Evaluation of 11 ionic liquids as potential extraction solvents for benzodiazepines from whole blood using liquid-liquid microextraction combined with LC-MS/MS

Ionic liquids (ILs) are becoming a trending topic in sample preparation technology, due to their low volatility, low flammability and tunable physiochemical properties. The latter affords the opportunity for creating task-specific solvents. In toxicology, these tailored ILs were not introduced yet; however, they can be significant for drug extraction purposes. This study screens 11 commercially available ILs as potential extraction media for benzodiazepines from blood samples via liquid-liquid microextraction, coupled to liquid chromatography - tandem mass spectrometry (LC-MS/MS). Structure-extraction relationships were deducted from recovery and matrix effect results (n = 5), allowing us to devise some of the favorable features in a tailored IL for benzodiazepine extraction. Overall, long alkyl chains are to be avoided, as they may sterically hinder desirable π-stacking interactions. For the same reason, aromatic planar cations, as imidazolium and pyridinium, were more effective in comparison with ammonium and pyrrolidinium. Furthermore, viscosity negatively impacted both recoveries and matrix effects. High viscosities limited mass transfer during dispersion and impeded electrospray ionization processes. In conclusion, this study evaluates which physicochemical features an IL should possess to efficiently extract benzodiazepines from whole blood.