Sulphamethizole-Cyclodextrin-Hydroxy Propylmethyl Cellulose Multicomponent Complexes

The effect of cyclodextrin complexation of sulphamethizole (SM) was studied. Two systems were prepared with two cyclodextrin derivatives, β-cyclodextrin (BCD) and hydroxypropyl-β-cyclodextrin (HPBCD): binary complexes and multicomponent systems (cyclodextrins and a hydroxylpropylmethyl cellulose K4M). Inclusion complexes were prepared by freeze-drying and characterized by thermal analysis (DSC) and X-ray diffractometry. The presence of the polymer in the solution increases the effect of cyclodextrins – specially BCD – on the solubility of SM. In solid state, binary inclusion complexes enhance the dissolution behaviour of SM but, from the multi-component complexes, the polymer controls the release of the drug. This revised version was published online in August 2006 with corrections to the Cover Date.     

Solubilty and dissolution studies of antifungal drug:hydroxybutenyl-β-cyclodextrin complexes

The solubilities of voriconazole, ketoconazole, and clotrimazole with and without hydroxybutenyl-β-cyclodextrin (HBenBCD) in aqueous media were examined. The solubility of these antifungal drugs was significantly improved by complexation with HBenBCD. Both the pH and the type of buffer used to adjust the medium pH had a very significant effect on drug solubilities and the apparent binding constants of the drug:cyclodextrin complexes. Additionally, the stereochemistry of tartrate buffers was found to influence both the electrostatic interaction between drug and tartrate as well as complexation of the drug-tartrate aggregate by HBenBCD. We also compared the solubilization of these antifungal drugs by HBenBCD to other cyclodextrin derivatives with different substituents under identical experimental conditions and found that the amount of drug solubilized was in some cases influenced strongly by the nature of the cyclodextrin. Solid antifungal drug:HBenBCD complexes were prepared and their dissolution profiles were obtained which showed that HBenBCD improved both the rate of dissolution and the amount of drug dissolved.     

Complexation behavior of antiestrogen drug tamoxifen citrate with natural and modified β-cyclodextrins

Inclusion complexes of the poorly-soluble antiestrogen drug tamoxifen citrate (TMX) were prepared with β-cyclodextrin (β-CD) and 2,3-di-O-hexanoyl-β-cyclodextrin (β-CDC6) being natural and amphiphilic cyclodextrins, respectively using the co-lyophilization technique. Complexation occurred in aqueous medium for natural cyclodextrin β-CD and a medium of water:ethanol mixture for the amphiphilic cyclodextrin β-CDC6. The complexes were characterized using analytical techniques including Differential Scanning Calorimetry (DSC), Fourier Transform Infrared spectroscopy (FTIR) and proton Nuclear Magnetic Resonance Spectrometry (¹H NMR). Anticancer efficacies of the complexes were determined against MCF-7 human breast carcinoma cell line with MTT assay. It was found that tamoxifen citrate can be incorporated in the cavity for β-CD and both in the cavity and the aliphatic chains for β-CDC6. The latter having two hydrophobic sites for inclusion of water-insoluble drug exhibited significantly higher anticancer efficacy accordingly.     

Inclusion Complex Formation Between Modified Cyclodextrins and Riboflvin and Alloxazine in Aqueous Solution

Inclusion complex formation of hydroxypropylated α-, β- and γ-cyclodextrins with riboflavin (vitamin B₂) and alloxazine was studied by spectroscopic and solubility methods. Alloxazine, which is a structural analog of riboflavin, was considered in order to evaluate the role of ribityl and methyl substituents in complexation. Thermodynamic parameters for 1:1 complex formation were obtained and analyzed in terms of influence of the reagent structure on the binding process. It was shown that the cavity of hydroxypropyl-β-cyclodextrin is more appropriate for formation of stable complexes. The complexes are enthalpy stabilized, due to prevalence of van der Waals interactions and possible hydrogen bonding. The partial insertion of riboflavin into the cyclodextrin cavity was revealed by ¹H NMR and computer modeling. The ribityl side chain, which prevents deep inclusion, is located nearby the wider rim of the cyclodextrin molecule and can undergo destruction. Penetration of the alloxazine molecule into the macrocyclic cavity is deeper and accompanied by formation of more stable inclusion complexes. Hydroxypropyl-β-cyclodextrin was found to be the more efficient solubilizing agent for riboflavin and alloxazine, whereas a stabilization action of cyclodextrins towards riboflavin was not observed.     

