Continuous Crystallization Processes in Pharmaceutical Manufacturing: A Review

Abstract

This scientific paper presents an overview of continuous solution crystallization in the pharmaceutical industry. Since the specific knowledge spectrum of precipitation is very broad, topics covering the following were analyzed and assessed in detail: a comparison between batch and continuous crystallizers, their engineering advantages/disadvantages, the introduction of the solid form structuring to continuously oriented chemical production, and the usage of the online process analytical technology (PAT) methodologies in interacting functional systems. Furthermore, mechanistic multiscale modeling, whose understanding is of decisive importance for further control application development, was thoroughly discussed as well. The multiscale modeling section also includes the simulation of processes and the optimization of crystallizers. In the last section, model-based predictive control (MPC) is considered, which also covers the intensification approach methods in the field of crystal formation and the introduction of new, highly potential continuous systems, e.g. the coiled flow inverter (CFI) crystallizer, in industry and academia. In the mentioned main sections, individual theme-related articles are collected, discussed, and compared; therefore, a reader can get acquainted with pieces of research, their found results, which have been developed until now, and various emerging perspectives. With regard to the importance of crystallization in the pharmaceutical industry, a reader can already find literature on continuous crystallization. However, due to the growing tendency toward the synthesis of products with specific properties which cannot be achieved with conventional approaches, more attention has been paid in the present work to the establishment of continuous systems for the production of specific fine chemicals. In addition, continuous crystallization could also enable more efficient and “on-demand” production, modeling for optimization, MPC, and intensification approaches. A review of the literature classifying studies according to the choice of a continuous system and their description was omitted in this study, as such reviews are already available in the literature.