The United States
`PharmaCOpeia
`
`WW I
`
`“I:
`
`I.
`
`1.5‘
`
`w e;
`
`D;
`
`X
`‘
`J V
`
`TWENTIETH REVISION
`
`Officialfrom July 1, 1980
`
`The National
`Formulary {
`
`FIFTEENTH EDITION
`
`Ofiicialfiom July 1, 1980
`
`-u/v
`
`United States I’hurmncupcuu \_,
`.
`l I lL.
`I I l l v L 1 1 l 1k J I I .
`1.760] 'l'\\inbmnk I’IH'I\\\L1V.ROL‘I\\IIIC.\I(I‘
`“0857,
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 001
`
`

`

`United States Pharmacopeia XX
`
`National F0 rmulary XV
`
`OFFICIAL COPY
`J
`
`I,
`Officzal coupon
`Do not remove
`
`I
`
`NOTICE AND WARNING
`
`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.
`
`Concerning Laws of Other Countries
`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 IJnited
`States of America desiring to enforce these standards within their jurisdictions,
`
`18042
`
`Concerning U. S. Patent or Trademark Rights
`The inclusion in the Pharmacopeia or in the National Formulary of a monograph on any drug
`in respect to which patent or trademark rights may exist shall not be deemed, and is 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 without express permission, authority, or license
`secured from such patent or trademark owner.
`
`© 1979 The United States Pharmacopeial Convention, Inc.
`12601 Twinbrook Parkway, Rockville, Md. 20852
`
`All rights reserved
`ISSN 0195-7996
`
`ISBN O~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.
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 002
`
`

`

`The United States
`
`TWENTIETH REVISION
`
`By authority ofthe United States Pharmacopeial Convention, Inc,
`meeting at Washington, D. C, March 22, 1975. Prepared by
`the Committee ofReuision and published by the Board of Trustees
`
`PharmaCOpeia
`
`8 O
`
`Oflieialfrom July 1, J980
`
`V—"
`
`United States Pharmacopeial Convention, Inc.
`
`....‘
`.fi
`12601 lwmbrOOK Parkway, Roma/me, Md. 20852
`
`}
`
`ET.
`S
`
`12
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 003
`
`

