Analyzing Nitrosamines with Hydrogen Carrier Gas: GC/MS/MS Analysis of Nitrosamines in Sartan Drugs

Importance of the Topic

The analysis of nitrosamine impurities in sartan drug substances and products is critical for patient safety and regulatory compliance. Rising concerns over helium scarcity and cost have driven interest in alternative carrier gases such as hydrogen. Evaluating hydrogen for GC/MS/MS workflows addresses both supply challenges and potential chemical reactivity of nitrosamines under hydrogen conditions.

Objectives and Study Overview

This study examines the suitability of hydrogen as a carrier gas for the quantification of eight nitrosamine impurities (NDMA, NMEA, NDEA, NEIPA, NDIPA, NDPA, NDBA, NPIP) in valsartan, irbesartan, losartan, and olmesartan APIs. Key aims include comparing spectral match quality, chromatographic performance, linearity, detection limits, repeatability, and long-term stability against conventional helium methods.

Methodology

Sample preparation involved weighing 500 mg of drug substance, spiking with an NDMA-d6 internal standard solution (~50 ng/mL), vortexing, centrifugation, and filtration of the organic phase into GC vials. GC parameters used pulsed splitless injection, a temperature program from 40 °C to 250 °C, and mid-column backflushing when using hydrogen. The method applied both 30 m and 60 m VF-WAXms columns depending on carrier gas, with constant gas flow rates (1 mL/min H2 or 1.2 mL/min He).

Instrumentation Used

• Agilent 8890 GC with 7000E or 7010 Triple Quadrupole MS
• HES and HydroInert ion sources
• VF-WAXms capillary columns (30 m×0.25 mm×0.25 µm and 60 m×0.25 mm×0.25 µm)
• MassHunter 13 software for acquisition and Quantitative analysis
• OpenLab ECM XT for data management and compliance

Results and Discussion

• Library match scores with hydrogen exceeded 90% on the HES source and 80% on HydroInert, comparable to helium performance.
• Calibration was linear across 0.1–50 ng/mL with detection limits as low as 3 ng/mL for all analytes.
• Signal-to-noise ratios at the lowest calibration levels met or exceeded regulatory S/N criteria (>10).
• Injection repeatability over 150 consecutive runs showed area RSDs below 10% and concentration RSDs below 7%.
• Switching between helium and hydrogen over a six-month period maintained consistent retention times, ion ratios, and match scores.

Benefits and Practical Applications

Adopting hydrogen carrier gas offers faster separations, improved chromatographic resolution, and reduced dependency on a limited helium supply. The validated method meets pharmacopeial requirements and supports routine quality control of sartan drugs.

Future Trends and Applications

Further applications may include expanding hydrogen-based methods to other drug classes, implementing real-time monitoring with automated sampling, and integrating advanced data analytics for rapid impurity screening. Ongoing improvements in ion source design and column chemistry will enhance sensitivity and robustness.

Conclusion

The Agilent 7000E and 7010 GC/TQ systems with HydroInert and HES sources demonstrate that hydrogen can replace helium without sacrificing performance. This approach provides a reliable, cost-effective solution for nitrosamine analysis in pharmaceutical QC.

References

1. Agilent Technologies. EI GC/MS Instrument Helium to Hydrogen Carrier Gas Conversion, User Guide publication number 5994-2312EN, 2020.