Thymol-Based Hydrophobic Deep Eutectic Solvents as a Green Approach for Screening Polar Nitrosamines in Sartans Pharmaceutical Products by Ultrasound-Assisted Dispersive Liquid-Liquid Microextraction Combined with HPLC-DAD

Nitrosamines are carcinogens substances firstly detected in sartans drugs in 2018, leading to new regulations and monitoring programmes that raised the costs and challenges to the pharmaceutical industry. Therefore, reliable and cost-effective methods for screening nitrosamines in medicines are highly desirable. Hydrophobic deep eutectic solvents (HDES), a novel "eco-friendly" alternative to solvents commonly used in microextraction techniques, can meet these requirements. In this study, a simple and rapid method of ultrasound-assisted dispersive liquid-liquid microextraction using thymol-based HDES followed by HPLC-DAD detection was developed for the determination of n-nitrosodimethylamine (NDMA) and n-nitroso-n-methylamino butyric acid (NMBA) from candesartan, irbesartan, losartan, olmesartan, telmisartan and valsartan drug substances, and from losartan tablets. Various influencing factors (such as HDES type, HDES:sample ratio, salt addition and sample pH) were investigated. Best extraction efficiencies were achieved with thymol:benzyl alcohol HDES. Under optimal conditions, the linearities ranged from 15 to 1000 ng mL-1 for both NDMA and NMBA (R² > 0.99), with recoveries between 81.8-104.2% and precision from 0.2 to 14.6%. The limits of detection were 17.3 - 220.0 ng g-1 and 16.3 - 290.0 ng g-1 for NDMA and NMBA, consecutively. Finally, the proposed method was successfully applied in spiked sartans drug substances and in losartan potassium tablets collected in the market.