Stereoselective interaction of ketoprofen enantiomers with β-cyclodextrin: ground state binding and photochemistry (original) (raw)
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Circular dichroism spectra of cyclodextrins–ketoprofen inclusion complexes
Analytica Chimica Acta, 2000
The formation of inclusion complexes among various cyclodextrins (viz. ␣, , ␥, trimethyl--and hydroxypropyl-cyclodextrin) and the S(+) and R(−) enantiomers of ketoprofen was studied by using the circular dichroism (CD) technique. All the cyclodextrins studied, except ␣-cyclodextrin, introduce marked differences between the CD spectra for the S(+) and R(−) enantiomer. A new method for determining the enantiomeric purity in mixtures of both ketoprofen enantiomers based on the use of -cyclodextrin as chiral selector and partial least-squares regression (PLSR) for calibration is proposed. The method provides relative standard errors (RSE) of calibration and prediction of the order of 2%. It was also applied to the determination of the enantiomeric excess of eutomer S(+) in the presence of distomer R(−) contents below 5%. The good results provided by the proposed method and its analytical expeditiousness make it a competitive alternative to chromatographic methods for the same purpose.
Chemical Physics, 2014
Enantiomeric recognition of Propranolol by complexation with b-Cyclodextrin was studied by PM3 method and molecular dynamics (MD) simulation. Gas phase results show that the R-enantiomer complex is more stable than the S-enantiomer complex by 8.54 kJ/mol (Hartree-Fock energy). Using polarized continuum model, solution phase of R-enantiomer complex was found to be more stable than S-enantiomer complex by 25.95 kJ/mol. Both complexes hardly occur at room temperature freeenergy-wise, though, complexation with R-enantiomer is more favorable than with S-enantiomer enthalpy-wise. Also, complexes were studied by molecular dynamics simulation in gas and solution phases. More stability of R-enantiomer complex in gas phase is confirmed by MD van der Waals energy (5.04 kJ/mol) and closely by the counterpart PM3 binding energy (8.54 kJ/mol). Simulation in solution phase indicates more stability of R-enantiomer complex. Finally, simulated transport property provides insight into the high anisotropic atoms motion according to which S-Propranolol found possessing significantly higher dynamics.
The Journal of Physical Chemistry B, 2016
Inclusion of drugs in cyclodextrins is a recognised tool for modifying several properties such as solubility, stability, bioavailability and more. The photoreactive behavior of the β-Cyclodextrin/Ketoprofen complex upon UV exposure showed a significant increase of the photo-decarboxylation while the secondary degradation products by hydroxylation of the benzophenone moiety were inhibited. The results may account for an improvement of Ketoprofen photophysical properties upon inclusion, thus fostering better its topical use. To correlate the structural details of the inclusion with these results a NMR spectroscopic study of Ketoprofen upon inclusion in β-Cyclodextrin was performed. Effects of the magnetically anisotropic centers of ketoprofen, changing their orientations upon inclusion giving chemical shift variations, were specifically correlated to the results of the molecular dynamic simulations and ab initio calculations. In the large variety of papers focusing on the structural analysis of β cyclodextrin complexes, this work represents one of the few examples in which a detailed analysis of these simultaneous upfield-downfield NMR shifts of the same aromatic molecule upon inclusion is reported. Interestingly the results demonstrate that the observed upfield and downfield shifts upon inclusion are not related to any direct magnetic role of the β cyclodextrin. The conformational change of Ketoprofen upon the inclusion process consists in a slight reduction of the angle between the two phenyl rings and in a remarkable reduction of the mobility of the carboxyl group, the latter being one of the main contributions to the NMR resonances shifts. These structural details help in understanding of the inclusion complex features and, eventually, of the driving force for its formation.
Chirality, 2013
The enantiomers of ketoprofen were separated by capillary electrophoresis using the (2,3,6-triO methyl)-derivatives of a-, band nd g-cyclodextrin (CyD) as chiral selectors. The affinity pattern of the ketoprofen enantiomers toward these CyDs changed depending on their cavity size. Thus, with hexakis (2,3,6-triO methyl)-a-CyD and heptakis (2,3,6-triO methyl)-b-CyD, the R enantiomer of the drug migrated first, whereas the enantiomer migration order was reversed in the presence of octakis(2,3,6-triO methyl)-g-CyD. The change in the migration order was rationalized on the basis of changes in the structure of the complexes between the ketoprofen enantiomers and the chiral selectors as derived from nuclear magnetic resonance spectroscopy experiments.
