The United States
`Pharmacopeia
`
`TWENTIETH REVISION
`
`Officialfrom July 1, 1980
`
`The National
`Formulary
`
`FIFTEENTH EDITION
`
`Officialfrom July 1, 1950
`
`UnitedStatesPharmacoperConvention,lic.. USE|5
`
`
`20| ne
`
`12601 Twinbrook Pa
`
`rkway, Rockville, Md,
`
`208:
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 001
`
`

`

`|
`
`United States Pharmacopeia XX
`National Formulary XV
`
`OFFICIAL COPY
`J 63477
`
`Official coupon
`Do not remove
`
`NOTICE AND WARNING
`
`Concerning U.S. Patent or Trademark Rights
`The inclusion in the Pharmacopeia or in the National formulary of a monograph on anydrug
`in respect to which patent or trademark rights may exist shall not be deemed, and is noi
`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 without express permission, authority, or license
`secured from such patent 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 fromthe Secretary of the
`USPC Board of Trustees.
`
`Concerning Laws of Other Couniries
`in establishing the Pharmacopeial and National Formulary standards, the USP Committee of
`Revision does not attempt to take into account the laws of countries other than the Lnited
`States of America desiring to enforce these standards within their jurisdictions.
`
`© 1979 The United States Pharmacopeial Convention, Inc.
`12601 Twinbrook Parkway, Rockville, Md. 20852
`
`All rights reserved
`ISSN 0195-7996
`ISBN 0-912734-30-2 (cloth)
`0-912734-31-0 (leather)
`
`Typeset and printed by Mack Printing Company, Easton, Pa.
`
`18042
`
`Distributed by Mack Publishing Company, Easton, Pa.
`
`18042
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 002
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 002
`
`

`

`USP XX
`
`The United States
`Pharmacopeia
`
`TWENTIETH REVISION
`
`By authority of the United States Pharmacopeial Convention, Inc.,
`meeting at Washington, D. C., March 22, 1975. Prepared by
`the Committee of Revision and published by the Board of Trustees
`
`Officialfrom July I, 1980
`
`United States Pharmacopeial Convention,Inc.
`12601 Twinbrook Parkway, Rockville, Md. 20852
`
`wo
`
`
`
`| Uap
`tl EST
`1820
`
`et
`
`
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 003
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 003
`
`

`

`Contents
`
`USP XX
`
`
`
`
`
`General
`
`see page 859 for detailed contents
`General Tests and Assays ....
`General Requirements for
`Tests and Assays .......
`Apparatus for Tests and
`ASSAYS 0. ee eee
`Microbiological Tests .....
`Biological Tests and Assays
`Chemical Tests and Assays
`Physical Tests and
`Determinations ........
`General Information ........
`
`861
`
`861
`
`870
`873
`882
`905
`
`936
`992
`
`a R
`
`1041
`Reagents .....-...00ee eee
`Indicators and Indicator Test
`1098
`Papers 2.22... eee e eae
`1100
`Solutions ............260--
`1100
`Buffer Solutions .........
`1101
`Colorimetric Solutions
`....
`1102
`Test Solutions ...........
`1109
`Volumetric Solutions
`.....
`
`
`eagents
`
`xix
`XX
`
`People
`
`Officers of the Convention ...
`Board of Trustees ..........
`Resources Development
`Advisory Council ......
`USPC Headquarters Staff...
`General Committee of
`Revision ........-..--
`Exccutive Committee of
`Revision and
`Subcommittees ........
`Reference Standards
`Committee .........--
`Advisory Panels .........
`Special Consultants ........
`Assistants during 1975-1980
`Membersof the United States
`Pharmacopeial
`Convention ...........
`
`vill
`Vill
`
`vill
`xli
`
`ix
`
`x
`
`x
`x1
`xil
`xii
`
`xiii
`
`i P
`
`reamble
`
`Articles of Incorporation ....
`Constitution and Bylaws
`....
`Abstract of Proceedingsof the
`U.S. Pharmacopeial
`Convention, 1975 ......
`History of the Pharmacopetia
`of the United States ....
`Preface to USP XX ........
`
`XXVIli
`
` Xxxi
`XXXIV
`
`Tables
`
`...
`
`{117
`
`1121
`
`1160
`
`Containers for Dispensing
`Capsules and Tablets
`Description and Relative
`Solubility of USP and
`NF Articles ...........
