beta-CD Inclusion Complexes Research Articles

Thermo-sensitive amphiphilic supramolecular assembly based on cyclodextrin inclusion

The ionic self-assembled organic microrods are obtained through complexing two functional molecules, sodium deoxycholate and 1-adamantanamine hydro-chloride. Meanwhile, the amphiphilicity of the complex could be changed by a supramolecular approach with cyclodextrin (CD) inclusion to obtain a thermo-sensitive system. The microrod morphology and structure are characterized by optical microscopy, scanning electron microscopy, single crystal analysis and X-ray powder diffraction. The mechanism of thermo-sensitivity induced by beta-CD inclusion complex is discussed in view of dynamic balance between the host beta-CDs and guest molecules. Experimental results indicate the feasibility of single crystal culture in ionic self-assembly and potential application of CDs in thermo-sensitive supramolecular systems.

Determination of Individual Proton Affinities of Ofloxacin from its UV−Vis Absorption, Fluorescence and Charge-Transfer Spectra: Effect of Inclusion in β-Cyclodextrin on the Proton Affinities

Individual proton affinities of the four dissociable functional groups of (+/-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (commonly called "ofloxacin" and to be denoted henceforth as OflH), have been determined from the pH-dependent variation of the UV-vis absorption and fluorescence spectra of the compound itself and of its charge transfer complexes (CT) with p-bromanil and p-chloranil (in aqueous medium containing 0.1% ethanol, v/v). To utilize the CT spectra for determination of the proton affinity of the anilinic N, the CT absorption band of the ofloxacin-p-bromanil complex has been studied by changing the pH of the medium. Further, the effect of inclusion on the proton affinities of the four dissociable groups of OflH has been studied in presence of beta-cyclodextrin (beta-CD). Two pK(a) values corresponding to anilinic and tertiary N atoms change, whereas those corresponding to phenolic -OH and aromatic -COOH groups remain unchanged by the addition of beta-CD, a fact that indicates partial inclusion of the ofloxacin molecule in beta-CD. Formation constant and related thermodynamic parameters for the OflH(2)(+).beta-CD inclusion complex in aqueous solution have been determined from absorption intensities. A general relation between pK(a) values of guests having proton-releasing functional groups and formation constants of the inclusion complexes of the protonated and deprotonated forms with a host molecule has been utilized for determination of the formation constant of the OflH(3)(+2).beta-CD complex from the pK(a) values of OflH(3)(+2) in the presence and absence of beta-CD, along with the formation constant of the OflH(2)(+).beta-CD complex. Results of the present study reveal that the N-methylpiperazinyl moiety of ofloxacin is included in beta-CD, and the remaining part of the guest molecule remains outside. Also, in molecular interaction with quinone-type electron acceptors, charge transfer occurs from the aromatic part of the ofloxacin molecule, which is conjugated with the anilinic N atom of ofloxacin.

Inclusion Behavior of β‐Cyclodextrin with Bipyridine Molecules: Factors Governing Host‐Guest Inclusion Geometries

The 1:1 complexation of beta-cyclodextrin (beta-CD) with structurally similar bipyridine guests which lead to the formation of six inclusion complexes (1-6) of beta-CD with 4,4'-vinylenedipyridine, 2,2'-vinylenedipyridine, 1-(2-pyridyl)-2-(4-pyridyl)ethylene, 4,4'-ethylene-dipyridine, 4,4'-dithiodipyridine, and 2,2'-dithiodipyridine has been investigated comprehensively by X-ray crystallography in the solid state and by (1)H NMR spectroscopy and microcalorimetric titration in aqueous solution. The complex formation constants (K(S)) for the stoichiometric 1:1 host-guest inclusion complexation of beta-CD with the bipyridine derivatives were determined in aqueous solution by microcalorimetry and the host-guest inclusion geometries of the complexes were deduced from (1)H ROESY NMR spectroscopy. It transpires that the guest bipyridine molecules are included in the beta-CD cavity with a range of different inclusion geometries. In the solid state, the crystal superstructures for the beta-CD complexes 1, 4, and 5 are characterized by the triclinic crystal system (space group P1) commensurate with AAAA type supramolecular aggregation. By contrast, the beta-CD complexes 2, 3, and 6 display either monoclinic (space group P2(1)) or orthorhombic (space group C222(1)) crystal systems, characteristic of ABAB type supramolecular aggregation. The results demonstrate that the relative locations of the nitrogen atom positions and the bridge-bond links between the two pyridine rings in these bipyridine guests, not only lead to distinct crystal systems and space groups, but also to different binding geometries and thermodynamical parameters on complexation of the bipyridines with beta-CD. The knowledge obtained from this research improves our understanding of the molecular recognition and self-assembly processes exhibited by beta-CD, both in the solid state and in aqueous solution.

