Mechanism of solvent-mediated polymorphic transformation to prepare axitinib form XLI controlled by water activity†

Abstract

Axitinib (AXI) is widely used in the treatment of renal cancer. Due to its molecular structure containing multiple hydrogen bond acceptors and donors, AXI has been reported to exist in five solvent-free polymorphs and over 60 solvates. Among these, form XLI is utilized in clinical treatments due to its stability and efficacy. However, obtaining form XLI through direct solution crystallization is challenging. In this study, a new strategy for the preparation of form XLI was developed, enabling the acquisition of form XLI crystals within a minimum of 140 min via solvent-mediated polymorphic transformation (SMPT) using the AXI S_DMF solvate as the precursor. Powder X-ray diffraction (PXRD) and Raman spectroscopy were used to monitor the SMPT process, revealing that the formation of AXI form XLI strongly depended on the water activity of the solvent system. The dissolution of form IV and the nucleation of form XLI were identified as the rate-limiting steps. Online infrared spectroscopy demonstrated that the solvent environment significantly influenced the polymorphic transformation by affecting the molecular conformation and assembly of AXI in solution. Additionally, the effects of temperature, solid content, and solvent composition on the SMPT process were investigated to enhance control over the transformation. Our study provides an efficient method for the preparation of AXI form XLI.