Rapamycin-cyclodextrin complexation: improved solubility and dissolution rate

The objective of this study was to improve poor aqueous solubility and dissolution properties of anticancer drug rapamycin through formation of inclusion complexes with natural and modified cyclodextrins. Of the cyclodextrins tested, ??-cyclodextrin and hydroxypropyl-??-cyclodextrin did not complex with rapamycin. However, complexes of rapamycin with ??-cyclodextrin, methyl-??-cyclodextrin and hydroxypropyl-??-cyclodextrin were prepared and characterized by techniques such as Fourier Transform infrared spectroscopy, differential scanning calorimetry, phase solubility analysis and in vitro dissolution studies. According to the characterization data for the complexes, rapamycin water solubility was highly enhanced by all three ??-cyclodextrins with methyl-??-cyclodextrin complex resulting in particularly higher solubility enhancement. FTIR spectra and DSC thermograms supported the formation of inclusion complexes. The complexes showed highly improved dissolution rate in water. Complexation with cyclodextrin derivatives such as methyl-??-cyclodextrin and hydroxypropyl-??-cyclodextrin can provide promising alternatives for the formulation of rapamycin.     

Host–Guest Interaction Study of Resveratrol With Natural and Modified Cyclodextrins

The aim of this work is to increase the stability and water solubility of resveratrol by complexation with different cyclodextrins. Furthermore, physical–chemical properties of each inclusion compound were investigated. Complexes of resveratrol with cyclodextrins both native (α, β, γ) and modified (2-hydroxypropyl-β-cyclodextrin, dimethyl-β-cyclodextrin) were obtained by using the suspension method. An inclusion complex with β-cyclodextrin was also prepared by using the microwave. Solid state characterization of the products was carried out using Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction (DRX); solution studies were performed by UV–Vis spectrophotometry and ¹H-NMR spectroscopy. Phase solubility profiles with all cyclodextrins employed were classified as A_N type, indicating the formation of 1:1 stoichiometric inclusion complexes. Stability constants (K _c) from the phase solubility diagrams were calculated. Stability studies in the solid state and in solution were performed; the photodegradation by UV–Vis spectrophotometry was monitored. The isomerization rate trans to cis, in ethanol solution, decreased with inclusion. The dissolution studies revealed that resveratrol dissolution rate was improved by the formation of inclusion complexes.     

Solid-state characterization and dissolution properties of ezetimibe–cyclodextrins inclusion complexes

The objectives of this research were to prepare and characterize inclusion complex of Ezetimibe (EZE) with cyclodextrins (β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HPβ-CD)) and to study the effect of complexation on the dissolution rate of EZE, a water insoluble drug. Phase solubility curve was classified as A _P -type for both cyclodextrins, indicating the 2:1 stoichiometric ratio for β-CD–EZE and HPβ-CD – EZE inclusion complexes. The inclusion complexes in the molar ratio of 2:1 (β-CD–EZE and HPβ-CD–EZE) were prepared by various methods such as kneading, coevaporation and physical mixing. The molecular behaviors of drug in all samples were characterized by fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies. The results of these studies indicated that complex prepared by kneading and coevaporation methods showed inclusion of the EZE molecule into the cyclodextrins cavities. The highest improvement in in-vitro dissolution profiles was observed in complex prepared with hydroxypropyl-β-cyclodextrin using co-evaporation method. Mean dissolution time and similarity factor indicated significant difference between the release profiles of EZE from complexes and physical mixtures and from pure EZE.     

