Predicting the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol mixtures via molecular simulation

Abstract

We present a general framework to predict the excess solubility of small molecular solids (such as pharmaceutical solids) in binary solvents via molecular simulation free energy calculations at infinite dilution with conventional molecular models. The present study used molecular dynamics with the General AMBER Force Field to predict the excess solubility of acetanilide, acetaminophen, phenacetin, benzocaine, and caffeine in binary water/ethanol solvents. The simulations are able to predict the existence of solubility enhancement and the results are in good agreement with available experimental data. The accuracy of the predictions in addition to the generality of the method suggests that molecular simulations may be a valuable design tool for solvent selection in drug development processes.

Approaches for Calculating Solvation Free Energies and Enthalpies Demonstrated with an Update of the FreeSolv Database

“…67–70 Relative solubilities of a given chemical species between different solvents can also be assessed with these calculations. 24,71 Henry’s law solubility constants 72,73 and solubilities in supercritical fluids 74 can also be predicted using solvation free energies.…”

Computational prediction of drug solubility in water-based systems: Qualitative and quantitative approaches used in the current drug discovery and development setting

“…Essentially, calculating solubility from explicit MD simulations amounts to determining when the chemical potential of the solute in solution is equal to the chemical potential of the solute in its solid, crystalline form ( Paluch et al, 2015 ). This can most readily be achieved by running a series of free-energy calculations, but the chemical potential of the solid is still quite complicated to calculate, since it requires calculation of the fugacity of the solid ( Liu et al, 2016 ).…”

“…This can most readily be achieved by running a series of free-energy calculations, but the chemical potential of the solid is still quite complicated to calculate, since it requires calculation of the fugacity of the solid ( Liu et al, 2016 ). Recently, Mobley and co-workers have shown how to use molecular dynamics free energy calculations to calculate both relative and excess solubilities directly, thus circumventing the need to determine the fugacity ( Paluch et al, 2015 ). These calculations are done in the limit of infinite dilution for small compounds (see Fig.…”

“…The solubility of a particular solute, on the other hand, is readily measured. Mobley and co-workers have shown that MD simulations can be used to calculate both relative and excess solubility directly for a number of compounds ( Paluch et al, 2015 ). Relative solubility is the ratio of the solubility of two different compounds in the same solvent, while excess solubility is the solubility of a compound in the actual solution relative to that in an ideal solution ( Ellegaard et al, 2010 , O’Connell and Prausnitz, 1964 ).…”

Molecular Simulation of Chemical Reaction Equilibrium by Computationally Efficient Free Energy Minimization

“…10 This can also be viewed as a generalization of a somewhat related approach recently used by several research groups for solubility simulations of sparingly soluble solids. 29 − 32 The amounts and chemical potentials of the major species at the equilibrium composition calculated by omitting the minor species will be relatively unchanged from their values when the additional species are added to the system. In such cases, we calculate μ m res, NPT ;1 ( T , P ; x ~ ) for a single molecule of the minor species m in the equilibrium mixture, and use eqs 6 and 7 to approximate its chemical potential.…”