Efficient Estimation of the Equilibrium Solution-Phase Fugacity of Soluble Nonelectrolyte Solids in Binary Solvents by Molecular Simulation

Abstract

We present an efficient means to estimate the concentration-dependent solution-phase fugacity of soluble nonelectrolyte solids in binary solvents by molecular simulation. The underlying assumption of the proposed method is that the solute does not associate or interact with other solute molecules in solution. Solute–solvent and solvent–solvent interactions are taken into account by calculation of the solute solution-phase fugacity at infinite dilution by molecular simulation, and the concentration dependence of the fugacity is taken into account analytically by a combinatorial activity coefficient model. The required simulation data can be computed using any conventional free energy calculation methodology available in many open-source simulation software packages. Moreover, with knowledge of the fugacity of the solid phase, the equilibrium solubility can be calculated. The method has advantages over empirical descriptor-based methods in that the molecular simulations enable insight into the underlying driving forces of the process and do not require extensive parametrization against experimental data. Results are presented for acetaminophen in binary aqueous solvents of water/acetone and water/2-propanol. For both solvent systems, we compare five solute force fields, giving insight into force field selection to yield accurate predictions. Also, predictions are made using the UNIFAC group-contribution method and the state-of-the-art 2005 revised MOSCED model, demonstrating that the accuracy of molecular simulation can be comparable to that of conventional methods for predictive purposes