`Approximate Solubilities of
`USP and NF Articles ...
`Articles Admitted to USP
`USP and NF Pharmaceutic
`XIX and NF XIV by
`Ingredients, Listed by
`Supplement
`......---.
`Categories ............
`1168
`New Admissionsto the
`Atomic Weights .........--
`1171
`Official Compendia ....—xiiii
`Molecular Formulas and
`Changesin Official Titles
`...
`1
`Weights .........00---
`1172
`Articles Included in USP XIX
`Alcoholometric Table .......
`1187
`but Not Included in USP
`Thermometric Equivalents ...
`1188
`XX orinNFXV ......
`Equivalents of Weights and
`Articles Included in NF XIV
`Measures ..........005 1189
`but Not Included in NP
`Table of Metric- Apothecary
`XV orin USP XX .....
`Approximate Dose
`
`Equivalents
`...inside back cover
`es
`
`a A
`
`dmissions
`
`xhiii
`
`lit
`
`lit
`
`1273
`Antibiotic Regulations ......
`Appendix
`ee
`
`Notices
`
`General Notices and
`Requirements ........-
`
`1 M
`
`Combined Index to USP XX
`4
`Official Monographs of USP
`onographs
`1401
`and NE XV ...........
`XX oe cee eee sees
`eeaeEEEEEEEEE
`oe
`
`Index
`
`vil
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 004
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 004
`
`

`

`USF AA
`
`UWENETUL LVULICES
`
`J
`
`regardless of whether the values are expressed as per-
`centages or as absolute numbers, are considered sig-
`nificant to the last digit shown.
`Equivalence Statements in Titrimetric Proce-
`dures—-Thedirections for titrimetric procedures con-
`clude with a statementof the weight of the analyte thal
`is equivalent to each mlof the standardizedtitrant.
`In
`such an equivalence statement, it is to be understood
`that the numberofsignificant figures in the concen-
`tration of the titrant corresponds to the numberofsig-
`nificant figures in the weight of the analyte. Blank
`corrections are to be made for al] titrimetric assays,
`where appropriate (see Titrimetry (541)).
`The limits specified in the monographs for Phar-
`macopeialarticles are established with a view to the use
`of these articles as drugs, except where the monograph
`indicates that the article is intended for use in in-vitro
`diagnostic procedures or as a medical device. The use
`of the molecular formula for the active ingredient(s)
`namedin defining the required strength of a Pharma-
`copeial article is intended to designate the chemical
`entity or entities having absolute (100 percent) pu-
`rity.
`/
`The quantity of each ingredient used in preparing the
`dosage formsshall be equivalent to notless than 100
`percentof the quantity called for in the formula or of
`the amount declared on the label.
`The tolerances and limits stated in the definitions in
`the monographs for Pharmacopeialarticles allow for
`analytical error, for unavoidable variations in manu-
`facturing and compounding, and for deterioration to
`an extent considered insignificant under practical
`conditions. Notwithstanding these tolerances,
`the
`objective of the Pharmacopeiai standardsfor a dosage
`form or a finished device is to achieve a product whose
`strength is 100 percentof the quantityof the absolutely
`pure chemicalentity or entities named on the label as
`the active ingredient(s).
`The specified tolerances are based upon such at-
`tributes of quality as might be expected to characterize
`an article produced from suitable raw materials under
`recognized principles of good manufacturing prac-
`tice.
`The existence of compendial limits or tolerances does
`not constitute a basis for a claim thatan official sub-
`stance that more nearly approaches 100 percent purity
`“exceeds” the Pharmacopeial quality. Similarly, the
`fact that an article has been prepared to closer toler-
`ances than those specified in the monograph does not
`constitute a basis for a claim that the article “exceeds”
`the Pharmacopeial requirements.
`
`ALCONVOL
`
`All statements of percentages of alcohol, such as
`underthe heading, A/cohol content, refer to percentage,
`by volume, of CyHsOHat 15,.56°. Where reference
`is made to “C5Hs5OH,” the chemical entity possessing
`absolute (100 percent) strength is intended.
`Alcohol—Where “alcohol” is called for in formulas,
`tests, and assays, the monograph article Alcoholts to
`be used.
