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<p>The detection and quantification of genotoxic impurities, specifically nitrosamines, in pharmaceuticals have garnered high regulatory attention due to their potential carcinogenic effects. This study presents a comprehensive validation of a liquid chromatography with Atmospheric Pressure Chemical Ionization (APCI) Coupled with Triple Quardrapole Analyser (LC-MS/MS) method tailored for the determination of multiple nitrosamine impurities including N-nitrosodimethylamine (NDMA), N-nitroso methyl butyl amine (NMBA), N-nitrosodiethylamine (NDEA), N-nitroso diethyl isopropyl amine (NEIPA), N-nitrosodiisopropylamine (NDIPA), N-nitroso methyl ethyl amine (NMPA), N-nitroso propyl amine (NDPA), N-nitrosopiperidine (NPIP), N-nitrosopyrrolidine (NPYR), and N-nitroso butyl amine (NDBA) in telmisartan tablet formulations. The method was meticulously validated according to the International Council for Harmonisation (ICH) guidelines, focusing on critical parameters such as specificity, accuracy, precision, limit of detection (LOD), limit of quantification (LOQ), and filter compatibility. The specificity of the method was rigorously established, demonstrating unequivocal differentiation between nitrosamine impurities and potential interferences from excipients and active pharmaceutical ingredients (APIs). Recovery studies validated the method’s accuracy, yielding recoveries within the acceptable range of 70–120% across various concentration levels, confirming its reliability for routine analysis. Precision was assessed through the relative standard deviation (RSD) of multiple replicate analyses, with RSD values consistently below the ICH threshold of &lt; 15%, underscoring the method’s reproducibility. Sensitivity assessments revealed exceptional LODs as low as 10.76 ppb and LOQs around 33.00 ppb for several nitrosamines, significantly exceeding current regulatory limits for genotoxic impurities. Evaluations of filter compatibility indicated that both 0.22 µm PVDF and 0.2 µm nylon filters are effective for sample preparation, ensuring the integrity of the analytes during the filtration process. Upon application of the validated method to commercial 40 mg telmisartan tablets, all targeted nitrosamines were undetected, affirming the method’s applicability in routine quality control settings. This work culminates in the establishment of a highly sensitive, specific, and robust LC–MS/MS methodology for the detection of nitrosamine impurities in telmisartan, addressing regulatory concerns while ensuring patient safety. The low detection thresholds provided by this method position it as an invaluable tool for pharmaceutical manufacturers and regulatory bodies, facilitating stringent monitoring and compliance with safety standards, ultimately enhancing the safety profile of medicinal products in the market.</p>

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Chromatographic Separation and Trace Level Quantification of Ten Nitrosamine Genotoxic Impurities in a Single Chromatography Technique through Atmospheric Pressure Chemical Ionization (APCI) Coupled with Triple Quardrapole Analyser in Telmisartan Drug Products

  • 期刊论文

  • 发表日期：

    2025年1月27日

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  • Mehul Pathak,
  • Dhara D. Patel,
  • Dalip Kumar

摘要

The detection and quantification of genotoxic impurities, specifically nitrosamines, in pharmaceuticals have garnered high regulatory attention due to their potential carcinogenic effects. This study presents a comprehensive validation of a liquid chromatography with Atmospheric Pressure Chemical Ionization (APCI) Coupled with Triple Quardrapole Analyser (LC-MS/MS) method tailored for the determination of multiple nitrosamine impurities including N-nitrosodimethylamine (NDMA), N-nitroso methyl butyl amine (NMBA), N-nitrosodiethylamine (NDEA), N-nitroso diethyl isopropyl amine (NEIPA), N-nitrosodiisopropylamine (NDIPA), N-nitroso methyl ethyl amine (NMPA), N-nitroso propyl amine (NDPA), N-nitrosopiperidine (NPIP), N-nitrosopyrrolidine (NPYR), and N-nitroso butyl amine (NDBA) in telmisartan tablet formulations. The method was meticulously validated according to the International Council for Harmonisation (ICH) guidelines, focusing on critical parameters such as specificity, accuracy, precision, limit of detection (LOD), limit of quantification (LOQ), and filter compatibility. The specificity of the method was rigorously established, demonstrating unequivocal differentiation between nitrosamine impurities and potential interferences from excipients and active pharmaceutical ingredients (APIs). Recovery studies validated the method’s accuracy, yielding recoveries within the acceptable range of 70–120% across various concentration levels, confirming its reliability for routine analysis. Precision was assessed through the relative standard deviation (RSD) of multiple replicate analyses, with RSD values consistently below the ICH threshold of < 15%, underscoring the method’s reproducibility. Sensitivity assessments revealed exceptional LODs as low as 10.76 ppb and LOQs around 33.00 ppb for several nitrosamines, significantly exceeding current regulatory limits for genotoxic impurities. Evaluations of filter compatibility indicated that both 0.22 µm PVDF and 0.2 µm nylon filters are effective for sample preparation, ensuring the integrity of the analytes during the filtration process. Upon application of the validated method to commercial 40 mg telmisartan tablets, all targeted nitrosamines were undetected, affirming the method’s applicability in routine quality control settings. This work culminates in the establishment of a highly sensitive, specific, and robust LC–MS/MS methodology for the detection of nitrosamine impurities in telmisartan, addressing regulatory concerns while ensuring patient safety. The low detection thresholds provided by this method position it as an invaluable tool for pharmaceutical manufacturers and regulatory bodies, facilitating stringent monitoring and compliance with safety standards, ultimately enhancing the safety profile of medicinal products in the market.