Improving Crystal Morphology through Cocrystallization: A Case Study of Rufinamide-Trimesic Acid Cocrystal

Crystal morphology plays a pivotal role in the production process of pharmaceutical compounds and influences the properties of the final product. Achieving control over crystal morphology, especially for thin and needle-like crystals, presents significant challenges to the industry. In this study, we investigate the crystal morphology of rufinamide (RUF) as a model compound with a notorious thread-like morphology. RUF polymorphs crystallize with markedly poor aspect ratios, with the most stable form (form A) exhibiting the thinnest morphology among all. Our initial attempts to modulate RUF crystal morphologies using solvent screening and habit-modifying additives proved unsuccessful. We explored cocrystals as a novel approach to enhance crystal morphology, given their wide application in improving various physicochemical properties of pharmaceutical solids. We employed trimesic acid (TMA) as the auxiliary compound for cocrystallization, resulting in the synthesis of RUF-TMA. The cocrystal was then subjected to solvent screening in pursuit of crystals with isometric morphology. We successfully obtained RUF-TMA cocrystals with an improved morphology using 3-pentanone as the solvent. This study offers a detailed exploration of five crystal structures, encompassing three polymorphs of RUF and two polymorphs of RUF-TMA. The elucidation of crystal structures is accompanied by a comprehensive characterization, including SCXRD, powder X-ray diffraction, thermogravimetric analysis, and differential scanning calorimetry. This study provides valuable insights into controlling crystal morphology and highlights the potential of cocrystals in enhancing morphology when conventional techniques such as solvent and additive screening of pure active pharmaceutical ingredients fall short.