Study of Cycloxaprid Co-crystals: Characterization, Theory Calculation, Solubility, and Stability

Cycloxaprid (CYC) is a potentially commercially available pesticide with high activity, but its further development is limited due to the poor solubility and stability. In this paper, the co-crystallization strategy is applied to improve the physical and chemical properties of CYC for the first time. The cycloxaprid-succinimide (CYC-SM) co-crystal and the cycloxaprid-trifluoromethanesulfonamide (CYC-TS) co-crystal with a stoichiometric ratio of 1:1 between API and co-crystal former were successfully prepared through experimental screening and systemically characterized by powder X-ray diffraction, nuclear magnetic resonance, differential scanning calorimetry, thermogravimetry, Fourier trans- form infrared spectroscopy, and single-crystal X-ray diffraction techniques. The weak interaction of CYC-SM and CYC-TS co-crystals was quantified and analyzed by quantum chemistry calculations. Compared with CYC-TS, the molecular orbital and lattice energy calculation results of CYC-SM show lower chemical reactivity and better stability, which is consistent with the results of solid-state and solution stability tests. The partially weak interaction remained in the solution, and the weakly basic nature of SM and the relatively slow release of CYC from CYC-SM contributed to the promoted solution stability of CYC-SM. In addition, due to the introduction of SM molecules, the solubility of CYC-SM was significantly improved. The CYC-SM co-crystal could be a candidate solid-state form that provides an opportunity for the further development of CYC.