Structural identification and characterization of potential degradants of zotarolimus on zotarolimus-coated drug-eluting stents.
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.
Chen
Quan
Q
Global Analytical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA. quan.chen@abbott.com
Zielinski
Dorota
D
Chen
Jenny
J
Nowak
Steve
S
Zhou
Casey Chun
CC
D002626:Chemistry, Pharmaceutical / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004355:Drug Stability; D054855:Drug-Eluting Stents; D006358:Hot Temperature; D006813:Humidity; D006868:Hydrolysis; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008956:Models, Chemical; D008968:Molecular Conformation; D010100:Oxygen / Q000737:chemistry; D011714:Pyrans / Q000737:chemistry; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000032:analysis / Q000302:isolation & purification; D013056:Spectrophotometry, Ultraviolet / Q000379:methods
D011714:Pyrans; C489443:zotarolimus; D010100:Oxygen; D020123:Sirolimus