Solubility and Dissolution Rate of Progesterone-Cyclodextrin-Polymer Systems

ABSTRACT

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.     

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 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.     

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.     

Selection of Kavalactones by Complexation of Kava Extract with Cyclodextrins

Kavalactones, active ingredients extracted from Piper methysticum Forst. Piperaceae, have many therapeutic properties including relaxing, anaesthetic, analgesic, and antifungic properties. Kavalactones are insoluble in aqueous vehicles. These active ingredients are inclused in cyclodextrins to improve their water solubility and to realize a galenic form.

Gamma cyclodextrin (γ-CD) and beta cyclodextrin (β-CD) were used. The amounts of kavalactones inclused in cyclodextrins have been measured by HPLC with UV spectrophotometric detection.

The results showed that besides increasing the water solubility of kavalactones, the complexation leads to a selection of the most active compounds that are preferentially included.     

Effect of water-soluble carriers on dissolution characteristics of nifedipine solid dispersions

Solid dispersions of nifedipine (NP) with polyethylene glycols (PEG4000 and PEG6000), hydroxypropyl-β-cyclodextrin (HPβCD), and poloxamer 407 (PXM 407) in four mixing ratios were prepared by melting, solvent, and kneading methods in order to improve the dissolution of NP. The enhancement of the dissolution rate and the time for 80% NP dissolution T_80% depended on the mixing ratio and the preparation method. The highest dissolution rate and the T_80% as short as 15 min were obtained from PXM 407 solid dispersion prepared by the melting method at the mixing ratio of 1:10. The X-ray diffraction (XRD) patterns of solid dispersions at higher proportions of carriers demonstrated consistent with the results from differential scanning calorimetric (DSC) thermograms that NP existed in the amorphous state. The wettability and solubility were markedly improved in the PXM 407 system. The presence of intermolecular hydrogen bonding between NP and PEGs and between HPβCD and PXM 407 was shown by infrared (IR) spectroscopy.     

Multicomponent complexes of piroxicam with cyclodextrins and hydroxypropyl methylcellulose

The purpose of the study was to investigate the effect of hydroxypropyl methylcellulose (HPMC) on the complexation of piroxicam (PX) with β-cyclodextrin (β-CD) and dimethyl-β-cyclodextrin (DM-β-CD) in solution and in the solid state. Phase solubility study revealed a positive effect of the polymer on the drug complexation. Improvement in stability constants values, K_s, of ternary complexes clearly proves the benefit of the HPMC addition for promoting higher complexation efficiency. Solid binary and ternary complexes were prepared by spray drying. Drug-CD and drug-CD-polymer interactions were studied in the solid state by differential scanning calorimetry (DSC), zeta-potential measurements, and particle size distribution. A marked increase in the PX dissolution rate was observed even in binary and ternary complexes. The presence of HPMC in ternary complexes slightly retarded the release of PX. Cyclodextrin complexation increased the PX concentration gradient over the semipermeable membrane, resulting in an increased PX flux. The retarded diffusion of PX to the membrane interface decreased the PX flux values of the ternary complexes.     

Daidzein/cyclodextrin/hydrophilic polymer ternary systems

Objective: To evaluate the effect of different cyclodextrins (β-cyclodextrin [β-CD], methyl-β-cyclodextrin [Mβ-CD], or hydroxypropyl-β-cyclodextrin [HPβ-CD]) and/or hydrophilic polymers (carboxymethylcellulose, hydroxypropylmethylcellulose [HPMC], polyethyleneglycol, or polyvinylpyrrolidone [PVP]) on daidzein solubility in water.

Materials and methods: The corresponding associations were characterized in aqueous media using phase-solubility studies. The morphology of daidzein/cyclodextrin freeze-dried complexes was characterized using scanning electron microscopy, and their spatial configuration was proposed by means of nuclear magnetic resonance spectroscopy.

