Mass Spectrometric Quantitation of Chiral Drugs by the Kinetic Method

Abstract

A novel mass spectrometric method for rapid, accurate (2-4% ee) quantitation of chiral drugs is described. Copper(II)-bound complexes of seven model drugs (atenolol, DOPA, ephedrine, pseudoephedrine, isoproterenol, norepinephrine, propranolol) with chiral reference compounds (L-amino acids) are generated by electrospray ionization mass spectrometry. The trimeric complex ions (three chiral ligands--one of the analyte and two of the reference compound) are collisionally activated, and they undergo dissociation by competitive loss of either the neutral reference or the neutral drug molecule. The ratio of the two competitive dissociation rates, viz. the product ion branching ratio, is related via the kinetic method to the enantiomeric composition of the drug mixture. A two-point calibration curve, derived from the kinetic method, allows rapid quantitation of enantiomeric excess of drug mixtures. The chiral sensitivity of the method is such as to allow determination of mixtures with a few percent enantiomeric contamination.

Stereoselectivity in the collision-activated reactions of gas phase salt complexes

“…These differences can be exploited (i.e., by comparison to data for known standards) and used to determine the enantiomeric purity of a sample. Cooks [3][4][5][6][7][8][9][10][11][12][13][14][15][16], Dearden , , Speranza [27][28][29][30][31][32][33][34][35], and others have provided useful examples of this approach to stereochemical analysis.Along with methods for analyzing the enantiomeric purity of products, there is a growing need for the development of new reaction processes that are stereoselective. In general, these processes have been probed in the condensed phase, but there is no reason why mass spectrometry could not also be used to screen gas phase reactions for stereoselectivity [35,36].…”

“…These differences can be exploited (i.e., by comparison to data for known standards) and used to determine the enantiomeric purity of a sample. Cooks [3][4][5][6][7][8][9][10][11][12][13][14][15][16], Dearden , Lebrilla [21][22][23][24][25][26], Speranza [27][28][29][30][31][32][33][34][35], and others have provided useful examples of this approach to stereochemical analysis.…”

Quantitative determination of the enantiomeric composition of panthotenic acid solutions: a mass spectrometry experiment

“…It is possible to group the methods used for chiral recognition and for quantification of enantiomeric excess by mass spectrometry into four wide types: (a) generation of hostguest diasteromeric adducts using a chiral guest; 4,5 (b) determination of rates of ion/molecule reactions between an enantiomeric guest and a host molecule; 6 (c) collisioninduced dissociation (CID) of diasteromeric adducts in a MS/MS experiment; 7 (d) utilization of the kinetic method [8][9][10][11][12] to quantify the MS/MS chiral effect. 13 This last methodology has been successfully applied to quantitative analysis of aminoacids, 13,14 α-hydroxyacids, 15 sugars 16 and some drugs [17][18][19] and has been shown to be fast and to require very small amounts of sample.The chiral distinction based on the kinetic method approach, the subject of this paper, involves, as the first step, the choice of systems that can promote acceptable enantiomeric distinction. In order to do that, the singly-charged …”

Investigation of ion/molecule reactions as a quantification method for phosphorylated positional isomers: An FT-ICR approach

“…In terms of differentiating isomers of important biomolecules by mass spectrometry based techniques, several methods have been reported as classified and reviewed by Cooks and co-workers [16,17] and others [18 -28]. For example, chiral recognition based on gasphase ion/molecule reactions has been investigated by several research groups [18 -25].…”

“…Another mass spectrometric approach for isomeric recognition is based on unique collision-induced dissociation (CID) spectra of isomeric adducts formed from an analyte and a chiral reference [16]. Our laboratory has developed a multicomponent quantification methodology combined with diagnostic ions in CID spectra to determine the composition of mixtures of up to three isomeric species [29 -31].…”