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.     

Inclusion complexes of α- andβ-cyclodextrin with α-lipoic acid

A UV spectroscopic study has been performed in neutral aqueous solution to give the complex stability constants. Data analyses assuming 1:1 stoichiometry were successfully applied to both of the host-guest combinations employed, where 1:1 host-guest complex formations were observed at lower concentration of cyclodextrins (CDs). X-ray powder diffraction and IR spectroscopy measurements also demonstrated that inclusion complexes were formed in the solid state. Furthermore, thermogravimetry and DTA were used to investigated the thermal properties of these complexes. The differential thermal analysis, as well as temperature variation experiments below 100°C, indicated that after complexing the 1,2-thiolane moiety of -lipoic acid (LP) penetrated into the cavity of the CD and the S-S linkage was protected against heat.     

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.     

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.     

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.     

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.     

Inclusion of acaricides by complexation withβ-cyclodextrin

Many synthetic pesticides (herbicides, insecticides, fungicides etc.) can be complexed with cyclodextrins. The inclusion complexes of acaricides such as Fenson, Chlorfenson and Genite were prepared. The formation of inclusion complexes was established by UV and X-ray diffraction techniques. The host-to-guest ratio was determined by UV spectral and GLC methods.This paper is dedicated to Professor A.B. Kulkarni on his 75th birthday.     

Inclusion Complex of Carprofen with Hydroxypropyl-β-cyclodextrin

The aim of this study was to investigate the characteristics ofhydroxypropyl--cyclodextrin (HPCD) on the solubility,photostability and dissolution of carprofen (CP). It was found that the solubility of carprofen increased 52-fold when16% HPCD was added to H₂O (w/v). The phase-solubility diagram revealed the formation of a 1 : 1 inclusion complex of CP-HPCD with a stability constant (k_s) of 487 M^-1. Formation of the inclusion complex of CP-HPCD was analyzed using differential scanning calorimetry (DSC). Changes in chemical shifts of the ¹H-nuclear magnetic resonance spectra of CP-HPCD demonstrated that the inclusion site of CP by HPCD was carbazolyl aromatic ring skeleton rather thanthe side chain of propanoic acid. The photostability study revealed that theCP-HPCD complex could not significantly decrease the rate of photodegradation of CP, implying that the rate-determining step of CP mainly occurredat the side chain. The dissolution rates of CP were significantly enhanced as the proportions of HPCD increasedin the prepared discs. The dissolution of the physical mixture (in a 1 : 3 molarratio) increased by about 6-fold in comparison with the parent drug. The improvement of wettability and solubility of CP by complexing to HPCD was reflected in theenhanced dissolution rate.     

Inclusion complexes ofγ-cyclodextrin with coronene in aqueous methanol

Coronene has been found to form an inclusion complex with -cyclodextrin (-CD) in methanol-H₂O (6:4 v/v). The inclusion complex, which has a 2 : 1 stoichiometry of -CD to coronene, tends to bind methanol. Upon addition of 1-adamantanol or adamantane to a solution of -CD and coronene, the absorption spectrum of coronene underwent changes in a manner similar to that observed when the -CD concentration was increased in a coronene solution, indicating the formation of a ternary complex composed of -CD, coronene, and 1-adamantanol or adamantane. The complex-forming equilibrium was investigated on the basis of fluorescence measurements.     

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.     

Interaction between hypocrellin and aliphatic amines

The interaction of hypocrellin, including hypocrellin A (HA) and hypocrellin B (HB), with aliphatic amines in deaerated solutions has been studied by ESR and nanosecond transient absorption spectra. In polar solvents, the acid-base interaction between hypocrellin and amines was observed without irradiation. The signals of semiquinone radical anions of hypocrellm and the spin-trapping adduct of α-phenyl-N-tertbutyl-ratrone (PNB) with the aminoalkyl radicals have been detected in photoinduced ESR studies. The transient absorption of excited triplet state of HA and semiquinone radical anion of HA have been observed in laser flash photolysis studies.     

Inclusion complexes of prochiral heterocyclic ketones with β-cyclodextrins and their reduction with sodium borohydride

Alkyl(2-furyl), alkyl(2-thienyl), and methyl pyridyl ketones form stoichiometric inclusion complexes with -cyclodextrins. Reduction of these complexes in aqueous solution of Na₂CO₃ at room temperature yields the corresponding secondary alcohols with an optical yield which attains 27%.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1621–1627, December, 1993.     

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.     

Inclusion complexes of phosphorylated daidzein derivatives with β-cyclodextrin: Preparation and inclusion behavior study

In the present work the feasibility of β-cyclodextrin in complexation was explored, as a tool for improving the solubility and biological ability of daidzein derivatives. A series of phosphorylated daidzein derivatives featuring different chain lengths were synthesized through a modified Atherton-Todd reaction and their inclusion complexes with βCD were prepared by coprecipitation method. The inclusion complexation behavior was studied by fluorescence, UV, FT-IR, MS and (1)H NMR. The results showed that only phosphorylated daidzein derivative carrying small substituent group ((C(2)H(5)O)(2)PO) entered the cavity of βCD and formed 1:1 inclusion complex. The formation constant was 175(mol/L)(-1).     

