare a control
`by mixing 1.0 mL ofthe saturated solution of dibasic sodium phos-
`phate, 3.0 mL of 2.5 N sodium hydroxide, 80 ug of acetone; and 5.0
`moL of water. To each solution add 1 mL offurfural solution (1 in
`100), allow to stand for 10 minutes, then to 1.0 mL-of each solution
`add 3 mL of hydrochloric acid:
`any pink color producedin the test
`solution is not more intense than that.in the control.
`Methanol—To1 drop add 1 drop of water, 1 drop of dilute phospho-
`ric acid (1 in 20), and 1 drop of potassium permanganate solution (1
`in 20). Mix, allow to stand for 1 minute, and add sodium metabisulfite
`solution (1. in 20), dropwise, until the permanganate coloris dis-
`charged. Ifa brown color remains, add 1 drop ofthe dilute phosphoric
`acid. To the colorless solution add 5 mL offreshly prepared chromo-
`
`10C(R,/R3),
`
`inwhich C is the concentration, in mg per mL, ofUSP Alclometasone
`Dipropionate RS in the Standard preparation, and Ry and Rg are the
`peak height ratios obtained from the andthe Standard preparation,
`respectively.
`
`fe
`
`AQUESTIVE EXHIBIT 1078 Page 0004
`AQUESTIVE EXHIBIT 1078 Page 0004
`
`

`

`60
`
`Alcohol
`
`/ Official Monographs
`
`USP 26
`
`any
`tropic acid TS, and heat on a water bath at 60° for 10 minutes:
`violet color should not exceed that produced by 0.04 mg ofmethanol
`in 1 mL ofwater, treated in the same way as the sample.
`
`Dehydrated Alcohol
`
`HyC~ “OH
`
`of 2.5 N sodium hydroxide, and 80 ig of acetone in 9 mL. To each
`solution add 1 mL offurfural solution (1 in 100), and allow to stand
`for 10 minutes, then to 1.0 mL ofeach solution add 3 mL of hydro-
`chloric acid:
`any pink color producedin thetest solution is not more
`intense than that im the control.
`Methanol—To 1 drop add | drop of water, 1 drop ofdilute phospho-
`ric acid (1 in 20), and 1 drop ofpotassium permanganate solution(1
`in 20). Mix, allow to stand for 1 minute, and add sodium metabisulfite
`solution (1 in 20), dropwise, until the permanganate color is dis-
`charged. Ifa brown color remains, add 1 drop ofthe dilute phosphoric
`acid. To the colorless solution add 5 mL offreshly prepared chromo-
`tropic acid TS, and heat on awater bath at 60° for 10 minutes:
`no
`violet color appears.
`
`C,H,O 46.07
`Ethanol.
`Ethyl alcohol—[64-17-5].
`Dehydrated Alcohol Injection
`
`» Dehydrated Alcoholcontains not less than 99.2 per-
`cent, by weight, correspondingto notless than 99.5 per-
`cent, by volume, at 15.56°, of C,H.OH.
`
`»» Dehydrated Alcohol Injection is Dehydrated Alcohol
`suitable for parenteral use.
`
`Packaging and storage—Preserve in single-dose containers, pre-
`ferably of Type I glass. The container may contain an inert gas in
`the headspace.
`not more than 0.8035 at 15.56°, indicating
`Specific gravity (841):
`notless than 96.8%, by weight, of C,H,OH.
`i
`Acidity—To 50 mL,in a glass-stopperedflask, add 50 mL ofrecently
`boiled water. Add phenolphthalein TS, and titrate with 0.020 N so-
`dium ‘hydroxide to a pink color that persists for 30 seconds:
`not
`more than -10.0 mL of 0.020 N sodium hydroxide is requiredfor neu-
`tralization.
`
`Other requirements—It meets the requirements for Identification,
`Limit ofnonvolatile residue, Water-insoluble substances, Aldehydes
`and otherforeign organic substances, Amylalcohol and nonvolatile,
`carbonizable substances, Ultraviolet absorbance, Limit of acetone
`and isopropyl alcohol, and Methanol under Dehydrated Alcohol,
`and meets the requirements under Injections (1).
`
`Packaging and storage—Preservein tight containers, remote from
`fire.
`i
`Identification—
`A: Mix 5 drops in a small beaker with 1 mL of potassium per-
`manganate solution (1 in 100) and 5 drops of 2 N sulfuric acid, and
`cover the beaker immediately with a filter paper moistened with a
`solution recently prepared by dissolving 0.1 g of sodium nitroferri-
`cyanide and 0.25 g of piperazine in 5 mL of water:
`an intense blue
`color is produced onthefilter paper, the color becomingpaler after.a
`few minutes.
