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.     

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.     

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.     

Theoretical study of β- and γ-cyclodextrin complexes with ferrocene-containing azoles

The interaction between cyclodextrins (β- and γ-CD) and ferrocenyl azoles (i.e., pyrazole ferrocenes (I, III–V) and benzimidazole ferrocenes (VI, VII)), along with 1-ferrocenylethanol (II), each in the form of (R)- and (S)-enantiomers, in forming inclusion complexes is studied for the first time using detailed quantum chemical calculations. Compounds are calculated in terms of the density functional theory (DFT), using the Becke–Lee–Yang–Parr (B3LYP) approach in the 6-31G* basis sets. For the considered CD complexes with enantiomers of I–VII, structures in which a guest partially enters a host cavity from the side of the heterocyclic substituent (pyrazole or benzimidazole) are found to be energetically advantageous. It is shown that for successful resolution of (R,S)-enantiomers on chiral phases containing cyclodextrins, we must consider the interaction between outer hydroxyl groups on the CD cone’s surface, in addition to the correspondence of geometric dimensions. The calculated data correlate well with the data from the chromatographic separation of guest enantiomers on cyclodextrin sorbents.     

Spectral properties and structures of supramolecular complexes of naphthylpyridine with β-cyclodextrin

The electronic absorption and fluorescence spectra of 4-(2-naphthyl)pyridine (1) and N-methyl-4-(2-naphthyl)pyridinium perchlorate (2 ⁺·ClO₄ ^–) were studied in aqueous solutions in the absence and presence of -cyclodextrin (-CD). In aqueous solutions and organic solvents in the presence of water or H⁺ ions, compound 1 exhibits intense fluorescence with a maximum at 21 270 cm^–1, and its quantum yield in an aqueous solution is 0.9±0.09. The same fluorescence spectrum was detected for an aqueous solution of 2 ⁺·ClO₄ ^–. In an aqueous solution, compound 1 and -CD form stable fluorescing supramolecular 2:2 complexes, whose structure was calculated by the quantum-chemical MNDO/PM3 method. The formation of these complexes induces a hypsochromic shift of the fluorescence maximum of 1 by 5000 cm^–1. The stability constant of the complex is 2·10³ L mol^–1. A decrease in the pH results in the formation of a protonated form of 1(1·H⁺) and destruction of the complex, thus favoring the escape of the substrate from the -CD cavity. The quantum-chemical calculations showed that the insertion of 1 into the -CD cavity is thermodynamically more favorable than hydration; on the contrary, the formation of 1·H⁺ increases dramatically the hydration energy, which promotes the escape of 1·H⁺ from the -CD cavity; cation 2 ⁺ does not form a complex with -CD; in the thermodynamically most favorable 2:2 complex, the naphthalene fragments of two molecules 1 are parallel to each other in a broad section of the -CD dimer constructed according to the head-to-head type.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2420–2425, November, 2004.     

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.     

Modeling and conformation analysis of β-cyclodextrin complexes

Summary A series of -cyclodextrin complexes containing various guest molecules was studied using computer-aided molecular modeling and conformation analysis techniques. The geometry of each complex was studied using crystallographic data. The positions of the glycosidic O4 atoms indicate that the -cyclodextrin molecules are elliptically distorted. This distortion can be related to the van der Waals volume of the guest molecules. This correlation is different for aromatic and non-aromatic guest compounds. Rigid body docking experiments demonstrated that in crystal structures the guest molecule occupies a position in the cavity of nearly minimum interaction energy when there are no other molecules having interactions with the guest molecule. From the crystallographic data several rules could be deduced which seem to determine the conformation of -cyclodextrin molecules in complexes. A procedure was developed to construct -cyclodextrin molecules that are able to encompass guest molecules having a given van der Waals volume.     

Novel adamantane-bearing anilines and properties of their supramolecular complexes with β-cyclodextrin

Several novel anilines bearing 1-adamantyl substituents that are useful for drug modification were synthesised from the corresponding 1-adamantyl (nitrophenyl) ketones. The host–guest systems of these prepared ligands with β-cyclodextrin (β-CD) were studied using electrospray ionisation mass spectrometry, NMR spectroscopy, titration calorimetry and semi-empirical calculations. The complexes with 1:1 stoichiometry were found to predominantly exist as pseudorotaxane-like threaded structures with the adamantane cage sitting deep in the cavity of β-CD close to the wider rim. Such geometry was observed for all examined amines and is independent of their structure and/or presence of protic substituents.     

