Microscopic Interpretations of Drug Solubility

by Bondesson, Laban

The development of computational models for predicting drug solubility has increased drastically during the last decades. Nevertheless these models still have difficulties to estimate the aqueous solubility as accurately as desired. Different aspects that are known to have a large impact on the aqueous solubility of a molecule have been studied in detail in this thesis using various theoretical methods with intension to provide a microscopic view on drug solubility. The first aspect studied is the hydrogen bond energies. The validity of the additive model, often used in the field of solubility models has been tested using density functional theory by examining eight drug molecules. The impact of hydrogen bonds in Infrared and Raman spectra of three commonly used drug molecules has also been demonstrated. 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 is shown that the calculated volumes is strongly dependent on the computational methods employed, especially for larger molecules. The interaction energy between a molecule and the surrounding solute can be estimated in different ways. In this thesis a new computational scheme has been developed for calculating solute-solvent interaction energies. It applies molecular dynamics simulations to generate structures of solute-solvent complexes and linear scaling quantum chemical methods to calculate the electronic structures of the selected complexes and the interaction energies. Some technical details, such as the convergence of solute-solvent interaction energies with respect to the number of solute molecules included, the use of mixed basis sets and the basis set superposition error, have also been provided. 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 found that the concentration close to the interface was almost three times iii higher than in the bulk. This results from the fact that the energy gap between the interface and the gas phase is larger than that between the bulk and the gas phase. iv Preface The work presented in this thesis has been carried out at the Department of Theoretical Chemistry, Royal Institute of Technology, Stockholm, Sweden. List of papers included in the thesis Paper I Density functional theory calculations of hydrogen bonding energies of drug molecules, L. Bondesson, K. V. Mikkelsen, Y. Luo, P. Garberg and H. ?Agren, J. Mol. Struct. (THEOCHEM) 81, 776 (2006). Paper II Hydrogen bonding effects on infrared and Raman spectra of drug molecules, L. Bondesson, K. V. Mikkelsen, Y. Luo, P. Garberg and H. ?Agren, Spectrochimica Acta A: Mol. Bio. Spectro. 66, 213 (2007). Paper III Solvation of N? 3 at the water surface: the Polarizable Continuum Model approach, L. Bondesson, L. Frediani, H. ?Agren and B. Menucci, J. Phys. Chem. B. 110, 11361 (2006). Paper IV Calculations of the cavitation volumes and partial molar volumes of drugs in water, L. Bondesson and H. W. Hugosson, in preparation. Paper V A linear scaling study of solvent-solute interaction energy of drug molecules in aqua solution, L. Bondesson, E. Rudberg, Y. Luo and P Salek, submitted, 2007 Paper VI Basis set dependence of solvent-solute interaction energy of benzene in water: A linear scaling ab initio study, L. Bondesson, E. Rudberg, Y. Luo and P Salek, submitted, 2007. v Comments on my contribution to the papers included • I was responsible for calculations and for writing of Paper I. • I was responsible for calculations and for writing of Paper II. • I was responsible for calculations and part of writing of Paper III. • I was responsible for calculations and part of writing of the first draft for Paper IV. • I was responsible for calculations and for writing of Paper V. • I was responsible for calculations and for writing of Paper VI. vi