(270f) Dynamic Modeling of a Continuous Reactive Crystallization Process

Authors: 
Yazdanpanah, N., U.S. Food and Drug Administration
O'Connor, T., U.S. Food and Drug Administration
Cruz, C. N., U.S. Food and Drug Administration
Pharmaceutical and fine chemical companies often employ reactive crystallization to make intermediates and final products. The particle formation rate, particle size and shape, and growth rate are influenced by two temperature and concentration dependent phenomena: A) the reaction, via temperature and concentration dependent kinetic and reaction rate and activation energy; B) crystallization, via temperature and concentration dependent supersaturation ratio and nucleation and crystal growth rate. Therefore, the critical process parameters in productivity (reaction yield) and control of particle size distribution could be manipulated to achieve desirable quality and economics.

Determining the impact of operating temperature on the particle size distribution could be challenging when higher temperature would advance the reaction rate (more solute generation/concentration), but may impact supersaturation ratio and crystal growth rate (more solubility at higher temperature). Beside temperature, the reagents concentration (flow-rate) would impact the reaction rate and generating solute molecule that would lower supersaturation. Effect of micromixing and local supersaturation is not studied in this project.

Most of the reactive crystallization processes have been in batch mode. The reactive crystallization can be used in continuous fashion for API synthesis. The continuous reactive crystallization in a MSMPR (CSTR) method has been less studied and published. In this work, a dynamic process simulation was developed for a continuous reactive crystallization, where the effect of temperature and concentrations (reagents’ flow-rates) were studied on the system response and particle size distribution. The dynamic mode case studies cover a variation of CPPs disturbances and demonstrate system dynamic in terms of the particle size distribution and response rate in comparison to the RTD of the continuous reactive crystallizer.