Determination of Nitrosamine Impurities in Sartan Drug Products by GC-MS/MS Method

Importance of the Topic

Nitrosamine impurities in sartan pharmaceuticals pose a health risk as potent genotoxic carcinogens. Recent recalls by regulatory agencies highlighted the need for sensitive, reliable analytical methods. A robust workflow addresses public safety and supports compliance with stringent guidelines.

Objectives and Study Overview

This work aimed to develop and validate a direct injection GC-MS/MS assay capable of quantifying seven nitrosamine compounds in sartan drug products including NDMA, NDEA, NDBA, NMEA, NDPA, NPYR and NPIP. Four commercial formulations containing olmesartan, losartan, irbesartan and valsartan were evaluated.

Methodology and Instrumentation

Standard stock and working solutions were prepared in dichloromethane with NMDA-D6 as an internal standard. Tablet samples were powdered, extracted with DCM and filtered. Direct injections of 2 µl were performed using a temperature-programmed GC method and MRM acquisition. System suitability, calibration and matrix effects were assessed over 2.5 to 100 ng/ml.

Used Instrumentation

• GCMS-TQ8050 NX triple quadrupole with electron ionization
• SH-Rxi-624Sil MS capillary column (30 m × 0.25 mm × 1.40 µm)
• Helium carrier gas, constant linear velocity mode
• Multiple reaction monitoring transitions for each analyte

Main Results and Discussion

Calibration curves exhibited excellent linearity (R2 ≥ 0.999) and signal-to-noise ratios far exceeding 10 at the 5 ng/ml level. Precision (%RSD) ranged from 1.74 to 5.61 %. No target nitrosamines were detected in any of the four drug products under the defined identification criteria. Matrix-related baseline shifts were observed but mitigated by column conditioning. Instrument recovery and matrix effects above 100 % indicate sample enhancement and support the value of matrix-matched calibration.

Advantages and Practical Applications

The method provides high sensitivity, specificity and throughput for routine quality control and regulatory compliance. Direct injection simplifies sample preparation and reduces analysis time.

Future Trends and Potential Uses

Emerging directions include automated sample processing, extension to other drug classes, adoption of high-resolution mass spectrometry and further integration of isotopic dilution strategies to enhance accuracy and traceability under evolving regulatory frameworks.

Conclusion

A validated GC-MS/MS direct injection procedure demonstrates robust performance for trace-level nitrosamine determination in sartan products, ensuring reliable safety monitoring and adherence to regulatory standards.

References

• European Medicines Agency Sartan Medicines Review on Nitrosamine Impurities EMA/44960/2019
• US Food and Drug Administration Angiotensin II Receptor Blocker Recalls of Valsartan and Losartan FDA Safety Communication 2019
• FDA Center for Drug Evaluation and Research Combined Direct Injection NDMA and NDEA Impurity Assay by GC/MS Short Form Report