Operating regions in cooling cocrystallization of caffeine and glutaric acid in acetonitrile

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. © 2010 American Chemical Society.