Robust and Sensitive Azido Impurities Quantitative Analysis in Five Sartan Drug Substances

Importance of the topic

Angiotensin II receptor antagonists known as sartan drugs are widely prescribed for hypertension management. Recent recalls due to nitrosamine contamination have heightened regulatory scrutiny. Alongside nitrosamines, mutagenic azido impurities such as AZBT and AMBBT have been identified in sartan APIs. These impurities pose potential carcinogenic risk and must be controlled below the threshold of toxicological concern to ensure patient safety and meet ICH M7 guidelines.

Study objectives and overview

The primary aim was to establish a single liquid chromatography–triple quadrupole mass spectrometry method for the simultaneous quantitation of two azido impurities in five sartan substances (olmesartan, losartan, irbesartan, valsartan, candesartan) using the Shimadzu LCMS-8060 platform. The workflow was designed for high sensitivity, robustness and minimal runtime.

Methodology

Sample and standard preparation

• AZBT and AMBBT standards formulated from 1000 µg/mL stocks in methanol and diluted to cover 0.01–500 ng/mL range
• Sartan drug substances dissolved at ~5 mg/mL in 90% methanol–water, vortexed and sonicated

Chromatographic conditions

• Shim-pack Velox SP-C18 core shell column (100 x 2.1 mm, 2.7 µm)
• Gradient elution from 50 to 98% methanol over 8.5 min at 0.4 mL/min
• Column at 40 °C, autosampler at 4 °C, injection 5 µL

Used instrumentation

• Shimadzu LCMS-8060 triple quadrupole mass spectrometer with SPD-M40 PDA detector
• Electrospray ionization in positive MRM mode with optimized transitions for AZBT and AMBBT
• Divert valve programming directed bulk API to waste and impurities to MS to prevent contamination
• Data acquired and processed with LabSolutions Insight software

Main results and discussion

The method achieved baseline separation of five sartan drugs and both azido impurities in 8.5 min. System suitability over ten injections showed retention time and peak area RSDs below 3%. LOD and LOQ were 0.005 and 0.01 ng/mL respectively with signal-to-noise ratios above 6 and 15. Calibration curves were linear (R2 > 0.999) across four orders of magnitude. Recovery studies at multiple spike levels returned values within the acceptable 70–130% range. No significant carryover was detected.

Benefits and practical applications

This single LC–MS method delivers high throughput and robust quantitation of trace mutagenic impurities in sartan APIs. The divert valve protects the mass spectrometer from matrix overload, extending instrument uptime. Rapid runtime and broad linear range make it ideal for routine quality control and regulatory monitoring.

Future trends and potential applications

Advances in column technologies and MS sensitivity are expected to further lower detection limits for trace impurities. Integration of high-resolution MS and automated sample preparation could streamline workflows. Applying similar strategies to other drug classes will enhance overall pharmaceutical safety monitoring.

Conclusion

A robust sensitive LC–MS/MS workflow was developed for simultaneous analysis of AZBT and AMBBT in five sartan APIs. Key performance metrics including separation speed, linearity, reproducibility and recovery meet stringent regulatory requirements, supporting effective impurity control in pharmaceutical production.

References

• ICH Q2B Validation of Analytical Procedures Methodology November 1996
• ICH M7 Assessment and Control of DNA Reactive Mutagenic Impurities March 2017
• Health Canada Recall of Irbesartan Losartan and Valsartan Drugs 2021
• EDQM Risk of Mutagenic Azido Impurities in Losartan Active Substance