非布司他副反应及降解杂质的分离和鉴定  

Isolation and identification of impurities after side reactions and degradation of febuxostat

作　　者：吴强[1] 刘伟[1] 李丰[1] 何广卫[1] 

机构地区：[1]合肥医工医药有限公司,合肥230601

出　　处：《药物分析杂志》2015年第3期440-446,共7页Chinese Journal of Pharmaceutical Analysis

摘　　要：目的:分离和鉴定非布司他的副反应及降解有关物质。方法:采用LC-MS技术对非布司他原料中的3个杂质进行了鉴定,色谱柱为Diamonsil C18(200 mm×4.6 mm,5μm),流动相为甲醇-0.1%醋酸(60∶40),流速1.0 m L·min-1;利用制备高效液相色谱从非布司他原料中分离制备了其中2个杂质,并进一步采用红外光谱及核磁共振技术进行结构确证。结果:推测副反应产物为2-(3-((羟基亚胺)甲基)-4-异丁氧苯基)-4-甲基噻唑-5-羧酸和5-(5-(乙氧羰基)-4-甲基噻唑-2-基)-2-异丁氧苯甲酸,主要降解产物为2-(3-氨甲酰基-4-异丁氧苯基)-4-甲基噻唑-5-羧酸。结论:本法为非布司他的质量控制提供科学依据。Objective： To isolate and identify impurities after side reactions and degradation of febuxostat.Methods： LC- MS was adopted to analyze the structure of three impurities. The HPLC was performed on a Diamonsil C18（ 200 mm ×4. 6 mm,5 μm） column with methanol-0. 1% acetic acid（ 60∶ 40） as the mobile phase at a flow rate of 1. 0 m L·min- 1. Two impurities were separated from febuxostat by prep- HPLC,and their structures were further identified by IR and NMR. Results： The structures of impurities A,B after side reactions were presumed as 2-（ 3-（（ hydroxyimino） methyl）-4- isobutoxyphenyl）-4- methylthiazole-5- carboxylic acid,5-（ 5-（ ethoxycarbonyl）- 4- methylthiazol- 2- yl）- 2- isobutoxybenzoic acid,and the main degradation product impurity C was presumed as 2-（ 3- carbamoyl- 4- isobutoxyphenyl）- 4- methylthiazole- 5- carboxylic acid. Conclusion： This study on identification of impurities is a sound scientific basis for the quality control of febuxostat.

关 键 词：XOR酶抑制剂 非布司他 有关物质 副反应杂质 降解产物 杂质鉴定 液相色谱-质谱联用 核磁共振 红外光谱 

分 类 号：R917[医药卫生—药物分析学]