New applications of electron diffraction in the pharmaceutical industry: polymorph determination by using a combination of electron diffraction and synchrotron X-ray powder diffraction techniques.

Electron diffraction has been recently used in the pharmaceutical industry to study the polymorphism in crystalline drug substances. While conventional X-ray diffraction patterns could not be used to determine the cell parameters of two forms of the microcrystalline GP IIb/IIIa receptor antagonist roxifiban, a combination of electron single-crystal and synchrotron powder diffraction techniques were able to clearly distinguish the two polymorphs. The unit-cell parameters of the two polymorphs were ultimately determined using new software routines designed to take advantage of each technique's unique capabilities. The combined use of transmission electron microscopy (TEM) and synchrotron patterns appears to be a good general approach for characterizing complex (low-symmetry, large-unit-cell, micron-sized) polymorphic pharmaceutical compounds.

Crystalline versus amorphous content of lumaxistrade mark analog XP280 using X-ray and electron diffraction methods.

In the course of the development of Lumaxistrade mark (roxifiban), the physical state of XP280 (the besylate salt of the active metabolites of roxifiban) and SC887 (the mesylate salt of the free base of roxifiban) were characterized. Powder X-ray diffraction patterns of XP280 were ambiguous in that a high degree of background signal was present and potentially indicative of the existence of an amorphous phase. Herein the results of combined synchrotron X-ray diffraction and electron microscopy (diffraction and imaging) studies on XP280 and SC887 are reported. The combination of these two techniques allowed an unambiguous assessment of the crystallinity, as well as determination of four of the unit cell parameters of XP280 and complete determination of the unit cell parameters for SC887.

Polymorph determination for the GP IIb/IIIa antagonist, roxifiban, using a combination of electron diffraction and synchrotron X-ray powder diffraction techniques.

Unit cell parameters of two polymorphs of roxifiban have been determined by a combination of transmission electron microscopy (TEM) single-crystal and synchrotron X-ray powder diffraction techniques. While it was difficult to differentiate the two forms by their standard X-ray diffraction patterns, the high-resolution synchrotron patterns clearly showed striking differences. Unit cells for the two forms required the use of cell parameters derived from TEM diffraction patterns. The two unit cells are, not surprisingly, very similar except for a doubling of one of the axes for form II. The combined use of TEM and synchrotron patterns appears to be a good general approach for characterizing complex (low-symmetry, large unit cell) polymorphs.

Synthesis and Single-Crystal X-ray Structure of a Highly Symmetrical C60 Derivative, C60Br24.

C(60) and liquid bromine react to form C(60)Br(24), a crystalline compound isolated as a bromine solvate, C(60)Br(24)(Br(2))(x), The x-ray crystal structure defines a new pattern of addition to the carbon skeleton that imparts a rare high symmetry. The parent C(60) framework is recognizable in C(60)Br(24), but sp(3) carbons at sites of bromination distort the surface, affecting conformations of all of the hexagonal and pentagonal rings. Twenty-four bromine atoms envelop the carbon core, shielding the 18 remaining double bonds from addition. At 150 degrees to 200 degrees C there is effectively quantitative reversion of C(60)Br(24) to C(60) and Br(2).

Oxygen Isotope Effect and Structural Phase Transitions in La2CuO4-Based Superconductors.

The oxygen isotope effect on the superconducting transition temperature (alpha(o)) varies as a function of x in La2-xSrxCuO(4) and La2-xBaxCuO(4), with the maximum alpha(o) values (alpha(o) >/= 0.5) found for x near 0.12. This unusual x dependence implies that the isotope effect is influenced by proximity to the Abma --> P4(2)/ncm structural phase transition in these systems. Synchrotron x-ray difaction measurements reveal little change in lattice parameters or orthorhombicity due to isotope exchange in strontium-doped materials where alpha(o) > 0.5, eliminating static structural distortion as a cause of the large isotope effects. The anomalous behavior of alpha(o) in both strontium- and barium-doped materials, in combination with the previously discovered Abma --> P4(2)/ncm structural phase-transition in La(1.88)B(0.12)CuO(4), suggests that an electronic contribution to the lattice instability is present and maximizes at approximately 1/8 hole per copper atom. These observations indicate a dose connection between hole doping of the Cu-O sheets, tilting instabilities of the CuO(6) octahedra, and superconductivity in La(2)CuO(4)-based superconductors.