Degradation study of the investigational anticancer drug clanfenur.
Clanfenur belongs to a new group of substituted benzoylphenylureas. The drug shows both in vitro and in vivo antitumour activity. To assess its chemical stability, a study was carried out in which the effect of pH, temperature, ionic strength and buffer concentration on the reaction rate constant k(obs) were examined. A stability-indicating reversed-phase high performance liquid chromatography (RP-HPLC) system was used. The pH-log k(obs) degradation profile, obtained at 70 degrees C, shows that clanfenur has its maximum stability in the pH region 4-5. At pH 7, half-lives were calculated by extrapolation of the Arrhenius plot; at 4 degrees C the half-life was calculated to be 141 years and at 25 degrees C 9. 5 years. The activation energy was calculated to be 114 kJ/mol. In acidic, neutral, and alkaline media, the ionic strength has no effect on the degradation. The buffer concentration of citrate, phosphate, borate, and carbonate did not affect the value of k(obs). An RP-HPLC chromatogram of degraded clanfenur shows the presence of four degradation products, three of which were identified by LC-ESI-MS as p-chloroaniline, p-chlorophenylurea and 2-fluoro-6-dimethylaminobenzamide.
Sluiter
C
C
Sigma Coatings, B.V. Oceanenweg 2, P.O. Box 58061, 1040 HB, Amsterdam, The Netherlands.
Kettenes-van den Bosch
J J
JJ
Hop
E
E
van der Houwen
O A
OA
Underberg
W J
WJ
Bult
A
A
D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002021:Buffers; D002851:Chromatography, High Pressure Liquid; D004132:Diflubenzuron / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004355:Drug Stability; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D013058:Mass Spectrometry; D009994:Osmolar Concentration; D015203:Reproducibility of Results; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet; D014867:Water / Q000737:chemistry
D000970:Antineoplastic Agents; D002021:Buffers; D012996:Solutions; D014867:Water; D004132:Diflubenzuron; C086806:clanfenur