Stereoselectivity in β-cyclodextrin complexation of 1,4-dihydropyridine derivatives

Structure–interaction relationships, stereoselectivity, and solubility enhancement in inclusion compexation of β-cyclodextrins (CDs) with some racemic and enantiomerically pure 1,4-dihydropyridine derivatives (DHPs) were investigated. 1:1 and 1:2 (mole ratio) complexes were prepared and characterized by X-ray powder diffraction, differential scanning calorimetry (DSC), MS-FAB spectrometry, ¹H-NMR spectroscopy, water and phase solubility. The solubility studies have revealed different complexation equilibria for optically pure DHP enantiomers, and corresponding racemic mixtures in water solutions. By means of ¹H-NMR chemical shift measurements, the inclusion of aromatic fragments of racemic and enantiomerically pure DHP molecules within the cavities of different CDs was elucidated. Considerable stereoselectivity in complexation interactions was observed. The results indicate the potential use of cyclodextrins as chiral selectors for enantiomeric resolution of 1,4-DHP calcium antagonists. © 1993 Wiley-Liss, Inc.     

Enhancement of Oral Bioavailability of Cilostazol by Forming its Inclusion Complexes

The study was designed to investigate the effect of cyclodextrins (CDs) on the solubility, dissolution rate, and bioavailability of cilostazol by forming inclusion complexes. Natural CDs like β-CD, γ-CD, and the hydrophilic β-CD derivatives, DM-β-CD and HP-β-CD, were used to prepare inclusion complexes with cilostazol. Phase solubility study was carried out and the stability constants were calculated assuming a 1:1 stoichiometry. Solid cilostazol complexes were prepared by coprecipitation and kneading methods and compared with physical mixtures of cilostazol and cyclodextrins. Prepared inclusion complexes were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. In vitro dissolution study was performed using phosphate buffer pH 6.4, distilled water, and HCl buffer pH 1.2 as dissolution medium. The optimized inclusion complex was studied for its bioavailability in rabbit and the results were compared with those of pure cilostazol and Pletoz-50. Phase solubility study showed dramatic improvement in the solubility of drug by formation of complexes, which was further increased by pH adjustment. The dissolution rate of cilostazol was markedly augmented by the complexation with DM-β-CD. DSC and XRD curves showed sharp endothermic peaks indicating the reduction in the microcrystallinity of cilostazol. Selected inclusion complex was also stable at ambient temperature up to 6 months. The in vivo study revealed that DM-β-CD increased the bioavailability of cilostazol with low variability in the absorption. Among all cilostazol–cyclodextrins complexes, cilostazol–DM-β-CD inclusion complex (1:3) prepared by coprecipitation method showed 1.53-fold and 4.11-fold increase in absorption along with 2.1-fold and 2.97-fold increase in dissolution rate in comparison with Pletoz-50 and pure cilostazol, respectively.     

Use of cyclodextrins as a cosmetic delivery system for fragrance materials: Linalool and benzyl acetate

The aim of this study was to increase the stability and water solubility of fragrance materials, to provide controlled release of these compounds, and to convert these substances from liquid to powder form by preparing their inclusion complexes with cyclodextrins (CDs). For this purpose, linalool and benzyl acetate were chosen as the fragrance materials. The use of beta-cyclodextrin (beta CD) and 2-hydroxypropyl-beta-cyclodextrin (2-HP beta CD) for increasing the solubility of these 2 fragrance materials was studied. Linalool and benzyl acetate gave a B-type diagram with beta CD, whereas they gave an A(L)-type diagram with 2-HP beta CD. Therefore, complexes of fragrance materials with 2-HP beta CD at 1:1 and 1:2 molar ratios (guest:host) were prepared. The formation of inclusion complexes was confirmed using proton nuclear magnetic resonance ((1)H-NMR) spectroscopy and circular dichroism spectroscopy. The results of the solubility studies showed that preparing the inclusion complex with 2-HP beta CD at a 1:1 molar ratio increased the solubility of linalool 5.9-fold and that of benzyl acetate 4.2-fold, whereas the complexes at a 1:2 molar ratio increased the solubility 6.4- and 4.5-fold for linalool and benzyl acetate, respectively. The stability and in vitro release studies were performed on the gel formulations prepared using uncomplexed fragrance materials or inclusion complexes of fragrance materials at a 1:1 molar ratio. It was observed that the volatility of both fragrance materials was decreased by preparing the inclusion complexes with 2-HP beta CD. Also, in vitro release data indicated that controlled release of fragrances could be possible if inclusion complexes were prepared.     