Inclusion complexes of β-cyclodextrin with pyrazinamide and piperazine: Crystallographic and theoretical studies

The inclusion complexes of β-cyclodextrin (β-CD) with pyrazinamide (PYA) and piperazine (PIZ) have been investigated both in the solid phase by single-crystal X-ray diffraction analysis and in the gas phase by semi-empirical PM3 calculation. In the crystalline phase, the disordered PYA and PIZ molecules are entirely embedded in the β-CD cavity. The PYA pyrazine-centre displaces upwards by 1.15(1) Å from the β-CD plane, whereas the PIZ centre shifts downwards by 0.76(1) Å from the β-CD plane. The inclusion scenario changed in the gas phase. Two inclusion geometries of the PYA molecule are comparatively stable with binding energies of ? 22.28 and ? 25.29 kJ mol^? 1: the pyrazine centre shifts upwards by 0.5 Å and downwards by 2.0 Å from the β-CD plane. The PIZ molecule positioning at 2.0 Å below the β-CD plane gives a more stable inclusion complex than does the PYA molecule by 22–25 kJ mol^? 1.

Structural distinction of the β-CD–PYA and β-CD–PIZ inclusion complexes in the solid phase (by X-ray crystallography) and gas phase (by PM3 calculation) is a paradigm of the CD conformational flexibility, the induced-fit mechanism and the dynamics of the inclusion process.     

Influence of different techniques on formulation and comparative characterization of inclusion complexes of ASA with β-cyclodextrin and inclusion complexes of ASA with PMDA cross-linked β-cyclodextrin nanosponges

Acetyl salicylic acid (ASA), a non-steroidal anti-inflammatory drug, was formulated into inclusion complexes by grinding and precipitation with β-cyclodextrin and freeze drying with pyromellitic dianhydride (PMDA) cross-linked β-cyclodextrin nanosponges. Particle size, zeta potential, encapsulation efficiency, accelerated stability study, in vitro and in vivo release studies were used as characterization parameters. TEM studies showed that the particle sizes of different inclusion complexes of ASA have diameters ranging from 40.12?±?8.79 to 59.53?±?15.55?nm. It also revealed the regular spherical shape and sizes of complexes that are even unaffected after drug encapsulation. Zeta potential was sufficiently high to obtain a stable colloidal formulation. The in vitro and in vivo studies indicated a slow and prolonged ASA release from PMDA cross-linked β-cyclodextrin nanosponges over a long period. XRPD, DSC and FTIR studies confirmed the interactions of ASA with nanosponges. XRPD showed the crystalline nature of ASA decreased after encapsulation. These results indicate that ASA nanosponges formulation can be used for oral delivery.     

Inclusion complexes of β-cyclodextrin with dihydroxyphenols of various nature

The ways for the practical preparation of stable inclusion complexes of β-cyclodextrin with dihydroxyphenols of various nature are developed. Mutual orientation of hydroxy groups and the nature of the bridge in the bisphenols are shown to affect considerably their ability to the complex formation.     

Binary,ternary and microencapsulated celecoxib complexes with β-cyclodextrin formulated via hydrophilic polymers

Cyclodextrins are cyclic oligosaccharides, capable of forming inclusion complexes with many active substances. This way, the aqueous solubility and rate of dissolution of active substances can be changed. For this research we have selected celecoxib as the model active substance, due to its low water solubility, high lipophilicity, and high intestinal permeability. Usually, the amount of cyclodextrin complex that can be incorporated into a pharmaceutical dosage form is limited. The usage of hydrophilic polymers can overcome this problem. In this study, we wanted to point out the potential of various types of hydrophilic polymers for enhancing the complex formation efficiencies, and to highlight the possible use of alginate as a solubility stabilizer/enhancer and as a microsphere matrix polymer. The phase solubility investigation showed greater stability constants (> 250 M^?1) in ternary complexes than in the binary complex, which is a good indicator of the complex formation enhancer properties of these hydrophilic polymers. The relative solubilizing efficiency decreased in the next order: PVP K25 (6.49) > Sodium alginate (6.26) > PEG 6000 (5.72) > without polymer (4.81). The DSC curves showed that all samples that were prepared with β-cyclodextrin (both complexes and physical mixtures) had lower melting endotherms at 160 °C than pure celecoxib. XRD confirmed the complex formation by partial celecoxib amorphisation. The dissolution studies of the prepared microspheres revealed that all samples had different release rates (shown by the similarity factor f₂, which was 36.37, 42.46 and 38.11 % respectively) and that the use of β-cyclodextrin increased the dissolution rate of celecoxib from alginate microspheres in a controlled manner. We concluded that sodium alginate could act as a complex stabilizing/enhancing agent and as a microsphere matrix polymer, at the same time.     

Structure and energy of formation of β- and γ-cyclodextrin complexes with amino acid enantiomers

The interaction between cyclodextrins (CyD), β-CyD, and γ-CyD, and the L- and D-optical isomers of several amino acids (Ala, Leu, His, Phe) are calculated using DFT. It is found that the L-forms of the investigated amino acids bond more strongly to CyD, due to the different numbers of hydrogen bonds that form. The structures of the resulting complexes are analyzed.     

