Inclusion compounds of some water-soluble β-cyclodextrin derivatives with phenolphthalein

Cyclodextrins and some of their water-soluble derivatives form with phenolphthalein host-guest complexes whose stability depends on the structure, position, and number of substituents.Translated from Zhurnal Obshchei Khimii, Vol. 74, No. 12, 2004, pp. 2034–2037.Original Russian Text Copyright © 2004 by Glazyrin, Grachev, Kurochkina, Nifantev.This revised version was published online in April 2005 with a corrected cover date.     

Preparation and evaluation of inclusion complexes of diacerein with β-cyclodextrin and hydroxypropyl β-cyclodextrin

The objective of this research was to improve the aqueous solubility, dissolution rate and, consequently, bioavailability of diacerein, along with avoiding its side effect of diarrhea, by complexation with β-cyclodextrin (β-CD) and HP-β-cyclodextrin (HP-β-CD). Phase solubility curve was classified as an A_N type for both the CDs, which indicated formation of complex of diacerein with β-CD and HP-β-CD in 1:1 stoichiometry and demonstrating that both CDs are proportionally less effective at higher concentrations. The complexes were prepared by kneading method and were evaluated to study the effect of complexation on aqueous solubility and rate of dissolution in phosphate buffer (pH 6.8). Based on the dissolution profile HP-β-CD was selected for preparing fast disintegrating tablet of diacerein which was compared with marketed formulation (MF-J). The HP-β-CD complex was probed for Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction studies which evidenced stable complex formation and increase in amorphousness of diacerein in complex. In brief, the characterization studies confirmed the inclusion of diacerein within the non-polar cavity of HP-β-CD. HP-β-CD complex showed improved in vitro drug release profile compared to pure drug and similar to that of marketed formulation respectively.     

Synthesis,characterization of inclusion compounds of amygdalin with β-cyclodextrin and sod-like activity and cytotoxicity on hela tumor cells

In this work is presented the synthesis of the inclusion complexes of amygdalin with β-cyclodextrin by three methods: kneading, co-precipitation and freeze drying and their characterization.The inclusion compounds were synthesized using a molar ratio of amygdalin: β-cyclodextrin of 1:1. Synthesized compounds were analyzed by FTIR spectroscopy, X-rays, thermal analysis and the results confirm the formation of inclusion compounds by amygdalin with β-cyclodextrin.The studies carried out have shown the protective effect of amygdalin-β-cyclodextrin compounds obtained by freeze drying, kneading and coprecipitation against free radicals (SOD-like activity in vivo) and the results of in vitro cell cytotoxicity of the compounds on HeLa cell line compared to pure amygdalin. Compound obtained by freeze drying has the best SOD-like activity and cytotoxicity on HeLa tumor cells, so it may be considered as potential therapeutic agent.     

pH-dependent complex formation of amino acids with β-cyclodextrin and quaternary ammonium β-cyclodextrin

Stability constants for the complexes of anionic, neutral (zwitterionic) and protonated forms of l- and d-enantiomers of eight amino acids with β-cyclodextrin and the positively charged quaternary ammonium β-cyclodextrin (QA-β-CD, DS?=?3.6?±?0.3) have been determined by spectrophotometric and pH-potentiometric methods. The highest stability constants have been obtained for the aromatic amino acids phenylalanine, tyrosine and tryptophan. Except the dianion of tyrosine and QA-β-CD, values for the anions in the range of 80–120 have been found, the stability constants for the zwitterionic forms are much smaller and complex formation is negligible with the protonated species. In the case of the other amino acids the differences are less pronounced. The results are interpreted in terms of hydrogen bonding, steric effects and electrostatic interactions between the amino acid moiety and the rims of the cyclodextrins, in addition to the inclusion of the side chain, and are supported by ¹H and ¹³C NMR investigations on the systems containing l-phenylalanine and l-tyrosine. The differences between the complex formation constants of the l- and d-enantiomers do not exceed the limits of experimental error in most cases.     

Interaction of p-cymene with β-cyclodextrin

In this investigation, the study of inclusion complexes formation between p-cymene and ??-cyclodextrin using the methods of physical mixture, paste (PC) and slurry (SC), was evaluated. The results of DSC and TG/DTG showed that the products prepared by PC and SC methods were able to incorporate greater amounts of p-cymene, as evidenced by the weight loss of 7.15 and 3.97%, respectively, which occurred between 120 and 270?°C. SEM images showed decreased size of the household, especially in the SC product. The absorption bands in the IR spectrum, characteristic of p-cymene, were also identified in the preparations, indicating the presence of the compound in the complex.     