Cyclodextrins as Enhancers of the Aqueous Solubility of the Anthelmintic Drug Mebendazole: Thermodynamic Considerations

Summary.  Inclusion complexes of mebendazole with α-, β-, and γ-cyclodextrins, hydroxylpropyl-β-cyclodextrin (HP-β-CD), and methyl-β-cyclodextrin (Me-β-CD) were investigated employing the Higuchi and Connors solubility method. The solubility of mebendazole increased as a function of cyclodextrin concentration showing an A_L phase diagram indicating the formation of soluble complexes with 1:1 stoichiometry. The Gibbs free energies of transfer of the drug from aqueous solution to the cavity of cyclodextrin are negative and increase negatively with increasing cyclodextrin concentration. The solubility of mebendazole as well as the stability constant of its complex with Me-β-CD are found to be affected by the pH of the medium. The Me-β-CD cavity was found to have a greater affinity for the unionized mebendazole rather than the protonated one. Effects of methanol and temperature on these interactions were also investigated to gain further knowledge on the mechanism of the inclusion process. It was found that the interaction between the drug and the cyclodextrin is weakened as the medium becomes more apolar and the temperature increases. Moreover, the thermodynamic parameters for the binding were derived from the dependence of the stability constants on the temperature (van’t Hoff analysis). The formation of the inclusion complexes between the drug and β-CD or its derivatives was found to be enthalpy controlled, with |ΔH °| > T|ΔS °|. This suggests that hydrophobic and van der Waals interactions as well as solvent reorganization are the main driving forces. Furthermore, the size of the cavity of cyclodextrins plays an important role in the association process. Permanent address: Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt. E-mail: i.shehatta@uaeu.ac.ae Received November 30, 2001. Accepted (revised) December 27, 2001     

A new example of reversal of the order of migration of enantiomers, as a function of cyclodextrin concentration and pH, by cyclodextrin-modified capillary zone electrophoresis: enantioseparation of 6,6′-dibromo-1,1′-binaphthyl-2,2′-diol

Enantioseparation of 6,6′-dibromo-1,1′-binaphthyl-2,2′-diol (DBBD) by cyclodextrin-modified capillary zone electrophoresis (CD-CZE) was studied using the three native α, β, and γ cyclodextrins, the three hydroxypropylated cyclodextrins (2-hydroxypropyl-α, β, and γ), heptakis-2,6-di-O-methyl-β-CD (DM-β-CD), and heptakis-2,3,6-tri-O-methyl-β-cyclodextrin (TM-β-CD). First, the acidity constants of DBBD were determined using capillary electrophoresis, before performing enantioseparation. The influence of the concentrations of the studied cyclodextrins on the enantioseparation was explored and the experimental optimal concentrations were determined and compared to the theoretical optimal concentrations. Moreover, the apparent complexation constants between each studied cyclodextrin and the two DBBD enantiomers were evaluated using a non-linear curve fitting method and three linear plotting methods (x-reciprocal, y-reciprocal and double reciprocal). For TM-β-CD, the order of migration of the enantiomers of DBBD reversed as a function of TM-β-CD concentration. The influence of the nature of methylated cyclodextrin derivatives (methyl-β-CD (M-β-CD) and DM-β-CD) was then studied. Inversion of the order of migration of the enantiomers of DBBD was observed for DM-β-CD, whereas the S enantiomer of DBBD always migrated first for M-β-CD.     

Interactions of xanthine and its derivatives with cyclodextrins in aqueous solutions

Using calorimetry, ¹H NMR, UV spectroscopy, and solubility methods, the interactions of natural and hydroxypropylated 6h-, β-, and γ-cyclodextrins with xanthine and its methylated derivatives (theophylline, theobromine, and caffeine) were studied in aqueous solutions at 298.15 K. Cyclodextrins revealed low complexation ability toward xanthine and its methylated derivatives. Hydroxypropyl-γ-cyclodextrin with the largest internal cavity is the most effective solubilizing agent for this type of compounds. The calculated thermodynamic parameters are discussed in terms of structural effects of cyclodextrins and purine alkaloids on the character of their intermolecular interactions in aqueous medium.     

