Development of prothioconazole solvates by prediction and experiment to enhance solubility and stability

Propiconazole has a large number of potential hydrogen bond sites, indicating easy formation of solvates with many solvents. Developing different solvates of PRO is essential to enhance physicochemical property. In this study, by using model prediction and screening procedures, we screened out several solvates and solvent-free forms of PRO in different solvent systems. The COSMO-RS model has been applied to predict the potential of PRO to form solvates with different types of solvent molecules, and the results showed that the hydrogen bond donor (HBD) type solvents have a preference to form solvates with PRO molecules. Inspired by this, systematically screening experiments were carried out with different crystallization methods for the generally employed HBD type and hydrogen bond acceptor (HBA) type solvents, respectively. The outcomes of experiment verified the accuracy of the prediction. Two anhydrous crystalline forms and three solvates of PRO were obtained and systematically characterized with powder X-ray diffraction, Fourier transform infrared spectroscopy, thermal analysis and Hirshfeld surfaces analysis. Furthermore, four crystal structures were determined by single-crystal X-ray diffraction, including the metastable Form I and two solvates were solved for the first time. Finally, we compared the solubility of different solvates and solvent-free forms in different solvents, and rationalized the reasons for the discrepancy in solubility and stability by detailed molecular structure and stacking pattern analysis. This provides a certain reference for the efficient screening of solvent used in the development of solvates.