Molecular dynamics of drug crystal dissolution: simulation of acetaminophen form I in water

In order to gain molecular level understanding of drug dissolution into aqueous media, we report the first molecular dynamics (MD) simulation of a drug crystal dissolving. The simulation was performed for acetaminophen crystal Form I dissolving in 0.15 M aqueous NaCl solution at 37 °C. The 10 ns simulation revealed interesting details of the dissolution process. Dissolution of the molecules from the crystal surface is far from a random process. On the contrary, the order in which molecules enter the solution depends on their initial positions in or on the crystal. Molecules located on the corners and edges dissolved first followed by those located on {100}, {010}, and {001) surfaces with slight variation. This corner and edge effect that has been observed in our real dissolution experiment conducted under polarized light microscope was successfully predicted at molecular scale by the MD simulation. Further analyses identified the underlying mechanism: the differences in the molecular interaction energetics between the drug and water molecules. The molecules located on corners and edges of the parallelepiped crystal are not as tightly bound to their surrounding neighbors as those located in other positions, but they are more strongly interacting with the surrounding water molecules. The extent of molecular release is strongly correlated with the interplay between interaction forces with solvent molecules and with other drug molecules in the crystal lattice. These findings, especially the significant "corner and edge effect", will help us gain additional fundamental understanding in the relationship between dissolution rate and particle size and morphology and, thus, are very relevant in the context of particle size reduction in delivering poorly water-soluble compounds. This study has also demonstrated that MD simulation is a powerful tool in studying dissolution phenomena.