Hydrates and Solvates of Acotiamide Hydrochloride: Crystallization, Structure, Stability, and Solubility

This paper elucidated eight crystal structures of acotiamide hydrochloride (AH) via single-crystal X-ray diffraction (SCXRD) with water (1AH-1W-I, 1AH-3W), methanol (1AH-1M), methanol and water (1AH-1W-1M-I, 1AH-1W-1M-II), ethanol (1AH-1E), ethanol and water (1AH-1W-1E), and n-propanol (1AH-1P). Two influencing factors, water content and solvent type, were investigated for their effects on the formation of distinct hydrates and solvates. In addition, the stability and solubility of these solid phase forms were analyzed based on their structures. The results of SCXRD revealed that AH tends to crystallize together with a solvent as both a hydrogen bond donor and acceptor. The control experiments in methanol-water, ethanol-water, n-propanol-water, and acetone-water systems showed that the final crystal form varied with an increase in the water content. The eight crystals fall into three types based on their spatial stacking, corresponding interestingly to different stability and solubility. Furthermore, the relationship between changes in solubility curves and the solid phase forms of the undissolved samples was preliminarily elucidated.