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.     

Characterization and mechanism study of micrometer-sized secondary assembly of β-cyclodextrin

We herein report a β-cyclodextrin-based secondary assembly (β-CD SA) obtained from an aqueous solution. It was found that the addition of a very small amount of organic molecule 2-phenyl-5-(4-diphenylyl) 1,3,4-oxadiazole (PBD) into an aqueous solution of 10 mM β-CD led to the formation of a micrometer-sized rodlike SA, which made the mixture turbid immediately. After careful characterization, the structure and the formation mechanism of the β-CD SA were suggested. PBD first induces β-CDs to form rigid nanotubes through head-to-head or tail-to-tail routes. Using the "solid" nanotubes as recrystallization centers, other β-CDs assembled to channel in the c axis direction and hexagonally aligned in the b axis direction, leading to the formation of a β-CD SA. In the β-CD SA, most of the β-CDs were not occupied by PBD. In the course of formation , intermolecular hydrogen-bonding plays a prominent role. The results reported herein would be helpful in constructing cyclodextrin-based architectures in water.     

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.     

A quartz crystal microbalance study of β-cyclodextrin self assembly on gold and complexation of immobilized β-cyclodextrin with adamantane derivatives

Quartz crystal microbalance (QCM) was used to study the self-assembly of per-6-thio-β-cyclodextrin (t₇-βCD) on gold surfaces, and the subsequent inclusion interactions of immobilized βCD with adamantane-poly(ethylene glycol) (5,000 MW, AD-PEG), 1-adamantanecarboxylic acid (AD-C) and 1-adamantylamine (AD-A). From a 50 μM solution of t₇-βCD in 60:40 DMSO:H₂O, a t₇-βCD layer was formed on gold with surface density of 71.7 ± 2.7 pmol/cm², corresponding to 80 ± 3% of close-packed monolayer coverage. Gold sensors with immobilized t₇-βCD were then exposed alternately to six different concentrations of AD-PEG, 500 μM AD-C or 500 μM AD-A aqueous solutions for association, and water for dissociation. Association of AD-PEG conformed to a Langmuir isotherm, with a best fit equilibrium constant K = 125,000 ± 18,000 M⁻¹. For AD-C and AD-A, association (k _a ) and dissociation (k _d ) rate constants were extracted from kinetic profiles by fitting to the Langmuir model, and equilibrium constants were calculated. The parameters for AD-C were found to be: k _a = 100 ± 5 M⁻¹ s⁻¹, k _d = 110 (±18) × 10⁻⁴ s⁻¹, and K = 9,400 ± 1,700 M⁻¹. For AD-A, k _a = 58 ± 6 M⁻¹ s⁻¹, k _d = 154 (±7) × 10⁻⁴ s⁻¹, and K = 3,800 ± 400 M⁻¹. The results demonstrate the utility of QCM as a tool for studying small molecule surface adsorption and guest–host interactions on surfaces. More specifically, the kinetic and thermodynamic data of AD-C, AD-A, and AD-PEG inclusion with immobilized t₇-βCD form a basis for further surface association studies of AD-X conjugates to advance surface sensory and coupling applications.     

Study on inclusion behaviour of forsythiaside A with β-cyclodextrin

Inclusion behaviour of forsythiaside A with β-cyclodextrin (β-CD) was investigated by fluorescence spectrum, nuclear magnetic resonance (NMR) and molecular modelling. A ratio of 1:1 stoichiometry has been proposed for the inclusion complex of forsythiaside A with β-CD in aqueous media according to the continuous variation Job’s method based on the fluorescence spectroscopy data. The stability constant (K) of the inclusion complex was 669 M^?1. The pH, ionic strength and temperature of solution showed great effect on the formation of inclusion complex. The spatial configuration of complex demonstrated that the B ring of forsythiaside A might be embedded inside the lipophilic cavity of β-CD and the A ring of the forsythiaside A might be exposed outside the cavity of β-CD according to NMR spectra and molecular modelling.     

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.     

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.     

A printed SWCNT electrode modified with polycatechol and lysozyme for capacitive detection of α-lactalbumin

The authors describe an electrochemical sensor for the breast cancer marker α-lactalbumin (αLA). It is based on the use of printed single-walled carbon nanotube (SWCNT) electrodes that were modified with polycatechol. Impedance-derived electrochemical capacitance spectroscopy (ECS) is applied for detection at an applied potential of ?0.14 V vs. Ag/AgCl reference electrode. The electrode was prepared in a two-step process. First, a dispersion of SWCNTs was drop-cast onto the surface of a poly(ethylene terephthalate) substrate to act as the working electrode. Next, catechol was electrochemically polymerized on the SWCNTs, prior to the immobilization of lysozyme. The strong interaction between lysozyme and αLA induced changes in the redox capacitance which are detected by ECS. The latter shows the device to be capable of detecting αLA in the 20 to 80 ng·mL^?1 concentration range. The limit of detection is 9.7 ng·mL^?1 at an S/N ratio of 3. The device was used to detect αLA in human blood serum with good recovery results.

