By authority of the United States Pharmacopeial
`Convention, Inc., meeting at Washington, D.C.,
`March 8-10, 1990. Prepared by the Committee of
`Revision and published by the Board of Trustees
`
` THE UNITED STATES PHARMACOPEIA
`
`UNITED STATES PHARMACOPEIAL CONVENTION,INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`*X{11723.1
`ctavis - IPR2017-01100, Ex. 1026, p. 1 of 6
`
`THE NATIONAL FORMULARY
`
`Official from January 1, 1995
`
`1 a i¥ {ay wenn,
`WINSToad ats
`arg pe,
`
`
` roses
`;LIBRARY
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` Actavis - IPR2017-01100, Ex. 1026, p. 1 of 6
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`

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`
`NOTICE AND WARNING
`
`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 suchrights andprivileges 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
`vel Pies
`Attention is called to the fact that USP.and NFtextis 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.
`
`The United States Pharmacopeial Convention, Inc.
`© 1994
`12601 Twinbrook Parkway, Rockville, MD 20852.
`All rights reserved
`ISSN 0195-7996
`ISBN 0-913595-76-4 (cloth)
`0-913595-81-0 (leather)
`
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`Printed by Rand McNally, 1133 County Street, Taunton, MA.02780-3795 -
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`Actavis - IPR2017-01100, Ex. 1026, _p. 2 of 6
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`1
`
`Officers of the Convention .........
`Board of Trustees’ ....... ccc eee
`_ General Committee of Revision ....
`Executive Committee of Revision ..
`_JSP Drug Nomenclature
`Committee .......ce eee eee eee
`Drug Standards Division Exécutive
`Committee and
`Subcommittees ..........0..00, ‘vii
`USP. Reference Standards
`Committee vici.. cece eee eee ee
`USP-FDA Joint Committee on
`Bioequivalence ..............55
`USP-FDA Antibiotic Monograph
`Subcommittee ...........0.000.
`Drug Standards Division Panels ....
`Drug Information Division
`Executive Committee ..........
`_ Drug Information Division
`Advisory Panels ............565
`Assistants During 1990-1995 ......
`Members of the United States
`Pharmacopeial Convention .....
`xiv
`
`
`xxii
`Articles of Incorporation ...........
`Kxili
`Constitution and Bylaws ...........
`Xxxi
`Rules and Procedures
`..........055
`USPC Communications Policy...... XXxvi
`
`USPC DocumentDisclosure
`Indicators and Indicator Test
`Policy... cc se eee e seen reece KXXVii
`2047
`Papers ...... cee e eee ee eee ee eee
`ProceedingS ....... cece e seen eenees
`XXKIX
`2049
`Solutions .........0.cecceeeeee reece
`History of the Pharmacopeia of the
`2049
`Buffer Solutions
`........... e000
`xlii
`United States
`......... cece eee
`2050
`Colorimetric Solutions ...........
`
`_ Preface to USP 23 ......... 00.0 nee liti
`Test Solutions
`..............0005 2050
`Volumetric Solutions ............
`2057
`
`Reagents—Reagents 00.0.0... eeeeeeee ees 1987
`
`
`
`..
`
`Admissions Articles Admitted to USP XXII
`and NF XVII by Supplement
`New Admissions to the Official
`Compendia ..........e cece eee
`Official Titles Changed by
`Supplement
`...............005-
`Changes in Official Titles .........
`Articles Included in USP XXII but
`Not Included in USP 23 or in
`NE 18 voc cece eee eeen eeeeeens
`Articles Included in NF XVII but
`Not Included in NF 18 or in
`USP 23 voccccccccatveceneseees
`
`_xlvi
`
`xlviii
`
`xlviii
`xlix
`
`xlix
`
`Tables
`
`Containers for Dispensing Capsules
`and Tablets ...........000ce aes
`Description and Relative Solubility
`of USP and NFArticles .......
`Approximate Solubilities of USP
`2116
`and NF Articles ...............
`Atomic Weights ...............0055 2123
`Alcoholometric Table ..............
`2126
`Thermometric Equivalents .........
