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`1
`E
`A
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`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
`
`Official from January I, 1995
`
`
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC;
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`><><(m 2.48.!
`ctaVIs - IPRZ 17-01100, Ex. 1026, p. 1 of 6
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`NOTICE AND WARNING
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`Concerning US. Patent 0r 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 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.
`
`,.
`.
`I
`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.
`
`The United States Pharmacopeial Convention, Inc.
`© 1994
`12601 Twinbrook Parkway, Rockville, MD 20852.
`All rights reserved
`ISSN 0195-7996
`ISBN 0-913 59 5—7 6-4 (cloth)
`0-913595-81-0 (leather)
`
`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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`Contents
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`Officers of the Convention .
`Board of Trustees .2.
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`, General Committee of Revision .
`Executive Committee of Revision ..
`JMSP Drug Nomenclature
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`Committee .
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`Drug Standards Division Executive
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`Subcommittees .
`USP Reference Standards
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`‘ Committee .
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`USPeFDA Joint Committee on
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`Bioequivalence .L .
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`USP—FDA Antibiotic Monograph
`Subcommittee .
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`viii
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`Notices
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`General Notices and
`Requirements .
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`4
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`v 1
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`Monographs Official Monographs for
`USP 23 .
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`15
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`General
`Chapters
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`1650
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`1650
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`ix
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`Preamble
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`Articles of Incorporation .
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`Constitution and Bylaws .
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`Rules and Procedures
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`USPC Communications Policy.
`USPC Document Disclosure
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`Policy .
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`Proceedings .
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`History of the Pharmacopeia of the
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`United States
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`. .............., Preface to USP 23 . liii
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`xxii
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`xxxix
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`Drug StandardsDivision Panels
`Drug Information Division
`Executive Committee .
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`’ Drug Information Division
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`Advisory Panels .
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`Assistants During 1990—1995 .
`Members of the United States
`Pharmacopeial Convention
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`xii
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`Admissions Articles Admitted to USP XXII
`and NF XVII by Supplement
`New Admissions to the Official
`Compendia .
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`Official Titles Changed by
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`Supplement
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`Changes in Official Titles
`Articles Included in USP XXII but
`Not Included in USP 23 or in
`NF 18 .
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`Articles Included in NF XVII but
`Not Included in NF 18 or in
`USP 23 .
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`see page 1648 for detailed contents
`General Tests and Assays .
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`General Requirements for Tests
`and Assays .
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`Apparatus for Tests
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`and Assays .
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`Microbiological Tests
`Biological Tests and Assays
`Chemical Tests and Assays .
`Physical Tests and
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`Determinations .
`General Information .
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`Reagents
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`Reagents ........................ ..
`Indicators and Indicator Test
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`Solutions .
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`Test Solutions
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`Containers for Dispensing Capsules
`and Tablets .
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`Description and Relative Solubility
`of USP and NF Articles .
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`Approximate Solubilities of USP
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`Atomic Weights .
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`1673
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`1845
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`1987
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`2047
`2049
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`2065
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`2071
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`Tables
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`Thermometric Equivalents .
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`1
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`Actavis - IPR2017-01100, Ex. 1026, p. 3 of 6
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`iii
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` Actavis - IPR2017-01100, Ex. 1026, p. 3 of 6
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`1 iv
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`Contents
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`USP 23—NF I8
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`NUTRITIONAL
`SUPPLEMENTS
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`
`Tables
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`USP and NF Pharmaceutic
`Ingredients, Listed by
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`Categories .
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`See also USP 23, page 2065
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`2205
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`________________—_—-——-———————
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`; Monographs Official Monographs
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`2129
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`see page 2179 for detailed contents
`General
`Chapters
`General Tests and Assays .
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`2180
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`NF 18
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`See USP 23, page v
`People
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`Preamble
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`History of the National
`Formulary .
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`Preface to NF 18 .
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`2203
`Admissions Articles Official in NF 18 ....... ..
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`___________________-———————-—-—-
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`Notices
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`General Notices and
`Requirements .
