Application of high-performance liquid chromatographic chiral stationary phases to pharmaceutical analysis structural and conformational effects in the direct enantiomeric resolution of α-methylarylacetic acid antiinflammatory agents

Abstract A series of four α-methylarylacetic acids of pharmaceutical interest were directly resolved as enantiomeric amide derivatives on a high-performance liquid chromatographic chiral stationary phase consisting of covalently bound ( R )-N-(3,5-dinitrobenzoyl)phenylglycine. Enantiomers of ibuprofen, naproxen fenoprofen and benoxaprofen all exhibited optimum separation (α = 1.12, 1.23, 1.12 and 1.10, respectively) as 1-naphthalenemethylamides. Derivatives of ibuprofen were studied in detail; measurable separations were observed for secondary and tertiary amides of diverse structural types, but not for the primary amide or for ester derivatives. The results, which are consistent with an interaction model involving stacking of amide dipoles, with or without supplementary π—π and hydrogen-bonding effects, appear to be strongly dependent on conformational requirements of both the solute and the chiral stationary phase.