Sensitive Quantification of N-Nitroso Dibutylamine Impurities in Tramadol Tablets Using Optimized LC-MS/MS Method.

Abstract

BACKGROUND: NDBA, a recognized genotoxic and carcinogenic impurity in pharmaceutical products, is employed as a model compound. As a result, regulatory agencies worldwide have imposed stringent testing requirements for Nitrosamine impurities, and there is a demand for sensitive and selective analytical methods for their detection. OBJECTIVE: The purpose of this study was to develop and validate a Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) method for the accurate determination of NDBA impurities in Tramadol tablets, thereby overcoming the limitations of High Performance Liquid Chromatography (HPLC) in identifying low-level impurities. METHODS: Selectivity and sensitivity of the LC-MS/MS method were optimized, and the Limit of Quantitation (LOQ) was set to 5% and the Limit of Detection (LOD) to 3% of the specification limit. The linearity was characterised over a range of 5% to 150% relative to the specification limit. At several concentration levels within the analytical range, the precision and accuracy were determined. RESULTS: In the specified range, the developed method was found to be linear (R² > 0.999). Low relative standard deviation precision studies yielded results consistent with those obtained with this analytical method, and accuracy assessments demonstrated that the method could quantitatively measure NDBA over a range of concentrations. The method was suitable for routine quality control and met and exceeded regulatory performance requirements (LOQ and LOD). DISCUSSION: The developed LC-MS/MS method demonstrated high sensitivity, specificity, and reproducibility for the quantification of NDBA in Tramadol tablets. The method met ICH validation criteria, including acceptable precision (%RSD <5%), strong linearity (r2 = 0.9980), and satisfactory recovery (97.8-115%). The low LOD (0.002 ppm) and LOQ (0.003 ppm) confirm its suitability for detecting trace-level genotoxic impurities, ensuring regulatory compliance and pharmaceutical safety. CONCLUSION: It was established that a validated LC-MS/MS method provides a reliable, sensitive, and selective approach for determining NDBA impurities in Tramadol tablets. The use of this method enables compliance with the most stringent regulatory standards for pharmaceutical product safety and efficacy.

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