Analysis of Impurities in Montelukast Using Single Quadrupole Mass Spectrometer

Significance of Topic

In pharmaceutical development and quality assurance, identifying and characterizing impurities at trace levels is critical to ensure patient safety and regulatory compliance. Montelukast sodium, used in asthma and allergic rhinitis therapies, requires stringent purity evaluation to meet pharmacopeial standards.

Study Objectives and Overview

This study demonstrates the application of the Shimadzu Nexera series high performance liquid chromatograph coupled with the LCMS-2050 single quadrupole mass spectrometer for rapid detection, mass determination, and structural elucidation of impurities in montelukast sodium. The goal was to integrate molecular weight data seamlessly with UV chromatograms and to leverage in-source CID for fragment analysis.

Methodology and Instrumentation

Sample preparation involved dissolving montelukast sodium to 1 mg/mL according to JP guidelines. Chromatographic separation was achieved with a phenyl column under a gradient of water and acetonitrile, both containing formic acid. The LCMS-2050 operated in positive ion mode, performing full MS scans from m/z 100 to 1000 and utilizing in-source CID at elevated collision voltages to generate fragment ions.

Used Instrumentation

• Liquid chromatograph: Nexera XR
• Column: Shim-pack Scepter Phenyl-120 50 mm × 2.1 mm, 1.9 µm
• Mobile phases: A) water/formic acid 2000:3 B) acetonitrile/formic acid 2000:3
• Flow rate: 0.25 mL/min with gradient from 45 % to 65 % B
• Column temperature: 30 °C
• Injection volume: 10 µL
• Detection: UV at 238 nm
• Mass spectrometer: LCMS-2050 with ESI/APCI dual ion source
• Nebulizing gas: 3.0 L/min Drying gas: 5.0 L/min Heating gas: 7.0 L/min
• DL temperature: 250 °C Desolvation temperature: 400 °C
• Interface voltage: 3.0 kV Qarray voltage: 80 V

Main Results and Discussion

The UV chromatogram revealed montelukast at approximately 9.7 min, with five impurity peaks detected before and after the main component. Corresponding total ion chromatogram peaks matched these impurities. Mass spectra determined the protonated molecular ions for impurities 1 to 5, aligning with related substances listed in the Japanese Pharmacopoeia. In-source CID of impurity 4 produced fragment ions that matched theoretical values, confirming structural assignments.

Benefits and Practical Applications

This approach enables rapid acquisition of molecular weight information and structural insights directly from standard LC runs, streamlining impurity identification workflows in pharmaceutical laboratories. The compact LCMS-2050 design allows easy integration into existing chromatographic systems.

Future Trends and Opportunities

Advancements in single quadrupole MS sensitivity and in-source fragmentation techniques will expand applications in trace impurity profiling. Coupling with high-throughput automation and data analytics, including machine learning approaches, promises to further accelerate structural elucidation and regulatory compliance in drug development.

Conclusion

The Shimadzu LCMS-2050 provides robust, efficient analysis of montelukast impurities by combining UV detection with mass spectrometric molecular weight confirmation and in-source CID-driven structural analysis. This methodology supports stringent quality control requirements in pharmaceutical research and production.

Reference

• Japanese Pharmacopoeia, 17th Edition
• European Pharmacopoeia
• United States Pharmacopeia