Drug leads emerging from high-throughput screening are often highly lipophilic which results in low aqueous solubility and thus unfavourable ADME properties. Since the oral route is by far the most preferred administration, the low and variable absorption of poorly water-soluble drugs (PWSD) may be enhanced through a plethora of formulation strategies, designed to increase drug solubilisation in the gastro-intestinal tract (GIT). In spite of the recent technological advances, the factors affecting absorption of drugs from the GIT and more precisely from bile in the small intestine remain insufficiently understood to permit reliable prediction of in vivo performance.

Molecular dynamics (MD) simulations are the technique of choice to aid in the elucidation of the molecular structure of aggregates, thereby providing an adequate atomistic-scale model of drug dispersion and dynamics. However, the fixed protonation scheme applied in MD is a limitation in the analysis of biomolecular systems, since protonation states of titratable residues directly affects their aggregation behaviour.

This work aims to characterize human bile composition by investigating the phase behaviour of colloidal systems at physiological conditions. Moreover it aims to depict the effect of the changing GIT environmental pH on the colloidal structures formed upon digestion. In the first study, simulations were performed of a ternary system containing digested phospholipid (LPC and oleic acid), bile salt (GDX) and water, with adapted protonation state and ratios according to the simulation pH.  In the second study, MD simulations were run in which cholesterol was added to investigate possible changes in aggregate structure, phase behaviour and phase boundary of the system. Both studies were complemented with experimental results to validate the computational models, thereby contributing to a better understanding of oral drug delivery and the formulation of PWSD.