The Interaction of Piroxicam with Neutral (HP-β-CD) and Anionically Charged (SBE-β-CD) β-cyclodextrin

The interaction of piroxicam (PX) with sulfobutylether-β-cyclodextrin (SBE-β-CD) was studied by fluorescence spectroscopy and compared with that of hydroxypropyl-β-cyclodextrin (HP-β-CD). The stability constants (K) values for the PX-CDs complexes were obtained by steady-state fluorescence measurements. Inclusion conditions including concentrations of the two cyclodextrins and pH values were investigated for the complex formation in detail. The results suggested that the interaction of PX with charged CD (SBE-β-CD) is much stronger than that with uncharged CD (HP-β-CD) at any pH studied, in terms of a synergetic effect of hydrophobic and additional electrostatic interactions.     

Study on the Association Phenomenon of Cyclodextrin to Porphyrin J-aggregates by NMR Spectroscopy

The nuclear magnetic resonance (NMR) spectroscopy demonstrated that the inclusion complexes of meso-tetrakis- (p-sulfonatophenyl) porphyrin (TPPS) with β-, Hydroxypropyl-β- and Methyl-β-cyclodextrin (β-, HP-β- and Me-β-CD) are formed, which resulted in the dissociation of TPPS J-aggregates efficiently under certain acidity. There are no significant differences in binding affinities and basic complexation mechanisms between TPPS and β-cyclodextrin (β-CD) or hydroxypropyl-β-cyclodextrin (HP-β-CD), i.e. porphyrin is included through the wide side of the cavity of β-CD or HP-β-CD. Alternatively, porphyrin is included through the narrow side of the Me-β-CD cavity.     

Inclusion Complexation and Dissolution Properties of Nimesulide and Meloxicam–hydroxypropyl-β-cyclodextrin Binary Systems

The purpose of the work is physicochemical characterization of nimesulide (NI) and meloxicam (ME)–hydroxypropyl-β-cyclodextrin (HP-β-CD) binary systems both in solution and solid states and to improve the pharmaceutical properties of NI and ME via inclusion complexation with HP-β-CD. Binary systems of NI and ME with HP-β-CD have been characterized both in solution and solid state by different physicochemical methods. Three types of drug–HP-β-CD binary systems, namely physical mixtures (PM), kneaded systems (KS) and co evaporated systems (CS) in 1:1 and 1:2 molar ratios (1:1 and 1:2 M) were prepared. Phase solubility and ¹H-NMR spectroscopic studies in solution state revealed 1:1 M complexation of NI and ME with HP-β-CD. A partial inclusion of NI with HP-β-CD at both molar ratios of kneaded and co evaporated systems and a true inclusion of ME with HP-β-CD at both molar ratios of co evaporated systems in solid state was confirmed by differential scanning calorimetry (DSC), powder X-ray diffractometry (powder X-RD) and scanning electron microscopy (SEM) studies. Dissolution properties of NI and ME–HP-β-CD binary systems were superior when compared to corresponding pure drugs. The aqueous solubility and dissolution properties of NI and ME can be improved by inclusion complexation with HP-β-CD. Author for correspondence: E-mail: nbnaid2@E-mail.uky.edu     

Binary Systems of Nifedipine And Various Cyclodextrins in The Solid State. Thermal,FTIR, XRD studies

Nifedipine complexes with β-cyclodextrin (β-CD), γ-cyclodextrin (γ-CD), 2-hydroxypropyl-β-cyclodextrin (2HP-β-CD), randomly methylated-β-cyclodextrin (RM-β-CD) and heptakis(2,6-O-dimethyl)-β-cyclodextrin (DM-β-CD) have been prepared by both kneading and heating methods and their behaviour studied by differential scanning calorimetry (DSC), diffuse reflectance mid-infrared spectroscopy (FTIR) and X-ray diffractometry (XRD). DSC revealed the nifedipine melting endotherm with onset at approximately 171°C for the kneaded mixtures with β-CD, γ-CD and 2HP-β-CD, thus confirming the presence of nifedipine in the crystalline state, while some decrease in crystallinity was observed in the DM-β-CD kneaded mixture. With RM-β-CD, however, broadening and shifting of the nifedipine endotherm and reduction in its intensity suggested that the kneading could have produced an amorphous inclusion complex. These differing extents of interaction of nifedipine with the cyclodextrins were confirmed by FTIR and XRD studies. This revised version was published online in August 2006 with corrections to the Cover Date.     

