Control of Crystal Size during Oiling Out Crystallization of an API

The oiling out crystallization of a pharmaceutical compound API-T dissolved in acetone/water was conducted using a 100 mL crystallizer, and the effect of oil droplets on the resulting crystal size was investigated. The size of oil droplets was controlled by varying agitation speed, and the resulting crystal size decreased with an increase in the size of oil droplets, namely, with a decrease in agitation speed. The observed phenomenon could be explained by the difference of nucleation rate in large and small droplets. The generation of small crystals was caused by the ease of primary and secondary nucleation in large droplets. A decrease in oil droplet size restrained the primary nucleation and also the secondary nucleation. In this case, the small amount of crystals that were released to the continuous phase grew by absorbing small droplets. On the other hand, in single-phase crystallization without liquid–liquid phase separation, the crystal size did not depend on agitation speed.