Interaction of pyromellitic diimide derivatives with beta-cyclodextrin and anthracene-appended beta-cyclodextrin: rim binding vs inclusion complexation

Complex formation of pyromellitic diimide derivatives with beta-cyclodextrin and anthracene-appended beta-cyclodextrin was studied with use of induced circular dichroism and 1H NMR spectroscopies. It is revealed that pyromellitic diimides form rim-binding type complexes with beta-CD and in these complexes the pyromellitic diimides lie just outside of the narrow rim of the CD. With anthracene-appended beta-CD the pyromellitic diimides form true inclusion complexes. Implications of the formation of rim-binding type complexes are also discussed.     

Solubility and dissolution enhancement of saquinavir mesylate by inclusion complexation technique

The objective of the present study was to formulate inclusion complex of saquinavir mesylate to improve the aqueous solubility and dissolution rate. Saquinavir mesylate is a BCS class II drug having low aqueous solubility and therefore low oral bioavailability. In the present study, inclusion complex of saquinavir mesylate with hydroxypropyl-β-cyclodextrin were prepared by kneading method. Inclusion complex were characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), ¹H NMR studies, and Fourier transform infrared spectroscopy and evaluated for in vitro dissolution, and phase solubility studies. DSC and XRD study demonstrated that there was a significant decrease in crystallinity of pure drug present in inclusion complex, which resulted in an increased dissolution rate of saquinavir mesylate and ¹H NMR studies strongly, confirmed that the inclusion complex has formed. Inclusion complexation results in improvement in solubility and dissolution rate. The inclusion complexation would be suitable method for dissolution and bioavailability enhancement of saquinavir mesylate.     

The inclusion compound of a new ionizable derivative of beta-cyclodextrin with ferrocenium drug.

A new beta-cyclodextrin (beta-CD) derivative, mono[6-deoxy-6-(2-butenedinitrile-2,3-dimercapto sodium salt)]-beta-CD (6-mnt-beta-CD), and its inclusion compound with a ferrocenium drug, have been prepared and characterized by IR, UV, 13C-NMR spectroscopy, and mass spectrometry, elemental analysis, thermogravimetry, and cyclic voltammetry (CV). The interplay between the side-arm anion of beta-CD and the ferrocenium (guest) in the inclusion compound 6-mnt-beta-CD-/Fc+ has been investigated by 13C-NMR, UV, IR, and thermogravimetric methods. Charge transfer from the anion to the cation in 6-mnt-beta-CD-/Fc+ was then experimentally identified. The interaction between the guest and the host with side-arm in 6-mnt-beta-CD-/Fc+ resulted in smaller positive potential shifts compared to that in the inclusion compound [beta-CD/Fc+]BF4-.     

Bridged bis(beta-cyclodextrin)s possessing coordinated metal center(s) and their inclusion complexation behavior with model substrates: enhanced molecular binding ability by multiple recognition.

To investigate quantitatively the cooperative binding ability of several beta-cyclodextrin oligomers bearing single or multiligated metal center(s), the inclusion complexation behavior of four bis(beta-cyclodextrin)s (2-5) linked by 2,2'-bipyridine-4,4'-dicarboxy tethers and their copper(II) complexes (6-9) with representative dye guests, i.e., methyl orange (MO), acridine red (AR), rhodamine B (RhB), ammonium 8-anilino-1-naphthalenesulfonic acid (ANS), and sodium 6-(p-toludino)-2-naphthalenesulfonate (TNS), have been examined in aqueous solution at 25 degrees C by means of UV-vis, circular dichroism, fluorescence, and 2D NMR spectroscopy. The results obtained indicate that bis(beta-cyclodextrin)s 2-5 can associate with one or three copper(II) ion(s) producing 2:1 or 2:3 bis(beta-cyclodextrin)-copper(II) complexes. These metal-ligated oligo(beta-cyclodextrin)s can bind two model substrates to form intramolecular 2:2 host-guest inclusion complexes and thus significantly enhance the original binding abilities of parent beta-cyclodextrin and bis(beta-cyclodextrin) toward model substrates through the cooperative binding of two guest molecules by four tethered cyclodextrin moieties, as well as the additional binding effect supplied by ligated metal center(s). Host 6 showed the highest enhancement of the stability constant, up to 38.3 times for ANS as compared with parent beta-cyclodextrin. The molecular binding mode and stability constant of substrates by bridged bis- and oligo(beta-cyclodextrin)s 2-9 are discussed from the viewpoint of the size/shape-fit interaction and molecular multiple recognition between host and guest.     

