ScholarWorks@중앙대학교

초록

Mutagenic azido impurities, including azidomethyl biphenyl tetrazole (AZBT) and a losartan-derived azido impurity, have been identified in sartan pharmaceuticals, requiring careful control to safeguard patient health. With the growing use of fixed-dose combinations (FDCs), analytical methods that detect trace impurities in complex drug matrices are required. Nitrosamines are also critical manufacturing by-products, and their concurrent assessment with azido impurities could potentially improve pharmaceutical quality-control efficiency. To provide comprehensive control, a method applicable to FDC monitoring was combined with another for active pharmaceutical ingredient (API) analysis. Two complementary liquid chromatography–tandem mass spectrometry (LC-MS/MS) methods were established: the first quantified AZBT, azidomethyl biphenyl carbonitrile (AZBC), and the Losartan Azido impurity in sartan FDCs, while the second enabled simultaneous measurement of AZBT and N-nitrosodimethylamine (NDMA) in sartan APIs. Both methods were refined from a prior AZBT method by optimizing mobile-phase composition, column selection and ionization conditions, and the sample-preparation workflow was modified to improve reproducibility. Validation according to ICH Q2(R1) assessed the specificity, linearity, accuracy, precision, robustness, and limits of quantification (LOQ). LOQs of 0.005–0.05 μg/g were obtained for the FDC azido impurities, 0.007–0.02 μg/g for AZBT, and 0.03–0.1 μg/g for NDMA in the APIs, meeting regulatory thresholds. Recoveries ranged from 94.5 to 116.3 %, with intra- and inter-day precisions ≤5.8 % relative standard deviation. Applicability was demonstrated across 15 FDC and API products for azido impurities and nine API samples for simultaneous AZBT/NDMA determination. These complementary LC-MS/MS methods provide reliable tools for controlling mutagenic impurities in sartan-based pharmaceuticals and support regulatory compliance.

키워드