Choosing Co-Crystal Partners for Plant-Derived Drug Candidates Using Molecular Complementarity, Solid-State Interactions, Solubility Gain, and Developability Constraints

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Co-crystallization has emerged as a promising strategy to enhance the physicochemical properties of plant-derived drug candidates, which often suffer from poor aqueous solubility and limited oral bioavailability. The selection of an appropriate co-crystal partner is a critical step that directly influences the success of co-crystal formation and the developability of the final solid form. This study proposes a systematic framework for choosing co-crystal partners for plant-derived drug candidates by integrating molecular complementarity, solid-state interactions, solubility gain, and developability constraints. Molecular complementarity was assessed through hydrogen-bonding capability, functional group matching, and molecular shape compatibility between the drug and potential co-formers. Solid-state interactions were evaluated using crystal packing analysis, interaction energy calculations, and thermal and spectroscopic characterization. Solubility gain was predicted and experimentally verified through equilibrium solubility studies, while developability constraints including stability, toxicity, regulatory status, and manufacturing feasibility were considered to ensure practical applicability. The proposed approach was applied to several plant-derived drug candidates, and the results demonstrated that a balanced combination of complementarity and solid-state interaction criteria leads to more reliable co-crystal partner selection. The framework provides a rational and efficient tool for screening co-formers, reducing trial-and-error experiments, and accelerating the development of co-crystalline formulations with improved solubility and developability for plant-derived drugs.