The influence of polyvinylpyrrolidone on naproxen complexation with hydroxypropyl-beta-cyclodextrin.

The combined effect of hydroxypropyl-beta-cyclodextrin (HPbetaCD) and polyvinylpyrrolidone (PVP) on the solubility of naproxen (NAP) was studied. Phase-solubility analysis at different temperatures was used to investigate interactions in aqueous solution between NAP and the carriers, either alone or in combination. Equimolar NAP-HPbetaCD solid systems, in the presence or the absence of 15% (w/w) PVP, were prepared by cogrinding, kneading, coevaporation or freeze-drying, and characterized by differential scanning calorimetry, X-ray powder diffraction analysis, infrared spectroscopy and dissolution rates. The combined use of PVP and HPbetaCD resulted in a synergistic increasing effect of the aqueous solubility of NAP (120 times that of the pure drug). The phenomenon was interpreted in terms of the strongest complexation capacity of HPbetaCD towards NAP, which was reflected by an about 65% increase in the apparent stability constant of the NAP-HPbetaCD complex in the presence of only 0.1% (w/v) PVP. Variations in thermodynamic parameters accounted for a PVP role in the formation of a NAP-HPbetaCD-PVP ternary complex. The positive effect of PVP also reflected on NAP dissolution rates from solid preparations, because all ternary systems, with the exception of physical mixtures, dissolved faster than the corresponding NAP-HPbetaCD binary systems. The results of solid state studies accounted for the occurrence of mechanically- and/or thermally-induced stronger interactions in ternary than in binary systems, that in some cases led to a complete loss of NAP crystallinity.     

Characterization of the complexation of diflunisal with hydroxypropyl-beta-cyclodextrin

The equilibrium dialysis method was applied to the determination of drug cyclodextrin stability constants using diflunisal and 2-hydroxypropyl-beta-cyclodextrin (HPBCD) as a model system. Analysis of the data showed the existence of a linear Scatchard plot, indicative of the formation of a 1:1 diflunisal:HPBCD complex. The mean complexation constant (Kc) +/- S.D. was 3,892 +/- 360 M(-1). The stoichiometry of the complex was verified using the appropriate mass action law equation. The diflunisal:HPBCD complex was also investigated using titration microcalorimetry. A Kc of 3,394 M(-1) was obtained together with an enthalpy change (deltaH) of -20.76 kJ/mol(-1). The Kc values obtained here using the equilibrium dialysis and microcalorimetric methods were comparable to one reported previously using a potentiometric method (5,564 +/- 56 M(-1)).     

Inclusion complexation of the sunscreen agent 2-ethylhexyl-p-dimethylaminobenzoate with hydroxypropyl-beta-cyclodextrin: effect on photostability

The interaction between the UV filter, 2-ethylhexyl-p-dimethylaminobenzoate, and unmodified and modified alpha-, beta- or gamma-cyclodextrins was studied in water by phase-solubility analysis. Of the cyclodextrins available, only hydroxypropyl-beta-cyclodextrin caused a marked increase in the aqueous solubility of 2-ethylhexyl-p-dimethylaminobenzoate. The data from the solubility study indicated the formation of a 1:1 (sunscreen-cyclodextrin) complex. The inclusion of the sunscreen agent into the hydroxypropyl-beta-cyclodextrin cavity was confirmed by thermal analysis and by nuclear magnetic resonance spectroscopy. Irradiation-induced degradation of 2-ethylhexyl-p-dimethylaminobenzoate was reduced by complexation with hydroxypropyl-beta-cyclodextrin, this effect being more pronounced in solution (the extent of degradation was 25.5% for the complex compared with 54.6% for free 2-ethylhexyl-p-dimethylaminobenzoate) than in the emulsion vehicle (the extent of degradation was 25.1% for the complex compared with 33.4% for free 2-ethylhexyl-p-dimethylaminobenzoate). Although photodegradation of the sunscreen agent is significantly reduced by formation of the inclusion complex it is important to design a suitable vehicle. Inclusion of 2-ethylhexyl-p-dimethylaminobenzoate-DMAB into the hydroxypropyl-beta-cyclodextrin cavity limits interaction of the UV filter with the skin reducing the side-effects of the formulation.     

Improvements in solubility and stability of thalidomide upon complexation with hydroxypropyl-beta-cyclodextrin.

