Hypothesis
Solubilization is a fundamental process that underpins various technologies in the pharmaceutical and chemical industry. However, knowledge of the location, orientation and interactions of solubilized molecules in the micelles is still limited. We expect all-atom molecular dynamics simulations to improve the molecular-level understanding of solubilization and to enable its in silico prediction.
Methods
The solubilization of six drugs in intestinal mixed micelles composed of taurocholate and dioleoyl phosphatidylcholine was simulated by molecular dynamics in explicit water and measured experimentally by liquid chromatography. The location and orientation of the solubilized drugs were visualized by cumulative radial distribution functions and interactions were characterized by radial distribution function ratios and hydrogen bonding.
Findings
A new simulation-derived parameter was defined, which accounts for drug-micelle and drug-water interactions and correlates (R2 = 0.83) with the experimentally measured solubilization. Lipophilicity was found to govern the location of all drugs in the micelle (hydrophobic core, palisade layer or on the surface), while hydrogen bonding was crucial for orientation and solubilization of two of the molecules. The study demonstrates that explicit, hydrogen bond-forming water molecules are vital for accurate prediction of solubilization and provides a comprehensive framework for quantitative studies of drug location and orientation within the micelles.