Characterization of Cyclodextrin Inclusion Complexes of the Anti-HIV Non-Nucleoside Reverse Transcriptase Inhibitor UC781

The highly potent anti-HIV agent UC781 is being evaluated for use in topical microbicides to prevent HIV transmission. However, UC781 is extremely hydrophobic with poor water solubility, a property that may complicate appropriate formulation of the drug. In this study, we examined the ability of several cyclodextrins, beta-cyclodextrin (beta CD), methyl-beta-cyclodextrin (M beta CD), and 2-hydroxylpropyl-beta-cyclodextrin (HP beta CD), to enhance the aqueous solubility of UC781. Each of the cyclodextrins provided dramatic increases in UC781 aqueous solubility, the order being M beta CD>HP beta CD>beta CD. The complexation constants (K (1:1)) of the inclusion complexes were determined via a phase solubility technique using high-performance liquid chromatography and showed that UC781 solubility increased linearly as a function of cyclodextrin concentration. Ultraviolet spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and 2D (1)H ROESY NMR spectroscopy were used to further characterize these UC781/cyclodextrin complexes. The inhibitory potency of UC781 and its HP beta CD inclusion complex were evaluated using an in vitro HIV-1 reverse transcriptase inhibition assay The inhibitory potency of the UC781/HP beta CD complex was 30-fold greater than that of UC781 alone, showing that the complexed drug is able to provide substantial inhibition of its target. The enhancement of UC781 aqueous solubility is essential for the development of a useful vaginal microbicide dosage form, and our data suggest that UC781/cyclodextrin inclusion complexes may be useful in this context.

A Comparative Study on the Binding Behaviors of β-Cyclodextrin and Its Two Derivatives to Four Fanlike Organic Guests

Four fanlike organic compounds, 1-ethoxybenzene (EOB), 1-butoxybenzene (BOB), 1-dodecyloxybenzene (DOB), and 1-(dodecyloxy)-2-methoxybenzene (DOMB), were chosen as guests, and beta-cyclodextrin (beta-CD) and its two derivatives, mono(2-O-2-methyl)-beta-CD and mono(2-O-2-hydroxy-propyl)-beta-CD, were chosen as hosts. Energy changes involved in host-guest inclusion processes were clearly obtained by applying semiempirical PM3 calculations. According to this, probable structures of the host-guest inclusion complexes were proposed. The inclusion systems in aqueous solution were investigated by UV-vis spectroscopy and nuclear magnetic resonance ((1)H NMR) titration, and the formation constants (K) of the inclusion complexes were determined using the Benesi-Hildebrand equation. Moreover, two solid inclusion complexes of beta-CD with EOB and DOB were prepared and characterized by Fourier transform infrared spectra, X-ray powder diffraction, (1)H NMR, electrospray ionization mass spectrometry, and thermogravimetric analyses. Results showed that the host-guest stoichiometries in the inclusion complexes were all 1:1 both in solid state and in aqueous solution. As for the same host, the values of K increased in the order EOB < BOB < DOB, in strong association with the fan handle in the fanlike molecules; that is to say, the K values increased with increasing carbon chain length of substituent on benzene ring. In addition, the K values of DOMB complexes were larger than those of DOB complexes for the same CD, indicating that the introduction of an extra o-methoxyl group on DOB further stabilized the CD inclusion complexes. The decomposition activation energies of EOB-beta-CD and DOB-beta-CD were very similar but significantly larger than that of free beta-CD.

Development of Nonsurfactant Cyclodextrin Nanoparticles Loaded With Anticancer Drug Paclitaxel

