`Pharmacopeia.
`
`TWENTIETH REVISION
`
`Officia/fi'0m July 1, 1980
`
`The National
`Formulary
`
`FIFTEENTH EDITION
`
`O_[7icial_from July I, 1980
`
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`
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`MYLAN - EXHIBIT 1022
`
`MYLAN - EXHIBIT 1022
`
`
`
`United States Pharmacopeia XX
`
`National Formulary XV
`
`OFFICIAL COPY
`J
`
`I
`
`Official coupon
`Do not remove
`
`NOTICE AND WARNING
`
`Concerning U. 5. 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.
`
`Concerning Use of USP or NF Text
`Attention is called to the fact that USP and N F 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 United
`States of America desiring to enforce these standards within their jurisdictions.
`
`© 1979 The United States Pharmacopeial Convention, Inc.
`12601 Twinbrook Parkway, Rockville, Md. 20852
`
`Ail rights reserved
`ISSN 0195-7996
`
`ISBN 0-912734-30-2 (cloth)
`0~912734-31-0 (leather)
`
`T:
`. ypeset and printed by Mack Printing Company, Easton, Pa.
`
`18042
`
`Distributed by Mack Publishing Company, Easton, Pa.
`
`18042
`
`
`
`USP XX
`
`The United States
`
`Pharmacopeia
`
`TWENTIETH REVISION
`
`By authority ofthe United States Pharmaeopeial Convention, Inc.,
`meeting at Washington, D. C., March 22, 1975. Prepared by
`the Committee ofReuision and published by the Board of Trustees
`
`Oflieialfrom July I, J980
`
`United States Pharmacopeial Convention, Inc.
`
`12601 Twinbrook Parkway, Rockviile, Md. 20852
`
`USP
`
`1820
`
`EST.
`
`
`
`Contents
`
`USP XX
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`Officers of the Convention .
`Board of Trustees .
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`Resources Development
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`Advisory Council
`USPC Headquarters Staff .
`General Committee of
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`Revision .
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`Executive Committee of
`Revision and
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`Subcommittees .
`Reference Standards
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`Committee .
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`Advisory Panels
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`Special Consultants .
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`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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`ix
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`x
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`x
`xi
`xii
`xii
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`xiii
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`General
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`see page 859f0r detailed contents
`General Tests and Assays .
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`General Requirements for
`Tests and Assays .
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`Apparatus for Tests and
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`Assays .
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`Microbiological Tests .
`Biological Tests and Assays
`Chemical Tests and Assays
`Physical Tests and
`Determinations .
`General Information .
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`861
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`861
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`870
`873
`8-8_2
`905
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`936
`992
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`Reagents
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`1041
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`Reagents .
`Indicators and Indicator Test
`1098
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`Papers
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`1100
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`Solutions .
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`1100
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`Buffer Solutions
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`1101
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`Colorimetric Solutions
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`1102
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`Test Solutions .
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`Volumetric Solutions
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`1109
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`Preamble
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`xix
`xx
`
`Tables
`
`.
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`Articles of Incorporation .
`.
`.
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`Constitution and Bylaws
`.
`Abstract of Proceedings of the
`U. S. Pharmacopeial
`.
`.
`Convention, 1975 .
`.
`History of the Pharmacopeia
`of the United States .
`.
`Preface to USP XX .
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`xxviii
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`xxxi
`xxxiv
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`Admissions
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`Articles Admitted to USP
`XIX and NF XIV by
`Supplement
`.
`.
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`New Admissions to the
`.
`.
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`Official Compendia .
`.
`.
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`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
`lii
`XVorinUSPXX
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`xliii
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`xliii
`1
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`.
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`lii
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`Notices
`
`General Notices and
`Requirements
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`1 O
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`Monographs
`
`fficial Monographs of USP
`1 1
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`.
`XX .
`.
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`.
` —-j——-—
`
`Appendix
`Antibiotic Regulations
`.
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`.
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`1273
`
`
`Index
`
`Combined Index to USP XX
`1401
`.
`.
`and NF XV .
`.
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`
`vii
`
`Containers for Dispensing
`Capsules and Tablets
`Description and Relative
`Solubility of USP and
`.
`NF Articles .
`.
`.
`.
`.
`.
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`Approximate Solubilities of
`USP and NF Articles .
`USP and NF Pharmaceutic
`Ingredients, Listed by
`Categories .
`.
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`Atomic Weights
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`Molecular Formulas and
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`Weights .
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`Alcoholometric Table .
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`Thermometric Equivalents .
`Equivalents of Weights and
`.
`Measures .
`.
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`.
`.
`Table of Metric—Apothecary
`Approximate Dose
`Equivalents
`.
`. .inside back cover
` .~_:T_
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`1117
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`.
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`.
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`1121
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`1160
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`1168
`1171
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`1172
`1187
`1188
`
`1189
`
`
`
`Ubl’ A/1
`
`U6/LCIIUI IVULLCK.)
`
`J
`
`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 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.
`(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 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 (11).)
`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 PROCESSES
`
`Pharmacopeial dosage forms and finished devices are
`prepared from ingredients that meet the requirements
`
`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»-The 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 of a Pharma-
`copeial article is intended to designate the chemical
`entity or entities having absolute (100 percent) pu-
`r1t
`he 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 of the 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 or 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.
