Inclusion complexes of Sulconazole with β-cyclodextrin and hydroxypropyl β-cyclodextrin: characterization in aqueous solution and in solid state

Complexation between sulconazole (SULC), an imidazole derivative with in vitro antifungal and antiyeast activity, and β-cyclodextrins (β-CD and HP-β-CD) was studied in solution and in solid states. Complexation in solution was evaluated using solubility studies and nuclear magnetic resonance spectroscopy (¹H-NMR). In the solid state, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM) and RX diffraction studies were used. Solubility studies suggested the existence of inclusion complex between SULC and β-CD or HP-β-CD. ¹H-NMR spectroscopy studies showed that the complex formed occurs by complexation of imidazole ring into inner cavity. DSC studies showed the existence of a complex of SULC with β-CD. The TGA and RX studies confirmed the DSC results of the complex. Solubility of SULC in solid complexes was studied by the dissolution method and it was found to be much more soluble than the uncomplexed drug.     

Complex formation between α-cyclodextrin and amines in water and DMF solvents

Complexation between -cyclodextrin (-CD) and aliphatic amines in water and DMF solvents was studied by calorimetry. Amines form complexes with -CD in both solvents but the nature of the complexes is quite different. In DMF the amines donate a hydrogen from the amine N–H group to the cyclodextrin forming a normal hydrogen bonded complex. In DMF solutions with large amine concentrations, complexes other than 11 are observed. In contrast, in aqueous environment the amines form inclusion complexes in which the amine alkyl group penetrates the -CD cavity and is stabilized by van der Waals interactions. The equilibrium constants for the complexes formed in water solvent increase with increasing alkyl chain length due to an entropy effect.     

Inclusion of Paracetamol into β-cyclodextrin nanocavities in solution and in the solid state

We report on steady-state UV-visible absorption and emission characteristics of Paracetamol, drug used as antipyretic agent, in water and within cyclodextrins (CDs): β-CD, 2-hydroxypropyl-β-CD (HP-β-CD) and 2,6-dimethyl-β-CD (Me-β-CD). The results reveal that Paracetamol forms a 1:1 inclusion complex with CD. Upon encapsulation, the emission intensity enhances, indicating a confinement effect of the nanocages on the photophysical behavior of the drug. Due to its methyl groups, the Me-β-CD shows the largest effect for the drug. The observed binding constant showing the following trend: Me-β-CD>HP-β-CD>β-CD. The less complexing effectiveness of HP-β-CD is due to the steric effect of the hydroxypropyl-substituents, which can hamper the inclusion of the guest molecules. The solid state inclusion complex was prepared by co-precipitation method and its characterization was investigated by Fourier transform infrared spectroscopy, 1H NMR and X-ray diffractometry. These approaches indicated that Paracetamol was able to form an inclusion complex with CDs, and the inclusion compounds exhibited different spectroscopic features and properties from Paracetamol.     

Solubilization of cholesterol in aqueous solution by two β-cyclodextrin dimers and a negatively charged β-cyclodextrin derivative

Two βCD dimers (linked by succinic acid, 2, or ethylenediaminetetraacetic acid, EDTA, 3, bridges) and a negatively charged monomer derivative of βCD, 1, have been synthesized and their ability to solubilize cholesterol in aqueous solution was studied. The three compounds exhibit a great capacity in solubilizing cholesterol as, for instance, concentrations up to 6 mM of cholesterol were measured in the presence of 25 mM of 3. The phase-solubility diagrams of the two dimers exhibit A _L type profiles while the monomer 1 follows an A _P isotherm. The cholesterol/dimer complexes have 1:1 stoicheiometries while monomer 1 forms two complexes with molar ratios of 1:1 and 1:2 (cholesterol/1). The equilibrium constants are K _1:1 = (5.9 ± 0.3) × 10⁴ M^?1 and K _1:1 = (8.8 ± 0.2) × 10⁴ M^?1 for 2 and 3, respectively, and K _1:1 = 73 ± 19 M^?1 and K _1:2 = 204 ± 65 M^?1 for 1. The comparison of K _1:1(3) with the product K _1:1 × K _1:2 (1) reveals that a chelate effect in binding the cholesterol by 3 exists. The structure of the cholesterol/3 complex was studied by ROESY experiments and by molecular dynamics simulations.     

