Metoprolol impurity testing by charged aerosol detection: method transfer and optimization of a USP method

Significance of the Topic

The accurate quantification of nonchromophoric impurities in metoprolol succinate is critical for ensuring drug purity and regulatory compliance. The replacement of TLC with HILIC coupled to charged aerosol detection (CAD) addresses the detection gap for analytes lacking UV chromophores.

Objectives and Overview of the Study

This study aims to transfer and optimize the USP monograph method for determination of related compounds H and I in metoprolol succinate from the legacy Thermo Scientific Corona ultra RS CAD to the next generation Vanquish Flex CAD (VCAD). Key goals included defining optimal data acquisition settings and verifying method performance under USP requirements.

Methodology and Instrumentation

The separation employed a HALO Penta HILIC column (4.6 x 150 mm, 5 μm) with a mobile phase of 85% acetonitrile and 15% 0.1 M ammonium formate at pH 3.2, flow rate 1.0 mL/min, column temperature 25 °C. Injection volume was doubled from 10 to 20 μL for enhanced sensitivity. Instrumentation comprised a Thermo Scientific Vanquish Flex Quaternary UHPLC system and either a Corona ultra RS CAD or a Vanquish Flex CAD with concentric flow nebulizer. Data were acquired in Chromeleon 7.2.8.

Key Results and Discussion

Optimization of data acquisition parameters identified a power function value (PFV) of 1.30, evaporation temperature (Evap T) of 35 °C, and a digital filter time of 5 seconds as the optimal balance between signal to noise ratio and chromatographic resolution. Under these conditions, the method achieved linear responses for impurities H and I with correlation coefficients above 0.9995. System suitability met USP limits with resolution between H and I exceeding 5.4 and peak area reproducibility below 2.1% RSD using the doubled injection volume. The transfer from Corona ultra RS CAD to VCAD maintained or improved method performance.

Benefits and Practical Applications of the Method

The optimized CAD method enables reliable detection of low-level metoprolol impurities lacking chromophores without modification to the chromatographic conditions. Doubling the injection volume is fully compliant with USP guidelines and improves sensitivity. The protocol supports routine QC and impurity profiling in pharmaceutical environments.

Future Trends and Opportunities

Advances in CAD detector technology and automation could further streamline method transfers and routine analysis. Integration with laboratory information management systems may facilitate data traceability. Expanding the approach to other nonchromophoric pharmaceutical impurities offers broad applicability.

Conclusion

The USP monograph method for metoprolol succinate impurity testing was successfully transferred to the Thermo Scientific Vanquish Flex CAD. Recommended parameters of PFV 1.30, Evap T 35 °C, and a 5 second filter, combined with a 20 μL injection volume, yield performance that meets or exceeds USP requirements. The method provides a robust, sensitive, and compliant solution for QC laboratories.

References

• United States Pharmacopeia and National Formulary USP 38-NF33, USP 41(3) In-Process Revision Metoprolol Succinate chapter.
• Xu Q, Tan S, Petrova K. Development and validation of a HILIC–CAD method for nonchromophoric alpha-hydroxyamines in J Pharm Biomed Anal. 2016;118:242–250.