Molecular Dynamics Insights into Ibuprofen Nanocrystal Dissolution Put in the Context of Classical Nucleation Theory

Molecular dynamics (MD) simulations of ibuprofen nanocrystal dissolution in water reveal that spherical particles below the critical size (e.g., with radius, r = 20 Å) that are metastable, as predicted by classical nucleation theory (CNT), dissociate predominantly through a nonclassical mechanism whereby groups of molecules periodically detach and reattach themselves to the moisture-infiltrated, swollen particle. This behavior leads to oscillations in the dissolution profile and a generally poor fit to the Noyes–Whitney (N–W) equation. Conversely, larger particles (e.g., r = 60 Å), which are predicted to be thermodynamically stable per CNT, are more likely to exhibit classical N–W kinetics on the nanosecond time scale. In either case, crystallinity is lost very rapidly, within the first ∼20 ps of simulation time due to water intrusion into the lattice. For consistency, the single-particle dissolution kinetics are investigated at similar concentrations (ibuprofen/water, ∼17% w/w). Because saturation is expected in the long-time limit due to the poor water solubility of the drug, only the first 10 ns of dissolution time is used to quantitatively assess the kinetics where sink conditions are expected. The H-bonding count between ibuprofen and water molecules in each frame of the output MD trajectory is used as a surrogate measure of the extent of ibuprofen dissolution at each point in time, recognizing that it does not distinguish between particle swelling and the dissociation of ibuprofen molecules (or groups of molecules) from the particle surface. While larger particles appear to obey N–W kinetics, simulations presented herein demonstrate that they prefer to form and maintain interior pockets of water on the time scale of the simulations, rather than to dissolve completely in the traditional sense of that equation. This finding could have implications for the biorelevant dissolution behavior of poorly water-soluble drugs and drug delivery mechanisms of nanocrystal formulations.