Binding forces in complexation ofp-alkylphenols withβ-cyclodextrin and methylatedβ-cyclodextrins

Fluorescence spectroscopy has been used to determine the binding constants (K) for inclusion complexes of six kinds ofp-Akyphenols with-cyclodextrin (-CDx), heptakis(2,6-di-O-methyl)--CDx (DMe--CDxg), and heptakis(2,3,6-tri-O-methyl)--CDx (TMe--CDx). The stability of the inclusion complex of each cyclodextrin increases with increasing alkyl chain length of thep-alkylphenol. TheK values decrease in the order of DMe--CDx,-CDx, and TMe--CDx for each guest. In complexation of 3-(p-hydroxyphenyl)-1-propanol (3) with-CDx as well as with DMe--CDx, negative enthalpy (H) and positive entropy changes (S) have been obtained, suggesting both van der Waals and hydrophobic interactions as binding forces. The inclusion of 3 by TMe--CDx, however, is an enthalpically favorable but entropically unfavorable process. The van der Waals interactions may be the main binding forces for complexing3 with TMe--CDx.     

Spectrofluorimetric study and determination of desipramine in the presence of β-cyclodextrin

The native fluorescence intensity of desipramine was enhanced in the presence of β-cyclodextrin in aqueous solution. The inclusion complex formation between these compounds was studied by spectrofluorimetry. A stable complex with a 2: 1 stoichiometry of β-cyclodextrin to desipramine was formed (logβ₂ = 9.29 ± 0.01). In the presence of an optimum concentration of β-cyclodextrin, the fluorescence intensity was linearly proportional to desipramine concentration in the range of 0.1–100 μg/mL (7.2 × 10^?7?1.0 × 10^?4 M) with a limit of detection of 7 × 10^?8 M. The method was successfully applied to the detection of desipramine in its tablets.     

Preparation and evaluation of inclusion complexes of diacerein with β-cyclodextrin and hydroxypropyl β-cyclodextrin

The objective of this research was to improve the aqueous solubility, dissolution rate and, consequently, bioavailability of diacerein, along with avoiding its side effect of diarrhea, by complexation with β-cyclodextrin (β-CD) and HP-β-cyclodextrin (HP-β-CD). Phase solubility curve was classified as an A_N type for both the CDs, which indicated formation of complex of diacerein with β-CD and HP-β-CD in 1:1 stoichiometry and demonstrating that both CDs are proportionally less effective at higher concentrations. The complexes were prepared by kneading method and were evaluated to study the effect of complexation on aqueous solubility and rate of dissolution in phosphate buffer (pH 6.8). Based on the dissolution profile HP-β-CD was selected for preparing fast disintegrating tablet of diacerein which was compared with marketed formulation (MF-J). The HP-β-CD complex was probed for Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction studies which evidenced stable complex formation and increase in amorphousness of diacerein in complex. In brief, the characterization studies confirmed the inclusion of diacerein within the non-polar cavity of HP-β-CD. HP-β-CD complex showed improved in vitro drug release profile compared to pure drug and similar to that of marketed formulation respectively.     

Encapsulation of quercetin in β-cyclodextrin and (2-hydroxypropyl)-β-cyclodextrin cavity: In-vitro cytotoxic evaluation

The formation of host-guest inclusion complex of Quercetin (QRC) with β-Cyclodextrin (β-CD) and (2-Hydroxypropyl)-β-Cyclodextrin (HP-β-CD) is prepared by various methods such as physical method (PM), kneading method (KM) and co-precipitation method (CP). The solid inclusion complex is characterized by UV, Fluorescence, FT-IR, SEM, powder XRD and TG/DTA analysis. The cytotoxic activity of the solid complex is performed against breast cancer cell line and it is noticed that there is better activity than the QRC alone. Hence, the solid complex showed an improvement in the anticancer activity against MDA MB 231 cell line.     

