Inclusion Complexation of Lorazepam with β — Cyclodextrin

The preparation of an inclusion complex of Lorazepam, a benzodiazepine antianxiety agent with β -cyclodextrin is described. The inclusion compound was prepared by the homogeneous coprecipitation method in the molar ratio of 1:2 of the drug and β -cyclodextrin respectively. The formation of inclusion complex was evaluated by UV spectral studies, IR studies, X-ray diffractometry, and Differential Thermal Analysis. The solubility and in-vitro drug release studies indicated that the complex form of the drug significantly increase the solubility and the dissolution rate compared to the free form. Tablets prepared with Lorazepam- β -cyclodextrin complex also showed a significant increase in dissolution of the drug indicating that P-cyclodextrin plays an important role in the solubilization of the drug.     

Influence of the substitution of β-cyclodextrins by cationic groups on the complexation of organic anions

The inclusion complexation of the organic anion, dansyl-acid, by cationic derivatives of β-cyclodextrin has been investigated. A series of cationic β-cyclodextrins with various positive charge has been synthesized by selective functionalization of the primary face of β-cyclodextrin with amino groups. The complexes were of the 1:1 stoichiometry; the stability constants (K₁₁) have been evaluated from UV–Vis measurements by application of the Benesi–Hildebrand equation. The presence of amino groups increased the complexation ability. β-cyclodextrin fully substituted at the primary face with amino groups showed the strongest inclusion binding ability towards the dansyl-acid guest. The enhanced complexation for anions was ascribed to the cationic amino groups. A simple thermodynamic model of the electrostatic contribution to the complexation is presented.     

Inclusion Complexes of Tolnaftate with β-Cyclodextrin and Hydroxypropyl β-Cyclodextrin

Tolnaftate, an antifungal agent, was found to form inclusion complexes with both β-cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrins (HPBCDs) with two different degrees of substitution [HPBCD(A)-8% and HPBCD(B)-3%]. Complex formation in the solution state was studied using phase solubility and spectral shift methods. Solid complexes were prepared by the coprecipitation method. Solubilities and dissolution rates were determined for each solid complex, its corresponding physical mixture, and free drug. The increase in solubility of tolnaftate with added HPBCD was found to be significantly greater than with added β-CD. For both HPBCD(A) and HPBCD(B), over the concentration range 0-0.05 M. 1:1 complexes with stability constants of 1460 ± 139 M^-1 and 1860 ± 165 M^-1 were observed, respectively. Over the β-CD concentration range 0-0.02 M, a 1:1 complex with a stability constant of 1190 ± 105 M^-1 was observed. At higher HPBCD concentrations, the increase in solubility was observed to show a positive deviation from linearity (type A_p phase diagram). Using the spectral method, in a 2 5% v/v methanol in water system, the stability constants were determined to be 1020 ± 150 M^-1 1110 ± 120 M^-1 and 1100 ± 260 M^-1 for HPBCD(A), HPBCD(B) and β-CD, respectively. The solid complexes prepared showed improved dissolution over physical mixtures and free drug.     

Inclusion of Vitamin D2 in β-Cyclodextrin. Evaluation of Different Complexation Methods

Evaluation of inclusion complexation of vitamin D2 with β-cyclodextrin in aqueous solution and solid state was performed by Phase Solubility Diagramm, HPLC, DSC, X-RAY Diffractometry, NMR. Solid inclusion complexes were prepared by spray-drying, kneading and solid dispersion. The dissolution profiles of the complex either in powder or in tablets were studied in order to select the best inclusion process.     

Study of Surfactants/β-Cyclodextrin Interactions Over Mequitazine Dissolution

Surfactant/β-cyclodextrin interactions were investigated by studying the dissolution of mequitazine in different binary (aqueous solutions of β-CD or surfactants) and ternary (aqueous solution of β-CD and surfactants) dissolution media. Results were compared with those obtained from binary media with 50, 250, and 500 mg of surfactants (preceding paper). Results show that there is an interaction between β-cyclodextrin and surface-active agent, and that the type and extent of interaction are controlled by the nature and the amount of the surface-active agent. A decrement in drug dissolution rate was obtained from all of the ternaly media containing β-cyclodextrin and sodium lauryl sulfate as surfactant in the ratio of 1:1 mol/mol. These facts suggest that sodium lauryl sulfate and β-cyclodextrin form an inclusion compound in the molecular ratio of 1:1.     

