No abstract

A complete temperature-dependent solute-solute-solvent phase diagram is an essential starting point for cooling cocrystallization process development. In this study, the phase diagram of caffeine-glutaric acid-acetonitrile in the temperature range of 10-35 °C was charted using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy to measure concentrations in situ. Solution-mediated phase transformation was exploited to locate the eutectic points. The operating region was then prescribed according to the stoichiometry of the cocrystal, and the boundary of stability zones at the initial and final temperatures of cooling crystallization. It was demonstrated that cocrystal purity could be compromised when crystallization occurs outside the safe operating region. The complete phase diagram has laid the foundation for further cocrystallization process development of the model system.

On-line attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy and focused-beam reflectance measurement (FBRM) were used to monitor and control anti-solvent crystallization of paracetamol from an acetone-water mixture, which was conducted isothermally in a 1-L crystallizer with a flat bottom. After analyzing the particle size distribution (PSD) and transient relative supersaturation data from constant anti-solvent addition rate experiments, a simple calculation method for the set point of anti-solvent addition rate, to maintain constant supersaturation via ATR-FTIR, was developed and implemented for feedback control of unseeded and seeded crystallization. The results of the controlled feeding rate experiments show that the particle size and PSD, as well as the total batch time, can be favorably manipulated simultaneously.