Monitoring and feedback control of supersaturation using ATR-FTIR to produce an active pharmaceutical ingredient of a desired crystal size

Automation, in situ monitoring, and process control tools are implemented to understand and control the crystallization of an active pharmaceutical ingredient in development. As a first step in the study, the metastable zone is generated automatically by linking a laser backscattering probe to an automated laboratory reactor. Using the metastable zone as a guide, crystallization experiments with varying cooling rates and seeding protocols are conducted and monitored. The evolution of solution concentration and supersaturation is determined by transmitting data from an in situ total reflectance Fourier transform infrared (ATR-FTIR) spectroscope to the laboratory reactor. Supersaturation profiles coupled with data from the laser backscattering probe demonstrate the prevalence of primary and secondary crystal nucleation in the process. A cascaded proportional-integral controller is tuned and implemented to promote crystal growth over nucleation by maintaining supersaturation at low constant values. Nonlinear temperature profiles that result in crystals of larger size are thereby generated.