Improvement of antifungal activity of carboxin by inclusion complexation with cucurbit[8]uril

Interaction between cucurbit[8]uril (Q[8]) with a fungicide, carboxin in aqueous solution, was investigated by ¹H-NMR, electronic absorption spectroscopy, and fluorescence spectroscopy. Spectroscopy analysis established a basic interaction model which formed an inclusion complex with a host:guest ratio of 1:1. ¹H-NMR showed that Q[8] encapsulated the phenyl ring into its cavity and the rest of the guest molecule stayed outside the host. Comparative in vitro evaluations of the growth inhibitory effects of the inclusion complex solution toward Rhizoctonia solani demonstrated appreciable improvements in the antifungal activity of carboxin through the addition of Q[8]. In comparison with the positive control, improvement was evaluated in terms of area covered by the mycelia of R. solani and their growth inhibition rate. Inclusion complexation of carboxin with Q[8] suggests a potential means for production of an environmentally friendly carboxin-based fungicide to counteract R. solani.     

Resolution of hydrocarbons by inclusion complexation with a chiral host compound

Some racemic unsaturated hydrocarbons, 3- and 4-methyl and 4-vinylcyclohexene, bicyclo[4.3]nonane-2,5-diene, and 3-chloro- and 3,4-dichloro-1-butene were resolved as inclusion complex crystals with a chiral host compound derived from tartaric acid. The inclusion complexation, purified by repeating recrystallization from ether twice and decomposed by heating in vacuo, gave optically active hydrocarbons of 28–75% ee by distillation. The optical resolution by inclusion complexation in a water suspension medium and by fractional distillation in the presence of a chiral host was also applied to these hydrocarbons.     

Resolution of omeprazole by inclusion complexation with a chiral host BINOL

Both (S)-(−)- and (R)-(+)-enantiomers of omeprazole were directly resolved by inclusion complexation with a chiral host compound (S)-(−)- or (R)-(+)-2,2′-dihydroxy-1,1′-binaphthyl in high enantiomeric excess (>99% e.e.).     

Synthesis of a new bifunctional chelating agent for samarium complexation

A novel bifunctional chelating agent for samarium complexation has been synthesised in eight steps. A novel synthetic approach involving the introduction of methanephosphonic functions has been developed. The complexing properties of this compound has also been confirmed by labelling with ¹⁵³Sm.     

Synthesis and spectral investigation of Al(III) catechin/beta-cyclodextrin and Al(III) quercetin/beta-cyclodextrin inclusion compounds

Al-catechin/beta-cyclodextrin and Al-quercetin/beta-cyclodextrin (beta-CD) inclusion compounds were synthesized and characterized by IR, UV-vis, 1H and 13C NMR and TG and DTA analyses. Because quercetin is sparingly soluble in water, the stability constants of the Al-quercetin/beta-CD and Al-catechin/beta-CD compounds were determined by phase solubility studies. The AL-type diagrams indicated the formation of 1:1 inclusion compounds and allowed calculation of the stability constants. The thermodynamic parameters were obtained from the dependence of the stability constants on temperature and results indicated that the formation of the inclusion compounds is an enthalpically driven process. The thermal decomposition of the solid Al-quercetin/beta-CD and Al-catechin/beta-CD inclusion compounds took place at different stages, compared with the respective precursors, proving that an inclusion complexation process really occurred.     

Improvement of some pharmaceutical properties of carmoful by cycrodextrin complexation

Inclusion complexation of carmoful (1-hexylcarbamoyl-5-fluorouracil, HCFU) with three cyclodextrins (-, - and -CyDs) were studied by solubility method and X-ray diffractometry. On the basis of the phase solubility diagrams, solid complexes of HCFU with -, - and -CyDs were obtained in the molar ratios (host:guest) of 21, 11 and 11, respectively. The dissolution rate of HCFU from the solid complexes was much greater than that of HCFU itself (-CyD > complex > -CyD complex > -CyD complex > HCFU alone). The hydrolysis of HCFU was suppressed by -CyD, while no appreciable inhibition was observed by - and -CyDs. The rapid dissolving form of HCFU-CyD complexes was found to increase significantly the serum levels of the drug after oral administration to rabbits.     

