In Silico Prediction of Drug Solubility:  2. Free Energy of Solvation in Pure Melts

The solubility of drugs in water is investigated in a series of papers and in the current work. The free energy of solvation, Δ , of a drug molecule in its pure drug melt at 673.15 K (400 °C) has been obtained for 46 drug molecules using the free energy perturbation method. The simulations were performed in two steps where first the Coulomb and then the Lennard-Jones interactions were scaled down from full to no interaction. The results have been interpreted using a theory assuming that Δ = ΔG_cav + E_LJ + E_C/2 where the free energy of cavity formation, ΔG_cav, in these pure drug systems was obtained using hard body theories, and E_LJ and E_C are the Lennard-Jones and Coulomb interaction energies, respectively, of one molecule with the other ones. Since the main parameter in hard body theories is the volume fraction, an equation of state approach was used to estimate the molecular volume. Promising results were obtained using a theory for hard oblates, in which the oblate axial ratio was calculated from the molecular surface area and volume obtained from simulations. The Coulomb term, E_C/2, is half of the Coulomb energy in accord with linear response, which showed good agreement with our simulation results. In comparison with our previous results on free energy of hydration, the Coulomb interactions in pure drug systems are weaker, and the van der Waals interactions play a more important role.