Characterization of an unknown impurity in doxofylline using LC-MS and NMR.
During quality control of doxofylline, a novel impurity was detected, which was above the identification threshold defined by ICH. First, a liquid chromatographic method compatible with mass spectrometric (MS) detection was developed. Based on tandem multistage MS and high resolution MS data, the unknown impurity was found to consist of two theophylline groups connected by a methylene group. The structure was further confirmed by 1D and 2D nuclear magnetic resonance (NMR) experiments after semi-preparative isolation. In addition, the formation of the impurity was also discussed.
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, Zhejiang, China; KU Leuven, University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, Herestraat 49, O&N2, PB 923, 3000 Leuven, Belgium; Zhejiang Institute for Food and Drug Control, Hangzhou 310053, Zhejiang, China.
Peixi
P
Zhu
Zhejiang Institute for Food and Drug Control, Hangzhou 310053, Zhejiang, China.
Jingxian
J
Lu
Zhejiang Institute for Food and Drug Control, Hangzhou 310053, Zhejiang, China.
Liya
L
Hong
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, Zhejiang, China.
Weike
W
Su
KU Leuven, University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, Herestraat 49, O&N2, PB 923, 3000 Leuven, Belgium.
Ann
A
Van Schepdael
KU Leuven, University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Pharmaceutical Analysis, Herestraat 49, O&N2, PB 923, 3000 Leuven, Belgium. Electronic address: erwin.adams@pharm.kuleuven.be.
Erwin
E
Adams
D002851:Chromatography, High Pressure Liquid; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D013806:Theophylline / Q000031:analogs & derivatives* / Q000032:analysis
D013806:Theophylline; C029797:doxofylline
Doxofylline; Impurity; LC–MS; NMR