Cyclodextrin complex-formation

Aqueous a-cyclodextrin solutions seem to be generally applicable for TLC separation of a wide variety of substituted aromatics on polyamide thin-layer stationary sheet (13-14). In most cases, the compounds moved as distinct spots and their R, values were dependent on the concentration of the cyclodextrin in tne mobile phase. In a given family of compounds, (o-, m-, and p-nitrophenols, for example) the isomer with the largest stability constant for a-cyclodextrin complex formation had the larger value. In general, the para-substituted isomers have larger R values than the meta-isomers, which in turn have larger R values than the ortho substituted ones. 

Armstrong et al. developed a chromatographic technique which could be used to evaluate the stoichiometry and all relevant binding constants for most substrate-CD systems (8). This method was not dependent on a solute s spectroscopic properties, conductivity, electrochemical behavior, or solubility. This work presented theory and chromatographic evidence for multiple cyclodextrin complex formation. Previous theoretical work considered only 1 1 complex formation (9-12). A two to one complexation equation was derived by expanding on the equation first used in 1981 to describe the 1 1 complexation behavior of a solute in a pseudophase system (13.14). Using this method, it was demonstrated that closely related compounds such as structural isomers of nitroaniline could exhibit different binding behaviors (8). 

Jones, S.P. and Parr, G.D., Detection of Beta-Cyclodextrin Complex Formation in Aqueous Solution. J. Pharm. Pharmac., 35 (1983) 5P. Jones, S.P. and Parr, G.D., Study of the Inclusion Complex Formation of Barbitone and 3"Cyclodextrin Using the Filtration Cell. 

As a final example we consider noncovalent molecular complex formation with the macrocyclic ligand a-cyclodextrin, a natural product consisting of six a-D-glucose units linked 1-4 to form a torus whose cavity is capable of including molecules the size of an aromatic ring. Table 4-3 gives some rate constants for this reaction, where L represents the cyclodextrin and S is the substrate ... 

Table 4-3. Binding Constants and Rate Constants for Complex Formation between a-Cyclodextrin and Azo Dyes ...

The theory and development of a solvent-extraction scheme for polynuclear aromatic hydrocarbons (PAHs) is described. The use of y-cyclodextrin (CDx) as an aqueous phase modifier makes this scheme unique since it allows for the extraction of PAHs from ether to the aqueous phase. Generally, the extraction of PAHS into water is not feasible due to the low solubility of these compounds in aqueous media. Water-soluble cyclodextrins, which act as hosts in the formation of inclusion complexes, promote this type of extraction by partitioning PAHs into the aqueous phase through the formation of complexes. The stereoselective nature of CDx inclusion-complex formation enhances the separation of different sized PAH molecules present in a mixture. For example, perylene is extracted into the aqueous phase from an organic phase anthracene-perylene mixture in the presence of CDx modifier. Extraction results for a variety of PAHs are presented, and the potential of this method for separation of more complex mixtures is discussed. 

Cyclodextrins can solubilize hydrophobic molecules in aqueous media through complex formation (5-8). A nonpolar species prefers the protective environment of the CDx cavity to the hulk aqueous solvent. In addition, cyclodextrins create a degree of structural rigidity and molecular organization for the included species. As a result of these characteristics, these macrocycles are used in studies of fluorescence and phosphorescence enhancement (9-11), stereoselective catalysis (.12,13), and reverse-phase chromatographic separations of structurally similar molecules (14,15). These same complexing abilities make cyclodextrins useful in solvent extraction. 

Complex Formation of Cyclodextrins with Hydrophilic Polymers. 144... 

Addition of an aqueous solution of PEG to a saturated aqueous solution of a-CD at room temperature did not lead to complex formation unless the average molecular weight of PEG exceeded 200 [46]. Moreover, carbohydrate polymers such as dextran and pullulan failed to precipitate complexes with PEG, and the same was true for amylose, glucose, methyl glucose, maltose, maltotriose, cyclodextrin derivatives, such as glucosyl-a-CD and maltosyl-a-CD, and water-soluble polymers of a-CD crosslinked by epichlorohydrin. These facts suggested to Harada et al. the direction for further research. 

Table 1 Complex formation between cyclodextrins and polyesters...

Figure 5.2. Spectral changes on incremental addition of p-nitrophenolate to a-cyclodextrin illustrating complex formation (from Cramer, Saenger Spatz, 1967).

Lopez-Nicolas JM, Nunez-Delicado E, Perez-Lopez AJ, Carbonell A and Cuadra-Crespo P. 2006. Determination of stoichiometric coefficients and apparent formation constants for (3-cyclodextrin complexes of trans-resveratrol using reversed-phase liquid chromatography. J Chromatogr A 1135 158—165. 

The magnitude of association between a drag compound and various cyclodextrins depends critically on the details of the fit of the substrate into the cyclodextrin cavity. As shown in Table 6, the experimental compound RS-82856 forms the strongest complexes with /3-cyclodextrin, while maximal solubility is reached with y-cyclodextrin [62], Formation of the /8-cyclodextrin complex dramatically increased the dissolution rate of the compound as well. For RS-82856 itself, 20% dissolved within 20 minutes, while more than 80% of the drug-/3-cyclodextrin complex was found to be dissolved at the same time point. 

Table 6 Formation Constants, K, and Maximum Solubilities for the Various Cyclodextrin Complexes with the Experimental Compound RS-82856...

CE has been applied extensively for the separation of chiral compounds in chemical and pharmaceutical analysis.First chiral separations were reported by Gozel et al. who separated the enantiomers of some dansylated amino acids by using diastereomeric complex formation with Cu " -aspartame. Later, Tran et al. demonstrated that such a separation was also possible by derivatization of amino acids with L-Marfey s reagent. Nishi et al. were able to separate some chiral pharmaceutical compounds by using bile salts as chiral selectors and as micellar surfactants. However, it was not until Fanali first showed the utilization of cyclodextrins as chiral selectors that a boom in the number of applications was noted. Cyclodextrins are added to the buffer electrolyte and a chiral recognition may... 

The majority of reported studies of formation of cyclodextrin inclusion complexes in solution have been mainly concerned with determination of the stability constants by using equilibrium spectroscopic techniques, and the measurement of the enthalpy and entropy changes characterizing the complexation reaction. The aim of much of this work has been to determine the driving force of complex-formation. Despite the amount of research in this area, however, no general agreement has been reached, and... 

In order to determine the mechanism of complex-formation, however, kinetic methods must be used. Consider one host-two guests complex-ation. The two possible mechanisms are dimerization of the guest outside the cyclodextrin cavity followed by inclusion, and dimerization within the cyclodextrin cavity. Equilibrium measurements alone cannot distinguish between these two possibilities. The same is the case for 2 2 complex-formation, where a larger number of possible mechanisms exist. 

Although Freudenberg s hypothesis that complex-formation occurred by inclusion within the cavity was generally accepted, there was no direct evidence for this, either in solution or in the solid state. Broser and Lautsch had found by spectrophotometric titration that the complexes of a series of dyes with the cyclodextrins in solution obeyed the mass action law with a stoichiometry of 1 1. They suggested that association on the outside of the ring might not have a defined stoichiometric composition, and they thus interpreted their results as being consistent with inclusion by cyclodextrin. Their results were not conclusive, however. 

Values of AH° and AS° for complex-formation between alpha and beta cyclodextrin and a variety of guest molecules are shown in Tables II and III. If AH° is plotted against AS°, a linear relationship is observed, in which AH° and AS° are compensating (see Figs. 4 and 5). The slope of the graph is called the compensation temperature or isoequilibrium... 

---