Improvement of Steroid Biotransformation with Hydroxypropyl-β-Cyclodextrin Induced Complexation

The inclusion complexes induced by cyclodextrins and its derivates have been shown previously to enhance the biotransformation of hydrophobic compounds. Using hydroxypropyl-β-cyclodextrin (HP-β-CD; 20% w/v), the water solubility of cortisone acetate increased from 0.039 to 7.382 g L⁻¹ at 32 °C. The solubilization effect of HP-β-CD was far superior to dimethylformamide (DMF) and ethanol. The dissolution rate also significantly increased in the presence of HP-β-CD. The enzymatic stability of Δ¹-dehydrogenase from Arthrobacter simplex TCCC 11037 was not influenced by the increasing concentrations of HP-β-CD contrary to the organic cosolvents which negatively influenced in the order DMF > ethanol. The activity inhibition effect caused by HP-β-CD was not so conspicuous as ethanol and DMF. Inactivation constants of ethanol, DMF, and HP-β-CD were 5.832, 4.541, and 1.216, respectively. The inactivation energy (E _a) was in the order of HP-β-CD (55.1 kJ mol⁻¹) > ethanol (39.9 kJ mol⁻¹) > DMF (37.1 kJ mol⁻¹).     

Pseudorotaxane complexes of naphthylpyridines and naphthylbipyridyl with β-cyclodextrin and hydroxypropyl-β-cyclodextrin

The electronic absorption spectra and fluorescence spectra of 4-(2-naphthyl)pyridine (1), 2-(4-methyl-2-pyridyl)-4-(2-naphthyl)pyridine (2), and 4-(2-naphthyl)-2-phenylpyridine (3) in solutions and in complexes with β-cyclodextrin (β-CD) and well water-soluble hydroxy-propyl-β-cyclodextrin (HP-β-CD) were studied. Fluorescence near 475 nm observed in aqueous solutions of compounds 1–3 arises from protonated forms of these compounds produced in the excited state. Results of DFT quantum chemical calculations show an increase in proton affinity energies of excited-state naphthylpyridines 2 and 3. The formation of inclusion complexes with cyclodextrins makes protonation of compounds 2 and 3 more difficult, which manifests in large hypsochromic shifts of fluorescence band maxima. The stability constants of the complexes 1·HP-β-CD and 2·HP-β-CD determined from their fluorescence spectra are 3425 and 3760 L mol⁻¹, respectively. The stability constant of the complex 3·HP-β-CD (5500±600 L mol⁻¹) was found from the changes in the solubility of naphthylpyridine 3 in water upon complexation. Semiempirical quantum chemical calculations of the molecular structures and thermodynamic characteristics of pseudorotaxane inclusion complexes of trans-2, cis-2, and trans-2·H₂O with HP-β-CD were carried out. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 272–280, February, 2007.     

Pattern recognition methods as supplementary techniques for identification of salicylamide — cyclodextrins inclusion complexes

The objective of this study was to learn whether or not the pattern recognition methods, such as agglomerative cluster analysis (CA) and principal component analysis (PCA), can be used as supplementary techniques for identification of salicylamide (SAA) inclusion complexes with β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). To do this, phase-solubility of SAA in the presence of the cyclodextrins was studied by the Higuchi-Connors method, which showed that the cyclodextrins enhanced the solubility of SAA in water as compared to that of the drug. Next, the solid phase complexes of the drug with β-CD and HP-β-CD were prepared by using the coprecipitation, precipitation-evaporation, and kneading methods. Identification of the inclusion complexes was performed by using thermal analysis, infrared spectroscopy, and wide angle X-ray scattering. Two multivariate statistical methods, CA and PCA, were used as the supplementary techniques for identification of the inclusion complexes. The results of the statistical analysis have shown that CA and PCA are helpful for interpretation of the thermoanalytical and spectral data. Moreover, these methods enabled proper classification of the products in all doubtful cases. They can be used as supplementary techniques to verify the conclusions of the above-mentioned standard methods.      

Spectroscopic investigation of Rose Bengal/cyclodextrin interactions in aqueous solution: the case of the hydroxypropyl-cyclodextrins

The interaction of Rose Bengal (RB) with hydroxypropyl-α-cyclodextrin (HP-α-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD) and hydroxypropyl-γ-cyclodextrin (HP-γ-CD) has been studied in water and in acetate buffer at pH 4.5 by UV–Vis absorption, fluorescence spectroscopy and Induced Circular Dichroism at 298 K. Evidence of the complex formation between the RB and all HP-CDs have been obtained both in water and in buffer. Binding constants and stoichiometry of RB/HP-CD complexes in water have been determined by applying the modified Benesi-Hildebrand equation to the fluorescence measurements.     

