Control of Crystallization Processes in the Pharmaceutical Industry

An overview of the control of crystal properties in the crystallization of pharmaceutical solids will be presented. Two case studies will be considered: first, crystallization of stavudine with emphasis on the effect of process variables is investigated. Next, crystallization of paracetamol from water-isopropanol using a real-time optimal control will be discussed. The concentration and chord length counts were measured using an in-situ ATR-FTIR and an in-situ FBRM probe, respectively. A two-input two-output control strategy (cooling rate and flow-rate of anti-solvent as inputs and the mean size and the total chord length counts, as outputs) was used for the optimal control. The nucleation and growth kinetic parameters of paracetamol in an isopropanol-water cooling, anti-solvent batch crystallizer were estimated by non-linear regression in terms of the moments of the crystal population density. Moments of crystal population were estimated using the measured chord length distribution (CLD), generated by the FBRM, and the supersaturation was measured by ATR-FTIR spectroscopy. The real-time optimal control resulted in an increase in the volume-weighted mean size by approximately 100 μm and 15% of theoretical yield compared to the best result obtained in an offline optimal control strategy.