DSPindex guides dose selection to extend drug supersaturation lifetime during cocrystal dissolution

Abstract

Synchronising both cocrystal dissolution and drug precipitation processes is the key for the development of cocrystal systems with desired dissolution-supersaturation-precipitation (DSP) behaviours. Our findings with ketoconazole (KTZ) − p-aminobenzoic acid (PABA) 1:1 cocrystal show that this can be achieved by generating non-stoichiometric coformer concentrations that allow us to modulate the maximum theoretical cocrystal supersaturation SA (thermodynamic limit) below the drug critical supersaturation σ_crit (kinetic limit). The application of our conceptual graphical approach combined with the two metrics SA and the DSP_index answer the question of how much additional coformer is needed to target optimal sustained drug supersaturation levels. Modulating SA < σ_crit and DSP_index > 1 allowed for a stable and sustained KTZ release system with supersaturation levels of 6 by 24 h. Findings provide a direct approach for better early decisions regarding cocrystal dose design and/or coformer concentration to be added to formulations to ultimately fine-tune drug supersaturation by coupling dissolution and precipitation processes.