Microscopic Interpretations of Drug Solubility

Abstract

The development of computational models for predicting drug solubility has increased dras- tically during the last decades. Nevertheless these models still have difficulties to estimate the aqueous solubility as accurate as desired. In this thesis different aspects that are known to have a large impact on the aqueous solubility of a molecule have been studied in de- tail using various theoretical methods with intension to provide microscopic view on drug solubility. The first aspect studied is the hydrogen bond energies. Eight drug molecules have been calculated using density functional theory and the validity of additive model that has often been used in solubility models is examined. The impact of hydrogen bonds in Infrared and Raman spectra of three commonly used drug molecules has also been demon- strated. The calculated spectra are found to be in good agreement with the experimental data. Another aspect that is important in solubility models is the volume that a molecule occupies when it is dissolved in water. The volume term and its impact on the solvation energy has therefore also been calculated using three different methods. It was shown that the calculated volume differed significantly dependent on which method that had been used, especially for larger molecules. Most of the solubility models assume the solute molecule to be in the bulk of the solvent. The molecular behavior at the water/gas interface has been investigated to see how it differs from bulk. It was seen that the concentration close to the interface was almost three times higher than in the bulk. The increase in concentration close to the surface depends on the larger gap between the interface energy and the gas phase energy than between the bulk energy and the gas phase energy.