Stability constants, cyclodextrins

The stability constant of complexes between /1-cyclodextrine and p-nitroaniline is higher than that of aniline because the resonace charge delocalization (and London dispersion interactions) is an important factor influencing the stability of these complexes62. This behaviour parallels that of corresponding phenols. 

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 a study of the formation of an inclusion complex between beta cyclodextrin and indole, the stability constant in aqueous solution was found, on the addition of formamide, to decrease, accompanied by a... 

The most important property of cyclodextrins is in their ability to accommodate guest molecules within their cavity, which has a volume of 262 per molecule or 157 mL per mol of [3-CD (cavity diameter 6.0-6.5 A). In aqueous solution, this cavity is filled with molecules of water the displacement of which by a less polar guest leads to an overall decrease in free energy. Stability constants and thermodynamic parameters for complexation of a vast number of guest molecules can be found in ref. [3]. 

J Berglund, L Cedergren, SB Andersson. Determination of the stability constant for the inclusion complex between / -cyclodextrin and nicotine using capillary electrophoresis. Int J Pharm 156 195-200, 1997. 

Thus, as shown earlier, CE represents a suitable technique for the determination of enantioselective binding constants between chiral drugs and cyclodextrins. The results obtained under appropriate conditions are reasonable and can be applied for optimization purposes as well as for a better understanding of the fine nuances of chiral CE separations. On the other hand, some care must be taken for the proper application of CE methods for the determination of the binding constants as well as when applying these data. A critical review of the calculation of stability constants for the chiral selector-enantiomer interactions from electrophoretic mobilities has been published by Vespalec and Bocek (40). 

Table 1 Stability constants of complexes of (3-cyclodextrin and tetrahelicenes...

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. 

Ono, N. Hirayama, F. Arima, H. Uekama, K. Determination of stability constant of P-cyclodextrin complexes using the membrane permeation technique and the permeation behavior of drug-competing agent-P-cyclodextrin ternary systems. Eur. J. Pharm. Sci. 1999, 8 (2), 133-139. 

Wang, M. Ueda, H. Nagai, T. Simple prediction of stability constants for inclusion complexes of P-cyclodextrin with various drug molecules using P-cyclodextrin bonded phases (Cyclobond 1 Column). Drug Dev. Ind. Pharm. 1990,16 (4), 571-579. 

Table 12 Apparent stability constants for complexes of a-, P-, and y-cyclodextrins...

Seo et have shown the dependence of stability constant and overall solubility upon cyclodextrin ring size for spironolactone. From the data given in Fig. 19, it can be seen that for the relatively large spironolactone molecule (Fig. 9) the stability constant increases with size of the host cavity that is reflected through an increase in the linear slopes. The lowest maximum solubility was obtained with the p-cyclodex-trin, which has the lowest solubility of the three cyclo-dextrins. ... 

Stability constants (equilibrium constants for complex formation, Kc) for many steroids in a-, P and y-cyclodextrin have been reported (IX) for hydrocortisone and simple substitutions, they typically have magnitudes of Kc = 2000 to 4000 M 1 for P and f- CD s, and Kc = 50 to 200 for O- CD. They are hydrophilic and water soluble. We tested them for angiogenic activity in combination with hydrocortisone, with negative success. 

Reversed-phase liquid chromatography and gas-liquid chromatography have been applied to studies on the complexation of cyclodextrin with isomeric dime-thylnaphthalenes (DMN) 19-22. Both / - and y-CyD have been found to form inclusion complexes with them. With the exception of the complex of 1,8-DMN 22 with yS-CyD, all other complexes under investigation are of weak stability. The stability constant of the former complex is always about 1.5-2.0 orders of magnitude greater than the corresponding value for the other isomers [47]. For example, at 40 °C in 40% of ethanol in water solvent, the stability constants of the complexes of yS-CyD with 1,8-DMN 22 and 1,3-DMN 19 are equal to ca. 500 and ca. 8 respectively. 

