Comparative performance of concentration and temperature controlled batch crystallizations

An increased interest has been directed towards the crystallization of pharmaceuticals and proteins in recent years, which have additional complications compared to the extensively studied inorganic batch and continuous crystallizations. Recent advances in process analytical technology have enabled the improved modeling and control of batch crystallization. This paper compares simulations and experiments between the classical temperature control approach developed in the 1970–1990s with the concentration-control approach developed more recently. The latter approach, which uses attenuated total reflection–Fourier transform infrared (ATR–FTIR) spectroscopy and feedback control to follow a setpoint trajectory in the solution concentration as a function of temperature, results in reduced sensitivity of the product quality to certain disturbances. The resulting guidelines from the simulations are applied to the experimental investigation of the crystallization of paracetamol in water.