Cocrystal Strategy for Modulating Solubility, Dissolution, and Biological Activity of Triflumezopyrim: Preparation, Characterization, and Theoretical Calculations

The cocrystal strategy holds promise in enhancing the advantages of pesticides by modulating properties, such as stability and solubility. Triflumezopyrim is a crucial insecticide for managing resistant rice hoppers. Thus, enhancing its biological activity is crucial for reducing the dosage. In this study, nine triflumezopyrim cocrystals were successfully prepared and characterized by powder X-ray diffraction (PXRD), Fourier transform infrared (FT-IR), and thermal analysis, with the crystal structures of six novel cocrystals determined via single-crystal X-ray diffraction (SCXRD). Their stability, dissolution rate, and aqueous solubility were systematically evaluated. Cocrystallization with naphthoic acid derivatives led to reduced solubility, whereas hydroxybenzoic acid derivatives enhanced solubility to varying extents. These solubility trends were interpreted by using solvation free energy and lattice energy calculations. Notably, biological assays against Nilaparvata lugens revealed that the cocrystal of triflumezopyrim with 6-hydroxy-2-naphthoic acid exhibited significantly enhanced insecticidal activity compared to pure triflumezopyrim, with a relative activity index of 338.94. This study highlights the potential of cocrystal engineering to simultaneously modulate solubility, dissolution behavior, and bioactivity, providing a promising direction for the further development of triflumezopyrim formulations.