Solubility measurement, model evaluation and molecular simulations of aprepitant (form I) in eight pure solvents

Abstract In this work the solubility of the form I of aprepitant in eight pure solvents including methanol, ethanol, propanol, butanol, acetone, acetonitrile, ethyl acetate and 1,4-dioxane was firstly determined using the laser dynamic method over the temperature range of (283.15 to 323.15) K under atmospheric pressure. Meanwhile, the experimental solubility was correlated by commonly used models such as the modified Apelblat equation, the Buchowski-Ksiazczak λh equation and the empirical quartic polynomial equation. The results showed that the solubility of aprepitant (form I) was positively related with temperature in all selected solvents, and all the above models gave satisfactory correlation results in which the empirical quartic polynomial equation stood out to be more suitable with higher accuracy than the other two equations. Then the enthalpy and entropy changes of dissolution were evaluated using the van't Hoff equation and the results revealed that the dissolution of aprepitant (form I) was an endothermic process driven by entropy. Finally, molecular simulations were conducted to estimate the solvation free energies between the solute and the various organic solvents which can well explain the experimental results.