1. Structural identification and characterization of potential degradants of zotarolimus on zotarolimus-coated drug-eluting stents
- Author
-
Jenny Chen, Dorota Zielinski, Casey Chun Zhou, Quan Chen, and Steve Nowak
- Subjects
Drug ,Hot Temperature ,Magnetic Resonance Spectroscopy ,Chemistry, Pharmaceutical ,media_common.quotation_subject ,Clinical Biochemistry ,Molecular Conformation ,Pharmaceutical Science ,Mass spectrometry ,High-performance liquid chromatography ,Analytical Chemistry ,Hydrolysis ,Drug Stability ,Liquid chromatography–mass spectrometry ,Drug Discovery ,medicine ,Zotarolimus ,Chromatography, High Pressure Liquid ,Spectroscopy ,Pyrans ,media_common ,Sirolimus ,Chromatography ,Chemistry ,Drug-Eluting Stents ,Humidity ,Carbon-13 NMR ,Oxygen ,Models, Chemical ,Proton NMR ,Spectrophotometry, Ultraviolet ,medicine.drug - Abstract
Identification and characterization of unknown zotarolimus impurities on zotarolimus-coated drug-eluting stents is an important aspect of product development since the presence of impurities can have a significant impact on quality and safety of the drug product. Four zotarolimus degradation products have been characterized by LC/UV/PDA, LC/MS, LC/MS/MS and NMR techniques in this work. Zotarolimus drug substance and zotarolimus-coated stents were subjected to degradation under heat, humidity, acid or base conditions. The HPLC separation was achieved on a Zorbax Eclipse XDB-C8 column using gradient elution and UV detection at 278 nm. All four impurities generated through the degradation were initially analyzed by LC/MS and/or LC/MS/MS for structural information. Then the isolation of these degradants was carried out by semi-preparative HPLC method followed by freeze-drying of the collected fractions. Finally the degradants were studied by 1H and 13C NMR spectrometry. Based on LC/MS, 1H NMR and 13C NMR data, the structures of these impurities were proposed and characterized as zotarolimus ring-opened isomer (1), zotarolimus hydrolysis product, 16-O-desmethyl ring-opened isomer (2) and zotarolimus lower fragment (3). Degradants 1, 2 and 3 have been observed on degraded zotarolimus-coated stent products.
- Published
- 2009