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 antisolvent could be manipulated to suit the demands of the crystallization. Four set point control experiments, three seeded and one unseeded, were investigated for comparison and were compared using FBRM, particle size distribution (PSD), and offline microscope image analysis. The results of the controlled feeding rate experiments show an increase in the final particle size measured by PSD, a decrease in the total batch time, and a reasonable elimination of agglomeration in the system.