Quantitative Determination of NDMA Impurity in Ranitidine Drug Products – Examples of Actual Samples Analysis by LCMS-8060 with APCI

Significance of the Topic

The detection of NDMA impurity in ranitidine is critical due to its classification as a probable human carcinogen and regulatory limits on daily exposure. Reliable quantitation of NDMA supports drug safety and compliance.

Objectives and Overview

The primary aim of this study was to establish a sensitive and robust LCMS-8060 method with APCI interface for the quantitative analysis of NDMA in ranitidine API and drug formulations. Modifications of the 2019 FDA reference method were implemented to optimize performance.

Methodology

Sample preparation involved crushing solid dosage forms or diluting non solid products in a water methanol mixture with formic acid, followed by shaking, centrifugation and filtration. Calibration standards of NDMA were prepared across a range of 1 to 200 ng/mL in the same diluent. System suitability was assessed using multiple injections of a 1 ng/mL standard, targeting relative standard deviations below 10 percent.

Instrumentation Used

• Triple quadrupole LCMS 8060 with APCI interface
• Shim pack Scepter C18 column (3.0 150 mm, 1.9 microns)
• Mobile phases water and methanol each with 0.1 percent formic acid

Main Results and Discussion

The method achieved a linear calibration with R squared 0.998 over the 1 to 200 ng/mL range. Limits of detection and quantitation met regulatory requirements. System suitability tests showed RSDs under 6 percent across two days. Analysis of ranitidine tablets, syrups and injection solutions revealed NDMA levels above the acceptable intake of 0.32 ppm in all samples.

Benefits and Practical Applications

• High sensitivity and specificity for regulatory compliance
• Rapid sample throughput suitable for routine quality control
• Applicability to diverse ranitidine matrices including tablets, syrups and injections

Future Trends and Opportunities

Advances in high resolution mass spectrometry and automated sample preparation could further lower detection limits and increase throughput. Integration of AI for data analysis may enhance anomaly detection and streamline reporting. Green chemistry approaches may reduce solvent use and environmental impact.

Conclusion

A modified FDA-based LCMS-8060 method with APCI interface provides a reliable and efficient approach for quantifying NDMA in ranitidine substances and formulations, ensuring adherence to safety guidelines. All tested samples exceeded the acceptable threshold, highlighting the need for ongoing monitoring.

Reference

1. US FDA Statement alerting patients and health care professionals of NDMA found in samples of ranitidine (13 Sep 2019)
2. US FDA LC MS MS Method for the Determination of NDMA impurity in Ranitidine Drug Substance or Solid Dosage Drug Product (10 Oct 2019)