`

`Contents
`
`USP xx
`
`Officers of the Convention .
`Board of Trustees i
`.
`.
`.
`.
`.
`.
`.
`Resources Development
`.
`.
`.
`.
`Advisory Council
`USPC Headquarters Staff .
`General Committee of
`Revision
`Executive Committee of
`Revision and
`.
`Subcommittees .
`Reference Standards
`Committee
`.
`.
`.
`.
`.
`.
`.
`Advisory Panels
`.
`.
`.
`.
`.
`Special Consultants .
`Assistants during 1975—1980
`Members of the United States
`Pharmacopeial
`Convention .
`.
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`viii
`viii
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`viii
`xli
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`xi
`xii
`xii
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`xiii
`
`—________-_——————
`
`Preamble
`
`.
`.
`.
`Articles of Incorporation .
`.
`.
`.
`Constitution and Bylaws
`.
`Abstract of Proceedings of the
`U. S. Pharmacopeial
`.
`.
`Convention, 1975 .
`.
`History of the Pharmacopeia
`xxxi
`.
`.
`of the United States .
`.
`xxxiv
`.
`.
`Preface to USP XX .
`.
`.
`.
`.
`.
`____—__—__—_——_—-
`
`.
`
`.
`
`xxviii
`
`Notices
`
`General Notices and
`Requirements
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
`
`.
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`
`Official Monographs of USP
`Monographs
`11
`XX .
`.
`.
`.
`4
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`i ..
`________fl______d_—————
`
`Antibiotic Regulations
`.
`.
`.
`.
`.
`.
`Appendix
`—_____————.————_
`
`Index
`
`Combined Index to USP xx
`1401
`and NF XV .
`.
`.
`.
`.
`.
`.
`.
`. ..
`——__,___.—_—————-
`
`General
`
`seepage 859f0r detailed contents
`General Tests and Assays .
`.
`.
`.
`General Requirements for
`Tests and Assays .
`.
`.
`.
`.
`Apparatus for Tests and
`Assays
`.
`i
`.
`Microbiological Tests .
`Biological Tests and Assays
`Chemical Tests and Assays
`Physical Tests and
`.
`.
`.
`.
`.
`.
`.
`Determinations .
`.
`.
`.
`.
`V
`.
`.
`General Information .
`—_—————-—
`
`.
`
`.
`
`.
`
`861
`
`861
`
`870
`873
`882
`905
`
`Reagents
`
`Reagents
`Indicators and Indicator Tcst
`Papers
`.
`.
`.
`.
`.
`.
`Solutions .
`Buffer Solutions
`Colorimetric Solutions
`Test Solutions .
`.
`.
`.
`.
`.
`Volumetric Solutions
`
`.
`
`.
`
`.
`
`.
`.
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`.
`
`.
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`
`.
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`.
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`.
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`.
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`.
`.
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`.
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`
`.
`
`.
`
`.
`.
`
`.
`
`.
`
`.
`
`.
`.
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`.
`.
`.
`
`.
`
`1117
`
`1121
`
`1160
`
`1168
`1171
`
`1172
`1187
`1188
`
`1189
`
`Admissions
`
`Articles Admitted to USP
`XIX and NF XIV by
`Supplement
`New Admissions to the
`.
`.
`.
`Official Compendia .
`.
`.
`.
`Changes in Official Titles
`Articles Included in USP XIX
`but Not Included in USP
`XX or in NF XV
`Articles Included in NF XIV
`but Not Included in NF
`XVorinUSPXX H...
`
`.
`,
`
`.
`i
`
`1273
`
`Containers for Dispensing
`Capsules and Tablets
`Description and Relative
`Solubility of USP and
`.
`NF Articles .
`.
`.
`.
`.
`.
`.
`Approximate Solubilities of
`USP and NF Articles 1
`USP and NF Pharmaceutic
`Ingredients, Listed by
`Categories i
`.
`.
`.
`.
`.
`_
`i
`Atomic Weights
`.
`.
`.
`.
`.
`.
`.
`Molecular Formulas and
`.
`.
`.
`Weights .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Alcoholometric Table .
`.
`Thermometric Equivalents .
`Equivalents of Weights and
`.
`Measures .
`.
`.
`.
`.
`.
`.
`.
`.
`i
`Table of MetriceApothecary
`Approximate Dose
`Equivalents
`.
`. .inside back cover
`___’__—____———rr———
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 004
`
`

