Solubility prediction from first principles: a density of states approach.

Simon Boothroyd,Jamshed Anwar,David Buttar,Anders Broo,Andy Kerridge

doi:10.1039/c8cp01786g

Abstract

Solubility is a fundamental property of widespread significance. Despite its importance, its efficient and accurate prediction from first principles remains a major challenge. Here we propose a novel method to predict the solubility of molecules using a density of states (DOS) approach from classical molecular simulation. The method offers a potential route to solubility prediction for large (including drug-like) molecules over a range of temperatures and pressures, all from a modest number of simulations. The method was employed to predict the solubility of sodium chloride in water at ambient conditions, yielding a value of 3.77(5) mol kg-1. This is in close agreement with other approaches based on molecular simulation, the consensus literature value being 3.71(25) mol kg-1. The predicted solubility is about half of the experimental value, the disparity being attributed to the known limitation of the Joung-Cheatham force field model employed for NaCl. The proposed method also accurately predicted the NaCl model's solubility over the temperature range 298-373 K directly from the density of states data used to predict the ambient solubility.

Highlights

There are three main approaches to solubility prediction: empirical, correlation-based methods,[6] quantum mechanical (QM) continuum solvation models such as COSMO-RS,[7] and molecular simulation.[8]
Correlation methods include quantitative structure property relationships (QSPR) based on molecular descriptors, with the parameters being optimised against a dataset of molecular structures with known solubilities
Such models are limited in their usage, breaking down when predicting solubility for molecules that are distinct from the training set

Summary

Introduction

There are three main approaches to solubility prediction: empirical, correlation-based methods,[6] quantum mechanical (QM) continuum solvation models such as COSMO-RS,[7] and molecular simulation.[8]. Calculation of the chemical potential of the solute in solution is more demanding, though the methods are well established and include thermodynamic integration,[13,14] the so-called perturbation approach,[15,16,17] expanded ensembles,[18,19] and variations on these.[20] These methods involve ‘growing’ the solute molecule from its reference state reversibly in the solvent. The method in principle is able to predict solubility for a range of temperatures, pressures and solid forms using a single, density of states It is more efficient than thermodynamic integration and the perturbation approach. We have successfully applied the methodology to predict the aqueous solubility of sodium chloride

Solubility from density of states

Technical details

Results and discussion