`Dehydrated Alcohol—Where “dehydrated alcohol”
`(absolute alcohol) is called for in tests and assays, the
`
`reagent Dehydrated Alcohol(see in the section, Re-
`agents, Indicators, and Solutions) is to be used.
`Denatured Alcohol—In the manufacture of Phar-
`macopeial preparations in which alcoholis used only
`as a solvent and does not remain in the finished product,
`alcohol specially denatured by the addition ofvolatile
`substances, in accordance with federal statutes and
`regulations of the Internal Revenue Service, may be
`substituted but the preparations so made must be
`identical with those prepared by the processes given in
`the monographs and must conform to the Pharmaco-
`peial standardsset forth.
`
`REAGENT STANDARDS
`
`The proper conduct of the Pharmacopeial tests and
`assays and thereliability of the results depend, in part,
`upon the quality of the reagents used in the performance
`of the procedurcs. Unless otherwise specified, reagents
`are to be usedthat conformto the standards set forth
`in the current edition of Reagent Chemicals published
`by the American Chemical Society. Where such ACS
`reagent standardsarenot available or where for various
`reasons the required purity differs, compendial speci-
`fications for reagents of acceptable quality are provided.
`(See Reagents, Indicators, and Solutions.) Listing
`of these reagents, including the indicators and solutions
`employed as reagents, in no way implies that they have
`therapeutic utility; furthermore, any reference to USP
`in their labcling shall include also the term “reagent”
`or “reagent grade.”
`
`REFERENCE STANDARDS
`
`USP Reference Standards and U. S. Reference
`Standardsfor antibiotics are authentic specimens that
`have been verified for suitability for use as comparison
`standards in compendial tests and assays.
`(See USP
`Reference Standards (11).)
`Where first referred to ina monograph, the name of
`a USP Reference Standardis generally spelled out in
`full. However, where a USP Reference Standard is
`referred to thereafter in an assayora test in this com-
`pendium,the words “Reference Standard” are abbre-
`viated to “RS.”
`Wherea test or an assay calls for the use of a com-
`pendial article, rather than a USP Reference Standard,
`as a material standard ofreference, a substance meeting
`all of the requirements of the monographforthatarticle
`is to be used.
`
`UNITS OF POTENCY
`
`For those products for whichit is necessary to express
`the potencyin termsofunits by reference to a suitable
`working standard (usually a USP Reference Standard),
`the individual monographs refer to USP Units of ac-
`tivity. Unless otherwise indicated, USP Units are
`equivalent to the corresponding international units,
`where such exist, and to the units of activity established
`by the Food and Drug Administration im the case of
`antibiotics and biological products.
`INGREDIENTS AND PROCESSES
`
`Pharmacopeial dosage forms and finished devices are
`prepared from ingredients that meet the requirements
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 005
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 005
`
`

`

`4
`
`General Notices
`
`of the compendial monographs for those individual
`ingredients for which monographsare provided. Water
`used as an ingredient in the preparation of compendia!
`dosage forms meets the requirements for Purified
`Water, or for Water for Injection, or for one of the
`sterile forms of water covered by a monographin this
`Pharmacopeia.
`Potable water may be used in the preparation of of-
`ficial substances.
`It meets the requirements for
`drinking water as set forth in the regulations of the
`federal Environmental Protection Agency.
`Preparations for which a complete composition is
`given in this Pharmacopeia, unless specifically ex-
`empted herein or in the individual monograph,are to
`contain only the ingredients named in the formulas.
`However, there may be deviation from the specified
`processes or methods of compounding, though not from
`the ingredients or proportions thereof, provided the
`finished preparation conformsto the relevant standards
`laid down herein and to preparations produced byfol-
`lowing the specified process.
`Where a monograph on a preparation calls for an
`ingredient in an amount expressed on the dried basis,
`the ingredient need not be dried prior to use if due al-
`lowance is made for the water or other volatile sub-
`stances present in the quantity taken.
`Unless specifically exempted elsewhere in this
`Pharmacopeia, the identity, strength, quality, and pu-
`rity of an official article are determined by the defini-
`tion, physical properties, tests, assays, and other spec-
`ifications relating to the article, whether incorporated
`in the monographitself, in the General Notices, or in
`the section, General Chapters.
`Uniformity of Composition—While a demonstration
`of homogeneity in individual units of a given lot of a
`Pharmacopeial dosage form or finished device.may not
`always be practicable, variations in composition are
`undesirable and substantial differences in the content
`of active ingredient(s) among individual capsules,
`tablets, and other finished forms are to be avoided.
