Multivariable real‐time optimal control of a cooling and antisolvent semibatch crystallization process

This article presents an experimental study of simultaneous optimization with respect to two variables (cooling rate and flow‐rate of antisolvent) in an offline and online (real‐time) manner on a semibatch crystallizer. The nucleation and growth kinetic parameters of paracetamol in an isopropanol‐water cooling, antisolvent batch crystallizer were estimated by nonlinear regression in terms of the moments of the crystal population density. Moments of crystal population were estimated from the measured chord length distribution, generated by the FBRM®, and the supersaturation was calculated from the measured concentration by attenuated total reflectance‐fourier transform infrared spectroscopy. The results of real‐time optimization showed a substantial improvement of the end of batch properties (the volume‐weighted mean size and yield). For the same objective function, the real‐time optimization method resulted in an increase in the volume‐weighted mean size by ∼100 μm and 15% of theoretical yield compared with the best result obtained in an offline optimization manner.