Thalidomide is in clinical use for the treatment of graft-versus-host disease in leukemia patients after bone marrow transplant. Low levels of the drug in plasma after oral administration have made an intravenous thalidomide formulation desirable. Thalidomide, however, is sparingly soluble in aqueous solution (50 micrograms/mL) and unstable. Complexation with hydroxypropyl-beta-cyclodextrin has significantly improved the aqueous solubility and stability of thalidomide. Results obtained with HPLC and 1H NMR spectrometry have demonstrated that the solubility is increased to 1.7 mg/mL and the half-life of a diluted solution is extended from 2.1 to 4.1 h. Hence, an intravenous thalidomide-hydroxypropyl- beta-cyclodextrin solution has the potential to significantly improve current therapy for graft-versus-host disease by providing sustained high levels of drug in the plasma.     

The effect of pH on cyclodextrin complexation of trifluoperazine

The characteristics of host-guest complexation between cyclodextrins (beta-CD, DM-beta-CD, HP-beta-CD) and protonated (pH 1.9, 6.2) or basic (pH 10.2) forms of trifluoperazine (TF) were investigated by spectrometric method. The association constants of complexes obtained at different temperatures and pH were calculated using Scott's equation and the thermodynamic parameters (deltaH, deltaS and deltaG) associated with the inclusion process were determined from Van't Hoff plot. The influence of pH and CD complexation on photostability of TF in solutions of different pH was followed. It was found that the photochemical decomposition of TF alone and in the presence of CD proceeds according to the first order reaction. It was also established that the increase in the TF photostability was dependent on the stability of TF-CD association. Spatial configuration of obtained complexes has been proposed on the basis of 2D NMR technique.     

Influence of hydroxypropyl-beta-cyclodextrin complexation on piroxicam release from buccoadhesive tablets.

Interaction of piroxicam (PX) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) was investigated in solution and in the solid state. Solubility studies demonstrated the formation of the PX-HPbetaCD inclusion complex with 1:1 stoichiometry. Equimolecular PX-HPbetaCD solid systems were prepared and characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and X-ray diffractometry. Modification of the release of a sparingly water-soluble drug, PX, from hydrophilic matrices using cyclodextrin complexation was evaluated. The buccoadhesive controlled release tablets for the delivery of PX were prepared by direct compression of hydroxypropylmethyl cellulose (HPMC) and Carbopol 940 (C940), which showed superior bioadhesion properties compared to HPMC. The tablets were evaluated for their dissolution, swelling and mucoadhesive properties. The in vitro release results demonstrated that matrix tablets containing the PX-HPbetaCD solid complex displayed faster PX release compared to those containing a physical mixture or "free" drug. Differences in release rates of PX from the tablets could be attributed to the presence of the polymers and to cyclodextrin complexation. The effect of the polymers on PX release can affect the drug solubility (complexation) and polymer water uptake (swelling). Higher polymer water uptake may result in higher drug solubility and diffusivity in a hydrated polymeric environment. Drug complexation affected also its diffusivity through the semipermeable membrane.     

Study of ascorbic acid interaction with hydroxypropyl-beta-cyclodextrin and triethanolamine, separately and in combination

Complexation between ascorbic acid, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and triethanolamine (TEA), separately and in combination, was studied in solution and solid state. The freeze-drying method was used to prepare solid complexes, while physical mixtures being obtained by simple blending. These complexes were characterized in the solid state using differential scanning calorimetry (DSC) and infrared spectroscopy (IR). Nuclear magnetic resonance spectroscopy ((1)H and (13)C NMR) was used in aqueous solutions to obtain information about the mode of interaction. The degradation rate of each complex in solution was determined, and the stability constant of the complexes and the degradation rate of the ascorbic acid within the complexes were obtained. NMR studies provided clear evidence of partial inclusion into the HP-beta-CD cavity, but the stability constant value was very small indicating a weak host-guest interaction. The influence of complexation on the degradation rate of ascorbic acid was evaluated, and the data obtained showed a pronounced enhancement of aqueous stability with the TEA association complex, while this effect was lower with the HP-beta-CD inclusion complex. NMR experiments showed evidence of the formation of aggregates.     

