Evaluation of host-guest complex formation between a benzimidazolic derivative and cyclodextrins by UV-VIS spectrophotometry and differential scanning calorimetry

Interactions between a benzimidazolic derivative, omeprazole (OME), beta-cyclodextrin (βCD) and a chemically modified βCD, methyl-beta-cyclodextrin (MβCD) were investigated in aqueous solution by UV-VIS spectroscopy and in solid state by differential scanning calorimetry (DSC). Phase solubility studies were used to evaluate the complexation in aqueous solution. The two solubility diagrams obtained were A_L type, indicating the formation of a drug-cyclodextrin complex with 1:1 stoichiometry. The complex of OME with MβCD showed a higher stability constant (K _S) than those with βCD. Some evidences of inclusion complexation in solid state were obtained from DSC. Only in thermal curves of OME-βCD lyophilized product and in OME-MβCD spray-dried and lyophilized systems the melting point of the drug disappeared completely suggesting the possible formation of an inclusion complex.     

Preparation and characterization of inclusion complexes containing fixolide, a synthetic musk fragrance and cyclodextrins

AHTN (7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene), commercially known as fixolide or tonalide, is a synthetic fragrance widely used in replace of natural musk odor which is more expensive. It is a popular fragrance material added in the manufacturing of personal care and household products, such as perfumes, soaps, shampoos, detergents, and fabric softeners. AHTN is semivolatile and is degraded under light exposure and high temperature. This work focuses on the complexation of AHTN with cyclodextrins in the effort to stabilize the fragrance material. AHTN was complexed with β-cyclodextrin, methyl (MβCD), and hydroxypropyl (HPβCD) derivatives in the mole ratio 1:1, 1:2, and 1:3 guest:host, and the complexes formed by physical mixing, co-precipitation, kneading, and freeze-drying were analyzed by DSC and FTIR. Percent AHTN included in the complex was also determined by hexane extraction and GC analysis. It was found that no inclusion complex was formed in the physical mixture. When co-precipitation method was performed, only βCD could form inclusion complex with AHTN, while the other two derivatives could not. Using 1:2 AHTN:βCD, no free AHTN was left in the complex as evidenced by DSC and FTIR spectrum. In kneading and freeze-drying methods, complexes could be formed with all CDs tested. However, co-precipitation method with 1:2 AHTN:βCD and kneading method with 1:2 AHTN:MβCD provided the highest complex yield with highest amount of AHTN included in the complex. AHTN in the complex form was more stable against high temperature and UV exposure than its free form.     

Compositions for health products obtained by treatment of tomato with beta-cyclodextrin

The aim of this work was to produce lycopene-containing powders from tomato products by a solvent-free method making use of β-cyclodextrin (βCD). Powders were prepared by spray-drying a tomato concentrate (TC), one of the most bioavailable form of lycopene, after mechanical treatment with βCD in different weight ratios. The obtained product was centrifuged to eliminate partly food matrix and characterized for the amount of lycopene hydrodispersed/hydrosolubilized in the aqueous fraction. The chemical antioxidant activity of sera was evaluated too. Powders obtained by spray-drying sera exhibited good flow properties, a lycopene content between 0.4 and 1.09 mg/g and excellent water dispersability. The process developed, which makes use of βCD for the treatment of tomato products, turns to be of great interest to obtain a bulk material for nutraceuticals displaying superior biovailability of lycopene.     

Photostability and solubility improvement of β-cyclodextrin-included tretinoin

In this work, we investigated the influence of β-cyclodextrin on the photostability of tretinoin and compared the photo-chemical stability of tretinoin, either in methanol or complexed with β-cyclodextrin, when exposed both to UV and fluorescent light. The physico-chemical characterization of tretinoin-β-cyclodextrin complexes, prepared by the freeze-drying process, using different tretinoin:β-cyclodextrin molar ratios (1:1 and 1:3), was carried out in solution by phase solubility studies, ¹H-NMR spectroscopy, and in solid state by infrared spectroscopy (FT-IR); these analyses confirmed the existence of an inclusion compound. Solubility study results showed that tretinoin solubility was enhanced by inclusion in β-cyclodextrin as a function of increasing concentrations of β-cyclodextrin in aqueous solution at different pH values (i.e., 3.0, 5.5, and 7.0). Moreover, the complexation of the tretinoin with β-cyclodextrin effectively protected the photolabile drug and reduced the degradation of tretinoin induced by UV and fluorescent light, improving its photo-chemical stability in comparison with free drug in methanol. Indeed, dissolved tretinoin in methanol degraded very quickly and completely, while β-cyclodextrin-included tretinoin decomposition was delayed and, after 30 days under UV exposure, the percentage of remaining drug was about 20–25% (depending on the tretinoin concentration). The photodegradation of tretinoin in methanol under fluorescent light was slower: after 5 days of irradiation it reached a photostationary state and intact tretinoin remained constant (6.6%). In conclusion, the β-cyclodextrin complexation always led to a reduction of degradation, depending on the tretinoin:β-cyclodextrin molar ratio and on the drug concentration (0.2 mg/ml or 0.4 mg/ml).     

