Analysis of impurities in topiramate by HPLC with charged aerosol detection and a single quadrupole mass spectrometer

Significance of the Topic

Impurities in pharmaceutical compounds such as topiramate can compromise efficacy, safety and regulatory compliance. Reliable detection and identification of trace-level impurities support quality control throughout drug development and manufacturing. Combining universal detectors with mass spectrometry enhances both quantitation and structural insight, meeting stringent pharmacopeial requirements.

Objectives and Study Overview

This study aims to demonstrate the advantages of coupling a single quadrupole mass spectrometer to an HPLC system equipped with charged aerosol detection (CAD) for comprehensive impurity profiling of topiramate. The approach seeks to quantify all known impurities in one run, confirm peak purity, obtain molecular weight and fragment information, and improve detection sensitivity, especially for semi-volatile impurities.

Methodology and Instrumentation

Topiramate and its pharmacopeial impurities A–D were analyzed according to the European Pharmacopoeia HPLC-CAD method using an Accucore PFP column (100×4.6 mm, 2.6 µm). Mobile phase A was 25 mM ammonium acetate (pH 3.5) and phase B was acetonitrile, with a gradient from 20 % to 50 % B over 15 min at 1.0 mL/min and 40 °C. CAD was set at 35 °C evaporation temperature, 10 Hz data rate and power function 1.0. The eluent was split 1:3 between the CAD and a single quadrupole ISQ EM MS in positive HESI mode. Both full scan (m/z 100–800) and selected ion monitoring were used. In-source CID voltages of 30–40 V generated structural fragments for impurity confirmation.

Key Results and Discussion

• Peak Purity Confirmation: MS spectra collected at front, apex and tail confirmed a single, pure API peak with no co-elution.
• Unified Impurity Detection: CAD quantified impurities B–D at 0.1 % levels, while MS detected impurity A, overcoming its weak CAD response.
• Sensitivity Improvement: MS detection limits reached 0.0125 µg/mL for several impurities, improving sensitivity by an order of magnitude over CAD.
• Structural Insights: In-source CID fragment ions matched predicted patterns, enabling confirmation of known impurities and structural proposals for unknowns.

Benefits and Practical Applications

• Comprehensive Profiling: Simultaneous quantitation of all pharmacopeial impurities, including semi-volatile species.
• Enhanced Sensitivity: Detection of trace-level impurities below regulatory thresholds for robust risk assessment.
• Peak Purity Analysis: Confirms API peaks are free from co-elution, strengthening quality control.
• Structural Elucidation: Fragmentation data support impurity identification and investigation of formation pathways.

Future Trends and Opportunities

Integration of single quadrupole MS with universal detectors is poised to become standard in pharmaceutical QC, driven by regulatory demands for impurity identification. Advances in AI-driven spectral interpretation, higher-resolution MS coupling and automated split-flow interfaces will further increase throughput, compliance and structural elucidation capabilities.

Conclusion

Coupling a single quadrupole mass spectrometer to an HPLC-CAD system delivers a powerful, sensitive and user-friendly platform for topiramate impurity profiling. It enables unified detection of all pharmacopeial impurities, confirms peak purity, provides molecular weight and fragment information, and surpasses traditional detection limits, thus enhancing quality control and regulatory compliance.

References

1. Görög, S. Journal of Pharmaceutical and Biomedical Analysis, 2008, 48(2), 247–253.
2. Görög, S. Trends in Analytical Chemistry, 2006, 25(8), 755–757.
3. ICH Q3A–Q3D Guidelines on Impurities.
4. Takahashi et al. Journal of Chromatography A, 2008, 1193(1-2), 151–155.
5. Ilko et al. Charged Aerosol Detection for Liquid Chromatography, 2017.