Influence of water soluble polymers on hydroxypropyl-beta-cyclodextrin complexation of rofecoxib

Rofecoxib (Rb) is a nonsteroidal anti-inflammatory drug (NSAID) with poor aqueous solubility. The present study was undertaken to investigate the influence of water-soluble polymers namely sodium carboxymethyl cellulose (Na CMC), polyvinylpyrrolidine (PVP) and polyethylene glycol (PEG-6000) on hydroxypropyl beta-cyclodextrin (HP beta-CD) complexation of Rb. The complexes were prepared by kneading, autoclaving and precipitation techniques in 1:1 and 1:2 molar ratios. The aqueous solubility enhancement of Rb by these polymers is found to be of the following order: Na CMC > PVP > PEG-6000. Complexes were characterized by Fourier transform infrared (FTIR) spectroscopy, Nuclear magnetic resonance (NMR) and X-ray diffractometry (XRD) techniques. In vitro dissolution studies were carried out on tablets formulated from molar ratios of the complexes prepared by different techniques.     

Sertaconazole/hydroxypropyl-beta-cyclodextrin complexation: isothermal titration calorimetry and solubility approaches

Complexation of sertaconazole (SN) with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was characterized by phase-solubility diagram measurements and isothermal calorimetry (ITC) in aqueous medium, and by differential scanning calorimetry (DSC), Raman spectroscopy and X-ray diffractometry in solid state. The strongest interaction was observed at pH 1.2, at which two different 1:1 complexes can be formed depending on the hydrophobic ring of the drug involved in the process. At pH 5.8 and 7.4 the likelihood of 1:2 stoichiometry increases as a consequence of the simultaneous complexation of the nonprotonized imidazolyl and the dichlorophenyl groups. In the presence of 20% HP-beta-CD, SN solubility is enhanced by a factor of 116, 107, and 5 at pH 1.2, 5.8, and 7.4, respectively. Complexation enthalpy recorded by ITC showed the same tendency which confirms the practical interest of this technique for fast screening of the potential of CDs as drug solubilizers. Solubility and dissolution rate of the drug from compacts prepared with freeze-dried complexes were significantly greater than those obtained with SN powder or compacts made with physical blends.     

Optimized transdermal delivery of ketoprofen using pH and hydroxypropyl-beta-cyclodextrin as co-enhancers.

The role of pH and pK(a) of ionizable drugs in transdermal delivery has been well documented by the pH partition hypothesis. Similarly the role of pH in complexation has also been addressed by many studies. Reports contrary to the well believed theory that both molecular encapsulation by hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and transdermal delivery are considered a phenomenon of unionized drug species prompted investigation into the combined effect of pH and HP-beta-CD on transdermal delivery of ketoprofen. In order to optimize the delivery of ketoprofen, solubility studies and permeation studies were conducted in vitro at pH 3.0, 4.5 and 6.0 at various concentrations of cyclodextrin. The stability constants for unionized and ionized drugs were calculated. The solubility of the ionized complex of the drug was 2.5 fold greater than the unionized complex. The flux increased linearly with increasing HP-beta-CD concentration at all the pH values. However, the increase was significant at pH 6.0 where the drug is predominantly in the ionized state. The flux of the ionized drug at 10% w/v HP-beta-CD concentration was enhanced to an order of approximately eight times compared to the intrinsic permeability of the unionized drug. The study shows that at higher pH, HP-beta-CD can be utilized to achieve greater transdermal flux of ketoprofen.     

Detecting and identifying the complexation of nimodipine with hydroxypropyl-beta-cyclodextrin present in tablets by Raman spectroscopy

For CD-based formulations, it is important to directly monitor the complexation status of the drug present in final dosage form pharmaceuticals. In this work, Raman spectroscopy was explored for the detection and identification of the Nimodipine/hydroxypropyl-beta-cyclodextrin (NMD/HPbetaCD) complexation present in the tablet. The evident, consistent Raman spectral changes in the shift, height ratio and area ratio for the characteristic bands of NMD molecule were featured in the NMD/HPbetaCD complex, and employed to distinguish between complexed and uncomplexed NMD in tablets. A number of practical issues for the Raman measurements performed on the tablets were considered and addressed. The Raman approach and dissolution test were applied to different tablets prepared experimentally at variable granulations. The results demonstrated that the Raman approach can serve as a promising methodology for tablet identification on the complexation. Wet granulation facilitated the process-induced transformations in the complexation. The adequate ethanol in the granulating fluid appeared optimized for the complexation of the two components. The spectral characteristics for dissociation in the tablets were in full accordance with the observations of their diminished initial dissolution parameters. It implied the possibility that the tablet dissolution can be predicted from the Raman interpretation.     