In the current formulation of clinical use paclitaxel (PCX) is associated with solubilizers that may produce severe side effects. In this study, PCX was complexed to an amphiphilic cyclodextrin (CD), 6-O-CAPRO-beta-CD, capable of forming nanoparticles spontaneously in order to mask its physicochemical properties via the formation of inclusion complexes of the drug with amphiphilic CD before the nanoparticle is formed. Complexes have been characterized with various techniques such as (1)H NMR, Fourier Transform Infrared (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) confirming the formation of inclusion complex between PCX and 6-O-CAPRO-beta-CD. Nanospheres and nanocapsules were prepared directly from the preformed PCX/6-O-CAPRO-beta-CD inclusion complex by the nanoprecipitation technique, showing a size from 150 to 250 nm for nanospheres and from 500 to 500 nm for nanocapsules. Zeta potentials of the nanospheres and nanocapsules indicate stable colloidal dispersions within the range of -18 to -39 mV. A 12-month physical stability was demonstrated for blank nanoparticles. PCX encapsulation was high with three-fold increase in loading when nanoparticles are prepared directly from preformed inclusion complexes of the drug with 6-O-CAPRO-beta-CD. In vitro liberation profiles of PCX from CD nanoparticles show a prolonged release profile for this drug up to 12 h for nanospheres and 24 h for nanocapsules.

Complexation of tauro‐ and glyco‐conjugated bile salts with three neutral β‐CDs studied by ACE

Complexation of the bile salts (BS) taurocholate, tauro-beta-muricholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, glycodeoxycholate, and glycochenodeoxycholate common in rat, dog, and man with natural beta-CD and the chemically modified beta-CDs 2-hydroxypropyl-beta-CD and 2-O-methyl-beta-CD was studied using mobility shift ACE. The CDs were selected due to their frequent use in preformulation and drug formulation as oral excipients for the solubilization of drug substances with low aqueous solubility. ACE was demonstrated to be a feasible and efficient technique for investigation of the interactions between BS and beta-CDs. All the investigated BS possessed affinity for the three CDs with stability constants ranging from 2x10(3) to 4x10(5) M(-) (1). The requirements and assumptions related to the use of ACE for estimating high affinity stability constants were discussed. The extent and pattern of hydroxylation significantly influenced the affinity of the glyco- and tauro-conjugated BS toward the beta-CDs (chenodeoxycholates >> deoxycholates > cholates) whereas the nature of the beta-CD derivatization and BS conjugation played a minor role only. The results indicate that displacement of drug substances from beta-CD inclusion complexes is likely to occur in the small intestine where BS are present potentially influencing drug bioavailability.

Structure and intramolecular flexibility of β‐cyclodextrin complex with (−)‐epigallocatechin gallate in aqueous solvent

The probable structure of the inclusion complex of beta-cyclodextrin (beta-CD) and (-)-epigallocatechin gallate (EGCg) in D2O was investigated using several NMR techniques. EGCg formed a 1:1 complex with beta-CD, in which the A ring and a portion of the C ring of EGCg were included at the head of the phenolic hydroxyl group attached to C7 of EGCg in the beta-CD cavity from the wide secondary hydroxyl group side. In the 1:1 complex with beta-CD, EGCg maintained the conformation in which the B and B' rings of EGCg took pseudoequatorial and pseudoaxial positions with respect to the C ring, respectively. The structure of the inclusion complexes of beta-CD and EGCg obtained from NMR experiments supported those determined from AM1 semiempirical SCF MO calculations well.

Assembly behavior of inclusion complexes of β-cyclodextrin with 4-hydroxyazobenzene and 4-aminoazobenzene

To further reveal the factors governing the supramolecular assembly of beta-cyclodextrin (beta-CD) inclusion complexes, two aggregates (1 and 2) were prepared from the inclusion complexes of beta-CD with 4-hydroxyazobenzene and 4-aminoazobenzene, respectively, and their binding behavior were investigated by means of X-ray analysis, UV-vis, NMR, and circular dichroism spectra in both solution and the solid state. The obtained results indicated that the beta-CD/4-hydroxyazobenzene complex 1 could form head-to-head dimers (triclinic system, space group P1) in the solid state, which were further self-assembled to a linear supramolecular architecture by the intra- and interdimer hydrogen bond interactions as well as the intradimer pi-pi interactions. However, when the included guest 4-hydroxyazobenzene was switched to a 4-aminoazobenzene, the resultant beta-CD/4-aminoazobenzene complex 2 (monoclinic system, space group P2(1)) could be self-assembled to a wave-type supramolecular aggregate under similar conditions. Furthermore, the combination of crystallographic and spectral investigations jointly revealed the inclusion complexation geometry of beta-CD with 4-hydroxyazobenzene and 4-aminoazobenzene in both solution and the solid state, which demonstrated that the disparity of substituents in the azobenzenes played an important role in the inclusion complexation and molecular assembly, affecting not only the structural features of aggregates but also the binding abilities of azobenzenes with beta-CD.