Numerous chromatographic studies have also been carried out to investigate possible applications of CyDs as multifunctional drug carriers, discussed in more detail in Chapters 14 and 15. For example the retention of psoralen derivatives was investigated on a C-18 column with HP-) -cyclodextrin as mobile phase additive [62]. Assuming 1 1 stoichiometry, in a 52 48 (v/v) methanol water mixture and temperature —5 °C, the corresponding stability constants were 30, 75, and 40 for the complexes of 8-methoxypsoralen, 5-methoxypsoralen and trimethylpsoralen with HP-yS-CyD, respectively. 

A palladium complex with cyclodextrin modified with propionitrile and benzoylnitrile groups 73-74 was active in Wacker oxidation of higher 1-alkenes (Experiment 11-4, Section 11.7), and its activity was much higher than the activity of a catalj ic system prepared as a mixture of cyclodextrin and the palladium complex owing to the cooperative substrate binding and to the increase in the stability constant of the catalyst-substrate complex. As in hydroformylation, the catalyst was more active in the reaction with an aromatic substrate, styrene, than with linear alkenes [59,210-211], The catalyst activity depended on the 1-alkene chain length and was maximum for 1-heptene. 

A common picture emerged from these studies the amphiphilic cyclodextrin acts as a host, wrapping the hydrophobic substrate and transferring it into the water phase, where the reaction occurs. The stability constant of the new host-guest complex is lower, and the product is then released into the organic phase (Fig. 5). 

The stability constants of the copper(n) mixed-ligand complexes with 6-deoxy-6-(N-histamino)-P-cyclodextrin 1 (CDhm) and aliphatic or aromatic amino acids [39] are reported in Table I. 

In order to obtain independent evidence for the involvement of the cyclodextrin cavity, fluorescence measurements were carried out for copper(II) ternary complexes with L- or D-tryptophan. In fact, the fluorescence spectrum of tryptophan has already been shown to be sensitive to the polarity of the microenvironment in which it is located and has been used in many studies as a probe for the conformation of proteins and peptides [53]. As for many fluorophores, the indole fluorescence of Trp is quenched by the copper(II) ion this effect has been used as a measure of the stability constants of copper(II) complexes [54, 55]. In a recent work, it has been shown that the fluorescence of dansyl derivatives of amino acids undergo enantioselective fluorescence quenching by chiral copper(n) complexes and that fluorescence measurements can be used for the study of enatioselectivity in the formation of ternary complexes in solution [56]. Bearing this in mind, we performed the same type of experiments by adding increasing amounts of the [Cu(CDhm)] + complex to a solution of D- or L-tryptophan [36]. The fluorescence titration curve shows that the artificial receptor inhibits the indole... 

Fig.7. Theoretical blood level curves obtained after oral administration of free drug or its cyclodextrin complexes with different stability constants.

Theoretical blood level curves after administering free drug or its cyclodextrin complex with solid cyclodextrin in excess ( stability constant of the complex is 1000 litre mole ad ). 

The spreading applications of prostanoids-especi-ally that of the prostacyclin, the effective antiplatelet and cytoprotective agent - is limited by their instability To overcome this problem either ne tf, more stable aiialogues are synthetized, or the endogeneous substance is stabilized by cyclodextrin complexation / /. The rates of hydroly-sis of prostacyclin /PGI / and its methyl-ester /PGI Me/ in aqueous solution are significantly retarded by c(-, p-and jj -cyclodextrin /8/ The highest stability constant could be rendered to PGI Me-(S-CD complex ... 

The synergistic effect on solubility of complexes and complexation efficiency by the addition of small amounts of water-soluble polymers has been reported by various authors. In the case of complexation of ionizable drugs with cyclodextrins, pH adjustments have to be done [27-29] to increase the intrinsic solubility of drug, which consequently leads to enhanced CD solubilization of drug [30]. Stability constant of such ionized drug-cyclodextrin system can also be increased by addition of water-soluble polymers, which results in enhanced drug solubilization [31]. 

Celecoxib HP-P-CD PVP, HPMC, PEG Kneading Water containing 1% sodium lauryl sulphate Upon addition of water-soluble polymers, increased solubilization strength of cyclodextrins and apparent stability constants of systems along with marked enhancement in dissolution rate [67]... 

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