`

`UQI’A/I
`
`UCHHI'LU IVULLCZ.)
`
`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-
`dureszhe directions for titrimetric procedures con-
`clude with a statement of the weight of the analyte that
`is equivalent to each ml of the standardized titrant.
`In
`such an equivalence statement, it is to be understood
`that the number of significant figures in the concen-
`tration of the titrant corresponds to the number of sig—
`nificant figures in the weight of the analyte. Blank
`corrections are to be made for all titrimetric assays,
`where appropriate (see Titrimetry, (541)).
`The limits specified in the monographs for Phar-
`macopeial articles 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)
`named in defining the required strength ofa 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 forms shall be equivalent to not less than 100
`percent of 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 Pharmacopeial articles 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 Pharmacopeial standards for a dosage
`form or a finished device is to achieve a product whose
`strength is 100 percent ofthe quantity of the absolutely
`pure chemical entity 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—
`tree.
`
`The existence of compendial limits er tolerances does
`not constitute a basis for a claim that an 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.
`
`ALCOHOL
`
`All statements of percentages of alcohol, such as
`under the heading, Alcohol content, refer to percentage,
`by volume, of CZHSOH at 15.56°. Where reference
`is made to “C2H50H,” the chemical entity possessing
`absolute (100 percent) strength is intended.
`Alcohol—Where “alcohol” is called for in formulas,
`tests, and assays, the monograph article Alcohol is to
`be used.
`
`Dehydrated Alcohol—W here “dehydrated alcohol”
`(absolute alcohol) is called for in tests and assays, the
`
`prepared from ingredients that meet the requirements
`
`reagent Dehydrated Alcohol (see in the section, Re-
`agents, Indicators, and Solutions) is to be used.
`Denatured Alcoholiln the manufacture of Phar-
`macopeial preparations in which alcohol is used only
`as a solvent and does not remain in the finished product,
`alcohol specially denatured by the addition of volatile
`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 standards set forth.
`
`REAGENT STANDARDS
`
`The proper conduct of the Pharmacopeial tests and
`assays and the reliability of the results depend, in part,
`upon the quality of the reagents used in the performance
`of the procedures. Unless otherwise specified, reagents
`are to be used that conform to the standards set forth
`in the current edition of Reagent Chemicals published
`by the American Chemical Society. Where such ACS
`reagent standards are not available or where for various
`reasons the required purity differs, compendial speci-
`fications for reagents of acceptable quality are provided.
`(SeeReagents, 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 labeling shall include also the term “reagent”
`or “reagent grade.”
`
`REFERENCE STANDARDS
`
`USP Reference Standards and U. S. Reference
`Standards for antibiotics are authentic specimens that
`have been verified for suitability for use as comparison
`standards in compendial tests and assays.
`(See USP
`Reference Standards (1 1).)
`Where first referred to in a monograph, the name of
`a USP Reference Standard is generally spelled out in
`full. However, where a USP'Reference Standard is
`referred to thereafter in an assay or a test in this com-
`pendium, the words “Reference Standard” are abbre-
`viated to “RS.”
`Where a test or an assay calls for the use of a com-
`pendial article, rather than a USP Reference Standard,
`as a material standard of reference, a substance meeting
`all of the requirements of the monograph for that article
`is to be used.
`
`UNITS OF POTENCY
`
`For those products for which it is necessary to express
`the potency in terms of units 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 in the case of
`antibiotics and biological products.
`INGREDIENTS AND I’ROCESSES
`
`Pharmacopeial dosage forms and finished devices are
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 005
`
`

`

`4
`
`General Notices
`
`USP XX
`
`piece of equipment, or the name and address of a
`
`of the compendial monographs for those individual
`ingredients for which monographs are provided. Water
`used as an ingredient in the preparation of compendial
`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 monograph in 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 conforms to the relevant standards
`laid down herein and to preparations produced by fol-
`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 monograph itself, 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 devicemay 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, 3 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 may be
`added to a Pharmacopeial dosage form or finished de»
`vice to enhance its 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
`
`therapeutic efficacy of the dosage form, and if 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 forms or finished devices, except
`those intended for parenteral 0r 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 may impair bio-
`availability of the active ingredients are to be avoided.
`Tablets may be coated.
`Parenteral and Topical Preparations—For the
`preservation of preparations intended for parenteral
`administration or topical application, suitable antiox-
`idants, antimicrobial agents, buffers, and/or stabilizers
`may be added unless interdicted 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 container of an 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 Suppositoriesuln the preparation
`of ointments and suppositories, the proportions of the
`substances constituting the base may be varied to
`maintain a suitable consistency under different climatic
`conditions, provided the concentrations of active in-
`gredients are not varied,
`
`TESTS AND ASSAYS
`
`Apparatust specification for a definite size or type
`of container or apparatus in a test or assay is given solely
`as a recommendation. Where volumetric flasks Or
`other exact measuring, weighing, or sorting devices are
`specified, this or other equipment of 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 sensitivity and accuracy may be
`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
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 006
`
`

