Context <p>The drug solubilization is still a significant challenge in pharmaceutical research. This study examined the sigma-surface, sigma-profile, and sigma potential of 35 water insoluble drugs using deep eutectic solvents (DES) made up of a strong hydrogen bond acceptor (HBA) choline chloride (ChCl) and several hydrogen bond donors (HBDs) at the molecular level. The combinations of ChCl and 75 HBDs include acid (C1-C10), alcohol (C1-C10), aldehyde (C1-C10), amide (C1-C10), amine (C1-C10), ester (C2-C10), ether (C2-C10), and ketone (C3-C10). Analysis showed that the presence of HBD and HBA in the drugs has an impact on solubility, as ChCl has shown better interaction with drugs that contain the donor groups such as carboxyl (-COOH), amino (-NH₂), and hydroxyl (-OH) due to their strong hydrogen-bonding ability, high polarity, and large hydrogen-bond networks. These results show that acid, alcohol, and amide-based DESs can be potential carriers for poorly soluble drugs and the necessity of understanding their physiochemical characteristics to maximize solubility.</p> Methods <p>COSMOthermX (Version: 19.0.5) and TURBOMOLE (TmoleX21.0.1) were utilized to gather and process the data presented here. Turbomole was used for COSMO simulations to evaluate solvation effects at various levels and characteristics as input for the COSMOtherm software. Geometry optimizations were performed using density functional theory (DFT) at the BP86 (Becke–Perdew) functional level with the triple zeta valence polarization (TZVP) basis set. COSMO files were created using the BP_TZVP_19.ctd parameterization in COSMOthermX (version 19.0.5).</p>