Cyclodextrin complexation, stabilizing effects

Upon formulating these relationships, phenols with branched alkyl substituents were not included in the data of a-cyclodextrin systems, though they were included in (3-cyclodextrin systems. In all the above equations, the n term was statistically significant at the 99.5 % level of confidence, indicating that the hydrophobic interaction plays a decisive role in the complexation of cyclodextrin with phenols. The Ibrnch term was statistically significant at the 99.5% level of confidence for (3-cyclo-dextrin complexes with m- and p-substituted phenols. The stability of the complexes increases with an increasing number of branches in substituents. This was ascribed to the attractive van der Waals interaction due to the close fitness of the branched substituents to the (3-cyclodextrin cavity. The steric effect of substituents was also observed for a-cyclodextrin complexes with p-substituted phenols (Eq. 22). In this case, the B parameter was used in place of Ibmch, since no phenol with a branched... 

The results were simple and clear-cut Only the two terms ofa° and Emin were involved for the a-cyclodextrin systems, and the two terms of k and Emin, for (S-cyclodextrin systems. This means that the stabilities of the inclusion complexes are mainly governed by the electronic and steric interactions in a-cyclodextrin systems and by the hydro-phobic and steric interactions in (i-cyclodextrin systems, regardless of the position of the substituents in the phenols. These observations agree well with those by Harata23), who showed that there is no appreciable difference in thermodynamic parameters between cyclodextrin complexes of m- and p-di substituted benzenes and that the contribution of the enthalpy term to the complexation is more significant in a-cyclodextrin systems than in P-cyclodextrin systems, where the inhibitory effect... 

Some modifications to the cyclodextrin structure have also been found to improve their complexing ability. Casu and coworkers prepared 2,3,6-tri-O-methyl and 2,6-di-O-methyl derivatives of alpha and beta cyclodextrin. They observed that tri-O-methyl-alpha cyclodextrin shows an almost ten-fold increased stability of the complex with the guest, Methyl Orange, compared with the unmodified alpha cyclodextrin. A possible reason for this increase in stability is that the methyl groups are responsible for an extension of the hydrophobic cavity of the cyclodextrin. Other workers,however, observed a much smaller enhancement of stability of complexes on methylation of the cyclodextrin, and a decrease in stability has even been reportedfor the one host-two guests complex of tropaeolin with beta cyclodextrin. Thus, the effect of methylation on the stability of a complex varies with the guest species involved, and cannot be readily predicted. 

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. 

The present paper is intended to provide a survey on the stabilizing effects of cyclodextrin complexation. Beyond this,other practical consequences of the molecular entrapment of flavors will also be mentioned. 

Tirucherai, G.S., and A.K. Mitra. 2003. Effect of hydroxypropyl beta cyclodextrin complexation on aqueous solubility, stability, and corneal permeation of acyl ester prodrugs of gancyclovir. AAPS Pharm Sci Tech 4 E45. 

Multicomponent liposomes reveal optimal UV protection in combination with me y-cyclodextrin complex of me vitamin present in me aqueous phases and lipid-soluble protectors (UV absorbers and antioxidants) present in me lipid phases (Loukas et al., 1995). The experimental photochemical half-life of riboflavin can be increased up to 266-fold by these complex liposome formulations. The liposomal composition is also important for me stabilizing effect obtained as incorporation of riboflavin into neutral and negatively charged liposomes increases photochemical stability, while association with positively charged liposomes leads to a decreased photochemical stability (Habib and Asker, 1991). Incorporation of retinol into multilamellar liposomes is demonstrated to extend the shelf-life of retinol under various conditions of pH, temperature, and light exposure (Lee et al., 2002). 

Zejtli, J., Bolla-Pusztai, E., Szab6, P, and Ferenczy, T. (1980) Enhancement of stability and biological effect of cholecalciferol by P-cyclodextrin complexation, Pharmazie, 35, 779-787. 

Cevallos, R A. R, Buera, M. R, and Elizalde, B. E. (2010). Encapsulation of cinnamon and thyme essential oils componenk (cinnamaldehyde and thymol) in P-cyclodextrin Effect of interactions with water on complex stability. Journal of Food Engineering, 99, 70-75. 

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 ... 

