Investigation of Carcinogenic Impurities of N-Nitrosamines in Sartan Pharmaceutical Products Marketed in Brazil: Development and Validation of Method Based on High-Performance Liquid Chromatography-Tandem Mass Spectrometry.

N-nitrosamines (NA) impurities have unexpectedly been found in sartan products, angiotensin II receptor antagonists that are used to control hypertension, representing an urgent concern for industry, global regulators and for the patients. In this study, an HPLC-MS/MS method was developed and validated for the quantification of six NA (N-nitrosodimethylamine, N-Nitroso-N-methyl-4-aminobutyric acid, N-Nitrosodiethylamine, N-ethyl-N-nitroso-2-propanamine, N-nitroso-diisopropylamine and N-nitroso-di-n-butylamine) in losartan, valsartan, olmesartan, irbesartan, candesartan and telmisartan products. The method was validated in terms of sensitivity, linearity, accuracy, precision, robustness and stability. The limits of quantification were 100, 31.25, 250, 33, 312.5 and 125 µg kg-1 in losartan, valsartan, olmesartan, irbesartan, candesartan and telmisartan samples, respectively, which met the sensitivity requirements for the limits set by Food and Drug Administration of the United States. The standard curves showed good linearity. The recoveries ranged from 93.06 to 102.23% in losartan matrix, 83 to 85.9% in valsartan, 96.1 to 101.2% in olmesartan, 89.2 to 97.5% in irbesartan, 93.4 to 132.0% in candesartan and 62.3 to 106.2% in telmisartan matrix. The other parameters met the validation criteria, the good sensitivity and precision, high accuracy and simple and fast analysis provides a reliable method for quality control of NA in sartan pharmaceutical products. The developed method was successfully applied for the determination of N-nitrosamines in 71 sartan products marketed in Brazil.

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.