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.     

Mebendazole complexes with various cyclodextrins: preparation and physicochemical characterization

Mebendazole is an antihelmintic drug, active against many intestinal parasites. Its systemic efficacy is limited by its poor water solubility. The use of natural or derivatized cyclodextrins permeated to multiply notably its apparent solubility, especially with permethyl β-cyclodextrine (PM β-CD) (multiplied by 4700). The inclusion complex formation between mebendazole and this methylated β-cyclodextrin, was characterized by mass spectrometry, powder X-ray diffractometry and Fourier transform infrared spectroscopy: mebendazole seemed to be included in permethyl β-cyclodextrin by its aromatic rings. To prepare inclusion complex of mebendazole and PMβ-CD by solvent evaporation, acetone may be used and the ratio using lower amount of cyclodextrin (MBZ:CD, 1:2) should be used.     

Application of combined thermoanalytical techniques in the investigation of cyclodextrin inclusion complexes

Citronellol and citronellyl acetate have been entrapped with α-, β- and γ-cyclodextrin (CD). Evolved gas detection and TG-MS coupling was applied to prove the actual inclusion complex formation between monoterpens and CDs. The terpene content was determined by UV-VIS specrophotometry and RP-HPLC and the effect of storage time on the terpene content was also investigated. The α- and γ-cyclodextrin inclusion complexes showed higher thermal stabilities vs. dynamic heating compared to the β-CD complexes. On the contray, the retention of guest using β-cyclodextrin even after 10 years of storage was much more pronounced. Experimental data other than 1:1 complex compositions are assumed. Molecular modeling experiments also suggested multiple complex compositions.     

Cyclodextrins-Kaempferol Inclusion Complexes: Spectroscopic and Reactivity Studies

The slightly water-soluble flavonoid kaempferol (KAE) and its inclusion complexes with β-cyclodextrin (βCD), hydroxypropyl-β-cyclodextrin (HPβCD) or heptakis-2,6-O-dimethyl-β-cyclodextrin (DMβCD) were investigated. The stoichiometric ratios and association constants describing the extent of the formation of the complexes have been determined. Binding constants, estimated from fluorescence studies at different temperatures, were analyzed so as to gain information about the mechanisms involved in the association processes. The thermodynamic data for the inclusion of KAE in DMβCD and HPβCD indicated that it is mainly enthalpy-driven whereas for βCD it is an entropy-driven process. Complex formation was monitored by two-dimensional ROESY experiments through the detection of intramolecular dipolar interaction. ROESY experiments provided data indicating that the B-ring of kaempferol is immersed in the apolar cavity with the A- and C-ring protruding from the wider rim for the three cyclodextrins studied. The antioxidant studies of KAE and CDs complexes showed an increment in its antioxidant activity. The complexes behave as better antioxidants than kaempferol alone.     

Spironolactone and its Complexes with β-cyclodextrin: Modern NMR Characterization and Structural DFTB-SCC Calculations

In the present work, inclusion complexes of spironolactone (SP) with β-cyclodextrin (β-CD) in solid phase and aqueous solution were studied by solubility methods, NMR spectroscopy and thermal analysis. The results showed different kinds of complexations when freeze-drying and kneading methods were used. The freeze-drying product (1:1, SP:β-CD) showed lower degree of complexation and stability than the (1:2, SP:β-CD) compound obtained by kneading method. The spironolactone molecule was also studied by NMR spectroscopy at 400 MHz. The chemical shifts of all spironolactone atoms and their inclusion compounds were assigned. Extensive use of 1D and 2D NMR techniques, including ROESY experiment, allowed verifying the position of the spironolactone molecule inside the cyclodextrin cavity in both situations. In addition, DFTB-SCC quantum mechanical calculations of the inclusion compounds were performed. The predicted structural properties are in good agreement with ROESY NMR results.     

Stability and enzymatic studies with omeprazole:hydroxypropyl-β-cyclodextrin

Omeprazole (OME) exhibits low stability to light, heat and humidity. In stress conditions OME stability should improve under inclusion complex form with hydroxypropyl-β-cyclodextrin (HPβCD). Stability of OME, its physical mixture (PM) with HPβCD and OME:HPβCD inclusion complex was assessed during 60 days. The inclusion complexes were prepared by kneading and freeze-drying techniques and characterized by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). A molecular modelling was also held to predict the most probable tridimensional conformation of inclusion complex OME:HPβCD. The inhibitory activity of free and complexed OME on selected enzymes, namely, papain (protease model of the proton pump) and acetylcholinesterase (enzyme present in cholinergic neurons and also involved in Alzheimer’s disease) was compared. The results obtained show that HPβCD do not protect against OME degradation, in any prepared powder, in the presence of light, heat and humidity. This may indicate that the reactive group of OME is not included in the HPβCD cavity. This fact is supported by molecular modelling data, which demonstrated that 2-pyridylmethyl group of OME is not included into the cyclodextrin cavity. In relation to enzymatic assays it was observed that free OME and OME in the binary systems showed identical inhibitory activity on papain and acethylcolinesterase, concluding that HPβCD do not affect OME activity on these two enzymes.     

