Optimization of a Crystallization Process for Orantinib Active Pharmaceutical Ingredient by Design of Experiment To Control Residual Solvent Amount and Particle Size Distribution

Orantinib is obtained as a final active pharmaceutical ingredient (API) through crystallization by neutralizing the potassium salt of orantinib in a mixed solvent of isopropyl alcohol (IPA) and H2O. However, the amount of residual IPA in the orantinib API varies, and the neutralizing crystallization makes control of the particle size distribution of the orantinib API difficult. We performed 36 experiments using the design of experiment approach to screen and optimize the process parameters for an orantinib API crystallization process. The screening clarified the strength and trends in the effects of various parameters on the amount of residual IPA and the particle size, and the temperature and solvent ratio were critical process parameters. Next, we constructed a design space for the temperature and solvent ratio by optimizing the process parameters, prepared a response surface model, and calculated the optimal conditions under which both the amount of residual IPA and the particle size distribution could be controlled. Finally, we performed verification experiments under the optimal conditions and obtained the orantinib API with the desired amount of residual IPA and particle size distribution.