Characterization of the tableting properties of β-cyclodextrin and the effects of processing variables on inclusion complex formation, compactibility and dissolution

The tableting properties of a number of commercially available β-cyclodextrins were characterized. Fluidity was insufficient for routine direct compression. Compactibility varied by source but was excellent. Lubrication requirements were minimal. An inclusion complex of β-cyclodextrin/Progesterone was formed and the tableting properties of the complex were compared to those of a physical mixture in both directly compressed and wet granulated products. Inclusion complexes spontaneously formed during wet granulation processing. Substantial differences in tableting properties were found as processing variables were changed. β-cyclodextrin exhibits considerable promise as a standard filler binder in tableting.     

Comparative study on Inclusion compounds of 4-Biphenylacetic acid with β-Cyclodextrin, Hydroxypropylated-β-Cyclodextrins, and methylated-β-Cyclodextrins

The inclusion behavior of Hydroxypropyl-β-Cyclodextrin (HP-β-Cyd) and of methylated-β-Cyclodextrins, heptakis-(2,6-di-O-methyl)-β-Cyclodextrin (DM-β-Cyd) and heptakis-(2,3,6-tri-O-methyl)-β-Cyclodextrin (TM-β-Cyd), in solution and solid state was compared with that of natural β-Cyclodextrin (β-Cyd) using an anti-inflammatory drug, 4-biphenylacetic acid (BPAA), as a guest molecule. The solubility of BPAA with β-Cyd and β-Cyd derivatives in aqueous solution were determined. Stability constants were calculated by phase solubility method at various pH values and temperatures. The formation of inclusion complexes with β-Cyd and β-Cyd derivatives in the solid slate were confirmed by infrared spectroscopy, differential scanning calorimetry and X-Ray diffractometry, and in the liquid phase by ultraviolet spectroscopy, circular dichroism and NMR studies. Dissolution rate and “in vitro” release of BPAA from complexes were examined. The results obtained suggest that DM-β-Cyd is more effective than other β-Cyclodextrins in improving the pharmaceutical properties of BPAA.     

Solubilization of Glibenclamide with β-Cyclodextrin & its Derivatives

Gilbenclamide, a widely used potent hypoglycaemic agent was solubllized using β -Cyclodextrin and β -Cyclodextrin derivatives. Complexes were prepared by kneading method in a molar ratio of 1:1 of the drug and the cyclodextrlns respectively. The Glibenclamide β -Cyelocextrin complex was characterized and evaluated by I.R. studies, Differential Scanning Calorimotry 6 X-ray diffractometry. The in-vitro dissolution rates of drug from inclusion complexes of β Cyclodextrins and its derivatives were compared. A significant Improvement In dissolution lor, rates of Gllbenclamide was observed with Inclusion complexes of all the Cyclodextrins. However, the solubilizing effect was more in case of β-Cyclodextrin derivatives.     

Inclusion complexation of vitamin a palmitate with β-cyclodextrin in aqueous solution

Study of the inclusion complex between vitamin A palmitate and β-cyclodextrin in aqueous solution was performed to determine the stoichiometry and the association constant of the complex by the phase solubility diagram and fluorescence intensity measurements.     

STABILITY STUDIES ON THE WATER-SOLUBLE β-CYCLODEXTRIN-[60]FULLERENE INCLUSION COMPLEX

[60]Fullerene was found to form an inclusion complex with β-cyclodextrin, which formed a stable yellow-colored solution in water. The stability constant of the 2 : 1 complex, measured from absorbance measurements and using the Benesi-Hildebrand equation, was found to be 1.69  ×  10⁵ dm⁶ mol^-2. The 2 : 1 composition of the inclusion complex was confirmed by thermogravimetric analysis.     

Physico-chemical study of inclusion compound Phenothiazine-β-Cyclodextrin

In this work, the authors have made many assays to prove the inclusion of phenothiazine in β-cyclodextrin.

The inclusion compound was prepared in two various ways and we have checked the inclusion using NMR and Differential Thermal Analysis tests.

This experimentation leads to other assays making inclusion compounds with molecules using the phenothiazine core and used in humans medicines.     

The Influence of β-Cyclodextrin on the Solubility of Chlorthalidone and Its Enantiomers

The solubility of chlorthalidone in 16 solvent systems was determined in the absence and presence of different amounts of β-cyclodextrin (β-CD). Chlorthalidone (CT) was shown to be more soluble in hydrophilic organic solvents, with the highest solubility in ethylacetate (EtOAc) saturated with water. The solubility of CT in water, butanol, octanol, and dichloromethane (DCM) was enhanced by the addition of β-cyclodextrin. The enantioselective partitioning of CT between water and EtOAc, DCM, butan-1-ol, butan-2-ol, and octan-1-ol was determined in the presence of β-CD at pH 5, 7, and 9. According to the results, both the solubility and partition- ing properties of CT are affected by β-CD in aqueous solution. It was also shown that the solubility of the individual enantiomers differs in the presence of β-CD.     

