Mimicking the Dissolution Mechanisms of pH‐Responsive Drug Release Formulations in Atomistic MD Simulations

Abstract

AbstractAtomistic molecular dynamics (MD) simulations of poly(acrylic acid) (PAA)‐doxorubicin (DOX) formulations dissolved in water are performed to mimic three common drug release mechanisms of pH‐responsive polymer–drug formulations. The effect of formulation matrix swelling in a reverse manner is mimicked by performing sequential water removal during the MD simulations followed by re‐equilibration, until an amorphous state devoid of water is achieved. Then, MD simulations for different PAA and DOX compositions are performed that mimic the different dissolution stages of an eroding and non‐swellable matrix, respectively. An Arrhenius law dependence of diffusion coefficient is established on the changes in PAA–DOX interaction energy, which in turn shows power law dependence on concentration. Together, the three sets of simulations demonstrate how the molecular‐level interactions (e.g., hydrogen bonding, ionic complexation) drive macroscopic changes in the drug release behavior described in terms of drug/water diffusion coefficients, and also highlight the potential of atomistic simulations in the prediction of drug release behavior of novel polymer–drug formulations using the diffusion coefficients obtained in atomistic simulations.