Simultaneous design and control framework for multi-segment multi-addition plug-flow crystallizer for anti-solvent crystallizations

Tubular reactors, which are often assumed to behave as plug-flow reactors, have many applications in chemical reaction engineering, because of their narrow residence time distribution and ease of scaling-up. In the pharmaceutical industries, the requirements of fast development and scalable design have also made the tubular crystallizer a promising platform for continuous manufacturing and crystallization processes which are widely recognized as an emerging technology for pharmaceutical manufacturing which aims to replace conventional capital- and labor-intensive batch operations. However, the interaction of effects, such as supersaturation, seed loading, nucleation and crystal growth, tube configuration and mean residence time have not yet been fully understood and optimized, from a process systems engineering (PSE) perspective, to achieve the most promising product qualities, such as the crystal size distribution. In this study, standardized modules representing plug-flow crystallizer (PFC) segments are assembled into a multi-segment multi-addition plug-flow crystallizer (MSMA-PFC) to facilitate the versatile design and control of anti-solvent crystallization processes, in which the total number, locations, and distribution of anti-solvent addition are to be optimized. An anti-solvent crystallization system of paracetamol-acetone-water was used as an example to compare the performances of different crystallizer configurations operated under optimal design. It was noticed that the proposed design outperforms the previous designs in literature which considered equally-spaced anti-solvent additions. Furthermore, the possibility of replacing existing batch crystallizers by MSMA-PFC is also discussed.