Preparation and physicochemical characterization of omeprazole:methyl-beta-cyclodextrin inclusion complex in solid state

In this work, we illustrate the usefulness of cyclodextrins, namely, methyl-β-cyclodextrin (MβCD), an amorphous, methylated derivative of the natural β-cyclodextrin (βCD), as a tool to form an inclusion complex with omeprazole (OME), a poorly water soluble drug. Solid binary systems between OME and MβCD were prepared experimentally in a stoichiometry 1:1 by different techniques (physical mixing, kneading, spray-drying and freeze-drying). Afterward these products were characterized by Fourier transformation-infrared spectroscopy (FTIR); X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The results obtained suggest that spray-drying and freeze-drying methods yield a higher degree of amorphous entities suggesting the formation of inclusion complexes between OME and MβCD.     

A novel differential scanning calorimetric method to study the complexation of β-cyclodextrin with steroid in solid state

This communication demonstrates that, by simply minotiring the evaporation of water molecules included in β-cyclodextrin cavity, complexation of β-cyclodextrin with steroid in solid state can be studied. The reported method is simple, rapid and novel.     

Thermal study of complex formation of triamterene with β-cyclodextrin by spray-drying and co-grinding

The formation of crystalline inclusion complex of triamterene with β-cyclodextrin (β-CD) was studied, evaluating the thermal behaviour and dispersion state of this drug in different types of binary systems. Spray-drying and co-grinding (oscillating mill) mixtures of triameterene with β-CD were prepared in 1∶1 molar ratio. The changes of crystalline properties of original (untreated) triamterene, β-CD, and composites obtained by co-grinding and spray-drying were investigated in comparison with those produced in simple physical mixtures. The thermal behaviour of the different samples was investigated using DTA. X-ray diffraction was applied as a complementary technique. The results have been explained by formation of amorphous drug particles on spray-drying samples and co-grinding or alternatively by means of a solid dispersion formation or a combination of these two. A contamination effect by grinding media was also observed as increasing grinding time.     

Debittering of Tangerine Citrus Reticulata Blanco Juice by β-Cyclodextrin Polymer

The use of insoluble β-cyclodextrin polymer for the reduction of limonin in Thai tangerine juice by batch, column and fluidized bed processes were studied and compared. Direct correlation between complexation of limonin and amount of β-cyclodextrin polymer was observed. The binding was not affected by temperature when tested at cold room and room temperatures. Using 3 g% β-CD polymer at room temperature, limonin reduction by the batch and column processes were 70 and 94% respectively. In a fluidized bed column (50 × 3 cm i.d.) under the condition of 15 g β-cyclodextrin polymer with a feed flow rate of 100 mL/min at room temperature, the initial efficiency of debittering was about 90% and gradually decreased. Increasing the flow rate or amount of the cyclodextrin bed did not improve the efficiency at the present study condition.     

1H NMR spectroscopic investigation of β-cyclodextrin inclusion compounds with parecoxib

The inclusion complexes of β-CD and parecoxib [PRB] in aqueous solution were investigated using ¹H NMR spectroscopic study revealed the existence of four different equilibria for 1:1 inclusion complexes in which both the aromatic rings of the guest are tightly held by the host cavity. The NMR spectra of the PRB studied in the presence of β-CD are fully assigned and interpreted by means of COSY spectrum for the unambiguous assignment of guest aromatic ring protons. The parallel interpretation of β-CD chemical shift changes and dipolar contacts, with the aid of 2D ROESY, allows the mode of binding to be established for four possible structures of 1:1 PRB-β-CD inclusion complexes.     

Complexation of Fluvastatin Sodium with β-Cyclodextrin: NMR Spectroscopic Study in Solution

¹H NMR spectroscopic study of fluvastatin sodium (FLU), β-Cyclodextrin (β-CD) and their mixtures confirmed the formation of FLU/β-CD inclusion complex in solution. The stoichiometry of the complex was determined to be 1:1 and the overall binding constant (K _s) was calculated to be 340 M⁻¹. Two dimensional COSY, ROESY and DEPTO experiments were performed for the unambiguous assignment of aromatic proton resonances and it was found that two isomeric forms of FLU are present in solution. It was confirmed with the help of ROESY spectral data that only F-substituted aromatic ring penetrates the β-CD cavity and there is chiral differentiation by the β-CD as one of the isomer binds more strongly, which is indicated by the intensity of correlation peaks. The mode of penetration of the guest into the β-CD cavity was also established and structure of the complex has been proposed.     

