Cocrystal Solubility Advantage and Dose/Solubility Ratio Diagrams: A Mechanistic Approach To Selecting Additives and...

Two of the main questions regarding cocrystal selection and formulation development are whether the will be stable and how fast can it dissolve the drug dose. Dissolving the drug dose may require cocrystals with a high solubility advantage over drug (SA = S_CC/S_D), but these may have limited potential to sustain drug supersaturation. Thus, we propose a twofold approach to mitigate the risk of drug precipitation by optimizing thermodynamic (SA) and kinetic factors (nucleation inhibitors). This risk can be evaluated by considering the cocrystal SA and drug dose/solubility ratio (D_0D = C_dose/S_D), which in tandem represent the maximum theoretical supersaturation that a cocrystal may generate, the driving force for drug precipitation, and the potential for dose-/solubility-limited absorption. cocrystals with SA and D_0D values above critical supersaturation are prone to rapid precipitation, often negating their utility as a solubility enhancement tool. This work presents a mechanistic approach to controlling the dissolution-supersaturation-precipitation behavior of cocrystal systems, whereby relationships between SA, D_0D, and the drug-solubilizing power of surfactants (SP_D = S_D,T/S_D,aq) are used to fine-tune cocrystal-inherent supersaturation by rational additive selection. Experimental results with danazol-vanillin cocrystal demonstrate how SA, D_0D, and SP_D are key thermodynamic parameters to understanding the kinetic cocrystal behavior and how the risks of cocrystal development may be mitigated through the mechanistic formulation design.