Simultaneous Enhancement of Thermal Stability and Preferred Isomer Enrichment in Difenoconazole: the Dual Facets of Cocrystal Engineering

The challenge of increasing the proportion of dominant isomers and poor thermal stability in pesticides significantly impacts their bioavailability, production, and application. This study addresses these issues by forming cocrystals of the low-melting-point and chiral fungicide, difenoconazole (DZ), with the two coformers succinic acid (SA) and fumaric acid (FA). The cocrystals were characterized by powder and single-crystal X-ray diffraction, nuclear magnetic resonance (1H NMR) spectra, high-performance liquid chromatography (HPLC) analysis, Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and hot-stage microscopy. Quantum chemical calculations were employed to systematically quantify and analyze the interactions of the DZ-SA and DZ-FA cocrystals. The melting points of DZ-SA and DZ-FA cocrystals are markedly elevated to 116 and 126 °C respectively, compared to DZ (80 °C), with no premelting thermal decomposition observed, denoting notable thermal stability for solid agrochemicals. Excitingly, it was established through 1H NMR and HPLC that higher proportions of cis-DZ are involved in the formation of DZ-SA and DZ-FA cocrystals, which are approximately twice that in commercial DZ, signifying successful enrichment of the preferred isomers of DZ. These results suggest that the cocrystallization of APIs is simultaneously useful for isomer enrichment and thermal stability enhancement in fungicides.