`
`.T
`
`ALCOHOL
`
`All statements of percentages of alcohol, such as
`under the heading, Alcohol content, refer to percentage,
`by volume, of C2H5OH at l5.56°. Where reference
`is made to “C2H5OH,” 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
`
`
`
`4
`
`General Notices
`
`USP XX
`
`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 na.med 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, 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 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 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 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 Supp0sit0ries—~In 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
`
`ApparatusvA 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
`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
`
`
`
`
`
`3-70<f‘*.“.‘f“(‘J-<r-.-—-—-\._._m_.._.._._
`
`
`
`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-pl 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% ofp-chloroacetanilide.
`Assay#Dissolve 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 100-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 CgH9N O2 in the Acetaminophen taken by the
`formula 10C(AU/A5), in which C is the concentration, in pg per
`ml, of USP Acetaminophen RS in the Standard solution, and AU
`and A5 are the absorbances of the solution ofAcetaminophen 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 CgH9NO2.
`
`Packaging and storage——Preserve in tight containers.
`Reference standard4USP Acetaminophen Reference Stan-
`dard—Dry 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-
`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 1 drop of ferric chloride TS, and mix:
`a violet—blue color is
`produced.
`Weight variation (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 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
`CgH9NO2 in the portion of the Capsules taken by the formula
`31 .25C(/iu/A3), in which C is the concentration, in pg per ml, of
`USP Acetaminophen RS in the Standard preparation, and AU and
`A5 are the absorbances of 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 CgH9NO2.
`
`Packaging and storage—Preserve in tight containers, and avoid
`continuous exposure to excessive cold.
`Reference stand-ard—USP Acetaminophen Reference Stan-
`dard—Dry over silica gel for 18 hours before using.
`Identiiication—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 C;H5OH,
`determined by the gas-liquid chromatographic procedure, acetone
`being used as the internal standard.
`Assa —
`Stiindard preparation—Transfer about 80 mg of USP Acet-
`aminophen RS, accurately weighed, to a 100-ml volumetric flask,
`add methanol to volume, and mix. Transfer 10.0 ml of this 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 of fine glass wool in
`the base of a chromatographic tube (25-mm X 250-mm tube to
`which is fused a 5-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 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 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 of purified siliceous earth. Mix, and
`transfer to the chromatographic column. Scrub the beaker with
`1 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
`ml of water-saturated chloroform, and discard the eluate. Elute
`the acetaminophen with 150 ml of water-saturatedether, 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 acet.aminophen.] 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 1-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 CgH9NO2 in each ml of Elixir
`taken by the formula 3l.25(C/V)(AU/A5), in which C is the con-
`centration, in pg per ml, of USP Acetaminophen RS in the Stan-
`dard preparation, V is the volume, in ml, of Elixir taken, and AU
`and A5 are the absorbances of the Assay preparation and the
`Standard preparation, respectively.
`
`Acetaminophen Tablets
`
`anc
`
`» Acetaminophen Tablets contain not less than 95.0
`
`
`
`16
`
`Acetophenazine / Official Monographs
`
`Procedur_e—Inject a suitable volume, typically about 5 pl, of
`Acetone into a suitable gas chromatograph, and record the chro-
`matogram. Calculate the percentage of C3H6O 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
`
`CH2CH2CH2—N
`
`N—CH2CH2OH
`
`l
`
`*4
`
` N COCH3
`
`S
`
`2 Hfi-'CO0H
`HC—COOH
`
`643.71
`C23H29N302S.2C4H404
`Ethanone, 1-[10-[3-[4-(2-hydroxyethyl)-1-piperaziny1]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-I].
`» Acetophenazine Maleate, dried at 65° for 4 hours,
`contains not less than 97.0 percent and not more than
`l03.0 pC1‘C€1’1'[ Of C23H29N3O2S . 2C4H4O4.
`Packaging and storage~—Preserve in tight containers.
`Reference standard—USP Acetophenazine Maleate Reference
`Standard—Dry at 65° for 4 hours before using.
`ldentification—
`A: The infrared absorption spectrum of a mineral oil dispersion
`of it, previously dried, exhibits maxima only at the same wavelengths
`zlgssthat of a similar preparation of USP Acetophenazine Maleate
`B: The ultraviolet absorption spectrum ofa 1 in 100,000 solu-
`tion in methanol exhibits maxima and minima at the same wave-
`lengths as that ofa similar solution ofUSP 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 pl
`of this solution and 10 pl 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 (9525) 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:
`the Rf value of the main spot obtained from
`thp test solution corresponds to that obtained from the-Standard
`so utlon.
`Loss on drying (731 )—Dry it at 65° for 4 hours:
`it loses not more
`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 green—yellow 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 C231-l29N3O2S.2C4H4O4.
`
`Acetophenazine l‘v’1laleate Tablets
`
`» Acetophenazine Maleate Tablets contain not less
`than 90.0 percent and not more than 110.0 percent of
`ll16 labeled amount Of C23H29l\l3O2S . 2C4H4O4.
`
`Packaging and storage—Preserve in tight containers.
`Reference standard—USP Acetophenazine Maleate Reference
`Stana'ard—Dry at 65° for 4 hours before using.
`
`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—pl portion
`of the filtrate responds to Identification 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 pg per ml.
`Assay preparation—Weigh and finely powder not less than 20
`Acetophenazine 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 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 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.
`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 N hydrochloric acid as the
`blank. Calculate the quantity, in mg, of C;;_3H29N3O2S . 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
`
`ritncocn,
`H
`HSCHz----('1----COOH
`
`163.19
`C5H9NO3S
`L-Cysteine, N-acetyl-.
`N-Acetyl-L-cysteine
`[616-9'1-1].
`» 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 storage—Preserve 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 ofl N sodium hydroxide, 50 ml ofl M monobasic
`potassium phosphate, and sufficient water to make 100 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 about 50
`mm of mercury fo