(762c) Process Dynamics of Continuous Cooling Crystallization of Carbamazepine in a Mixed Suspension Mixed Product Removal (MSMPR) System

Authors: 
Acevedo, D. A., U.S. Food and Drug Administration
Yang, X., U.S. Food and Drug Administration
Mohammad, A., U.S. Food and Drug Administration
O'Connor, T., U.S. Food and Drug Administration
Lee, S., U.S. Food and Drug Administration
Faustino, P. J., Food and Drug Administration
Nagy, Z. K., Purdue University
Cruz, C. N., U.S. Food and Drug Administration
Pavurala, N., Office of Testing and Research, U.S. Food and Drug Administration
Wu, W. L., Food and Drug Administration
Current pharmaceutical manufacturing is mainly based on batch processing which has inherent drawbacks and disadvantages. To overcome these drawbacks, emerging technologies such as continuous manufacturing (CM) have been highlighted in the industry in the past few years [1, 2]. As the final purification and isolation step, crystallization has a significant impact on the final physicochemical properties of drug substance and is considered one of the critical process steps in the continuous manufacturing of drug substances. The ability to monitor process dynamics of a continuous process is critical for successful control of crystal quality attributes, such as size distribution. PAT tools such as Focused Beam Reflectance Measurement (FBRM) and spectroscopy based system (i.e. NIR, FTIR, and Raman) can be used to monitor the crystallization process. In this work, a systematic framework to evaluate and understand process dynamics using PAT tools is presented.

The continuous cooling crystallization of carbamazepine (CBZ) in ethanol in a multi-stage MSMPR system is used as the case study. FBRM and Raman spectroscopy are implemented for on-line monitoring. Various startup conditions are evaluated to determine the optimal scenario for the continuous system of interest. The impact of disturbances on the process dynamics and state of operation are evaluated by implementing pulse or step changes to the temperature, flowrate, feed solution concentration, and polymorphic form. Slurry samples for all experiments are obtained and characterized by off-line HPLC, laser diffraction and XRPD before and after the disturbances. The on-line and off-line data obtained are used to characterize the effect on crystal properties (i.e. size and form) and process parameters (i.e. solution concentration). Moreover, simulation studies for the crystallization process are conducted using population balance models to further understand the impact of process disturbances on quality attributes for the continuous cooling crystallization of CBZ.

1. Lee, S.L., et al., Modernizing pharmaceutical manufacturing: from batch to continuous production. Journal of Pharmaceutical Innovation, 2015. 10(3): p. 191-199.

2. Poechlauer, P., et al., Continuous processing in the manufacture of active pharmaceutical ingredients and finished dosage forms: an industry perspective. Organic Process Research & Development, 2012. 16(10): p. 1586-1590.