Open image in new window

Graphical abstract A sensitive biosensor for αLA was prepared by modifying SWCNT electrode with polycatechol and lysozyme. The electrochemical capacitance spectroscopy was used for the first time to selectively detect αLA in the blood in the range from 20 to 80 ng·mL^?1.

     

A novel approach for fixation of β-cyclodextrin on cotton fabrics

Cyclodextrins are cyclic oligosaccharides, which form complexes with different organic substances such as drugs, odors, and etc. Due to the complexing abilities of cyclodextrins (CDs), they may also be used in textile industry as an auxiliary in washing, dyeing, and wastewater treatment. Fixation of CDs on textiles is possible using reactive derivatives of cyclodextrins or crosslinking agents. In this study we have investigated the use of polyaminocarboxylic acids (PACAs) as novel crosslinking agents for the fixation of β-CD on cotton fabrics. Fixation of β-CD on cotton fabric has been quantified by measuring the weight increase of the treated samples. The influence of the concentration of the catalyst (sodium hypophosphite) was studied, too. The presence of β-CD on the cotton has been investigated by the phenolphthalein test and host–guest complexation with organic volatile molecules: cyclohexene, chlorobenzene, cyclohexene-1-one and toluene.     

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.     

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.     

Investigation of inclusion complexes of citronella oil, citronellal and citronellol with β-cyclodextrin for mosquito repellent

The aim of this study was to prepare the inclusion complexes of citronella oil, citronellal or citronellol with β-cyclodextrin and evaluate their physicochemical properties using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). A kneading method was employed to prepare the inclusion complexes and weight ratios of each of the active substance to β-cyclodextrin were 1:1 (1:1 CPX) and 1:2 (1:2 CPX). For comparison purposes, physical mixtures of these active compounds and β-cyclodextrin were also prepared and investigated. Unlike the physical mixtures, the SEM technique revealed drastic changes in the shapes and morphologies of the particles for the inclusion complexes. Furthermore, the FTIR and DSC results seemed to reveal some interactions between the active substance and β-cyclodextrin. The o/w lotions, which contained 10% w/w citronella oil (normal citronella oil; 1:1 CPX or 1:2 CPX), were formulated using Cremophors as emulsifiers. With modified Franz diffusion cell and synthetic membrane, the release rates of citronella oil from the lotions containing the inclusion complexes were significantly lower than that from the prepared lotion containing normal citronella oil. The mosquito (Aedes aegypti) repellent efficacy of the lotions containing citronella oil, citronellal or citronellol (both normal and inclusion complexes) was further evaluated by human-bait technique. The highest mosquito repellent activity was observed in the formulation which contained citronella oil–β-cyclodextrin inclusion complex at weight ratio of 1:1.     

Chitosan sponge matrices with β-cyclodextrin for berberine loading

Biocompatible polymer sponge materials based on biodegradable natural polymer chitosan, which can be loaded with clinician-selected drugs are still in the centre of interest for their wide use in clinical practice. This study shows possibilities of the technology which combines simple addition of β-cyclodextrin (β-CD), with dialdehyde starch (DAS) as a cross-linking agent of chitosan, to chitosan solutions for subsequent formation of sponge matrix. The advantage of such system is in avoiding chemical modifications and working only with natural substances. It is shown that, in matrix formation during lyophilisation, β-CD molecules tend to accumulate on the surface of the porous matrix structure. This was confirmed by a study of the known inclusion complex of β-CD and salicylic acid (SA) in heptane. The same study was applied to berberine (BER) which can also form an inclusion complex with β-CD in a water solution. Moreover, adsorption of drugs on the surface of the porous structure has to be also taken into account. This enables the production of sponge topical medical preparations useful for sustained release of BER.     

Difference in formation mechanism of inclusion complex between configuration isomers of gallate-type catechin and β-cyclodextrin

Journal of Thermal Analysis and Calorimetry - The formation mechanism of inclusion complex between (-)-epigallocatechin gallate (EGCg), which is the main catechin in tea leaves, or...     

Electrochemical and associated techniques for the study of the inclusion complexes of thymol and β-cyclodextrin and its interaction with DNA

Journal of Solid State Electrochemistry - Thymol, a potent agent for microbial, fungal, and bacterial disease, has low aqueous solubility and it is genotoxic, i.e., is capable of damaging...