Analysis of Impurities in Montelukast Sodium

Importance of the Topic

The analysis of pharmaceutical impurities is critical to ensure drug safety, efficacy, and regulatory compliance. Montelukast sodium, a leukotriene receptor antagonist used in asthma management, requires thorough impurity profiling to meet stringent quality standards. Advanced liquid chromatography–mass spectrometry (LC–MS) methods provide the sensitivity and selectivity necessary for detecting and characterizing trace-level contaminants.

Study Objectives and Overview

This study aims to develop and validate a robust reversed-phase UHPLC–MS/MS protocol for the separation, detection, and structural elucidation of five key impurities in montelukast sodium. The method leverages a phenyl stationary phase to achieve high-resolution separation and employs tandem mass spectrometry for confirmatory identification.

Methodology and Instrumentation

• Chromatographic system: Shimadzu Nexera™ X3 UHPLC
• Column: Shim-pack® Scepter™ Phenyl-120, 50 mm × 2.1 mm I.D., 1.9 µm
• Mobile phases: A: water/formic acid (2000:3, v/v), B: acetonitrile/formic acid (2000:3, v/v)
• Gradient program: 45% B (0–3 min) to 65% B (at 16 min), hold, then return to 45% B (16.1–25 min)
• Flow rate: 0.25 mL/min; column temperature: 30 °C; injection volume: 10 µL; UV detection at 238 nm
• Mass spectrometer: Shimadzu LCMS-9030; ESI positive mode; full MS and MS/MS scanning; nebulizing gas: 3.0 L/min; drying gas: 10.0 L/min; heating gas: 10.0 L/min; DL temperature: 250 °C; block heater: 400 °C; interface: 300 °C

Main Results and Discussion

The optimized method achieved baseline separation of five components: Impurity 1, Impurity 2/3 (coeluting isomers), Montelukast, Impurity 4, and Impurity 5 within a 25-minute run. Peak resolution exceeded pharmacopeial requirements, and retention times were highly reproducible (RSD < 0.5%). MS/MS spectra provided diagnostic fragment ions, enabling unambiguous identification of each impurity. The phenyl phase exhibited enhanced selectivity for aromatic moieties, improving separation of structurally related compounds.

Benefits and Practical Applications of the Method

• High sensitivity and specificity for trace impurity detection
• Rapid throughput suitable for routine quality control
• Comprehensive structural information from tandem MS
• Robust performance with minimal method drift

Future Trends and Potential Applications

Emerging advances in high-resolution mass spectrometry and automated data processing promise even greater analytical depth and throughput. Coupling these developments with advanced stationary phases (core-shell and monolithic materials) could further accelerate impurity profiling. The methodology may be extended to other small-molecule drugs requiring stringent impurity analysis.

Conclusion

A validated UHPLC–MS/MS method using a phenyl-functional column successfully separates and identifies five impurities in montelukast sodium. The protocol meets regulatory guidelines for precision, accuracy, and detection limits, supporting reliable quality control in pharmaceutical development and manufacturing.

References

Shimadzu Corporation. Analysis of Impurities in Montelukast Sodium. Application News 01-00017 (JP/ENG), First Edition, September 2024.