Effect of cyclodextrins on the solubility and antimycotic activity of sertaconazole: experimental and computational studies.

This study investigated the effects of the complexation of sertaconazole nitrate with different cyclodextrin (CD) derivatives (alpha-CD, beta-CD, gamma-CD, hydroxypropyl-beta-CD, and hydroxypropyl-gamma-CD) on the aqueous solubility and antimycotic activity of the drug. Phase solubility studies indicated that the solubility of sertaconazole in enzyme-free simulated gastric- and enzyme-free simulated enteric fluids was significantly increased in the presence of cyclodextrins. The observed order of solubility increasing effect was: gamma-CD > HPgamma-CD > HPbeta-CD > beta-CD > alpha-CD. Solid-state sertaconazole-cyclodextrin complexes were prepared by freeze drying, and characterized by X-ray powder difractometry, differential scanning calorimetry (DSC), and infrared spectroscopy (FTIR). Freeze-dried complexes showed markedly higher solubility than both physical mixtures and sertaconazole alone. The antimycotic activities of sertaconazole-cyclodextrin complexes in solution were evaluated by inhibition zone assays with Candida albicans. The activity ranking agrees with the solubility ranking observed for these complexes, with the gamma-CD-sertaconazole complex showing the strongest antimycotic activity. Finally, molecular modeling studies were carried out using the MM2 force field method, for complexes in vacuum and in water. This enable indentification of the preferred orientation of sertaconazole in the gamma-CD cavity and of the main structural features responsible for the enhancement of its solubility and antimycotic activity.

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.

The interaction between dexamethasone sodium phosphate (DSP) and four cyclodextrin (CyD) derivatives [2,6-di-O-beta-cyclodextrin (DIMEB), gamma-cyclodextrin (gamma-CyD), and hydroxypropyl-beta-cyclodextrin with either 2.7 or 4.6 degrees of substitution (HPbetaCyD 2.7 and HPbetaCyD 4.6, respectively)] was investigated by proton nuclear magnetic resonance spectroscopy (1H NMR). The data suggested the formation of inclusion complexes in solution in which B and C rings of the molecule are located inside the cavity. Nevertheless, the structure, in terms of depth within CyD, depends on the derivative considered. Molecular mechanics calculations of DSP complexes with DIMEB and gamma-CyD support the NMR results. The potential displacement of DSP from the CyD cavity by usual ophthalmic drugs (e.g., polymyxin B, trimethoprim, and benzalkonium chloride) was determined by NMR. The technique has been found useful to analyze this problem in pharmaceutical preparations.

Combination of 2D-, 3D-connectivity and quantum chemical descriptors in QSPR. Complexation of alpha- and beta-cyclodextrin with benzene derivatives.

Quantitative models are found to describe the complexation of alpha- and beta-cyclodextrin with mono- and 1,4-disubstituted benzene derivatives by using combinations of 2D-, 3D-connectivity and quantum chemical molecular descriptors. The association constants (K(a)) for the inclusion complexation of cyclodextrins and benzene derivatives are calculated by the models found with a high degree of precision. These models also permit the interpretation of the driving forces of such complexation processes. In the case of the complexation of alpha-cyclodextrin with benzene derivatives these driving forces are mainly the electronic repulsion between frontier orbitals of the host and guest molecules. However, the complexation of beta-cyclodextrin with benzene derivatives is controlled by topological and topographic parameters indicating the relevance of the van der Waals and hydrophobic interactions. We also carried out molecular modeling studies showing that for alpha-cyclodextrin complexes the benzene ring is outside the cavity of the cyclodextrin, while in beta-cyclodextrin they penetrate deeply into the apolar and hydrophobic cavity of the host, which explain the differences in the driving forces for both complexation processes.

Can 3D structural parameters be predicted from 2D (topological) molecular descriptors?

The dihedral angle between both phenyl rings determined by photoelectron spectroscopy in a series of seven alkylbiphenyl is described by the local spectral moments of the bond matrix. This series is extended to 78 alkylbiphenyl compounds by estimating the dihedral angle from molecular mechanics force field calculations. The linear correlation obtained between this angle and the local spectral moments shown a correlation coefficient of 0.9838. This result proves that 2D (topological) descriptors can account for 3D structural parameters. A new substituent constant is calculated as the contribution of groups to the studied rotational angle by using the information encoded into the local spectral moments. This substituent constant is not linearly related to the Taft's steric constants E(S) as they have a correlation coefficient of only 0.75. These steric constants are able to account only for 71% of the variance in the studied 3D parameter. The implications for QSPR/QSAR studies of the demonstration that 2D (topological) descriptors can describe 3D structural parameters are also analyzed.

Improvement of water solubility of sulfamethizole through its complexation with beta- and hydroxypropyl-beta-cyclodextrin. Characterization of the interaction in solution and in solid state.

The aim of this study was to increase the solubility of sulfamethizole in water by complexing it with beta-cyclodextrin (BCD) and hydroxypropyl-beta-cyclodextrin (HPBCD). The interaction of sulfamethizole with the cyclodextrins was evaluated by the solubility, 1H NMR spectrometry and molecular modelling. The stability constants calculated from the phase solubility method increase in order HPBCD

Molecular modeling (MM2 and PM3) and experimental (NMR and thermal analysis) studies on the inclusion complex of salbutamol and beta-cyclodextrin.

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.