Baertschi Steven W, Brunner Heiko, Bunnell Charles A, Cooke Gary G, Diseroad Benjamin, Dorman Douglas E, Jansen Patrick J, Kemp Craig A J, Maple Steven R, McCune Karen A, Speakman Jeffrey L
Eli Lilly and Company, Analytical Sciences Research and Development, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
J Pharm Sci. 2008 Feb;97(2):883-92. doi: 10.1002/jps.21146.
Two impurities found in both stressed and aged solid-state formulations of olanzapine have been identified as (Z)-1,3-dihydro-4-(4-methyl-1-piperazinyl)-2-(2-oxopropylidene)-2H-1,5-benzodiazepin-2-one (1) and (Z)-1-[1,2-dihydro-4-(4-methyl-1-piperazinyl)-2-thioxo-3H-1,5-benzodiazepin-3-ylidene]propan-2-one (2). The structures indicate that the two impurities are degradation products resulting from oxidation of the thiophene ring of olanzapine. The impurities were isolated by preparative HPLC from a thermally stressed formulation, and characterized by UV, IR, MS, and NMR. A synthetic preparation of compounds 1 and 2 by reaction of olanzapine with the singlet oxygen mimic 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) is presented. The structure of 2 was also determined by single-crystal X-ray diffraction analysis. A degradation pathway for the formation of 1 and 2 is proposed.
在奥氮平的加速老化和长期老化固态制剂中均发现的两种杂质已被鉴定为(Z)-1,3-二氢-4-(4-甲基-1-哌嗪基)-2-(2-氧代亚丙基)-2H-1,5-苯并二氮杂䓬-2-酮(1)和(Z)-1-[1,2-二氢-4-(4-甲基-1-哌嗪基)-2-硫代-3H-1,5-苯并二氮杂䓬-3-亚基]丙烷-2-酮(2)。结构表明这两种杂质是奥氮平噻吩环氧化产生的降解产物。通过制备型高效液相色谱法从热加速老化制剂中分离出这些杂质，并通过紫外、红外、质谱和核磁共振进行表征。本文介绍了通过奥氮平与单线态氧模拟物4-苯基-1,2,4-三唑啉-3,5-二酮(PTAD)反应合成化合物1和2的方法。化合物2的结构也通过单晶X射线衍射分析确定。提出了形成1和2的降解途径。
