Solubility determination and thermodynamic modelling of Progesterone in twelve pure solvents and three binary solvents at 278.15 to 323.15 K

The solubility of Progesterone at T = 278.15–323.15 K was measured by static equilibrium method combined with HPLC in twelve solvents (methanol, ethanol, isopropanol, n-propanol, n-butanol, acetone, tetrahydrofuran, 1,4-dioxane, n-heptane, ethyl acetate, acetonitrile, and toluene) and three binary solvents (tetrahydrofuran + n-heptane, 1,4-dioxane + n-heptane, and toluene + n-heptane). The results showed that progesterone has the highest solubility in toluene (0.2249 in mole fraction) and other low-dielectric constant solvents, and the smallest in n-heptane (1.120 × 10⁻⁴ in mole fraction). Moreover, the solubility increases as the temperature rise both in pure and mixed solvents. As expected, the DSC and XRDP results showed that there was no crystal form difference between the raw material and all the precipitate. Herein, the Modified Apelblat model, Buchowski-Ksiazaczak λh model, Jouyban-Acree model, CNIBS/R-K model, and SUN model were employed to fit the experimental data. As a result, the maximum RAD doesn't exceed 5.0%, and the maximum RMSD was less than 0.1%. Furthermore, we chose KAT-LSER model to explore the solubility of progesterone and the solute-solvent interaction relationships. The results showed that when hydrogen bond acidity and polarizability/dipolarity of solvents increases, the solubility of progesterone increases. Meanwhile, comparing the experimental data and the fitting results, it can be concluded that the experimental data was reliable and almost consistent with the fitting results. Furthermore, it also proved that the above mentioned five thermodynamic equations were advantageous and trustworthy.