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.     

Selective monoallylation of β-cyclodextrin

Reaction of β-cyclodextrin with allyl bromide in dimethyl sulfoxide affords 2-О-allyl-β-cyclodextrin, while in dimethylformamide 6-О-allyl-β-cyclodextrin is formed. Optimal conditions of the reaction were found allowing to obtain the target products in quantitative yield.     

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.     

Silylation of 2-hydroxypropyl-β-cyclodextrin

The effect of the reaction conditions or the nature of the silylating agents on the silylation of hydroxypropyl-β-cyclodextrin with tert-butyldimethylchloro- and diphenyl-methylchlorosilanes is investigated.     

Water-soluble polymeric derivatives of β-cyclodextrin

On the basis of hydrophilic copolymers of N-vinylamides??N-vinylpyrrolidone and N-methyl-N-vinylacetamide??that contain carboxylic or activated ester groups, new polymeric ??-cyclodextrin derivatives are synthesized via polymer-analogous transformations. Their solubility in water depends on the content of ??-cyclodextrin and the types of hydrophilic and reactive comonomers.     

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.     

Alkyl capped carbonates ofβ-cyclodextrin

The synthesis is described of alkyl capped carbonates of-cyclodextrin, obtained from diols activated with carbonyldiimidazole. The reaction preferentially gave monocapped derivatives which were characterized by HPLC, TLC, FT-IR and¹³C-NMR. These compounds are stable at pH <7, and methyl orange was found to form stronger inclusion compounds with capped-cyclodextrin than with the parent-cyclodextrin. Paramagnetic Gd(III) complexes were also studied, but they were found to be included into capped-cyclodextrin as well as into-cyclodextrin.Part of this work was presented at the 7th International Symposium on Cyclodextrins, 1994, Tokyo, April 25–28, Book of Abstract, page 54.     

Binding of vitamin A byβ-cyclodextrin and heptakis(2,6-O-dimethyl)-β-cyclodextrin

Inclusion complexation of all-trans-retinol, retinal and retinoic acid with -cyclodextrin (-CD) and heptakis(2,6-O-dimethyl)--cyclodextrin (DM--CD) were investigated by means of UV-vis spectroscopy. The association constants (K _a) obtained for vitamin A with DM--CD is greater than with -CD. On the other hand, for the same host compoundK _a values of retinol, retinal and retinoic acid are very close to each other.     

The terfenadine/β-cyclodextrin inclusion complex

Terfenatine (TFN) is a very hydrophobic antiallergic drug. It exists in three polymorphic and two solvated forms and is practically insoluble in water. These properties make a pharmaceutical formulation with acceptable biopharmaceutical characteristics difficult to prepare. Inclusion complexation with -cyclodextrin (CD) may eliminate such problems. The properties of the TFN/CD system have been studied in liquid, gaseous and solid phases by¹H and¹³C NMR spectroscopy, powder X-ray diffractometry, differential scanning calorimetry and fast atom bombardment mass spectrometry. The solubility phase diagram was also recorded. In solution and in the gaseous phase the 11 complex prevails, whereas a 12 TFN/CD complex has been isolated by precipitation from homogeneous solution.     

Noncovalent columnar structures based on β-cyclodextrin

A new method for the synthesis of associates of cyclodextrins (CDs) of the columnar type consisting of the precipitation of CDs from aqueous solutions into acetone at lowered temperatures is developed. It is shown that columnar structures exist in both a crystalline state and in aqueous solutions. Hydrodynamic radii and molecular masses of noncovalent columnar structures (NCSs) in aqueous solutions are determined by the dynamic and static light scattering methods. The degree of association of noncovalent columnar polymers is ～40. It is revealed the NCS associates based on β-CD are stable and their hydrodynamic radius R _h is equal to 100 ± 10 nm. The kinetics of interactions of initial β-CD and NCS with poly(propylene oxide) (PPO) is studied. The pattern of kinetic curves of R _h growth upon interaction between NCS and PPO indicates that the aggregation of the particles of polymer inclusion complex proceeds in the regime of reaction-limited cluster-cluster aggregation. Kinetic curves describing the interaction processes between β-cyclodextrin and PPO are characterized by the presence of induction period t ₀. At t > t ₀, R _h ∞ t ^0.56 which is typical for the diffusion-limited cluster-cluster aggregation. Schemes of the formation of polymer inclusion complexes between initial β-CD or NCS and poly(propylene oxide) are proposed. Comparison of kinetic data on the complexation of β-CD in solution in the form of associates of two types with PPO demonstrates that columnar forms of associates are reactive species acting as macroreceptors.     

