Advances in the Control of Pharmaceutical Crystallization Processes
Abstract
Increased emphasis is being placed on the control of pharmaceutical crystallizers to produce a robust and consistent crystal product. Advances in pharmaceutical crystallization are described for the design of batch control systems for pharmaceutical crystallization processes. A robust nonlinear control approach to batch control design is compared and contrasted with the classical control approach. The robust nonlinear control system is designed to follow a supersaturation profile in the metastable zone by nonlinear adjustment of the rate of cooling or antisolvent addition based on the in-process solution concentration measurements from ATR-FTIR spectroscopy coupled with chemometrics. This approach has low sensitivities to most practical disturbances and variations in the crystallization kinetics, and requires no on-line tuning. All information needed to design the controller is obtained by an automated procedure. The classical control approach, which uses a linear controller to follow the time-varying optimal temperature or antisolvent addition trajectory, is shown to be inherently sensitive to disturbances and model uncertainties. Some more general statements are made concerning the suitability of this robust nonlinear control design approach to other processes.