Hollow fiber liquid-phase microextraction based on restricted-access alkyl carboxylic acid–hexafluoroisopropanol supramolecular solvent for the determination of antiarrhythmic drugs in human plasma

Alkyl carboxylic acid–HFIP SUPRAS was developed as an ideal extractant for HF-LPME. • Reversed micellar SUPRAS forms with low HFIP and is stable at low salt levels. • Hollow fiber and restricted-access SUPRAS synergistically reduce matrix effects. • Multiclass antiarrhythmic drugs in human plasma are detected by LC-MS/MS. • Low solvent/sample consumption and an AGREEprep score of 0.5 ensure eco-friendliness. An alkyl carboxylic acid–hexafluoroisopropanol (HFIP) supramolecular solvent (SUPRAS) was developed as a restricted-access solvent for hollow fiber liquid-phase microextraction (HF-LPME) and applied to the determination of seven antiarrhythmic drugs (mexiletine, propranolol, diltiazem, amlodipine, propafenone, verapamil, and amiodarone) in human plasma. SUPRAS formation required only a low HFIP dosage (<10%, v /v for alkyl carboxylic acid ≤4%, w / v ) and was minimally affected by low ionic strength (NaCl <50 mM) or low organic solvent content (methanol <5%, v /v). The SUPRAS consisted of reversed micellar aggregates with hydrophobic outer surfaces and hydrophilic inner cavities. The SUPRAS exhibited restricted-access behavior, efficiently excluding macromolecular proteins (extraction efficiency <18.3%, solubility <4.5 mg mL −1 ) via the synergistic effects of protein denaturation/flocculation induced by HFIP and octanoic acid and size exclusion by the SUPRAS matrix. After systematic optimization, the proposed method coupled with high-performance liquid chromatography-tandem mass spectrometry demonstrated acceptable analytical performance. Satisfactory linearity was achieved, with correlation coefficients ranging from 0.9903 to 0.9997. Method limits of detection (S/N = 3) ranged from 0.01 to 0.10 μg L −1 , while method limits of quantification (S/ N  = 10) were 0.03–0.33 μg L −1 . Acceptable recoveries were obtained for spiked samples (86.5–126.6%), with only two analytes slightly exceeding 130% at the low concentration level, and intra- and inter-day precisions were below 19.3%. Owing to the combined microfiltration capability of the hollow fiber and the restricted-access properties of the SUPRAS, the method exhibited manageable matrix effects (70.6–132.5%) and eliminated the need for a separate protein precipitation step, while consuming only 25 μL of SUPRAS per extraction. Greenness assessment using AGREEprep software yielded a score of 0.5, confirming satisfactory eco-friendliness and sustainability. This SUPRAS-HF-LPME method is simple, efficient, and environmentally benign, serving as a promising pretreatment and quantification strategy for antiarrhythmic drugs in complex human plasma matrices. Download: Download high-res image (265KB) Download: Download full-size image