Monitoring continuous crystallization of paracetamol in the presence of an additive using an integrated PAT array and multivariate methods
journal contributionposted on 15.07.2016 by Keddon Powell, Ali N. Saleemi, Chris Rielly, Zoltan Nagy
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In this study, an automated intelligent decision support (IDS) framework was applied to monitor the continuous crystallization of form I paracetamol (PCM) and determine steady-state operation. A modified single-stage mixed suspension mixed product removal (MSMPR) crystallizer was used to investigate methods to minimize early onset of fouling and encrustation by carrying out crystallizations in the presence and absence of hydroxyl propyl methyl cellulose (HPMC) additive. The effectiveness of HPMC toward controlling the crystallization process and alleviating fouling and encrustation for prolonged operation of the MSMPR was investigated over a range of concentrations. HPMC was found to suppress nucleation and growth, thereby controlling the crystallization and alleviating fouling and encrustation over extended operating periods. HPMC also affected the product crystal morphology, leading to predominantly tabular shaped crystals. Steady state in the MSMPR was characterized using the IDS, which consisted of an integrated and ancillary array of process analytical technologies (PAT), including the application of Raman spectroscopy with multivariate calibration for solution phase concentration measurement.
The authors would like to thank the EPSRC (EP/I033459/1) and the Centre for Continuous Innovation in Continuous Manufacturing and Crystallization (CMAC) for the financial support of this work and the European Research Council under the European Union’s Seventh Framework Program (FP7/ 2007-2013)/ERC grant agreement no. [280106-CrySys] (for equipment and financial support). Special thanks to Rajesh Gurang for creating the TOC artwork.
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