`Where, because of the small amount of active sub-
`stance(s) in the individual finished forms, the Weight
`variation test (see (931)) cannot give the necessary
`assurance that successive units from the same container
`will contain substantially uniform amounts,a test for
`Content uniformity (see (681)) is provided wherever
`practicable.
`(See also Preface.)
`Added Substances—An official substance, as dis-
`tinguished from a dosage form, contains no added
`substances except where specifically permitted in the
`individual monograph. Where such addition is per-
`mitted, the label indicates the name(s) and amount(s)
`of any added substance(s).
`Unless otherwise specified in the individual mono-
`graph, or elsewhere in the General Notices, suitable
`substances such as bases, carriers, coatings, colors,
`flavors, preservatives, stabilizers, and vehicles maybe
`added to a Pharmacopeia] dosage form or finished de-
`vice to enhanceits stability, usefulness, or elegance, or
`to facilitate its preparation. Such substances may be
`regarded as suitable only if they are harmless in the
`amounts used, if they do not exceed the minimum
`quantity required to provide their intended effect, if
`their presence does not impair the bioavailability or the
`
`USP XX
`
`therapeutic efficacy of the dosage form, andif they do
`not interfere with the assays and tests prescribed for
`determining compliance with the Pharmacopeial
`standards.
`Colors—Added substances employed solely to im-
`part color may be incorporated into Pharmacopeial
`articles that are dosage formsorfinished devices, except
`those intended for parenteral or ophthalmic use,
`in
`accordance with the regulations pertaining to the use
`of colors in drugs issued by the Food and Drug Ad-
`ministration, provided such added substances are oth-
`erwise appropriate in all respects.
`(See also Added
`Substances under Injections (1).)
`Capsules and Tablets—Capsules and tablets may
`be made with suitable diluents, colors,
`lubricants,
`disintegrants, and adhesives, such as starches, lactose,
`sucrose, and other innocuous materials. Tablets and
`the contents of capsules that are intended to be homo-
`geneous are uniform in appearance within a given lot.
`Excessive amounts of substances that mayimpair bio-
`availability of the active ingredientsare to be avoided.
`Tablets may be coated.
`the
`Parenteral and Topical Preparations-——For
`preservation of preparations intended for parenteral
`administration or topical application, suitable antiox-
`idants, antimicrobial agents, buffers, and/or stabilizers
`may be added unlessinterdicted in the monograph.
`For requirements concerning the presence and pro-
`portions of added substances in parenteral preparations,
`and the pertinent labeling requirements, see Added
`Substances and Labeling under Injections (1).
`The air in a containerofan article for parenteral use
`may be evacuated or be replaced by carbon dioxide,
`helium, or nitrogen, or by a mixture of these gases,
`which fact need not be declared on the label unless
`otherwise specified in the individual monograph.
`Ointments and Suppositories —In the preparation
`of ointments and suppositories, the proportions of the
`substances constituting the base may be varied to
`maintain a suitable consistencyunderdifferent climatic
`conditions, provided the concentrations of active in-
`gredients are not varied.
`
`TESTS AND ASSAYS
`
`Apparatus—A specification for a definite size or type
`of container or apparatusin a test or assay is given solely
`as a recommendation. Where volumetric flasks 6r
`other exact measuring, weighing, or sorting devices are
`specified, this or other equipmentof at least equivalent
`accuracy shall be employed.
`(See also Volumetric
`Apparatus (31).)
`Where an instrument for physical measurement,
`such as a spectrophotometer, is specified in a test or
`assay by its distinctive name, another instrument of
`equivalent or greater sensilivity and accuracy may be
`used.
`In order to obtain solutions having concentra-
`tions that are adaptable to the working range of the
`instrument being used, solutions of proportionately
`higher or lower concentrations may be prepared, ac-
`cording to the solvents and proportions thereof that are
`specified for the procedure.