Solubilization of itraconazole as a function of cyclodextrin structural space

Cyclodextrins are functional pharmaceutical excipients, which can dynamically include poorly water-soluble drugs and drug candidates resulting in improved solubility, stability and oral bioavailability. A number of formulations containing “natural” and chemically modified cyclodextrins have reached the market and are enjoying widespread attention and use. One such example is itraconazole, a broad-spectrum antifungal agent which is available in an aqueous hydroxypropyl-β-cyclodextrin (HPβCD) vehicle for both oral and parenteral use (Sporanox Oral Solution and Sporanox Intravenous Injection^®). While the interaction of itraconazole and HPβCD is well described, its ability to form complexes with other cyclodextrins is less understood. This creates an intriguing opportunity of screening the structural space of available cyclodextrin derivates by assessing their complexation with a single chemical probe, in this case itraconazole. To this end, a number of cyclodextrin derivatives were assess with regard to their ability to improve the water solubility of the test substrate. In some instances, more detail assessments including the effect of pH and the physical form of the drug probe were also completed. The various cyclodextrins solubilized itraconazole to varying extents (micrograms to milligrams) and by varying inclusion mechanisms and stoichiometries.     

Cyclodextrin solubilization of celecoxib: solid and solution state characterization

The low aqueous solubility of celecoxib (CCB) hampers its oral bioavailability and permeation from aqueous environment through biological membranes. The aim of this study was to enhance the aqueous solubility of CCB by complexation with cyclodextrin (CD) in the presence of water-soluble polymer. The effects of different CDs (αCD, βCD, γCD, 2-hydroxypropyl-β-cyclodextrin and randomly methylated β-cyclodextrin (RMβCD)) and mucoadhesive, water-soluble polymers (hydroxypropyl methylcellulose (HPMC), chitosan and hyaluronic acid) were investigated. The phase solubility profiles and CCB/CD complex characteristics were determined. RMβCD exhibited the greatest solubilizing effect of the two CDs tested. However, γCD was also selected for further investigations due to its safety profile. Addition of polymer to the aqueous CD solutions enhanced the CD solubilization. Formation of CCB/RMβCD/HPMC and CCB/γCD/HPMC ternary complexes resulted in 11 and 19-fold enhancement in the apparent complexation efficiency in comparison to their CCB/CD binary complex, respectively. The size of ternary complex aggregates in solution were determined to be from about 250 to about 350 nm. The data obtained from Fourier transform infra-red, differential scanning calorimetry and powder X-ray diffraction indicated presence of CCB/CD inclusion complexes in the solid state. Proton nuclear magnetic resonance data demonstrated that CCB was partially and totally inserted into the hydrophobic central cavities of RMβCD and γCD.     

Inclusion complexation of diclofenac with natural and modified cyclodextrins explored through phase solubility, 1H-NMR and molecular modeling studies

Guest–host interactions were examined for neutral diclofenac (Diclo) and Diclofenac sodium (Diclo sodium) with each of the cyclodextrin (CD) derivatives: α-CD, β-CD, γ-CD and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), all in 0.05 M aqueous phosphate buffer solution adjusted to 0.2 M ionic strength with NaCl at 20 °C, and with β-CD at different pHs and temperatures. The pH solubility profiles were measured to obtain the acid–base ionization constants (pK _as) for Diclo in the presence and absence of β-CD. Phase solubility diagrams (PSDs) were also measured and analyzed through rigorous procedures to obtain estimates of the complex formation constants for Diclo/CD and Diclo sodium/CD complexation in aqueous solutions. The results indicate that both Diclo and Diclo sodium form soluble 1:1 complexes with α-, β-, and HP-β-CD. In contrast, Diclo forms soluble 1:1 Diclo/γ-CD complexes, while Diclo sodium forms 1:1 and 2:1 Diclo/γ-CD, but the 1:1 complex saturates at 5.8 mM γ-CD with a solubility product constant (pK _sp = 5.5). Therefore, though overall complex stabilities were found to follow the decreasing order: γ-CD > HP-β-CD > β-CD > α-CD, some complex precipitation problems may be faced with aqueous formulations of Diclo sodium with γ-CD, where the overall concentration of the latter exceeds 5.8 mM γ-CD. Both ¹H-NMR spectroscopic and molecular mechanical modeling (MM⁺) studies of Diclo/β-CD indicate the possible formation of soluble isomeric 1:1 complexes in water.     

