A Robust and Sensitive Instrument for Quantification of N-Nitroso-N-Des Methyl Diltiazem Impurity in Diltiazem Drug Product

Importance of the Topic

Control of nitrosamine-related impurities in pharmaceutical products is critically important due to the potential carcinogenic risk these compounds pose. Diltiazem, a widely prescribed calcium channel blocker, can form N-Nitroso derivatives during manufacturing or storage. Regulatory guidelines require highly sensitive and specific analytical methods to detect these impurities at trace levels and ensure patient safety.

Objectives and Study Overview

This study demonstrates a robust LC-MS/MS approach for quantifying the N-Nitroso-N-Des methyl Diltiazem impurity in Diltiazem drug products. The primary aims were to achieve low limits of quantification, high reproducibility, and efficient separation of the impurity from the active pharmaceutical ingredient (API) using Waters instrumentation.

Methodology

An Acquity H-Class Plus UPLC system was used for chromatographic separation on an Atlantis™ Premier BEH C18 AX column (100 × 2.1 mm, 2.5 µm). Samples underwent a targeted extraction protocol prior to injection. Detection was carried out on a Xevo TQ-S Micro Cronos triple quadrupole mass spectrometer employing multiple reaction monitoring (MRM). The RADAR scanning mode alternated between full-scan MS and MRM to monitor matrix components, placebo peaks, and degradants while accurately quantifying the target nitrosamine impurity.

Used Instrumentation

• UPLC: Waters ACQUITY H-Class Plus
• Mass spectrometer: Waters Xevo TQ-S Micro Cronos triple quadrupole
• Column: Atlantis™ Premier BEH C18 AX, 100 × 2.1 mm, 2.5 µm

Key Results and Discussion

The method achieved a signal-to-noise ratio greater than 80 at 0.006 ppm impurity concentration relative to API. The limit of quantification (LOQ) was determined to be 0.03 ppm, with an instrument LOQ of 0.006 ppm. Calibration was linear over the range 0.006–5.0 ppm. Spike recovery studies yielded recoveries of 82 %, within the acceptable 70–120 % range. RADAR scans effectively separated the nitrosamine impurity from the API peak and enabled diverting the latter to waste, minimizing instrument contamination and enhancing robustness.

Benefits and Practical Applications

This analytical method offers pharmaceutical quality control laboratories a highly sensitive, selective, and reproducible tool for monitoring trace nitrosamine impurities in Diltiazem drug products. Its rapid turnaround and robustness make it suitable for routine compliance testing under stringent regulatory requirements.

Future Trends and Opportunities

Advances may include integration of automated sample preparation workflows, high-resolution mass spectrometry for structure confirmation, and AI-driven method optimization. Expansion of this approach to other nitrosamine impurities and portable LC-MS platforms could further enhance on-site testing capabilities and support continuous quality assurance.

Conclusion

A sensitive and robust LC-MS/MS method using UPLC separation and Xevo TQ-S Micro detection has been established for quantifying N-Nitroso-N-Des methyl Diltiazem impurity. The approach meets regulatory sensitivity requirements, demonstrates excellent linearity and recovery, and minimizes maintenance through RADAR-enabled waste diversion of the API signal.