Chemical stabilization strategy for cymoxanil: synthesis and characterization of cocrystals with small organic acids

Abstract

Cymoxanil (CX), an essential fungicide, effectively controls fungal diseases but its environmental instability often leads to decreased efficacy and frequent applications, increasing costs and environmental risks. We propose to address this issue by cocrystal engineering, particularly, utilizing organic small acids as coformers to enhance the stability of CX in alkaline and neutral conditions. This study reports the synthesis of two CX cocrystals with succinic acid (SA) and salicylic acid (SCA). The prepared cocrystals were evaluated using X-ray diffraction, FT-IR spectroscopy, differential scanning calorimetry, thermogravimetric analysis, chemical stability experiment, and solubility and dissolution measurements. Hirshfeld surface analysis was applied to quantify the molecular interactions in CX–SA and CX–SCA cocrystals. Notably, the cocrystals preserve high CX residuals in PBS buffer at pH 5.8 and 8.0 and in pure water after 20 days, demonstrating their ability to enhance chemical stability of CX. The findings related to solubility and dissolution rates further underscore the utility of the cocrystals. This work may facilitate the design of a practical system through the cocrystallization of APIs that exhibit instability or other challenges.