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`2208
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`2209
`Monographs Official Monographs for NF 18
`______________________———
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`General
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`see page 1648 for detailed contents
`General Tests and Assays See
`USP 23, page 1650
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`General Information See USP 23,
`page 1845
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`_______________—_—————————-
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`Reagents
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`Reagents See USP 23, page 1987
`Indicators and Indicator Test
`Papers See USP 23, page 2047
`Solutions See USP 23, page 2049
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`________________—.——-—-—————-
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`Index
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`Combined Index to USP 23 and
`2321
`NF 18 ........
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`Actavis - IPR2017-01100, Ex. 1026, p. 4 of 6
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` Actavis - IPR2017-01100, Ex. 1026, p. 4 of 6
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`USP 23
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`Physical Tests / X-ray Diffraction
`
`(941)
`
`1843
`
`, Procedure—Place in 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 Vof metal foil of a size that will just
`paSs through theneck of the flask. If the substance is likely to
`cause bumping, add enough dry, washed sand to cover the bottom
`of the flask, or a number of capillary melting-point tubes, about
`100 mm in length, sealed at the upper end. Place about 200 mL
`of toluene in the flask, connect the apparatus, and fill the re-
`ceiving tube E with toluene pdured through the top of the con-
`denser. Heat the flask gently for 15 minutes and, when the tol-
`uene begins to 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
`apparently all 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 volume of water, and
`calculate the percentage that was present in the substance.
`
`METHOD III (GRAVIMETRIC)
`
`Procedure for Chemicals—Proceed as directed in the individual
`monograph preparing the chemical as directed under Loss on
`Drying (731).
`Procedure for Biologics—Proceed as directed in the individual
`monograph.
`-
`v
`~
`Procedure for Vegetable Drugs—Place about 10 g of the drug,
`prepared as directed (see Vegetable Drugs—Methods ofAnalysis
`(561)) and accurately weighed, in a tared evaporating dish. Dry
`at 105° for 5 hours, and weigh. Continue the drying and weighing
`at lahour intervals until the difference between two successive
`weighings corresponds to not more than 0.25%.
`r
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`(941) X-RAY DIFFRACTION I
`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 and the relative intensities of the diffracted maxima
`can be used for qualitative and quantitative analysis of crystalline
`materials. Powder diffraction techniques are most commonly em-
`ployed for routine identificationand the determination of relative
`purity of crystalline materials. Small amounts of impurity, how- ,
`eVer, are not normally detectable by the X-ray diffraction method,
`and for quantitative measurements it 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 compounds are 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—A solid substance can be classified as being crystalline,
`noncrystalline, or a mixture of the two forms.
`In crystalline ma-
`terials, the molecular or atomic species are ordered in a three-
`dimensional array, called a lattice, within the solid particles. This
`ordering of molecular components is lacking in noncrystalline
`material. Noncrystalline solids sometimes are 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
`have well-defined visible external morphologies (their habits), this
`is not a necessity for X—ray diffraction analysis.
`
`The relativelyrandom arrangement of molecules in noncrys-
`talline substances makes them poor coherent scatterers of X—rays,
`resulting in broad, diffuse maxima in diffraction patterns. Their
`X-ray patterns are quite distinguishable from crystalline speci-
`mens, which give sharply defined diffraction patterns.
`Manylcompounds are capable of crystallizing 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
`polymorph to the stable one can be quite slow, it is not uncommon
`to find several polymorphs of crystalline pharmaceutical com-
`pounds existing under normal handling conditions.
`In addition to exhibiting polymorphism, many compounds form
`crystalline solvates in which the solvent molecule is an integral
`part of the crystal structure. Justias every polymorph has its own
`characteristic X-ray patterns, so does every solvate. Sometimes
`the differences in the diffraction patterns of different polymorphs
`are relatively minor, and must be 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 drug are 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 phenomenon is described by Bragg’s law, which
`states that diffraction (constructive interference) can occur only
`when waves that are scattered from different regions of the crys-
`tal, in a specific direction, travel distances differing by integral
`numbers (n) of the wavelength ()x). Under such circumstances,
`the waves are in phase. This condition is described by the Bragg
`equation:
`
`
`n/\
`2 sin 0
`
`= dhkl,
`
`in which dth denotes the interplanar spacings and 0 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 lengths of the spacings along
`the three axes, a, b, c, and the angles between them, a, B, and
`7. The interplanar spacing for a specific set of parallel planes
`hkl is denoted by aim. Each such family of planes may show
`higher orders of diffraction where the d values for the related
`families of planes nh, nk, nl are diminished by the factor l/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 )x).
