Generation of Fine Pharmaceutical Particles via Controlled Secondary Nucleation under High Shear Environment during Crystallization − Process Development and Scale-up

A unique semibatch crystallization process, coupling with a high-speed rotor-stator device, was developed for generation and control of fine particles. The key underlying mechanism of this process is controlled secondary nucleation under a high shear environment during crystallization, in contrast to the conventional particle breakage mechanism, i.e., milling, after the crystallization. A recycle mode operation is employed to control the residence time of the batch in the high shear domain so as to ensure the scalability of this process. In this work, the operational sensitivity to the supersaturation and particle size were first explored in the laboratory. Based on the results of the laboratory investigation, this process was successfully demonstrated in multiple 1000-L pilot scale production batches. The practical issues for the large scale operation are also illustrated.