`2127
`
`
`2065
`
`2071
`
`Actavis - IPR2017-01100, Ex. 1026, p. 3 of 6
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`
`iil
`
`Contents ©
`
`
`
`
`
`
`
`
`People
`
`Notices
`
`General Notices and
`Requirements ............. cee
`
`v
`v
`v
`vii
`
`vii
`
`Monographs Official Monographs for
`USP 23 wo. cece eee eee eee eens
`
`15
`
`
`
`.
`
`Vili
`
`viii
`
`viii
`..», viii
`
`ix
`
`ix
`xii
`
`General
`Chapters
`
`see page 1648 for detailed contents
`General Tests and Assays ..........
`General Requirements for Tests
`and Assays .....s.eseeee aeenene
`Apparatus for Tests:
`and Assays ......... eee eee ees
`Microbiological Tests
`...........
`Biological Tests and Assays
`.....
`Chemical Tests and Assays ......
`Physical Tests and
`Determinations ................
`General Information ...............
`
`1650
`
`1650
`
`1673
`1681
`1690
`1721
`
`1760
`1845
`
`Preamble
`
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`

`

`
`
`iv
`Contents
`NUTRITIONAL
`SUPPLEMENTS
`
`
`
`2129
`» MonographsOfficial Monographs ..............
`
`
`
`
`
`
`
`
`
`
`USP 23-NF 18
`
`nen
`
`Tables
`
`USP and NF Pharmaceutic
`Ingredients, Listed by
`Categories ......cee cece eee nes
`See also USP 23, page 2065
`
`2205
`
`ree
`
`Notices
`
`General Notices and
`Requirements .........-0+0e ees
`
`2208
`
`see page 2179 for detailed contents
`General
`Chapters
`2180
`General Tests and Assays ........-.
`
`
`2209
`MonographsOfficial Monographs for NF 18 ....
`anaann
`
`General
`
`see page 1648 for detailed contents
`General Tests and Assays See
`USP 23, page 1650
`General Information See USP 23,
`page 1845
`
`OOO
`
`Reagents
`
`Reagents See USP 23, page 1987
`Indicators and Indicator Test
`Papers See USP 23, page 2047
`Solutions See USP 23, page 2049
`
`i I
`
`Combined Index to USP 23 and
`2321
`NF 18 .......0s eveeeeseeees
`a
`
`ndex
`
`NF 18
`
`
`
`See USP 23, page v
`People
`
`
`Preamble
`
`History of the National
`Formulary .....0.0-0ee sree eens
`Preface to NF 18 .......-- essere ee
`
`2196
`2201
`
`ns
`
`2203
`Admissions Articles Official in NF 18 .........
`
`
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`USP 23
`
`Physical Tests / X-ray Diffraction
`
`(941)
`
`1843
`
`_ Procedure—Placein the dry flask a quantity of the substance,
`weighed accurately to the nearest centigram, which is expected
`to yield 2 to 4 mL of water.
`If the substance is of a pasty
`character, weigh it in a boat of metal foil of a size that will just
`pass through the neck of the flask. If the substanceis likely to
`cause bumping, add enoughdry, washedsandto cover the bottom
`of the flask, or a numberof capillary melting-point tubes, about
`100 mminlength, sealed at the upper end. Place about 200 mL
`of toluene in the flask, connect the apparatus, and fill the re-
`ceiving tube £ with toluene poured through the top of the con-
`denser. Heat the flask gently for 15 minutes and, whenthetol-
`uenebeginsto boil, distil at the rate of about 2 drops per second
`until most of the water has passed over, then increase the rate
`of distillation to about 4 drops per second. When the water has
`apparentlyall distilled over, rinse the inside of the condenser tube
`with toluene while brushing down the tube with a tube brush
`attached to a copper wire and saturated with toluene. Continue
`the distillation for 5 minutes, then remove the heat, and allow
`the receiving tube to cool to room temperature. If any droplets
`of water adhere to the walls of the receiving tube, scrub them
`down with a brush consisting of a rubber band wrapped around
`a copper wire and wetted with toluene. When the water and
`toluene have separated completely, read the volumeof water, and
`calculate the percentage that was present in the substance.
`
`METHODIl (GRAVIMETRIC)
`Procedure for Chemicals—Proceedasdirectedin the individual
`monograph preparing the chemical as directed under Loss on
`Drying (731).
