Beta-cyclodextrin Complexes Research Articles

Effect of hydroxypropyl beta cyclodextrin complexation on aqueous solubility, stability, and corneal permeation of acyl ester prodrugs of ganciclovir.

The purpose of the study was to investigate the effect of hydroxypropyl beta cyclodextrin (HPbetaCD) on aqueous solubility, stability, and in vitro corneal permeation of acyl ester prodrugs of ganciclovir (GCV). Aqueous solubility and stability of acyl ester prodrugs of Ganciclovir (GCV) were evaluated in pH 7.4 isotonic phosphate buffer solution (IPBS) in the presence and absence of HPbetaCD. Butyryl cholinesterase-mediated enzymatic hydrolysis of the GCV prodrugs was studied using various percentage w/v HPbetaCD. In vitro corneal permeation of GCV and its prodrugs (with and without 5% HPbetaCD) across isolated rabbit cornea was studied using side-by-side diffusion cells. HPbetaCD-prodrug complexation was of the A(L) type with values for complexation constants ranging between 12 and 108 M(-1). Considerable improvement in chemical and enzymatic stability of the GCV prodrugs was observed in the presence of HPbetaCD. The stabilizing effect of HPbetaCD was found to depend on the degree of complexation and the degradation rate of prodrug within the complex. Five percent w/v HPbetaCD was found to enhance the corneal permeation of only the most lipophilic prodrug GCV dibutyrate (2.5-fold compared with 0% HPbetaCD). All other prodrugs showed little or no difference in transport in the presence of 5% w/v HPbetaCD. Agitation in the donor chamber largely influenced the transport kinetics of GCV dibutyrate across cornea. Results indicate the presence of an unstirred aqueous diffusion layer at the corneal surface that restricts the transport of the highly lipophilic GCV dibutyrate prodrug. HPbetaCD improves corneal permeation by solubilizing the hydrophobic prodrug and delivering it across the mucin layer at the corneal surface.

Side chain assignments of Ile delta 1 methyl groups in high molecular weight proteins: an application to a 46 ns tumbling molecule.

A sensitive 3D NMR pulse scheme, (H)C(CA)NH-COSY, is presented for the assignment of (13)C(delta)(1) Ile chemical shifts in large perdeuterated, methyl-protonated proteins. The nonlinearity of branched amino acids, such as Ile, significantly degrades the quality of TOCSY schemes which transfer magnetization from methyl carbons to the backbone (13)C(alpha) positions, and in applications to high molecular weight proteins (correlation times on the order of 40-50 ns), this compromises the sensitivity of spectra used for methyl assignment. The experiment presented utilizes COSY-based transfer steps and refocuses undesirable (13)C-(13)C scalar couplings that degrade the efficiency of TOCSY transfers. The (H)C(CA)NH-COSY scheme is tested on an (15)N,(13)C,(2)H-[Leu, Val, Ile (delta 1 only)]-methyl-protonated maltose binding protein (MBP)/beta-cyclodextrin complex at 5 degrees C (molecular tumbling time 46 +/- 2 ns), facilitating the assignment of (13)C(delta 1) chemical shifts for 18 of the 19 Ile residues for which backbone assignments were previously obtained. Both sensitivity and resolution of the resulting spectra are shown to be significantly better than those for a similar TOCSY-based approach.

Crystallization of two forms of a cyclodextrin inclusion complex containing a common organic guest.

The isolation and structural elucidation by single crystal X-ray diffraction of triclinic and monoclinic modifications of an inclusion complex of beta-cyclodextrin with the same guest, methylparaben, are reported.

Use of beta-cyclodextrins to prevent modifications of the properties of carbopol hydrogels due to carbopol-drug interactions.