Results and discussion: In the presence of 6?mM of cyclodextrins, the solubility of daidzein in water was significantly enhanced: 5.7-fold (β-CD), 7.2-fold (Mβ-CD), and 9.4-fold (HPβ-CD). The analysis of the three solid complexes proved that the formation of inclusion complexes occurred through the insertion of the B and C rings of daidzein molecule into the cyclodextrins cavity. The association of daidzein/cyclodextrin complexes to the hydrophilic polymers HPMC or PVP (1%, w/w) was able to improve the solubility of daidzein even further.

Conclusion: The highest solubilizing effect was obtained for daidzein/HPβ-CD/PVP ternary system (12.7-fold).     

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.     

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.     

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     

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.     

The physicochemical characteristics of freeze-dried scutellarin-cyclodextrin tetracomponent complexes

In an effort to improve the solubility of the insoluble drug scutellarin, a novel complexation of scutellarin with β-cyclodextrin (β-CD) was studied. Tetracomponent freeze-dried complex was prepared with scutellarin, β-CD, Hydroxypropyl Methylcellulose (HPMC), and triethanolamine. To confirm complex formation, complex was characterized by Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction, and differential scanning calorimetry (DSC). Phase-solubility analysis suggested the soluble complexes having 1:1 stoichiometry. The β-CD solubilization of scutellarin could be improved significantly by combining water-soluble polymer and pH adjuster. Comparing the binary, ternary solid systems with tetrary systems, tetracomponent freeze-dried complex showed the best effect of solubilization. A maximal solubility of scutellarin (23.65 mg/ml) was achieved with tetracomponent freeze-dried complex, up to 148-fold increase over scutellarin solubility in water, and the solubility of scutellarin is 15.35 ug/ml (up to 6-fold) in simulated gastric fluid.     

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     

Study of the complexation behavior of tenoxicam with cyclodextrins in solution: improved solubility and percutaneous permeability

Complexation of tenoxicam (TEN) with γ-, HPγ-, β-, HPβ-, and Mβ-cyclodextrin (CD) in aqueous solution at pH 7.4 has been investigated using phase solubility diagrams. TEN formed soluble complexes with 1:1 stoichiometry with all the CDs studied, although the inclusion stability constants (K_1:1) obtained had low values. The presence of propylene glycol (PG) in the dissolution medium decreased the stability constants and led to a higher fraction of free drug by competitive displacement and by an increase in the lipophility of the media.

Among the CDs tested, MβCD was chosen for further studies since TEN-MβCD complexes yielded the best results: good solubility and the highest stability constant. The effect of MβCD and PG on the TEN partitioning coefficient was also studied in skin-buffer systems. Although each substance reduced the partitioning value, the combination of PG and MβCD increased this parameter.

The noticeable increase in solubility of the drug found in the presence of MβCD allowed the formulation of carbopol gels with higher doses of TEN and a reduced amount of cosolvent. The presence of MβCD improved the percutaneous penetration of TEN through abdominal rat skin by increasing the solubility of the drug in the vehicle and by affecting the partitioning behavior of TEN in the skin. In addition, TEN retention in the skin was found to be related to the flux values attained with the corresponding gels.     

Solubility enhancement of miconazole nitrate: binary and ternary mixture approach

Context: Enhancement of aqueous solubility of very slightly soluble Miconazole Nitrate (MN) is required to widen its application from topical formulation to oral/mucoadhesive formulations.

Objective: Aim of the present investigation was to enhance the aqueous solubility of MN using binary and ternary mixture approach.

Materials and methods: Binary mixtures such as solvent deposition, inclusion complexation and solid dispersion were adopted to enhance solubility using different polymers like lactose, beta-cyclodextrin (β-CD) and polyethylene-glycol 6000 (PEG 6000), respectively. Batches of binary mixtures with highest solubility enhancement potentials were further mixed to form ternary mixture by a simple kneading method. Drug polymer interaction and mixture morphology was studied using the Fourier transform infrared spectroscopy and the scanning electron microscopy, respectively along with their saturation solubility studies and drug release.

Results: An excellent solubility enhancement, i.e. up to 72 folds and 316 folds of MN was seen by binary and ternary mixture, respectively. Up to 99.5% drug was released in 2?h from the mixtures of MN and polymers.

