Glyceride lipid formulations: Molecular dynamics modeling of phase behavior during dispersion and molecular interactions between drugs and excipients

Little is known about the microstructure of lipid-based formulations, or how their structure changes as they disperse in the lumen of the gastrointestinal tract. We used molecular dynamics (MD) simulation to study such formulations at the molecular level as they interact with water during dispersion. We studied a simple lipid formulation, by itself and in the presence of drugs. The formulation contained mono- and di-lauroyl glycerides at 0-75 (w)/(w) water. Acyclovir, danazol, hydrocortisone, ketoprofen or progesterone, were included to investigate their dynamic behavior and localization during dispersion. Micro-structuring of the formulation was evident at all water concentrations. As the water content increased, the microstructure evolved from a continuous phase containing isolated water molecules, to a reverse micellar solution and finally to a system containing lamellar lipids with large pools of free water. Drugs partitioned into the aqueous and lipid domains principally under the influence of hydrogen bonding and hydrophobic interactions. Drugs located preferentially to the interfaces between water and lipid where they are able to make both hydrophobic and hydrophilic interactions. Molecular dynamics simulations offer an unprecedented view of the structure of lipid-based formulations and has considerable potential as an in silico tool for formulators.