Carbomers are carboxyvinylic derivatives that are widely used in the manufacture of hydrogel dosage forms. Because of their anionic nature and large number of acid groups, they tend to interact with cationic substances, and with other hydrophilic polymers containing alcohol groups. Here, we report a study of interactions between the carbomer Carbopol and the cationic drug propranolol hydrochloride in the solid state and in solution, and of the effects of such interactions on the properties of the hydrogel. We found that the drug forms an insoluble ionic complex with the polymer, modifying all of the hydrogel properties studied (swelling, release, bioadhesion). The inclusion of beta-cyclodextrin in the formulation reduces polymer/drug interactions, so that hydrogel properties remain unchanged. This is probably attributable to formation of inclusion complexes of beta-cyclodextrin and the drug, so that the drug is prevented from interacting with the polymer.

A Comparative Study of Naproxen – Beta Cyclodextrin Complexes Prepared by Conventional Methods and Using Supercritical Carbon Dioxide

Naproxen is a poorly soluble anti-inflammatorydrug, the solubility of which canbe enhanced by complexation withbeta-cyclodextrin. Besides that, the inclusioncomplex reduces the incidence of gastrointestinal side effects of the drug. The aim of this work was to compare the physicochemical characteristics of the solid complexes prepared by traditional methods (kneading, freeze-drying and spray-drying) and using a supercritical fluid technology. The unusual solvent properties of carbon dioxide above their critical temperature and pressure were exploited in order to prepare inclusion compounds. Complexes prepared using supercritical fluid technology showed similar properties to those of freeze-drying andspray-drying complexes as proved by DSC, FT-IRand UV.

A joint structural, kinetic, and thermodynamic investigation of substituent effects on host-guest complexation of bicyclic azoalkanes by beta-cyclodextrin.

Derivatives of the azoalkane 2,3-diazabicyclo[2,2,2]oct-2-ene (1a) with bridgehead 1,4-dialkyl (1b), 1,4-dichloro (1c), 1-hydroxymethyl (1d), 1-aminomethyl (1e), and 1-ammoniummethyl (1f) substituents form host-guest inclusion complexes with beta-cyclodextrin. They were employed as probes to assess substituent effects on the kinetics and thermodynamics of this complexation by using time-resolved and steady-state fluorimetry, UV spectrophotometry, induced circular dichroism (ICD) measurements, and (1)H NMR spectroscopy. The kinetic analysis based on quenching of the long-lived fluorescence of the azoalkanes by addition of host provided excited-state association rate constants between 2.6 x 10(8) and 7.0 x 10(8) M(-)(1) s(-)(1). The binding constants for 1a (1100 M(-1)), 1b (900 M(-1)), 1c (1900 M(-1)), 1d (180 M(-1)), 1e (250 M(-1)), and 1f (ca. 20 M(-1)) were obtained by UV, NMR, and ICD titrations. A positive ICD signal of the azo absorption around 370 nm was observed for the beta-cyclodextrin complexes of 1a, 1d, and 1f with the intensity order 1a >> 1d approximately 1f, and a negative signal was measured for those of 1b, 1c, and 1e with the intensity order 1c < 1b approximately 1e. The ICD was employed for the assignment of the solution structures of the complexes, in particular the relative orientation of the guest in the host (co-conformation).

Combination of 2D-, 3D-connectivity and quantum chemical descriptors in QSPR. Complexation of alpha- and beta-cyclodextrin with benzene derivatives.

Quantitative models are found to describe the complexation of alpha- and beta-cyclodextrin with mono- and 1,4-disubstituted benzene derivatives by using combinations of 2D-, 3D-connectivity and quantum chemical molecular descriptors. The association constants (K(a)) for the inclusion complexation of cyclodextrins and benzene derivatives are calculated by the models found with a high degree of precision. These models also permit the interpretation of the driving forces of such complexation processes. In the case of the complexation of alpha-cyclodextrin with benzene derivatives these driving forces are mainly the electronic repulsion between frontier orbitals of the host and guest molecules. However, the complexation of beta-cyclodextrin with benzene derivatives is controlled by topological and topographic parameters indicating the relevance of the van der Waals and hydrophobic interactions. We also carried out molecular modeling studies showing that for alpha-cyclodextrin complexes the benzene ring is outside the cavity of the cyclodextrin, while in beta-cyclodextrin they penetrate deeply into the apolar and hydrophobic cavity of the host, which explain the differences in the driving forces for both complexation processes.

