Crystal structure of febuxostat marketed polymorph determined by electron diffraction and reinforced by X-ray crystallography

Abstract

This article demonstrates the ability of electron diffraction (3D ED, or simply ED) for solving complex structures of active pharmaceutical ingredients (API) and its relevance in the drug development process. The study focuses on febuxostat (FEB), a selective inhibitor used for treating gout. FEB exhibits multiple solid forms, with the crystal structure of the marketed polymorph (form A) being unknown despite its commercial availability. In this work, the crystal structure of form A was successfully determined using both ED and single-crystal X-ray diffraction techniques (SC-XRD). Notably, the crystal growth attempts delivered very small crystals, suitable for ED only, while larger single-crystals for SC-XRD were unintentionally obtained in an experiment aiming for the co-crystallization of FEB with benzoic acid. The results show that ED is a valuable and reliable tool for crystal structure determinations, with comparable accuracy to X-ray crystallography. This study highlights the possibility of incorporating ED in the pharmaceutical research and development process, offering a reliable and efficient approach for crystal structure analysis. It emphasizes the significance of combining crystal structure knowledge with theoretical methods in understanding complex polymorphic systems. Furthermore, it addresses the ED potential in overcoming the challenges in characterizing solid forms across the drug development process.