Structure and dynamics of glyceride lipid formulations, with propylene glycol and water

We report on the aggregation and dynamic behavior of excipients in type I and surfactant-free lipid formulations containing water-soluble cosolvents. Specifically we have investigated the internal structure of mixed glyceride formulations, with and without propylene glycol, in the anhydrous state and during dilution into water. We performed molecular dynamics (MD) simulations using GROMACS 3.1.4 (www.gromacs.org) to investigate the aggregation structures and phase changes which would occur on dispersion and dilution of the product in the gastrointestinal tract. MD experiments on mixed glyceride lipid formulations, revealed that they form microstructural features even in the presence of trace amounts of water, typical of what would be anticipated in capsule formulations in practice. These formulations are typically thought of as homogeneous mixtures, a view which has prevailed to some extent because the chemical diversity (chain length and degree of saturation) in excipients derived from vegetable oils prevents analysis of their microstructure by spectroscopic techniques. Our MD simulations suggest that a considerable depth of structure exists in the formulations, and that drugs partition into the various domains under the influence of intermolecular interactions, often dominated in the presence of water by hydrogen bonding. The lipid formulations consist of distinct regions of hydrophobic and hydrophilic character, essentially exhibiting reverse micellar character under low-water-content conditions. MD modeling has great potential as a predictive tool, in particular to identify drugs which may be prone to precipitation on dilution or dispersion of the lipid formulation.