Molecular recognition in cyclodextrin complexes of amino acid derivatives. 1. Crystallographic studies of beta-cyclodextrin complexes with N-acetyl-L-phenylalanine methyl ester and N-acetyl-L-phenylalanine amide pseudopeptides.

Cyclodextrins (CDs) are widely utilized in studies of chiral and molecular recognition. By changing the functionality of the guest molecule, the effect of such changes on recognition by the host CD molecule can be examined. We report crystal structure determinations for two nearly isomorphous complexes of phenylalanine derivatives: beta-CD/N-acetyl-L-phenylalanine methyl ester and beta-CD/N-acetyl-L-phenylalanine amide. The complexes crystallize as hydrated head-to-head host dimers with two included guest molecules in space group P1. The crystal packing is such that it presents a nonconstraining hydrophobic pocket adjacent to a hydrophilic region, where potential hydrogen-bonding interactions with hydroxyl groups of neighboring cyclodextrin molecules and waters of hydration can occur. The two host molecules display very similar conformations; only a few of the primary hydroxyl groups are conformationally disordered. There are a number of changes in the location of water of hydration molecules, some of which are the result of different hydrogen-bonding interactions. For the different guest molecules, similar modes of penetration are observed in the CD torus; however, there is a 0.985-A shift in the position of the guest molecules in the host torus, which takes place without changing the hydrophobic interactions displayed by the phenyl side chains. This observation and the thermal motion of the guest molecules in the ester complex are taken as evidence that complex binding forces are weak. The pseudopeptides experience a significant degree of flexibility in the crystalline environment provided by CD dimers. Conformational differences of the pseudopeptide backbones and the presence of disordered water molecules in the host-guest interface provide examples of different hydrogen-bonding schemes of similar potential energy. The crystal system presents an opportunity to establish a database of molecular interactions for small peptides and peptide analogues with waters of hydration and functional groups in nonconstraining binding environments.

Co-conformational variability of cyclodextrin complexes studied by induced circular dichroism of azoalkanes.

The solution structures of the beta-cyclodextrin complexes between 2,3-diazabicyclo[2.2.2]oct-2-ene (1) and its 1-isopropyl-4-methyl derivative 2 have been investigated by means of induced circular dichroism (ICD) and MM3-92 force-field calculations, which considered the effect of solvation within a continuum approximation. Of primary interest was the so-called co-conformation of the host-guest complex, i.e., the relative orientation of the guest within the host. A pool of low-energy complex structures, which were located by means of a Monte Carlo simulated annealing routine, was generated to evaluate the dynamic co-conformational variability of the complexes. The ICD effects were calculated for the computed low-energy structures by applying a semiempirical method. The experimental and theoretical ICD as well as the calculated low-energy complex geometries suggest solution co-conformations in which the parent compound 1 adapts a lateral arrangement with the ethano bridge of the guest penetrating deepest into the cavity and the azo group aligning parallel to the plane of the upper rim. In contrast, the alkyl derivative 2 prefers a frontal co-conformation with the isopropyl group penetrating deepest into the cavity and the azo group aligning perpendicular to the plane of the upper rim. The validity of the predictions of the Harata rule regarding the sign and the intensity of the ICD signals for the n(-)pi, n(+)pi, and pipi transition of the azo chromophore in dependence on the complex co-conformation are discussed. With respect to the co-conformational variability of the complexes of the two azoalkanes, it was observed that the nearly spherical guest 1 forms a geometrically better defined complex than the sterically biased, alkyl-substituted derivative 2. This dichotomy is attributed to the largely different modes of binding for azoalkanes 1 and 2. It is concluded that the goodness-of-fit in a host-guest complex cannot be directly related to the "tightness-of-fit".

In Vivo Absorption Studies of Insulin from an Oral Delivery System

Alginate microspheres prepared by an emulsion-based process were loaded with insulin by a remote loading process. We observed that the time of exposure, pH of the remote loading medium, and beta-cyclodextrin complexation of insulin influenced drug loading. In vivo absorption studies of insulin from optimized microspheres were carried out in diabetic albino rats. Serum sugar levels on administration of multiple oral doses of the microspheres and a radioimmunoassay for serum insulin indicated absorption of insulin from the gastrointestinal region. This process could be utilized for the development of an oral insulin delivery system.

