Adaptive concentration control of cooling and antisolvent crystallization with laser backscattering measurement

The paper presents a thorough simulation and experimental evaluation of the concentration control approach for batch and semibatch crystallization. The sensitivity of concentration feedback control is assessed in the case of various disturbances that result in excessive nucleation events. The enhanced robustness of the concentration control is demonstrated against the widely used direct operation approach, which directly implements the temperature or anti-solvent addition rate versus time. Two adaptive supersaturation control approaches are proposed that employ measurement of the number of particle counts per unit time provided by in-situ laser backscattering, to detect the onset of nucleation and adapt the operating curve accordingly, further enhancing the robustness of the approach. Simulation and experimental results indicate that adaptive concentration control is robust to variations in the nucleation, growth, or dissolution rates due to scale-up or other changes in the process conditions.