Quantification of Caffeine Interactions in Choline Chloride Natural Deep Eutectic Solvents: Solubility Measurements and COSMO-RS-DARE Interpretation

Abstract

Solubility of active pharmaceutical ingredients is an important aspect of drug processing and formulation. Although caffeine was a subject of many studies aiming to quantify saturated solutions, many applied solvents suffer from not being environmentally friendly. This work fills this gap by presenting the results of solubility measurements in choline chloride natural deep eutectic solvents, ccNADES, comprising one of seven of the following polyalcohols: glycerol, sorbitol, xylitol, glucose, sucrose, maltose and fructose. The ratio of ccNADES components was optimized for maximizing caffeine solubility at room temperature. Additionally, temperature dependent solubility was measured for the first four systems exhibiting the highest solubility potential, both in their neat forms and in mixtures with water. Results were used for intermolecular interactions assessments using the COSMO-RS-DARE approach, which led to a perfect match between experimental and computed solubility values. An important methodological discussion was provided for an appropriate definition of the systems. Surprising linear trends were observed between the values of fitting parameters and water-ccNADES composition. In addition, comments on selection of the values of the fusion thermodynamic parameters were provided, which led to the conclusion that COSMO-RS-DARE solubility computations can effectively compensate for the inaccuracies of these important physicochemical properties.

Computational screening for prediction of co-crystals: method comparison and experimental validation

“…However, we note that none of the implementations reproduces exactly the experimentally measured solubilities. Similar observations have been reported by Jeliński et al 100,101 where they compared the calculated caffeine solubilities in neat and binary solvents with the available experimental data and found that the solubility of caffeine in some of these solvents is not well captured. The absence of fusion data poses an additional hurdle in predicting solubilities using COSMO-RS.…”

“…Therefore, predicting solubilities in these systems using COSMO-RS becomes challenging and less reliable due to the reliance on fusion data for accurate predictions. 101 Although accurate solubility estimations via COSMO-RS simulation packages are not easily achieved, we can nonetheless use fast and efficient computational screening of solvents to limit candidate solvents for a given API and immediately rule out the solvents with very unfavorable solubility across multiple predictive approaches. The solubility of caffeine in selected solvents ranked by three COSMO-RS implementations is shown in Fig.…”

Intermolecular Interactions of Edaravone in Aqueous Solutions of Ethaline and Glyceline Inferred from Experiments and Quantum Chemistry Computations

“…There is an additional interesting aspect worth emphasizing. According to our earlier studies [ 53 , 54 , 55 ], the addition of water to the DES systems may improve the solubility of active pharmaceutical ingredients even more compared to neat eutectic systems. Therefore, the best-performing compositions for both studied DES systems were chosen for further experiments and used in mixtures with water in different proportions.…”

Solubility of dapsone in deep eutectic solvents: Experimental analysis, molecular insights and machine learning predictions

“…[40][41][42] The DES have proven to have the ability to significantly increase the solubility and bioavailability of many active pharmaceutical ingredients. [43][44][45] Also our research group has successfully demonstrated the usefulness of using DES for the dissolution of many active substances, including sulfonamides, 46 curcumin, 47 caffeine, 48 and edaravone. 49 Therefore, it seems natural to apply DES in the case of DAP.…”