Two‐Step Crystal Dissolution: A Molecular Mechanism to Rationalize Empiric Models of Drug Release from API Formulations for Oral Administration

Abstract The kinetics of drug release from molecular crystals is commonly described by the Nernst‐Brunner model created in 1904 – and since then, numerous empirical evidence supporting its suitability as a mathematical approximation has been collected. However, providing mechanistic rationales turned out to be much more complicated. Elaborating on the molecular mechanisms of acid‐induced carbamazepine (CBZ) dissolution, we suggest a molecular simulation case study of “Nernst‐Brunner type” drug release to an aqueous solution featuring an interfacial “diffusion” layer. Mimicking pH = 2, we find drastic protonation of the drug crystallite model, followed by the dissolution of both single CBZH + solutes and fragments of the crystal edges. The latter lead to the release of [CBZH n ] n+ aggregates (with n = 2–8) into the solution, thus fueling a dynamic interplay of different solute species. In some analogy to so‐called two‐step crystal nucleation, we therefore suggest a two‐step crystal dissolution mechanism encompassing solute aggregates within a “dense‐solutes domain”. Within an interfacial region between the crystal and the bulk solvent, such aggregates are suggested as “puffer species” that account for a constant concentration of the fully solvated solute species.