Quick Analysis of N-nitrosodimethylamine (NDMA) in Ranitidine Drug Substance and Drug Product by HPLC/UV

Importance of the Topic

NDMA is a probable human carcinogen capable of causing DNA mutations; controlling its levels in pharmaceuticals is critical to safeguard patient health and comply with regulatory standards.

Objectives and Study Overview

This work demonstrates a fast and reliable HPLC-UV method for detecting N-nitrosodimethylamine in both ranitidine drug substance and tablet products, with added confirmation via mass spectrometry.

Methodology and Instrumentation

Ranitidine samples (30 mg/mL) were extracted in water, centrifuged, and filtered. NDMA calibration standards (10–300 ng/mL) were prepared from a 250 μg/mL stock. Separation was achieved on an XSelect HSS T3 column (4.6×100 mm, 3.5 μm) at 40 °C, 1.0 mL/min using a gradient from water with 0.02% formic acid to acetonitrile. UV detection was performed at 245 nm; mass confirmation used an ACQUITY QDa detector in ESI+ mode (m/z 50–500).

Used Instrumentation

• ACQUITY Arc System with 2998 PDA and QDa detectors
• XSelect HSS T3 Column (4.6×100 mm, 3.5 μm)
• Mobile Phase A: water + 0.02% formic acid; B: acetonitrile; gradient 95:5 to 5:95
• PDA scan range 210–400 nm, quantitation at 245 nm
• QDa MS: ESI+; m/z range 50–500; divert valve at 2.70 min

Main Results and Discussion

The method achieved baseline separation of NDMA (retention ∼2.2 min) from ranitidine in both substance and tablet matrices. Unspiked samples contained detectable NDMA; spiking at 50 ng/mL yielded an average recovery of 85%, demonstrating method accuracy and robustness. Mass spectral data provided rapid identity confirmation.

Benefits and Practical Applications

• Rapid sample preparation and analysis
• High sensitivity for trace NDMA detection
• Dual detection improves selectivity and confidence
• Applicable to raw API and finished dosage forms

Future Trends and Opportunities

Advances may include high-resolution MS for broader nitrosamine profiling, automated sample processing, inline process monitoring, and application to other pharmaceutical contaminants.

Conclusion

The proposed HPLC-UV method with mass confirmation offers a quick, accurate, and robust approach for controlling NDMA impurities in ranitidine products, supporting quality assurance and regulatory compliance.

References

1. ICH M7(R1), Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals, ICH, 2018.
2. FDA statement on NDMA found in ranitidine products, 2019.
3. Maziarz M, Rainville P. Reliable HPLC/UV Quantitation of Nitrosamine Impurities in Valsartan and Ranitidine Drug Substances, Waters Technology Brief 720006775EN, 2020.