Continuous Crystallization of Atorvastatin Calcium at a Multitonnage Scale Using Dynamically Mixed Flow Reactors for Target Polymorph Control

At Dr Reddy’s, we have developed an integrated continuous manufacturing process for the generation of atorvastatin calcium drug substance encompassing a series of three reactions, followed by downstream unit operations of crystallization, filtration, and drying. The current work focuses on the design of the continuous crystallization process while integrating with upstream reactions and downstream filtration and minimizing the risk of fouling. The batch process was successfully translated to flow by understanding the critical process parameters and designing a crystallization strategy to achieve the desired polymorph (trihydrate, Form-I) and crystal size distribution. A novel and important feature of the present work is the utilization of Coflore dynamically mixed flow reactors in process development and manufacturing. The ability to achieve excellent macromixing in the dynamically mixed flow reactors irrespective of the flow rates helped in crystal growth with minimal fouling. This enabled better filtration for integration with downstream continuous operations. Overall, a continuous seeded antisolvent plus cooling crystallization process was established with a system consisting of Coflore reactors, followed by three CSTRs in series for a controlled cooling profile to promote uniform crystal growth and maximize yield. This process was successfully demonstrated at lab scale (5.6 g/h) and plant scale (12 kg/h of API output) while seamlessly integrating it within the continuous manufacturing train.