`Procedure for Biologics—Proceedas directed in the individual
`monograph.
`a
`Procedure for Vegetable Drugs—Place about 10 g of the drug,
`preparedasdirected (see Vegetable Drugs—MethodsofAnalysis
`(561)) and accurately weighed, in a tared evaporating dish: Dry
`at 105° for 5 hours, and weigh. Continuethe drying and weighing
`at I-hour intervals until the difference between two successive
`weighings corresponds to not more than 0:25%.
`a
`
`(941) X-RAY DIFFRACTION |
`
`Every crystal form of a compound produces its own charac-
`teristic X-ray diffraction pattern. These diffraction patterns can
`be derived either from a single crystal or from a powdered spec-
`imen (containing numerous crystals) of the material. The spac-
`ings between andtherelativeintensities of the diffracted maxima
`can be used for qualitative and quantitative analysis of crystalline
`materials. Powderdiffraction techniques are most commonly em-
`ployed for routine identificationand the determination ofrelative
`purity of crystalline materials. Small amounts of impurity, how- .
`ever, are not normally detectable by the X-ray diffraction method,
`and for quantitative measurementsit is necessary to prepare the
`sample carefully to avoid preferred orientation effects.
`The powder methods provide an advantage over other means
`of analysis in that they are usually nondestructive in nature (spec-
`imen preparation is usually limited to grinding 'to ensure a ran-
`domly oriented sample, and deleterious effects of X-rays on solid
`pharmaceutical compoundsare not commonly encountered). The
`Principal use of single-crystal diffraction data is for the deter-
`mination of molecular weights and analysis of crystal structures
`at the atomic level. However, diffraction established for a single
`crystal can be used to support a specific powder pattern as being
`truly representative of a single phase.
`Solids—Asolid substance can beclassified as beingcrystalline,
`noncrystalline, or a mixture of the two forms.
`In crystalline ma-
`terials, the molecular or atomic species are ordered in a three-
`dimensionalarray, called a lattice, within the solid particles. This
`ordering of molecular components is lacking in noncrystalline
`material. Noncrystalline solids sometimesare referred to as glasses-
`or amorphous solids when repetitive order is nonexistent in all
`three dimensions. . It is also possible for order to exist in only one
`or two dimensions,resulting in mesomorphic phases(liquid crys-
`tals). Although crystalline materials are usually considered to
`havewell-definedvisible external morphologies(their habits), this
`is not a necessity for X-ray diffraction analysis.
`
`The relatively. random arrangement of molecules in noncrys-
`talline substances makes them poor coherent scatterers of X-rays,
`resulting in broad,diffuse maximain diffraction patterns. Their
`X-ray patterns are quite distinguishable from crystalline speci-
`mens, which give sharply defined diffraction patterns.
`Many compoundsarecapable ofcrystallizing in more than one
`type of crystal lattice. At any particular temperature and pres-
`sure, only one crystalline form (polymorph) is thermodynamically
`stable. Since the rate of phase transformation of a metastable
`polymorphto the stable one can be quite slow,it is not uncommon
`to find several polymorphs of crystalline pharmaceutical com-
`poundsexisting under normal handling conditions.
`In addition to exhibiting polymorphism, many compounds form
`crystalline solvates in which the solvent molecule is an integral
`partof the crystal structure, Just as every polymorph hasits own
`characteristic X-ray patterns, so does every solvate. Sometimes
`the differences in the diffraction patterns of different polymorphs
`are relatively minor, and mustbe very carefully evaluated before
`a definitive conclusion is reached.
`In some instances,
`these
`polymorphs and/or solvates show varying dissolution rates.
`Therefore, on the time scale of pharmaceutical bioavailability,
`different total amounts of drugare dissolved, resulting in potential
`bioinequivalence of the several forms of the drug.
`Fundamental Principles—A collimated beam of monochro-
`matic X-rays is diffracted in various directions when it impinges
`upon a rotating crystal or randomly oriented powdered crystal.
