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 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     

The influence of diluent on the release of theophylline from hydrophilic matrix tablets

The role of β-cyclodextrin (β-CD) on the apparent solubility of theophylline was investigated by the solubility method. Binary systems of theophylline and β-CD were prepared using the dry co-grinding method. Their characterization was performed by differential scanning calorimetry (DSC). The dissolution rate of theophylline and theophylline/β-CD and dissolution studies of matrix tablets prepared from mixtures containing theophylline and ground theophylline were carried out. It can be concluded that β-CD is related to an increase in the apparent solubility and dissolution rate of the drug, promoting improvement on the release of theophylline from matrices manufactured with hydroxypropylmethylcellulose (HPMC). This can be attributed to the amorphous state and the increased wettability of the 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.     

Inclusion complexation of nimesulide with beta-cyclodextrins

Nimesulide (NM), a nonsteroidal anti-inflammatory drug (NSAID) has poor aqueous solubility. The present study describes the complexation of NM with β-cyclodextrin (β-CD) and its derivative hydroxypropyl β-cyclodextrin (HPβ-CD). The complexation was studied by phase solubility method, Fourier transformed infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffractometry (XRD). The complexes were prepared by a freeze-drying technique. The in vitro dissolution rate of drug-HPβ-CD complex was faster compared to the drug-β-CD complex and drug alone.     

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.     

Etodolac and Solid Dispersion with P-Cyclodextrin

Etodolac/β-cyclodextrin (Eto/β-CD) dispersions were prepared with a view to study the influence of β-CD on the solubility and dissolution rate of this poorly soluble drug. Two systems were used: physicai mixture of Eto/β-CD and kneading solid dispersion of Eto/β-CD. Physical characterization of the prepared systems was carried out by scanning electron microscopy (SEM), differential scanning calorimetric (DSC), x-ray, and IR studies. The solubility and dissolution rate of Eto were increased with β-CD physical mixture as well us with Eto/β-CD kneading solid dispersion. However, enhancement was not statistically different among various cyclodextrin dispersions.     

Terfenadine-β-Cyclodextrin Inclusion Complex with Antihistaminic Activity Enhancement

Terfenadine, an antihistaminic drug, has relatively low bioavailability after oral administration due to its limited solubility in water. To enhance the antihistaminic activity of terfenadine, the terfenadine-β-cyclodextrin (1 : 2) inclusion complex was prepared by the neutralization method. The solubility and dissolution of the inclusion complex were carried out, and its antihistaminic activity was then evaluated and compared with terfenadine powder by the passive subcutaneous anaphylaxis method in rats. The formation constant of the inclusion complex was higher at lower pH, while its formation ratio was 1 : 2 irrespective of pH. For terfenadine, it improved the solubility 200 times and the dissolution rate 5 times. It gave a low histamine level at 30 min, followed by a sustained low level until 60 min, while terfenadine powder gave a low histamine level at 60 min, suggesting that it had faster and more effective antihistaminic activity than terfenadine powder in rats due to fast dissolution and absorption of terfenadine. It is concluded that this inclusion complex enhanced the antihistaminic activity of terfenadine following the enhanced solubility and dissolution of terfenadine.     

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.     

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.     

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     

Development of fast-dissolving tablets of flurbiprofen-cyclodextrin complexes

The present study was aimed at developing a tablet formulation based on an effective flurbiprofen-cyclodextrin system, able to allow a rapid and complete dissolution of this practically insoluble drug. Three different cyclodextrins were evaluated: the parent β-cyclodextrin (previously found to be the best partner for the drug among the natural cyclodextrins), and two amorphous, highly soluble β-cyclodextrin derivatives, i.e., methyl-β-cyclodextrin and hydroxyethyl-β-cyclodextrin. Equimolar drug-cyclodextrin binary systems prepared according to five different techniques (physical mixing, kneading, sealed-heating, coevaporation, and colyophilization) were characterized by Differential Scanning Calorimetry, x-ray powder diffractometry, infrared spectroscopy, and optical microscopy and evaluated for solubility and dissolution rate properties. The drug solubility improvement obtained by the different binary systems varied from a minimum of 2.5 times up to a maximum of 120 times, depending on both the cyclodextrin type and the system preparation method. Selected binary systems were used for preparation of direct compression tablets with reduced drug dosage (50 mg). Chitosan and spray-dried lactose, alone or in mixture, were used as excipients. All formulations containing drug-cyclodextrin systems gave a higher drug dissolved amount than the corresponding ones with drug alone (also at a dose of 100 mg); however, the drug dissolution behavior was strongly influenced by formulation factors. For example, for the same drug-cyclodextrin product the time to dissolve 50% drug varied from less than 5 minutes to more than 60 minutes, depending on the excipient used for tableting. In particular, only tablets containing the drug kneaded with methyl-β-cyclodextrin or colyophilized with β-cyclodextrin and spray-dried lactose as the only excipient satisfied the requirements of the Food and Drug Administration (FDA) for rapid dissolving tablets, allowing more than 85% drug to be dissolved within 30 minutes. Finally, it can be reasonably expected that the obtained drug dissolution rate improvement will result in an increase of its bioavailability, with the possibility of reducing drug dosage and side effects.     