Enhanced Aqueous Solubility of Phenolic Antioxidants Using Modified β-Cyclodextrins

Phenolic antioxidants are useful additives with a possible role in cancer chemoprevention. This study describes inclusion complexation between phenolic antioxidants (butylated hydroxyanisole, BHA; butylated hydroxytoluene, BHT) and hydroxypropyl-β-cyclodextrins (HPB) or hydroxyethyl-β-cyclodextrin (HEB) and their characterization by phase solubility analysis, Xray diffraction and infrared (IR) spectroscopy. The complexes were prepared by shaking an aqueous mixture of the antioxidant with each of the cyclodextrins (1:1 molar) at 40 °C for six days and lyophilizing the resulting clear solution. Each of the complexes dissolved instantaneously in water. Phase solubility analysis indicated a more pronounced increase in the aqueous solubility of BHA compared to that of BHT. Xray diffraction patterns of the antioxidant-cyclodextrin complexes indicated a shift from crystalline pattern of the antioxidant to an amorphous pattern for the complexes. Also, the IR spectra of the BHA-cyclodextrin complexes indicated an almost complete disappearance or at least a shift in the -C-O-C- stretch (1200 cm^-1) compared to the corresponding stretch observed for BHA alone or a physical mixture (1:1) of BHA and each of the cyclodextrins. Furthermore, the sharp -OH absorption (3600 cm^-1) is retained in a physical mixture of BHT with either cyclodextrin (1:1) whereas this stretch is not observed in the IR spectra of either BHT-cyclodextrin complexes. These evidences indicate the formation of an inclusion complex between the antioxidants and each of the cyclodextrins.     

Interactions between preservatives and 2-hydroxypropyl-β-cyclodextrin

The interactions between several commonly used preservatives, i.e. benzalkonium chloride, chlorhexidine gluconate, chlorobutanol, methylparaben and propylparaben, and 2-hydroxypropyl-β-cyclodextrin were investigated. The interactions were shown to be twofold. Firstly, the preservative molecules can displace the drug molecules from the cyclodextrin cavity, thus, reducing the solubilizing effects of the cyclodextrin. Secondly, the antimicrobial activity of the preservatives were reduced by formation of preservative-cyclodextrin inclusion complexes. The magnitude of the interactions were dependent on the degree of complexation.     

Emulsions of β-cyclodextrins grafted to silicone for the transport of antifungal drugs

The transport of pharmaceutical or cosmetic active substances that are not soluble in water requires their solubilisation or encapsulation in a suitable dosage form. A material combining the solubilising properties of β-cyclodextrins and the biocompatibility of silicone has been prepared as an aqueous emulsion and used for the encapsulation of an antifungal molecule.

β-cyclodextrins have been chemically grafted to the poly(methylhydrosiloxane) polymer or poly(methylhydrosiloxane-co-dimethylsiloxane) copolymer through hydrosilylation reaction. The multi-step synthesis includes the regioselective attachment of tosyl group to one of the primary hydroxyls, its conversion into allylic derivative and subsequent acetylation of the remaining hydroxyl groups. The final step consists in grafting the cyclodextrin derivative to silicone polymer by means of hydrosilylation reaction.

Such polymers that bear peracetylated β-cyclodextrins have been emulsified by the “spontaneous emulsification” method, giving stable emulsions with sizes ranging between 200 and 500 nm. The emulsions could encapsulate the antifungal substance griseofulvin inside the β-cyclodextrin cavity by formation of inclusion complex. The encapsulation rate was limited to the 1:1 stoichiometry of the complex. Supplementary amount of griseofulvin could not be encapsulated and slowly precipitated as crystalline particles. Emulsions of silicone oil investigated as reference formulations did not incorporate even a small amount of griseofulvin.     

Some Pharmaceutical Properties of 2,3,6-partially Methylated-β- cyclodextrin and its Solubilizing and Stabilizing Abilities

The pharmaceutical properties of 2,3,6-partially methylated-β-cyclodextrin(PMCD) were investigated. The aqueous solubility of PMCD was much higher than that of the parent βCyD, and it exhibited endothermic dissolution in contrast to that of the conventional heptakis-(2,6-di-O-methyl)-β-cyclodextrin(DMCD). The acid-catalyzed hydrolysis rate of PMCD was faster than those of the parent β-CyD and DMCD. The hemolytic activity (human erythrocytes) of PMCD was similar to that of DMCD. PMCD was a more effective solubilizer for poorly water-soluble drugs than the parent β-CyD; however PMCD is not as effective as DMCD. The stabilizing effect of PMCD on chemically unstable drugs was higher than that of the parent β-CyD.