Inclusion complexes of sulfanilamide with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin

Sulfanilamide belongs to the group of drugs that have a bacteriostatic effect on different pathogenic microorganisms. This activity originates from the competitive antagonism with p-aminobenzoic acid, which is an integral part of folic acid. The safe use of sulfanilamide is limited due to poor solubility in the aqueous medium. Therefore, the aim of this paper is the synthesis of sulfanilamide, as well as preparing and structural characterization of its inclusion complexes with cyclodextrins. The crude sulfanilamide was obtained in the synthesis between acetanilide and chlorosulfonic acid according to the standard procedure. The synthesized sulfanilamide was recrystallized from water in order to obtain the satisfactory purity of the substance. Sufanilamide was complexed with β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin by the co-precipitation method. A molecular encapsulation of sulfanilamide was confirmed by using FTIR, ¹H-NMR, XRD and DSC methods. Phase-solubility techniques were used to assess the formation of the inclusion complex between sulfanilamide and cyclodextrins. The photostability of sulfanilamide and its inclusion complexes was estimated by UVB irradiation in a photochemical reactor by applying the UV–Vis method. Based on the UV–Vis analysis, sulfanilamide:2-hydroxypropyl-β-cyclodextrin complex was presented as more photostable than sulfanilamide:β-cyclodextrin complex and sulfanilamide. The obtained results enable the potential use of these inclusion complexes for the preparation of oral formulations due to the enhanced solubility of sulfanilamide.     

Determination of carbaryl and carbofuran in fruits and tap water by β-cyclodextrin enhanced fluorimetric method

The effect of β-cyclodextrin (CD) and hydroxypropyl-β-cyclodextrin (HPCD) in water solutions on the UV-Vis and fluorescence spectra of carbaryl (1-naphthyl-N-methylcarbamate, CY) and carbofuran (2,2-dimethyl,2-3-dihydro-7-benzofuranyl-N-methylcarbamate, CF) was investigated. Host-guest interactions were observed by UV-Vis and spectrofluorimetry and the association constants for the 1:1 complexes (K_A, mol⁻¹ dm³) with CD and HPCD were determined. The values obtained were 190±10 and 123±7 mol⁻¹ dm³ for CF and 350±50 and 644±53 mol⁻¹ dm³ for CY, respectively. The values of the fluorescence quantum yield ratios (φ_complexed/φ_free) were 1.24±0.01 with CD and 1.310±0.007 with HPCD for CY, but much higher for CF being 7.0±0.1 with CD and 9.3±0.4 with HPCD. The limits of detection (LOD) for the fluorimetric determination under the better conditions were 14.5 ng cm⁻³ for the complex CF:CD and 1.94 ng cm⁻³ for the complex CY:CD in water, with notable improvement specially in the case of CF. We observed higher analytical sensitivity with the cyclodextrins (CDs) in presence of alcohols but not better LOD. The method is rapid, simple, direct and sensitive and the recovery of CY and CF was found to be between 100 and 112% in fruits and 97 and 109% in tap water. The allowed level of carbamates in banana can be detected by the proposed method.     

Cyclohexadecanone derivative/γ-cyclodextrin complexes MD simulations and AMSOL calculations in vacuo and in aquo compared with experimental findings

The complex formations of cis- and trans-cyclohexadecenone (cis-CHDC and trans-CHDC) and cyclohexadecanone (CHDH) with γ-cyclodextrin (γ-CD) in the presence of water are investigated. In the experiment [cis-CHDC//γ-CD] complexes are found to be slightly preferred over [trans-CHDC//γ-CD] complexes, with an energy difference of less than 1 kcal/mol. Molecular dynamics (MD) simulations in vacuo showed that energetically favourable complexes are formed, whereby (contrary to experiment) trans-CHDC has the best complexation energy, followed by cis-CHDC, (their calculated energy difference being less than 3 kcal/mol) and then cyclohexadecanone (CHDH). MD simulations in aqueous solution reveal positive complexation energies for all three compounds of about 12 to 25 kcal/mol, i.e., these practically do not exist in aquo, which is in agreement with the experimental observation that about 99% precipitate is formed. AMSOL calculations of the hydration energies support the low solubility of all three CHDC derivatives and the high solubility of γ-CD. Therefore, the simulations in aquo showed that hydration can play such an important role, that although complexation is possible in vacuo, the complexes are not formed in water.     

