Development of dispersive inclusion complex microextraction for the analysis of nitrosamines in medicinal products

Abstract

A new dispersive inclusion complex microextraction (DICM) approach coupled with ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for the determination of n-nitrosamine impurities in different medicinal products is demonstrated for the first time. The proposed DICM procedures consist of a dispersive liquid phase microextraction steps employing cyclodextrin as an inclusion complex agent to extract n-nitrosamines namely N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N-ethyl-N-nitrosoisopropylamine (NEIPA) and N-nitroso-di-n-butylamine (NDBA) present in the medicinal products. The sample solutions were prepared by mixing 5% (m/v) NaCl solution with 1.5 mM β-cyclodextrin and 20 mM sodium dodecyl sulphate to form a stable inclusion complex and subsequently extracted into dichloromethane as an extraction solvent. The enriched solution was reconstituted into aqueous solution prior to UPLC-MS/MS analysis. The method showed good linearity in the range of 0.036–1 ng/mL with a correlation coefficient of at least 0.995, acceptable reproducibility (RSD 0.5–5.8%, n=5), low limits of detection (0.011–0.018 ng/mL), and satisfactory relative recoveries (96–105%). The results obtained were found to be at least 10-fold more sensitive comparable to those obtained using validated direct sample dissolutions coupled with UPLC-MS/MS approach.