Tetrahedron, 2006
In this paper, we analyze the energetic and conformational preferences involved in the chiral discrimination of ibuprofen (Ibu) isomers by beta-cyclodextrin (b-CD) when forming inclusion complexes in water. This study was performed by means of atomistic molecular mechanics simulations upon four different penetration modes of the guest, and a structural 2D NMR experiment. The trajectories of these simulations were treated with the MM/GBSA method in order to obtain the relative weights of the different free energy components. The resulting values of the free energy of binding and other geometrical features indicate that this chiral selectivity is influenced by a preferred penetration mode involving the S-(C)-Ibu isomer. The calculated DDG of binding is in good agreement with published experiments. q
Molecules, 2021
Racemic ketoprofen (KP) and β-cyclodextrin (β-CD) powder samples from co-precipitation (1), evaporation (2), and heating-under-reflux (3) were analysed using X-ray techniques and nuclear magnetic resonance (NMR) spectroscopy. On the basis of NMR studies carried out in an aqueous solution, it was found that in the samples obtained by methods 1 and 2, there were large excesses of β-CD in relation to KP, 10 and 75 times, respectively, while the sample obtained by method 3 contained equimolar amounts of β-CD and KP. NMR results indicated that KP/β-CD inclusion complexes were formed and the estimated binding constants were approximately 2400 M−1, showing that KP is quite strongly associated with β-CD. On the other hand, the X-ray single-crystal technique in the solid state revealed that the (S)-KP/β-CD inclusion complex with a stoichiometry of 2:2 was obtained as a result of heating-under-reflux, for which the crystal and molecular structure were examined. Among the methods used for the ...
Analytica Chimica Acta, 2004
Studies of the perturbing effect of chiral solvating agents (CSAs) 5a and mostly of 5c upon the NMR spectra of chiral ⌬ 2-oxazoline 1 demonstrated the ability of these fluoroalcohols to afford diastereomeric solvates from these solutes. Thus, for all tested ⌬ 2-oxazolines 1Aa-d, 1Ba, and 1e there is at least one possibility to proceed to their enantiomeric discrimination either by 1 H or 19 F NMR using these CSAs (see Fig. 1). NMR results are discussed from substrate and CSA structure standpoints and a solvation model is proposed on the basis of the inequivalence senses generally observed. Then the method was applied to extracts of incubated locust tissues obtained by solid phase extraction (SPE) after a partial unmasking of the substrate 1.
Journal of Encapsulation and Adsorption Sciences, 2012
Although enantiomers of 2-phenylpropionic acids (2-PPAs), or profens are important group of nonsteroidal anti-inflammatory drugs (NSAIDs) and have been in clinical use for many years, there is no literature covering its binding interaction in particular with cyclodextrins. NSAIDs are marketed as racemates, chiral discrimination and knowledge of enantiomeric bioavailability is essential. Circular dichroism (CD) spectroscopy is the technique of choice for elucidating chirality and monitoring and characterizing molecular recognition phenomena in solution. Methods employing the fundamentals of the simultaneous measurements of absorbance and CD and a novel efficient titration method have been developed to study the binding of β-Cyclodextrin (β-CyD) and the two enantiomers of 2-PPA as a function of pH. The effect on physicochemical properties and bioavailability was investigated. The binding constant, stoichiometry and pKa for both the free and the bound drugs were determined using a Levenburg-Marquadt non-linear equation. The exact nature of the enantiomer discriminating interactions by cyclodextrins (CyDs) is not well understood. In this work, the interactions and co-conformations of both enantiomers of 2-PPA with β-CyD were explained and estimated using spectroscopic variations upon complexation. The results indicated a change in the physicochemical properties of 2-PPAs upon complexation and highlighted the enantioselective binding of β-CyD as a function of pH. The charge on the guest molecule and its stereochemistry are of great importance in regulating the stability of the guest/β-CyD complexes; hence the bioavailability of drugs. This work elucidates 2-PPAs/β-CyD binding interactions and highlights the effect of β-CyD on drugs with an effective novel method for binding titration and the potential of the simultaneous measurements of absorbance and CD in future chiral drug interactions studies.