An Efficient Workflow to Access Cocrystal Eutectics across a Wide Solubility Range and Evaluate Determinants of Cocrystal Solubility

Abstract Pharmaceutical cocrystals offer a promising strategy to improve the performance of solubility-limited drug candidates, but determining the total equilibrium cocrystal solubility (SCC,T) remains challenging for highly soluble and potentially highly desirable cocrystals prone to solution-mediated phase transformations. This work establishes a material-efficient approach to access eutectic compositions and to determine SCC,T across cocrystals with a broad range of coformer solubilities, using only drug and coformer solubility information and targeted experiments, avoiding resource-intensive trial-and-error experiments. Ten naringenin cocrystals, spanning a wide range of coformer-to-drug solubility ratios (SCF,T/SD,T), were evaluated in biorelevant media. For five highly soluble and kinetically unstable cocrystals (SCF,T/SD,T > 5000), eutectic compositions were successfully achieved using a predissolving coformer strategy, enabling the determination of key cocrystal solution parameters, mainly the apparent solubility product, cocrystal solubility, and solution stability. The coformer concentration required to reach the eutectic point was cocrystal-dependent and strongly correlated with SCF,T/SD,T (R2 = 0.955), enabling an a priori estimation of the eutectic point and minimizing the experimental burden and API consumption. Across the resulting broad range in SCC,T, only a modest log−log correlation with SCF,T/SD,T was observed, indicating coformer solubility alone is an insufficient predictor of cocrystal solubility. Exploratory multivariate analyses showed coformer solubility, lattice energetics, coformer lipophilicity, and drug-coformer intermolecular interactions collectively provided improved descriptive performance over coformer solubility alone. Overall, this work provides a practical and efficient approach for rationally accessing eutectic conditions and determining cocrystal solubility with limited material across cocrystals with diverse solubilities. This study lays the groundwork to expand the SCC,T database and better establish coformer−cocrystal performance relationships to anticipate cocrystal solution performance and support the rational selection of coformers for pharmaceutical cocrystal design.