Powder Crystallography of Large-Volume Pharmaceuticals

The crystal structure provides the fundamental basis for understanding the physical properties of a solid-state material. Perhaps surprisingly, the crystal structures of a significant fraction of the largest dollar volume pharmaceuticals are unpublished; at least part of the reason is that it is difficult or impossible to obtain the single crystals normally needed for structure determination. X-ray powder diffraction is typically used for phase identification and quantitative analysis in analytical laboratories, but crystal structures can increasingly be solved using powder diffraction data. A project has been established by the International Centre for Diffraction Data (producer of the Powder Diffraction File database), IIT, and the Advanced Photon Source at Argonne to generate high-quality reference powder data for pharmaceutical compounds and to determine the crystal structures when they are not available. After a brief introduction to powder diffraction, the processes used for determining such crystal structures using powder data will be described, as well as the crystal structures of a number of compounds. Density functional calculations are essential to complete the crystal structures, and to understand the bonding, particularly the hydrogen bonding. The interplay between experiment and theory is critical for a complete understanding of the structures of these compounds.