Chiral detection of entecavir stereoisomeric impurities through coordination with R-besivance and Zn-II using mass spectrometry
Chiral detection of entecavir stereoisomeric impurities through coordination with R-besivance and Zn-II using mass spectrometry
复制标题
使用质谱法与 R-besivance 和 Zn-II 配合手性检测恩替卡韦立体异构杂质
DOI：
10.1002/jms.4060
复制
发表时间：
2018
影响因子：
2.3
通讯作者：
Zeng Su
中科院分区：
文献类型：
--
作者：
Wang Yali;Wang Lu;Chen Xiaolei;Sun Cuirong;Zhu Yixin;Kang Yu;Zeng Su
在这项研究中，基于质谱（MS）的动力学方法（KM）被证明可以成功地对多手性中心药物立体异构体恩替卡韦（ETV）进行定性和定量分析。在KM的基础上，在MS/MS中设置二价配合离子[MII(A)(ref*)2]2+（MII=二价金属离子，A =分析物，ref* =手性参比物）为前体离子。实验结果表明，当使用手性参考物-辅助度（R - B）配位时，ETV及其同分异构体具有很强的手性选择性。由于参比物和分析物的竞争性损失，碎片离子丰度比的对数与对映体百分比（%）表现出很强的线性关系。产物离子对[ZnII(R‐B)A‐H]+(m/z733)和[ZnII(R‐B)2‐H]+(m/z849)以及[R‐B + H]+(m/z394)和[A + H]+(m/z278)可实现对ETV及其所有手性异构体的鉴定。采用6‐31G*和LanL2DZ基的B3LYP函数进行了理论计算，阐明了这两种二价配合离子结构差异的机理。结果表明，MS - KM可用于检测光学杂质，无需手性色谱柱和繁琐的样品前处理。建立的方法已用于测定ETV药材中小于0.1%的立体异构体杂质，证明了该方法对立体异构体杂质的快速检测简单有效。
In this study, a mass spectrometry (MS)‐based kinetic method (KM) is shown to be successful at analyzing a multichiral center drug stereoisomer, entecavir (ETV), both qualitatively and quantitatively. On the basis of the KM, the bivalent complex ion [MII(A)(ref*)2]2+(MII= divalent metal ion, A = analyte, and ref* = chiral reference) was set as precursor ion in MS/MS. The experiment results suggest strong chiral selectivity between ETV and its isomers when using ZnIIcoordinated with the chiral referenceR‐besivance (R‐B). The logarithm of the fragment ion abundance ratio and the enantiomeric percentage (%) exhibits a strong linear relation because of the competitive loss of the reference and analyte. The product ion pair [ZnII(R‐B)A‐H]+(m/z733) and [ZnII(R‐B)2‐H]+(m/z849), together with [R‐B + H]+(m/z394) and [A + H]+(m/z278), can realize the identification of ETV and all of its chiral isomers. Theoretical calculation were also performed using the B3LYP functional with the 6‐31G* and LanL2DZ basis set to clarify the mechanism of structural difference of these bivalent complex ions. The results reveal that MS‐KM can be used to detect optical impurities without a chiral chromatographic column and fussy sample pretreatment. The established method has been used to determine stereoisomeric impurities of less than 0.1% in ETV crude drug, a demonstration of its simple and effective nature for rapid detection of stereoisomeric impurities.