Crystallisation thermodynamics

This study investigated two important thermodynamic parameters of crystallisation: the activity coefficient and solubility. The influence of composition and temperature on the activity coefficient was investigated to provide a better approximation of the driving force of crystallisation. It was found that the influence of temperature on the activity coefficient was generally much smaller than the influence of composition. Based on an analysis that was performed, a new estimation of the driving force was suggested. Since the driving force is also dependent on solubility, it is important to have an accurate estimation of solubility. Three models were used to calculate a solubility curve: “original NRTL-SAC”, “temperature-dependent NRTL-SAC” and “Pharma UNIFAC”. A comparison between the performances of these three models was presented. It was found that introducing a temperature-dependent binary interaction parameter to the original NRTL-SAC model could improve this model’s performance in calculating solubility. However, as the experimental determination of solubility has a huge influence on the yield of harvested crystals, the solubilities of two APIs – tolbutamide and butamben – were measured experimentally. The solubility of both APIs increased with increasing temperature in all solvents. The thermodynamics of the compound butamben in solution was also investigated in this project.