Molecular Modeling (MM2 and PM3) and Experimental (NMR and Thermal Analysis) Studies on the Inclusion Complex of Salbutamol and β-Cyclodextrin

The inclusion complex of salbutamol and beta-cyclodextrin (beta-CD) is studied by computational (MM2 and PM3) and experimental techniques. Molecular modeling calculations predict two different orientations of salbutamol in the beta-CD cavity in vacuo and in aqueous solution. In vacuo calculations show that the introduction of the aromatic ring of salbutamol is preferred to the introduction of the tert-butyl group into the beta-CD cavity. However, in aqueous solution both computational methods predict the introduction of the alkyl chain instead of the aromatic ring in the beta-CD cavity contrary to experimental results published previously. These quantitative predictions were experimentally confirmed here by studying the inclusion complex in solution by NMR. A 1:1 stoichiometry was found by (1)H NMR studies for this complex. A 2D ROESY (rotating-frame Overhauser enhancement spectroscopy) experiment shows that there are no cross-peaks between the aromatic protons of salbutamol and any of the protons of beta-CD. Cross-peaks for the protons of the tert-butyl group and protons inside the cavity of beta-CD demonstrate the full involvement of this group in the complexation process and confirm the orientation of the complex predicted by molecular modeling. The solid-state complex was prepared and its stoichiometry (beta-CD.C(13)H(21)NO(3).8H(2)O) and dissociation process studied by thermogravimetric analysis.

Molecular orbital studies on pericyclic reactions of cinnamyl xanthates in beta-cyclodextrin cavities.

The solid beta-cyclodextrin (beta-CyD) complex of O-cinnamyl S-methyl dithiocarbonates (xanthate, 1a), upon heating at 45 degrees C, underwent asymmetric [3,31-sigmatropic rearrangement to give the optically S-(1-phenylallyl) S-methyl dithiocarbonate (2a) with 60% ee. Heating the beta-CyD complex of 2a at 120 degrees C caused extrusion of COS to give cinnamyl methyl sulfide (3a) in high yield. The reaction behavior and role of beta-CyD are discussed based on molecular orbital calculation data.

Crystal Structures of the Inclusion Complexes of β-Cyclodextrin with Aliphatic Monoacids Tridecanoic Acid and (Z)-Tetradec-7-enoic Acid. Formation of [3]Pseudorotaxanes

The structures of the inclusion complexes of beta cyclodextrin with the aliphatic mono-acids tridecanoic acid (1) and (Z)-tetradec-7-enoic acid (2) have been determined at room temperature. Both compounds crystallise in P1, a = 15.654(6) A, b = 15.650(6) A, c = 15.937(6) A, α = 101.58(1)°, β = 101.59(1)°, γ = 103.58(1)°, Z = 1, for 1 and a = 15.6259(9) A, b = 15.623(1) A, c = 15.935(1) A, α = 101.547(2)°, β = 101.555(2)°, γ = 103.642(2)°, Z = 1, for 2. One molecule of the monoacids threads through two cyclodextrin macrocycles arranged in dimers thus forming [3]pseudorotaxanes. The host dimers are aligned along a channel in order to create a hydrophobic environment for the terminal methyl group of the guest and isolate it from the aqueous environment that surrounds the cyclodextrin dimeric units. The guests exhibit disorder over two orientations resulting in hydrogen bonding between the carboxyl groups of adjacent guest molecules along the channel and formation of carboxylic dimers. This crystal packing differs from that of β-CD complexes of homologous dicarboxylic acids.