`The crystal acts as a three-dimensional diffraction grating to this
`radiation. This phenomenonis described by Bragg’s law, which
`states that diffraction (constructive interference) can occur only
`when wavesthat are scattered from different regions of the crys-
`tal, in a specific direction, travel distances differing by integral
`numbers (n) of the wavelength (A). Under such circumstances,
`the waves are in phase. This condition is described by the Bragg
`equation:
`
`
`nr
`2 sin @
`
`= din
`hkl
`
`in which d,,; denotes the interplanar spacings and @ is the angle
`of diffraction.
`A family of planes in space can be indexed by three whole
`numbers, usually referred to as Miller indices. These indices are
`the reciprocals, reduced to smallest integers, of the intercepts
`that a plane makes along the axes corresponding to three non-
`parallel edges of the unit cell (basic crystallographic unit). The
`unit cell dimensions are given by the lengthsof the spacings along
`the three axes, a, 5, c, and the angles between them, a, 8, and
`y. The interplanar spacing for a specific set of parallel planes
`hkl is denoted by d,,; Each such family of planes may show
`higher orders of diffraction where the d values for the related
`families of planes nh, nk, ni are diminished by the factor 1/n (n
`being an integer: 2, 3, 4, etc.). Every set of planes throughout
`a crystal has a corresponding Bragg diffraction angle associated
`with it (for a specific d).
`The amplitude of a diffracted X-ray beam from anyset of
`planes is dependent upon the following atomic properties of the
`crystal:
`(1) position of each atom in the unit cell; (2) the re-
`spective atomic scattering factors; and (3) the individual thermal
`motions. Other factors that directly influence the intensities of
`the diffracted beam are: (1) the intensity and wavelength of the
`incident radiation; (2) the volume ofcrystalline specimen; (3) the
`absorption of the X-radiation by the specimen; and (4) the ex-
`perimental arrangementutilized to record the intensity data. Thus,
`the experimental conditions are especially important for mea-
`surement of diffraction intensities,
`Only a limited number of Bragg planes are in a position to
`diffract when monochromatized X-rays pass through a single
`crystal. Techniques of recording the intensities of all of the pos-
`sible diffracting #k/ planes involve motion of ‘the single crystal
`and the recording media. Recording of these data is accom-
`plished by photographic techniques (film) or with radiation de-
`tectors.
`A beam passing through a very large number of small, ran-
`domly oriented crystals produces continuous cones of diffracted
`rays from each set of lattice planes. Each cone corresponds to
`the diffraction from various planes having a similar interplanar
`spacing. The intensities of these Bragg reflections are recorded
`by either film or radiation detectors. The Bragg angle can be
`measuredeasily from a film, but the advent of radiation detectors
`
`Actavis - IPR2017-01100, Ex. 1026, p. 5 of 6
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` Actavis - IPR2017-01100, Ex. 1026, p. 5 of 6
`
`

`

`(941) X-ray Diffraction / Physical Tests
`1844
`has madepossible the construction of diffractometers that read
`this angle directly. The intensities and d spacings are more ‘con-
`veniently determined with powder diffractometers employing ra-
`diation detectors than. by film methods. Microphotometers are
`frequently used for precise intensity measurementsoffilms.
`An example of the type of powder patterns obtained for four
`different solid phases of ampicillin are shown in the accompa-
`nying figure. These diffraction patterns were derived from a
`powder diffractometer equipped with a Geiger-Miiller detector;
`nickel-filtered Cu Ka radiation was used. -
`:
`
`Noncrystalline (anhydrous)
`
`-
`
`Trihydrate
`
`Ml
`
`
`
`\ _Anhydrousform1
` Abe
`
`
`
`Anhydrous form 2
`
`Lad
`5
`10
`15
`2200S 25-80
`26> -
`
`USP 23
`
`tized. The choice of radiation to be used depends upon the ab-
`sorption characteristics of the material and possible fluorescence
`by atoms present in the specimen.
`Caution—Care must be taken in the use of suchradiation,
`Those not familiar with the use ofX-ray equipment should seek
`expert advice. Improper use can result in harmful effects to the
`operator.’
`3
`Test Preparation—In an attempt to improve randomnessin the
`orientation of crystallites’ (and, for film techniques, to avoid a
`grainy pattern), the specimen may be ground in a mortar to a
`fine powder. Grinding pressure has been known to induce phase
`transformations: therefore,it is advisable to check the diffraction
`pattern of the unground sample.