Spectrofluorimetric Study of an Inclusion Complex of 2-Hydroxypropyl-β-Cyclodextrin with the Antitumour 11-Methyl Benzophenothiazine. Analytical Application to Urine

The electronic absorption and fluorescence spectral properties of 11-methyl-12H-benzo[a]phenothiazine (11-MeBPHT) were investigated in various media (water, ethanol, β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) aqueous solutions). Fluorescence quantum yields were respectively about 20 and 2 times larger in HP-β-CD and β-CD than in water. The formation of a 1:1 stoichiometry inclusion complex between 11-MeBPHT and HP-β-CD (association constant K _f=118±3 M⁻¹ at 20 °C) was studied in aqueous medium by fluorescence spectroscopy. Analytical figures of merit were satisfactory for 11-MeBPHT with linear dynamic ranges over at least two orders of magnitude and limits of detection (LODs) between 0.2 and 1 ng/ml according to the medium. An analytical application to the determination of 11-MeBPHT in human urine samples by the standard addition procedure led to satisfactory recovery percentages (91–108%).     

Spectroscopic properties,structure, and photoinduced motion of 4-(2-naphthyl)pyridine in cyclodextrin cavities

Spontaneous and photoinduced protonation of 4-(2-naphthyl)pyridine (1) in solutions and in complexes with β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was studied using the absorption and fluorescence spectroscopies. The structures and stabilities of complexes of compound 1 and its quaternized derivative, 1-methyl-4-(2-naphthyl)pyridinium perchlorate (3), with β-CD and HP-β-CD were examined by ¹H NMR titration (logK = 1.5–2.3). The molecule of naphthylpyridine 1 is always in the cyclodextrin cavity, regardless of the pH value of the solution. 2-Hydroxypropyl-β-cyclodextrin binds better the neutral form of compound 1 than does β-CD, while naphthylpyridinium salts exhibit nearly equal affinities to both cavitands. According to spectroscopic data, pK _a (1) is 5.12 in water, which favors protonation of the N atom both in the ground and excited states; as a result, the fluorescence spectrum exhibits only the band of the protonated form with a lifetime of 15 ns. The addition of HP-β-CD to a solution of naphthylpyridine 1 results in the formation of inclusion complex 1@HP-β-CD, lowers pK _a to 4.62, and gives rise to a fluorescence band of the nonprotonated form of compound 1 with a lifetime of 1.25 ns. Therefore, the presence of compound 1 in the HP-β-CD cavity precludes its protonation in the excited state. The initial portions of the fluorescence curves for compound 1 in solution and in its complex with HP-β-CD obtained upon pulsed excitation were compared to propose the initiation mechanism of short-lived fluorescence of the nonprotonated form of naphthylpyridine 1. Quantum chemical modeling of the protonation and complexation of compound 1 in the presence of water was performed. Based on the results obtained, a reversible photoinduced mechanical motion of naphthylpyridine 1 in the HP-β-CD cavity was suggested.     

Thermoanalytical Studies on Complexes of Furosemide with β-Cyclodextrin Derivatives

Solid formulas obtained between furosemide and two β-cyclodextrin derivatives (HP-β-CD and RAMEB) were prepared by different methods and in various ratios (1:1 and 1:2). The inclusion complex formation between the drug and the β-CDs of 1:1 ratio was evaluated by mean of thermal analysis (DSC, TG and EGD). Supplementary techniques, such as X-ray diffraction, were also applied to interpret the results of the thermal study of physically mixed and kneaded products. Both studies demonstrated the formation of inclusion complexes in all samples except the physical mix samples; formation of true inclusion complexes was then possible only when the components were in melted form. The complexation increased the solubility and the rate of dissolution of the drug. RAMEB was found to be a better complexing agent than HP-β-CD; in both ratios it can be selected as a vehicle in furosemide tablet preparations. This revised version was published online in August 2006 with corrections to the Cover Date.     

