Quantification of Nitrosamine Impurities in Sartan Drugs Using an Agilent GC/TQ with Hydrogen Carrier Gas

Importance of the topic

The quantification of nitrosamine impurities in sartan drugs is critical due to their carcinogenic potential and strict regulatory limits. Concurrently, helium supply constraints have driven laboratories to explore hydrogen as a GC carrier gas. While hydrogen offers faster separations and improved chromatographic resolution, its reactivity with analytes necessitates thorough evaluation to maintain accurate identification and quantification.

Objectives and study overview

This application note assesses hydrogen carrier gas performance for eight nitrosamine impurities (NDMA, NMEA, NDEA, NEIPA, NDIPA, NDPA, NDBA, NPIP) in valsartan, irbesartan, losartan, and olmesartan. Two Agilent GC/TQ configurations—a 7010 Series with a high-efficiency ion source (HES) and a 7000E with the HydroInert source—were compared against helium-based methods. Key metrics included spectral fidelity, calibration linearity, sensitivity, repeatability, recovery, and long-term stability.

Methodology and instrumentation

Sample preparation involved weighing 500 mg of drug substance, spiking with NDMA-d6 internal standard in dichloromethane, vortex mixing, centrifugation, and filtration into GC vials. Calibration standards ranged from 0.3 to 50 ng/mL. Analyses were performed in dynamic MRM mode on:

• Agilent 8890 GC coupled to a 7010 Series GC/TQ with HES
• Agilent 8890 GC coupled to a 7000E GC/TQ with HydroInert source

Separation used a J&W VF-WAXms capillary column (60 m × 0.25 mm, 0.25 µm) with optional midcolumn backflush. Data acquisition and management utilized MassHunter Acquisition 13.0 and OpenLab ECM XT for compliance and workflow optimization.

Main results and discussion

Spectral match scores against NIST exceeded 90 for the HES and 80 for HydroInert using hydrogen. Calibration curves exhibited R2 > 0.99 with LOQs at or below 0.03 ppm, meeting regulatory guidelines. Switching between helium and hydrogen over six months showed consistent spectral fidelity, ion ratios, and sensitivity. In a 150-injection sequence, peak area RSDs were < 10% and concentration RSDs < 7%. Midcolumn backflush delivered stable retention times and peak areas over 100 consecutive runs.

Benefits and practical applications

Hydrogen carrier gas reduces dependence on helium, shortens analysis time, and maintains analytical performance. The validated method reliably quantifies nitrosamines at required LOQs, and backflush capability prolongs column life and minimizes maintenance.

Future trends and possibilities

Extending hydrogen-based GC/MS to other trace contaminants and complex matrices will broaden its application in pharmaceutical and environmental analysis. Ongoing improvements in ion source designs will enhance compatibility, and deeper integration with laboratory informatics will further streamline data management and regulatory compliance.

Conclusion

This study demonstrates that hydrogen is a viable carrier gas alternative for GC/TQ analysis of nitrosamine impurities in sartan drugs. Both HES and HydroInert sources preserve spectral integrity, meet sensitivity requirements, and sustain long-term stability, supporting resilient laboratory workflows amid helium shortages.

References

1. Food and Drug Administration. Control of Nitrosamine Impurities in Human Drugs: Guidance for Industry, 2021.
2. Agilent Technologies. EI GC/MS Instrument Helium to Hydrogen Carrier Gas Conversion Guide, 2020.
3. Miles et al. EPA TO-15 Analysis Using Hydrogen Carrier Gas and the Agilent HydroInert Source, 2022.
4. Quimby & Andrianova. VOC Analysis in Drinking Water with Hydrogen Carrier Gas, Agilent application note, 2022.
5. Quimby et al. PAH Analysis with Hydrogen Carrier Gas and HydroInert Source, Agilent application note, 2023.