D Anna F, Riela S, Lo Meo P, Grattadauria M, Noto R. The binary pyrene/heptakis-(6-amino-6-deoxy)-P-cyclodextrin complex a suitable chiral discriminator. Spectrofluorimet-ric study of the effect of some a-amino acids and esters on the stability of the binary complex. Tetrahedron Asymmetry 2002 13 1755-60. 

ANTITUMOR CYTOTOXICITY The stabilization effect of benzaldehyde by a-cyclodextrin is also reflected in the in vitro antitumor cytotoxicity against human tumor cell lines A-549 (non-small-cell lung carcinoma), MCF-7 (breast adenocarcinoma) and HT-29 (colon adenocarcinoma) (Table III). a-Cyclodextrin-benzaldehyde inclusion complex is about 5-8 fold more cytotoxic than ftee ben dehyde. 

Cyclodextrins have found particular application for the formulation of poorly water soluble, volatile, or unstable herbicides. Among the advantages of cyclodextrin complexes of pesticides are enhanced stabilization, reduced volatility, masked bad odor, enhanced wettability, solubility and bioavailability, and controlled release properties. Of the cyclodextrins, BCD is the only one available at a reasonid)le price, and its use may be economically feasible within a few years (. Several herbicides that have been frequently implicated in groundwater contamination (1-2) were selected as candidates for complexation with BCD in an attempt to develop formulations that could prevent entry of the chemical into the groundwater while maintaining effective weed control. 

Shan-Chen Y, Bochot A, Le Bas G, Cheron, Mahuteau J, Grossiord JL, Seiller M, Dnchene D. 2003. Effect of camphor/cyclodextrin complexation on the stability of O/W/O multiple emulsions. Int J Pharmaceut 261 1-8. 

To end this overview, let me say a few words about the likely evolution of the calculations devoted to theoretically analyze the stability and reactivity of cyclodextrin complexes. Hybrid methods have recently opened the door for the most sophisticated ab initio and DFT methods to deal with molecular systems with hundreds or even thousands of atoms if the reactive center is well localized within a particular zone of the whole macromolecular system. As computers keep on growing in capacity and theoretical methods are progressively more well established, theoretical work on host guest complexes will be ready to make a jump from the qualitative predictions, already available now, to the quantitative results. This will provide a powerful tool for the experiments as theory will be helpful not just to explain reactions already known but to predict new reactions and effects of the supramolecular environment that have been until now out of reach of precise measurements (as intermolecular forces are quite tenuous, their theoretical evaluation is subject to noticeable relative errors). On the other hand, it is to be noted that electronic calculations alone are not able to disclose the rich molecular dynamics of such a large molecular systems. Up to now MC and MD procedures have been restricted to find the more stable conformations but they are able to tell us more details about the mechanism of the inclusion process and reactivity inside CD and other large guests. The applicability of these methods to such problems has also been... 

By virtue of their complexing ability, CDs may influence the course of chemical reactions in respect of rates and/or product selectivity. In consequence, there is a large body of data in the literature on the effect of CDs on many types of reactions (Fendler and Fendler, 1975 Bender and Komiyama, 1978 Szejtli, 1982 Tabushi, 1982 Sirlin, 1984 Ramamurthy, 1986 Ramamurthy and Eaton, 1988). The present review concentrates on reactions for which sufficient kinetic data are available to allow quantification of the effects of CDs on transition state stability, in an attempt to understand how cyclodextrins influence reactivity in either a positive or negative sense. 

Decene was hydrocarboxylated with a [PdClaj/TPPTS catalyst in acidic aqueous solutions (pH adjusted to 1.8) in the presence of various chemically modified cyclodextrins (Scheme 10.11) [18]. As in most cases, the best results were obtained with DiOMe-P-CD. In an interesting series of reactions 1-decene was hydrocarboxylated in 50 50 mixtures with other compounds. Although all additives decreased somewhat the rate of 1-decene hydroformylation, the order of this inhibitory effect was 1,3,5-trimethylbenzene < cumene < undecanoic acid, which corresponds to the order of the increasing stability of the inclusion complexes of additives with p-CD, at least for 1,3,5-trimethylbenzene (60 M ) and cumene (1200 M ). These results clearly show the possible effect of competition of the various components in the reaction mixture for the cyclodextrin. 

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