Routine Accurate Mass Measurement for the Identification of Impurities in Quetiapine Fumarate API Using the SmartMS-Enabled ACQUITY RDa Detector

Importance of the Topic

The chemical stability of active pharmaceutical ingredients (APIs) directly influences drug safety and efficacy. Detailed impurity profiling is crucial to detect degradation products that may reduce potency or introduce toxicological risks. High-resolution mass spectrometry (HRMS) has become a preferred tool for such analyses due to its sensitivity and accuracy.

Objectives and Study Overview

This application note outlines a streamlined workflow for routine accurate mass measurement and identification of quetiapine fumarate impurities. It demonstrates the integration of the SmartMS-enabled ACQUITY RDa Detector with the UNIFI software workflow, highlighting both development and routine implementation in impurity characterization studies.

Methodology and Instrumentation

• Sample Preparation: Quetiapine fumarate solution (5 mg/mL) in an acetonitrile–buffer mixture.
• Chromatography: ACQUITY UPLC I-Class PLUS System with XBridge C18 column (4.6 × 150 mm, 3.5 µm), 45 °C column temperature, gradient elution at 1.5 mL/min, UV detection at 250 nm.
• Mass Spectrometry: ACQUITY RDa Detector operated in full scan with fragmentation (pseudo-MSE) mode, positive ionization (50–2000 m/z), capillary voltage 1.5 kV, variable fragmentation cone voltage (50–90 V), scan rate 5 Hz.
• Data Processing: UNIFI Application within the waters_connect platform for automated accurate mass measurement, spectral alignment, fragment analysis, and structural elucidation.

Main Results and Discussion

• Simultaneous low- and high-energy acquisition yielded both precursor and fragment ion spectra from a single injection.
• All impurity peaks were annotated with elemental compositions, sub-2 ppm mass accuracy, and isotope pattern scoring.
• Nine known quetiapine-related impurities were identified with an average mass error of approximately 2 ppm.
• The Discovery Tool enabled rapid identification via ChemSpider and custom scientific libraries; the Transformations Tool predicted likely degradation products (e.g., oxidations, dealkylations).
• Combined detection and processing workflows provided clear chromatographic and spectral views for confident impurity assignment.

Benefits and Practical Applications

• Accessible HRMS for non-expert users through automatic instrument setup and intuitive software.
• Efficient, end-to-end workflow supporting regulatory compliance and data integrity.
• Rapid impurity profiling accelerates stability testing, method development, and quality control of APIs.

Future Trends and Potential Applications

• Extension of HRMS-enabled workflows to broader pharmaceutical degradation and stability studies.
• Integration with artificial intelligence and machine learning for predictive impurity profiling.
• Automated compliance reporting and cloud-based collaboration for global laboratories.

Conclusion

By combining the SmartMS-enabled ACQUITY RDa Detector with the UNIFI software platform, this workflow delivers rapid, accurate, and comprehensive impurity profiling of quetiapine fumarate. The demonstrated approach enhances confidence in identification and supports routine application in both research and regulated environments.

References

• Anderson S, Vande J. Quetiapine for Insomnia: A Review of the Literature. Am J Health Syst Pharm. 2014;71(5):394–402.
• Bharathi C et al. Identification, Isolation, Synthesis and Characterization of Impurities of Quetiapine Fumarate. Pharmazie. 2008;63:14–19.
• Fisher D et al. Plasma Concentrations of Quetiapine and Metabolites in Relation to Dose and Formulation. Ther Drug Monit. 2012;34(4):415–421.
• Jones MD et al. Analysis of an Unknown Degradant Found in Quetiapine Fumarate. Waters Corporation. 2009;720003079EN.
• Waters Corporation. Impurity Isolation and Scale-up from UPLC: Analysis of an Unknown Degradant Found in Quetiapine Fumarate. 2009;720003078EN.