Mechanistic Elucidation of Pharmaceutical Partitioning into Hydrophobic Deep Eutectic Solvents in Microfluidic Liquid–Liquid Extraction

Abstract Understanding the molecular mechanisms governing pharmaceutical partitioning is essential for developing effective liquid–liquid extraction systems. Conventional green solvent batch extraction methods are limited by mass transfer throughput and operational discontinuity. Herein, a continuous-flow poly(dimethylsiloxane) (PDMS)-based microfluidic device was developed for liquid–liquid microextraction of ciprofloxacin and fluconazole using two DL-menthol–fatty acid-based hydrophobic deep eutectic solvents (HDESs). The influence of flow rate, residence time, and the DES/water mass ratio on extraction efficiency was evaluated. The microfluidic platform achieved higher extraction efficiencies of 89% and 75% for ciprofloxacin and fluconazole, respectively, using DL-menthol:decanoic acid (1:1) DES with a DES/water mass ratio of 1:1. Density functional theory (DFT) and molecular dynamics (MD) simulations were employed to elucidate the molecular mechanisms governing drug partitioning into DL-menthol:decanoic acid (1:1) and DL-menthol:dodecanoic acid (2:1) HDESs. Interaction energies, radial, spatial, and combined distribution functions, hydrogen bonding, noncovalent interactions (NCI), and diffusional behavior were analyzed. The findings revealed that the drug partitioning is governed by a collaborative network of hydrogen bonding (O–H···N) involving the hydroxyl/carboxyl groups of the HDES components and van der Waals dispersion interactions. The mean squared displacement (MSD) profiles further indicated reduced molecular mobility of the drug molecules within the DES-rich microenvironment, while the trajectory analysis revealed the hydrophobic nature of the DES phase. Overall, the combined experimental and molecular analysis provides mechanistic insights into drug partitioning in HDESs and illustrates how molecular interactions influence extraction performance under microfluidic liquid–liquid extraction conditions.