Grafting of cyclodextrins onto filter paper

Grafting of cyclodextrins and cyclodextrins derivatives on cellulosic surface, such as paper or filter paper, provides hosting cavities that can include a large variety of chemicals for specific cellulose finishing. In this study grafting of monocholorotriazinyl-β-cyclodextrin (MCT-β-CD) and β-cyclodextrin (β-CD) to filter paper has been performed. β-cyclodextrin has been bonded to filter paper using 1,4-butanediol diglycidyl ether as the crosslinking agent. The untreated and treated filter papers were characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), demonstrating the covalent binding of cyclodextrins to filter paper. The quantification of β-CD and MCT-β-CD grafted to filter paper was determined by the dye extinction method with the inclusion of phenolphthalein. The final β-CD content amounted to 15.9 μmol per gram of support (1.8% by weight), and 72.8 μmol per gram of support (11.3% by weight) for MCT-β-CD.     

Combined effect of hydroxypropyl methylcellulose and hydroxypropyl-β-cyclodextrin on physicochemical and dissolution properties of celecoxib

Investigation on the influence of hydroxypropyl methylcellulose (HPMC) on solubility and dissolution properties of celecoxib/hydroxypropyl-β-cyclodextrin system was carried out, with the ultimate goal of enhancing the drug bioavailability. ¹H-NMR and ¹³C-NMR spectroscopy were first performed to elucidate the type of interactions between celecoxib (CEL) and hydroxypropyl-β-cyclodextrin (HP-β-CD). Then, solubility studies in the absence and in the presence of HPMC were carried out in aqueous solution. After heating in autoclave of CEL/HP-β-CD/HPMC suspensions a synergistic increasing effect on the aqueous solubility of CEL was observed. In fact, the presence of both HP-β-CD (0.05 M) and HPMC (0.25% w/v) gave rise to a 330-fold CEL solubility increase, whereas the cyclodextrin alone provided a 34-fold increase. Gibbs free energy values calculated from phase solubility data were all negative, indicating the spontaneous nature of CEL solubilization, and they decreased in the presence of HPMC, demonstrating that the solubilization conditions became more favorable. CEL/HP-β-CD and CEL/HP-β-CD/HPMC solid systems (physical mixtures and coevaporated products) were characterized by differential scanning calorimetry and infrared spectroscopy. Results suggested that the coevaporation method yields a high degree of amorphous entities and indicated the formation of a CEL/HP-β-CD complex in the coevaporated products. The positive effect of HPMC is particularly evident when looking at the CEL dissolution rate from the binary and ternary solid systems. Specifically, the percent of CEL dissolved after 10 min. resulted 84.21% for ternary coevaporated product and 50.18% for binary coevaporated product with respect to 13.10% for the drug alone.     

Inclusion complexation of Itraconazole with β-and 2-hydroxypropyl-β-cyclodextrins in aqueous solutions

The inclusion behavior of Itraconazole (Itra) with β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was investigated by using phase solubility and molecular mechanics techniques. The effects of pH and temperature on complex stabilit were also explored. The aqueous solubility of Itra was significantly enhanced as CD concentration increased. Itra tends to form 1: 3 complexes with β-and HP-β-CD at pH ≥ 4 and 1: 2 at pH 2. Thermodynamic parameters for Itra/HP-β-CD show that the 1: 1 complex is driven by enthalpy but retarded by entropy changes. In contrast, the formation of 1: 2 and 1: 3 complexes is largely favored by entropy due to higher desolvation induced by total enclosure of Itra with two (or three) favorably interacting CD molecules. The inclusion mode of Itra/β-CD complexes was proved by molecular mechanics technique, which provided a powerful means for understanding inclusion interactions and processes. Published in Russian in Zhurnal Fizicheskoi Khimii, 2006, Vol. 80, No. 7, pp. 1200–1205. The text was submitted by the authors in English.     

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.     

Enhancement of cyclosporine aqueous solubility using α- and hydroxypropyl β-cyclodextrin mixtures

Cyclodextrins (CDs) are cyclic oligosaccharides that form inclusion complexes with lipophilic molecules through their hydrophobic central cavity. In this study, the effect of α-CD, hydroxylpropyl-β-CD (HP-β-CD) and mixtures of these two CDs on the aqueous solubility of cyclosporine A (CyA) was investigated. Infrared spectroscopy and thermal analysis were used to confirm CyA-CD complex formation. CyA aqueous solubility was increased by 10 and 80 fold in the presence of α-CD and HP β-CD, respectively. The phase-solubility profile for HP-β-CD was linear while that for α-CD had positive deviation from linearity. In the presence of constant concentration of α-CD (15% w/v), aqueous solubility of CyA was further increased upon addition of HP-β-CD up to a concentration of 20% w/v. At higher HP-β-CD concentrations, aqueous solubility of CyA was observed to decrease. Addition of sodium acetate (up to 5% w/v) to aqueous solutions containing 20% w/v HP-β-CD and increasing concentrations of α-CD resulted in a significant reduction in CyA solubility. Complex formation between CyA and both α-CD and HP-β-CD was confirmed by differential scanning calorimetry (DSC). No significant changes were observed in the IR spectra of either CyA or CD following complex formation suggesting chemical interaction between CyA and the CD was unlikely. Phase-solubility studies showed that α-CD had a much greater effect on the solubility of CyA than HP-β-CD. Addition of HP-β-CD to aqueous solutions of α-CD affected the solubility of CyA in these systems. A mixture of 15% w/v α-CD and 20% w/v HP-β-CD was optimal for increasing aqueous solubility of CyA.     

