Calculations of excess/relative/absolute solubility for drugs in solvents and physiologically relevant media
Solubility drives a huge range of biological and physical processes, and so prediction and control of solubility is a key challenge for modeling in the physical and biological sciences. For example, crystallization is an important solid-liquid separation process capable of creating high purity products, but control of crystallization requires knowledge of the equilibrium solubility of the solid solute(s) of interest. Here, we are particularly interested in solids of small molecules, such as pharmaceutical solids. Since solubility plays such a key role in molecular and process design, we want efficient methods which can predict the ability of a given solvent to dissolve a particular solute. These methods could not only guide the design process by predicting solubility in advance of experiment but could also provide new insight into mechanisms driving solubility. But, as a consequence of the many competing intermolecular forces, the development of such methods is extremely challenging. Thus, we seek efficient methods which predict solubility from physical principles. In an earlier snic-project, we have studied the structural and dynamic features of simple model systems containing two important constituents of intestinal fluid, lecithin (DLiPC) and taurocholate (TCH). The main conclusions from this phase of the project is that spontaneous aggregation of TCH and DLiPC requires intermolecular hydrogen bonding, and that this is an important factor in determining the overall TCH and DLiPC configuration(s) (M Holmboe, P Larsson, J Anwar and CAS Bergström, Langmuir, 2016, submitted). Here, we would like to extent these results to incorporate explicit calculations of solubility for a number of model drugs. In a first subproject, we want to study how the change of solvent (such as introduction of the assemblies we have seen in earlier work above) affects the solubility of a given compound. That is, we calculate relative solubilities. We use MD simulations to calculate relative solubility and compare our calculated values with experiment. These calculations are relatively straight-forward, and boil down to running a series of free-energy calculations in a relevant thermodynamic cycle. In parallel to this, we also propose to calculate the excess solubility of the different drug compounds. One of our experimental partners (P. Augustijns, University of Loeven in Belgium) has recently determined the inter-individual variability of human intestinal fluids, and we want to use these measurements as a comparator for our calculated values. Here we are going to build on earlier work by D. Mobley (J Phys Chem., 2015) but increase the complexity of the solvent environment. Finally, to be able to calculate absolute solubilities for a particular compound in a solvent, we also need to take into account the properties of the solid compound to calculate the property known as the fugacity. The method involves the calculation of the residual chemical potential and the molar volume of the solute at the conditions of interest. For substances that are solid at the conditions of interest, simulations may be performed at elevated temperatures and extrapolated to subcooled conditions (Paluch, 2015).