Inclusion complexes of 2-phenoxyethanol and alkoxyethanols in cyclodextrins: an 1H NMR study

The association in aqueous solutions of small amphiphilic molecules [2-phenoxyethanol, PhE₁, and some α-n-alkyl-ω-hydroxyoligo(oxiethylenes], C₄E₁, C₄E₂ and C₆E₂) with β-cyclodextrin (βCD), heptakis(2,6-di-O-methyl)-β-cyclodextrin (DIMEB) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TRIMEB) was investigated by ¹H NMR spectroscopy. The upfield shifts observed for the H3 and H5 NMR signals due to anisotropic shielding confirm that the host–guest associations are of inclusion type. The stoichiometries and the apparent inclusion constants, K _app, were determined by ¹H NMR spectroscopy using the H5 and H3 signals. The relative differences in the K _app values for βCD inclusion complexes seem to reflect the hydrophobic/hydrophilic balance of the guests. The K _app values for the PhE₁ inclusion complexes can be related to the degree of methylation and hydrophobicity variation within the considered hosts. In addition, a comparative study between βCD and TRIMEB inclusion complexes using 2D ROESY (Rotating-frame Overhauser Enhancement SpectroscopY) NMR spectra provides structural features for these complexes which are inaccessible by other experimental methods.     

Inclusion Complexes of Cyclodextrins with Galangin: a Thermodynamic and Reactivity Study

The formation of the complexes of galangin (GAL) with native β-cyclodextrin (βCD), and with its substituted counterparts such as dimethyl-βCD (DMβCD) and hydroxypropyl-βCD (HPβCD), was studied by fluorescence spectra in aqueous medium. The binding association constants (K _a) of the complexes were determined at different temperatures. The formation constants obtained have the following trend upon complex formation at the three temperatures studied: HPβCD > DMβCD > βCD. The thermodynamic data for the inclusion of GAL in DMβCD and HPβCD indicated that is mainly enthalpy driven whereas for βCD it is an entropy-driven process.     

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.     

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.     

How does β-cyclodextrin affect the aggregation of sodium perfluoroheptanoate in aqueous solution: a 19F NMR study

¹H and ¹⁹F NMR spectra were recorded for D₂O solutions of sodium perfluoroheptanoate with defined concentrations up to 200 mM, in the absence and presence of β-cyclodextrin (15 mM). Analysis of ¹H chemical shift data obtained by the method of continuous variations (Job’s method) confirms the formation of 1:1 inclusion complexes for the perfluoroheptanote anion in β-cyclodextrin and leads to an estimate for the apparent inclusion constant (≥10⁴ M⁻¹). In addition, analysis of ¹⁹F chemical shift data based on two simplifying assumptions (monodisperse perfluoroheptanoate solutions below the critical micellar concentration (CMC), and a single self-associated state after the CMC) enables to interpret all the experimental chemical shift data and allows to determine CMC values for the absence and presence of β-cyclodextrin (104 and 116 mM). It is shown that the self-association of perfluoroheptanoate and its inclusion in β-cyclodextrin lead to shielding and deshielding of the fluorine atoms, respectively.     

Interaction of Valdecoxib with β-cyclodextrin: Experimental and Molecular Modeling Studies

This study aimed to investigate the effect of β-cyclodextrin on aqueous solubility and dissolution rate of valdecoxib and also to get an insight of molecular interactions involved in formation of valdecoxib‐β-cyclodextrin inclusion complex. Phase solubility analysis indicated complex with possible stoichiometry of 1:1 and a stability constant of 234.01 M⁻¹. Thermodynamic studies in water indicated exothermic nature of inclusion complexation.␣Valdecoxib‐β-cyclodextrin complexes (1:1 M) were prepared by kneading method, solution method and␣freeze–drying method. The complex was characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (P-XRD), Fourier transform infrared (FTIR) spectroscopy and nuclear magnetic resonance␣(¹H-NMR) spectroscopy. Molecular modeling was used to help establish the mode of interaction of β-cyclodextrin with valdecoxib. ¹H-NMR analysis suggested that the unsubstituted phenyl ring of valdecoxib display favorable interaction with the hydrophobic cavity of β-cyclodextrin, which was confirmed by molecular dynamic simulations. An inclusion complex model has been established for explaining the observed enhancement of solubility of valdecoxib in water by β-cyclodextrin. Dissolution studies in water showed that the valdecoxib in freeze-dried complex dissolved much faster than the uncomplexed drug and physical mixture. This improvement in dissolution rate is attributed to the increased solubility and wettability due to encapsulation along with decreased crystallanity caused by complex formation, which is evident by DSC and P-XRD studies.     

