Navigating the complexities in characterization of NDSRIs using advanced analytical techniques

Area of Science:

• Analytical Chemistry
• Pharmaceutical Science
• Organic Chemistry

Background:

• Accurate detection and quantification of nitrosamine drug substance related impurities (NDSRIs) are essential for pharmaceutical quality control.
• The structural complexity of NDSRIs often necessitates in-house synthesis and characterization of analytical standards.
• Alternative synthetic pathways can lead to unexpected impurities, complicating analysis.

Purpose of the Study:

• To explore the application of LC-MS and NMR spectroscopy for characterizing NDSRIs.
• To identify new process-related impurities formed during NDSRI synthesis.
• To highlight the importance of advanced analytical techniques for ensuring pharmaceutical product quality.

Main Methods:

• Liquid chromatography-mass spectrometry (LC-MS) for separation and preliminary identification.
• Nuclear magnetic resonance (NMR) spectroscopy, including ¹⁵N 2D NMR, for detailed structural elucidation.
• In-house synthesis and characterization of NDSRI standards.

Main Results:

• LC-MS and NMR spectroscopy were successfully applied to characterize NDSRIs.
• Three new process-related impurities were identified during NDSRI synthesis.
• Distinguishing C- and N-nitroso analogs was challenging using MS alone due to identical mass, underscoring the value of NMR.

Conclusions:

• Advanced analytical techniques, particularly LC-MS and NMR spectroscopy, are vital for accurate identification of NDSRIs.
• The study emphasizes the utility of ¹⁵N 2D NMR for investigating impurity formation mechanisms.
• Enhanced characterization of NDSRIs ensures higher pharmaceutical product quality and safety.