Continuous crystallization of carbamazepine

As continuous manufacturing makes inroads in drug production, the process of continuous crystallization—in which active pharmaceutical ingredients are purified via solidification from a liquid phase—has proven to be a major roadblock. Looking to understand the risks involved with such systems and how they might be mitigated, scientists led by Celia N. Cruz at the U.S. Food & Drug Administration’s Office of Pharmaceutical Quality designed and built a lab-scale continuous crystallization platform for the anticonvulsant compound carbamazepine (Org. Process Res. Dev. 2017, DOI: 10.1021/acs.oprd.7b00130). Carbamazepine has four crystalline polymorphs, making it a good model compound for troubleshooting. The continuous crystallization system uses an automated, two-stage mixed-suspension and mixed-product removal platform and integrates two process analytical technology tools, Raman microscopy and focused-beam reflectance microscopy, to monitor the crystallization process in real time. The researchers were able to use the analytical tools to address two major problems with continuous crystallization—clogging and particle settling. They plan to optimize the system further to evaluate more advanced strategies for controlling continuous crystallization processes.