Quantitation of 7 Nitrosaminesin API by HSGC-MS/MS as per proposed USP General Chapter <1469>

Importance of the topic

Nitrosamine impurities have drawn global attention after detection of NDMA in valsartan products. These compounds pose significant carcinogenic risk and strict regulatory limits have been established by agencies such as USFDA and USP. Accurate and sensitive methods are essential to ensure pharmaceutical safety and compliance.

Objectives and study overview

This study demonstrates a headspace gas chromatography tandem mass spectrometry method to quantify seven nitrosamines in Losartan API according to the proposed USP General Chapter 1469 procedure 2. The work aims to cover more nitrosamines than the four addressed in the USP draft, achieving lower limits of quantitation and robust performance for quality control.

Methodology and instrumentation used

• Headspace gas chromatography tandem mass spectrometry with Shimadzu GCMS-TQ8050 NX and HS-20 system
• Column: SH-Stabilwax 30 m x 0.32 mm i.d., 1.0 µm film
• Carrier gas helium, column flow 1.8 mL/min, split injection
• GC temperature program from 45 to 240 °C with defined ramp rates
• Electron ionization at 250 °C and multiple reaction monitoring for target transitions
• Sample preparation: 200 mg Losartan API with imidazole, internal standard in acetonitrile, headspace equilibration and injection

Main results and discussion

• Calibration curves for each nitrosamine were linear over defined ranges with correlation coefficients above 0.999
• Limits of quantitation ranged from 2.5 ppb to 25 ppb, outperforming USP 1469 criteria by up to eightfold
• Repeatability at LOQ showed relative standard deviations below 15% for all analytes
• Spike recovery at LOQ level in Losartan API ranged between 90% and 127%, meeting acceptance criteria
• The method quantifies seven nitrosamines including NDMA, NDEA, NEIPA, NDIPA, NDPA, NDBA and NMPrZ, whereas the USP draft covers only four

Benefits and practical applications

• Enhanced sensitivity and precision for trace level detection of nitrosamines in active pharmaceutical ingredients
• Expanded scope to include additional nitrosamines beyond those in the proposed USP chapter
• Robust sample throughput using headspace sampling reduces matrix interferences
• Compliance with regulatory limits for single and total nitrosamine intake in drug substances

Future trends and opportunities

Advances in GCMS technology and high sensitivity detectors will drive lower detection limits and faster analysis. Integration with automated sample preparation and data processing tools may further streamline nitrosamine testing. Emerging regulations may extend control to additional impurity classes and complex drug matrices.

Conclusion

The Shimadzu GCMS-TQ8050 NX with HS-20 headspace system delivers a powerful and reliable solution for quantitative analysis of seven nitrosamines in pharmaceutical APIs. The method meets and exceeds current draft USP requirements, offering improved sensitivity, repeatability and recovery for critical quality control applications.

References

• Proposed USP General Chapter 1469 on Nitrosamine Impurities in Sartans
• USFDA Guidance on Control of Nitrosamine Impurities
• Shimadzu Application Note 06-SAIP-079-GC-024-EN