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

Abstract

A mass spectrometric method is introduced for rapid and accurate chiral quantification by examining a trimeric metal complex into which a chiral reference is incorporated with the analyte. Several metal ions (CuII, NiII, MgII, MnII, CoII, and ZnII) were selected as the central metal ion, and chiral drugs ezetimibe (EZM) and ambrisentan (AMB) were used as the reference to each other for isomeric differentiation by using electrospray ionization quadrupole time‐of‐flight mass spectrometry. Doubly charged trimeric cluster ions instead of the singly charged clusters were applied in this study. Kinetic method (KM) and chiral recognition (CR) method were used for construction of a calibration curve for chiral quantitation. The results from the two methods were found to be complementary to each other, which improved quantitative analysis of stereoisomers for EZM. Furthermore, we have successfully used S‐AMB as reference for the chiral differentiation of enantiomeric atorvastatin (ATO), which is frequently combined with EZM as a codrug. Experimental results showed that the binary mixture of EZM and ATO enantiomers can be determined simultaneously without prior separation steps. The direct measurement of chiral purity within 5% was demonstrated. This mass spectrometric method represents an effective alternative to commonly used chromatographic techniques as means of chiral purity determination and is of potential use in rapid screening experiments.

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.…”

“…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][13][14] sugars, [15][16][17][18][19] and several chiral drugs. [20][21][22][23][24][25][26][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. In recent research, we successfully achieved chiral recognition using zinc ions or (À)-camphanic acid chlorides as ligands.…”

Improving the Current European Pharmacopoeia Enantio-Selective HPLC Method for the Determination of Enantiomeric Purity in Atorvastatin Calcium Salt Drug Substance

“…Given the importance of the drug, it was surprising to find that only a few enantioselective HPLC methods for ATV have been described in the literature [4,5]. These The main problems of this method are the very long analysis time and high solvent consumption.…”

“…Given the importance of the drug, it was surprising to find that only a few enantioselective HPLC methods for ATV have been described in the literature [4,5]. These methods have been developed in combination with normal-phase conditions without considering the presence of other potential impurities and not verifying the chemo-selectivity and diastereo-selectivity of the analytical conditions.…”

“…Since the total run time is 1.2 times the retention time of ATV, 76 mL of the mobile phase is used for each analysis. Another critical aspect to consider is the potential presence of other impurities in the drug substance that could interfere with the analysis by coeluting with the enantiomer peak or eluting after the ATV peak, further increasing the analysis time.Given the importance of the drug, it was surprising to find that only a few enantioselective HPLC methods for ATV have been described in the literature[4,5]. These methods have been developed in combination with normal-phase conditions without considering…”