DODC aggregation inβ-cyclodextrin followed by temperature-dependent visible absorption and CD spectroscopy and singular value decomposition

The concentration and temperature dependent dimerization of 1,1-diethyloxadicarbocyanine iodide (DODC) in aqueous solutions of -cyclodextrin (-CyD) is studied by UV/vis and circular dichroism (CD) spectroscopy. The spectroscopic data are analyzed by singular value decomposition and yield equilibrium constants in agreement with known values. Thermodynamic parameters are obtained and discussed. The almost constant dissymmetry factor of the induced CD over the whole experimental range is further evidence of a free monomer and complexed dimer of DODC.     

The interaction of biliar acids with 2-hydroxypropyl-β-cyclodextrin in solution and in the solid state

The interaction of two biliar acids (chenodeoxycholic acid and cholic acid) with 2-hydroxypropyl--cyclodextrin (HPCD) in solution and in the solid state was studied using different techniques. The formation of an inclusion complex with a 1:1 stoichiometry was suggested by the phase solubility studies. Both differential scanning calorimetry and X-ray diffractometry exhibited the amorphous state of the complex. The inclusion of both biliar acids into the HPCD cavity was confirmed by the¹³C-NMR studies. Cholic acid showed a weaker affinity with respect to chenodeoxycholic acid probably owing to the presence of a hydroxyl group onC(12) (12) close to the complexation site.     

Study of host–guest interaction between ß-cyclodextrin and alkyltrimethylammonium bromides in water

Cyclodextrins were found to play important roles in self-assembly systems of surfactants. The interactions between host molecule ß-cyclodextrin (CD) and model cationic surfactants, alkyltrimethylammonium bromides with different alkyl chain length: dodecyl-(C₁₂TAB), tetradecyl-(C₁₄TAB) and hexadecyl-(C₁₆TAB) are studied by means of conductivity measurements at 313.2 K. The data obtained indicate that inclusion complexes (CD:S⁺) had formed, and apparent critical micelle concentration (CMC*) is equivalent to the combined concentrations of surfactant monomers complexed with the CD and that of a free dissolved monomer in equilibrium with the micellized surfactant without CD. Inclusion complexes were characterized by an equilibrium binding constant K ₁₁, which value increases as the length of alkyl chains, and consequently the hydrophobicity, increases. From mathematical model the concentrations of the uncomplexed cyclodextrin, uncomplexed surfactant ion, and inclusion complex in the submicellar, as well as in the micellar range were calculated. The competition between the micellization and complexation processes leads to the existence of a significant concentration of free CD in equilibrium with the micellar aggregates. The percentage of uncomplexed cyclodextrin in equilibrium with the micelles is independent on cyclodextrin concentration for a particular ternary system and is 31, 37, and 34 % for C₁₂TAB/water/ß-CD, C₁₄TAB/water/ß-CD and C₁₆TAB/water/ß-CD, respectively. By using standard Gibbs free energy for micellization and surfactant complexation by CD, we can explain the observed behavior.     

Inclusion of parabens in β-cyclodextrin: A solution NMR and X-ray structural investigation

A parallel study was conducted of the inclusion of alkyl parabens (guests) in the host β-cyclodextrin (β-CD). ¹H NMR data indicated an insertion of the guest phenyl ring into the β-CD cavity. The stoichiometry of each complex was 1:1, as determined by a continuous variation method that utilises the chemical shifts of the host protons. These chemical shifts were additionally used to determine the association constant yielding K values of 1631, 938, 460 and 2022 M^? 1 at 298 K for the methyl-, ethyl-, propyl- and butyl paraben solution state complexes, respectively. NOE experiments conducted on the methyl paraben solution complex indicated that the phenolic group of the guest was located at the secondary rim of the cyclodextrin cavity. Solid state structure analyses of the methyl and propyl paraben β-CD complexes were performed. Both complexes crystallised at ambient temperature in the space group C2, Z = 4 with a host to guest ratio of 1:1. Additionally, a second crystal structure between methyl paraben and β-CD is reported. This complex crystallised at 7^oC in the space group P1, Z = 2 with a 1:1 host–guest stoichiometry.