The Role of <Emphasis Type="SmallCaps">l</Emphasis>-arginine in Inclusion Complexes of Omeprazole with Cyclodextrins

In this study, we investigate how the effect of l-arginine (ARG) and cyclodextrins upon omeprazole (OME) stability and solubility. The effect of the presence of ARG on the apparent stability constants (K_1:1) of the inclusion complexes formed between OME and each cyclodextrin, β-cyclodextrin (βCD), and methyl-β-cyclodextrin (MβCD) is studied by phase solubility diagrams and nuclear magnetic resonance (NMR) spectroscopy. The interaction of OME with those cyclodextrins, in the presence of ARG, is characterized using NMR spectroscopy and molecular dynamics simulations. ARG significantly increases the drug solubility and complex stability, in comparison to inclusion complexes formed in its absence. The effect is more pronounced for the OME:βCD complex. ARG also contributes to a larger stability of OME when free in aqueous solution. The combination of ARG with cyclodextrins can represent an important tool to develop stable drug formulations.     

Interaction of sulfadiazine with cyclodextrins in aqueous solution and solid state

The main objective of this work was to increase the solubility of sulfadiazine by formation of inclusion complexes with β-cyclodextrin, and methyl-β-cyclodextrin. The apparent stability constants have been determined by phase solubility studies in water and buffer solutions of pH values of 2 and 8. The stoichiometry of all complexes was found to be 1:1 but different relative affinities were found for each cyclodextrin. It was possible to obtain a greater overall solubility by using a combined approach of pH adjustment and complexation with cyclodextrins. Guest-host interactions have been investigated using nuclear magnetic resonance. Complexes were prepared in solid state by different methods and were characterized using differential scanning calorimetry, thermogravimetric analysis, Fourier-transform infrared spectroscopy, X-ray diffractometry and scanning electron microscopy. The dissolution rate of the drug from the inclusion complex made by freeze-dried was much faster than this of the pure drug.     

Improvement of Aripiprazole Solubility by Complexation with (2-Hydroxy)propyl-β-cyclodextrin Using Spray Drying Technique

Due to the fact that the number of new poorly soluble active pharmaceutical ingredients is increasing, it is important to investigate the possibilities of improvement of their solubility in order to obtain a final pharmaceutical formulation with enhanced bioavailability. One of the strategies to increase drug solubility is the inclusion of the APIs in cyclodextrins. The aim of this study was to investigate the possibility of aripiprazole solubility improvement by inclusion in (2-hydroxy)propyl-β-cyclodextrin (HPBCD) and simultaneous manipulation of pH of the medium and addition of polyvinylpyrrolidone. Aripiprazole-HPBCD complexes were prepared by spray drying aqueous drug-HPBCD solutions, and their properties were compared with those prepared by solvent-drop co-grinding and physical mixing. The obtained powders were characterized by thermoanalytical methods (TGA and DSC), FTIR spectroscopy, their dissolution properties were assessed, while the binding of aripiprazole into the cavity of HPBCD was studied by molecular docking simulations. The solubilization capacity was found to be dependent on pH as well as the buffer solution's ionic composition. The presence of PVP in the formulation could affect the solubilization capacity significantly, but further experimentation is required before its effect is fully understood. On the basis of solubility studies, the drug/HPBCD stoichiometry was found to be 1:3. The spray-dried products were free of crystalline aripiprazole, they possessed higher solubility and dissolution rate, and were stable enough over a prolonged period of storage. Spray drying of cyclodextrin solutions proved to be an appropriate and efficient technique for the preparation of highly soluble inclusion compounds of aripiprazole and HPBCD.     