`

`Acetaminophen Elixir
`)) Acetaminophen Elixir contains not less than 95.0
`percent and not more than 105.0 percent of the labeled
`amount of Cgi'lgNoz.
`
`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~
`matographic silica gel mixture, apply 200 pl of the supernatant
`liquid, in 40—p1 portions, to obtain a single spot not more than 10 mm
`in diameter. Similarly apply 40 pl ofa Standard solution in ether
`containing 10 pg ofp-chloroacetanilide per ml, and allow the spots
`to dry, 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 under test,
`at an Rf 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 Standard solution, corresponding to not more than
`0.001% of p—chloroacetanilide.
`AssaygDissolve about 120 mg of Acetaminophen, accurately
`weighed, in 10 ml of methanol in a 500-ml volumetric flask, dilute
`with water to volume, and mix. Transfer 5.0 ml of this solution to
`a lGO-ml volumetric flask, dilute with water to volume, and mix.
`Concomitantly determine the absorbances of this solution and of
`a Standard solution of USP Acetaminophen RS, in the same me—
`dium, at a concentration of about 12 pg per ml in l-cm cells, at the
`wavelength of maximum absorbance at about 244 nm, with a suit-
`able spectrophotometer, using water as the blank. Calculate the
`quantity, in mg, of CgHgNOz in the Acetaminophen taken by the
`formula 10C(AU/AS), in which C is the concentration, in pg per
`ml, of USP Acetaminophen RS in the Standard solution, and AU
`and A5 are the absorbanees of the solution ofAcetaminophen and
`the Standard solution, respectively.
`
`
`
`
`
`» Acetaminophen Tablets contain not less than 95.0
`
`Packaging and storage—Preserve in tight containers, and avoid
`continuous exposure to excessive cold.
`Reference standardiUSP Acetaminophen Reference Stan-
`dard—Dry over silica 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 minima at the same wavelengths
`as that ofa similar solution of USP Acetaminophen RS, concomi-
`tantly measured.
`pH (791): between 3.8 and 6.1.
`Alcohol content (611):
`between 6.5% and 10.5% of C2H50H,
`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, to a lOO-ml volumetric flask,
`add methanol to volume, and mix. Transfer 10.0 ml of this solution
`to a second lOO—ml volumetric flask, dilute with methanol to volume,
`and mix, Transfer 10.0 m1 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 columni Pack a pledget of fine glass wool in
`the base of a chromatographic tube (ZS-mm X 250-mm tube to
`which is fused a 5—cm length of 74mm 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 of purified siliceous
`earth in a 100-ml beaker add 2.0 ml of a solution containing 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 preparationflTransfer 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 of purified siliceous earth. Mix, and
`transfer to the chromatographic column, Scrub the beaker with
`l g of purified siliceous earth mixed with 2 drops of water, transfer
`the washings to the column, and tamp gently. Place a pledget of
`fine glass wool on top of the column. Wash the column with 100
`m1 of water-saturated chloroform, and discard the eluate. Elute
`the acetaminophen with 150 ml of water-saturated'ether, collecting
`the eluate in a 400—ml beaker. Evaporate the ether on a steam bath
`with the aid of a current of air just to dryness.
`[NOTE—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-ml 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 l—cm cells at
`the wavelength of maximum absorbance at about 249 nm, with a
`suitable spectrophotometer, using a solvent mixture consisting of
`1 ml of 0.1 N hydrochloric acid per 100 ml of methanol as the blank.
`Calculate the quantity, in mg, of CgHoNOZ in each ml of Elixir
`taken by the formula 31.25(C/V)(AU/A5), in which C is the con-
`centration, in pg per ml, of USP Acetaminophen RS in the Ston-
`dard preparation, V is the volume, in ml, of Elixir taken, and AU
`and A3 are the absorbances of the Assay preparation and the
`Standard preparation, respectively,
`
`Acetaminophen Capsules
`
`» Acetaminophen Capsules contain not less than 95.0
`percent and not more than 105.0 percent of the labeled
`amount of C8H9N02.
`
`Packaging and storagewPreserve in tight containers.
`Reference standardAUSP Acetaminophen Reference Stan—
`dardfiDry over silica gel for 18 hours before using.
`Identification—
`A: The ultraviolet absorption spectrum of the solution of the
`Capsules prepared for the measurement of absorbance in the Assay
`exhibits maxima and minima at the same wavelengths as that ofa
`similar solution of USP Acetaminophen RS, concomitantly mea-
`surcd.
`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 1 drop of ferric chloride TS, and mix:
`a violet—blue color is
`produced.
`Weight variation (931 ): meet the requirements for Capsules.
`Assayfi
`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 m1 of 1 N
`sodium hydroxide, dilute with water to volume, mix, and filter,
`discarding the first 20 ml of the filtrate. Proceed as directed for
`Assay preparation in the Assay under Acetaminophen Elixir, be—
`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
`C3H9N02 in the portion of the Capsules taken by the formula
`31 .25C(AU/A5), in which C is the concentration, in pg per ml, of
`USP Acetaminophen RS in the Standard preparation, and AU and
`A 5- are the absorbances of the Assay preparation and the Standard
`preparation, respectively.
`
`Acetaminophen Tablets
`
`Par Pharm., Inc., et al.
`Exhibit 1022
`Page 007
`
`