Cyclodextrins and the Biopharmaceutics Classification System of Drugs

Although the biopharmaceutics classification system (BCS) was originally developed for solid oral dosage forms this system can be extended to other types of drug delivery forms. According to the BCS aqueous solubility and permeability are the most important parameters affecting drug bioavailability. Cyclodextrins can enhance the aqueous solubility of lipophilic drugs without changing their intrinsic ability to permeate biological membranes. Thus, through cyclodextrin complexation it is possible to move Class II drugs, and sometimes even Class IV drugs, into Class I. However, cyclodextrins can decrease bioavailability of Class I drugs and will in most cases not improve bioavailability of Class III drugs. Through formation of drug/cyclodextrin/polymer ternary complexes it is possible to enhance the complexation efficacy of cyclodextrins and at the same time improve drug bioavailability from cyclodextrin containing drug formulations.     

Binding behaviors of scutellarin with α-, β-, γ-cyclodextrins and their derivatives

A series of cyclodextrin/scutellarin inclusion complexes were prepared from α-cyclodextrin, β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin with scutellarin (SCU), and their inclusion complexation behaviors, such as stoichiometry, complex stability constants and inclusion mode, were investigated by means of UV/Vis spectroscopy, ¹H NMR and 2D NMR. The results showed that the SCU could be efficiently encapsulated in the cyclodextrin cavity in aqueous solution to produce complexes that were more soluble than free SCU. The enhanced binding ability of cyclodextrins towards SCU was discussed from the viewpoint of the size/shape-fit and multiple recognition mechanism between host and guest.     

Inclusion Complex of 4-Hydroxycoumarin with Cyclodextrins and Its Characterization in Aqueous Solution

The physicochemical properties of 4-hydroxy-7-methoxy-3-phenyl-2H-chromen-2-one (4HC) and β-cyclodextrins (CDs) inclusion complexes were investigated. The phase solubility profile of 4HC with β-cyclodextrin derivatives was classified as A_L-type. Stability constants for complexes with 1:1 molar ratios were calculated from the phase solubility diagrams and indicate the following trend: DMβCD>HPβCD>βCD. The highest value of the binding constant was for 4HC-DMβCD; the binding association constant (K _a) for this complex was determined at different temperatures and the thermodynamic data indicate that 4HC-DMβCD association is mainly an entropically driven process. ¹H NMR and ROESY were carried out, revealing that 4HC is embedded in the apolar cavity of DMβCD with the 4OH group buried in the cyclodextrin cavity with the phenyl group outside, near the primary rim. These results are in agreement with ORAC_FL values; the decrease in the antioxidant activity of 4HC-DMβCD is explained by the effective protection of the hydroxyl group due to complexation.     