Effect of Cyclodextrin Complexation on the Aqueous Solubility and Solubility/Dose Ratio of Praziquantel

Praziquantel (PZQ), the primary drug of choice in the treatment of schistosomiasis, is a highly lipophilic drug that possesses high permeability and low aqueous solubility and is, therefore, classified as a Class II drug according to the Biopharmaceutics Classification System (BCS). In this work, β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) were used in order to determine whether increasing the aqueous solubility of a drug by complexation with CDs, a BCS-Class II compound like PZQ could behave as BCS-Class I (highly soluble/highly permeable) drug. Phase solubility and the kneading and lyophilization techniques were used for inclusion complex preparation; solubility was determined by UV spectroscopy. The ability of the water soluble polymer polyvinylpyrolidone (PVP) to increase the complexation and solubilization efficiency of β-CD and HP-β-CD for PZQ was examined. Results showed significant improvement of PZQ solubility in the presence of both cyclodextrins but no additional effect in the presence of PVP. The solubility/dose ratios values of PZQ-cyclodextrin complexes calculated considering the low (150 mg) and the high dose (600 mg) of PZQ, used in practice, indicate that PZQ complexation with CDs may result in drug dosage forms that would behave as a BCS-Class I depending on the administered dose.     

Solubility and Stability of ??-Cyclodextrin?CTerpineol Inclusion Complex as Affected by Water

In the present work, inclusion complexes of α-terpineol (Terp) and β-cyclodextrin (BCD) were prepared by the coprecipitation method. Phase solubility studies were performed and thermodynamic parameters involved in the complex formation were calculated. The solubility of Terp increased linearly as the concentration of BCD was increased, confirming the 1:1 stoichiometry of the complex. The stability constants decreased along with increasing temperature. The negative value of the enthalpy and of the Gibbs free energy demonstrated that the process is exothermic and spontaneous. Since complexation gives more ordered systems, the negative value obtained for the entropy change evidenced the encapsulation of Terp. Terp was completely encapsulated in BCD at the preparation conditions and studied molar ratios, as confirmed in the freeze-dried samples by differential scanning calorimeter. The presence of Terp greatly modified the BCD water sorption curves, and the amount of adsorbed water was lower for the complexes. The limited water solubility of Terp could be overcome by the formation of BCD inclusion complexes, and the complexes were stable at different storage conditions (relative humidities 11–97% and 25 °C). The obtained phase solubility data are useful for food or pharmaceutical products formulation involving cyclodextrins and stability predictions.     

SN-38-Cyclodextrin Complexation and Its Influence on the Solubility,Stability, and In Vitro Anticancer Activity Against Ovarian Cancer

SN-38, an active metabolite of irinotecan, is up to 1,000-fold more potent than irinotecan. But the clinical use of SN-38 is limited by its extreme hydrophobicity and instability at physiological pH. To enhance solubility and stability, SN-38 was complexed with different cyclodextrins (CDs), namely, sodium sulfobutylether β-cyclodextrin (SBEβCD), hydroxypropyl β-cyclodextrin, randomly methylated β-cyclodextrin, and methyl β-cyclodextrin, and their influence on SN-38 solubility, stability, and in vitro cytotoxicity was studied against ovarian cancer cell lines (A2780 and 2008). Phase solubility studies were conducted to understand the pattern of SN-38 solubilization. SN-38-βCD complexes were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction analysis (XRPD), and Fourier transform infrared (FTIR). Stability of SN-38-SBEβCD complex in pH 7.4 phosphate-buffered saline was evaluated and compared against free SN-38. Phase solubility studies revealed that SN-38 solubility increased linearly as a function of CD concentration and the linearity was characteristic of an A_P-type system. Aqueous solubility of SN-38 was enhanced by about 30–1,400 times by CD complexation. DSC, XRPD, and FTIR studies confirmed the formation of inclusion complexes, and stability studies revealed that cyclodextrin complexation significantly increased the hydrolytic stability of SN-38 at physiological pH 7.4. Cytotoxicity of SN-38-SBEβCD complex was significantly higher than SN-38 and irinotecan in both A2780 and 2008 cell lines. Results suggest that SBEβCD encapsulated SN-38 deep into the cavity forming stable inclusion complex and as a result increased the solubility, stability, and cytotoxicity of SN-38. It may be concluded that preparation of inclusion complexes with SBEβCD is a suitable approach to overcome the solubility and stability problems of SN-38 for future clinical applications.     