The Dimeric Complex of Beta-Cyclodextrin with 1,13-tridecanedioic acid

The structure of the complex of beta cyclodextrin (βCD) with 1,13-tridecanedioic acid has been determined at low temperature. The compound crystallizes in P1, a = 18.207(6), b = 15.510(5), c = 15.280(6) Å, α = 103.02(3), β = 113.13(3), γ = 99.79(3)° and Dc = 1.339 gcm−3 for Z=1. Refinement based on 13134 observed MoKα reflections led to a final R = 0.076. The diacid molecules thread through two βCD arranged in dimers thus, forming [3]pseudorotax-anes. The aliphatic chain of the guest has a few weak, non-bonded interactions with the host inside the long hydrophobic cavity. However, the end carboxyl groups form several strong H-bonds with the solvent in a fashion similar to other βCD/ carboxylic acid complexes that have similar building blocks as the present one: βCD dimers and carboxylic groups of the guest emerging from their two primary faces. Conversely, in the corresponding complexes with aliphatic monocarboxylic acids the carboxyl groups form carboxylic dimers because they are isolated from the environment inside hydrophobic channels.

Effect of p‐Cyclodextrin Complexation on the Photochemical and Photosensitizing Properties of Tolmetin: A Steady‐State and Time‐Resolved Study

The effects of beta-cyclodextrin complexation on the photochemical and photosensitizing properties of tolmetin have been investigated. Absorption, emission, circular dichroism and NMR measurements were used to characterize the host-guest complex. Nanosecond laser flash photolysis and steady-state photolysis experiments were performed to clarify the photoreactivity of the drug in the macrocycle. The decarboxylation of the drug is markedly reduced upon inclusion and the rate constants of the decay of the transient intermediates involved in tolmetin photodecomposition were slowed down due to their incorporation in the hydrophobic cavity. This also influenced the distribution of the stable photoproducts. A remarkable cyclodextrin-mediated protection against the tolmetin-photoinduced damage on biological substrates was observed. A rationale for these biological effects is provided.

Stability of the dimerization domain effects the cooperative DNA binding of short peptides.

The basic region peptide derived from the basic leucine zipper protein GCN4 bound specifically to the native GCN4 binding sequences in a dimeric form when the beta-cyclodextrin/adamantane dimerization domain was introduced at the C-terminus of the GCN4 basic region peptide. We describe here how the structure and stability of the dimerization domain affect the cooperative formation of the peptide dimer-DNA complex. The basic region peptides with five different guest molecules were synthesized, and their equilibrium dissociation constants with a peptide possessing beta-cyclodextrin were determined. These values, ranging from 1.3 to 15 microM, were used to estimate the stability of the complexes between the dimers with various guest/cyclodextrin dimerization domains and GCN4 target sequences. An efficient cooperative formation of the dimer complexes at the GCN4 binding sequence was observed when the adamantyl group was replaced with the norbornyl or noradamantyl group, but not with the cyclohexyl group that formed a beta-cyclodextrin complex with a stability that was 1 order of magnitude lower than that of the adamantyl group. Thus, cooperative formation of the stable dimer-DNA complex appeared to be effected by the stability of the dimerization domain. For the peptides that cooperatively formed dimer-DNA complexes, there was no linear correlation between the stability of the inclusion complex and that of the dimer-DNA complex. With the beta-cyclodextrin/adamantane dimerization domain, the basic region peptide dimer preferred to bind to a palindromic 5'-ATGACGTCAT-3' sequence over the sequence lacking the central G.C base pair and that with an additional G.C base pair in the middle. Changing the adamantyl group into a norbornyl group did not alter the preferential binding of the peptide dimers to the palindromic sequence, but slightly affected the selectivity of the dimer for other nonpalindromic sequences. The helical contents of the peptides in the DNA-bound dimer with the adamantyl group were decreased by reducing the stability of the dimer-DNA complex, which was possibly caused by deformation of the helical structure proximal to the dimerization domain.

Regression analysis for the host-guest interaction of beta-cyclodextrin with mono- and 1,4-disubstituted benzenes

A multiple regression model was generated, which can satisfactorily estimate the association constants (K-a) for the inclusion complexation of beta-cyclodextrin with mono- and 1,4-disubstituted benzenes. It was found that lnK(a) was correlated with the substituent molar refraction (R-m), hydrophobic constant (pi) and Hammett constant sigma) of the guest compounds with a correlation coefficient of 0.95. The main driving forces for beta-cyclodextrin complexation was concluded to consist of van der Waals forces and hydrophobic interactions, while the influence of electronic effects was small.

