Solubility parameter based methods have long been a valuable tool for solvent formulation and selection. Of these methods, the MOdified Separation of Cohesive Energy Density (MOSCED) has recently been shown to correlate well the equilibrium solubility of multifunctional non-electrolyte solids. However, before it can be applied to a novel solute, a limited amount of reference solubility data is required to regress the necessary MOSCED parameters. Here we demonstrate for the solutes methylparaben, ethylparaben, propylparaben, butylparaben, lidocaine and ephedrine how conventional molecular simulation free energy calculations or electronic structure calculations in a continuum solvent, here the SMD or SM8 solvation model, can instead be used to generate the necessary reference data, resulting in a predictive flavor of MOSCED. Adopting the melting point temperature and enthalpy of fusion of these compounds from experiment, we are able to predict equilibrium solubilities. We find the method is able to well correlate the (mole fraction) equilibrium solubility in non-aqueous solvents over four orders of magnitude with good quantitative agreement.

An efficient method to predict modified separation of cohesive energy density model (MOSCED) parameters for nonelectrolyte solids using electronic structure calculations in SMD and SM8 continuum solvents is proposed and applied to acetanilide, acetaminophen, and phenacetin. The resulting parameters are ultimately used to predict the equilibrium solubility in a range of solvents over a range of temperatures. By combining MOSCED with SMD and SM8, we are able to leverage the strengths of both methods while eliminating shortcomings that would prevent their use alone for solvent selection in design processes involving nonelectrolyte solid solutes. Comparing to 77 non‐aqueous experimental solubilities of acetaminophen over the range 10–30°C, the proposed method has an average absolute error of 0.03 and 0.04 mol fracs for SMD and SM8 regressed parameters, respectively. Aqueous solubilities of acetaminophen over this temperature range are predicted with an average error of 0.030 and 0.0023 mol fracs, respectively. © 2016 American Institute of Chemical Engineers AIChE J, 63: 781–791, 2017

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We present blind predictions using the solubility parameter based method MOSCED submitted for the SAMPL5 challenge on calculating cyclohexane/water distribution coefficients at 298 K. Reference data to parameterize MOSCED was generated with knowledge only of chemical structure by performing solvation free energy calculations using electronic structure calculations in the SMD continuum solvent. To maintain simplicity and use only a single method, we approximate the distribution coefficient with the partition coefficient of the neutral species. Over the final SAMPL5 set of 53 compounds, we achieved an average unsigned error of [Formula: see text] log units (ranking 15 out of 62 entries), the correlation coefficient (R) was [Formula: see text] (ranking 35), and [Formula: see text] of the predictions had the correct sign (ranking 30). While used here to predict cyclohexane/water distribution coefficients at 298 K, MOSCED is broadly applicable, allowing one to predict temperature dependent infinite dilution activity coefficients in any solvent for which parameters exist, and provides a means by which an excess Gibbs free energy model may be parameterized to predict composition dependent phase-equilibrium.

Methods to predict the equilibrium solubility of nonelectrolyte solids are indispensable for early-stage process development, design, and feasibility studies. Conventional analytic methods typically require reference data to regress parameters, which may not be available or limited for novel systems. Molecular simulation is a promising alternative, but is computationally intensive. Here, we demonstrate the ability to use a small number of molecular simulation free energy calculations to generate reference data to regress model parameters for the analytical MOSCED (modified separation of cohesive energy density) model. The result is an efficient analytical method to predict the equilibrium solubility of nonelectrolyte solids. The method is demonstrated for the wastewater contaminants monuron, diuron, atrazine and atenolol. Predictions for monuron, diuron and atrazine are in reasonable agreement with MOSCED parameters regressed using experimental solubility data. Predictions for atenolol are inferior, suggesting a potential limitation in the adopted molecular models, or the solvents selected to generate the necessary reference data.