`Where a particular brand or source of a material or
`piece of equipment, or the name and address of a
`
`OAerrael
`
`aoO
`
`TC
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 006
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 006
`
`

`

`
`
`
`
`12
`
`Acetaminophen / Official Monographs
`
`for 30 minutes, and centrifuge at 1000 rpm for 15 minutes or until
`a clean separation is obtained. On a suitable thin-layer chroma-
`tographic plate (see (621)), coated with a 0.25-mm layer of chro-
`matographicsilica gel mixture, apply 200 pl of the supernatant
`liquid, in 40-21 portions,to obtain a single spot not more than 10mm
`in diameter. Similarly apply40 jl of a Standard solution in ether
`containing 10 peg of p-chloroacetanilide per ml, and allow the spots
`todry. Develop the chromatogram,in an unsaturated chamber,
`with a solvent system consisting of solvent hexane and acetone
`(75:25), until the solvent front has moved three-fourths of the length
`of the plate. Remove the plate from the developing chamber, mark
`the solvent front, and allow the solvent to evaporate. Locate the
`spots in the chromatogram by examination under short-wavelength
`ultraviolet light: any spot obtained from the solution undertest,
`at an Ry value corresponding to the main spot from the Standard
`solution, is not greater in size or intensity than the main spot ob-
`tained from the Standardsolution, corresponding to not more than
`0.001% of p-chloroacetanilide.
`Assay—Dissolve about 120 mg of Acetaminophen, accurately
`weighed, in 10 ml of methanol in a S00-ml volumetric flask, dilute
`with water to volume, and mix. Transfer 5.0 mlofthis solution to
`a 100-ml! volumetric flask, dilute with water to volume, and mix.
`Concomitantly determine the absorbances ofthis solution and of
`a Standard solution of USP Acetaminophen RS, in the same me-
`dium, at a concentration of about 12 yg per mlin }-cm cells, at the
`wavelength of maximum absorbanceat about 244 nm, with a suit-
`able spectrophotometer, using water as the blank. Calculate the
`quantity, in mg, of CgH9NOzin the Acetaminophen taken by the
`formula 10C(Ay/As), in which C is the concentration, in wg per
`ml, of USP Acetaminophen RSin the Standard solution, and Ay
`and Ag are the absorbancesofthe solution of Acetaminophen and
`the Standard solution, respectively,
`
`Acetaminophen Capsules
`
`» Acetaminophen Capsules contain not less than 95.0
`percent and not more than 105.0 percent of the labeled
`amount of CgHgNO3.
`
`Packaging and storage—Preservein tight containers.
`Reference standard—-USP Acetaminophen Reference Stan-
`dard—Dryoversilica gel for 18 hours before using.
`Identification—
`A:
`Theultraviolet absorption spectrum ofthe solution of the
`Capsules prepared for the measurementof absorbancein the Assay
`exhibits maxima and minima at the same wavelengthsas that of a
`similar solution of USP Acetaminophen RS, concomitantly mea-
`sured.
`B: Triturate an amount of the contents of the Capsules,
`equivalent to about 1 g of acetaminophen, with 30 ml of warm al-
`cohol, cool, and filter. To 3 ml of the filtrate add 10 ml of water
`and | drop of ferric chloride TS, and mix:
`a violet-blue coloris
`produced.
`Weightvariation (931): meet the requirements for Capsules.
`Assay—
`Standard preparation and Chromatographic column—Prepare
`as directed in the Assay under Acetaminophen Elixir.
`Assay preparation—Weigh the contents of not fewer than 20
`Acetaminophen Capsules. Mix the contents, and transfer an ac-
`curately weighed portion of the powder, equivalent to about 250 mg
`of acetaminophen,to a 250-ml volumetric flask, add 2 ml of 1 N
`sodium hydroxide, dilute with water to volume, mix, and filter,
`discarding the first 20 mlof the filtrate. Proceed as directed for
`Assay preparation in ile Assay under Acetaminophen ENxir, bee
`ginning with “Transfer 2.0 ml of this solution to a 100-ml
`beaker.”
`Procedure—Proceed as directed for Procedure in the Assay
`under Acetaminophen Elixir. Calculate the quantity, in mg, of
`CaHoNOsin the portion of the Capsules taken by the formula
`31.25C(Au/As), in which C is the concentration, in wg per mi, of
`USP Acetaminophen RSin the Standard preparation, and Ay and
`Asare the absorbancesof the Assay preparation and the Standard
`preparation, respectively.
`
`USP XX
`
`Acetaminophen Elixir
`» Acetaminophen Elixir contains not less than 95.0
`percent and not more than 105.0 percent of the labeled
`amount of CeHyNOp.
