Development Strategies of Polymorphs and Solvates for Enhancing Powder Properties: A Case Study of Thiothiamine

Crystals with an acicular shape are a "nightmare" to many chemical engineers due to their poor powder properties, posing numerous challenges in purification, filtration, washing, and subsequent processing. However, these challenges may be circumvented by engineering new crystal forms with better morphology using a crystal engineering strategy. Herein, we demonstrated the validity of this strategy with the case of thiothiamine, an essential intermediate in the production of vitamin B1, which exhibits a needle-like crystal morphology in polymorph I. Another two polymorphs (forms II and III) and 14 solvates were discovered and developed using a combination of computational prediction and experimental screening with X-ray diffraction, IR spectroscopy, and thermal analysis. Crystal structures of form II and six solvates were fully determined for the first time by single crystal X-ray diffraction. First, compared to form I, form II exhibits a notably larger grain size. Furthermore, the desolvation of solvates can retain its original superior morphology. These optimization strategies targeting crystal morphology directly contribute to the enhancement of the powder performance. Specifically, the filtration time was significantly reduced by over 70%, and the flowability of the powder was also greatly improved. Crystal structure analysis reveals that inclusion of small solvent molecules in a disordered manner contributes to solvate formation, while hydrogen bonding interactions contribute to the formation of methanol solvate. This study can serve as a valuable reference for addressing filtration and flowability challenges in industry by using crystal engineering strategies to develop polymorph or solvate alternatives.