For 2,3,6 partially methylated-β-CyD(PMCD), in which the hydroxyl groups of cyclodextrin are substituted by a methyl group, the methylation ratios are as follows: 58-62% at the 2-position, 48∼52% at the 3-position, and 98∼100% at the 6-position¹⁾. This novel cyclodextrin derivative is synthesized by MERCIAN CORPORATION²⁾. The aqueous solubilities of conventional heptakis-(2,6-di-O-methyl)-β-cyclodextrin(DMCD) and heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin(TMCD) usually decreased with increasing temperature; however, PMCD exhibited endothermic dissolution in a manner similar to that of the parent β-cyclodextrin (PCyD). PMCD has received considerable attention in the pharmaceutical field; therefore, in this study some of the physicochemical properties of PMCD, such as surface activity, hemolytic activity and chemical stability in acid medium were investigated. In addition, the solubilizing and stabilizing abilities of PMCD for pooly water-soluble drugs were compared with those of β-CyDand DMCD.     

Effect of Hydrotropic Substances on the Complexation of Clotrimazole with β-Cyclodextrin

The phase diagrams of clotrimazole/β-cyclodextrin (β-CD) in phosphate buffer, pH = 7.1, containing 0.5 M of various hydrotropic agents were constructed. The water structure disruptors, urea and nicotinamide, increased the intrinsic solubility of the antimycotic drug clotrimazole while the water structure forming agents, sorbitol and fructose, decreased the solubility. Concerning the complex constant between clotrimazole and β-CD, it was the other way around. The connection between the slopes of the phase diagrams, the intrinsic solubility of clotrimazole and the complex constant was discussed. Nicothamide decreased the solubility of β-CD in the buffer solution. The results reported in this study are in disagreement with the claim that addition of water structure forming agents to cyclodextrin solutions can be used to increase the total solubility of drugs     

Characterization and Properties of γ-Cyclodextrin-C60 Complex In Aqueous Solution

Water soluble fullerene was prepared by complexing C₆₀ with γ-cyclodextrin. The stoichiometry of the complex [2:1, γ-CD: C₆₀] was determined by thermo gravimetric analysis. The complex was characterized by ¹H NMR, FTIR, SEM, circular dichroism and fluorescenc techniques.     

The Dislocation Structure of a Single-Crystal γ + γ′ Two-Phase Alloy After Tensile Deformation

The dislocation structures of an industrial single-crystal γ + γ′ two-phase alloy DD3 after tensile deformation from room temperature to 1273K were studied by transmission electron microscopy. The strength of this alloy decreased with an increase in the temperature, and showed a strength peak at 1033K. At room temperature, the dislocations shearing the γ′ particles were found to be 1/3<112> partial dislocations on the dodecahedral slip system <112>{111}. Some dislocation pairs on the cubic <110>{100} system that blocked the glide of dislocations were found at a medium temperature of 873K. As a result, dislocation bands were formed. Shearing of γ′ particles by 1/3<112> partial dislocations on the dodecahedral slip system <112>{111} was also found at this temperature. At the peak temperature of 1033K, because of the strong interaction between dislocations on the {111} and {100} planes, the extent of dislocation bands with high dislocation densities was extensive. The 1/3<112> partial dislocations on the dodecahedral slip system <112>{111} also existed. When the temperature reached the high temperature of 1133K, the range of dislocation bands was limited. The γ′ particles were sheared by <110> dislocation pairs on the octagonal <110>{111} system and the cubic <110>{100} system. At 1273K, the regular hexagonal dislocation networks were formed in the γ matrix and at the γ/γ′ interface. The Burgers vectors of the network were found to be b₁ = 1/2[110], b₂ = 1/2[1–10], b₃ = [100], and the last one was formed by the reaction of b₁ + b₂ → b₃. Dislocations shearing the γ′ particles were found to be <110> dislocation pairs on the octagonal system <110>{111} and cubic slip system <110>{100} at 1273K.     

Effect of Grinding of β-Cyclodextrin and Glibenclamide on Tablet Properties. Part I. in vitro

Physical properties including dissolution characteristics of glibenclamide (GB) tablets were studied. Directly compressed and wet-granulated GB tablets gave only 35% and 40% drug dissolved, respectively. Physical mixing, kneading, and grinding of β-cyclodextrin (CD) with GB were investigated. It was found that the grinding method could markedly enhance the release of drug from the tablets. The physical properties of these tablets were unchanged after they had been stored at 40°C and 75% RH for at least 3 months. The GBKD mixture at a ratio of 1 to 4, ground for 24 or 48 hr, exhibited superior dissolution and chemical stability. Differential scanning calorimetry indicated that an inclusion complex was produced. Decreasing grinding time or CD concentration could result in incomplete formation of the inclusion complex. It was concluded that pretreatment of the drug with CD by the grinding method could significantly improve the dissolution and stability of GB tablets.