Quantification of Nine Nitrosamine Impurities in Sartan Drugs Using an Agilent GC-TQ

Importance of the topic

The detection and quantification of nitrosamine impurities in sartan drugs has become a global regulatory requirement due to health risks associated with N-nitrosodimethylamine (NDMA) and related compounds. Even trace levels can lead to product recalls and impact patient safety. Reliable analytical methods are essential for routine quality control and regulatory compliance in the pharmaceutical industry.

Study objectives and overview

This application note describes the development and validation of a GC-MS/MS method for nine N-nitrosamines in sartan drug substances and finished products. The goals were to achieve low limits of quantification (LOQs), robust repeatability over long sequences, satisfactory recovery in drug matrices, and to compare column performances under fast (12-minute) and extended (20-minute) GC programs.

Methodology and instrumentation

The analytical system comprised an Agilent 8890 GC equipped with an Agilent 7693A autosampler and an Agilent 7010B triple quadrupole MS. Sample preparation involved spiking 500 mg of drug substance or homogenized tablets with deuterated NDMA internal standard, extraction into dichloromethane, filtration, and 2 µL injections.

Stationary phases evaluated included:

• Agilent J&W VF-WAXms (30 m × 0.25 mm × 0.25 µm)
• Agilent J&W DB-Select 624 UI (30 m × 0.25 mm × 1.4 µm)
• Agilent J&W DB-1701 (30 m × 0.25 mm × 1.0 µm)

GC methods used pulsed splitless injection at 250 °C with helium carrier gas (1 mL/min) and two oven programs: 12.33 min total and 20.25 min total. MS detection employed electron impact ionization at 70 eV, unit resolution, and nitrogen collision gas. Multiple Reaction Monitoring (MRM) transitions were optimized using MassHunter Optimizer.

Results and discussion

All nine nitrosamines showed excellent linearity (R² > 0.997) over 0.06–500 ng/mL (for NDEA, NEIPA, NDIPA) or 0.1–500 ng/mL (others) with LOQs down to 0.0006 ppm in drug substance. Inter-column comparison revealed that DB-1701 offered symmetric peaks and best separation from dimethylformamide (DMF), a common pharmaceutical solvent. VF-WAXms suffered NDMA peak tailing when DMF exceeded 100 mg/L. Long-term repeatability (150 injections at 30 ppb) yielded RSDs <8% for all analytes and <5% after internal standard correction. Recoveries in fortified sartan substrates and products ranged from 80% to 120%. S/N ratios at low-ppb levels exceeded 10, indicating potential for even lower LOQs.

Benefits and practical applications

• Meets stringent regulatory demands for nitrosamine impurity testing in APIs and finished dosage forms
• High sensitivity enables trace-level detection and quantification
• Robust workflow supports routine QC with excellent precision and recovery
• Flexibility in choosing column and program based on sample matrix and throughput needs

Future trends and opportunities

• Extension to other drug classes and synthetic routes to monitor a broader range of nitrosamines
• Integration with automated data analysis for high-throughput screening
• Coupling GC-MS/MS with isotopically labeled internal standards for quantitative certainty
• Development of faster gradients and shorter columns while maintaining resolution

Conclusion

The Agilent 8890/7010B GC-MS/MS platform provides a reliable, sensitive, and reproducible solution for quantifying nine nitrosamine impurities in sartan drugs. The DB-1701 column in a 20-minute method delivered optimal separation from DMF, robust linearity, and precision. This approach fulfills regulatory requirements and supports ongoing quality assurance in pharmaceutical manufacturing.

Reference

Analysis of Five Nitrosamine Impurities in Drug Products and Drug Substances Using Agilent GC/MS/MS Instrumentation. Agilent publication 5994-1821EN, 2020.