Characterization of Loratadine API and Simultaneous Quantification of Seven Potential Genotoxic Nitrosamine Impurities in Single Method by LC-MS/MS in Loratadine API and its Dosage Forms

Abstract

Active pharmaceutical ingredients (APIs) of loratadine were characterized using spectroscopic methods such as infrared spectroscopy, mass spectroscopy, differential scanning calorimetry (DSC), 1H NMR, 2D nuclear magnetic resonance (2D-NMR) and 13C NMR. Nitrosamine impurities, which are considered under concern cohort according to the S2 FDA and ICH M7 guidelines, are highly genotoxic and their trace-level quantity must be controlled in drugs for safe human consumption. In this study, an ultra-sensitive, rapid and simple LC-MS/MS technique is developed to detect seven nitrosamine impurities (N-nitroso dimethylamine (NDMA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitroso diethylamine (NDEA), N-nitroso ethyl isopropylamine (NEIPA), N-nitroso diisopropylamino (NDIPA), N-nitroso methyl phenylamine (NMPA) and N-nitroso dibutylamine (NDBA) in loratadine drug) with potential genotoxicity. Chromatographic separation was attained by employing the Zorbax SB C18 of 150 × 3 mm and a column of 3.5 μ with 0.1% formic acid in water and methanol as mobile phases A and B, respectively. At the total run time of 20 min, the flow rate was 0.3 mL/min in the gradient mode of elution. Through multiple reaction monitoring (MRM), all the seven nitrosamine impurities were successfully ionized and then quantified in the positive mode of atmospheric pressure chemical ionization (APCI). The method was validated according to the ICH guidelines by estimating quantification and detection limits. For all the seven nitrosamine impurities, the method provided excellent S/N ratios with a high linearity range of 0.8-5.30 ppm for loratadine sample concentrations with a regression coefficient of >0.99. The recovery for the method was established with a protocol of three-step sample preparation and was satisfactory within 15-115%. The proposed method can be employed for the routine detection of nitrosamines in loratadine APIs and its doses.