Influence of Hydroxypropyl β-Cyclodextrin on Solubility and Dissolution Profile of Ketoprofen in Its Solid Dispersions

Solid dispersions of hydroxypropyl β-cyclodextrins (HPB), a highly water soluble derivative of β-cyclodextrin and ketoprofen (KPF), were prepared by kneading, coevaporation, and freeze-drying. X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy were used to investigate characteristics of the solid dispersions and to study the possibility of complexation of the drug with HPB. A marked difference in characteristics of dispersions was observed due to their methods of preparation. The solubility of KPF in the solid dispersions was studied by the dispersed powder technique and was found to have improved considerably over that of the drug pure alone. The dispersions had good compressibiliry. Tablets so compressed displayed good dissolution profiles.     

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.     

Evaluation of Stereoselective Dissolution of Racemic Salbutamol Matrices Prepared with Commonly Used Excipients and 1H-NMR Study

The purpose of this work was to examine the in vitro enantioselective dissolution of salbutamol from matrix tablets containing various chiral excipients, such as γ-cyclodextrin (γ-CD), heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), sulfobutyl-β-cyclodextrin (SBE-β-CD), hydroxypropylmethylcellulose (HPMC), and egg albumin. In this study, two types of tablets were prepared; the coated tablet contained the complex of racemic salbutamol and cyclodextrin (γ-CD, DM-β-CD, and SBE-β-CD), and the uncoated tablet was composed of the drug with either HPMC or egg albumin. Subsequently, these formulations were evaluated for enantioselective release. The results revealed that the formulations containing either SBE-β-CD, HPMC, or egg albumin had no enantioselective release, while the formulation with DM-β-CD gave slightly different release of the two enantiomers at the end of the dissolution profile. The formulation containing γ-CD provided significant stereoselectivity throughout the dissolution profile. The release of the eutomer R-salbutamol was higher than that of the distomer S-salbutamol from the γ-CD tablet. In addition, the enantioselective interaction for the γ-CD inclusion complex was investigated by ¹H-NMR (nuclear magnetic resonance) spectroscopy and gave evidence to support the enantioselectivity obtained on dissolution.     

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.     

A Study of the Complexation Between Danazol and Hydrophilic Cyclodextrin Derivatives

Complexation between danazol, a steroid used for endometriosis, and both hydroxypropyl- β-cyclodextrin (HPCD) and sulfobutyl ether-β-cyclodextrin (SBE) was studied in solution and solid state. Complexation was evaluated in solution using solubility studies and proton magnetic resonance (¹H NMR) spectroscopy, and in the solid state using x-ray diffraction, Fourier-transform infrared spectroscopy (FTIR)), and dissolution studies. Solubility studies suggested the existence of a 1:1 complex between danazol and either HPCD or SBE. ¹H NMR showed that complexation occurs by inclusion of the isoxazole ring of danazol into the cyclodextrin cavity in both cases. Powder x-ray diffraction indicated that danazol existed in a crystalline noncomplexed form at low danazol-to-cyclodextrin ratios in the coprecipitates prepared by solvent evaporation method, while at higher ratios danazol existed in an amorphous complexed form. This ratio was 1:10 w/w for HPCD and 1:20 for SBE; the higher ratio in the case of SBE is attributed to early precipitation of danazol from the solvent used for preparation. FTIR studies showed that the complexation was accompanied by a shift of the O-H stretching of danatol hydroxyl group to a higher frequency, which is attributed to the disruption of the intermolecular hydrogen bonding. The dissolution rate of danazol from HPCD coprecipitates was higher than crystalline danazol in aqueous-isopropanolic medium, while SBE coprecipitates showed reduced dissolution rates due to the low solubility of SBE in isopropanol. However, SBE coprecipitates showed higher dissolution rates in water than in the isopropanolic medium.     

Improvement of dissolution and bioavailability of nitrendipine by inclusion in hydroxypropyl-beta-cyclodextrin

A significant increase in solubility and dissolution rate of nitrendipine, a slightly soluble calcium channel blocker, was achieved by inclusion complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD). The inclusion complex was prepared by solvent evaporation method and characterized by phase solubility method, x-ray diffractometry, infrared spectroscopy, and differential scanning calorimetry. The solubility of nitrendipine increased linearly as a function of HP-β-CD concentration, resulting in A_L-type phase solubility diagram which revealed a formation of inclusion complex in a molar ratio of 1:1, with the apparent association constant of 108.3 M^-1. The in vitro dissolution rate of nitrendipine in pH 7.4 phosphate buffer was in the order of inclusion complex, physical mixture, and nitrendipine powder. These three different forms of nitrendipine were administered orally to rats with a dose of 10 mg/kg equivalent to nitrendipine. The AUC of inclusion complex was significantly larger than that of nitrendipine powder. T_max of inclusion complex was significantly shorter and C_max was significantly higher than those of nitrendipine powder. C_max of physical mixture was higher than that of nitrendipine powder. T_max of physical mixture, however, remained the same. The results indicated that the bioavailability of nitrendipine could be improved markedly by inclusion complexation, possibly due to an increased dissolution rate.     

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.