A Robust and Sensitive Instrument for Quantification of N-Nitroso Propranolol Impurity in Propranolol Hydrochloride Drug Product

Importance of the Topic

N-nitroso impurities in pharmaceutical products pose significant health risks due to their potential carcinogenicity. Propranolol Hydrochloride, a widely used beta-adrenergic antagonist, may form its nitrosamine analogue during synthesis or storage, necessitating reliable detection at trace levels to meet stringent regulatory guidelines and ensure patient safety.

Objectives and Study Overview

This study aimed to develop a robust LC–MS/MS assay for the sensitive and accurate quantification of N-Nitroso propranolol impurity in Propranolol Hydrochloride drug formulations. The method was designed to achieve low limits of quantification, high precision, and reliable recovery across relevant concentration ranges.

Used Instrumentation

• Waters Xevo TQ-S Cronos triple quadrupole mass spectrometer
• Waters Acquity UPLC H-Class Plus system
• Symmetry C8 column for chromatographic separation
• RADAR acquisition mode enabling simultaneous MRM and full-scan MS data collection

Methodology

Samples of Propranolol Hydrochloride were spiked with known amounts of N-Nitroso propranolol and processed using an optimized extraction protocol. Chromatographic separation employed a C8 stationary phase, while detection was performed in multiple reaction monitoring (MRM) mode. The RADAR mode facilitated the concurrent acquisition of full-scan spectra to monitor matrix interferences and ensure peak purity. Calibration curves were established over the range 0.002 to 2.0 ppm, with a method limit of quantification (LOQ) set at 0.01 ppm relative to the active pharmaceutical ingredient (API).

Main Results and Discussion

The method exhibited excellent linearity (0.002–2.0 ppm) and demonstrated an instrument LOQ of 0.002 ppm, confirming its high sensitivity. Signal-to-noise ratios exceeded 70 at 0.002 ppm, and spiked recovery experiments yielded results of 84 %, indicating method accuracy. The RADAR acquisition effectively separated the API from the nitrosamine impurity and reduced spectral contamination, enhancing method robustness.

Benefits and Practical Applications

• Regulatory compliance: meets current guidelines for nitrosamine impurity screening
• High sensitivity and low LOQ enable trace-level detection
• Robust performance through RADAR acquisition reduces matrix effects
• Applicable for routine quality control in pharmaceutical manufacturing

Future Trends and Possibilities

Advancements in acquisition modes and instrument design will further improve sensitivity and throughput of nitrosamine analyses. Integration of automated sample preparation and data processing workflows can enhance efficiency. Expanding this approach to other nitrosamine impurities across diverse drug products will support broader regulatory and safety objectives.

Conclusion

The developed LC–MS/MS method using the Xevo TQ-S Cronos system provides a reliable, sensitive, and robust solution for quantifying N-Nitroso propranolol impurity in Propranolol Hydrochloride formulations. It satisfies regulatory requirements and offers a practical workflow for routine impurity monitoring in pharmaceutical quality control.

Reference

Waters Corporation. Xevo TQ-S Cronos Application Note, March 2023.