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<p>Unlike small-molecule nitrosamines, nitrosamine drug substance-related impurities (NDSRIs) exhibit API-specific structural similarity, posing notable analytical challenges because of their close resemblance to the parent drug and related impurities. Rivaroxaban was recently flagged by the European Medicines Agency (EMA) with five concerning NDSRIs, each assigned an acceptable daily intake limit of 1500&#xa0;ng. This threshold is derived from structure–activity relationship analysis and the threshold of toxicological concern. It corresponds to Category 4 under the Carcinogenic Potency Categorization Approach (CPCA), which reflects structural alerts indicative of genotoxic potential.</p><p>To enable rapid and sensitive detection of these trace-level impurities, this study developed and validated a simultaneous analytical method for five NDSRIs in rivaroxaban drug substances and products using liquid chromatography–triple quadrupole-tandem mass spectrometry (LC–TQ-MS/MS).</p><p>Critical method parameters—including chromatographic separation with various column chemistries, gradient elution, and electrospray ionization in positive and negative modes—were carefully optimized. Moreover, sample dissolution solvents and extraction techniques were refined to maximize the recovery of five NDSRIs.</p><p>The method validation, performed per ICH Q2(R2) guidelines, demonstrated excellent linearity (<i>r</i><sup>2</sup> ≥ 0.995 across 10–120&#xa0;ng/mL), high recovery rates (89.1–94.7%), and a lower limit of quantification of 10&#xa0;ng/mL, representing only 10% of the daily intake threshold of the EMA.</p><p>Application to commercial rivaroxaban formulations confirmed the suitability of the method for routine pharmaceutical quality control, supporting regulatory compliance and enhancing drug safety.</p>

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Development and Validation of a Liquid Chromatography–Triple Quadrupole-Tandem Mass Spectrometry-Based Method for the Simultaneous Determination of Five Nitrosamine Drug Substance-Related Impurities in Rivaroxaban

  • 期刊论文

  • 发表日期：

    2025年12月13日

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  • Miyoung Kim,
  • Seohyeon Jung,
  • Jeongmi Lee

摘要

Unlike small-molecule nitrosamines, nitrosamine drug substance-related impurities (NDSRIs) exhibit API-specific structural similarity, posing notable analytical challenges because of their close resemblance to the parent drug and related impurities. Rivaroxaban was recently flagged by the European Medicines Agency (EMA) with five concerning NDSRIs, each assigned an acceptable daily intake limit of 1500 ng. This threshold is derived from structure–activity relationship analysis and the threshold of toxicological concern. It corresponds to Category 4 under the Carcinogenic Potency Categorization Approach (CPCA), which reflects structural alerts indicative of genotoxic potential.

To enable rapid and sensitive detection of these trace-level impurities, this study developed and validated a simultaneous analytical method for five NDSRIs in rivaroxaban drug substances and products using liquid chromatography–triple quadrupole-tandem mass spectrometry (LC–TQ-MS/MS).

Critical method parameters—including chromatographic separation with various column chemistries, gradient elution, and electrospray ionization in positive and negative modes—were carefully optimized. Moreover, sample dissolution solvents and extraction techniques were refined to maximize the recovery of five NDSRIs.

The method validation, performed per ICH Q2(R2) guidelines, demonstrated excellent linearity (r2 ≥ 0.995 across 10–120 ng/mL), high recovery rates (89.1–94.7%), and a lower limit of quantification of 10 ng/mL, representing only 10% of the daily intake threshold of the EMA.

Application to commercial rivaroxaban formulations confirmed the suitability of the method for routine pharmaceutical quality control, supporting regulatory compliance and enhancing drug safety.