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

Abstract

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.

Solvates of acotiamide hydrochloride: characterization and phase transformation

“…The overlap diagrams of the acotiamide cations (Figs. S1a and S1b in the supporting information) show that all N4 atoms bound to the isopropyl group are protonated, and research papers SÁ Á ÁO4 intramolecular interactions are observed in the five AH solvates, consistent with the eight previously reported crystals (Zhang et al, 2019).…”

“…Similar to the eight previously reported crystals (Zhang et al, 2019), the intramolecular hydrogen bonds in 1AH-1W-1DMF and 1AH-1W-1DMSO generated six-membered ringlike structures (Fig. S1a) via the interactions between the O1H group and the C O4 group.…”

“…In the present study, five crystals, namely, 1AH-1W-1DMF, 1AH-1DMSO-I, 1AH-1DMSO-II, 1AH-1W-1DMSO and 2AH-2DMSO-1EA, were obtained. They represent four novel phases and differ from the previously reported types (Zhang et al, 2019). It was further confirmed that AH preferentially crystallizes with a solvent as both a hydrogen-bond acceptor and a hydrogen-bond donor to form a ring-like structure in 1AH-1W-1DMF and 1AH-1W-1DMSO.…”

“…2). The five crystals could be divided into four types that are distinct from the three previously reported types (Zhang et al, 2019). From the packing similarity dendrogram (Fig.…”

“…Crystal forms of AH, which have been well studied in water-alcohol systems and water-acetone systems, include two hydrates, three solvates and three mixed hydrates and solvates (Zhang et al, 2019). These crystal forms could be divided into three isostructural types.…”