Comparison between 2-hydroxypropyl-��-cyclodextrin and 2-hydroxypropyl-��-cyclodextrin for inclusion complex formation with danazol

Complexation in solution between danazol and two different cyclodextrins [2-hydroxypropyl-??-cyclodextrin (HP-??-CD) and 2-hydroxypropyl-??-cyclodextrin (HP-??-CD)] was studied using phase solubility analysis, and one- and two-dimensional ¹H-NMR. The increase of danazol solubility in the aqueous cyclodextrin solutions showed a linear relationship (A_L profile). The apparent stability constant, K _1:1, of each complex was calculated and found to be 51.7 × 10³ and 7.3 × 10³ M^?1 for danazol?CHP-??-CD and danazol?CHP-??-CD, respectively. ¹H-NMR spectroscopic analysis of varying ratios of danazol and the different cyclodextrins in a mixture of EtOD?CD₂O confirmed the 1:1 stoichiometry. Cross-peaks, from 2D ROESY ¹H-NMR spectra, between protons of danazol and H3?? and H5??of cyclodextrins, which stay inside the cyclodextrin cavity, proved the formation of an inclusion complex between danazol and the cyclodextrins. For HP-??-CD, the inclusion complex is formed by entrance of the isooxazole and the A rings of danazol in the cyclodextrin cavity. For HP-??-CD, two different inclusion structures may exist simultaneously in solution: one with the isooxazole and A ring in the cavity and the other with the C and D ring inside the cavity. DLS showed that self-aggregation of the CD??s was absent in the danazol HP-??-CD system up to a CD concentration of 10% and in the danazol HP-??-CD system up to a CD concentration of 5%.     

Inclusion complexes of alcohols with α-cyclodextrin

Calorimetric studies of the inclusion complexes of straight and branched alcohols and of diols with alpha-cyclodextrin (-CD) have been carried out in water solvent. The data suggest that straight and branched chain alcohols enter the cavity of -CD alkyl end first. The hydroxyl group hydrogen bonds to the outer oxygen ring of the cyclodextrin. For branched chain alcohols the longer alkyl part of the molecule penetrates the -CD cavity up to the hydroxyl group. Diols form two hydrogen bonds to the outer oxygen ring of the cyclodextrin with some penetration into its interior.     

Solubility characteristics ofβ-cyclodextrin inclusion complexes

Some inclusion complexes of-cyclodextrin (cyclomaltoheptaose) have been investigated, particularly with respect to their solubility. The mathematical characterization of the equilibrated host-guest system containing both solid and solution phases is discussed (first of all those, which contain 1:1 or 1:1 + 2:1 species) and demonstrated by different examples.     

Complexation of ebastine with β-cyclodextrin derivatives

Complexation of ebastine (EB) with hydroxypropyl and methyl-β-cyclodextrin (HP-β-CD and Me-β-CD) was studied in aqueous solutions and in the solid state. The formation of inclusion complexes in aqueous solutions was analysed by the solubility method. The assays were designed using low CD concentrations compared with the solubility of these derivatives in order to avoid non-inclusion phenomena and to obtain a linear increase in EB solubility as a function of CD concentration. The values of complexation efficiency for HP-β-CD and Me-β-CD were 1.9 × 10^?2 and 2.1 × 10^?2, respectively. It seems that the non polar character of the methyl moiety slightly favoured complexation. In relation to solid state complexation, 1:1 EB:CD systems were prepared by kneading, and by heating a drug-CD mixture at 90 ºC. They were analysed using X ray diffraction analysis by comparison with their respective physical mixtures. A complex with a characteristic diffraction pattern similar to that of the channel structure of β-CD was formed with Me-β-CD in 1:1 melted and 1:2 EB:CD kneaded systems. Complexation with HP-β-CD was not clearly evidenced because only a slight reduction of drug crystallinity was detected. Finally, the loading of EB in two β-CD polymers cross-linked with epichlorohydrin yielded 7.3 and 7.7 mg of EB/g polymer respectively.     

