NMR crystallography of ezetimibe co-crystals.

An efficient, simplified protocol for solvent-drop assisted co-crystal preparation of ezetimibe (a drug for the treatment of primary hypercholesterolemia) with both imidazole and l-proline has been derived. The structures of the white powders were successfully solved via "NMR crystallography" combining solid-state NMR, powder X-ray diffraction and DFT chemical shift computations. Detailed insights into the likely crystallization mechanism were obtained from competition experiments, where efficient co-crystallization was feasible using ezetimibe monohydrate as precursor indicating that the crystal water acts as "molecular catalyst". It was also found that co-crystallization of imidazole is favored over l-proline, thus suggesting a clear preference of neutral hydrogen bonds compared to charge-assisted motifs.