`Packaging and storage—Preserve in tight containers, and avoid
`continuous exposure to excessive cold.
`Reference standard—USP Acetaminophen Reference Stan-
`dard—Dryoversilica gel for 18 hours before using.
`Identification—The ultraviolet absorption spectrum of a portion
`of the Assay preparation employed for measurement of absorbance
`in the Assay exhibits maxima and minimaat the same wavelengths
`as that of a similar solution of USP AcetaminophenRS, concomi-
`tantly measured.
`pH (791): between 3.8 and 6.1.
`Alcohol content (611):
`between 6.5% and 10.5%of C,H;0H,
`determined by the gas-liquid chromatographic procedure, acetone
`being used as the internal standard.
`Assay—
`Standard preparation—Transfer about 80 mg of USP Acet-
`aminophen RS, accurately weighed, toa 100-ml volumetricflask,
`add methanol to volume, and mix. Transfer 10.0 mtofthis solution
`to a second 100-ml volumetric flask, dilute with methanol to volume,
`and mix. Transfer 10.0 ml of the resulting solution to a 100-ml
`volumetric flask, add 1 ml of 0.1 N hydrochloric acid, then add
`methanol to volume, and mix.
`Chromatographic column— Pack a pledget offine glass wool in
`the base of a chromatographic tube (25-mm X 250-mm tube to
`which is fused a S-cm length of 7:mm tubing) with the aid of a
`tamping rod about 45 cm in length and having a disk with a diameter
`about 1 mm less than that of the tube. To 2 g ofpurified siliceous
`earth in a 100-ml beaker add 2.0 mlof a solutioncontaining 1.0 g
`of sodium bicarbonate and 4.5 g of sodium carbonate in each 100
`ml, and mix until a fluffy mixture is obtained. Transfer the mixture
`to the chromatographic tube, and tamp gently to compress the
`material to a uniform mass.
`Assay preparation—Transfer an accurately measured volume
`of Acetaminophen Elixir, equivalent to about 250 mg of acetami-
`nophen,to a 250-ml volumetric flask, add 2 ml of 1 N sodium hy-
`droxide, dilute with water to volume, and mix. Transfer 2.0 ml of
`this solution to a 100-ml beaker, add 1 drop of hydrochloric acid,
`swirl to mix, then add 3.0 g ofpurified siliceous earth. Mix, and
`transfer to the chromatographic column. Scrub the beaker with
`1 g of purified siliceous earth mixed with 2 dropsof water, transfer
`the washings to the column, and tamp gently. Place a pledget of
`fine glass wool on top of the column. Wash the columnwith 100
`mi of water-saturated chloroform, and discard the eluate. Elute
`the acetaminophenwith 150 mlof water-saturatedether, collecting
`the eluate in a 400-mlbeaker. Evaporate the ether on a steam bath
`with the aid of a current ofair just to dryness.
`[NoTB—Avoid
`prolonged drying, to prevent loss of acetaminophen.] Without
`delay, dissolve the residue in a solvent mixture consisting of 1 ml
`of dilute hydrochloric acid (1 in 100) per 100 ml of methanol, and
`transfer to a 50-m! volumetric flask. Rinse the beaker with the
`solvent mixture, adding the rinsings to the flask, dilute with the
`solvent mixture to volume, and mix. Transfer 10.0 ml of this so-
`lution to a second 50-ml volumetric flask, dilute with the solvent
`mixture to volume, and mix.
`Procedure-—Concomitantly determine the absorbances of the
`Standard preparation and the Assay preparation in |-cm cells at
`the wavelength of maximum absorbanceat about 249 nm, with a
`suitable spectrophotometer, using a solvent mixture consisting of
`1 ml of0.1 N hydrochloric acid per 100 ml of methanolas the blank.
`Calculate the quantity, in mg, of CgHyNO> in each ml of Elixir
`taken by the formula 31.25(C/V)(Au/As), in which C is the con-
`centration, in zg per ml, of USP Acetaminophen RSin the Stan-
`dard preparation, V is the volume, in ml, of Elixir taken, and Ay
`and As are the absorbances of the Assay preparation and the
`Standard preparation, respectively.