Solubility of cyclomaltooligosaccharides (cyclodextrins) in H2O and D2O: a comparative study

Cyclomaltooligosaccharides (cyclodextrins, CDs) are cyclic oligomers having six, seven, or eight units of alpha-D-glucose, named as cyclomaltohexaose (alpha-CD), cyclomaltoheptaose (beta-CD) and cyclomaltooctaose (gamma-CD), respectively. The molecule of CD has a cavity in which the interior is hydrophobic relative to its outer surface. The solubility of cyclodextrins in water is unusual, as an irregular trend is observed in the series of the cyclic oligomers of glucose. beta-CD is at least nine times less soluble than the others CDs. This intriguing behavior has been investigated, and some interesting explanations in terms of the effect caused by CD on the water lattice structure have been proposed. In this work a comparative study on the solubility of alpha, beta, and gamma-cyclodextrins was carried out in H2O and D2O and reveals a much lower solubility of the three CDs in D2O. The solid-phase structure of the CDs in equilibrium with the solution is quite similar with both solvents. The results are discussed in terms of the CD molecular structure and the differences in the hydrogen bonds formed between H2O and D2O.     

Enhanced Solubilisation of Six PAHs by Three Synthetic Cyclodextrins for Remediation Applications: Molecular Modelling of the Inclusion Complexes

Solubilisation of six polycyclic aromatic hydrocarbons (PAHs) (acenaphthene, anthracene, fluoranthene, fluorene, phenanthrene and pyrene) by three synthetic cyclodextrins (CDs) (2-hydroxypropyl-β-CD, hydroxypropyl-γ-CD and ramdomly methylated-β-CD) was investigated in order to select the CD which presents the greatest increase in solubility and better complexation parameters for its use in contaminated scenarios. The presence of the three cyclodextrins greatly enhanced the apparent water solubility of all the PAHs through the formation of inclusion complexes of 1∶1 stoichiometry. Anthracene, fluoranthene, fluorene and phenanthrene clearly presented a higher solubility when β-CD derivatives were used, and especially the complexes with the ramdomly methylated-β-CD were favoured. On the contrary, pyrene presented its best solubility results when using 2-hydroxypropyl-γ-CD, but for acenaphthene the use of any of the three CDs gave the same results. Complementary to experimental phase-solubility studies, a more in-depth estimation of the inclusion process for the different complexes was carried out using molecular modelling in order to find a correlation between the degree of solubilisation and the fit of PAH molecules within the cavity of the different CDs and to know the predominant driving forces of the complexation.     

Formation of inclusion complexes between cyclodextrins and aromatic compounds under pressurized carbon dioxide

The effects of moisture content, pressure and temperature on the formation of inclusion complexes with cyclodextrins under pressurized carbon dioxide (CO₂) were studied to determine the optimal conditions for the recovery of aromatic compounds after extraction with supercritical or liquid CO₂. The presence of water in the cyclodextrin was essential for the formation of inclusion complex. However, an excess of water lowered the amount of inclusion complex due to inhibition of contact with CO₂. As the pressure increased under a constant temperature, the amount of inclusion complex increased until CO₂ became liquid, where the formation of inclusion complex started to decline. The amount of inclusion complex for modified cyclodextrins was very little, because the cyclodextrins became paste- or candy-like by the addition of a small amount of water.     

