Optimization, thermodynamic characteristics and solubility predictions of natural deep eutectic solvents used for sulfonamide dissolution.

The limited water solubility of sulfonamides provokes a search for new solvents offering not only increased solubility but also environmental and health safety. Therefore, six sulfonamides were studied in a series of natural deep eutectic solvents (NADES) comprising choline chloride with multi-hydroxyl compounds. Experimental screening aimed at finding the optimized NADES composition revealed that unimolar proportion of choline chloride and glycerol offers the highest solubility advantage, equal up to 43 times compared with water at 37 °C. Besides, quantum chemistry computations based on the COSMO-RS protocol were conducted in order to gain an insight into the thermodynamic characteristics of the systems and to explain the origin of the observed solubility increase. It was found that the factor responsible for the solubility gain in NADES are the interactions between choline chloride and sulfonamide drug molecules, having the highest affinities expressed in terms of Gibbs free energy of corresponding reactions. Finally, utilizing the obtained results together with artificial neural networks led to a perfect match between experimental and predicted solubility, documented by the mean absolute percentage error value below 2.5%. The developed protocol seems to be so general and accurate that screening of potential new API-NADES systems can be significantly simplified.