Changes in the reactivity of the fluorescent reagents carbazole-9-carbonyl chloride and 9-carbazolylacetic acid in the presence of cyclodextrins

Carbazole-9-carbonyl chloride (C9CC) and 9-carbazolylacetic acid (9CAA) were selected as model fluorescent reagents. The effect of different chemically modified cyclodextrins (CDs) added to the aqueous solutions of these reagents was studied in water and in buffered aqueous solutions at pH 4.5 and 8.8. The CDs employed were 2-hydroxypropyl-β-cyclodextrin (HP-βCD), 2,3-di-O-methyl-β-cyclodextrin (DM-βCD) and 2,3,6-tri-O-methyl-β-cyclodextrin (TM-βCD). The inclusion of these reagents inside the cavities of the CDs was verified and this process can affect the derivatization reaction because CDs can modify the reactivity of the guest molecules. The basic conditions necessary for the derivatization reaction between C9CC and amines lead to the formation of carbazole anion through hydrolysis followed by decarboxylation. In the presence of CDs, the hydrolysis-decarboxylation of carbazole-9-carbonyl chloride is faster than in buffered aqueous homogeneous solutions. The behaviour observed for these reagents in aqueous solutions of CDs was compared to the one observed in basic ethanolic solutions. These changes are particularly noticeable in the case of 2,3-di-O-methyl-β-CD and 2-hydroxypropyl-β-CD. The characteristics of the fluorescent reagents are compared to carbazole and 9-methylcarbazole as model compounds. This paper was presented at XIIIth International Cyclodextrin Symposium. Torino, Italy, May 14–17, 2006.     

Characterization of lidocaine:hydroxypropyl-β-cyclodextrin inclusion complex

An inclusion complex was prepared between the local anesthetic lidocaine (LDC) and hydroxypropyl-β-CD (HP-β-CD). The complex was characterized by thermal analysis (differential scanning calorimetry, DSC), UV absorption and high-pressure liquid chromatography (HPLC). DSC results were indicative of complexation, due to the loss of the characteristic endothermic peak of LDC (77 °C). Phase-solubility diagrams allowed the determination of the association constant between LDC and HP-β-CD (35.7 ± 4.7 M⁻¹). The rate of LDC release decreased after complexation and thermodynamic parameters from the HPLC studies (ΔG° = −2.65 kJ/mol) revealed that a stable complex was formed.     

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.     

Improvement of Solubility and Stability of Valsartan by Hydroxypropyl-\boldbeta-Cyclodextrin

Aim of the present work was to investigate the effect of hydroxypropyl-β-cyclodextrin (HP-β-CD) on the solubility, dissolution rate and stability of Valsartan (VAL), a drug used orally for the treatment of hypertension. Phase solubility studies demonstrated the ability of the HP-β-CD to complex VAL and to increase drug solubility. The dissolved amount of VAL increased linearly with the addition of HP-β-CD according to an A_L type plot. The apparent stability constant of the complex, calculated supposing a 1:1 stoichiometry, was 296±7 M⁻¹. VAL/HP-β-CD interactions were also studied by ¹³C-NMR spectroscopy. Equimolar VAL/HP-β-CD solid systems were prepared by physical-mixing and freeze-drying, and their properties in the solid state studied by DSC and FT-IR analysis. The results provided clear indications of the formation of a new solid phase corresponding to the inclusion complex in the freeze-dried sample. The dissolution profiles of the drug from each solid system were affected by its physico-chemical properties, the freeze-dried being the most rapidly dissolving form. The thermal stability of the complex was studied, also determining the number and identity of the decomposition products of the drug. The stability studies revealed that the VAL/HP-β-CD complex significantly decreases the rate of VAL degradation. These results suggest that CD technology would be a very useful method to overcome the solubility and the stability problems of VAL.