`
`Acetaminophen Tablets
`» Acetaminophen Tablets contain notless than 95.0
`
`the
`fer
`Re
`anc
`
`hycanc
`mir
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 007
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 007
`
`

`

`16
`
`Acetophenazine / Official Monographs
`
`Procedure—Inject a suitable volume, typically about 5 yl, of
`Acetoneinto a suitable gas chromatograph,and record the chro-
`matogram. Calculate the percentage of C3H,O in the Acetone,
`on the anhydrousbasis, by dividing the area under the acetone peak
`by the sum ofthe areas underall of the peaks and multiplying by
`100.
`[NOTE—No separate correction is applied for water content,
`since water does not respond to the flame-ionization detector-]
`
`Acetophenazine Maleate
`
`CHyCHyCHy—N
`|
`N
`
`oa
`COCH,
`
`O A ©
`
`N—CH,CH,OH
`
`HC—COOH
`HC—COOH
`
`USP XX
`
`finely powdered Tablets,
`Identification—Heat a quantity of
`equivalent to about 20 mg of acetophenazine maleate, with 20 ml
`of methanol on a steam bath for $ minutes, with occasional swirling.
`Cool to room temperature, add methanolto restore to original
`yolume,shake vigorously for 2 minutes, and filler. A 10-l portion
`of the filtrate respondsto /dentification test C under Acetophena-
`zine Maleate.
`Disintegration (701): 30 minutes.
`Content uniformity (681): meet the requirements for Tablets.
`Assay—
`Standard preparation—Transfer about 20 mg of USP Aceto-
`phenazine Maleate RS, accurately weighed, to a separator, and
`proceed as directed under Assay preparation, beginning with “add
`50 ml of sodium chloride solution (1 in 5).” The concentration of
`USP Acetophenazine Maleate RS in the Standard preparation is
`about 10 ug per ml.
`Assay preparation—Weigh andfinely powdernotless than 20
`Acctophenazine Maleate Tablets. Transfer an accurately weighed
`portion of the powder, equivalent to about 20 mg of acetophenazine
`maleate, to a separator, add SO ml of sodium chloride solution (1
`in 5) andsufficient 2.5 N sodium hydroxide to adjust toa pH of 11,
`and allow to cool to room temperature. Extract with four 40-ml
`portions of solvent hexane. Extract the combined solvent hexane
`solution with three 50-ml portions of 0.1 N hydrochloric acid,
`combining the acid extracts in a 200-ml volumetric flask. Dilute
`with 0.1 NV hydrochloric acid to volume, and mix. Transfer 10.0
`ml of this solution to a 100-ml volumetric flask, dilute with 0.1 N
`hydrochloric acid to volume, and mix.
`Procedure—Concomitantly determine the absorbances of the
`Assay preparation and. the Standard preparation in 1-cm cells at
`the wavelength of maximum absorbance at about 278 nm, with a
`suitable spectrophotometer, using 0.1 V hydrochloric acid as the
`blank. Calculate the quantity, in mg, of Cy3Hy9N 3028 . 2C4HyOu
`in the portion of the Tablets taken by the formula 2C(Ay/As), 9
`which C is the concentration,in jg per ml, of USP Acetophenazine
`Maleate RS in the Standard preparation, and Ay and As are the
`absorbancesof the Assay preparation and the Standard prepara-
`tion, respectively.
`
`HSCHo----G----COOH
`H
`
`
`
`it loses not more
`
`Acetophenazine Maleate Tablets
`» Acetophenazine Maleate Tablets contain not less
`than 90.0 percent and not more than 110.0 percentof
`the labeled amount of Cr3H29N 3008 . 2C4H4Og.
`Packaging and storage—Preservein tight containers.
`Reference standard-——USP Acetophenazine Maleate Reference
`Standard—Dryat 65° for 4 hours before using.
`
`at
`ck
`ce
`th
`
`io
`
`f
`lir
`As
`we
`mu
`co
`cu
`us
`nit
`
`»
`
`ty,
`Hy:
`no
`
`Acic
`
`yA
`notn
`calcu
`Packa
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 008
`
`643.71
`C23H29N 3008S . 2C4HyOg
`Ethanone, 1-[10-[3-[4-(2-hydroxyethyi)-1-piperaziny]| propy!]-
`10H-phenothiazin-2-yl]-, (2) 2-butenedioate (1:2) (salt).
`10-[3-[4-(2-Hydroxyethyl)-1-piperazinyl | propy!]phenothiazin-
`2-y! methyl! ketone maleate (1:2) (salt)
`{5714-00-1].
