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

Significance of the Topic

The presence of carcinogenic nitrosamine impurities in pharmaceutical products poses serious health risks and has led to regulatory recalls. Robust analytical methods are essential to monitor both trace-level nitrosamines and active pharmaceutical ingredients in a single analytical workflow, reducing time, cost, and complexity of quality control.

Objectives and Study Overview

This application note evaluates the performance of a novel GC–soft ionization–MS approach using the SICRIT® plasma source coupled to a triple quadrupole mass spectrometer. The study aims to demonstrate sensitive detection of a range of nitrosamine compounds alongside active drug substances in one run, and to compare ionization efficiency with conventional LC–ESI–MS and LC–APCI–MS methods.

Methodology and Instrumentation

• Instrumentation setup:

• Gas chromatograph: Agilent 8860 GC with RXI-5ms column (30 m × 0.25 mm, 0.25 µm)
• Mass spectrometer: Agilent Ultivo Triple Quad
• SICRIT® plasma ion source: 1.5 kV, 15 kHz with humidified nitrogen
• Carrier gas: Helium at 2 mL/min
• Injector temperature: 270 °C, splitless injection of 2 µL
• Oven program: 35 °C (1.5 min), ramp 10 °C/min to 100 °C, then 30 °C/min to 280 °C

• Analytical approach:

• Analytes: seven nitrosamine standards (NDMA, NDEA, NMEA, NDPA, NDBA, NPYR, NPIP)
• Ionization and detection: positive-mode dynamic MRM monitoring of [M+H]+ transitions
• Calibration: diluted standards to determine limits of detection

Main Results and Discussion

• Chromatographic separation and ionization: all target nitrosamines were resolved and ionized efficiently as protonated molecules.

• Sensitivity: LODs ranged from 0.1 to 1.2 ng/mL (ppt level), confirming excellent trace detection capability.

• Method transfer: MRM transitions established for ESI were successfully applied, facilitating database compatibility.

• Comparative evaluation: GC–SICRIT–MS outperformed LC–ESI–MS and LC–APCI–MS when analyzing NDMA and valsartan. Conventional ESI failed to ionize NDMA, APCI did not detect valsartan, whereas SICRIT ionization delivered highest signal-to-noise for both compounds in a single run.

Benefits and Practical Applications

• Unified workflow: simultaneous analysis of drug substances and nitrosamine impurities without changing instrument configuration.
• Enhanced sensitivity: detection limits in the ppt range support stringent regulatory requirements.
• Cost and time savings: reduced need for separate LC and GC methods for different analyte classes.
• Easy implementation: compatibility with existing MRM databases and minimal method development effort.

Future Trends and Opportunities

• Broader applicability: extension of SICRIT® soft ionization to other trace-level contaminants and drug classes.
• Instrument integration: development of hybrid platforms combining GC-soft ionization and LC modules.
• Automation and miniaturization: inline sampling and micro-GC interfaces for high-throughput screening.
• Advanced data analytics: coupling soft-ionization MS with machine learning for rapid impurity profiling.

Conclusion

GC–SICRIT®–MS provides a highly sensitive, universal approach for pharmaceutical quality control by enabling simultaneous detection of nitrosamine impurities and active drugs in one analytical run. This method streamlines workflows, meets regulatory demands, and offers significant advantages over traditional LC–MS techniques.

Reference

• None