Crystal structure elucidation and morphology study of pharmaceuticals in development

The structural characterization of drug substances by X-ray diffraction plays a central role during the development of pharmaceuticals. While powder diffraction is usually employed for the identification of solid phases, the single crystal technique yields detailed structural information, which is needed for purity control, understanding of polymorphism or pseudo-polymorphic behavior, physico-chemical property elucidation and morphology characterization. The structure determination of three active ingredients is discussed in this context. In the first case, we have solved the structure directly from high-resolution powder X-ray data, using the ‘direct-space’ methodology. The polymorphic behavior of the second substance has been rationalized by analyzing the intermolecular interactions and packing motifs of the two modifications in the solid state. For the third compound, we have predicted the morphology from the knowledge of its crystal structure. Solvent mixtures have been used to control the external crystal habit, based upon a detailed analysis of chemical groups emerging from the cleaved crystal surfaces of the calculated morphology.