Aggregation of cyclodextrins as an important factor to determine their complexation behavior

Here, we report a study on the complexation behavior of carotenoids with cyclodextrins (CDs) using solubility experiments and molecular-modelling methods. Carotenoids are an important group of naturally occurring dyes found in vegetables and fruits. Their antioxidant property has initiated investigations on their possible use as drugs. However, carotenoids are lipophilic molecules with very little inherent aqueous solubility. Cyclodextrin complexation has been widely used in order to increase the potential applications of hydrophobic compounds. Thus, the aim of our investigation was to design carotenoids with enhanced water solubility by cyclodextrin complexation. Molecular modelling of carotenoid-cyclodextrin complexes with a 1 : 1 stoichiometry successfully explained the experimentally observed capability of beta-cyclodextrins (beta-CDs) to form complexes with carotenoids as opposed to alpha-cyclodextrins (alpha-CDs) and gamma-cyclodextrins (gamma-CDs). Furthermore, molecular-dynamics calculations revealed that the aggregation properties of CD derivatives significantly influence their complexation behavior. Our docking calculations showed that RAMEB (random methylated beta-CD) is the beta-CD derivative that possesses the lowest tendency to aggregate. Solubility experiments yielded the same results, namely, RAMEB complexes possess the best water solubility. Our results showed that complexation of a ligand not buried inside of the CD cavity is dependent on two factors: i) the geometry of the inclusion part of the complex; ii) the self-aggregation property of the CD itself. The lower affinity the CDs possess for self-aggregation, the more likely are they involved in interactions with carotenoids. These results suggest that self-aggregation of CDs should be considered as an important parameter determining complexation in general.     

Synthesis and characterization of water-soluble hydroxybutenyl cyclomaltooligosaccharides (cyclodextrins)

We have examined the synthesis of hydroxybutenyl cyclomaltooligosaccharides (cyclodextrins) and the ability of these cyclodextrin ethers to form guest-host complexes with guest molecules. The hydroxybutenyl cyclodextrin ethers were prepared by a base-catalyzed reaction of 3,4-epoxy-1-butene with the parent cyclodextrins in an aqueous medium. Reaction byproducts were removed by nanofiltration before the hydroxybutenyl cyclodextrins were isolated by co-evaporation of water-EtOH. Hydroxybutenyl cyclodextrins containing no unsubstituted parent cyclodextrin typically have a degree of substitution of 2-4 and a molar substitution of 4-7. These hydroxybutenyl cyclodextrins are randomly substituted, amorphous solids. The hydroxybutenyl cyclodextrin ethers were found to be highly water soluble. Complexes of HBen-beta-CD with glibenclamide and ibuprofen were prepared and isolated. In both cases, the guest content of the complexes was large, and a significant increase in the solubility of the free drug was observed. Dissolution of the complexes in pH 1.4 water was very rapid, and significant increases in the solubility of the free drugs were observed. Significantly, after reaching equilibrium concentration, a decrease in the drug concentration over time was not observed.     

Physico-Chemical Characterization and In Vitro Dissolution Assessment of Clonazepam—Cyclodextrins Inclusion Compounds

