title: 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.
authors.affiliation: Department of Research and Development, Esteve-Quimica S.A., Barcelona, Catalonia, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Redondo
authors.forename: Anna
authors.initials: A
authors.lastname: Capdevila
authors.forename: Sonia
authors.initials: S
authors.lastname: Ciudad
mesh_terms: D000085:Acetates / Q000032:analysis* / Q000737:chemistry*; D018927:Anti-Asthmatic Agents / Q000032:analysis* / Q000737:chemistry*; D002930:Cinchona Alkaloids / Q000737:chemistry; D003521:Cyclopropanes; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D009281:Naphthalenes / Q000737:chemistry; D011804:Quinolines / Q000032:analysis* / Q000737:chemistry*; D012995:Solubility; D013237:Stereoisomerism; D013440:Sulfides; D014867:Water / Q000737:chemistry
chemical_list: D000085:Acetates; D018927:Anti-Asthmatic Agents; D002930:Cinchona Alkaloids; D003521:Cyclopropanes; D009281:Naphthalenes; D011804:Quinolines; C475744:S(-)2,2'-dihydroxy-1,1'-binaphthyl; D013440:Sulfides; D014867:Water; C041622:cinchonidine; C093875:montelukast
keywords: chiral shift agents; enantiodifferentiation; montelukast; nuclear magnetic resonance; optical purity monitoring