Determination of the Enantiomeric Purity of the Antiasthmatic Drug Montelukast by Means of ¹H NMR Spectroscopy

Abstract

In order to define an enantioselective nuclear magnetic resonance (NMR) method for the antiasthmatic drug montelukast, a series of nine easily available products were evaluated as NMR chiral solvating agents (CSAs): D-dibenzoyltartaric acid, D-ditoluoyltartaric acid, (+)-camphorsulfonic acid, (S)-BINOL, (S)-3,3'-diphenyl-2,2'-binaphthyl-1,1'-diol, (R)-3,3''-di-9-anthracenyl-1,1''-bi-2-naphthol, (R)-3,3''-di-9-phenanthrenyl-1,1''-bi-2-naphthol, Pirkle's alcohol, and (-)-cinchonidine. It was proved that most of the studied agents constitute diastereomeric complexes with both drug enantiomers in CD2 Cl2 or CDCl3 solutions, thus permitting the direct (1)H NMR detection of the unwanted S-enantiomer, even at levels of 0.75%. (-)-Cinchonidine was found to be the more convenient CSA in terms of NMR enantiodiscrimination power and ease of experimental requirements. The final method was validated and applied to the fast monitoring of the optical purity of montelukast "in-process" samples, circumventing the need for tedious and slower analytical procedures like enantioselective chromatography or capillary electrophoresis. In addition, a method for the enantiopurity control of the commercial drug (montelukast sodium salt) was also established using (S)-BINOL as NMR CSA.

Enantiodifferentiation of promethazine using (S)-(−)-BINOL as the NMR chiral solvating agent: determination of the enantiomeric purity and performance comparison with traditional chiral HPLC

“…In addition, enantiomeric atropoisomers of BINOL exhibit a wide range of potential applications as CSA since they were reported to be suitable tools for the enantiomeric excess determination of a plethora of structurally different chiral compounds including sulfoxides, 30 sulfinimines, 31 thiosulfinates, 32 phytoalexins, 33 and various APIs such as fenfluramine, sertraline, and paroxetine 34 as well as montelukast, 35 crispine A, 36 and omeprazole and its analogues. 37 Several different BINOL derivatives have also been found to be effective chiral solvating agents toward a-hydroxy carboxylic acids, 38 amino acids, 39 and amines.…”

A New Chirally Organized Trifluoromethylanthrylmethanol Derivative and Its Application as Chiral Solvating Agent

“…Herein, we report on the synthesis and the enantiodifferentiation behaviour of 1,1′‐(((10,10’‐(1,1′‐binaphthalene)‐2,2′‐diylbis(oxy))bis(methylene))bis(anthracene‐10,9‐diyl))bis(2,2,2‐trifluoroethanol), 4 , a new CSA which incorporates both, axial and central chirality, and additionally presents a remarkable increase of its aromatic surface. This new compound contains two anthracene subunits and a (1,1’‐binaphtalene)‐2,2’‐diol (BINOL) moiety, which has also been used previously as a CSA itself …”

“…This new compound contains two anthracene subunits [14][15][16][17] and a (1,1'-binaphtalene)-2,2'-diol (BINOL) moiety, which has also been used previously as a CSA itself. [18][19][20]…”

Simultaneous Determination of Montelukast Sodium S-Enantiomer and A5 Enantiomers in Montelukast Sodium Bulk Drug by Normal-Phase Chiral HPLC

“…Although a few analytical methods for determination of montelukast sodium S-enantiomer have been reported, for instance, Redondo et al [21] developed a test method with an enantioselective proton nuclear magnetic resonance ( 1 H NMR) spectroscopy by adding (-)-cinchonidine into montelukast sodium, but because of a low sensitivity, it was not used for quantitation of S-enantiomer at very low levels (below 0.5%), and the method established by Lida et al [22] and the method embodied in EP 8.0 all performed on an AGP chiral column with stationary phase of α-acid glycoprotein [23] , it is easily destroyed under various severe conditions, such as organic reagent, acidic or alkaline etc. Hence, its life time is too short conventionally.…”