The objectives of this research were to prepare and characterize inclusion complexes of clonazepam with β-cyclodextrin and hydroxypropyl-β-cyclodextrin and to study the effect of complexation on the dissolution rate of clonazepam, a water-insoluble lipid-lowering drug. The phase-solubility profiles with both cyclodextrins were classified as A_P-type, indicating the formation of 2:1 stoichiometric inclusion complexes. Gibbs free energy ( DG_tr^o ) \left( {\Delta {G_{tr}}^o} \right) values were all negative, indicating the spontaneous nature of clonazepam solubilization, and they decreased with increase in the cyclodextrins concentration, demonstrating that the reaction conditions became more favorable as the concentration of cyclodextrins increased. Complexes of clonazepam were prepared with cyclodextrins by various methods such as kneading, coevaporation, and physical mixing. The complexes were characterized by Fourier transform infrared spectroscopy and differential scanning calorimetry studies. These studies indicated that complex prepared kneading and coevaporation methods showed successful inclusion of the clonazepam molecule into the cyclodextrins cavity. The complexation resulted in a marked improvement in the solubility and wettability of clonazepam. Among all the samples, complex prepared with hydroxypropyl-β-cyclodextrin by kneading method showed highest improvement in in vitro dissolution rate of clonazepam. Mean dissolution time of clonazepam decreased significantly after preparation of complexes and physical mixture of clonazepam with cyclodextrins. Similarity factor indicated significant difference between the release profiles of clonazepam from complexes and physical mixture and from plain clonazepam. Tablets containing complexes prepared with cyclodextrins showed significant improvement in the release profile of clonazepam as compared to tablet containing clonazepam without cyclodextrins.     

Physicochemical characterization,in vitro dissolution behavior,and pharmacodynamic studies of rofecoxib-cyclodextrin inclusion compounds. Preparation and properties of rofecoxib hydroxypropyl β-cyclodextrin inclusion complex: A technical note

Conclusion  An inclusion complex of rofecoxib and HPβ-CD was prepared successfully by the spray-drying method in a molar ratio of 1∶1. The inclusion complex was found to have improved in vitro drug release compared with the pure drug. The solubility profile of complexes of rofecoxib prepared using HPβ-CD as the complexing agent in a molar ratio of 1∶1 by the spray-drying method in pH 1.2 and pH 7.4 indicated that the acid solubility of rofecoxib was enhanced considerably by formation of an inclusion complex with HPβ-CD. The above results also clearly demonstrated a significant decrease in the gastric ulcerogenic activity of rofecoxib through complexation with cyclodextrins. Even though the physical mixture of rofecoxib with cyclodextrins reduced ulcer formation, it was the spray-dried complex formation approach that minimized gastric ulceration. These findings are extremely important from a commercial point of view as the prepared complex removes a major drawback for rofecoxib in therapy. Published: September 20, 2005     

Physicochemical Characterization of Efavirenz–Cyclodextrin Inclusion Complexes

Efavirenz (EFV) is an oral antihuman immunodeficiency virus type 1 drug with extremely poor aqueous solubility. Thus, its gastrointestinal absorption is limited by the dissolution rate of the drug. The objective of this study was to characterize the inclusion complexes of EFV with β-cyclodextrin (β-CD), hydroxypropyl β-CD (HPβCD), and randomly methylated β-CD (RMβCD) to improve the solubility and dissolution of EFV. The inclusion complexation of EFV with cyclodextrins in the liquid state was characterized by phase solubility studies. The solid-state characterization of various EFV and CD systems was performed by X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy analyses. Dissolution studies were carried out in distilled water using US Pharmacopeia dissolution rate testing equipment. Phase solubility studies provided an A_L-type solubility diagram for β-CD and A_P-type solubility diagram for HPβCD and RMβCD. The phase solubility data enabled calculating stability constants (K _s) for EFV-βCD, EFV-HPβCD, and EFV-RMβCD systems which were 288, 469, and 1,073 M⁻¹, respectively. The physical and kneaded mixtures of EFV with CDs generally provided higher dissolution of EFV as expected. The dissolution of EFV was substantially higher with HPβCD and RMβCD inclusion complexes prepared by the freeze drying method. Thus, complexation with HPβCD and RMβCD could possibly improve the dissolution rate-limited absorption of EFV.     

