Impurity analysis of gabapentin by HPLC-UV-CAD

Importance of the Topic

Gabapentin is a critical therapeutic for focal seizures and neuropathic pain. Regulatory guidelines demand impurity reporting thresholds as low as 0.03 % due to high daily dosage. However, analysis is challenged by the lack of UV-absorbing chromophores and the volatility of certain impurities, requiring sensitive and versatile detection techniques.

Objectives and Study Overview

The study aimed to develop a single HPLC method combining ultraviolet detection and charged aerosol detection (UV-CAD) to replace two separate compendial HPLC-UV assays outlined in the European Pharmacopoeia. The goal was to achieve simultaneous quantitation of chromophore-deficient and volatile impurities at the required limits of quantitation (LOQs) while reducing analysis time and consumable usage.

Methodology and Instrumentation

The method employed a Thermo Scientific Vanquish UHPLC system with a C8 stationary phase (250 × 4.6 mm, 5 µm) and a 20 mM ammonium formate buffer (pH 2.8) in water and acetonitrile. A gradient from 25 % to 60 % organic modifier over 5 minutes, at 1.2 mL/min and 25 °C, ensured baseline separation of all analytes within a 15 min run time. UV detection at 210 nm covered the volatile impurity A, and CAD (evaporation temp 30 °C, power function value 1.3, 5 s filter) quantified the chromophore-deficient impurities B, D, E, and G.

Main Results and Discussion

The method achieved resolutions above 1.5 for all critical peak pairs. LOQs were below 10 ng for non-volatile impurities and 50 ng for semi-volatile or UV-detectable impurities, corresponding to a 0.03 % reporting threshold. Calibration curves were linear (R² > 0.999) over 0.03 % to 0.24 %. Accuracy ranged from 97 % to 105 %, and precision RSD values were below 8.4 %. The method proved robust against minor variations in flow rate, temperature, and mobile phase composition.

Benefits and Practical Applications of the Method

• Simultaneous detection of all relevant impurities in a single run
• Lower reporting threshold (0.03 %) in compliance with ICH Q3A(R2)
• Reduced solvent and sample consumption
• Shorter total analysis time and instrument workload

Future Trends and Opportunities

The UV-CAD hyphenation approach can be extended to other compounds with challenging impurity profiles. Future developments may include integration with mass spectrometry, further method miniaturization, and high-throughput screening for industrial QA/QC environments.

Conclusion

The developed HPLC-UV-CAD method provides a robust, sensitive, and efficient solution for comprehensive impurity profiling of gabapentin. By consolidating two compendial methods into one, the approach meets stringent regulatory requirements while reducing time and costs.

References

1. ICH Q3A(R2) Impurities in New Drug Products, 2006.
2. European Pharmacopoeia Monograph 2173, Pharmacopoeia 10.2, 2020.
3. Pawellek et al., J. Chromatogr. A 2021, 1637, 461844.
4. ICH Q2(R1) Validation of Analytical Procedures: Text and Methodology, 2005.