(172b) A Comparative Study of Residence Time Distribution and Cooling Crystallization in a Continuous Dynamic/Oscillatory Baffle Crystallizer Versus a Stirred Tank

Crystallization has become a predominant technique in particle design technology and it is widely applied in the pharmaceutical industry. Traditionally crystallization has been carried out in batch mode where operating conditions vary with time, often resulting in inconsistent products.¹ Continuous crystallization, on the other hand, has been identified to improve reproducibility, reduce operating cost and simplify scale-up.² A novel commercial dynamic baffle crystallizer(DBC) operated as a mixed-suspension-mixed-product-removal(MSMPR) system has been studied. It consists of a reactor tank and dynamic ‘donut’ shaped baffles to provide oscillatory flow resulting in more uniform mixing.³ Oscillatory systems have been well studied for batch reactions and synthesis but few studies have been carried out to study the DBC for continuous two-phase operations such as crystallization.

In the work proposed here, liquid and solid residence time distributions were studied systematically in the DBC in comparison with a traditional continuous stirred tank crystallizer(STC). In-situ process analytical technology(PAT) tools such as UV-vis, Infrared(IR), and focused beam reflectance measurement(FBRM) were used to measure system response to step or pulse changes in order to construct RTDs. It is observed that the uniformity of both liquid and solid RTDs was significantly improved in the DBC than the STC indicating potential improvement in size uniformity during crystallization processes. A preliminary continuous cooling crystallization of paracetamol was carried out for two different oscillating conditions in the DBC as well as the STC at the corresponding rotational speeds yielding (approximately) equal power density. Online PAT tools were used to monitor the processes in addition to sampling for offline characterization at every residence time (45min). Nucleation event took place earlier in the DBC than the STC possibly due to the improved mixing mechanism. At early stages of operation, DBC produced crystalline particles of comparable or improved size uniformity. At later stages of operation (>7 residence times), particle sedimentation or severe particle breakage occurred in the STC causing process deviation from steady state while such events did not take place in the DBC and steady state was maintained. In the RTD studies as well as the preliminary crystallization study, the DBC showed improved system uniformity and consistency demonstrating potentials for more in-depth crystallization studies in the DBC.

1. Nagy ZK, Aamir E. Systematic design of supersaturation controlled crystallization processes for shaping the crystal size distribution using an analytical estimator. Chem Eng Sci. 2012;84:656-670. doi:10.1016/j.ces.2012.08.048.
2. Alvarez AJ, Singh A, Myerson AS. Crystallization of Cyclosporine in a Multistage Continuous MSMPR Crystallizer. Cryst Growth Des. 2011;11(10):4392-4400. doi:10.1021/cg200546g.
3. Hewgill MR, Mackley MR, Pandit AB, Pannu SS. Enhancement of gas-liquid mass transfer using oscillatory flow in a baffled tube. Chem Eng Sci. 1993;48(4):799-809. doi:10.1016/0009-2509(93)80145-G.