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

Abstract

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.

Continuous Generation of Millimeter-Sized Glycine Crystals in Non-Seeded Millifluidic Slug Flow

“…The crystal size distributions were very different ( Figure 7A-C) among the different scales. These scale-up difficulties for batches have all been well-recognized [77][78][79][80]. In contrast, the crystal number density and size distribution for slug flow experiments of different scales were much closer to each other, as indicated from representative slug images (Figure 2 and Figure S3) and crystal statistics ( Figure 3, Table 2).…”

Materials Science Tetrahedron—A Useful Tool for Pharmaceutical Research and Development

“…A crystallization process is developed by the process chemistry group to supply API for preclinical and clinical evaluations. If needed, the particulate properties of the chosen crystal form may be further manipulated by a variety of processes, such as milling,5–7 controlled crystallization and precipitation,8–10 spherical crystallization 11–13. These activities have been recently reviewed from a materials science viewpoint 1, 2, 14.…”

Designs of continuous-flow pharmaceutical crystallizers: developments and practice

“…[54][55][56][57]121 Primary and secondary nucleation are accelerated when the solution goes through the wet mill with high shear. [54][55][56][57]121 Toothed rotor-stator mixers (Fig. 7) are used as wet mills for nucleation, with multiple tooth configurations (coarse, medium, fine, multi-stage).…”

“…57,122 Compared to impinging jet micromixers which are easy to implement in continuous flow, the rotor-stator mixers have industrial-scale equipment readily available, and do not need to balance the momentum of two streams. 121 For high primary nucleation, a small turnover number per residence time (defines how frequently the slurry in MSMPR is milled) within the wet mill is preferred (e.g., no recycle). 57 Other design parameters of wet milling are discussed in post-addition seed treatment subsection later.…”