Topiramate impurity analysis: Method migration from a legacy HPLC system to modern instrumentation

Importance of the topic

Topiramate is a widely used anticonvulsant with strict impurity limits defined by ICH Q3A(R2) and the European Pharmacopoeia. Its lack of chromophores prohibits UV detection, making charged aerosol detection (CAD) essential for accurate quantification of low-level impurities in pharmaceutical quality assurance.

Objectives and study overview

This application note evaluates the migration of an existing HPLC-CAD method for topiramate impurities from legacy instrumentation to a modern Vanquish Flex UHPLC system equipped with Vanquish Charged Aerosol Detector. The goal is to confirm method suitability, compare performance metrics, and identify procedural improvements.

Instrumentation

• Vanquish Flex UHPLC system (System Base, Dual Pump F, Split Sampler FT, Column Compartment H)
• Vanquish Charged Aerosol Detector H
• Thermo Scientific Corona Nitrogen 1010 generator
• Accucore PFP column (100 × 4.6 mm, 2.6 µm)

Methodology

Test and reference solutions were prepared per Ph. Eur. monograph 2616 with topiramate and impurity standards A–E. Chromatographic conditions employed a gradient of 25 mM ammonium acetate (pH 3.5) and acetonitrile on a PFP column. The legacy method runtime (20 min) and detector settings (evaporation 35 °C, power function 1.0, filter 3.6 s) were reproduced, then optimized by adjusting CAD evaporation temperature and introducing post-column acetonitrile addition.

Results and discussion

• Chromatographic separation and elution order matched between legacy and Vanquish systems. Resolution between impurity E and C improved from 4.96 to 6.25 with sharper peaks.
• Vanquish CAD showed higher baseline noise but overall superior sensitivity at low analyte masses when calibrated, with optimum evaporation at 50 °C.
• Impurities B, C, E were readily quantified; impurity A remained semi-volatile and below CAD quantitation limits, thus TLC is still recommended.
• Impurity D failed to elute within 20 min but was recovered by extending the high-organic hold by 5 min.

Benefits and practical applications

The migrated method meets Ph. Eur. criteria, offering improved resolution and versatile CAD control. Post-column acetonitrile addition enhances detection of challenging semi-volatile impurities. Use of high-purity solvents and modern UHPLC hardware increases robustness and reproducibility in pharmaceutical QC laboratories.

Future trends and opportunities

• Further CAD sensitivity enhancements through advanced evaporation control and noise reduction technologies.
• Integration with automated sample handling for high-throughput impurity profiling.
• Application of CAD in multi-attribute methods for complex drug substance analysis.
• Adaptation of method for novel topiramate formulations and related compounds.

Conclusion

The Vanquish Flex UHPLC with CAD successfully replicates and improves upon the legacy HPLC-CAD method for topiramate impurity testing. Optimized evaporation temperature, extended gradient hold, and post-column solvent addition provide enhanced performance, making this modern configuration a reliable choice for pharmaceutical quality control.

References

1. Topiramate dosage information. Drugs.com. Accessed October 2021.
2. ICH Q3A(R2) guideline on impurities in new drug substances, 2006.
3. European Pharmacopoeia Monograph 2616, 10.5 edition, EDQM, 2020.
4. Ilko D. et al. Comparison of evaporative light scattering and charged aerosol detection. In: Charged Aerosol Detection, Wiley, 2017.
5. Thermo Scientific Technical Note 73914: Factors influencing CAD performance.
6. Thermo Scientific Technical Note 71290: Method transfer to Vanquish CAD.