Solid–liquid equilibrium and thermodynamic aspects of salicylic acid solubility in ethaline and ethaline-ethanol mixtures

The limited aqueous solubility of many active pharmaceutical ingredients (APIs) remains a major bottleneck in pharmaceutical formulation, process design, and bioavailability optimization. Deep eutectic solvents (DESs) have emerged as promising green alternatives due to their low volatility, tunable physicochemical properties, and high solubilization capacity. This work investigates the solid–liquid equilibrium (SLE) and solubility enhancement of SA and ASA in an ethaline-based DES system (i.e., a mixture of choline chloride and ethylene glycol in a 1:2 molar ratio), as well as in mixed ethaline-ethanol solvents at different ratios. Saturated solutions were prepared using the shake-flask method, ensuring equilibrium through prolonged stirring and thermostatic control. The solubility was determined through UV-vis spectrophotometry at 280 nm, with each measurement performed in triplicate. The results demonstrate that both salicylic acid and acetylsalicylic acid exhibit significantly higher solubility in ethaline–ethanol mixtures than in pure ethaline. At 298.15 K, the solubility of salicylic acid increased from approximately 5.27 g /100 g in ethaline to nearly 24.93 g /100 g in a 1:1 (w/w) ethaline-ethanol mixture, while acetylsalicylic acid showed an increase from about 1.10 g /100 g to 4.88 g / 100 g under the same conditions. This pronounced enhancement is attributed to the combined effects of increased solvent polarity, and modification of the hydrogen-bonding network upon ethanol addition. Ethanol acts as a co-solvent that partially disrupts the strong intermolecular associations within the DES, thereby improving molecular mobility and facilitating stronger solute–solvent interactions. Besides reporting solubility data, this study highlights the relevance of DES-co-solvent systems as tunable and sustainable alternatives for pharmaceutical applications.