Excimer fluorescence and structures of the inclusion complexes of β-cyclodextrin with naphthalene and its derivatives

Fluorescence of the inclusion complexes with different compositions formed by naphthalene-h₈, naphthalene-d₈, 2,7-dimethylnaphthalene (DMN), and 2-benzylnaphthalene (BN) with β-cyclodextrin (β-CD) in water was studied. Two types of fluorescence are observed, monomer (MF) and excimer (EF_ fluorescence. The excimer fluorescence of the 2∶2 complex emitted by aggregated light-dispersing crystals forming a precipitate, whereas is the MF is concentrations, EF predominates for the resulting complexes. A proposed structure of the inclusion complexes was derived from MNDO/PM3 semiempirical quantum-chemical calculations. The EF is caused by the structure of the complex, in which both naphthalene molecules are separated by a distance of 4.7 Å: they lie in parallel orientation to each other, whereby one ring is displaced from the other by one-fourth of the length of the naphthalene ring. The complexes of 2,7-DMN and 2-benzylnaphthalene with β-CD do not exhibit EF. For the 2∶2 complex of 2,7-DMN with β-CD, this is due to the fact that the aromatic fragments are removed too far from one another 2-Benzylnaphthalene is unable to form an inclusion complex with β-CD, in whose structure the aromatic fragments inside the cavity could be arranged in parallel planes; instead, it forms a 1∶2 complex with β-CD.     

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.     

Carotenoids and β-cyclodextrin inclusion complexes: Raman spectroscopy and theoretical investigation

In the present study, the inclusion processes of β-carotene, astaxanthin, lycopene, and norbixin (NOR) into the β-cyclodextrin (β-CD) cavity were investigated by means of Raman spectroscopy and quantum mechanics calculations. The Raman ν(1) band assigned to C═C stretching was sensitive to the host-guest interaction and in general undergoes a blue shift (3-13 cm(-1)) after inclusion takes place, which is the consequence of the localization of single and double bonds. This is supported by the molecular modeling prediction, which inclusion complexes show the ν(1) band blue shifted by 1-8 cm(-1). The calculated complexation energies was small for most of derivatives and was found to be -11.1 kcal mol(-1) for inclusion of AST and +0.27 kcal mol(-1) for NOR. The stability order was qualitatively correlated to topological parameters accounting for the opening angle of the chain. This means that after inclusion the guest molecules assume a slightly more extended conformation, which enhances the host-guest contact, improving the interaction energy. The results discussed here clearly demonstrate the matrix effect on the carotenes' spectroscopic profile and should contribute to fully characterize the raw samples.     

Inclusion complexes of 5-flucytosine with β-cyclodextrin and hydroxypropyl-β-cyclodextrin: characterization in aqueous solution and in solid state

Complexation between 5-flucytosine (5-FC), a cytosine analogue with in vitro antifungal and antiyeast activity, and β-cyclodextrins (β-cyclodextrin and hydroxypropyl-β-cyclodextrin) was studied in solution and in solid states. Complexation in solution was evaluated using solubility studies, UV–vis and ¹H-NMR. In the solid state, differential scanning calorimetry (DSC), scanning electron microscopy (SEM), FT-IR and X-ray diffraction studies were used. UV–vis, FT-IR and ¹H-NMR spectroscopy studies showed that the complex formed occurs by complexation of piridinique base analogue into inner cavity. DSC studies showed the existence of a complex of 5-FC with β-CDs. X-ray studies confirmed the DSC results of the complex existence. Solubility studies showed that the complexed drug is forty times more soluble than free 5-FC, indicating the obtained systems as future, promising drug carriers.     

Study on preparation and inclusion behavior of inclusion complexes between β-cyclodextrin derivatives with benzophenone

In the paper, the two chemically modified β-cyclodextrin derivatives of 4,4´-diaminodiphenyl ether-bridged-bis-β-cyclodextrins (ODA-bis-β-CD) and p-aminobenzenesulfonic acid-β-cyclodextrin (ABS-β-CD) were synthesized, and then these two β-cyclodextrin derivatives were respectively formed into inclusion complexes with benzophenone (BP) by co-precipitation method. The structure of the inclusion complexes were characterized by UV/vis spectroscopy, FT-IR spectroscopy, elemental analysis, ¹H NMR spectroscopy and XRD. Spectral titration was performed to study the inclusion behavior of the inclusion complexes. These experiments indicated that two inclusion complexes were formed at a stoichiometric ratio of 1:1 and the inclusion stability constants at different temperatures were calculated using the Benesi–Hildebrand (B–H) equation. The thermodynamic parameters (ΔG°, ΔH°, ΔS°) were obtained. As a result, it was found that the two chemically modified β-cyclodextrins containing BP were exothermic and spontaneous process (ΔG°?<?0), and the processes of inclusion complexation were mainly enthalpy driven with negative or minor negative entropic contribution.