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Chiral detection of entecavir stereoisomeric impurities through coordination with R ‐besivance and Zn II using mass spectrometry
Author(s) -
Wang Yali,
Wang Lu,
Chen Xiaolei,
Sun Cuirong,
Zhu Yixin,
Kang Yu,
Zeng Su
Publication year - 2018
Publication title -
journal of mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.475
H-Index - 121
eISSN - 1096-9888
pISSN - 1076-5174
DOI - 10.1002/jms.4060
Subject(s) - chemistry , analyte , mass spectrometry , enantiomer , impurity , ion , analytical chemistry (journal) , selectivity , divalent , chromatography , stereochemistry , organic chemistry , catalysis
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 [M II (A)(ref*) 2 ] 2+ (M II  = 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 Zn II coordinated with the chiral reference R ‐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 [Zn II ( R ‐B)A‐H] + ( m/z 733) and [Zn II ( R ‐B) 2 ‐H] + ( m/z 849), together with [ R ‐B + H] + ( m/z 394) and [A + H] + ( m/z 278), 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.

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