Analysis of the phase solubility diagram of a phenacetin/competitor/beta-cyclodextrin ternary system, involving competitive inclusion complexation

The competitive inclusion complexations in the ternary phenacetin/competitors/beta-cyclodextrin (beta-CyD) systems were investigated by the solubility method, where m-bromobenzoic acid (m-BBA) and o-toluic acid (o-TA) were used as competitors. The solubility changes of the drug and competitors as a function of beta-CyD concentration in the ternary systems were formulated using their stability constants and intrinsic solubilities. The decrease in solubility of phenacetin by the addition of competitors could be quantitatively simulated by the formulation, when both drug and competitor give A(L) type solubility diagrams. On the other hand, when one of the guests gives a B(S) type solubility diagram, its solubility change was clearly reflected in that of the another guest, i.e., phenacetin gave an A(L) type solubility diagram in the binary phenacetin/beta-CyD system and o-TA gave a B(S) type diagram in the binary o-TA/beta-CyD system, but in the ternary phenacetin/o-TA/beta-CyD system, a new plateau region appeared in the original A(L) type diagram of phenacetin. This was explained by the solubilization theory of Higuchi and Connors. The solubility analysis of the ternary drug/competitor/CyD systems may be particularly useful for determination of the stability constant of a drug whose physicochemical and spectroscopic analyses are difficult, because they can be calculated by monitoring the solubility change of a competitor, without monitoring that of a drug. Furthermore, the present results suggest that attention should be paid to the type of the phase solubility diagram, as well as the magnitude of the stability constant and the solubility of the complex, for a rational formulation design of CyD complexes.     

Selective binding of steroids by 2,2'-biquinoline-4,4'-dicarboxamide-bridged bis(beta-cyclodextrin): fluorescence enhancement by guest inclusion

A novel bis(beta-cyclodextrin) was synthesized, and its binding behavior with steroids was investigated to demonstrate that the cooperative co-inclusion of guest and tether by two cyclodextrin moieties is operative to afford the highest molecular selectivity of up to 3.6 for deoxycholate over taurocholate.     

Resolution of α-aminolactams by inclusion complexation with chiral host compounds

3-Aminopiperidin-2-one and α-amino-ε-caprolactam were efficiently resolved by inclusion complexation with a chiral host compound, (R,R)-(−)-trans-4,5-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro[4.5]decane. The amino substituent on the lactam ring was found to play an important role in efficient chiral recognition in the inclusion crystals.     

Synthesis and characterization of beta-cyclodextrin inclusion complex containing di(8-hydroxyquinoline) magnesium

The beta-cyclodextrin (beta-CD) inclusion complex containing di(8-hydroxyquinoline)magnesium was prepared. The product was characterized by NMR, IR, differential thermal thermogravimetric analysis (DT-TGA), spectrofluorimetry, and elemental analysis, indicating the formation of inclusion complex in which the quinoline rings of the guest were encapsulated within the beta-CD cavities. The Job's method provided 2:1 stoichiometry for the inclusion complex between beta-CD and di(8-hydroxyquinoline)magnesium. The association constant calculated with the modified Benesi-Hildebrand equation at 25 degrees C was determined. And the mean association constant was 3577 (L/mol)2, R.S.D. was 2.58%. The thermal stability and solubility of di(8-hydroxyquinoline)magnesium were improved when forming inclusion complex.     

Preparation and properties of rotaxanes formed by dimethyl-beta-cyclodextrin and oligo(thiophene)s with beta-cyclodextrin stoppers

Novel cyclodextrin rotaxanes with oligothiophene as an axis molecule have been prepared by the Suzuki coupling reaction of 6-O-(4-iodophenyl)-beta-CD (6-I-Ph-beta-CD) with di(1,3,2-dioxaborolan-2-yl)-oligothiophene (oligothiophene diboric ethylene glycol esters) in aqueous solutions of dimethyl-beta-cyclodextrin (DM-beta-CD). These reactions gave [2]rotaxanes and [3]rotaxanes, which were isolated by reversed phase chromatography. The fluorescence intensities of rotaxanes are higher than those of dumbbell-shaped molecules (without DM-beta-CD) in aqueous solutions. The inclusion ratio and chain length of rotaxanes have been found to relate to the emission properties and emission intensities of oligothiophene. In aqueous solutions, fluorescence quantum yields of rotaxanes are higher than those of dumbbell-shaped molecules. The increase in the fluorescence efficiency of rotaxane is caused by suppression of intermolecular interactions, indicating the effect of insulated oligothiophene with DM-beta-CD. beta-CD at the both ends of rotaxanes functions not only as bulky stoppers but also as the recognition site for guest molecules, as verified by fluorescence quenching experiments.