H.G. Brittain, Ed. "Polymorphism in
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`Pharmaceutical Solids”,
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`Marcel Dekker, 1999, p. 236
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`/fnlvmnrnhism in
`Pharmaceutical
`Saflds/
`
`edited by
`Harry G. Brittain
`Discovery Laboratories, Inc.
`Milford, New Jersey
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`MJ\RCEl
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`E MARCEL DEKK1-:R,INc.
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`DEKKEI.
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`5 G
`
`eneration of Polymorphs,
`Hydrates, Solvates, and Amorphous
`Solids
`
`J. Keith Guillory
`
`The University of Iowa
`Iowa City, Iowa
`
`1. METHODS EMPLOYED TO OBTAIN UNIQUE
`POLYMORPHIC FORMS
`A. Sublimation
`B. Crystallization from a Single Solvent
`C. Evaporation from a Binary Mixture of Solvents
`D. Vapor Diffusion
`B.
`‘Thermal Treatment
`F. Crystallization from the Melt
`G. Rapidly Changing Solution pH to Precipitate Acidic or
`Basie Substances
`H. Thermal Desolvation of Crystalline Solvates
`1. Growth in the Presence of Additives
`J. Grinding
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`H. METHODS EMPLOYED TO OBTAIN HYDRATE FORMS
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`III. METHODS EMPLOYED TO OBTAIN SOLVATE FORMS
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`184
`1 86
`188
`194
`195
`195
`197
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`198
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`201
`202
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`202
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`Generation of Polymorphs
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`203
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`are described in various USP monographs. Hydrates can be prepared
`by recrystallization from water or from mixed aqueous solvents. They
`can also result, in some instances, from exposure of crystal solvates
`(such as rnethanolates or ethanolates) to an atmosphere containing wa-
`ter vapor.
`
`Crystalline substances often form with water molecules located
`
`at specific sites in the crystal lattice. which are held in coordination
`complexes around lattice cations. This type of water is denoted as water
`of crystallization and is common for inorganic compounds. For exam-
`ple, nickel sulfate forms a well-defined hexahydrate, where the waters
`of hydration are bound directly to the Ni(II) ion. Extraneous inclusion
`of water molecules can occur if a coprecipitated cation carries solvation
`molecules with it. Water also can be incorporated into random pockets
`as a result of physical entrapment of the mother liquor. Well-defined
`multiple hydrate species can also form with organic molecules. For
`example, raffinose forms a pentahydrate.
`Although most hydrates exhibit a whole-number-ratio stoichiom-
`etry, an unusual case is the metastable hydrate of caffeine, which con-
`tains only 0.8 moles of water per mole of caffeine. Only in a saturated
`water vapor atmosphere will additional amounts of water be adsorbed
`at the surface of the 4.35-hydrate to yield a 5:6 hydrate [59].
`In some instances, a compound of a given hydration state may
`crystallize in more than one form, so that the hydrates themselves ex-
`hibit polymorphism. One such example is nitrofurantoin, which forms
`two monohydrates that have distinctly different temperatures and en-
`thalpies of dehydration. The monohydrates have quite different packing
`arrangements, with Form I possessing a layer structure and Form ll
`exhibiting a herringbone motif. The included water molecules play a
`major role in stabilizing the crystal structures. Whereas water mole-
`cules are contained in isolated cavities in Form II, in Form I they are
`located in continuous channels, and this apparently facilitates the es-
`cape of water when these crystals are heated [60].
`Another example of hydrate polymorphism is amilolide hydro-
`
`chloride [6l], which can be obtained in two polymorphic dihydrate
`forms. These forms are indistinguishable by techniques other than x-
`ray powder diffraction.
`It is interesting that scopolamine hydrobromide has been reported
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`6 M
`
`ethods for the Characterization of
`Polymorphs and Solvates
`
`Harry G. Brittain
`
`Discovery Laboratories, Inc.
`Miiford, New jersey
`
`INTRODUCTION
`
`CRYSTALLOGRAPHY: X—RAY DIFFRACTION
`A. Single Crystal X—Ray Diffraction
`B. X-Ray Powder Diffraction
`
`MORPHOLOGY: MICROSCOPY
`
`A. Polarizing Optical Microscopy
`B. Thermal Microscopy
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`PHASE TRANSITIONS: THERMAL METHODS OF
`ANALYSIS
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`A. Thermogravimetry
`B. Differential Thermal Analysis
`C. Differential Scanning Calorimetry
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`236
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`Brittaln
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`moved along a proscribed path to determine the angles of the scattered
`radiation. Knowing the wavelength of the incident beam, the spacing
`between the planes (identified as the d-spacings) is calculated using
`Bragg’s law.
`'
`The XRPD pattern will therefore consist of a series of peaks de-
`tected at characteristic scattering angles. These angles. and their rela-
`tive intensities, can be correlated with the computed d-spacings to pro- .
`vide a full crystallographic characterization of the powdered sample.’
`After indexing all the scattered lines, it is possible to derive unit cell
`dimensions from the powder pattern of the substance under analysis
`[18]. For routine work, however, this latter analysis is not normally
`performed, and one typically compares the powder pattern of the ana-
`lyte to that of reference materials to establish the polymorphic identity.
`Since every compound produces its own characteristic powder pattem
`owing to the unique crystallography of its structure. powder x—ray dif-
`fraction is clearly the most powerful and fundamental tool for a speci-
`fication of the polymorphic identity of an analyte. The USP general
`cha ter on x-ra diffraction states that identity is established if the scat-
`tering angles of the ten strongest reflections obtained for an analyte
`agree to within i0.20 degrees with that of the reference material, and
`if the relative intensities of these reflections do not wig by more than
`:20 percent [19].
` r of XRPD as a means to establish the polymorphic
`identity of an analyte can be illustrated by considering the case of the
`anhydrate and trihydrate phases of ampicillin. The crystal structures of
`both phases have been obtained, and they differ in the nature of the
`molecular packing [20]. The amino group in the monoclinic anhydrate
`is hydrogen bonded to the ionized carboxyl groups of two molecules,
`while the amino group of the orthorhombic trihydrate is hydrogen
`bonded to a single carboxylate group and to the waters of hydration
`that link other molecules in the structure. The powder patterns of these
`two materials are shown in Fig. 3 and are seen to be readily distinguish-
`able from each other. Amoxycillin trihydrate has been found to crystal-
`lize in the same space group as does ampicillin trihydrate, and it exhib-
`its a very similar pattern of hydrogen bonding [21]. However,
`the
`dimensions of the two unit cells differ significantly, and this fact is
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