Stereoselective interaction of ketoprofen enantiomers with β-cyclodextrin: ground state binding and photochemistry

Abstract

The chiral recognition ability of β-cyclodextrin (β-CyD) vs.S- and R-ketoprofen (KP) enantiomers has been studied by circular dichroism (CD), isothermal titration calorimetry (ITC) and NMR. The association constants of the 1 : 1 complexes obtained from CD and ITC titration experiments resulted to be the same for both enantiomers within the experimental uncertainty. Well differentiated CD spectra were determined for the diastereomeric complexes. Their structure was assessed by molecular mechanics and molecular dynamics calculations combined with quantum mechanical calculation of the induced rotational strengths in the low energy KP:β-CyD associates, upon comparison of the calculated quantities with the corresponding experimental CD. The inclusion geometry is similar for both enantiomers with the aromatic carbonyl inserted in the CyD cavity, the monosubstituted ring close to the primary CyD rim and the carboxylate group exposed to the solvent close to the secondary rim. NMR spectra fully confirmed the geometry of the diastereomeric complexes. Tiny structural differences were sensibly probed by CD and confirmed by 2D ROESY spectra. Photoproduct studies with UV absorption and MS detection as well as nanosecond laser flash photolysis evidenced lack of chiral discrimination in the photodecarboxylation of KP within the cavity and formation of a photoaddition product to β-CyD by secondary photochemistry of 3-ethylbenzophenone.

β-cyclodextrin hinders PLGA plasticization during microparticle manufacturing

“…In microparticles containing the inclusion complex, ketoprofen does not act as a plasticizer when is included in βCDs but, once hydration takes place and ketoprofen is released from the inclusion complex, polymer plasticization and a fast diffusion occur. This reliable assumption is corroborated by molecular dynamics and previous data that showed a low energy of interaction in the complex [41]. In addition, once microparticle hydration takes place, the internal microenvironment becomes enough acid to completely protonated ketoprofen, a condition that allows hydrogen binding with polymer backbone carboxyls.…”

“…Predicted ∆∆G binding (kcal/mol) for the 4 possible inclusion complexes, expressed as a difference with the lowest value obtained (i.e., S-straight), together with the experimental binding free energies for R-and S-ketoprofen-βCD [41], are reported in Table 1.…”

“…Values are expressed in kcal/mol as differences with respect to the lowest value obtained (S-straight). b Experimental free energies of binding for R-and S-ketoprofen-β-cyclodextrin inclusion complexes according to Marconi et al[41]. a Predicted ∆∆G binding (kcal/mol) b Experimental ∆G binding (kcal/mol)…”

Chiral recognition for the complexation dynamics of β-cyclodextrin with the enantiomers of 2-naphthyl-1-ethanol

“…A comparable observation was reported for the binding of the enantiomers of ketoprofen with β-CD in a 1 : 1 (guest-CD) complex where the binding constants and the decarboxylation kinetics of the excited states were the same and subtle structural changes were only observed by circular dichroism and NMR experiments. 51 These results suggest that subtle changes in the structure of the complexes are not always detectable in photophysical experiments.…”

Comparative Enantioseparation of Ketoprofen with Trimethylated α‐, β‐, and γ‐Cyclodextrins in Capillary Electrophoresis and Study of Related Selector–Selectand Interactions Using Nuclear Magnetic Resonance Spectroscopy

“…13 At present, formulations containing racemic KT, as well as dexketoprofen, are commercially available. [13][14][15][16] Several studies have been published on the enantioselective interaction and complex formation of KT with native b-CyD, [17][18][19] as well as on the effect of complex formation on chromatographic separations 18 of enantiomers or photochemical transformations of this drug. 17,19 However, CE has not been applied in these studies.…”