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

Abstract

The solubility of caffeine in aqueous binary mixtures was measured in five aprotic proton acceptor solvents (APAS) including dimethyl sulfoxide, dimethylformamide, 1,4-dioxane, acetonitrile, and acetone. The whole range of concentrations was studied in four temperatures between 25 °C and 40 °C. All systems exhibit a strong cosolvency effect resulting in non-monotonous solubility trends with changes of the mixture composition and showing the highest solubility at unimolar proportions of organic solvent and water. The observed solubility trends were interpreted based on the values of caffeine affinities toward homo- and hetero-molecular pairs formation, determined on an advanced quantum chemistry level including electron correlation and correction for vibrational zero-point energy. It was found that caffeine can act as a donor in pairs formation with all considered aprotic solvents using the hydrogen atom attached to the carbon in the imidazole ring. The computed values of Gibbs free energies of intermolecular pairs formation were further utilized for exploring the possibility of using them as potential solubility prognostics. A semi-quantitative relationship (R2 = 0.78) between caffeine affinities and the measured solubility values was found, which was used for screening for new greener solvents. Based on the values of the environmental index (EI), four morpholine analogs were considered and corresponding caffeine affinities were computed. It was found that the same solute–solvent structural motif stabilizes hetero-molecular pairs suggesting their potential applicability as greener replacers of traditional aprotic proton acceptor solvents. This hypothesis was confirmed by additional caffeine solubility measurements in 4-formylmorpholine. This solvent happened to be even more efficient compared to DMSO and the obtained solubility profile follows the cosolvency pattern observed for other aprotic proton acceptor solvents.

New Screening Protocol for Effective Green Solvents Selection of Benzamide, Salicylamide and Ethenzamide

“…It is quite reasonable to ignore this parameter since PCOP is associated with the photochemical degradation in the atmosphere, which seems to be less important considering quite low volatility of DMSO and the absence of leaks in the technological equipment. Such simplification was already postulated [ 40 , 55 ]. Since, water is the most environmentally friendly solvent (EI = 0.02), with an increase in its proportion, the “green” potential of used solvents increases.…”

“…However, there is very little research on its solubilizing properties. A very few examples that can be found in the literature is solubility studies on methane, hydrogen sulfide, carbon dioxide [ 125 ], ethane [ 126 ], propane [ 127 ], and caffeine [ 55 ]. For this reason, it is worth exploring the solubility of benzamide and also other studied aromatic amides in 4FM and their mixtures with water.…”

“…Hence, theoretical screening enabling the rational selection of the most promising candidates seems indispensable. Unfortunately, despite great efforts [ 18 , 33 , 40 , 45 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ], there is no universal and reliable way of predicting solubility in binary aqueous solutions from the molecular structure. Methods developed for proper back-computations of measured solubility data such as Jouyban-Acree, van’t Hoff-Yaws, Wilson, Apelblat, Buchowski-Ksiazczak and Non-Random Two Liquid (NRTL) are interesting from the thermodynamic interpretation viewpoint [ 45 , 61 , 62 , 63 , 64 ], however rather of limited applicability as screening tools.…”

“…Methods developed for proper back-computations of measured solubility data such as Jouyban-Acree, van’t Hoff-Yaws, Wilson, Apelblat, Buchowski-Ksiazczak and Non-Random Two Liquid (NRTL) are interesting from the thermodynamic interpretation viewpoint [ 45 , 61 , 62 , 63 , 64 ], however rather of limited applicability as screening tools. Hence, the first principle approaches seem to be attractive, even if prediction accuracies are only semi-quantitative or qualitative [ 55 , 65 , 66 ] Among many of them the COSMO-RS methodology [ 67 ], is a very powerful tool applied for predicting various physicochemical properties using exclusively information of the chemical formula. In addition to many molecular affinity-related properties such as activity coefficients [ 68 , 69 ], equilibrium constants [ 70 , 71 , 72 ], cocrystals and solvates screening [ 10 , 11 , 67 , 73 , 74 , 75 , 76 , 77 ], phase diagrams [ 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 ], solubility in neat and multicomponent solvents [ 18 , 33 , 40 , 45 , 55 , 61 , 74 , 88 , 89 , 90 , 91 , 92 , 93 , ...…”

“…Hence, the first principle approaches seem to be attractive, even if prediction accuracies are only semi-quantitative or qualitative [ 55 , 65 , 66 ] Among many of them the COSMO-RS methodology [ 67 ], is a very powerful tool applied for predicting various physicochemical properties using exclusively information of the chemical formula. In addition to many molecular affinity-related properties such as activity coefficients [ 68 , 69 ], equilibrium constants [ 70 , 71 , 72 ], cocrystals and solvates screening [ 10 , 11 , 67 , 73 , 74 , 75 , 76 , 77 ], phase diagrams [ 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 ], solubility in neat and multicomponent solvents [ 18 , 33 , 40 , 45 , 55 , 61 , 74 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 ], solubility parameters estimation [ 96 , 97 , 98 , 99 ] and partition coefficients [ 92 , 100 ,…”