Characterization of Degradation Products of Macitentan under Various Stress Conditions Using Liquid Chromatography/Mass Spectrometry

Autor: Sukanya Pandeti, Jean-Claude Tabet, Jagadeshwar Reddy Thota, Naga Veera Yerra, Pavankumar Pallerla
Přispěvatelé: CSIR Indian Institute of Chemical Technology [Hyderabad] (IICT), Chimie Structurale Organique et Biologique (CSOB), Institut Parisien de Chimie Moléculaire (IPCM), Chimie Moléculaire de Paris Centre (FR 2769), Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Chimie Moléculaire de Paris Centre (FR 2769), Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Rapid Communications in Mass Spectrometry
Rapid Communications in Mass Spectrometry, Wiley, 2018, 32 (13), pp.1075--1084. ⟨10.1002/rcm.8138⟩
ISSN: 0951-4198
1097-0231
DOI: 10.1002/rcm.8138⟩
Popis: 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.
Databáze: OpenAIRE
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