A Critical N-Nitrosamine Impurity of Anticoagulant Drug, Rivaroxaban: Synthesis, Characterization, Development of LC–MS/MS Method for Nanogram Level Quantification
2022
Baksam, Vijaya Kumar | Saritha, Nimmakayala | Devineni, Subba Rao | Jain, Mohit | Kumar, Prashanth | Shandilya, Sanjeev | Kumar, Pramod
BACKGROUND AND PURPOSE: The product recall for detecting unacceptable levels of carcinogenic potential N-nitrosamine impurities has been a severe apprehension in recent years. The regulatory agencies issued guidelines for the pharmaceutical industries to monitor nitrosamine impurities in the drug products. In the present study, we have been developed a robust, simple and sensitive ultra-high-performance liquid chromatography (UHPLC) coupled with mass spectrometry (LC–MS/MS) method for the determination of possible N-nitrosamine impurity, N-(2-hydroxyethyl)-N-phenylnitrous amide in the drug molecule, Rivaroxaban at nanogram level. METHODS: Chromatographic experiments were optimized on VD-Spher100 C18 E (150 mm × 4.6 mm, 3 μm) column, mobile phase flow was operated in isocratic mode using 0.1% aqueous formic acid and methanol in the ratio of 1:1 (v/v) with a flow rate of 0.6 mL/min, and column oven temperature maintained at 40 °C. The developed method was validated by following Q2(R1) International Conference on Harmonization” (ICH) guidelines. RESULTS: The limit of detection (LOD) and quantification (LOQ) of this N-nitrosamine impurity was 0.045 ng mL⁻¹ and 0.15 ng mL⁻¹, respectively. The accuracy and precision of the method were found well within the specified range. In addition, the synthesis and characterization details of N-nitrosamine impurity, N-(2-hydroxyethyl)-N-phenylnitrous amide were provided. CONCLUSIONS: The developed method was applied well to determine N-nitrosamine impurity in bulk-scale samples of Rivaroxaban, revealing that the method could be worthwhile to use in the analysis of pharmaceutical dosage forms.
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