Study of isopropyl myristate microemulsion systems containing cyclodextrins to improve the solubility of 2 model hydrophobic drugs

The objectives of this project were to evaluate the effect of alkanols and cyclodextrins on the phase behavior of an isopropyl myristate microemulsion system and to examine the solubility of model drugs. Triangular phase diagrams were developed for the microemulsion systems using the water titration method, and the solubility values of progesterone and indomethacin were determined using a conventional shake-flask method. The water assimilation capacities were determined to evaluate the effective microemulsion formation in different systems. The alkanols showed higher microemulsion formation rates at higher concentrations. A correlation between the carbon numbers of the alkanol and water assimilation capacity in the microemulsions studied was observed; isobutanol and isopentanol produced the best results. The addition of cyclodextrins showed no effect or had a negative effect on the microemulsion formation based on the type of cyclodextrin used. Isopropyl myristate-based microemulsion systems alone could increase the solubility values of progesterone and indomethacin up to 3300-fold and 500-fold, respectively, compared to those in water. However, the addition of cyclodextrins to the microemulsion systems did not show a synergistic effect in increasing the solubility values of the model drugs. In conclusion, microemulsion systems improve the solubility of progesterone and indomethacin. But the two types of cyclodextrins studied affected isopropyl myristatebased microemulsion systems negatively and did not improve the solubilization of 2 model drugs.     

Diversity in the supramolecular interactions of 5,6-dichloro-2-(trifluoromethyl)-1H-benzimidazole with modified cyclodextrins: Implications for physicochemical properties and antiparasitic activity

The molecular interactions of 5,6-dichloro-2-(trifluoromethyl)-1H-benzimidazole (G2), an antiprotozoa with poor aqueous solubility, with 2-hydroxypropyl-α-cyclodextrin (HPαCD), methyl-β-cyclodextrin (MβCD) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) were examined. The aqueous solubility enhancement by cyclodextrins (CDs) was evidenced in phase-solubility diagrams, and the stoichiometry of G2/CD systems was determined by Job's plots. Two-dimensional NMR spectroscopic data revealed that a different mode of interaction took place between G2 and CDs in solution. With HPαCD, a non-inclusion complex was generated. In the case of MβCD, a typical host-guest system was obtained and with HPβCD a partial inclusion complex through the narrow side of the macrocycle was formed. ESI-mass spectrometric data confirmed the stoichiometry and mode of interaction of these systems in solution. Solid-state characterization (scanning calorimetry and powder X-ray diffraction) supported the inclusion complex formation. The leishmanicidal activity, trypanocidal activity and non-toxic profile of G2/MβCD showed the advantages of using this inclusion complex to promote the biological assays extension of G2.     

Inclusion complexes of paclitaxel and oligo(ethylenediamino) bridged bis(beta-cyclodextrin)s: solubilization and antitumor activity

The inclusion complexation behavior of paclitaxel with a series of oligo(ethylenediamino) bridged bis(beta-cyclodextrin)s possessing bridge chains in different length (1-4) has been investigated in order to improve the water solubility of paclitaxel. It is found that only the long-tethered bis(beta-cyclodextrin)s 1 and 2 can form the inclusion complexes with paclitaxel, which are characterized by NMR, SEM, XRD, FT-IR, TG-DTA, DSC, and microcalorimetry technology. The results obtained show that bis(beta-cyclodextrin)s 1 and 2 are able to solubilize paclitaxel to high levels up to 2 and 0.9 mg/mL, respectively. The high complex stability of bis(beta-cyclodextrin) 1 and paclitaxel is discussed from thermodynamic viewpoint. Furthermore, the cytotoxicity of these complexes assessed using a human erythroleukemia K562 cell line indicates that the IC(50) value of 1/paclitaxel complex is 6.0 x 10(-10) mol/dm(3) (calculated as paclitaxel molar concentration), which means that the antitumor activity of 1/paclitaxel complex is better than that of parent paclitaxel (IC(50) value 9.8 x 10(-10) mol/dm(3)). This high antitumor activity, along with the satisfactory water solubility and high thermal stability of the 1/paclitaxel complex, will be potentially useful for its clinical application as a highly effective antitumor drug.