Evaluation and validation of an HPLC procedure for the determination of the positional isomeric impurity in 2-[4-(1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl)-phenyl]-2-methylpropionic acid

A high-performance liquid chromatographic (HPLC) procedure was evaluated for the determination of a positional isomeric impurity in bulk 2-[4-(1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl)-phenyl]-2-methylpropionic acid HCl drug substance. The use of a β-cyclodextrin bonded-phase column with a mobile phase of 20/80 (v/v) acetonitrile/water containing an ammonium acetate buffer at apparent pH 4.0 and a flow rate of 0.45 mL/min resulted in an excellent separation of the isomers. Ultraviolet detection was used at 220 nm. A recovery study of known spike levels (0.1 to 1.5% w/w) showed that the procedure was accurate. A two-day, two-column repeatability study showed consistent results with the test batch of the bulk compound. The level of impurity in the tested lot of the compound had a mean level of 0.32% (w/w) and a standard deviation of 0.038% (w/w, n = 5). The text was submitted by the author in English.     

Direct synthesis of novel amphiphilic cyclodextrin

A novel amphiphilic cyclodextrin derivative was obtained by controlled esterification of lauric acid chloride on the primary face of the native β-cyclodextrin in a one step synthesis. The characterization of the substitution degree and isomer structure was performed by mass and NMR spectroscopies. A specific purification procedure by sublimation was developed in order to eliminate the excess of lauric acid molecules in the reaction product. The sublimation efficiency was assessed by differential scanning calorimetry (DSC) in quantifying the remaining fatty acid. In this way the duration of the sublimation process could be optimized.     

Chiral separation of chloroquine and pemoline by capillary zone electrophoresis with sulfobutyl ether β-cyclodextrin as buffer additive

Summary Cyclodextrin-mediated, capillary zone electrophoresis was used for the chiral separation of chloroquine and pemoline. Optimization experiments for the choice of cyclodextrins and the concentration of sulfobutyl ether β-cyclodextrin were performed. Complete separations were obtained with a resolution of 2.1 for chloroquine in 2.5 mM sulfobutyl ether β-cyclodextrin and a resolution of 1.4 for pemoline in 1.0 mM sulfobutyl ether β-cyclodextrin, respectively, from which further biomedical research, such as pharmacodynamic or pharmacokinetic study and quantitative determination, could subsequently be facilitated.     

Permethylated 6I-alkenoylamino-6I-deoxy β-cyclodextrin derivatives as modifiers of photoluminescence sensor response of porous silicon

A set of permethylated 6^I-(ω-alkenoyl)-6^I-amino-6^I-deoxy-β-cyclodextrin derivatives with different chain length of the alkenoyl group (used as a spacer) was synthesized. These derivatives were attached by photochemically activated hydrosilylation reaction to the surface of porous silicon. Photoluminescence response of the modified PS to controlled concentrations of various molecules in gas phase revealed strong host-guest interactions between β-cyclodextrin and the detected molecules. The strongest interaction was observed for aromatic molecules, which have the optimal size to fit into the β-cyclodextrin molecular cavity.     

Synthesis and electrochemical behavior of inclusion complexes based on β-cyclodextrin and alkylaromatic compounds: Electrochemical carboxylation of the β-cyclodextrin-1-(4-isobutylphenyl)ethylchloride inclusion complex on a glassy-carbon cathode in anhydrous dimethylformamide

Inclusion complexes of β-cyclodextrin with alkylaromatic compounds β-cyclodextrin-1-(4-isobutylphenyl)ethylchloride in the “guest-host” molar ratio of 1 : 2 and β-cyclodextrin-methyl-(4-isobutylphenyl)ketone in the “guest-host” molar ratio of 1 : 1, are synthesized, isolated, and characterized. It is shown that preparative electrocarboxylation of the inclusion complex β-cyclodextrin-1-(4-isobutylphenyl)ethylchloride on a glassy-carbon cathode with a dissolving magnesium anode in dimethylformamide affords S-forms of 2-(4-isobutylphenyl)propionic acid (S-Ibuprofen) in a high enantiomeric excess (97%). In addition to the acid, a dimer and a hydride form from the corresponding intermediates.     