¹H NMR and solid state structure analyses were conducted on the inclusion of alkyl parabens in the host β-cyclodextrin. Both indicated an insertion of the guest phenyl ring into the β-CD cavity.     

Inter-molecular physiochemical characterization for etodolac-hydroxypropyl-β-cyclodextrin polymeric systems in solid and liquid state

The purpose of this study was to explore the utility of hydroxypropyl-β-cyclodextrin (HP-β-CD) systems in forming inclusion complexes with the anti-rheumatic or anti-arthritic drug, etodolac (EDC), in order to overcome the limitation of its poor aqueous solubility. This inclusion system achieved high solubility for the hydrophobic molecule. The physical and chemical properties of each inclusion compound were investigated. Complexes of EDC with HP-β-CD were obtained using the kneading and co-evaporation techniques. Solid state characterization of the products was carried out using Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD) and Scanning electron microscopy (SEM). Studies in the solution state were performed using UV-Vis spectrophotometry and ¹H-NMR spectroscopy. Phase solubility profiles with HP-β-CD employed was found to be A_L type. Stability constants (K_c) from the phase solubility diagrams were calculated indicating the formation of 1:1 inclusion complex. Stability studies in the solid state and in liquid state were performed; the possible degradation by RP-HPLC was monitored. The dissolution studies revealed that EDC dissolution rate was improved by the formation of inclusion complexes.      

Crystallization and polymorphic transition behavior of chloramphenicol palmitate in 2-hydroxypropyl-β-cyclodextrin matrix

Chloramphenicol palmitate (CPP) was converted to an amorphous complex when spray-dried with 2-hydroxypropyl--cyclodextrin (HP--CyD), and no crystallization of CPP was observed for at least 2 months under the storage condition of 50°C and 50% relative humidity. The dissolution rate of CPP/HP--CyD complex in aqueous HCO-60 solution was much faster than CPP polymorphs (complex > metastable forms (B and subB) > stable form (A)), which was reflected in thein-vivo absorption behavior of CPP following oral administration in dogs.     

pH-dependent complex formation of amino acids with β-cyclodextrin and quaternary ammonium β-cyclodextrin

Stability constants for the complexes of anionic, neutral (zwitterionic) and protonated forms of l- and d-enantiomers of eight amino acids with β-cyclodextrin and the positively charged quaternary ammonium β-cyclodextrin (QA-β-CD, DS?=?3.6?±?0.3) have been determined by spectrophotometric and pH-potentiometric methods. The highest stability constants have been obtained for the aromatic amino acids phenylalanine, tyrosine and tryptophan. Except the dianion of tyrosine and QA-β-CD, values for the anions in the range of 80–120 have been found, the stability constants for the zwitterionic forms are much smaller and complex formation is negligible with the protonated species. In the case of the other amino acids the differences are less pronounced. The results are interpreted in terms of hydrogen bonding, steric effects and electrostatic interactions between the amino acid moiety and the rims of the cyclodextrins, in addition to the inclusion of the side chain, and are supported by ¹H and ¹³C NMR investigations on the systems containing l-phenylalanine and l-tyrosine. The differences between the complex formation constants of the l- and d-enantiomers do not exceed the limits of experimental error in most cases.     

Calorimetry to Evaluate Inclusion Mechanism in the Complexation Between 2-hydroxypropyl-β-cyclodextrin and Barbiturates in Aqueous Solution

Two different types (structures) of inclusion complexes with a 1:1 stoichiometry between barbiturates and 2-hydroxypropyl-β-cyclodextrin (HPCyD) were realized in aqueous solution using isothermal titration calorimetry and molecular dynamics simulation. The first type of complex with a higher association constant was entropy driven and the substituent R ₂ was inserted into the HPCyD cavity by hydrophobic interaction. The barbituric acid ring contributed to the second type of complex, which was characterized by large negative values of ΔH and small positive ΔS reflecting van der Waals interaction and/or hydrogen bonding formation between the hetero atoms in the barbituric acid ring and the secondary hydroxyl groups of HPCyD. This revised version was published online in July 2006 with corrections to the Cover Date.