Characterization of the complexation of tauro- and glyco-conjugated bile salts with γ-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin using affinity capillary electrophoresis

The complexation of seven bile salts, present in the small intestine of rat, dog and man, (taurocholate, tauro-β-muricholate, taurodeoxycholate, taurochenodeoxycholate, glycocholate, glycodeoxycholate and glycochenodeoxycholate) with γ-cyclodextrin and the chemically modified 2-hydroxypropyl-γ-cyclodextrin, was studied using affinity capillary electrophoresis (ACE). The cyclodextrins (CDs) were investigated due to their use in drug formulation as excipients for solubilisation of poorly soluble drugs and drug candidates. Using mobility shift ACE, the bile salt cyclodextrin interactions were characterized demonstrating 1:1 binding stoichiometry with stability constants ranging from 2 × 10³ to 8 × 10⁴ M^?1. The binding constants showed a systematic dependence on the number and position of hydroxyl groups on the steroid skeleton and the stability constants were in general higher for complexation with the native cyclodextrin than with the modified cyclodextrin. Based upon the size of the complexation constants, it was suggested that the interaction between the CDs and the bile salts takes place at the C and D ring of the steroid skeleton. The complexation of bile salts with the γ-cyclodextrins may compete with drug-γ-cyclodextrin complex formation and, thus, potentially affect drug absorption and efficacy.     

Effect of Hydrophilic Polymer on Solubilization of Fenofibrate by Cyclodextrin Complexation

The present work investigates the possibility of improvement of the complexation efficiency of cyclodextrin towards a drug by adding a third auxiliary component (hydrophilic polymer). Phase solubility Analysis at 25 °C was used to investigate the interaction of the drug in both the binary systems (viz. Drug-Cyclodextrin and Drug-Polymer) and the ternary system (Drug-Cyclodextrin-Polymer). The combined use of polymer and cyclodextrin was clearly more effective in enhancing the aqueous solubility of the fenofibrate in comparison with the corresponding drug-cyclodextrin or drug-polymer binary systems. Hydrophilic polymers increased the complexation efficacy of cyclodextrin towards fenofibrate (as shown by the increased stability constants of the complexes). Polyvinyl Pyrollidone (PVP) was found to be most effective in enhancing the solubilization of fenofibrate by β-Cyclodextrin, the best results were obtained in ternary system with β-Cyclodextrin in presence of 1%w/v (PVP). Formulated ternary system with optimized drug:cyclodextrin:polymer ratio of 1:3.5:1 w/w resulted in a significant improvement in the dissolution rate of fenofibrate and showed 90% dissolution efficiency (D.E) as compared to around 15% and 83% of the plain drug and binary system respectively. DSC studies was carried out to characterize the ternary complex.     

Structure selective complexation of cyclodextrins with five polyphenols investigated by capillary electrokinetic chromatography

The complexation of five polyphenols, namely trans‐resveratrol, astilbin, taxifolin, ferulic acid, and syringic acid (guest molecules) with α‐, β‐, and γ‐cyclodextrin (host molecules), was investigated by capillary electrokinetic chromatography. The binding constants were calculated based on the effective electrophoretic mobility change of guests with the addition of cyclodextrins into the background electrolyte. Because of cavity size, cyclodextrins showed structure‐selective complexation property to different guest. The stability of the trans‐resveratrol complexes was in the order of β‐ > α‐ > γ‐cyclodextrin. The cavity size of α‐cyclodextrin was too small for astilbin and taxifolin molecules, and thus they could not form complexes. The molecular size of syringic acid was too big for all cyclodextrins cavity, and no cyclodextrin could form complexes with it. Temperature studies showed that the binding constants decreased with the rise of temperature. Enthalpy and entropy values were calculated and the negative values of these parameters indicated that the complexation process was enthalpy‐controlled. Van der Waals force and release of high‐enthalpy water molecules from the cyclodextrins cavity played important roles in the process.     

Enhanced water-solubility of albendazole by hydroxypropyl-β-cyclodextrin complexation

The inclusion complexation of methyl (5-(propylthio)-1H-benzimidazol-2-yl) carbamate, albendazole (ABZ) with 2-hydroxypropyl--cyclodextrin (HPCD) in water was investigated with a view to improving the low aqueous solubility of the drug. The combination of albendazole and HPCD in a molar ratio of 1/10 resulted in a significant increase in the aqeous solublity of the drug, up to 3500 times. Albendazole/HPCD complexes could be recommended as a parenterally administered formulation because of its good solubility properties and the safety of the cyclodextrin used.