Preparation and characterization of inclusion complexes of carvedilol with methyl-β-cyclodextrin

Aim of the present work was to investigate the effect of methyl-β-cyclodextrin (MβCD) on the solubility and dissolution rate of carvedilol (CAR), a drug used orally for the treatment of hypertension. Phase solubility studies showed an A_L-type diagram indicating the formation of inclusion complex in 1:1 molar ratio. Solid binary systems of the drug with MβCD were prepared by various methods. Physicochemical characterizations were performed using Fourier Transformation Infrared Spectroscopy, Differential Scanning Calorimetry and powder X-Ray Diffractometry. It could be concluded that CAR can form inclusion complex with MβCD. The dissolution profiles of inclusion complexes were determined and compared with those of CAR alone and the physical mixture. The dissolution rate of CAR was increased by MβCD inclusion complexation remarkably.     

Preparation and characterization of the inclusion complexes of equol with sulfobutylether-β-cyclodextrin: their antioxidant activity and dissolution evaluation

The formation of inclusion complexes between S-(?)-equol (SEq) and cyclodextrins (CDs) was investigated. The binding constant (K_c) of the SEq/sulfobutylether-β-cyclodextrin (SBE-β-CD) inclusion complex was determined to be 1600 L/mol based on UV data. The phenyl ring of the SEq molecule was found to be inserted from the secondary hydroxyl face of the SBE-β-CD as evidenced from ¹H–¹H rotating frame nuclear Overhauser effect spectroscopy (ROESY) NMR. The thermal properties of the solid SEq/SBE-β-CD inclusion complexes prepared by physical mixing, kneading and freeze-drying methods were studied by differential scanning calorimetry. For the solid complex obtained by the freeze-drying method, the endothermic peak corresponding to the melting point of SEq disappeared. The solid SEq/SBE-β-CD complexes exhibited a high score in antioxidant activity evaluation tests compared to SEq alone. Dissolution test revealed that the solid complex obtained by freeze-drying method had improved dissolution of SEq.     

Characterisation of DM-β-cyclodextrin:prednisolone complexes and their formulation as eye drops

Several ocular treatment options have been developed to overcome a broad range of ocular infections and corneal pathologies. Even though, commonly used ophthalmic formulations are only able to promote a short therapeutic effect, demanding a frequent dosing regimen. This study took advantage of dimethyl-β-cyclodextrin to overcome prednisolone low water solubility through complexes formation. These complexes were characterized by phase-solubility studies (K_s = 732; CE = 0.864), ¹H-NMR, Differential Scanning Calorimetry and Fourier Transform Infrared Spectroscopy. Particle size distribution, prednisolone assay, rheology and osmolality were assessed to evaluate dimethyl-β-cyclodextrin and HPMC influence on the eye formulation main physicochemical properties. ¹H-NMR studies showed a 1:1 molar ratio complexes’ stoichiometry; and the other physical characterisation methods (FTIR spectra and DSC thermograms) proved a successful interaction between prednisolone and dimethyl-β-cyclodextrin. Dimethyl-β-cyclodextrin promoted a statistical significative water solubility increase of drug and the particle size of all suspensions prepared presented a d90 lower than 90 μm. The presence of dimethyl-β-cyclodextrin did not change the pseudoplastic behaviour of this HPMC-based suspension, but a lower viscosity was obtained in the presence of the complexes. As the final formulation was hypotonic its osmolality was adjusted with NaCl. Overall, dimethyl-β-cyclodextrin:prednisolone complexation in the presence of hydrophilic polymer HPMC appears to be an advantageous approach for the ocular administration of this drug.     

Inclusion complexes of ortho-anisidine and β-cyclodextrin: A quantum mechanical calculation

The structural aspects for the complexation of ortho-anisidine (O-AN)/β-cyclodextrin were explored by using PM6, density function theory B3LYP/6-31G*, M05-2X/6-31G*, B3PW91/6-31G*, MPW1PW91/6-31G*, HF/6-31G* methods and several combinations of ONIOM2 hybrid calculations. Calculations were performed upon the inclusion complexation of β-cyclodextrin (β-CD) with neutral (O-AN1) and cationic (O-AN2) species of ortho-anisidine. The obtained results with PM6 method clearly indicate that the formed complexes are energetically favored, the complex of O-AN2/β-CD in B orientation is significantly more favorable than the others energetically. The structures show the presence of several intermolecular hydrogen bond interactions that were studied on the basis of natural bonding orbital (NBO) analysis, employed to quantify the donor–acceptor interactions between ortho-anisidine and β-CD.     

Inclusion complexes of γ-cyclodextrin and carboxyl-modified γ-cyclodextrin with C60: synthesis, characterization and controlled release application via microgels

Carboxyl modified γ-cyclodextrin (CDSA) with a substitution degree of about 9.5 was prepared by the esterification of γ-cyclodextrin (CD) with succinic anhydride in pyridine at 90 °C. The chemical composition and the structure of CDSA were characterized by FT-IR, MALDI-TOF, X-ray diffraction pattern, potentiometric titration and TGA. Modified and native γ-cyclodextrin associate with fullerene (C₆₀) in DMF-toluene mixture resulting 1:1 CDSA:C₆₀ and CD:C₆₀ inclusion complexes. Aqueous solutions of native cyclodextrin, carboxyl-modified cyclodextrin and their inclusion complexes with C₆₀ were used as microgel solvent (or swelling agent) for controlled release application. The release of solutions was induced by shear stress and demonstrated using rheo-optical set-up.