Cocrystal Solubility Advantage Diagrams as a Means to Control Dissolution, Supersaturation, and Precipitation

Cocrystals are often more soluble than needed and pose unnecessary risks for precipitation of less soluble forms of the drug during processing and dissolution. Such conversions lead to erratic cocrystal behavior and nullify the cocrystal solubility advantage over parent drug (SA = S-cocrystal/S-drug). This work demonstrates a quantitative method for additive selection to control cocrystal disproportionation based on cocrystal solubility advantage (SA) diagrams. The tunability of cocrystal SA is dependent on the selective drug-solubilizing power of surfactants (SPdrug = (S-T/S-aq)(drug)). This cocrystal property is used to generate SA-SP diagrams that facilitate surfactant selection and provide a framework for evaluating how SA influences drug concentration-time profiles associated with cocrystal dissolution, drug supersaturation, and precipitation (DSP). Experimental results with indomethacin-saccharin cocrystal and surfactants (sodium lauryl sulfate, Brij, and Myrj) demonstrate the log-linear relationship characteristic of SA-SP diagrams and the dependence of sigma(max) and dissolution area under the curve (AUC) on SA with characteristic maxima at a threshold supersaturation where drug nucleation occurs. This approach is expected to streamline cocrystal formulation as it facilitates additive selection by considering the interplay between thermodynamic (SA) and kinetic (DSP) processes.