Prediction of Progesterone Solubility by Modern Quasi-Chemical and Classical Group Contribution Models

Progesterone is a hydrophobic steroid hormone that plays a crucial role in human health. Its limited aqueous solubility presents a significant challenge for both pharmaceutical applications and academic research, showing the importance of accurately predicting its solubility behavior in different solvents. This study assesses the performance of the modern quasi-chemical equation of state known as COSMO-SAC-Phi (CSP), in comparison with its underlying COSMO-SAC (CS) activity coefficient model when modeling solid–liquid equilibrium of progesterone in 14 different solvents. Pure compound parameters employed in CSP calculations were obtained from the vapor pressure and liquid volume data of each pure compound. No binary parameters were adjusted. The results were compared with experimental solid–liquid equilibrium data collected from the literature. As a reference, the classical UNIFAC (Do) group contribution method was also used. The CSP model generally provided more accurate predictions of phase equilibrium, captured solubility trends among similar solvents, and reproduced the correct deviations from ideality for most systems, whereas the CS model was often less accurate in these aspects. An intermediate performance was observed for UNIFAC (Do). The mean absolute deviation in log10 units from experimental solubility data highlights the advantage of the equation-of-state approach, yielding an average value of 0.26 for CSP compared to 0.60 for the underlying activity model and 0.37 for UNIFAC (Do). Nevertheless, CS should be sufficiently accurate for the preliminary screening of new solvent alternatives.