Experimental and theoretical analysis of the interaction of (±)-cis-ketoconazole with β-cyclodextrin in the presence of (+)-l-Tartaric acid

Abstract

1H NMR spectroscopy was used for determining the optical purity of cis-ketoconazole enantiomers obtained by fractional crystallization. The chiral analysis was carried out using beta-cyclodextrin in the presence of (+)-L-tartaric acid. The mechanism of the chiral discrimination process, the stability of the complexes formed, and their structure in aqueous solution were also investigated by 1H and 13C chemical shift analysis, two-dimensional NOE experiments, relaxation time measurements, and mass spectrometry experiments. Theoretical models of the three-component interaction were built up on the basis of the available NMR data, by performing a conformational analysis on the relevant fragments on ketoconazole and docking studies on the components of the complex. The model derived from a folded conformation of ketoconazole turned out to be fully consistent with the molecular assembly found in aqueous solution, as inferred from NOE experiments. An explanation of the different association constants for the complexes of the two enantiomers is also provided on the basis of the interaction energies.

Hetero-association of aromatic molecules in aqueous solution

“…The question may be asked whether three-or more-component hetero-associations may have some chemical or biochemical significance? Supporting evidence comes from the field of supramolecular chemistry expanding towards the construction of heterogeneous functional supramolecular polymers [64], and studies reporting improvement of the solubility of various drugs in multi-component systems including cyclodextrins and explained as being due to formation of triple and higher order complexes in solution [223,224]. The following hypothesis was formulated [225].…”

Effect of a mixture of caffeine and nicotinamide on the solubility of vitamin (B2) in aqueous solution

“…As can be seen in Fig.5b the enhancement of the solubilisation effect in this particular system is too small to be very useful but it shows how the effect depends on the relation between the intrinsic self-association and hetero-association constants in the three-component mixture. In addition the current methodology does not yet take into consideration the possibility of cooperativity in the formation of ternary molecular complexes, recently reported for cyclodextrin-containing systems [Redenti et al, 1999;Ribeiro et al, 2005].…”

“…Hence, this leads to the question of whether the effectiveness of the solubilization of RBF by CAF acts over the whole concentration range of the hydrotrope compared to NMD under the same conditions, or whether a decrease in the effect might be predicted because of the increased proportion of self-association of CAF? Recently an improvement of the solubility of various drugs has been reported in multi-component systems including cyclodextrins, which was explained as being due to formation of triple and higher order complexes in solution [Redenti et al, 1999;Ribeiro et al, 2005]. Hence, one may ask whether a mixture of CAF and NMD is more effective in solubilizing RBF than a single hydrotropic agent under the same solution conditions and total concentrations?…”

Inclusion complexes of cyclomaltooligosaccharides (cyclodextrins) with melatonin in solid phase

“…Substantial improvement of various parameters including stability, bioavailability, release control and palatability are also achieved. 28 In fact CDs are quite stable molecules made up by glucosidic residues which model a hydrophobic cavity, they resist to alkaline solutions but are sensible to strong acid solutions, which determine the ring opening. Generally CDs are useful to enhance the solubility of drugs in water and their clearance, to lower local and systemic toxicity and to act as artificial carrier for endogenous and exogenous lipophilic substances.…”