Macitentan: An overview of its degradation products, process-related impurities, and in silico toxicity.

Abstract

Macitentan is a dual endothelin receptor antagonist indicated for the treatment of pulmonary arterial hypertension, a chronic and complex disease. Under different stress conditions, such as changes in pH and temperature, the drug can generate a large number of degradation products, while many process-related impurities can occur during the four main synthetic routes. The assessment of the potential toxicity of these impurities is an essential regulatory requirement for the quality and safety of drugs. The goal of this study was to identify all metabolites and potential impurities for macitentan and evaluate their in silico toxicity. Thirty-five compounds related to macitentan were found reported in the literature, two of which were described simultaneously as metabolites, degradation products, and process-related impurities. In the present study, the main degradation products and the conditions under which they could be formed, and the major impurities according to the synthetic route, are discussed. The types and amounts of process-related impurities were dependent on the synthesis route and process controls, while macitentan was found to be more susceptible to degradation in acidic media resulting in the most different types of degradation products. The structure of each compound was generated and the potential risk for mutagenicity and carcinogenicity were determined using three different in silico platforms, in addition the metabolic substrate/inhibition profile for each compound was assessed. Overall, five compounds were considered critical as they had a possible toxicity risk in terms of mutagenicity, tumorigenicity, irritation, and reproductive effects. These data support the current legislation for raw materials and pharmaceutical products containing macitentan as to prevent any adverse effects from this drug.