Inclusion complexes of sulfanilamide with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin

Sulfanilamide belongs to the group of drugs that have a bacteriostatic effect on different pathogenic microorganisms. This activity originates from the competitive antagonism with p-aminobenzoic acid, which is an integral part of folic acid. The safe use of sulfanilamide is limited due to poor solubility in the aqueous medium. Therefore, the aim of this paper is the synthesis of sulfanilamide, as well as preparing and structural characterization of its inclusion complexes with cyclodextrins. The crude sulfanilamide was obtained in the synthesis between acetanilide and chlorosulfonic acid according to the standard procedure. The synthesized sulfanilamide was recrystallized from water in order to obtain the satisfactory purity of the substance. Sufanilamide was complexed with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin by the co-precipitation method. A molecular encapsulation of sulfanilamide was confirmed by using FTIR, ¹H-NMR, XRD and DSC methods. Phase-solubility techniques were used to assess the formation of the inclusion complex between sulfanilamide and cyclodextrins. The photostability of sulfanilamide and its inclusion complexes was estimated by UVB irradiation in a photochemical reactor by applying the UV–Vis method. Based on the UV–Vis analysis, sulfanilamide:2-hydroxypropyl-β-cyclodextrin complex was presented as more photostable than sulfanilamide:β-cyclodextrin complex and sulfanilamide. The obtained results enable the potential use of these inclusion complexes for the preparation of oral formulations due to the enhanced solubility of sulfanilamide.     

Interaction of native α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin and their hydroxypropyl derivatives with selected organic low molecular mass compounds at elevated and subambient temperature under RP-HPLC conditions

The main focus of this study was to explore the capability of native α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin and their hydroxypropyl derivatives for host-guest interaction with 7,8-dimethoxyflavone, selected steroids (estetrol, estriol, estradiol, estrone, testosterone, cortisone, hydrocortisone, progesterone and 17α-hydroxyprogesterone) and polycyclic aromatic hydrocarbons (toluene, naphthalene, 1,8-dimethylnaphthalene, 1-acenaphthenol, acenaphthylene and acenaphthene) under reversed-phase liquid-chromatography conditions. The study revealed that native cyclodextrins interact more efficiently with the analytes investigated than do their hydroxypropyl counterparts. In the low-temperature region, enormously high ratios were observed for polycyclic aromatic hydrocarbons, particularly 1,8-dimethylnaphthalene, acenaphthene and acenaphthylene chromatographed on a β-cyclodextrin-modified mobile phase. In such a case, the retention times of the polycyclic aromatic hydrocarbons were strongly reduced (e.g. from 127 to 1.2 min for 1,8-dimethylnaphthalene) and were close to the hold-up time of the high-performance liquid chromatography (HPLC) system (0.7 min). Moreover, chiral separation of 1-acenaphthenol optical isomers was observed and the elution order of the enantiomers was determined. Within the steroids group, strong interaction was observed for estradiol and testosterone. The results of cluster analysis indicate that β-cyclodextrin as well as γ-cyclodextrin and its hydroxypropyl derivative can be most effective mobile-phase additives under reversed-phase HPLC conditions for 3D-shape-recognition-driven separation, performed at subambient and elevated temperatures, respectively.     

Thermodynamics of the adsorption of volatile organic compounds in a binary polydimethylsiloxane-permethylated β-cyclodextrin stationary phase, as measured by gas chromatography

The sorption behavior of 29 organic compounds in a binary polydimethylsiloxane-permethylated β-cyclodextrin stationary phase is investigated using gas chromatography. The effect of the sorbates’ polarity, shape, and chirality on the formation of sorbate-cyclodextrin inclusion complexes is studied.     

