Determination of 18 nitrosamine impurities in sartan drug products using gas chromatography coupled with high-resolution Orbitrap mass spectrometry (GC-HRMS)

Importance of the Topic

The detection of trace nitrosamine impurities in sartan pharmaceuticals is critical due to their classification as probable human carcinogens. Regulatory agencies worldwide mandate stringent monitoring of these genotoxic compounds to ensure patient safety and product compliance.

Objectives and Study Overview

This study aimed to develop a straightforward, rapid quantitative assay for eighteen nitrosamine impurities in telmisartan and losartan finished drug products. The approach leverages full-scan high-resolution accurate mass (HRAM) gas chromatography–mass spectrometry (GC-HRMS) on the Thermo Scientific™ Orbitrap Exploris™ GC platform.

Methodology

Sample preparation followed EP 2.5.42 guidelines: tablets were pulverized, then 250 mg API equivalent was extracted with an alkaline acetonitrile–water mixture spiked with NDMA-D6 internal standard. The procedure involved vortex mixing, dichloromethane partitioning, centrifugation, and filtration.

Instrumentation

• GC system: Thermo Scientific™ TRACE™ 1610 with splitless injection on TraceGOLD™ TG-624 column (30 m×0.25 mm×1.4 µm).
• Ion source: Thermo Scientific™ ExtractaBrite™ EI, 30 eV, 240 °C.
• Mass analyzer: Orbitrap Exploris™ GC operating at 60 000 FWHM over 40–300 m/z in full-scan mode.
• Data system: Thermo Scientific™ Chromeleon™ CDS.

Main Results and Discussion

Chromatographic separation of all eighteen nitrosamines was achieved within a 15-minute runtime. The use of 30 eV electron energy enhanced ion yield. Limits of detection (LOD) ranged from 0.1 to 0.3 ng/mL, and limits of quantitation (LOQ) from 0.3 to 1 ng/mL (2.8–7.6 ng/g sample), well below the 30 ng/g regulatory threshold. Calibration exhibited excellent linearity (R² > 0.995) over 0.25–10 ng/mL. Recovery studies at four spike levels (3–30 ng/g) yielded 70–130% with RSDs below 20%, confirming method accuracy and precision. Blank and unspiked extracts showed negligible nitrosamine background.

Benefits and Practical Applications

The method offers rapid, high-throughput analysis with minimal sample cleanup and robust trace-level detection. Full-scan HRAM acquisition allows simultaneous targeted quantitation and non-targeted retrospective screening of unknown impurities, making it valuable for routine quality control and impurity profiling.

Future Trends and Perspectives

• Broader adoption of HRMS for multi-class impurity analysis in pharmaceuticals.
• Integration of advanced data mining for retrospective identification of emerging contaminants.
• Implementation of gas-saving modules and green analytical workflows.
• Automation and high-throughput platforms to support regulatory compliance in large product portfolios.

Conclusion

The developed GC-HRMS method on the Orbitrap Exploris GC platform delivers sensitive, precise, and rapid quantitation of eighteen nitrosamine impurities in sartan drug products, meeting regulatory requirements and enabling efficient routine and investigative analyses.

References

1. ICH M7(R1), Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals. March 2017.
2. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 89, 2006.
3. USP General Chapter 1469, Nitrosamine Impurities, 2022.
4. Schlingemann J. et al. Int. J. Pharm. 620:121740 (2022).
5. FDA Guidance, Combined NDMA/NDEA Assay by GC/MS-Headspace (Jan 2019).
6. FDA Guidance, Direct Injection NDMA/NDEA by GC/MS (Dec 2018).
7. FDA Guidance, GC-MS/MS Assay for NDMA, NDEA, NEIPA, NDIPA, NDBA (Apr 2019).
8. FDA Guidance, HS-GC-MS/MS for NDMA, NDEA, NEIPA, NDIPA (Apr 2019).
9. European Pharmacopoeia 10.6, Chapter 2.5.42, N-Nitrosamines in Active Substances.
10. Thermo Fisher TN-001218, GC Carrier Gas Conservation, 2022.
11. Thermo Fisher SL001585, Carrier Gas Conservation for Nitrosamine Analysis, 2022.
12. Thermo Fisher AN10753, Nitrosamine Determination in Metformin by GC-MS, 2021.
13. ICH Q2(R1), Validation of Analytical Procedures, 2005.