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Purpose <p>This study aimed to establish a comprehensive risk assessment strategy for identifying and evaluating nitrosamine drug substance-related impurities (NDSRIs) in fixed-dose combinations of sartans with hydrochlorothiazide (HCTZ). The focus was on both quantifying known nitrosamines and screening novel N-nitroso compounds formed under simulated worst-case nitrosating conditions.</p> Methods <p>A dual-purpose liquid chromatography coupled with triple quadrupole mass spectrometry (LC-TQ/MS) method was developed, one for quantification of eight known nitrosamines and another for screening unknown or newly formed nitrosamines. Forced nitrosation was carried out by incubating five sartan-HCTZ drug products (valsartan, losartan, olmesartan, irbesartan, and telmisartan) with acidic sodium nitrite at 37&#xa0;°C. The method’s sensitivity (LOQ 0.5–1.0 ng/mL), selectivity, and reproducibility were evaluated. In parallel, in silico toxicological predictions using ADMET Predictor were performed to estimate rat TD₅₀ values and assess compound-specific carcinogenic potency.</p> Results <p>The study confirmed formulation-specific formation of nitroso compounds under nitrosating conditions. Notably, irbesartan formed oxime derivatives instead of classical N-nitroso products, as confirmed by MS/MS and <sup>1</sup>H NMR. In silico predictions supported prioritization of detected compounds based on carcinogenic risk, aligning with FDA/ICH acceptable intact limits.</p> Conclusion <p>This integrated analytical and computational workflow provides a scientifically robust framework for early-phase nitrosamine risk assessment and control in combination drug products.</p> Graphical Abstract <p></p>

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Forced Nitrosation as a Tool for Proactive N-Nitrosamine Drug Substance Related Impurities Risk Assessment in Sartans Co-Formulated with Hydrochlorothiazide

  • 期刊论文

  • 发表日期：

    2025年10月20日

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  • Ravi Patel,
  • Ravisinh Solanki,
  • Chhaganbhai Patel

摘要

Purpose

This study aimed to establish a comprehensive risk assessment strategy for identifying and evaluating nitrosamine drug substance-related impurities (NDSRIs) in fixed-dose combinations of sartans with hydrochlorothiazide (HCTZ). The focus was on both quantifying known nitrosamines and screening novel N-nitroso compounds formed under simulated worst-case nitrosating conditions.

Methods

A dual-purpose liquid chromatography coupled with triple quadrupole mass spectrometry (LC-TQ/MS) method was developed, one for quantification of eight known nitrosamines and another for screening unknown or newly formed nitrosamines. Forced nitrosation was carried out by incubating five sartan-HCTZ drug products (valsartan, losartan, olmesartan, irbesartan, and telmisartan) with acidic sodium nitrite at 37 °C. The method’s sensitivity (LOQ 0.5–1.0 ng/mL), selectivity, and reproducibility were evaluated. In parallel, in silico toxicological predictions using ADMET Predictor were performed to estimate rat TD₅₀ values and assess compound-specific carcinogenic potency.

Results

The study confirmed formulation-specific formation of nitroso compounds under nitrosating conditions. Notably, irbesartan formed oxime derivatives instead of classical N-nitroso products, as confirmed by MS/MS and 1H NMR. In silico predictions supported prioritization of detected compounds based on carcinogenic risk, aligning with FDA/ICH acceptable intact limits.

Conclusion

This integrated analytical and computational workflow provides a scientifically robust framework for early-phase nitrosamine risk assessment and control in combination drug products.

Graphical Abstract