Polymeric adsorbents with peptide pendants as artificial receptors for β-lactam antibiotics by mimicking the binding sites of β-lactamases

A series of polymeric adsorbents with peptide pendants were designed as the artificial receptors of β-lactam antibiotics by mimicking the structures of binding site in β-lactamases. Crosslinked poly(N, N-dimethyl acrylamide) gel as a carrier was prepared by suspension copolymerization of N, N-dimethyl acrylamide and N. Ń-bisacryl-diaminoethane and then functionalized with ethylenediamine after partial hydrolysis. Using solid-phase peptide synthesis with symmetrical anhydride of protected amino acid step by step, various peptide pendants were respectively anchored onto the functionalized carrier. The adsorption properties of these peptide-containing adsorbents for β-lactam antibiotics such as ampicillin and cefotaxime were then studied. The results showed that only those adsorbents in which peptide chains contained more than one lysine residues could obviously adsorb both β-lactams and that static interaction as well as hydrogen bond played an important role during the adsorption. Project supported by the National Natural Science Foundation of China (No. 59493207).     

Spectral Characteristics of Bicalutamide Drug in Different Solvents and β-Cyclodextrin

Absorption and fluorescence spectra of bicalutamide (BCA) in different solvents and aqueous β-cyclodextrin (β-CD) solutions are reported. The solid inclusion complex of BCA with β-CD is prepared and investigated by FT-IR, ¹H NMR, differential scanning colorimetry (DSC) and scanning electron microscopy (SEM). The Stokes shift of BCA is correlated with various solvent polarity scales like E _T(30), BK and f(D,n). β-CD studies show that (i) the absorption and emission maxima of BCA are shifted to red, (ii) the absorbance is slightly decreased whereas emission intensity is increased largely with an increasing β-CD concentration, (iii) BCA forms 1:1 inclusion complex with β-CD and (iv) intramolecular charge transfer (ICT) emission is present in the excited state.     

Utilization of Supercritical Carbon Dioxide for the Preparation of 3-Hydroxyflavone and β-Cyclodextrin Complex

The solubility of 3-hydroxyflavone in water can be enhanced by forming complex with β-cyclodextrin (β-CD). In this study we introduced supercritical carbon dioxide as a substitute solvent to prepare 3-hydroxyflavone-β-cyclodextrin complex. The maximum drug loading determined by UV spectroscopy in complex was 14.7 wt.%, which was comparable to that of 1:1 complex (17.34 wt.% of 3-hydroxyflavone). The solubility of the drug loaded in the complex was better than that of pure drug in water. The enhanced solubility was attributed to the formation of the complex and the solubility of the β-cyclodextrin in water.     

Cyclodextrin-based Nanosponges for Drug Delivery

Nanosponges were prepared from β-cyclodextrins as nanoporous materials for possible use as carriers for drug delivery. The structure of β-cyclodextrin-based nanosponges was principally investigated by FT-IR, DSC and RX analyses. Sizes, morphology and toxicity were also examined. The capacity of the nanosponges to incorporate molecules within their structure was evaluated using drugs with different structures and solubilities. The nanosponges were found capable of carrying both lipophilic and hydrophilic drugs and of improving the solubility of poorly water-soluble molecules.     

Theoretical studies on the binding affinities of β-cyclodextrin to small molecules and monosaccharides

Equilibrium geometries and electronic structures of complexes between β-cyclodextrin (β-CD) and some small molecules as well as monosaccharides were investigated by Austin Model 1 (AM1) to obtain binding energy of the complexes. It was indicated that β-CD could bind the structurally similar solvent molecules and monosaccharides because of the negative binding energy of the complexes, and especially could show the chiral binding ability to monosaccharides with more hydroxyl groups, due to its chiral characteristics. The complexes were stabilized by the hydrogen bonding between β-CD and guests. Based on the AM1 optimized geometries, the IR spectra were calculated by AM1 method. Vibration frequencies of O-H bonds in the guests were red-shifted owing to the weakening of the O-H bonds with the formation of the complexes.     

Electrochemically aided solid phase microextraction: conducting polymer film material applicable for cationic analytes

The cation uptake and release properties of a poly(pyrrole-sulfated β-cyclodextrin) (PPy-SβCD) film electrode have been investigated under both open circuit and controlled potential conditions for prospective applications in electrochemically aided solid-phase microextraction (EA SPME). The EDAX and ion chromatography results show that the K⁺ and Na⁺ cation uptake is enhanced if a small negative potential is applied to the electrode in the range where PPy is in its neutral form. These cations are released rapidly from the film if the applied potential is switched to the value at which PPy is converted to its positively charged form, i.e., oxidized state. The cation ingress and egress mechanism is affected both by the cation exchange at the negative sulfate moiety on the cyclodextrin sites and electrostatic interactions generated by the applied potential. The electrochemical "switching" capability increases the speed of the cation uptake and release, presumably due to electro migration, as compared to the open circuit ion exchange which is controlled solely by diffusion. Our preliminary fundamental results show that the PPy-SβCD film is suitable for the future design of EA SPME devices. Electronic Publication     