Complexation of herbicide bentazon with native and modified β-cyclodextrin

For first time the complexation of bentazon (Btz) with native β-cyclodextrin (β-CD) and modified sulfobutylether-β-CD (SBE-CD) was studied by differential pulse voltammetry. In addition, a spectrophotometry UV–Visible study was carried out. In presence of CDs there is a decrease of the anodic peak current with the increase of the amount of CD. This decrease is due to the lower diffusion coefficient of Btz/CD complex compared with the free guest. Using the variation in current, association constants of 118 ± 20 and 317 ± 25 M^?1 for β-CD and SBE-CD were determined. The solubility of bentazon was 8 fold higher with SBE-CD as compared with bentazon-free. Phase solubility diagrams performed using UV–Vis experiments permit to obtain the same association constants which were compared with the values obtained by electrochemical techniques.     

Combined computational and experimental study on the inclusion complexes of β-cyclodextrin with selected food phenolic compounds

Phenolic compounds, such as caffeic acid, trans-ferulic, acid and p-coumaric acid that are commonly found in food products, are beneficial for human health. Cyclodextrins can form inclusion complexes with various organic compounds in which the physiochemical properties of the included organic molecules are changed. In this study, inclusion complexes of three phenolic compounds with β-cyclodextrin were investigated. The complexes were characterized by various analytical methods, including nuclear magnetic resonance (NMR) spectroscopy, Fourier IR (FT-IR) spectroscopy, mass spectrometry, differential scanning calorimetry, and scanning electron microscopy. Results showed that the phenolic compounds used in this study were able to form inclusion complexes in the hydrophobic cavity of β-cyclodextrin by non-covalent bonds. Their physicochemical properties were changed due to the complex formation. In addition, a computational study was performed to find factors that were responsible for binding forces between flavors and β-cyclodextrin. The quantum-mechanical calculations supported the results obtained from experimental studies. Thus, ΔH_f for the complex of p-coumaric acid and β-cyclodextrin has been found as ??11.72 kcal/mol, which was about 3 kcal/mol more stable than for inclusion complexes of other flavors. Energies of frontier orbitals (higher occupied molecular orbital (HOMO) and lower unoccupied molecular orbital (LUMO)) were analyzed, and it was found that H-L gap for the complex of p-coumaric acid and β-cyclodextrin had the largest value (8.19 eV) in comparison to other complexes, which confirmed the experimental findings of the most stabile complex.

     

Complexation of ebastine with β-cyclodextrin derivatives

Complexation of ebastine (EB) with hydroxypropyl and methyl-β-cyclodextrin (HP-β-CD and Me-β-CD) was studied in aqueous solutions and in the solid state. The formation of inclusion complexes in aqueous solutions was analysed by the solubility method. The assays were designed using low CD concentrations compared with the solubility of these derivatives in order to avoid non-inclusion phenomena and to obtain a linear increase in EB solubility as a function of CD concentration. The values of complexation efficiency for HP-β-CD and Me-β-CD were 1.9 × 10^?2 and 2.1 × 10^?2, respectively. It seems that the non polar character of the methyl moiety slightly favoured complexation. In relation to solid state complexation, 1:1 EB:CD systems were prepared by kneading, and by heating a drug-CD mixture at 90 ºC. They were analysed using X ray diffraction analysis by comparison with their respective physical mixtures. A complex with a characteristic diffraction pattern similar to that of the channel structure of β-CD was formed with Me-β-CD in 1:1 melted and 1:2 EB:CD kneaded systems. Complexation with HP-β-CD was not clearly evidenced because only a slight reduction of drug crystallinity was detected. Finally, the loading of EB in two β-CD polymers cross-linked with epichlorohydrin yielded 7.3 and 7.7 mg of EB/g polymer respectively.     

Dissolution enhancement of artemisinin with β-cyclodextrin

The main objective of this research is to improve the dissolution rate of artemisinin (ART) by fabrication with β-cyclodextrin (β-CD) as a hydrophilic carrier. Artemisinin nanoparticles and ART/β-CD complexes were successfully fabricated by means of evaporative precipitation of nanosuspension. Characterization of the samples was done by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and dissolution tester. Percent dissolution efficiency, mean dissolution time, relative dissolution and similarity factor were calculated for the statistical analysis of dissolution data. FT-IR showed some interaction between ART and β-CD, which can be due to the formation of some ART/β-CD complexes. XRD study indicated the presence of two polymorphs of ART, i.e. orthorhombic and triclinic form. Original ART particles and ART nanoparticles fabricated were orthorhombic whereas the free ART in the ART/β-CD complexes (not forming complex with β-CD) was of triclinic form. The crystallinity of ART reduced and more and more ART/β-CD complexes were formed with increasing concentration of β-CD as indicated by the DSC, XRD and FT-IR studies. Artemisinin nanoparticles and ART/β-CD complexes showed significantly faster dissolution than the pure drug due to smaller size (larger surface area), formation of the inclusion complex with β-CD, formation of the triclinic form for remaining free ART (not forming complex with β-CD), and amorphous state formation. Evaporative precipitation of nanosuspension was able to successfully fabricate artemisinin in the nanoparticles and complex forms with significantly faster dissolution rates than that of the original artemisinin. The two polymorphic forms of ART were also fabricated and studied.     

