2211059-05-9Relevant articles and documents
Characterization of degradation products of macitentan under various stress conditions using liquid chromatography/mass spectrometry
Yerra, Naga Veera,Pallerla, Pavankumar,Pandeti, Sukanya,Tabet, Jean-Claude,Thota, Jagadeshwar Reddy
, p. 1075 - 1084 (2018/06/11)
Rationale: Stress testing of a drug candidate is an important step in the drug discovery and development process. The presence of degradation products in a drug affects the quality as well as the safety and efficacy of drug formulation. Hence, it is essential to develop an efficient analytical method which could be useful for the separation, identification and characterization of all possible degradation products (DPs) of a drug. Macitentan (MT) is an endothelin receptor antagonist (ERA) drug used to treat high blood pressure in the lungs. Comprehensive stress testing of MT was carried out as per ICH guidelines to understand the degradation profile of the drug. Methods: MT was subjected to various stress conditions such as acidic, basic, neutral hydrolysis, oxidation, photolysis and thermal conditions; and the resulting degradation products were investigated using liquid chromatography/diode-array detection/electrospray ionization high-resolution mass spectrometry (LC/DAD/ESI-HRMS) and tandem mass spectrometry (MS/MS) techniques. An efficient and simple ultra-high-performance liquid chromatography (UHPLC) method has been developed using an Accucore C18 column (4.6?×?150?mm, 2.6?μm) using a gradient elution of 5?mM ammonium formate and acetonitrile as mobile phases. Results: MT was found to degrade under acid and base hydrolysis stress conditions; whereas it was stable under oxidation, neutral hydrolysis, thermal and photolytic conditions. MT formed nine DPs (DP1 to DP9) and one DP (DP10) under acidic and basic hydrolytic conditions, respectively. All the degradation products (DP1 to DP10) were identified and characterized by LC/MS/MS in positive ion mode with accurate mass measurements. Conclusions: MT was found to be labile under hydrolytic conditions. The structures of the DPs were characterized by appropriate mechanisms. The proposed method can be effectively used for the characterization of MT and its DPs.
The metabolism of the dual endothelin receptor antagonist macitentan in rat and dog
Treiber, Alexander,Miraval, Tommaso,Bolli, Martin H.,Funel, Jacques-Alexis,Segrestaa, Jerome,Seeland, Swen
, p. 253 - 267 (2016/02/05)
1. The metabolism of the endothelin receptor antagonist macitentan has been characterized in bile duct-cannulated rats and dogs.2. In both species, macitentan was metabolized along five primary pathways, i.e. conjugation with glucose (M9), oxidative depropylation (M6), aliphatic hydroxylation (M7), oxidative cleavage of the ethylene glycol linker (M4) and hydrolysis of the sulfamide moiety (M3). Most of the primary metabolites underwent subsequent biotransformation including conjugation with glucuronic acid or glucose, hydrolysis of the sulfamide group or secondary oxidation of the ethylene glycol moiety.3. Though there were species differences in their relative importance, all metabolic pathways were present in rat and dog. The depropylated M6 was the only metabolite present in plasma of both species.4. Metabolism was a prerequisite for macitentan excretion as relevant amounts of parent drug were neither detected in bile nor urine. Biliary excretion was the major elimination pathway, while renal elimination was of little importance.
