Losartan API and Nitrosamines Impurities-Stability Profile Investigation Using HPLC, LC-MS, and In Silico Assessment

Area of Science:

• Pharmaceutical Chemistry
• Analytical Chemistry
• Drug Stability

Background:

• Nitrosamines are genotoxic impurities with known mutagenic and carcinogenic effects.
• Their presence in pharmaceuticals like losartan necessitates understanding their impact on drug stability.
• Losartan is an angiotensin II receptor blocker frequently used in treating hypertension.

Purpose of the Study:

• To investigate the influence of four common nitrosamines (NDMA, NDEA, NDIPA, NDBA) on the stability profile of losartan Active Pharmaceutical Ingredient (API).
• To monitor losartan degradation rates and identify degradation products under various stress conditions in the presence of nitrosamines.
• To correlate experimental findings with in silico predictions of nitrosamine reactivity and degradation pathways.

Main Methods:

• Quantitative analysis of losartan residual content using High-Performance Liquid Chromatography (HPLC) and Liquid Chromatography-Mass Spectrometry (LC-MS).
• Exposure of losartan API to various stress conditions: photolysis, oxidation, acid, and basic media, in the presence of specific nitrosamines.
• In silico investigations using Zeneth Nexus and Spartan to predict degradation products, fragmentation pathways, and nitrosamine reactivity.

Main Results:

• Losartan degradation varied significantly based on the type of nitrosamine and stress condition applied.
• Photolysis resulted in 80%-90% losartan residual content, with increased decomposition in samples containing nitrosamines.
• Oxidative degradation showed increased decomposition, except in samples with NDMA. Acidic and basic conditions led to substantial decomposition (41%-52% and 28%-51% residual losartan, respectively).
• Nitrosamines were often undetected in degraded samples, suggesting their consumption, and potentially a protective effect against degradation due to their reactivity.

Conclusions:

• Nitrosamines significantly influence the degradation kinetics and pathways of losartan API.
• The reactivity of nitrosamines can lead to their consumption during degradation processes and may offer a protective effect on the drug.
• Seven degradation products were structurally proposed, with some predicted computationally, highlighting the complexity of losartan degradation in the presence of nitrosamines.