Molecular dynamics simulations of functional group effects on solvation thermodynamics of model solutes in decane and...

Triglycerides and related fatty acid esters constitute a large percentage of the lipid excipients employed in the development of lipid-based drug formulations. Computer simulations can provide useful information on the structural, dynamic, and thermodynamic properties of these systems and may ultimately be valuable in predicting relative drug solubilities in lipid vehicles. This study utilized all-atom molecular dynamics simulations to explore the solvation of several model solutes in lipid vehicles. First, a combined thermodynamic perturbation and integration approach was employed to calculate functional group contributions to the free energy of transfer from n-decane to tricaprylin for a set of polar substituents attached to the 9-position of anthracene. A scaling factor of 0.79 for all atomic charges in the dry lipid (where the unscaled charges were obtained at the level of the HF/6-31G* basis set) was necessary in order to match the calculated group contributions to the free energies of transfer with their experimental values at 37 degrees C. A second set of simulations was performed in water-saturated tricaprylin containing a single molecule of benzamide to explore the state of organization of solvent molecules, the distribution of water molecules, and the local environment surrounding the solute. Radial distribution functions revealed evidence of local structure in the liquid triglyceride. The dissolved water was found to exist approximately 50% as monomers and 50% as self-associated species. Substantial hydrogen-bonding of benzamide with ester carbonyl oxygen atoms was observed.