`

`l6
`
`Acetophenazine / OfficialMonographs
`
`Procedure—Inject a suitable volume, typically about 5 Mi, of
`Acetone into a suitable gas chromatograph, and record the chroe
`matogram. Calculate the percentage of C3H50 in the Acetone,
`on the anhydrous basis, by dividing the area under the acetone peak
`by the sum of the areas under all 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
`/_\
`crlzeHZCHrN
`NicHZCHZOH
`
`w
`
`l
`
`S
`
`HC—COOH
`
`643.71
`C23H39N3028.2C4H4O4
`Ethanone, 1-[10—[3—[4-(2-hydroxyethy1)-1-piperazinyl]propyl]—
`10H-phenothiazin-2—yl]—, (Z) 2—butenedioate (1:2) (salt).
`10—[3-[4-(2-Hydroxyethyl)»1-piperazinyl]propyl]phenothiazin—
`2—yl methyl ketone maleate (1 :2) (salt)
`[5714-00-1].
`
`
`
`it loses not more
`
`n
`i. N‘
`c. “Mtge.
`_
`i
`AcetOPhtuulluE i‘v/{uicate TabletS
`
`» Aeetophenazine Malcate Tablets contain not less
`than 90.0 percent and not more than 110.0 percent of
`the labeled amount of C23H29N3OZS . 2C4H4O4.
`
`Packaging and storage—Preserve in tight containers.
`Reference standard—USP Acetophenazine Maleate Reference
`Standard—Dry at 65° for 4 hours before using.
`
`Packa
`
`» Acetophenazine Maleate, dried at 65° for 4 hours,
`contains not less than 97.0 percent and not more than
`percent 017C23H29N3OZS . 2C4H4O4.
`Packaging and storage~ePreserve in tight containers.
`Reference standard—USP Acetophenazine Maleale Reference
`Standard—Dry at 65° for 4 hours before using.
`Identification—
`A: The infrared absorption spectrum of a mineral oil dispersion
`of it, previously dried, exhibits maxima only at the same wavelengths
`aRsSthat of a similar preparation of USP Acetophenazine Maleate
`B: The ultraviolet absorption spectrum of a l in 100,000 solu—
`tion in methanol exhibits maxima and minima at the same wave—
`lengths as that of a similar solution of USP Acetophenazine Maleate
`RS, concomitantly measured, and the respective absorptivities,
`calculated on the dried basis, at the wavelength of maximum ab—
`sorbance at about 243 nm do not differ by more than 3.0%.
`C:
`Prepare a solution in methanol containing 1 mg per ml. On
`a suitable thin-layer chromatographic plate (see (621)), coated with
`a 0.25-mm layer of chromatographic silica gel mixture, spot 10 ii]
`of this solution and 10 ul of a solution of USP Acetophenazine
`Maleate RS in methanol containing 1 mg per ml, Allow the spots
`to dry, and develop the chromatogram in a solvent system consisting
`of acetone and ammonium hydroxide (95:5) until the solvent front
`has moved about 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 using long—wave—
`length ultraviolet light:
`thc R; value of the main spot obtained from
`the test solution corresponds to that obtained from the Standard
`solution.
`Loss on drying (731 )—Dry it at 65° for 4 hours:
`than 0.5% of its weight.
`Residue on ignition (281); not more than 0.1%.
`Assay» Dissolve about 500 mg of Acetophenazine Maleate, pre»
`viously dried and accurately weighed, in 50 ml of glacial acetic acid,
