Impact of cocrystal dissolution-supersaturation-precipitation (DSP) behaviour on drug permeation across the PermeaPad® biomimetic barrier

The purpose of this study was to evaluate how the dissolution-supersaturation-precipitation (DSP) behaviour of cocrystals translates into drug permeation , employing the biomimetic PermeaPad® barrier in a side-by-side cell set-up. Building on our previous work, which demonstrated that reducing an unnecessarily high cocrystal solubility advantage (SA = S cocrystal /S drug ) through the generation of non-stoichiometric solution conditions can significantly extend the drug supersaturation, we now investigate this approach in the presence of an absorptive environment. Our findings with the 1:1 ketoconazole (KTZ) - p -aminobenzoic acid (PABA) cocrystal indicate the existence of an optimal SA value (7), where KTZ-PABA dissolution performance resulted in 8-fold AUC increase, translating to a 7-fold increase in cumulative KTZ permeation after 6 hours. This enhancement was achieved by dissolving cocrystal (based on the drug therapeutic dose) with an additional coformer solid phase, rationally designed using a graphical approach grounded in the cocrystal thermodynamic (K sp , S cocrystal , S drug ) and kinetic parameters (σ crit ). The strategy presented in this work can be readily applied during the pre-formulation stage of cocrystal development, enabling targeted selection of coformer concentrations for formulation development. Overall cocrystals offer unique flexibility as a formulation strategy for poorly water-soluble drugs, allowing for tailored DSP behaviour and drug transport over biological barriers based on mechanistic understanding , as demonstrated in this study.