Chiral detection of entecavir stereoisomeric impurities through coordination with R‐besivance and Zn^II using mass spectrometry

Abstract

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 (A)(ref*) ] (M = 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 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 (R-B)A-H] (m/z 733) and [Zn (R-B) -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.

Direct differentiation of stereoisomers of ezetimibe/ambrisentan/atorvastatin and their mechanism study by electrospray ionization quadrupole time‐of‐flight mass spectrometry

“…In the research, we chose the appropriate collision energy scale (2 to 8 eV) to explore the separation effect under different collision energies. 49 The breakdown curves in Figure 2 show the plots between two isomers keep similar trend from 2 to 8 eV. The result means that a certain collision energy change is not much an important effect on the stereoselectivity in the kinetic method.…”

“…All four isomeric identification could also be fulfilled by comparing their breakdown curves (Figure ). In the research, we chose the appropriate collision energy scale (2 to 8 eV) to explore the separation effect under different collision energies . The breakdown curves in Figure show the plots between two isomers keep similar trend from 2 to 8 eV.…”

Exploration of chiral drugs as references for chiral discrimination of valsartan and voriconazole by tandem mass spectrometry

“…Meanwhile, Gatlin et al investigated electrospray ionization (ESI) mass spectra of in‐situ‐formed ternary complexes of Cu 2+ and 1,10‐phenanthroline with the 20 essential amino acids (AA) and found [Cu (AA‐H)diimine] + have large stability constants in water or aqueous methanol; thus, they can be selected as a precursor ion 11 . To date, with factors such as metal ions as the center of complexes, chiral amino acids or modified amino acids, and chiral sugars as references, this method has been successfully applied in the chiral discrimination of amino acids, 9,10 peptides, 12–14 sugars, 15–19 and several chiral drugs 20–27 . However, adequate discrimination of many chiral drugs is still not possible, as applicable references that have chiral discrimination abilities for chiral drugs of interest are currently unavailable.…”

Analysis of stereoisomers of chiral drug by mass spectrometry

“…It proved to be fast (2 min for analysis of each sample) and to have accuracy comparable to chiral LC-MS/MS and LC-UV method. 40 In this method, the chiral analyte reacts with the host molecule in the presence of divalent metal ion such as Mn 2+ , Fe 2+ , Co 2+ , Ni 2+ , Cu 2+ , and Zn 2+ to form diastereomeric trimeric complexes. 38,39 Besides, the same group also applied this method in the differentiation of entecavir by forming complex with R-besivance and Zn II .…”

“…38,39 Besides, the same group also applied this method in the differentiation of entecavir by forming complex with R-besivance and Zn II . 40 In this method, the chiral analyte reacts with the host molecule in the presence of divalent metal ion such as Mn 2+ , Fe 2+ , Co 2+ , Ni 2+ , Cu 2+ , and Zn 2+ to form diastereomeric trimeric complexes.…”