Abstract
2-(2-Fluoro-4-biphenyl) propionic acid (flurbiprofen), from the phenylalkanoic acid family of nonsteroidal anti-inflammatory drugs (NSAID’s), is currently on the pharmaceutical market as a racemate. This racemic compound was tested for its propensity to undergo the self-disproportionation of enantiomers (SDE) phenomenon by various forms of chromatography (SDEvC), such as routine gravity-driven column chromatography, medium-pressure liquid chromatography (MPLC), preparative thin-layer chromatography (PTLC), and size-exclusion chromatography (SEC), as well as by sublimation (SDEvS). Furthermore, examination by nuclear magnetic resonance (NMR) in various solvents found that flurbiprofen exhibited the phenomenon of self-induced diastereomeric anisochronism (SIDA). By measurement of the diffusion coefficient (D), the longitudinal relaxation time (T1), and the transverse relaxation time (T2) using NMR, as well as by electrospray ionization-mass spectrometry (ESI-MS) examinations, the preferred intermolecular association was found to be solvent dependent, e.g., heterochiral association was preferred in toluene, while homochiral association was preferred in more polar solvents. This study also attempted, unsuccessfully, to correlate the NMR measurements of flurbiprofen with chromatographic outcomes for the rationalization and prediction of chromatographic results based on NMR measurements. Because the intermolecular hydrogen bonding of the acid groups in flurbiprofen overwhelmingly predominates over other intermolecular interactions, flurbiprofen seemed to represent a good test case for this idea. The behavior of scalemic samples of flurbiprofen is important, as, although it is currently dispensed as a racemate, clinical applications of the R enantiomer have been investigated. SDEvC and SDEvS both have ramifications for the preparation, handling, and storage of enantioenriched flurbiprofen, and this concern applies to other chiral drugs as well.
Highlights
Introduction distributed under the terms andStudies of both the nuclear magnetic resonance (NMR) phenomenon of self-induced diastereomeric anisotropy (SIDA) and the phenomenon of the self-disproportionation of enantiomers (SDE) have steadily progressed in recent years
We examined the SDE of 2-(2-fluoro-4-biphenyl)propionic acid, from the phenylalkanoic acid family of nonsteroidal anti-inflammatory drugs (NSAID’s), by several physicochemical processes to clearly demonstrate the danger that the SDE can pose to drug manufacture and storage if due care is not taken regarding the SDE
By the measurement of D, T1, and T2 using NMR, as well as by electrospray ionization-mass spectrometry (ESI-MS) examinations, NMR in various solvents found that flurbiprofen exhibited the phenomenon the preferred intermolecular association was found to be solvent-dependent, e.g., heteBy theassociation measurement of D, Tin
Summary
Studies of both the nuclear magnetic resonance (NMR) phenomenon of self-induced diastereomeric anisotropy (SIDA) and the phenomenon of the self-disproportionation of enantiomers (SDE) have steadily progressed in recent years. Associate in solution in a dynamic equilibrium that is fast on the NMR timescale have significant condition-dependent NMR chemical shifts (δ’s). In such systems, molecules can be present either as single molecules (SM), homochiral associates (HOM), or heterochiral associates (HET) in solution. As the equilibrium shifts with a change in conditions (e.g., concentration or temperature), the contributions of the δ’s from the SM, HOM, and HET states to the population-weighted average δ alter . The SIDA phenomenon with many fine examples in the literature [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18] has been well reviewed in the past [1,19]
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