Inclusion complexes formation with cyclodextrins

The most important applications of chiral mobile phase additives in liquid ehromatogra-phy are ehiral ion-pair chromatography (section 4.3.3) and inclusion complex formation with cyclodextrins and similar chiral selectors. Other ehiral mobile phase additives have been used only oeeasionally, and with modest sueeess [ 1,3,32,153]. Multifunctional ion-pair reagents, such as 10-camphorsulfonic acid [154], derivatives of tartatie acid (e.g. di-n-butyltartrate) [155,156], peptides (e.g. N-carbobenzoxyglyeine-L-proline) [157-161],... 

Figure 7 Schematic representation of three-step targeting approach based on guest inclusion complex formation with cyclodextrin. (Adapted from Ref. 31. Springer, 2007.)...

Polarography measures the electron distribution of guest molecule. Specific rotation, which is an inherent property of the optically active species, is measured by polarimetry, as it may be affected by complex formation. Solution conductivities are vividly affected by inclusion complex formation with cyclodextrins. 

The n values used here are derived from di-n-butylether/water partition coefficients since the ether phase was thought to better simulate the environment of the cavity of cyclodextrins. Eq 38 indicates that the principal driving force for the inclusion complex formation with P-cyclodextrin is the dehydration from surroundings of the guest molecule. 

In Eq. 39, substituents, the dimension of which is larger than 5.1 A in terms of the sum of the opposite-pair Bj values, are not included, since their log (1/Kd) values are much lower than those expected from the correlation for others. They are supposed not to be accomodated into the cavity of the a-cyclodextrin, the diameter of which is 4.5-5 A. Thus, the inclusion complex formation with a-cyclodextrin is more limited than that with P-cyclodextrin and the extent of dehydration is less significant. The term B in Eq. 39 implies that the larger the minimum width of substituents the maximum diameter of which is less than 5.1 A, the more uniform would be the van der Waals interaction with the cavity wall resulting in the more stable inclusion complex. 

Figure 4.6 shows the schematic diagrams of ciclodextrins, polyaniline with emeraldine base, and inclusion complex formation of cyclodextrins and a conducting polymer chain insulated molecular wire. 

A photostabilizing effect by complex formation with cyclodextrins has been reported for a number of biologically active compounds (Zejtli et al., 1980 Uekama et al., 1983 Ammar and El-Nahhas, 1995 Chen et al., 1996 Lin et al., 2000 Bayomi et al., 2002, Tpnnesen et al., 2002). However, formation of an inclusion complex does not necessarily lead to a stabilization of the guest molecule. This is clearly... 

Fig. 4. Plot of the changes of the C-chemical shifts in ppm) of the guest compounds on inclusion complex formation with a-cyclodextiin vs. the penetration depth (Z in A) the positive sign in 4 c shows an increase in shielding, and a positive sign in Z shows deeper penetration with respect to the plane ( Z = 0) comprised of the 6 H-3 atoms of a-cyclodextrin the numbering systems of the carbon atoms of the guest compounds are as follows ...

Historically, nuclear magnetic resonance (NMR) spectroscopy was the instrumental technique that provided the first experimental evidence for inclusion complex formation of cyclodextrins (CD) and guest molecules in the liquid phase [1]. Since that time NMR spectroscopy remains one of the key techniques for studying CD complexes with their ligands [2],... 

J. Manosroi, M.G. Apriyani, K. Foe, and A. Manosroi, Enhancement of the release of Azelaic acid through the synthetic membranes by inclusion complex formation with hydroxypropyl-(3-cyclodextrin, Int. / Pharm., 293,235-240,2005. 

The participation of van der Waals forces in inclusion-complex formation is also found to be consistent with crystal structure analyses. Interatomic distances between the guest and the cyclodextrin thus determined are characteristic of van der Waals interactions. Hydrogen bonding between the guest and the hydroxyl groups of the cyclodextrin has also... 

Thus, it seems that both the hydrophobic interactions and the van der Waals interactions undoubtedly play a part in inclusion-complex formation, although the relative contribution of each type of interaction may vary with the chemical properties of the guest this would account for the ability of the cyclodextrins to form complexes with a wide variety of guest molecules. The existence of a close spatial fit between the guest and the cyclodextrin cavity is, however, a necessary requirement for the formation of a stable inclusion-complex. 

Let us compare the methods applied by Pedersen for establishing the complex formation with a modern approach. Today tedious solubility studies are carried out almost exclusively with practical applications in mind, but they are not performed to prove the complex formation. For instance, one ofthe main reasons for the use of cyclodextrin complexes in the pharmaceutical industry is their solubilizing effect on drugs [8]. There, and almost only there, solubility studies are a must. As concerns spectroscopic methods, at present the NMR technique is one ofthe main tools enabling one to prove the formation of inclusion complex, carry out structural studies (for instance, making use of the NOE effect [9a]), determine the complex stability [9b, c] and mobility of its constituent parts [9d]. However, at the time when Pedersen performed his work, the NMR method was in the early stage of development, and thus inaccurate, and its results proved inconclusive. UV spectra retained their significance in supramolecular chemistry, whilst at present the IR method is used to prove the complex formation only in very special cases. 

Hirai, H., Toshima, N., and Uenoyama, S. (1985) Inclusion Complex Formation of y-Cyclodextrin. One Host-Two Guest Complexation with Water-soluble Dyes in Ground State, Bull. Chem. Soc. Jpn. 58, 1156-1164. 