Spectral properties and structures of supramolecular complexes of naphthylpyridine with β-cyclodextrin

The electronic absorption and fluorescence spectra of 4-(2-naphthyl)pyridine (1) and N-methyl-4-(2-naphthyl)pyridinium perchlorate (2 ⁺·ClO₄ ^–) were studied in aqueous solutions in the absence and presence of -cyclodextrin (-CD). In aqueous solutions and organic solvents in the presence of water or H⁺ ions, compound 1 exhibits intense fluorescence with a maximum at 21 270 cm^–1, and its quantum yield in an aqueous solution is 0.9±0.09. The same fluorescence spectrum was detected for an aqueous solution of 2 ⁺·ClO₄ ^–. In an aqueous solution, compound 1 and -CD form stable fluorescing supramolecular 2:2 complexes, whose structure was calculated by the quantum-chemical MNDO/PM3 method. The formation of these complexes induces a hypsochromic shift of the fluorescence maximum of 1 by 5000 cm^–1. The stability constant of the complex is 2·10³ L mol^–1. A decrease in the pH results in the formation of a protonated form of 1(1·H⁺) and destruction of the complex, thus favoring the escape of the substrate from the -CD cavity. The quantum-chemical calculations showed that the insertion of 1 into the -CD cavity is thermodynamically more favorable than hydration; on the contrary, the formation of 1·H⁺ increases dramatically the hydration energy, which promotes the escape of 1·H⁺ from the -CD cavity; cation 2 ⁺ does not form a complex with -CD; in the thermodynamically most favorable 2:2 complex, the naphthalene fragments of two molecules 1 are parallel to each other in a broad section of the -CD dimer constructed according to the head-to-head type.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2420–2425, November, 2004.     

Structural study of the inclusion compounds of thymol, carvacrol and eugenol in β-cyclodextrin by X-ray crystallography

The crystal structures of the inclusion compounds of thymol, carvacrol and eugenol, (components of essential oils of vegetable origin) in β-cyclodextrin have been determined. Thymol/β-CD crystallizes in the space group P1 containing two host molecules in its asymmetric unit whereas both carvacrol/β-CD and eugenol/β-CD complexes crystallize in the space group C2. In all three complexes two host molecules form head-to-head dimers their guest/host stoichiometry being: 1/2 (carvacrol/β-CD), 2/2 (thymol/β-CD) and 3/2 (eugenol/β-CD). In the cases of the thymol/β-CD and the carvacrol/β-CD complexes the β-CD dimers are arranged according to the channel packing mode. The accommodation of the geometrical isomer guests is performed solely by their hydrophobic groups revealing the leading role of the hydrophobic driving forces in the complexation process whereas the position of their hydroxyl group affects the stoichiometry of the formed dimeric complexes. In the case of the eugenol/β-CD dimeric complex one guest molecule is found lying between the β-CD groups in a sandwich fashion whereas the other two symmetry related guests protrude outwards the narrower rim of the hosts with only their hydrophobic allyl-chain located inside the hosts’ cavities. This arrangement prohibits the formation of a channel and the observed crystal packing is that of a Tetrad mode.     

Reactions of cyanofurazans with β-dicarbonyl compounds

In the presence of nickel acetylacetonate, -dicarbonyl compounds readily add at the nitrile group of 4-R-3-cyanofurazans to form enaminofurazans. The adducts obtained from 4-amino-3-cyanofurazan underwent intramolecular cyclization on heating with AcOH in EtOH to give furazano[3,4-b]pyridine derivatives in high yields.     