Effect of hydroxypropyl-beta-cyclodextrin and pH on the solubility of levemopamil HCl

Levemopamil was solubilized by varying the concentration of hydroxypropyl-beta-cyclodextrin (HPbetaCD) and by the alteration of pH. The drug molecule has two sites for possible complexation with HPbetaCD, creating the possibility of either 1:1 or 1:2 complexation. The solubility as a function of HPbetaCD concentration of the charged and uncharged forms of the drug follows the A(L) and Ap complexation models, respectively. This suggests that the charged drug forms a 1:1 complex, whereas the neutral drug forms both 1:1 and 1:2 complexes.     

Simultaneous effect of cyclodextrin complexation, pH, and hydrophilic polymers on naproxen solubilization

The effect of pH variation on complexation and solubilization of naproxen (pK(a) 4.2) with natural betaCyclodextrin (betaCyD) and various neutral, cationic and anionic betaCyD-derivatives has been investigated. The combined effect of pH variation and hydrophilic polymer addition on CyD solubilizing and complexing efficiency has also been determined. Phase-solubility analysis in buffered aqueous solutions (pH from 1.1 to 6.5) was used to study the interaction of the drug with each CyD, in the presence or not of the water-soluble polymer. A clear influence of the substituent type was observed, the methylderivative being the most efficient agent; on the contrary, unexpectedly, no influence of the CyD charge in the interaction with the ionizable drug was detected. As expected, total drug solubility increased with increasing pH; however, the solubility increment with respect to drug alone obtained by CyD complexation progressively decreased, with a parallel reduction of the complex stability, attributed to the reduced affinity of charged drug for the hydrophobic CyD cavity. The addition of the polymer in part counterbalanced the destabilizing effect obtained with increasing pH, by improving the CyD complexation power towards naproxen. In particular, the presence of PVP allowed an increase of the complex stability constant with hydroxypropyl betaCyD up to 60% with respect to the corresponding drug-CyD binary system. Therefore, the combined strategy of pH control and polymer addition to the CyD complexing medium can be successfully exploited to improve naproxen solubilization and reduce the amount of CyD needed. The construction of theoretical drug solubility curves as a function of pH for any given CyD and polymer concentration enables selection of the best experimental conditions for obtaining the desired drug solubility value.     

Development of parenteral formulation for a novel angiogenesis inhibitor, CKD-732 through complexation with hydroxypropyl-beta-cyclodextrin

The effect of hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) on the aqueous solubility and chemical stability of O-(4-Dimethylaminoethoxycinnamoyl)fumagillol (CKD-732), a new angiogenesis inhibitor, was investigated with an aim of preparing a stable and effective parenteral formulation. The CKD-732/HP-beta-CyD inclusion complex was obtained in solid state by freeze-drying and characterized in solution by proton nuclear magnetic resonance (1H NMR). Then, the pharmacokinetic profile in rats and the in vivo tumor growth inhibitory activity in mice following the parenteral administration of aqueous CKD-732/HP-beta-CyD complex were compared to those of CKD-732.hemioxalate solution having an equivalent concentration. The aqueous solubility of CKD-732 was markedly increased by the combination of pH adjustment and HP-beta-CyD complexation through a soluble 1:1 inclusion complex formation, which was supported by NMR spectroscopy. The hydrolysis of CKD-732 following pseudo first-order kinetics was decelerated moderately but significantly in acidic and basic solutions in the presence of HP-beta-CyD. The stability of lyophilized CKD-732/HP-beta-CyD complex was also drastically improved after storage in various conditions. The intravenous pharmacokinetic profile and the subcutaneous in vivo tumor growth inhibitory activity of aqueous CKD-732/HP-beta-CyD complex were not significantly different from those of CKD-732.hemioxalate solution with the favorable reduction of irritation. These results demonstrate that the CKD-732/HP-beta-CyD complex is an attractive formulation for use in the parenteral delivery of CKD-732.     