Grafting of cyclodextrins onto filter paper

Grafting of cyclodextrins and cyclodextrins derivatives on cellulosic surface, such as paper or filter paper, provides hosting cavities that can include a large variety of chemicals for specific cellulose finishing. In this study grafting of monocholorotriazinyl-β-cyclodextrin (MCT-β-CD) and β-cyclodextrin (β-CD) to filter paper has been performed. β-cyclodextrin has been bonded to filter paper using 1,4-butanediol diglycidyl ether as the crosslinking agent. The untreated and treated filter papers were characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), demonstrating the covalent binding of cyclodextrins to filter paper. The quantification of β-CD and MCT-β-CD grafted to filter paper was determined by the dye extinction method with the inclusion of phenolphthalein. The final β-CD content amounted to 15.9 μmol per gram of support (1.8% by weight), and 72.8 μmol per gram of support (11.3% by weight) for MCT-β-CD.     

Factors Contributing to Solubility Synergism of Some Basic Drugs with β-Cyclodextrin in Ternary Molecular Complexes

Ternary complexes exploiting solubility synergism (SSn) between basic drugs and β-cyclodextrin (β-CD) in the presence of an organic hydoxy acid have been reported to provide the pharmaceutical technology with highly soluble ternary complexes, even with the least soluble β-CD. In this work, phase solubility techniques were used to study factors affecting SSn in aqueous solution, which may help in understanding the mechanism involved in ternary complex formation in solution, under equilibrium conditions. The equilibrium solubility of both β-CD and each of 8 structurally unrelated drugs were measured in tandem in the presence of different acid types at low and high pHs, and at different time intervals over a period of 1–40 days. The results indicate that SSn is evident regardless of acid type (organic and inorganic) at low pH, but the extent of SSn is acid type dependant and is limited by the drug salt solubility product constant (pK _sp). Among different drugs, no apparent trend exists between drug salt solubility and the extent of SSn, but lowering drug salt solubility by increasing pH depresses SSn. The results also reveal no apparent trend between the magnitude of the complex formation constant (K _ij) and SSn. For example, drugs of low K _ij values such as astemizole, cisapride and sildenafil do not show any SSn, yet ketotifen and pizotifen, which also have low K _ij values, exhibit substantial SSn. However, the solublizing power of β-CD represented by the slope of phase solubility diagram can be used as a marker for SSn (slopes exceeding 0.4 induce SSn).     

Thermosensitive mucoadhesive gel formulation loaded with 5-Fu: cyclodextrin complex for HPV-induced cervical cancer

Human Papilloma Virus (HPV) infections are the major cause of cervical cancers. To achieve a better therapeutic efficacy and patient compliance in the treatment for HPV-induced cervical cancers, anticancer agent 5-fluorouracil has been formulated in a vaginal gel using the thermosensitive polymer Pluronic^® F127 together with alternative mucoadhesive polymers e.g., hyaluronic acid, Carbopol 934 and hydroxypropylmethylcellulose. To increase its aqueous solubility and to achieve the complete release of 5-FU from the gel, the drug was incorporated as its inclusion complex with 1:1 molar ratio with either β-cyclodextrin or hydroxypropyl-β-cyclodextrin. Following the characterization of drug:CD complexes, thermosensitive gel formulations containing different mucoadhesive polymers and the drug in free or complexed form were characterized in vitro by determining the gelation temperature and the rheological behavior of different formulations along with the in vitro release profiles of these formulations in pH 5.5 citrate buffer. It was observed that complexation with cyclodextrin accelerated the release of 5-FU with the exception of formulation containing Carbopol 934 as mucoadhesive polymer. As far as rheological properties are concerned, favorable thermosensitive in situ gelling properties were obtained with formulations containing HPMC as mucoadhesive polymer. Complete release of 5-FU from gels were obtained with both complexes of β-CD and HP-β-CD and cytotoxicity studies against HeLa human cervical carcinoma cells demonstrated that 1% 5-FU:CD complexes were equally effective as 1% free 5-FU indicating better therapeutic efficacy with lower dose.