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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

The Physicochemical Characteristics of Freeze-Dried Scutellarin-Cyclodextrin Tetracomponent Complexes

ABSTRACT

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.     

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).     

Transdermal Iontophoresis and Skin Retention of Piroxicam from Gels Containing Piroxicam : Hydroxypropyl-β-cyclodextrin Complexes

Iontophoretic transport of piroxicam (Px) across porcine ear skin in vitro was investigated. Cathodal iontophoresis of negatively charged Px was carried out from gel formulations containing Px as an inclusion complex with hydroxypropyl-β-cyclodextrin (HP-β-CD). From the gels, following a 7 h application period at 0.4 mA/cm², iontophoresis delivered 3.4 times more drug than passive diffusion. The formation of Px : HP-β-CD complexes did not increase the iontophoretic Px flux through the skin. However, Px complexation with HP-β-CD allowed us to increase the drug concentration in the gel; because of that, the amount of Px transported across the skin increased considerably. After iontophoretic experiments, the amount of Px retained in skin seemed to be related to the flux values obtained in each case. Skin pretreatment with 20% HP-β-CD, tested passively and iontophoretically for 3 h, followed by the application of gel containing Px : HP-β-CD complexes, showed no enhancing capacity in any case. The amount of Px retained in the skin after pretreatment experiments was found to be very similar to that obtained without skin pretreatment and was observed to be related to the Px flux through the skin.     

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.     

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.     

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.     

Evaluation of Compression Behavior of Paracetamol Tablets Produced with β Cyclodextrin Dispersions. Part II: Energy Distribution Study of Tablets

The compression behavior of three paracetamol/β-cyclodextrin solid dispersions (PAR/β-CD, ratio 1: 1 w/w), which differ in particle size, shape, and crystallinity, were studied using force-displacement measurements (F-D plots). The measured parameters included: effective work, expansion work, friction work, useful work, and plasticity derived from F-D plots at the tableting stage. The PAR/β-CD spray-dried solid dispersion has the best compressional behavior, compared to other dispersions (PAR/β-CD physical mixture and PAR/β-CD kneaded solid dispersion) and PAR alone. Energy distribution study also showed that β-CD has positive influence on the PAR compression characteristics.     

Carbamazepine/betaCD/HPMC solid dispersions. I. Influence of the spray-drying process and betaCD/HPMC on the drug dissolution profile

The aim of this study was to compare carbamazepine (CBZ) solid dispersions prepared by spray-drying of aqueous dispersions with the corresponding physical mixtures. The influence of the association of β-cyclodextrin (βCD) and hydroxypropyl methylcellulose (HPMC) on the CBZ dissolution profile of the preparations was investigated. Results demonstrated that CBZ release from solid dispersions is dependent on the ratio of βCD and HPMC. The spray-drying process confers better homogeneity to CBZ polymeric dispersions than the physical mixture process. In summary, we demonstrated the feasibility of obtaining a homogeneous polymeric solid dispersion of CBZ from an aqueous media by spray-drying and a clear influence of the βCD:HPMC ratio on the release profile of CBZ.     

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.     

Effects of Cyclodextrins and Phospholipids in Enhancing Dissolution of Indomethacin

Inclusion complexes of indomethacin (IND) and β-cyclodextrins (β-CD) were prepared by the freeze drying methods. Solid dispersion of IND and Dimyristoylphosphatidylcholine (DMPC) was prepared as coprecipitate (CPPT) by the solvent method. These formulations were characterized by X-ray diffractometry and dissolution rate determinations. Dissolution of IND from β-CD inclusion complex was found to be 133 times faster than the corresponding pure IND, whereas it was about 4 times faster from a DMPC CPPT sample. Various derivatives of β-CDs showed variable rates of dissolution of IND. β-CD and most of the other derivatives showed almost instantaneous dissolution of IND at a molar ratio of 1:1 (IND:β-CD) except dimethyl-β-cyclodextrin (DMB) derivative, which showed a fairly constant release of IND over 90 minutes. DMB may, therefore, have the potential for use in the formulation of a constant-release preparation. X-ray diffraction spectra showed that indomethacin remained as amorphous state in CPPT or in inclusion complex. Thus, these formulations may have the potential to produce faster onset of action, reduced dosing and decreased GI irritation.