`,
`Ho
`In general, the shapes of many crystalline particles tend to give
`a specimen that exhibits some degree of preferred orientation in
`the specimen holder. Thisis especially evident for needle-like or
`plate-like crystals where size reduction yields finer needles or
`platelets. Preferred orientation in the specimen influences the
`relative intensities of various reflections.
`Several specialized handling techniques may be employed to
`minimize preferred orientation, but further reductionof particle
`size is often the best approach.
`;
`Wherevery accurate measurement of the Bragg angles is nec-
`essary, a small amountof an internal standard can be mixedinto
`the specimen. This enables the film or recorder tracing to be
`calibrated. If comparisons to literature values (including com-
`pendiallimits) of d are being made,calibrate the diffractometer.
`NISTstandardsare available covering to a d-value of 0.998 nm.
`Tetradecanol! may be used(d is 3.963 nm) for larger spacing.
`The absorption of the radiation by any specimenis determined
`by the numberand kinds of atoms through which the X-ray beam
`passes. An organic matrix usually absorbs less of the diffracted
`radiation than: does an inorganic matrix. ‘Therefore, it is impor-
`tant in quantitative studies that standard curves relating amount
`of material tothe intensity of certain d spacings for that substance
`be determined in a matrix similar to that in which the substance
`will be analyzed.
`In quantitative analyses of‘materials, a known amountof stan-
`dard usually is added to a weighed amount of specimen to be
`analyzed, This enables the amount of the substance to be de-
`termined relative to the amountof standard added. The standard
`used should have approximately the samedensity as the specimen
`and similar absorption characteristics. More important, its dif-
`fraction pattern should not overlap to any extent with that of the
`material. to be analyzed. Under these conditions a linear rela-
`tionship.between line intensity and concentration exists.
`In fa-
`vorable cases, amounts of crystalline materials as small as 10%
`may be determinedin solid matrices.
`va
`Identification. of crystalline materials can be accomplished by
`comparison of X-ray powder diffraction patterns obtained for
`known?materials with those of the unknown. Theintensity ratio
`(ratio of the peak intensity of.a particular d spacing to: the in-
`tensity of the strongest maxima in the diffraction pattern) and
`the d spacing are used in the comparison. If a reference material
`(e.g., USP Reference Standard)is available, it is preferable to
`generate a primary reference pattern on the same equipmentused
`for running the unknown sample, and under the same conditions.
`For most organic crystals, it is appropriate to record the diffrac-
`tion pattern to include valuesfor 26 that range from as near zero
`degrees as possible to 40 degrees. Agreement between sample
`and reference should be within the calibrated precision of the
`diffractometer for diffraction angle (26 values should typically
`be reproducible to £0.10 or 0.20 degrees), while relative in-
`tensities between sample and reference mayvary up to 20 percent.
`For other types of samples (¢.g., inorganic salts), it may be nec-
`essary to extend the 20 region scanned to well beyond 40 degrees.
`It is generally sufficient to scan past the ten strongest reflections
`identified in the PowderDiffraction File.?
`
`Typical Powder Patterns Obtained for Four Solid Phases of
`
`
`~-Ampicillin ;
`1 Brindley, GW and Brown, G, eds., Crystal Structures ofClay
`Minerals and their X-ray Identification, Mineralogical Society
`Monograph No.5, London, 1980, pp. 318 ff. *
`2The International Centre for Diffraction Data, Newtown
`Square Corporate Campus, 12 Campus Boulevard, Newtown
`Square, PA 19073, maintains a file on more than 60,000 crys-
`talline ‘materials, both organic and inorganic, suitable for such
`comparisons.
`.
`
`Radiation—The principal radiation sources utilized for X-ray
`diffraction are vacuum tubesutilizing copper, molybdenum,iron,
`and chromium as anodes; copper X-rays are employed most com-
`monly for organic substances. For each of these radiations there
`is an element thatwillfilter off the K@ radiation and permit the
`Ke radiation to pass (nickelis used,in the case of copper radia-
`tion). In this manner the radiation is practically monochroma-
`Actavis - IPR2017-01100, Ex. 1026, p. 6 of 6
`a
`
` Actavis - IPR2017-01100, Ex. 1026, p. 6 of 6
`
`