Discussion: Results revealed that solubility enhancement by binary mixtures is achieved due to surface modification and by increasing wettability of MN. Tremendous increase in solubility of MN by ternary mixture could possibly be due to blending of water soluble polymers, i.e. lactose and PEG 6000 with β-CD which was found to enhance the solubilizing nature of β-CD.

Conclusion: Owing to the excellent solubility enhancement potential of ternary mixtures in enhancing MN solubility from 110.4?μg/ml to 57?640.0?μg/ml, ternary mixture approach could prove to be promising in the development of oral/mucoadhesive formulations.     

Preparation and Characterization of Quercetin and Rutin Cyclodextrin Inclusion Complexes

ABSTRACT

The objective of the present study is to prepare and characterize cyclodextrin inclusion complexes of quercetin and rutin to improve their aqueous solubility and dissolution properties. Inclusion complexes of quercetin and rutin with ß-cyclodextrin (ß-CD) and hydroxyl propyl-ß-cyclodextrin (HP-ß-CD) were prepared by kneading and coevaporation methods. Characterization of inclusion complexes was done by phase solubility analysis and was supported by X-ray powder diffractometry (XRD), differential scanning calorimetry (DSC), and Fourier-transform infra red spectroscopy (FT-IR) analysis. Inclusion complexes exhibited higher rates of dissolution than the corresponding physical mixtures and pure drug. Higher dissolution rates were observed with HP-ß-CD kneaded complexes in comparison to the products with ß-CD.     

Effect of water-soluble polymers on naproxen complexation with natural and chemically modified beta-cyclodextrins.

The combined effect of cyclodextrins (CDs) (beta-, methyl-beta-, hydroxypropyl-beta-cyclodextrins) and water-soluble polymers (sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone K30, polyethylene glycol 6000) on naproxen solubility improvement was studied. Phase solubility analysis at 25 degrees C was used to investigate the interaction of the drug with each cyclodextrin (or polymer, alone or in the presence of the different water-soluble polymers (or cyclodextrins). The combined use of polymer and cyclodextrin was always clearly more effective in enhancing the aqueous solubility of naproxen in comparison with the corresponding drug-polymer or drug-cyclodextrin binary systems, and the solubilization enhancement was not simply additive, but synergistic. Water-soluble polymers increased the complexation efficacy of cyclodextrins toward naproxen (as shown by the increased stability constants of the complexes), which resulted in enhanced drug solubility. No previous sonication or heating treatments of the drug-cyclodextrin-polymer suspensions was necessary to obtain this favorable effect. The best results were obtained in ternary systems with beta-cyclodextrin, which had a solubilizing effect toward naproxen in the presence of 0.25% w/v of the different hydrophilic polymers examined that was improved from 25% to about 80%, depending on the type of polymer.     

Valproic acid-hydrophilic cyclodextrin complexes and valproic acid-solid dispersions: evaluation of their potential pharmaceutical use

The purpose of this study was to evaluate the potential use of two novel solid formulations of valproic acid (VPA) prepared by complexation with hydrophilic cyclodextrins (CDs) as hydroxypropyl-β- and sulfobutylether-β-cyclodextrin and by solid dispersion (SD) in hydrophilic carriers as polyethylene glycol 6000 (PEG 6000) and polyvinylpyrrolidone K-30 (PVP K-30). The corresponding cyclodextrin-based complexes were prepared by the freeze-drying method while the solid dispersions were obtained by the solvent method. Valproic acid solubility improved by CDs complexation and solid dispersion techniques. Comparison of dissolution profiles with that of VPA sodium salt (NaVP) was made by using release parameters such as dissolution efficiency, percent of drug dissolved after 60 min, and difference and similarity factors. Based on difference and similarity factors, it can be concluded that all the VPA formulations possess dissolution profiles essentially equivalent to those of NaVP at pH 6. However, this conclusion is not confirmed by using the analysis of variance (ANOVA) approach, indicating some significant differences between some SD-based formulations and NaVP at that pH value. Preliminary pharmacological studies in the pentylenetetrazole test in rats showed some important differences among the SD-based formulations, NaVP, and VPA as oil/water emulsion. Some implications and limitations of the investigated formulations are discussed.     

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.