State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, No. 2 Linggong Road, Ganjingzi District, Dalian, Liaoning Province 116024, PR China.
Analyst. 2011 Aug 7;136(15):3149-56. doi: 10.1039/c1an15155j. Epub 2011 Jun 22.
A simple and stability-indicating reverse phase high performance liquid chromatographic (RP-HPLC) method was developed and validated for the determination of olanzapine (OLN) and related impurities in bulk drugs. Eight impurities were characterized respectively, and particularly a new process impurity from OLN synthesis was structurally confirmed as 1-(5-methylthionphen-2-yl)-1H-benzimidazol-2(3H)-one (Imp-7) by X-ray single crystal diffraction, MS, (1)H NMR, (13)C NMR and HSQC. A mechanism of formation pathway for Imp-7 was proposed. Optimum separation for OLN and eight related impurities was carried out on an Agilent Octyldecyl silica column (TC-C(18), 4.6 mm × 250 mm, 5 μm) using a gradient HPLC method. The method was validated with respect to specificity, linearity, accuracy, precision, LOD and LOQ. Regression analysis showed good correlation (r(2) > 0.9985) between the investigated component concentrations and their peak areas within the test ranges for OLN and eight impurities. The repeatability and intermediate precision, expressed as RSD, were less than 1.74%. The proposed stability-indicating method was suitable for routine quality control and drug analysis of OLN in bulk drugs.
建立并验证了一种用于测定奥氮平（OLN）及其原料药中有关物质的简单且专属性强的反相高效液相色谱法（RP-HPLC）。分别对 8 个杂质进行了特征鉴别，特别是通过 X 射线单晶衍射、MS、（1）H NMR、（13）C NMR 和 HSQC，对 OLN 合成中的一个新的工艺杂质进行了结构确证，将其确证为 1-（5-甲基噻吩-2-基）-1H-苯并咪唑-2（3H）-酮（Imp-7）。提出了 Imp-7 的形成途径机制。采用梯度 HPLC 法，在 Agilent Octyldecyl 硅胶柱（TC-C(18)，4.6mm×250mm，5μm）上对 OLN 和 8 个有关物质进行了最佳分离。对该方法进行了专属性、线性、准确度、精密度、检测限和定量限验证。回归分析表明，在所研究的 OLN 和 8 个杂质浓度范围内，其峰面积与浓度之间具有良好的相关性（r(2)＞0.9985）。重复性和中间精密度（用 RSD 表示）均小于 1.74%。该专属性方法适用于 OLN 原料药的常规质量控制和药物分析。
