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

Abstract

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.     

Nimesulide and beta-cyclodextrin inclusion complexes: physicochemical characterization and dissolution rate studies

Complex formation of nimesulide (N) and β-cyclodextrin (βCD) in aqueous solution and in solid state and the possibility of improving the solubility and dissolution rate of nimesulide via complexation with βCD were investigated. Phase solubility studies indicated the formation of a 1:1 complex in solution. The value of the apparent stability constant Kc was 158.98 M^-1. Solid inclusion complexes of N and βCD were prepared by kneading and coevaporation methods. Differential scanning calorimetry (DSC) studies indicated the formation of solid inclusion complexes of N-βCD at a 1:2 molar ratio in both the methods. Solid complexes of N-βD (1:1 and 1:2 M) exhibited higher rates of dissolution and dissolution efficiency values than the corresponding physical mixtures and pure drug. Higher dissolution rates were observed with kneaded complexes than with those prepared by coevaporation. Increases of 25.6- and 38.7-fold in the dissolution rate were observed, respectively, with N-βCD 1:1 and 1:2 kneaded complexes.     

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.     

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.     

Investigation and physicochemical characterization of clarithromycin-citric acid-cyclodextrins ternary complexes

The purpose of this study was to investigate the effect of citric acid (CA) on the complexation of clarithromycin (CLM) with β-cyclodextrin (βCD) in aqueous solutions and in the solid state. A phase solubility study revealed a positive effect of CA on the drug solubility. A B_s-type solubility with an apparent stability constant (K_c) of 102.4 M^-1 was obtained for CLM in βCD solution and 161.2 M^-1 for CLM in 6 mM βCD solution. Solid ternary complexes were prepared by coevaporation and lyophilization. CLM-βCD-CA interactions were studied in the solid state by differential scanning calorimetry (DSC), infrared spectroscopy, scanning electron microscopy and X-ray diffractometry. A part of the guest molecule was located in the βCD host cavity. The results obtained suggest that the lyophilization method yields a higher degree of amorphous entity than coevaporation.     

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     

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 4-Biphenylacetic Acid with β-Cyclodextrin

The preparation of an inclusion complex of 4-biphenylacetic acid (BPAA), a non-steroidal antiinflammatory drug, with β-cyclo-dextrin is described. The presumible structure of the inclusion system, the molar ratio, which was found 1:1, and the formation constant were calculated by the analysis of IR, UV, DSC, X-ray diffraction, and ¹H-NMR. Dissolution rate and solubility were also studied. BPAA solubility in water resulted significantly (4,2-fold) increased by complexation, such as its dissolution rate which appears, in the first 12 min, 18 times greater for the complex than the drug alone.     

Low-temperature, direct synthesis of β-SiC by metal vapor vacuum arc ion source implantation

Crystalline β-SiC surface layers with strong (111) preferred orientation were synthesized by direct ion implantation into Si(111) substrates at a low temperature of 400°C using a metal vapor vacuum arc ion source. Both X-ray diffraction and Fourier transform infrared spectroscopy reveal an augment in the amount of β-SiC with increasing implantation doses at 400°C. Scanning electron microscopy shows the formation of an almost continuous SiC surface layer after implantation at 400°C with a dose of 7×10¹⁷/cm². The full width at half maximum of the X-ray rocking curve of β-SiC(111) was measured to be 1.4° for the sample implanted at a dose of 2×10¹⁷/cm² at 700°C, revealing a good alignment of β-SiC with the Si matrix.     

Structural and optical characterization of β-FeSi2 layers on Si formed by ion beam synthesis

Structural and optical properties have been investigated for surface β-FeSi₂ layers on Si(100) and Si(111) formed by ion beam synthesis using ⁵⁶Fe ion implantations with three different energies (140–50 keV) and subsequent two-step annealing at 600 °C and up to 915 °C. Rutherford backscattering spectrometry analyses have revealed Fe redistribution in the samples after the annealing procedure, which resulting in a Fe-deficient composition in the formed layers. X-ray diffraction experiments confirmed the existence of /gb-FeSi₂ by annealing up to 915 °C, whereas the phase transformation from the β to phase has been induced at 930 °C. In photoluminescence measurements at 2 K, both β-FeSi₂/Si(100) and β-FeSi₂/Si(111) samples, after annealing at 900–915 °C for 2 h, have shown two dominant emissions peaked around 0.836 eV and 0.80 eV, which nearly coincided with previously reported PL emissions from the sample prepared by electron beam deposition. Another β-FeSi₂/Si(100) sample has shown sharp emissions peaked at 0.873 eV and 0.807 eV. Optical absorption measurements at room temperature have revealed the allowed direct bandgap of 0.868–0.885 eV as well as an absorption coefficient of the order of 10⁴ cm⁻¹ near the absorption edge for all samples.     

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.     

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.     

