Novel, Calibration-Free Strategies for Supersaturation Control in Antisolvent Crystallization Processes

In-situ attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy and focused-beam reflectance measurement (FBRM) were used to monitor and control the antisolvent crystallization of paracetamol from an acetone–water mixture, which was conducted in a 150 mL flat bottom crystallizer with a Mettler Toledo Easymax Reactor system. Following the monitoring of a series of unseeded and seeded crystallization experiments using a constant addition rate of antisolvent, a simple calculation method for the set point of antisolvent addition rate, to maintain constant supersaturation via ATR-FTIR, was developed and implemented for feedback control of unseeded and seeded crystallizations. The implemented technique used a single peak in the ATR-FTIR spectral region without any calibration to effectively maintain supersaturation to a prespecified set point. By developing a solubility curve in terms of peak height and knowing key information of the process at any given time, the addition rate of antisol...