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 transform 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.