A Robust and Sensitive Instrument for Quantification of Seven Nitrosamine Impurities in Quetiapine Drug Substance

Significance of the Topic

Quetiapine is a key antipsychotic agent widely used in treating schizophrenia and bipolar disorder. Recent regulatory scrutiny over genotoxic nitrosamine impurities in pharmaceuticals has highlighted the need for sensitive analytical methods. Controlling these impurities at trace levels is vital for patient safety and compliance with FDA guidelines.

Objectives and Overview of the Study

This study aims to develop and validate a single LC/MS/MS method for simultaneous quantification of seven nitrosamine impurities in quetiapine drug substance. By achieving a low limit of quantitation and robust performance, the method addresses industry demands for routine monitoring of potential carcinogenic contaminants.

Methodology and Instrumentation

The analysis was performed using a Waters Xevo TQ Absolute triple quadrupole mass spectrometer coupled to an ACQUITY UPLC H-Class Plus system. Chromatographic separation employed an ACQUITY UPLC HSS T3 column (2.1 × 100 mm, 1.8 µm). A RADAR scan feature enabled simultaneous MRM and full-scan acquisition, facilitating assessment of matrix effects and optimal diversion of quetiapine eluent to waste.

Main Results and Discussion

The method demonstrated linearity from 0.0006 to 0.3 ppm for each nitrosamine impurity. Instrumental limit of detection reached 0.0006 ppm, and quantitation limit was 0.003 ppm relative to the API. Recovery studies in spiked samples ranged from 70 % to 120 %, meeting regulatory acceptance criteria. The RADAR tool enhanced method robustness by tracking matrix interferences and ensuring clean mass detector operation.

Benefits and Practical Applications

• High sensitivity for trace nitrosamine detection in quality control environments
• Single-run analysis of seven impurities reduces runtime and consumable use
• RADAR-enabled matrix evaluation improves method reliability and reduces false positives

Future Trends and Applications

Advancements in machine learning and high-resolution mass spectrometry are expected to further refine impurity profiling. Integration of automated sample preparation and real-time data analytics will streamline regulatory compliance and support continuous monitoring of manufacturing processes.

Conclusion

The presented LC/MS/MS method on the Xevo TQ Absolute platform offers a robust, sensitive, and efficient solution for quantifying nitrosamine impurities in quetiapine. Its performance meets stringent regulatory requirements and supports reliable quality control in pharmaceutical production.