Covering of nanometric calcite with α-cyclodextrin

In the present experiments, the monodisperse calcium carbonate nanoparticles obtained in the reactor (three-phase reaction) with rotating discs have been covered with α-cyclodextrin. Both pure CaCO₃ nanoparticle and α-cyclodextrin-coated CaCO₃ powders were deeply analysed by the use of the scanning electron microscope, the dynamic light scattering and the thermogravimetric method. The experimental data have allowed for determination of effective diameter of the obtained particles (aggregates of ca. 30 nm single crystals) and their size distribution (almost monodisperse—ca. 390 nm) as well as for distinction between α-cyclodextrin molecules present on calcite surface or free α-cyclodextrin molecules if presented in the sample. It was found that the nanometric CaCO₃ obtained in the reactor with rotating discs can be covered with a maximum of 1.15% α-cyclodextrin monolayer. The maximal coverage of the CaCO₃ calcite particles with α-cyclodextrin can be done by 24-h shaking of 50 mg nanometric calcium carbonate with 25 mg of 36.79 mM α-cyclodextrin aqueous solution.

     

Enhancement of selectivity for producing γ-cyclodextrin

The production of cyclodextrins (CDs) by cyclodextrin-glycosyl-transferase (CGTase) from Bacillus firmus was studied, with respect to the effect of the source of starch upon CD yield and on the selectivity for producing γ-CD. Cyclodextrin production tests were run for 24 h at 50°C, pH 8.0, and 1 mg/L of CGTase, and substrates were maltodextrin or the starches of rice, potato, cassava, and corn hydrolyzed up to D. E. 10. Cornstarch was the best substrate for producing γ-CD. Later, glycyrrhizin (2.5% [w/v]), which forms a stable complex with γ-CD, was added to the cornstarch reaction medium and increased the yield of γ-CD to about four times that produced with only maltodextrin, but the total yield of CDs remained practically unchanged. Therefore, the results showed that the studied CGTase is capable of giving relatively high yield of γ-CD in the presence of glycyrrhizin as complexant and cornstarch as substrate.     

Dissolution enhancement of artemisinin with β-cyclodextrin

The main objective of this research is to improve the dissolution rate of artemisinin (ART) by fabrication with β-cyclodextrin (β-CD) as a hydrophilic carrier. Artemisinin nanoparticles and ART/β-CD complexes were successfully fabricated by means of evaporative precipitation of nanosuspension. Characterization of the samples was done by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and dissolution tester. Percent dissolution efficiency, mean dissolution time, relative dissolution and similarity factor were calculated for the statistical analysis of dissolution data. FT-IR showed some interaction between ART and β-CD, which can be due to the formation of some ART/β-CD complexes. XRD study indicated the presence of two polymorphs of ART, i.e. orthorhombic and triclinic form. Original ART particles and ART nanoparticles fabricated were orthorhombic whereas the free ART in the ART/β-CD complexes (not forming complex with β-CD) was of triclinic form. The crystallinity of ART reduced and more and more ART/β-CD complexes were formed with increasing concentration of β-CD as indicated by the DSC, XRD and FT-IR studies. Artemisinin nanoparticles and ART/β-CD complexes showed significantly faster dissolution than the pure drug due to smaller size (larger surface area), formation of the inclusion complex with β-CD, formation of the triclinic form for remaining free ART (not forming complex with β-CD), and amorphous state formation. Evaporative precipitation of nanosuspension was able to successfully fabricate artemisinin in the nanoparticles and complex forms with significantly faster dissolution rates than that of the original artemisinin. The two polymorphic forms of ART were also fabricated and studied.     

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.