Quantitation of 6 Nitrosamines in 5 Sartans by LC-MS/MS system as per the proposed USP General Chapter <1469>

Significance of the Topic

Accurate quantification of nitrosamine impurities in sartans is essential to ensure patient safety and meet stringent regulatory requirements. These compounds, classified as probable human carcinogens, must be controlled below defined acceptable intake limits under USP General Chapter <1469>.

Study Objectives and Overview

The study aimed to develop and validate a single LC-MS/MS method for simultaneous determination of six nitrosamines (NDMA, NMBA, NDEA, NEIPA, NDIPA, NDBA) in five sartan APIs (Olmesartan, Telmisartan, Irbesartan, Losartan, Valsartan) using the Shimadzu LCMS-8045 system, following procedure 3 of the proposed USP <1469>.

Instrumental Setup and Methodology

Ultra-high-performance liquid chromatography (UHPLC) Nexera™ XS equipped with a Raptor ARC-18 column (150 × 3.0 mm, 2.7 µm) at 60 °C was used. An APCI interface on the LCMS-8045 triple quadrupole mass spectrometer enabled rapid polarity switching and ultra-fast scanning. Six nitrosamines and four deuterated internal standards were monitored by MRM transitions. Mobile phases consisted of 0.1% formic acid in water (A) and methanol (B) with a multi-step gradient at 0.5 mL/min. Sample preparation involved vortex extraction, centrifugation, filtration, and direct injection (20 µL). A divert valve routed API peaks to waste to protect the MS.

Main Results and Discussion

Calibration curves over nine concentration levels showed excellent linearity (R² > 0.99) for all six analytes. Limits of quantitation ranged from 0.66 to 15.66 ppb with signal-to-noise ratios supporting sensitive detection well below 0.03 ppm. Repeatability at LOQ (n = 6) yielded RSD < 25%. Spike recovery studies in each sartan matrix at LOQ levels demonstrated recoveries between 70% and 130%, meeting USP acceptance criteria. Representative chromatograms confirmed clear separation and quantification of target nitrosamines without interference from API peaks.

Benefits and Practical Applications

• One-run quantification method for six nitrosamines in multiple sartans.
• High sensitivity and reliability enabling compliance with USP <1469> limits.
• Robustness across different sartan matrices confirmed by recovery studies.
• Streamlined workflow with simple sample preparation and direct injection.

Future Trends and Potential Applications

• Extension of the method to other drug classes and formulation types.
• Automation of sample preparation for higher throughput in quality control labs.
• Integration with data management systems for real-time regulatory reporting.
• Advancements in MS technology may further lower detection limits and expand analyte scope.

Conclusion

The developed LC-MS/MS method on the Shimadzu LCMS-8045 system fulfills the proposed USP <1469> requirements for six nitrosamines in five sartans. It offers high sensitivity, excellent linearity, and reliable recovery, providing an efficient tool for routine quality control of pharmaceutical APIs.

Reference

• USP General Chapter <1469> Nitrosamine Impurities–Procedures 3.
• Shimadzu Application Note 06-SAIP-082-LC-041-EN, April 2021.