Use of a Proprietary Polar Column Chemistry for the Separation of Nitrosamines in Sartan and Ranitidine Drug Substances

Significance of the Topic

n-nitrosamine impurities pose critical safety concerns due to their potent carcinogenicity and have led to recalls of ARB and ranitidine drugs. Reliable analytical methods are essential to detect and control trace levels of these compounds during pharmaceutical quality control. The proprietary XSelect HSS T3 column chemistry offers specific polar interactions to improve retention and separation of nitrosamines in complex drug matrices, supporting regulatory compliance and patient safety.

Objectives and Study Overview

This study aimed to demonstrate the capabilities of the Waters XSelect HSS T3 column coupled with UHPLC and dual detection (photodiode array and ACQUITY QDa mass detector) for simultaneous separation and identification of six regulated nitrosamines (NDMA, NDEA, NEIPA, NDIPA, NDBA, NMBA) in valsartan, losartan, irbesartan, and ranitidine drug substances.

Methodology and Instrumentation

• Sample preparation: Stock solutions of nitrosamines and drug substances at 5.0 mg/mL in methanol, diluted in water/methanol (80:20) at 0.1 mg/mL, spiked at 1 % impurity level.
• Chromatographic system: ACQUITY Arc UHPLC with XSelect HSS T3 column (100×2.1 mm, 2.5 µm), proprietary polar reverse-phase chemistry.
• Detection: Photodiode array for UV absorbance; ACQUITY QDa mass detector for mass confirmation; data processed with Empower 3 CDS.

Main Results and Discussion

The XSelect HSS T3 column delivered baseline separation of all six nitrosamines and the four drug substances within a single run. Unique polar interactions ensured enhanced retention and peak shapes. Mass spectral data from the QDa detector provided unambiguous identification of each analyte based on their monoisotopic masses. The method showed robust performance, reproducibility, and clear signal resolution essential for trace-level impurity analysis.

Benefits and Practical Applications

• Single, streamlined UHPLC method for multiple nitrosamines and APIs accelerates testing workflows.
• Enhanced selectivity and retention reduce co-elution risk and improve quantification accuracy.
• Dual detection allows simultaneous quantification and confirmation, boosting confidence in results.
• Applicable for routine QC labs and regulatory monitoring of pharmaceutical products.

Future Trends and Applications

Anticipated advancements include integration with high-resolution MS for even lower detection limits and expanded screening of emerging nitrosamine analogs. Further column chemistry innovations may extend applicability to other polar contaminants. Automation and in-line monitoring could facilitate real-time quality control in continuous manufacturing environments.

Conclusion

The demonstrated UHPLC method with XSelect HSS T3 column and dual detection provides a powerful tool for reliable separation, identification, and control of nitrosamine impurities in ARB and ranitidine drug substances. Its robustness and selectivity support pharmaceutical quality assurance and regulatory compliance.

References

• FDA update on ARB drug recalls and NDMA in ranitidine samples.
• ICH M7(R1) guideline: Assessment and control of mutagenic impurities in pharmaceuticals.