`The amplitude of a diffracted X-ray beam from any set 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 of crystalline specimen; (3) the
`absorption of the X—radiation by the specimen; and (4) the ex—
`perimental arrangement utilized 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 hkl 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
`measured easily from a film, but the advent of radiatlon detectors
`
`
`
`
`
`Actavis - IPR2017-01100, Ex. 1026, p. 5 of 6
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` Actavis - IPR2017-01100, Ex. 1026, p. 5 of 6
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`
`
`1844
`
`(941) X-ray Diffraction / Physical Test’s
`
`has made possible the construction of diffractometers that read
`this angle directly. The intensities and d spacings are morecon—
`veniently determined with powder diffractometers employing ra-
`diation detectors thanrby film methods. Microphotometers are
`frequently used for precise intensity measurements offilms.
`An example of the type of powder patterns obtained for four
`different solid phasesof ampicillin are shoWn in the accompa-
`nying figure. These diffraction patterns were derived from a
`powder diffractometer equipped with a Geiger-Muller detector;
`nickel-filtered Cu Ka radiation was used.
`‘
`»
`
`v
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`Noncrysta/line (anhydrous)
`
`:
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`Trihydrate
`
`.1, ,t
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`
`I
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`,Anhydrousfarm1
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`
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`Anhydrous form 2
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` m
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`5
`
`10
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`20
`15
`20>—_>‘
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`“25
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`.
`
`30
`
`Typical Powder Patterns Obtained for Four Solid Phases of
`-
`"
`Ampicillin
`
`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 'such‘ radiation.
`Those notfamiliar with the use ofX—ray equipment should seek
`expert advice. Improper use can result in‘ harmful effects to the
`operator.‘
`~
`'
`‘
`Test Preparation—In an attempt to improve randomness in 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.
`‘
`.,
`'
`In general, the shapes of many crystalline particles tend to give
`a specimen that exhibits some degree of preferred orientation in
`the specimen holder. This is especially evident for needle-like by
`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 reduction of particle
`size is often the best approach.
`,
`',
`Where very accurate measurement of the Bragg angles is nec-
`essary, a small amount of an internal standard can be mixed into
`the specimen. This enables the film or recorder tracing to be
`calibrated. If comparisons to literature values (including com-
`pendial limits) of d are being made, calibrate the diffractometer.
`NIST standards are available covering to a' d-value of 0.998 nm.
`Tetradecanoll may be used‘ ((1 is 3.963 nm) for larger spacing.'
`The absorption of the radiation by any specimen is determined
`by the number and 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 ofmaterials, a known amount of 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 amount of standard added. The standard
`used should have approximately the same density as the specimen
`and similar absorption characteristics. More important, its dif-
`fraction pattern should not overlap to any extent with that of the
`materialto beanalyzed. Under theseconditions a linear rela-
`tionshipgbetween line intensity and concentration exists.
`In fa-
`vorable cases, amounts of crystalline materials as small as 10%
`may be determined in solid matrices.
`-
`.
`Identification of crystalline materials can be accomplished by
`comparison of X-ray powder diffraction patterns obtained for
`knownz~ materials, with those of the unknown. The‘ intensity 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 equipment used
`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 values for 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 i0.10 or 0.20 degrees), ‘while relative in-
`tensities between sample and reference may vary up to 20 percent.
`For other types of samples (e.g., inorganic salts), it may be nec—
`essary to extend the 26 region scanned to well beyond 40 degrees.
`It is generally sufficient to scan past the ten strongest reflections
`identified in the Powder Diffraction File.2
`
`Radiation—The principal radiation sources utilized for X-ray ,
`diffraction are vacuum tubes utilizing 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 that will filter off the Kfi radiation and permit the
`Ka radiation to pass (nickel is 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
`#—————————_—#
`
`
`1 Brindley, GW and Brown, G, eds., Crystal Structures of Clay
`Minerals and their X—ray Identification, Mineralogical Society
`Monograph No. 5, London, 1980, pp. 318 ff.
`1"
`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.
`‘
`'
`‘
`
` Actavis - IPR2017-01100, Ex. 1026, p. 6 of 6
`
`