Molecular Modeling (MM2 and PM3) and Experimental (NMR and Thermal Analysis) Studies on the Inclusion Complex of Salbutamol and β-Cyclodextrin

Abstract

The inclusion complex of salbutamol and beta-cyclodextrin (beta-CD) is studied by computational (MM2 and PM3) and experimental techniques. Molecular modeling calculations predict two different orientations of salbutamol in the beta-CD cavity in vacuo and in aqueous solution. In vacuo calculations show that the introduction of the aromatic ring of salbutamol is preferred to the introduction of the tert-butyl group into the beta-CD cavity. However, in aqueous solution both computational methods predict the introduction of the alkyl chain instead of the aromatic ring in the beta-CD cavity contrary to experimental results published previously. These quantitative predictions were experimentally confirmed here by studying the inclusion complex in solution by NMR. A 1:1 stoichiometry was found by (1)H NMR studies for this complex. A 2D ROESY (rotating-frame Overhauser enhancement spectroscopy) experiment shows that there are no cross-peaks between the aromatic protons of salbutamol and any of the protons of beta-CD. Cross-peaks for the protons of the tert-butyl group and protons inside the cavity of beta-CD demonstrate the full involvement of this group in the complexation process and confirm the orientation of the complex predicted by molecular modeling. The solid-state complex was prepared and its stoichiometry (beta-CD.C(13)H(21)NO(3).8H(2)O) and dissociation process studied by thermogravimetric analysis.

NMR characterization of the host–guest inclusion complex between β‐cyclodextrin and doxepin

“…Similar ROESY cross peaks have been observed for the inclusion complexes formed between salbutamol and β-CD and for dexamethasone sodium phosphate and γ -CD. [31,32] The doxepin H-6, H-α, H-β, and H-γ resonances also have cross peaks only to the cyclodextrin H-3 proton that is located near the mouth of the cyclodextrin cavity. The cross peak between cyclodextrin H-3 and doxepin H-α is strongest of the nonaromatic protons followed by H-6, and then H-β, and H-γ .…”

Quetiapine Free Base Complexed with Cyclodextrins to Improve Solubility for Parenteral Use

“…Similar ROESY cross peaks have been observed for inclusion complexes formed be tween doxepin and βCD, salbutamol and βCD, and between dexamethasone sodium phosphate and γCD. 22,28,29) Mean while, cross peaks between βCD and fumaric acid have not been observed. Therefore, it was suggested that fumaric acid was not included in the βCD cavity.…”

Utility of nuclear magnetic resonance spectroscopy to characterize the structure of dexamethasone sodium phosphate inclusion complexes with cyclodextrins in solution and to analyze potential competitive effects

“…Molecular modeling has become a useful technique for studying host–guest complexes, especially as a complement to structural studies on the orientation of the host in guest cavities 28–30. In this sense, we have carried out molecular mechanics calculations toward the determination of the geometrical conformation of DSP in the cavities of γ‐CyD and DIMEB.…”