Structural characteristics of some soluble and insoluble β-cyclodextrin polymers

Several β-cyclodextrin polymers (βCDP) have been obtained by cross-linking β-cyclodextrin (βCD) with the reagent epichlorohydrin (EP). It is expected that these polymers are capable of retaining different organic molecules by adsorbing them on its network and also by forming inclusion complexes with βCDs. In this work, two soluble polymers containing 39% and 48% βCD and other insoluble ones with 65% and 74% βCD have been studied. The total amount of CD in the polymers could not be available for complexation. This parameter has been calculated by means of the decrease of colour intensity of phenolphthalein solutions when different amounts of βCDP were added. The insoluble polymer with 74% βCD appears to possess less CD available than that with 65% βCD, probably due to the higher cross-linking degree of the former. On the other hand, a higher availability of CD is found for the soluble polymer which contains 48% βCD. Moreover, the amount of glycerol monoether groups formed as a side effect during the cross-linking process has been determined and related to the epichlorohydrin content, structure and swelling properties of the polymers. It is concluded that, varying the synthesis conditions, it is possible to induce structural modifications in the hydrogel networks which can improve their practical applications.     

Differential Effects of Substituent and Pressure on Induced Inclusion Complexation of 6-O-α-D-Glucosyl-β-Cyclodextrin with 4-Substituted Phenols

The inclusion complexation of 6-O-α-D-glucosyl-β-cyclodextrin (G-β-CD), in which the glucosyl side chain is introduced to β-CD, with various kinds of phenols was studied spectrophotometrically at high pressures. The characteristic effects of substituent and pressure were found for the inclusion complexation of G-β-CD. The association constants K for the G-β-CD inclusion complexation increased with an increase in the bulkiness of the 4-substituent groups in phenols. As the external pressure increases, the inclusion constants for the G-β-CD complexation increased and the reaction volumes were estimated to be −3.8 to −19.4 cm³ mol⁻¹ from their pressure dependences. From analysis of the effect of pressure on the inclusion complexation with G-β-CD, the number of water molecules included in the G-β-CD cavity in water was estimated. The number of water molecules repelled from the CD cavity plays an important role in the change in volume upon inclusion. In addition, the structures of the inclusion complexes of G-β-CD with phenols have been established by 1D and 2D NMR measurements. Based on the results, we suggested that the ability of the G-β-CD inclusion complexation is enhanced by the interaction between guest molecules and the glucosyl side chain of G-β-CD.     

Thermoanalytical studies on complexes of clotrimazole with cyclodextrins

γ-Cyclodextrin and dimethyl-β-cyclodextrin were used as solubilizing agents for a very poorly water-soluble drug, an imidazole derivative antifungal agent, clotrimazole; with the aim of improving the physicochemical properties of the drug. Solid products were prepared by physical mixing, kneading, precipitation and spray-drying methods in 1:1 and 1:2 drug:cyclodextrin molar ratios. Drug interactions were studied by thermoanalytical methods such as DSC, DTA, TG and DTG, X-ray diffractometry and Fourier transformation-infrared spectroscopy. The results demonstrated the formation of inclusion complexes in some products. This revised version was published online in July 2006 with corrections to the Cover Date.     

Physicochemical study of solid-state benznidazole–cyclodextrin complexes

Although not being the ideal drug due to its low solubility and high toxicity, the benznidazole is the drug currently chosen for Chagas disease treatment. The deep knowledge about the characteristics of the drug in addition to the knowledge of more effective vectorization techniques of drugs in pharmaceutical forms allows a faster and cheaper development of a new therapeutic alternative in comparison to the introduction of a new molecule in the treatment. The aim of this study is the characterization of inclusion complexes Benznidazole and cyclodextrins in solid state. The interactions between Benznidazole (BNZ) and β-cyclodextrins (β-CD) modified: randomly methylated β-CD (RMβCD) and sulfobutylether β-CD (SBβCD) were studied by differential scanning calorimetry (DSC), fourier transform-infrared spectroscopy, RAMAN, and scanning electron microscopy. The preparation of solid-state binary systems by different techniques, namely, kneading, evaporated, and freeze-drying. The results suggest the formation of inclusion complexes of the drug with both CDs types in solid state by the techniques which were used, based on physicochemical data of interaction compared to the drug or the CDs/drug physical mixture. Thus, the preparation technique played an important role in the BNZ and modified CDs.