`-
`B:
`To 5 mL ofa solution (1 in 10) add 1 mL of 1.0 N sodium
`hydroxide, then slowly (over a period of 3 minutes) add 2 mL of
`0.1 N iodime:
`the odor of iodoform develops, and.a yellow precipi-
`tate is formed within 30 minutes.
`Specific gravity (841):
`not more than 0.7962 at 15.56°, indicating
`notless than 99.2% of C,H,OH by weight.
`Acidity——To 50 mL, in a glass-stoppered flask, add 50 mL ofrecently
`boiled water. Add phenolphthalein TS, and titrate with 0.020 N so-
`dium hydroxide to a pink colorthat persists for 30 seconds:
`not
`more than 0.90 mL of 0.020 N sodium hydroxideis required for neu-
`tralization.
`Limit of nonvolatile residue—Evaporate 40 mL in a tared dish on a
`water bath, and dry at 105° for 1 hour:
`the weightof the residue
`does not exceed 1 mg.
`Water-insoluble substances—Dilute it with an equal volume of
`water:
`the mixture is clear and remains clear for 30 minutes after
`»» RubbingAlcoholandall preparations underthe classi-
`cooling to 10°.
`;
`fication of Rubbing Alcohols are manufacturedinaccor-
`Aldehydes and other foreign organic substances—Place 20 mL in
`dance with the requirements of the U.S. Treasury
`a glass-stoppered:cylinder that has been thoroughly cleaned with hy-
`Department, Bureau of Alcohol, Tobacco, and Firearms,
`drochloric acid, then rinsed with water and finally with the Dehy-
`Formula 23-H (8 partsby volumeofacetone, 1.5 parts by
`drated Alcohol to be tested. Cool the contents to approximately
`15°, and add, by means of a carefully cleaned pipet, 0.10 mL of
`volumeofmethyl] isobutyl ketone, and 100 parts by voi-
`0.10 N- potassium permanganate, noting accurately the time of addi-
`ume.ofethyl alcohol) being used.It contains notless than
`tion. Mix atonce by inverting the stoppered cylinder, and allow it to
`68.5 percent and not more than 71.5 percent by volume
`stand at 15° for 5 minutes:
`the pink color does not entirely disap-
`of dehydrated alcohol, the remainderconsisting of water
`pear.
`and the denaturants, with or without color additives, and
`Amy] alcohol and nonvolatile, carbonizable substances—Allow
`perfume oils. Rubbing Alcohol contains, in each 100
`25 mL to evaporate spontaneously from a porcelain dish, carefully
`protected from dust, until the surface ofthe dish is barely moist:
`no
`mL, not less than 355 mgof sucrose octaacetate or not
`red or browncolor is produced immediately upon the addition of a
`less than 1.40 mg of denatonium benzoate. The prepara-
`few drops of sulfuric acid.
`tion may be colored with one or morecolor additives,
`Ultraviolet absorbance—Record the UV absorption spectrum be-
`listed by the FDA for use in drugs. A suitable stabilizer
`tween 340 nm and 235 nm in a 1-cm cell, with water in a matched
`may be added. Rubbing Alcohol complies with the re-
`cell in the-reference beam:_the absorbance is not more than 0.08 at
`240'nm, and 0.02 between 270 nm and 340 nm,and the curve drawn
`quirements of the Bureau of Alcohol, Tobacco, and Fire-
`through these points is smooth.
`arms of the U.S. Treasury Department.
`Limit of acetone and isopropyl alcohol—To 1.0 mL add 1 mL of
`NOTE—Rubbing Alcohol is packaged, labeled, and
`water, 1 mL ofa saturated solution of dibasic sodium phosphate, and
`sold in accordance with the regulations issued by the
`3 mL ofa saturated solution of potassium permanganate. Warm the
`U.S. Treasury Department, Bureau of Alcohol, Tobacco,
`mixture to’45° to 50°, and allow to stand until the permanganate color
`and Firearms.
`is discharged. Add 3 mL of 2.5 N sodium hydroxide, and filter, with-
`out washing, through a sintered-glassfilter. Prepare a control contain-
`ing 1 mL ofthe saturated solution of dibasic sodium phosphate, 3 mL
`
`Rubbing Alcohol
`
`AQUESTIVE EXHIBIT 1078 Page 0005
`AQUESTIVE EXHIBIT 1078 Page 0005 en
`
`