Detection and Quantitation of NDMA Impurity in Ranitidine Drug Substances and Products by LC-HRMS on LCMS-9030

Importance of the Topic

NDMA is a potent carcinogenic nitrosamine frequently detected in pharmaceuticals such as ranitidine. Chronic exposure through contaminated drugs poses serious health risks and has prompted global regulatory actions including market withdrawal of ranitidine products.

Objectives and Study Overview

This study introduces an orthogonal liquid chromatography high resolution mass spectrometry method on a Shimadzu LCMS 9030 Q TOF system to detect and quantify NDMA in ranitidine active ingredients and dosage forms. Six different ranitidine samples were analyzed and compared with previous LC MS MS data.

Methodology and Instrumentation

Calibration standards of NDMA (1 to 500 ng per mL) with an NDMA d6 internal standard were prepared. Ranitidine powders, tablets, syrup and injection samples were extracted using a methanol water formic acid mixture and filtered. Chromatographic separation employed a C18 reversed phase column under a water–methanol gradient with formic acid. Mass spectrometric detection used an APCI source in positive mode with targeted MS MS TOF acquisition, an isolation window of 2 m/z and extracted ion chromatogram mass tolerance of 15 ppm.

Instrumentation Used

• Shimadzu LCMS 9030 Q TOF mass spectrometer
• Shim-pack Scepter C18 3.0 x 150 mm 1.9 µm column

Main Results and Discussion

• The calibration curve showed linearity with R2 of 0.9996. LOD and LOQ were 0.4 and 1.3 ng per mL respectively, with repeatability RSD of 9.2%
• NDMA was detected in all samples at concentrations ranging from 0.75 to 21.07 ppm in the extracts
• Significant increases in NDMA levels were observed in API, tablets and syrup over ten months compared with previous LC MS MS results, indicating ongoing formation during storage
• The injection sample showed minimal change in NDMA content

Benefits and Practical Applications

The presented LC HRMS approach provides high sensitivity and specificity for NDMA analysis and serves as a reliable orthogonal confirmation to LC MS MS methods. It is well suited for quality control laboratories monitoring nitrosamine impurities and ensuring compliance with regulatory limits throughout product shelf life.

Future Trends and Possibilities

Expanding this high resolution mass spectrometry strategy to other nitrosamines and drug matrices could enhance contaminant surveillance. Integration with automated sample preparation and advances in HRMS instrumentation will further lower detection limits and improve throughput in pharmaceutical testing.

Conclusion

A targeted MS MS TOF method on the Shimadzu LCMS 9030 achieves trace level quantitation of NDMA in ranitidine products with performance comparable to FDA reference methods. The findings underscore the necessity for ongoing monitoring of nitrosamine impurities during manufacturing and storage.

References

1. US FDA LC MS MS Method for the Determination of NDMA Impurity in Ranitidine Drug Substance or Solid Dosage Drug Product 17 Oct 2019
2. US FDA LC HRMS Method for the Determination of NDMA in Ranitidine Drug Substance and Drug Product 13 Sep 2019
3. EMA Confirmed Recommendation to Suspend All Ranitidine Medicines in the EU 27 Nov 2020
4. Sun Z Zhan Z Quantitative Determination of NDMA in Ranitidine Drug Products Shimadzu Application News AD 0222 Apr 2020