`warming slightly to effect solution. Cool to room temperature, add
`10 ml of acetic anhydride, and allow to stand for 5 minutes. Add
`1 drop of crystal violet TS, and titrate with 0.1 N perchloric acid
`VS to a greeneyellow end-point. Perform a blank determination,
`and make any necessary correction. Each ml of 0.1 N perchloric
`acid is equivalent to 32.19 mg of C23H29N30282C4H404.
`
`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 5 minutes, with occasional swirling.
`Cool to room temperature, add methanol to restore to original
`volume, shake vigorously for 2 minutes, and filter. A 10—,ul portion
`of the filtrate responds to Identification test C under Acetophena-
`Zine Maledte.
`Disintegration (701): 30 minutes.
`Content uniformity (681 )2 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 pg per ml.
`Assay preparation—Weigh and finely powder not less 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 50 ml of sodium chloride solution (1
`in 5) and sufficient 2.5 N sodium hydroxide to adjust to a pH of11,
`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 ZOO-ml volumetric flask. Dilute
`with 0.1 N 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.
`Proeedure—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 N hydrochloric acid as the
`blank. Calculate the quantity, in mg, of C231129N302$ . 2C4H4O4
`in the portion of the Tablets taken by the formula 2C(AU/A5), in
`which C is the concentration, in pg per ml, of USP Acetophenazine
`Maleate RS in the Standard preparation, and AU and A5 are the
`absorbances of the Assay preparation and the Standard prepara-
`tion, respectively.
`
`Acetylcysteine
`
`tyHCOCHa
`H
`HSCHZ""('I“--COOH
`
`163.19
`C5H9NO3S
`L-Cysteine, N—acetyl-.
`N-Acetyl-L-cysteine
`
`[616-91—1].
`
`» Acetylcysteine contains not less than 98.0 percent
`and not more than 102.0 percent of C5H9NO3S, cal-
`culated on the dried basis.
`
`Packaging and storageiPreserve in tight containers.
`Reference standard—USP Acetylcysteine Reference Standard—
`Dry at 70° and at a pressure of about 50 mm of mercury for 4 hours
`before using.
`Identification——The infrared absorption spectrum of a mineral oil
`dispersion of it, previously dried, exhibits maxima only at the same
`wavelengths as that of a similar preparation of USP Acetylcysteine
`RS.
`
`Melting range, Class I (741 ): between 104° and 110°.
`Specific rotation (781 >—In a 25-ml volumetric flask mix 1.25 g
`with 1 ml of disodium ethylenediaminetetraacetate solution (1 in
`100), add 7.5 ml of 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 l N sodium hydroxide, 50 ml of 1 M monobasic
`potassium phosphate, and sufficient water to make 1.00 ml and,
`using a pH meter, adjusting to a pH of 7.0 :t: 0.1 by adding, as
`necessary, more of either solution):
`the specific rotation, calculated
`on the dried basis, compared with a blank prepared with the same
`amounts of the same reagents, is between +21° and +27°.
`pH (791): between 2.0 and 2.8, in a solution (1 in 100).
`Loss on drying (731 )—Dry it at 70° and at a pressure of abou