Potential use of complexes of y - CD with organic compounds, including polymers, was also reviewed by Szejtli [6, 12, 13], y - CD are able to incorporate metal ions as ligands to prepare magnetic nano - particles [7,14], Harada and Ka-machi [8,15] first found that poly (ethylene oxide) (PEO) thread a- CD rings to form polymer - cyclodextrin complex. Since their finding of inclusion complex formation of polymer chains with a- CD, a large number of studies on inclusion complexes of... 

Molecular model studies have shown that PMVE, PEVE, and PnPVE chains are capable to penetrate y -CD cavities. Model studies further indicate that the single cavity can accommodate three monomer units. The inclusion complex formation of polymers with cyclodextrins is entropically unfavorable. However, formation of the complexes is thought to be promoted by hydrogen bond formation between cyclodextrins. Therefore, the head - to - head and tail - to - tail arrangement, which results in a more effective formation of hydrogen bonds between cyclodextrins, is thought to be the most probable structure. This structure was proved by X-ray studies on a single crystal of the complex between y -CD and 1-propanol. 

The Effects of Eluent Temperature. m agreement with previous studies (67), both solute retention and separation selectivity were found to increase significantly as the eluent temperature was reduced from 30 to 0 C, as shown in Fig. 6 for the enantiomers of tryptophan. The change is much larger than what is observed on an octadecylsilica reversed-phase column and the improved separation selectivity is attributed to more pronounced inclusion complex formation. Solute retention decreases precipitously when the temperature of the eluent is raised to or above 60 C, an important fact that can be utilized advantageously for the rapid removed, of strongly adsorbed components (such as displacers) from the cyclodextrin-silica column. 

Cyclodextrins have been covalently modified for catalytic oxidation, such as compounds 57, 62-65 (Schemes 3.14 to 3.16) [44, 45]. Enantioselective epoxidation of styrene derivatives, and carene using 20-100 mol% of the CD-ketoester 57 has been achieved. The inclusion-complex formation was confirmed by aH NMR titration experiments, confirming the 1 1 substrate catalyst stoichiometry under the reaction conditions. In the oxidation of carene, NOE and ROESY experiments showed different behavior according to the size of the R group (Scheme 13.14). Evidence was found for the formation of inclusion complexes with compounds 58 and 59. On the other hand, compounds 60 and 61 proved to interact with the catalyst via a tail inclusion vide infra). The increased diastereoselectivity observed with compounds 58 and 59 might be explained by a closer proximity to the covalently linked dioxirane. 

Lamparczyk H, Zarzycki P, Ochocka RJ, Sybilska D. Structure-retention studies on the inclusion complex formation of some polycyclic aromatic hydrocarbons with (i-cyclodextrin. Chromatographia 1990 30 91-94. 

The plot of the reciprocal of k - kf against 1/[L] is linear, with a slope of 1 / [K(kc - kf)] and an intercept of 1 / (kc - kf). Figure 5.36 shows the stabilization of prostacyclin by the derivatives of P-cyclodextrin. However, not all inclusion complexes provide the stabilization of drugs. In many cases, drug degradation is enhanced via inclusion complex formation [e.g., prostaglandin E and E2/p-cyclo-dextrin (P-CD), aspirin/p-CD],... 

To improve the effectiveness of the chromatographic separation, a comparison study has been carried out on cyclodextrin and liquid crystal stationary phases Both materials function as "ordered" media with cyclodextrins the inclusion complex formation predominates, whereas the liquid crystals enable interaction of compounds with the ordered structure of the mesophase ... 

The rotaxane 57 has been obtained by initial formation of the 4,4 -diaminostil-bene inclusion complex of 3-cyclodextrin followed by reaction with the appropriate bulky blocking moieties. For this system, the UV-Vis and induced circular dichroism (CD) spectra confirmed that the central aromatic chromophore of the linear component was embedded in the cyclodextrin cavity. 

Nitrile oxide cycloaddition with mono- and trisubstituted alkenes affords almost exclusively 5-mono- and 4,5,5-trisubstituted isoxazolines, respectively, the regioselectivity being determined by steric effects. Reverse regioselectivity in nitrile oxide cycloaddition to terminal alkenes has been reported <1997CC1517> for example, 4-A t/-butylbenzoni-trile oxide was forced to reverse alignment for the cycloaddition by formation of the inclusion complex 470 with /3-cyclodextrin. Under these conditions, 90% of the 3,4-disubstituted cycloadducts were obtained, whereas in the absence of cyclodextrin the aromatic nitrile oxide afforded only the 5-substituted isoxazoline. 

Cyclodextrins are capable of forming inclusion complexes with compounds having a size compatible with the dimensions of the cavity. Complex formation with molecules significantly larger than the cavity may also be possible in such a way that only certain groups or side... 

Harada and coworkers went on to investigate the pseudorotaxane formation behavior of cyclodextrins with various kinds of organic polymers such as poly(methyl vinyl ether), poly(tetrahydrofuran), oligoethylene, and polyesters [94-107]. Wenz et al. reported inclusion complexation behavior between cyclodextrins and some organic polymers [108-110]. 

PithaJ and Teruhiko H. Effect of Ethanol on Formation of Inclusion Complexes of Hydroxypropyl Cyclodextrins with Testosterone or with Methyl Orange./rat JPharm 1992 243-251. 

One of the most important pieces of progress in recent years is the establishment of a method for the determination of the conformation of the inclusion complex in solution. The method, which takes advantage of the change of the H-chemical shifts of cyclodextrin on complex formation with the aromatic guest compound (mostly due to the anisotropic shielding effect of the aromatic ring of the guest), is briefly described as follows [7-9]. 

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