Two-Step Crystal Dissolution: A Molecular Mechanism to Rationalize Empiric Models of Drug Release from API...

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.