Coupling of GC and LCMS Systems via SICRIT Soft Ionization Source for Sensitive Detection of Nitrosamines

Significance of the topic

The presence of nitrosamine impurities in pharmaceuticals has become a critical safety concern following global recalls of drugs such as sartans, ranitidine and metformin. Regulatory bodies including the US FDA, EMA and MHLW emphasize sensitive, reliable assays to detect trace levels of these carcinogenic compounds in drug products.

Objectives and Study Overview

This study demonstrates the coupling of a gas chromatograph (Shimadzu GC-2030) to a triple quadrupole LC–MS (Shimadzu LCMS-8050) using the SICRIT® soft ionization source. The aim is to establish a quantitative method for seven nitrosamines, including NDMA, NDEA and NDBA, using minimal instrument optimization and default conditions.

Methodology and Used Instrumentation

Experiments employed:

• Shimadzu GC-2030 gas chromatograph
• Shimadzu LCMS-8050 triple quadrupole mass spectrometer
• Plasmion SICRIT® Soft Ionization Source with humidified N₂ makeup gas (0.5 L/min) and plasma settings (1.5 kV, 15 kHz)
• SH-RTX-5MS GC column (30 m × 0.25 mm, 0.25 µm)

Key GC conditions: split ratio 1:10, injector 270 °C, helium carrier (40.5 cm/s linear velocity), temperature program from 35 °C to 250 °C. MS acquisition in MRM mode employed publicly available transitions without further tuning. Calibration standards ranged from 0.2 to 20 000 ng/mL in dichloromethane, injected at 1 µL.

Main Results and Discussion

The seven nitrosamines were baseline separated with clear MRM chromatographic peaks. Early-eluting compounds showed some peak broadening due to the general-purpose column. Calibration curves for each analyte were linear (R² ≥ 0.998) over 0.2–2000 pg on column, meeting FDA criteria. Limits of quantitation ranged from 0.2 to 2.0 pg. Molecular ions predominated in spectra, indicating minimal fragmentation and high sensitivity.

Benefits and Practical Applications

• Soft ionization across polar and nonpolar nitrosamines yields intact molecular ions, aiding unambiguous identification.
• Achieved LOQs comparable to dedicated GC–MS/MS methods without extensive method development.
• Flexible interface allows laboratories with existing LC–MS platforms to perform GC analyses without dedicated GC–MS systems.

Future Trends and Applications

Advances may include optimized GC columns for early eluters, expanded screening of other volatile impurities and integration with high-resolution MS for non-targeted analysis. The soft-ionization approach could be extended to trace-level monitoring in food safety, environmental testing and metabolomics.

Conclusion

The SICRIT® soft ionization source effectively bridges GC and LC–MS workflows, enabling sensitive, selective quantitation of nitrosamines with minimal optimization. This hybrid approach offers an efficient alternative for pharmaceutical impurity testing using existing LC–MS infrastructure.

References

1. FDA U.S. Food & Drug Administration. Combined Direct Injection N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) Impurity Assay by GC/MS.
2. Shimadzu Application News AD-0199. Determination of Nitrosamine Impurities in Sartan Drug Products by GC-MS/MS Method.