(721b) Efficient Predictions of the Solubility of Pharmaceutical Solids by Molecular Simulation

Given the time and expense required for current rational drug design methods, molecular simulation holds a promising role as a drug design tool. We will present a simple method to estimate the solubility of sparingly soluble solids in pure and mixed solvents. The solubility limit of pharmaceutical solids is a critical thermodynamic property that is related to their bioavailability, and is also necessary for their synthesis and processing.

The method assumes that the activity coefficient of the solute is relatively insensitive to the solute composition, resulting in a simplified thermodynamic model that involves the calculation of the residual chemical potential of a single solute molecule in solution at a finite concentration using an appropriate free energy simulation technique. With knowledge of a single experimental solubility data point, difficult simulations of the solid phase and use of analytical reference states are avoided. 

The method has advantages over more empirical descriptor-based methods in that the simulations enable insight into the underlying molecular driving forces responsible for solubility trends. In this fashion, we will present simulation results that supplement solution theory to predict the existence of solubility enhancement in multi-component solvents. Results are presented for the solubility of paracetamol (acetaminophen) in pure and mixed solvents. We find that the methodology gives reasonable agreement with available experimental results, and is capable of predicting the existence of solubility enhancement in mixed solvents.