Determination of six nitrosamine impurities in angiotensin II receptor blocker drugs by LC-MS/MS

Significance of the topic

Carcinogenic nitrosamine impurities in angiotensin II receptor blockers (ARBs) have triggered widespread recalls and supply shortages. Their toxic potential at trace levels makes robust analytical methods essential to safeguard patient safety and ensure regulatory compliance.

Objectives and study overview

The primary goal was to develop and validate a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for simultaneous quantitation of six nitrosamines (NDMA, NDEA, NEIPA, NDIPA, NDBA, NMBA) in valsartan drug substance and drug product at sub-ppm concentrations.

Methodology and instrumentation

The sample preparation and analysis workflow included:

• Extraction of API or tablet powder in methanol and centrifugation.
• Reverse-phase separation on a solid-core C18 column (2.6 μm F5, 100 × 4.6 mm) at 40 °C with a formic acid–water/methanol gradient.
• Detection by Thermo Scientific Vanquish Flex LC coupled to TSQ Quantis triple quadrupole MS with APCI source.
• Quantitation via selected reaction monitoring (SRM) and comparison against mixed nitrosamine standards.

Key results and discussion

The validated method achieved limits of quantification (LOQs) down to 0.0025 ppm (0.25 ng/mL) for four analytes and 0.010 ppm for NDMA and NMBA, exceeding USFDA sensitivity requirements by 3–10×. Linearity was established from LOQ to 100 ng/mL (R²>0.99). Precision at LOQ yielded %RSD <5 and recoveries between 96 and 103% for all six compounds. System suitability criteria, including blank interference (<5% of standard peak) and retention time drift (<2%), were met consistently.

Benefits and practical applications of the method

This LC-MS/MS approach offers high throughput, minimal sample preparation, and simultaneous multi-analyte detection. It can be extended to other ARB drugs and manufacturing intermediates, facilitating routine quality control and forensic investigations of nitrosamine contamination.

Future trends and potential applications

Advances in high-resolution mass spectrometry and miniaturized chromatography may further lower detection limits and reduce analysis time. Emerging workflows could integrate automated sample handling and real-time monitoring, supporting continuous production quality assurance in pharmaceutical manufacturing.

Conclusion

The developed TSQ Quantis LC-MS/MS method delivers rapid, sensitive, and precise quantitation of six nitrosamine impurities in valsartan with LOQs well below regulatory limits. Its robustness and adaptability make it a valuable tool for pharmaceutical laboratories aiming to control carcinogenic contaminants and comply with global safety standards.

References

• U.S. FDA. Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) Method for the Determination of Six Nitrosamine Impurities in ARB Drugs.
• U.S. FDA. Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Method for the Determination of NDMA in Ranitidine Drug Substance and Solid Dosage Drug Product.