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 after their detection in several widely used medications. Regulatory agencies worldwide, including the FDA, EMA and MHLW, have mandated stringent controls and recalls of affected drug products. Sensitive and reliable analytical methods are therefore essential to ensure product quality and patient safety.

Objectives and Study Overview

This study demonstrates the coupling of a Shimadzu GC-2030 gas chromatograph with an LCMS-8050 triple quadrupole mass spectrometer via the Plasmion SICRIT soft ionization source to quantitatively analyze seven nitrosamine compounds, including those targeted by FDA guidelines.

Methodology and Instrumentation

A gas chromatograph GC-2030 was interfaced with an LCMS-8050 using the Plasmion SICRIT soft ionization source, which employs a cold plasma for gentle ionization across a broad polarity range. Experimental details included:

• GC conditions: SH-RTX-5MS column; initial temperature 35 °C (1.5 min), ramped to 100 °C at 10 °C/min, then to 250 °C at 30 °C/min; injector at 270 °C; split ratio 1:10; helium carrier gas at constant linear velocity.
• MS conditions: DL temperature 250 °C; heat block 300 °C; drying gas off; MRM acquisition mode.
• Ionic interface: SICRIT plasma at 1.5 kV and 15 kHz with humidified N₂ make-up gas at 0.5 L/min.
• Standards prepared in dichloromethane at concentrations from 0.2 to 20000 ng/mL; publicly available MRM transitions applied without further optimization.

Results and Discussion

Chromatographic separation of the seven nitrosamines was achieved, although early eluting compounds showed peak shape compromise on the general-purpose column. All analytes were monitored with one quantitative and one or two qualitative MRM transitions. Calibration curves exhibited excellent linearity with R² ≥ 0.998 over relevant concentration ranges. Limits of quantification ranged down to 0.2 pg on column, comparable to dedicated GC-MS systems. The SICRIT source produced spectra dominated by molecular ions and minimal fragmentation, enabling sensitive detection.

Benefits and Practical Applications

• Enables existing LCMS platforms to perform GC-based analyses without major system modifications.
• Soft ionization accommodates a wide variety of chemical structures and polarities.
• Achieves regulatory-compliant sensitivity for nitrosamine quantification using default parameters.

Future Trends and Opportunities

Further optimization of column chemistry and MRM parameters can improve peak shapes and separation. Integration with high-resolution mass spectrometry may facilitate non-targeted screening of unknown impurities. The soft ionization approach can be extended to other volatile and semi-volatile contaminants in pharmaceutical and environmental analysis.

Conclusion

The Plasmion SICRIT soft ionization source effectively bridges GC and LCMS technologies, enabling sensitive, high-throughput quantification of nitrosamine impurities on a single LCMS-8050 instrument without extensive method development.

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