(270d) Model Based Process Design on Continuous Cooling Crystallization

Authors: 
Acevedo, D. A., U.S. Food and Drug Administration
Liu, C. Y., Purdue University
Yang, X., U.S. Food and Drug Administration
Mohammad, A., U.S. Food and Drug Administration
Pavurala, N., Office of Testing and Research, U.S. Food and Drug Administration
Nagy, Z. K., Purdue University
Cruz, C. N., U.S. Food and Drug Administration
O'Connor, T., U.S. Food and Drug Administration
The use of first-principle models in the pharmaceutical industry presents great promise, as the models may significantly help on process design and control. Models can enhance scientific understanding of the process dynamics, and predict the behavior of a system at various conditions. As part of the effort to understand emerging technologies such as continuous manufacturing,1-2 the development and verification of a population balance model (PBM) for the continuous cooling crystallization of Carbamazepine (CBZ) is studied. A systematic experimental design will be followed to estimate the kinetic parameters for the stable and metastable form (CBZ form III and II, respectively); a series of batch cooling crystallization experiments were performed to determine the parameters for nucleation, growth and dissolution kinetics.

In addition, we will perform a design of experiment (DOE) to systematically determine the design space to produce products of a certain size and polymorphic composition range. The population balance model (PBM) will be used to simulate our continuous crystallization processes. Five factors considered in the determination of the design space are: feed concentration, initial concentration, seed loading, seed crystal size distribution, and residence time. Various points within the design space and at the boundaries were evaluated experimentally.

  1. Lee, S. L.; O’Connor, T. F.; Yang, X.; Cruz, C. N.; Chatterjee, S.; Madurawe, R. D.; Moore, C. M.; Lawrence, X. Y.; Woodcock, J., Modernizing pharmaceutical manufacturing: from batch to continuous production. J Pharm Innov 2015, 10 (3), 191-199.
  2. Yang, X.; Acevedo, D.; Mohammad, A.; Pavurala, N.; Wu, H.; Brayton, A. L.; Shaw, R. A.; Goldman, M. J.; He, F.; Li, S.; Fisher, R. J.; O’Connor, T. F.; Cruz, C. N., Risk Considerations on Developing a Continuous Crystallization System for Carbamazepine. Organic Process Research & Development 2017.