Solubility and dissolution rate of progesterone-cyclodextrin-polymer systems

This contribution focused on the solubility improvement of the poorly water-soluble steroid hormone progesterone which, in its natural state, presents a reduced oral bioavailability. In the first part of this study, two simple, reproducible methods that were candidates for use in the preparation of inclusion complexes with cyclodextrins were investigated. Solubility capacities of the progesterone complex with hydroxypropyl-β-CD (HPβ-CD), hydoxypropyl-γ-CD (HPγ-CD), permethyl-β-CD (PMβ-CD), and sulfobutylether-β-CD (SBEβ-CD), prepared by the freeze-drying and precipitation methods, were evaluated by Higuchi phase solubility studies. The results showed that HPβ-CD and PMβ-CD were the most efficient among the four cyclodextrins for the solubilization of progesterone, with the highest apparent stability constants. Therefore, dissolution studies were conducted on these latest progesterone/cyclodextrin complexes and physical mixtures. Two additional natural cyclodextrins, β-CD and γ-CD, were taken as references. Hence, the influence of more highly soluble derivatives of β-CD (HPβ-CD, PMβ-CD) on the progesterone dissolution rate, in comparison to pristine β-CD, alongside an increase in the cavity width for γ-CD versus β-CD, were investigated. The dissolution kinetics of progesterone dissolved from HPβ-CD, PMβ-CD, and γ-CD revealed higher constant rates in comparison to β-CD. Therefore, the aim of the second part of this study was to investigate the possibility of improving the dissolution rate of progesterone/β-CD binary systems upon formation of ternary complexes with the hydrophilic polymer, PEG 6000, as β-CD had the smallest progesterone solubility and dissolution capacity among the four cyclodextrins studied (β-CD, HPβ-CD, HPγ-CD and PMβ-CD). The results indicated that dissolution constant rates were considerably enhanced for the 5% and 10% progesterone/β-CD complexes in PEG 6000.

The interaction of progesterone with the cyclodextrins of interest on the form of the binary physical mixtures, complexes, or ternary complexes were investigated by differential scanning calorimetry (DSC) and Fourier transformed-infrared spectroscopy (FT-IR). The results proved that progesterone was diffused into the cyclodextrin cavity, replacing the water molecules and, in case of ternary systems, that the progesterone β-cyclodextrin was well dispersed into PEG, thus improving progesterone bioavailability for subsequent oral delivery in the same way as derivatized cyclodextrins. The present work proves that ternary complexes are promising systems for drug encapsulation.     

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.     

Emission probability measurement of γ-ray of Rh

¹⁰⁵Rh becomes a stable ¹⁰⁵Pd after β⁻-decay with a half-life of 35.36 h. The energies of especially strong γ-rays emitted from ¹⁰⁵Rh are 306.1 and 318.9 keV, and the emission probabilities are evaluated to be 5.1±0.3% and 19.1±0.6% by de Frenne et al. To improve the certainty, the γ-ray emission probabilities were determined from the disintegration rate and absolute γ-ray intensities measured using a 4πβ(ppc)-γ(HPGe) coincidence apparatus with two-dimensional data-acquisition system. The results for the 306.1 and 318.9 keV γ-rays were 4.76±0.05% and 16.99±0.17%, respectively.     

Dissolution Behavior of Oxazepam in Presence of Cyclodextrins: Evaluation of Oxazepam-Dimeb Binary Systemxs

The inclusion complex formation between oxazepam (Ox) and heptakis (2,6-di-O-methyl)-β-cyclodextrin (DIMEB) was studied in solution by solubility and ultraviolet spectroscopy methods, and in the solid state by differential scanning calorimetry, scanning electron microscopy, and powder x-ray diffractometry. The apparent stability constant, K_c, calculated by solubility and spectral data, was estimated as 642 and 588 M^-1, respectively. The solid complexes have been prepared by kneading and spray-drying techniques. The dissolution rate studies reveal that the better dissolution behavior corresponded to the spray-dried systems.     

Inclusion of Methoxybutropate in β-and Hydroxypropyl β-Cyclodextrins: Comparison of Preparation Methods

Interactions between methoxybutropate and β-cyclodextrin or hydroxypropyl β-cyclodextrin and the possibility of obtaining inclusion complexes have been evaluated by phase solubility diagram, HPLC, DSC, and x-ray diffractometry. Solid inclusion complexes were prepared by spray drying, kneading, and solid dispersion. The dissolution profiles of the obtained powders were studied in order to define the most appropriate cyclodextrin preparation method and molar ratio to use in the production of methoxybutropate inclusion complexes     

Solubilization of the neutral and charged forms of 2,4,6-trichlorophenol by beta-cyclodextrin,methyl-beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin in water

The solubilities of the neutral and charged forms of 2,4,6-trichlorophenol (TCP) in β-cyclodextrin (β-CD) and two of its most used derivatives: methyl-β-cyclodextrin (MCD) and hydroxypropyl-β-cyclodextrin (HPCD) solutions were investigated. The three cyclodextrins were found to form 1:1 inclusion complexes. Binding constants estimated from an enhancement solubility method revealed that the stability of the complexes was dependent on the polarity of the compound and on the cyclodextrin used.

In general, weaker binding constants were observed for TCP with β-CD than with HPCD or MCD. The solubilization efficiencies towards TCP can be ranked in the following order: MCD > HPCD > β-CD. For all cyclodextrins, the stability constant of neutral TCP (log K_ow=3.85) was larger than that of charged TCP (log K_ow=1.4).

A precipitation occurred in TCP/β-CD solution (around 10 g/l β-CD concentration) at pH 3. However, this phenomenon is not observed for TCP/β-CD solution at pH 8.8.     

Fracture strength testing of δ-alumina fibres with variable diameters and lengths

Tensile tests were performed on individual δ-alumina fibres (Saffil, RF grade). The results revealed a large scatter in strengths and a clear dependence of the fracture strength on the specimen volume. The tests were evaluated on the basis of the Weibull probability function, a special modification of the Weibull analysis being developed that successfully copes with the problem of testing fibres with various diameters and test lengths. For the sample studied the Weibull modulus, m, was found to be 2·2, with a scaling constant δ₀ = 6·0 MPa (units of volume mm³; i.e. V₀ = 1 mm³).     

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.