Pharmaceutical crystallisation processes from batch to continuous operation using MSMPR stages: modelling, design, and control
journal contributionposted on 27.02.2015 by Qinglin Su, Zoltan Nagy, Chris Rielly
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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.
The authors would like to acknowledge financial support from the UK EPSRC, AstraZeneca and GSK. This work was performed as part of the ‘Intelligent Decision Support and Control Technologies for Continuous Manufacturing and Crystallisation of Pharmaceuticals and Fine Chemicals’ (ICT-CMAC) Project [grant no. EP/K014250/1].
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