Solvation and aggregation of heteroaromatic drugs in the Reline deep eutectic solvent – a combined molecular dynamics simulation and DFT study

Molecular dynamics (MD) simulation and density functional theory (DFT) analyses were carried out on the solubilization of the heteroaromatic drugs allopurinol, losartan, and omeprazole in reline, which is a deep eutectic solvent (DES) composed of choline chloride/urea in 1 : 2 molar ratio. The aim was to gain a deep understanding of the molecular properties of the different components in the solutions and the dynamic interactions between them. Especially, the impact of hydrogen bonding and π-stacking interactions between rings planes in drug⋯drug interactions leading to unwanted aggregations was carefully evaluated using combined angular/radial distribution functions and also natural bond orbital theory. Addition of the drugs to the DES led to decreased conductivity and diffusion coefficients (ranging from 1.52 to 1.07 × 10^-12 m² s^-1). The effects of the small allopurinol on the DES structure are more pronounced compared with the larger losartan and omeprazole molecules. This is in line with the formation of aggregates, which are markedly smaller for allopurinol (∼2.6 molecules in average) than for omeprazole (∼4.3) and losartan (∼5.5). DFT-calculated dimers of the drug molecules are stabilized by π-stacking with energies ranging from -10 (allopurinol) to -32 kcal mol^-1 (losartan) and show interplanar distances ranging from 0.36 to 0.47 nm. Our observations might pave the way for designing optimized DES for drug delivery.