Quantifying more with less: Implementing charged aerosol detection to improve drug safety

Significance of the Topic

The precise quantification of active pharmaceutical ingredients and their impurities is critical for ensuring drug safety. Many compounds lack UV-absorbing chromophores or fail to ionize effectively, limiting the applicability of traditional UV or MS detection. Charged aerosol detection (CAD) expands analytical capabilities by providing near-universal sensitivity for semi-volatile and non-volatile analytes, enabling comprehensive impurity profiling in pharmaceutical quality control.

Aims and Study Overview

The University of Wuerzburg’s Pharmacy Department aimed to modernize legacy HPLC methods by integrating CAD alongside UV and MS detectors. Under the leadership of Prof. Dr. Ulrike Holzgrabe and her team of pharmacists and PhD students, the goal was to develop single methods capable of detecting all drug components, including those without chromophores, and to compare CAD performance against evaporative light scattering detection (ELSD) and earlier CAD systems.

Methodology

Samples containing active pharmaceutical ingredients (APIs), impurities, and excipients were separated by UHPLC using narrow-bore capillaries to minimize peak broadening. Both isocratic and gradient methods were employed. An inverse gradient configuration ensured consistent mobile phase composition at the CAD inlet, preserving detector response uniformity during gradient elution.

Used Instrumentation

• Thermo Scientific Vanquish Duo UHPLC system
• Thermo Scientific Vanquish Charged Aerosol Detector H
• Thermo Scientific Vanquish Flex UHPLC
• Thermo Scientific Chromeleon Chromatography Data System

Main Results and Discussion

CAD provided significantly higher sensitivity and precision compared to ELSD and earlier CAD models. In flow-injection tests, a selection of non-volatile standards exhibited nearly uniform response factors with under 5% RSD. For low-level impurity detection, the Vanquish CAD demonstrated superior limits of detection across the full mass range. Narrow-bore capillaries reduced peak dispersion between the column and detector, enhancing quantification of trace components. The user interface required minimal training, facilitating rapid adoption by new operators.

Benefits and Practical Applications

• Comprehensive detection of non-chromophoric and non-ionizable analytes
• Improved sensitivity and linear response for low-level impurities
• Streamlined workflows by combining UV, MS, and CAD in a single method
• Enhanced quality control of both APIs and excipients
• Reduced training time due to intuitive software design

Future Trends and Potential Applications

Further optimization of CAD power-function settings and evaporation temperature will refine linear response and detection limits. Integration with orthogonal detection techniques, such as DAD and MS, can support detailed impurity identification. Increasing regulatory acceptance of CAD in pharmacopoeial methods may drive its broader adoption in drug development and quality assurance. Emerging data analytics and AI tools could further enhance throughput and interpretation of complex chromatographic data.

Conclusion

The implementation of charged aerosol detection at the University of Wuerzburg has demonstrated robust, sensitive, and versatile analysis capabilities for pharmaceutical quality control. CAD complements existing UV and MS detectors to ensure no component is overlooked, supporting safer and more reliable drug products.

References

• Holzgrabe U, Schilling K, Pawellek R, Scherf-Clavel O. With united forces against impurities: Complementary detectors in pharmacopoeia analysis. Wiley Analytical Science Magazine. 2021 May 7.
• Pawellek R, Schilling K, Holzgrabe U. Impurity profiling of l-aspartic acid and glycine using high-performance liquid chromatography coupled with charged aerosol and ultraviolet detection. Journal of Pharmaceutical and Biomedical Analysis. 2020;183:113149.
• Walther R, Holzgrabe U. Simplification of pharmacopoeial liquid chromatography methods for related substances of statins by hyphenated ultraviolet and charged aerosol detection. Journal of Pharmaceutical and Biomedical Analysis. 2023;225:115218.
• Pawellek R, Holzgrabe U. Influence of the mobile phase composition on hyphenated ultraviolet and charged aerosol detection for the impurity profiling of vigabatrin. Journal of Pharmaceutical and Biomedical Analysis. 2021;201:114110.
• Pawellek R, Muellner T, Gamache P, Holzgrabe U. Power function setting in charged aerosol detection for the linearization of detector response – optimization strategies and their application. Journal of Chromatography A. 2021;1637:461844.