Pharmaceutical crystallisation processes from batch to continuous operation using MSMPR stages: modelling, design, and control

In pharmaceuticals manufacturing, the conversion of conventional batch crystallisations to continuous mode has the potential for intensified, compact operation and more consistent production via quality-by-design. A pragmatic conversion approach is to utilise existing stirred tank batch crystallisers as continuous mixed-suspension mixed-product removal (MSMPR) stages. In this study, a rigorous and general mathematical model is developed for a pharmaceutical crystallisation process under continuous MSMPR operation. In the proposed changeover from batch to continuous operation, concentration control (C-control), which has been well accepted in batch crystallisation operation, is further extended to facilitate the convenient design of the steady-state operating point of a continuous MSMPR crystalliser; an objective is to ensure that the start-up procedures and on-line control conditions fall within the design-space of the original batch operation. Both single-stage and cascaded two-stage MSMPR crystallisers were investigated and compared to the conventional batch operation. It was observed that despite the production of a smaller number-based mean crystal size, the proposed continuous MSMPR operation achieved higher production capacity with shorter mean residence time and comparable product yield to the batch operation. Lastly, the robustness of C-control strategy against uncertainties in crystallisation kinetics was also demonstrated for the proposed continuous MSMPR operation

Mathematical modeling, design, and optimization of a multisegment multiaddition plug-flow crystallizer for antisolvent crystallizations

In the pharmaceutical industries, the requirements of rapid process development and scalable design have made the tubular crystallizer a promising platform for continuous manufacturing and crystallization processes, capable of replacing conventional capital- and labor-intensive batch operations. This paper takes a process systems engineering (PSE) approach to the optimal design of a continuous antisolvent addition crystallizer to deliver the most promising product qualities, such as the crystal size distribution. A multisegment multiaddition plug-flow crystallizer (MSMA-PFC) is considered as an example of a continuous antisolvent crystallization process, in which the total number, location, and distribution of antisolvent additions are to be optimized. First-principles dynamic and steady-state mathematical models for the MSMA-PFC are presented, based on example kinetic models for nucleation and growth of paracetamol crystallizing in acetone, with water as the antisolvent. The performances of different crystallizer configurations operated under optimal design conditions are then compared. The configuration in which antisolvent could be added at a variety of different locations along the tube length and at optimal flow rates was able to outperform previous designs in the literature which considered equally spaced antisolvent additions. The use of dynamic models to detect problems during startup of an MSMA-PFC was also highlighted

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

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