Experimental and Theoretical Study on Theobromine Solubility Enhancement in Binary Aqueous Solutions and Ternary Designed Solvents

Abstract

The solubility of theobromine was studied both experimentally and theoretically. The solubility was determined spectrophotometrically at 25 °C in neat organic solvents, aqueous binary mixtures, Natural Deep Eutectic Solvents (NADES) and ternary NADES mixtures with water. It was found that addition of water in unimolar proportions with some organic solvents increases theobromine solubility compared to neat solvents. Additionally, using NADES results in a solubility increase of the studied compound not only in relation to water but also DMSO. The addition of water (0.2 molar fraction) to NADES is responsible for an even larger increase of solubility. The measured solubilities were interpreted in terms of three theoretical frameworks. The first one—belonging to the set of data reduction techniques—proved to be very efficient in quantitative back-computations of excess solubility of theobromine in all studied systems. The default approach utilizing the well-recognized COSMO-RS (Conductor-like Screening Model for Real Solvents) framework offered at most a qualitative solubility description. The extended search for possible contacts provided evidence for the existence of many intermolecular complexes that alter the electron density of the solute molecule, thus influencing solubility computations. Taking into account such intermolecular contacts by using the COSMO-RS-DARE (Conductor-like Screening Model for Realistic Solvation-Dimerization, Aggregation, and Reaction Extension) framework seriously increased the accuracy of solubility computations.

Application of the Solute–Solvent Intermolecular Interactions as Indicator of Caffeine Solubility in Aqueous Binary Aprotic and Proton Acceptor Solvents: Measurements and Quantum Chemistry Computations

“…Detailed results of this comparison can be found in Table S2 in Supplementary Materials , where the mole fractions of caffeine in various solvents at different temperatures were presented together with relative differences between datasets. This analysis, supported by the fact that the results obtained for the two other methylxanthines [ 1 , 2 ] match literature data, suggest the adequacy of the method used in the study.…”

“…Particularly interesting are the results of caffeine extraction from spent coffee grounds using cholinium-based ionic liquids [ 72 ]. Our research team has previously published the results of theophylline and theobromine solubilized in natural deep eutectic solvents utilizing choline chloride [ 1 , 2 ] and similar results regarding caffeine will follow.…”

“…Intermolecular interactions of caffeine were modeled using an advanced quantum chemistry level including electron correlation corrections and zero-point vibrational energy ZPE. The computational protocol follows an already presented methodology [ 2 , 78 , 79 , 80 , 81 ] and here only a brief summary is provided. It is assumed that the solute–solvent affinity between constituents of considered binary solvents can be expressed, as the first approximation, in terms of corresponding reactions of pair formation, namely X + Y = XY, where X and Y stand either for solute or solvent molecules.…”

“…Methylxanthines, belonging to a broad range of alkaloids, are an interesting group of compounds experiencing significant pharmacological activity. From the perspective of the pharmaceutical industry, there are three most important compounds in this category, namely theophylline (1,3-dimethylxanthine) [ 1 ], theobromine (3,7-dimethylxanthine) [ 2 ] and caffeine (1,3,7-trimethylxanthine). Methylxanthines are abundant in nature residing in tea and other plant leaves, coffee and cocoa beans, as well as cola seeds [ 3 ].…”

Experimental and Theoretical Screening for Green Solvents Improving Sulfamethizole Solubility

“…Application of aqueous mixtures, replacing hazardous organic solvents, is one of the main strategies. Alternatively, natural deep eutectic solvents (NADES) have also been applied [12,[20][21][22][23][24][25][26] for this purpose. In general, many multicomponent liquid mixtures, such as NADES [27][28][29][30][31][32], ionic liquids [30,[33][34][35], and organic solvent mixtures [36][37][38] are considered as promising green solvents.…”