Sensitive Detection of Nitrosamines for Drug Quality Control using SICRIT® Soft Ionization-MS

Importance of the Topic

Pharmaceutical nitrosamine impurities are potent carcinogens that pose serious health risks and regulatory challenges. Recent recalls of valsartan and ranitidine products by FDA and EMA underscore the critical need for robust analytical methods capable of detecting trace levels of nitrosamines during drug manufacturing and quality control.

Objectives and Overview

This study aims to demonstrate a sensitive and universal workflow for simultaneous determination of nitrosamine impurities and active pharmaceutical ingredients in a single run. By coupling gas chromatography (GC) with soft ionization mass spectrometry using the SICRIT® plasma source, the approach seeks to outperform traditional GC-MS and LC-MS methods in sensitivity, selectivity, and operational efficiency.

Methodology and Instrumentation

The experimental setup integrates an Agilent 8860 GC system with an Agilent Ultivo Triple Quad MS via the SICRIT® ion source. Key parameters include:

• GC column: RXI-5ms, 30 m × 0.25 mm ID, 0.25 µm film
• Carrier gas: Helium at 2 mL/min
• Injector: splitless, 2 µL injection, 270 °C
• Temperature program: 35 °C (1.5 min), then 10 °C/min to 100 °C, 30 °C/min to 280 °C
• SICRIT® plasma: humidified nitrogen, 1.5 kV, 15 kHz
• MS detection: positive MRM mode using pre-established transitions

Key Results and Discussion

All seven target nitrosamines (NDMA, NDEA, NMEA, NDPA, NDBA, NPYR, NPIP) were resolved chromatographically and ionized as [M+H]+ species. Instrumental limits of detection ranged from 0.1 ng/mL to 1.2 ng/mL (ppt level). Comparative tests with LC-ESI and LC-APCI on real valsartan formulation samples revealed:

• LC-ESI failed to ionize NDMA
• LC-APCI did not detect valsartan
• GC-SICRIT®-MS achieved high signal-to-noise ratios for both NDMA and valsartan in one run

These findings confirm the superior ionization breadth and sensitivity of the SICRIT® soft plasma source for complex drug impurity profiling.

Benefits and Practical Applications

The GC-SICRIT®-MS approach offers:

• Simultaneous analysis of active pharmaceutical ingredients and nitrosamines
• Enhanced sensitivity at trace levels with minimal method development
• Cost and time savings by consolidating separate assays
• Compatibility with existing ESI-based MRM databases for seamless method transfer

Future Trends and Applications

Emerging opportunities include:

• Extension to other classes of genotoxic impurities
• Integration into automated, high-throughput QC pipelines
• Coupling with high-resolution MS for non-targeted screening
• Application in continuous manufacturing and real-time release testing

Conclusion

The presented GC-SICRIT®-MS method demonstrates exceptional performance in detecting trace nitrosamine impurities alongside active drugs in a single analytical run. Its broad ionization capability, high sensitivity, and ease of integration make it a promising universal tool for pharmaceutical quality control.