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Orantinib is obtained as a final active pharmaceutical ingredient (API) through crystallization by neutralizing the potassium salt of orantinib in a mixed solvent of isopropanol (IPA) and H 2 O. However, the amount of residual IPA in the orantinib API varies, and the neutralizing crystallization makes controlling the particle size distribution of the orantinib API difficult. We performed 36 experiments by using the design of experiment approach to screen and optimize 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 particle size, and the temperature and solvent ratio were critical process parameters.Next, we constructed a design space for temperature and solvent ratio by optimizing the process parameters, prepared a response surface model, and calculated 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 orantinib API with the desired amount of residual IPA and particle size distribution.

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