`» Acetophenazine Maleate, dried at 65° for 4 hours,
`contains not less than 97.0 percent and not more than
`103.0 percent of Co3H19N3028 2C4H4Ou.
`Packaging and storage—Preservein tight containers.
`Pa
`con
`Reference standard—_USP Acetophenazine Maleate Reference
`Standard—Dryat 65° for 4 hours before using.
`pol
`Identification—
`Rel
`A: The infrared absorption spectrum of a mineraloil dispersion
`Drs
`bef:
`ofit, previously dried, exhibits maxima onlyat the same wavelengths
`phat of a similar preparation of USP Acetophenazine Maleate
`Ide
`of a
`B:
`Theultraviolet absorption spectrum of a | in 100,000 solu-
`S00
`tion in methanol exhibits maxima and minimaat the same wave-
`of a
`lengths as thalofa similar solution of USP Acetophenazine Maleate
`253
`RS, concomitantly measured, and the respective absorptivities,
`Allc
`calculated on the dried basis, at the wavelength of maximum ab-
`resiv
`Acetylcysteine
`sorbance at about 243 nm donot differ by more than 3.0%.
`afte
`C: Prepareasolution in methanol containing | mg per ml. On
`
`Ace
`NHCOCH,
`a suitable thin-layer chromatographic plate (see (621)), coated with
`Cyst
`a 0.25-mm layer of chromatographicsilica gel mixture, spot 10 yl
`Ster
`of this solution and 10 ul of a solution of USP Acetophenazine
`pH
`Maleate RS in methanol! containing | mg per ml. Allow the spots
`163.19
`CsH9NO3S
`Assi
`to dry, and develop the chromatogram in a solvent system consisting
`L-Cysteine, N-acetyl-.
`Solu
`of acetone and ammonium hydroxide (95:5) until the solvent front
`[616-91 -1].
`N-Acetyl-L-cysteine
`beak
`has moved about three-fourths of the length of the plate. Remove
`the plate from the developing chamber, mark the solventfront, and
`» Acetylcysteine contains not less than 98.0 percent
`(lir
`titra
`allow the solvent to evaporate. Locate the spots using long-wave-
`and not more than 102.0 percent of CsHgNQ38S,cal-
`length ultraviolet light:
`the R; value of the main spot obtained from
`pote
`culated on the dried basis.
`ml
`«
`the test solution correspondsto that obtained from the Standard
`solution.
`CsH
`Packaging and storage——Preserve in tight containers.
`Loss on drying (731)—Dryit at 65° for 4 hours:
`Reference standard—USP Acetyleysteine Reference Standard—
`than 0.5%of its weight.
`Dry at 70° and at a pressure of about 50 mm of mercuryfor 4 hours
`Residue on ignition (281): not more than 0.1%.
`before using.
`Assay— Dissolve about 500 mg of Acetophenazine Maleate, pre-
`Identification—The infrared absorption spectrum of a mineraloil
`viously dried and accurately weighed,in 50 ml of glacial acetic acid,
`dispersion ofit, previously dried, exhibits maximaonly at the same
`warming slightly to effect solution. Cool to room temperature, add
`wavelengthsas that of a similar preparation of USPAcetylcysteine
`10 ml of acetic anhydride, and allow to stand for 5 minutes. Add
`RS.
`Aci
`| drop of crystal violet TS, and titrate with 0.1 NV perchloric acid
`Melting range, Class 1 (741): between 104° and 110°.
`VS toa green-yellow end-point. Performablank determination,
`Specific rotation (781)—In a 25-ml volumetric flask mix 1.25 g
`and make any necessary correction. Each ml of 0.1 NV perchloric
`with 1 mlof disodium ethylenediaminetetraacetate solution (1 in
`acid is equivalent to 32.19 mg of Co3Ho9N3028.. 2C4H404.
`100), add 7.5 mlof sodium hydroxide solution (1 in 25), and mix
`to dissolve. Dilute to volume with pH 7.0 buffer (prepared by
`mixing 29.5 ml of 1 N sodium hydroxide, 50 ml of 1 M monobasic
`poiassium phosphate, and sufficient water to make 100 ml and,
`using a pH meter, adjusting to a pH of 7.0 + 0.1 by adding, as
`necessary, more ofeither solution):
`the specific rotation, calculated
`on the dried basis, compared with a blank prepared wit