Sluiter C, Kettenes-van den Bosch J J, Hop E, van der Houwen O A, Underberg W J, Bult A
Sigma Coatings, B.V. Oceanenweg 2, P.O. Box 58061, 1040 HB, Amsterdam, The Netherlands.
Int J Pharm. 1999 Aug 20;185(2):227-35. doi: 10.1016/s0378-5173(99)00160-x.
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.
氯苯呋脲属于一类新型的取代苯甲酰基苯基脲。该药物在体外和体内均显示出抗肿瘤活性。为评估其化学稳定性，开展了一项研究，考察了pH、温度、离子强度和缓冲液浓度对反应速率常数k(obs)的影响。使用了一种稳定性指示反相高效液相色谱（RP-HPLC）系统。在70℃下获得的pH-log k(obs)降解曲线表明，氯苯呋脲在pH 4-5范围内具有最大稳定性。在pH 7时，通过阿累尼乌斯图外推计算半衰期；在4℃下半衰期计算为141年，在25℃下为9.5年。计算得到的活化能为114 kJ/mol。在酸性、中性和碱性介质中，离子强度对降解无影响。柠檬酸盐、磷酸盐、硼酸盐和碳酸盐的缓冲液浓度不影响k(obs)值。降解后的氯苯呋脲的RP-HPLC色谱图显示存在四种降解产物，其中三种通过LC-ESI-MS鉴定为对氯苯胺、对氯苯基脲和2-氟-6-二甲基氨基苯甲酰胺。