Effect of some anionic polymers on pH of triethanolamine aqueous solutions

One of the suggested approaches in the management and prophylaxis of acne involves binding of free fatty acids in the form of soap with alcoholamines. Due to a possible irritating effect of alcoholamines associated with a relatively high pH of their aqueous solutions, complexation of alcoholamines with acid polymers is advocated. Triethanolamine is one of the best recognized alcoholamines. It was conventionally neutralized with Carbopols, Eudragits, alginic acid and pectin. During neutralization of polymer dispersions with triethanolamine, variations in the course of the neutralization curve have been observed among individual macromolecular compounds. The pH of 0.1 mol/l triethanolamine solution reaches 10.51, while following a complete neutralization with anionic polymers, such as Carbopols, Eudragits, alginic acid and pectin, pH ranges from 3.88 for systems neutralized with alginic acid to 8.50 for the system neutralized with Eudragit S-100. Complexation of triethanolamine with anionic polymers decreases its pH, and it is possible to find such pH range in which pH of the preparation containing the polymer and triethanolamine will correspond to the physiological pH of the skin.     

Improvement of water solubility of sulfamethizole through its complexation with beta- and hydroxypropyl-beta-cyclodextrin. Characterization of the interaction in solution and in solid state.

The aim of this study was to increase the solubility of sulfamethizole in water by complexing it with beta-cyclodextrin (BCD) and hydroxypropyl-beta-cyclodextrin (HPBCD). The interaction of sulfamethizole with the cyclodextrins was evaluated by the solubility, 1H NMR spectrometry and molecular modelling. The stability constants calculated from the phase solubility method increase in order HPBCD相似文献   

The crystal and molecular structure of sulfisoxazole

Sulfisoxazole, C₁₁H₁₈N₃O₃S, crystallized in the orthorhombic system, space group Pbca, with a=14.492(1), b=11.563(1), c=14.900(2) Å and Z=8. Intensities for 1867(1360 observed) unique reflections were measured on a four-circle diffractometer with CuKα radiation (λ=1.5418Å). The structure was solved by heavy atom methods and refined by full-matrix least-squares procedures to a final R of 0.094. The benzene ring plane makes an angle of 68° with the plane of the isoxazole ring, which is planar. The conformational angle formed by the torsional angle C(4)?S?N(2)?C(7) is 54°. There are two intermolecular hydrogen bonds in the structure. One of them is of the type N?H…O with the length 2.970Å, and another is of the type N?N…N with the length 2.915Å. Thus two dimensional networks of hydrogen bonds form infinite molecular sheets parallel to the (001) plane. Adjacent sheets are bound together by van der Waals forces.     

Effect of pH and complexation on transdermal permeation of gliquidone

Gliquidone, a second generation sulfonylurea has been investigated for transdermal delivery. The poor aqueous solubility of the drug prompted the use of hydroxypropyl-beta-cyclodextrin (HP-beta-CD), a cyclic oligosaccharide, which is known to facilitate transdermal permeation of many drugs by enhancing the solubility and thus improving the diffusible species of the drug molecules at the skin-vehicle interface. In order to optimize the transdermal delivery of gliquidone, the effect of pH along with complexation on the solubility and permeation has been investigated. The solubility profiles of the drug, on increasing the concentration of HP-beta-CD were of Higuchi's AL type at the three pH values evaluated. However, the solubilization slope of the drug at pH 7.0 was 22 times that at pH 3.0 as a result of greater intrinsic solubility of the ionized form of the drug at pH 7.0. Transdermal flux of gliquidone at pH 7.0 was significantly greater than the flux at pH 3.0 in the presence of 15% w/v HP-beta-CD, attributable to the better solubility of the drug at pH 7.0 in the presence of HP-beta-CD. The effect of increasing concentrations of HP-beta-CD investigated at variable drug loading in the donor phase at pH 7.4 endorsed the earlier observations from studies on other drugs, that the drug has to be present at saturation in HP-beta-CD aqueous vehicle to achieve an optimized flux. While at saturation, the steady state flux of gliquidone from the aqueous HP-beta-CD (25% w/v) vehicle was enhanced 31 times compared to pure drug suspension at pH 7.4, unsaturation in the donor phase resulted in the decreased flux of gliquidone. It was concluded from the present study that enhanced transdermal flux of gliquidone can be achieved by adjusting the pH and the concentration of HP-beta-CD to achieve a better solubility of the drug.