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.

Keywords: COSMO-RS; NADES; methylxanthines; solubility; theobromine.

Figure 1

Structural formula of theobromine.

Figure 2

FTIR-ATR spectra of theobromine sediments obtained in selected solvents.

Figure 3

Solubility of theobromine at 25 °C, expressed as its mole fraction, in ten neat organic solvents and water. Black circles represent measurements of this work, while gray crosses indicate values published by Zhong et al. [94].

Figure 4

Solubility of theobromine at 25 °C, expressed as its mole fraction, in binary solvents comprising water and five different organic solvents in varying compositions. On the abscissa, $x_2^{*}$ represents the mole fractions of organic solvent in solute free binary solutions.

Figure 5

Mole fraction solubility of theobromine determined in water-free natural deep eutectic solvents at 25 °C. All designed solvents were prepared in unimolar proportions. For comparison, the solubilities in neat DMSO and 1:1 dioxane-water mixture were highlighted.

Figure 6

Solubility profile of theobromine at 25 °C in mixtures comprising NADES successfully diluted with water. On the abscissa, ${\mathrm{x}}_{\mathrm{NADES}}^{*}$, represents values of the mole fractions of natural deep eutectic solvent in aqueous solutions. For comparison purposes solubility in DMSO + water was plotted as a function of $x_2^{*}$ (gray line).

Figure 7

Excess solubility values of theobromine ($x_1$) dissolved in aqueous binary mixtures at room temperature. On abscissa, $x_2^{*}$ denotes solute free mole fraction of the organic solvent.

Figure 8

Excess solubility values of theobromine ($x_1$) dissolved in aqueous ternary mixtures formed at room temperature. On abscissa, $x_2^{*}$ denotes solute free mole fraction of the 1:1 NADES in aqueous formulations.

Figure 9

Correlation between experimental and computed values of theobromine solubility.

Figure 10

The electron density distribution of the most representative complexes of theobromine with water.

Figure 11

The electron distribution of the most representative complexes of theobromine with selected aprotic solvents.

Figure 12

The electron distribution of the most representative complexes of theobromine with choline chloride and glycerol.

Figure 13

The values of interaction parameter H^int used in COSMO-RS-DARE computations of theobromine solubility in aqueous binary mixtures of organic solvents at room temperature.

Figure 14

The values of interaction parameter H^int used in COSMO-RS-DARE computations of Theobromine solubility in aqueous ternary NADES systems at room temperature.