Electrospray ionization mass spectrometry of cyclodextrin complexes with amino acids in incubated solutions and in eluates of gel permeation chromatography

1:1 complexes of beta-cyclodextrin (CD) with three amino acids (Gly, Phe and Trp) have been detected as ions in the gas phase using infusion positive and negative ion electrospray ionization mass spectrometry (ESI-MS). In contrast with the positive ion ESI mass spectra of simple aqueous solutions, the aggregates and adducts usually formed in the ESI process did not appear in the positive ion ESI spectra of solutions buffered with ammonium acetate (NH4Ac), even at higher analyte concentrations, These studies suggest that addition of buffer and/or use of a low analyte concentration should be used to overcome formation of aggregates and metal ion adducts in such mass spectrometry studies. Also, the deprotonated complexes are dissociated by collision induced dissociation (CID) to form an abundant product ion, the deprotonated CD, requiring transfer of a proton to the amino acid carboxyl group, To understand formation of complexes in the gas phase, gel permeation chromatography (GPC) was used to separate free amino acids (AAs) from complexes in an incubated solution. The ESI mass spectra of the GPC fractions show the presence of 1:1 complexes of both CD-aromatic amino acids and CD-aliphatic amino acids. Compared with CD-aliphatic amino acid complexes, CD-aromatic amino acid complexes appear to be destabilized in the gas phase, possibly because the hydrophobic interaction which binds the aromatic group of amino acids in the CD cavity in solution may become repulsive when solvent evaporates from the droplets during the electrospray process, whereas those complex ions formed as proton bound dimers are stabilized by electrostatic forces, the major binding force for such complexes in the gas phase. In addition, the GPC technique coupled with off-line ESI-MS can rapidly separate CD complexes by size, and provides some information on the character of the complexes in solution. (C) 1998 John Wiley & Sons, Ltd.

Beta-cyclodextrin induced room temperature phosphorescence from 1-bromonaphthalene in the presence of naphthalene and 1-butanol

Intense room temperature phosphorescence (RTP) from host-guest inclusion complex of beta-cyclodextrin (β-CD) with 1-bromonaphthalene (1-BrN), stabilized by naphthalene (N) and 1-butanol (B), has been investigated. The spectral characteristics of luminescence emission and optimal conditions involved are reported. It has been confirmed that N and B are incorporated into the nonpolar cavity of β-CD as the second and third guests. The extra space inside the cavity is more filled by N and B, and δ-CD more effectively shields 1-BrN from quencher in aqueous solution. B completely hinders the formation of N excimer. Greater rigidity of the complex was achieved. Consequently, much more intense fluorescence and phosphorescence appear in comparison with the ternary β-CD:1-BrN:B complex. The limit of detection is 7.38 × 10 −8mol 1 −1 for 1-BrN and 1.36 × 10 −6mol 1 −1 for N.

Hydrosilylation catalysts derived from cyclodextrin organometallic platinum inclusion compounds and their use in command-cure applications

Beta-cyclodextrin (β-CD) complexes of CODPtX2 (COD=1.5-cyclooctadiene.X=Cl, Br, and I) have been prepared and employed as hydrosilylation catalysts. When used in cross-linkable, silicone-containing systems, these catalysts provide a long shelf stability at ambient temperature but cure rapidly at elevated temperature. These systems thus have the property of “command-cure”. Extensive analytical investigations were undertaken to develop reproducible synthetic methodology for the preparation of inclusion compounds free of surface contamination of the guest platinum compound. Water plays a key role in the synthesis of such platinum inclusion compounds. Dried β-CD CODPtX2 compounds can be washed with organic solvent to remove residual uncomplexed CODPtX2, while organic solvent washing of wet inclusion compounds results in removal of the guest from the β-CD cavity. Examination of these catalysts in curable silicone systems is described.