Inclusion complexation of chloropropham with β-cyclodextrin: preparation, characterization and molecular modeling

An inclusion complex between the agrochemical chloropropham (CIPC) and β-cyclodextrin (β-CD) was prepared. A 2:1 host-guest stoichiometry was conformed by elemental analysis. From the phase solubility studies, the calculated stepwise stability constants were K(1)=224.6L/mol and K(2)=939.2L/mol, respectively. FT-IR, thermoanalysis and (1)H NMR spectra were applied to characterize the complex. It was speculated that the inclusion mode was two β-CD cavities included the chlorophenyl and the isopropyl moiety of one CIPC molecule, which was in agreement with the most predominant configuration optimized by molecular modeling. By complexation with β-CD, the water solubility and the thermal stability of CIPC were prominently improved.     

Influence of different techniques on formulation and comparative characterization of inclusion complexes of ASA with β-cyclodextrin and inclusion complexes of ASA with PMDA cross-linked β-cyclodextrin nanosponges

Acetyl salicylic acid (ASA), a non-steroidal anti-inflammatory drug, was formulated into inclusion complexes by grinding and precipitation with β-cyclodextrin and freeze drying with pyromellitic dianhydride (PMDA) cross-linked β-cyclodextrin nanosponges. Particle size, zeta potential, encapsulation efficiency, accelerated stability study, in vitro and in vivo release studies were used as characterization parameters. TEM studies showed that the particle sizes of different inclusion complexes of ASA have diameters ranging from 40.12?±?8.79 to 59.53?±?15.55?nm. It also revealed the regular spherical shape and sizes of complexes that are even unaffected after drug encapsulation. Zeta potential was sufficiently high to obtain a stable colloidal formulation. The in vitro and in vivo studies indicated a slow and prolonged ASA release from PMDA cross-linked β-cyclodextrin nanosponges over a long period. XRPD, DSC and FTIR studies confirmed the interactions of ASA with nanosponges. XRPD showed the crystalline nature of ASA decreased after encapsulation. These results indicate that ASA nanosponges formulation can be used for oral delivery.     

Inclusion complexes of Sulconazole with β-cyclodextrin and hydroxypropyl β-cyclodextrin: characterization in aqueous solution and in solid state

Complexation between sulconazole (SULC), an imidazole derivative with in vitro antifungal and antiyeast activity, and β-cyclodextrins (β-CD and HP-β-CD) was studied in solution and in solid states. Complexation in solution was evaluated using solubility studies and nuclear magnetic resonance spectroscopy (¹H-NMR). In the solid state, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM) and RX diffraction studies were used. Solubility studies suggested the existence of inclusion complex between SULC and β-CD or HP-β-CD. ¹H-NMR spectroscopy studies showed that the complex formed occurs by complexation of imidazole ring into inner cavity. DSC studies showed the existence of a complex of SULC with β-CD. The TGA and RX studies confirmed the DSC results of the complex. Solubility of SULC in solid complexes was studied by the dissolution method and it was found to be much more soluble than the uncomplexed drug.     

Enrichment and sensitive detection of polyphenolic compounds via β-cyclodextrin functionalized fluorescent gold nanorods

Microchimica Acta - We report on a simple and rapid method for the enrichment of polyphenolic compounds (pPhCs) by means of gold nanorods whose surface was functionalized with a monolayer of...     

Free energy perturbation and MM/PBSA studies on inclusion complexes of some structurally related compounds with β-cyclodextrin

Molecular dynamics (MD) simulations have been conducted to explore time-resolved guest–host interactions involving inclusion complex formation between β-cyclodextrin and organic molecules bearing two peripheral benzene rings in aqueous solution. Moreover, free energy perturbation (FEP) and thermodynamic integration (TI) methods at different simulation times have been employed to estimate the relative free energy of complexation. Also, the less computer-time demanding molecular mechanics/Poisson–Boltzmann surface area (MM/PBSA) method was used to estimate the free energy of complexation based on only 1-ns MD simulation. Results showed that both FEP and TI methods were able to reasonably reproduce the experimental thermodynamic quantities. However, long simulation times (e.g. 15 ns) were needed for benzoin mutating to benzanilide (BAN), while moderately shorter times were sufficient for BAN mutating to phenyl benzoate and for benzilic acid mutating to diphenylacetic acid. The results have been discussed in the light of the differences in the chemical structural and conformational features of the guest molecules. In general, it was apparent that the TI method requires less time for convergence of results than the FEP method. However, the less expensive MM/PBSA method proved capable of producing results that are in agreement with those of the more expensive TI and FEP methods.