OBJECTIVE  To optimize crystallization process of regorafenib to control the content of genotoxic impurities.

METHODS The solubility of the crude product and the increase of genotoxic impurities in different solvents were determined to identify the crystallization solvent system and crystallization mode. Suspension transformation experiments and FBRM online monitoring were used to determine the crystallization process conditions for the target crystal form. Grinding was employed to study preferred orientation. The changes in liquid phase concentration and solid phase morphology during crystal maturation were investigated to control the ripening time.

RESULTS  The crystallization process for Regorafenib Form Ⅰ had been established.

CONCLUSION The optimized crystallization process yields a product with low genotoxic impurity content, high crystal form purity, and easily controllable process parameters, making it suitable for industrial production.