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 sulphanilamide drugs and β-cyclodextrin: a theoretical approach

PM3 theoretical methodology was used to access and compare the relative stability of inclusion complexes formed by sulphadiazene, sulphisomidine, sulphamethazine and sulphanilamide with β-cyclodextrin (β-CD). The study predicted that (i) the heterocyclic ring is encapsulated in the hydrophobic part and aniline ring is present in the hydrophilic part of the β-CD cavity and (ii) intermolecular hydrogen bonds were formed between host and guest molecules. The negative free energy and enthalpy changes indicated that all the four inclusion complexation processes were spontaneous and enthalpy driven process. HOMO and LUMO orbital investigation confirmed that the stability increased in the inclusion complexes and also proved no significant change in the electronic structure of the guest and host molecules after complexation.     

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 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 lamotrigine and hydroxy propyl β-cyclodextrin: solid state characterization and dissolution studies

Lamotrigine (LMN) is an antiepileptic drug, with poor aqueous solubility, which might lead to erratic bioavailability. The objective of the present work was to improve the dissolution characteristics of the LMN using Hydroxy propyl β-cyclodextrin (HP β-CD), which might offer reliable bioavailability. The phase solubility profile was classified as A _L -type, revealing 1:1 stoichiometric complexation, with a stability constant (Ks) of 573 M^?1. Binary systems of LMN and HP β-CD were prepared in different molar ratios (1:1, 1:2, 1:3 and 1:4) by kneading method. The binary systems were characterized by Fourier Transform Infrared (FT-IR) Spectroscopy, Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction Analysis (PXRD). Results revealed that in the kneaded products the entire drug was entrapped inside the HP β-CD cavity and reduction in drug crystallinity also took place, which may be responsible for improved dissolution characteristics as compared to that of the pure drug as depicted from the dissolution studies.     

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).     

Inclusion complex of (−)-linalool and β-cyclodextrin

(?)-Linalool is a monoterpene alcohol which is present in the essential oils of several aromatic plants. Recent studies suggest that (?)-linalool has antimicrobial, anti-inflammatory, anticancer, antioxidant, and antinociceptive properties in different animal models. The aim of this study was to prepare and characterize inclusion complexes of (?)-linalool with β-cyclodextrin (β-CD). Equimolar binary (?)-linalool/β-CD systems were prepared by physical mixture, paste (PM), and slurry methods (SC) and characterized by differential scanning calorimetry, thermogravimetric analysis, FT-IR spectroscopy, X-ray diffractometry, Karl Fisher titration, and scanning electron microscopy. Thermal characterization indicates the occurrence of complexation, mainly in paste complexes, which is present in the interval from 140 to 280 °C a gradual mass loss (4.6 %), probably related to (?)-linalool loss. FT-IR spectra showed changes that may be related to the formation of intermolecular hydrogen bonds between (?)-linalool and β-CD. The new solid-phase formed using the PM and SC methods, had a crystal structure which was different from the original morphology of β-CD.     

Inclusion complexes of fluconazole with β-cyclodextrin: physicochemical characterization and in vitro evaluation of its formulation

Fluconazole (FZ) is a triazole antifungal drug administered orally or intravenously. It is employed for the treatment of mycotic infections. However, the efficacy of FZ is limited with its poor aqueous solubility and low dissolution rate. One of the important pharmaceutical advantages of cyclodextrins is to improve pharmacological efficacy of drugs due to increasing their aqueous solubility. The aim of present study was to prepare an inclusion complex of FZ and β-cyclodextrin (β-CD) to improve the physicochemical and biopharmaceutical properties of FZ. The effects of β-CD on the solubility of FZ were investigated according to the phase solubility technique. Complexes were prepared with 1:1 M ratio by different methods namely, freeze-drying, spray-drying, co-evaporation and kneading. For the characterization of FZ/β-CD complex, FZ amount, practical yield %, thermal, aqueous solubility, XRD, FT-IR and NMR (¹H and ¹³C) analysis were performed. In vitro dissolution from hard cellulose capsules containing FZ/β-CD complexes was compared to pure FZ and its commercial capsules and evaluated by f₁ (difference) and f₂ (similarity) factors. Paddle method defined in USP 31 together with high pressure liquid chromatographic method were used in in vitro dissolution experiments. It was found that solubility enhancement by FZ/β-CD complexes depends on the type of the preparation method. High release of active agent from hard cellulose capsules prepared with β-CD complexes compared to commercial capsules was attributed to the interactions between β-CD and active agent, high energetic amorphous state and inclusion complex formation.     

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.     

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 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.     

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.     

Inclusion complexes of pantoprazole with β-cyclodextrin and cucurbit[7]uril: experimental and molecular modeling study

The inclusion complexes of the proton pump inhibitor (PPI) pantoprazole sodium (PNZ_Na) with β-cyclodextrin (βCD) and cucurbit[7]uril (CB[7]) have been investigated. Fluorescence spectroscopy and electrospray ionization mass spectrometry (ESI-MS) were used to characterize these complexes. The fluorescence intensity of PNZ_Na was remarkably enhanced by both hosts, indicating the formation of the complexes. Nevertheless, the two hosts are of comparable cavity size their effect on the fluorescence of PNZ_Na was quite different. The ESI-MS data on the other hand confirmed the formation of a 1:1 PNZ_Na: host inclusion complexes for the two hosts. We further utilized molecular dynamics to shed more light on the mechanism of complexation and on the stability of these complexes in aqueous media. The complexes were stabilized over the 20 ns of simulation time mainly via hydrogen bonding interactions in addition to hydrophobic effects and van der Waals interactions. Snapshots collected during the simulations for both complexes have clearly shown that the mode of insertion of PNZ into the two host’s cavities are different which explain the difference in fluorescence enhancement of PNZ obtained in presence of each of these hosts.     

Inclusion of the Antidepressant Paroxetine in β-cyclodextrin

The X-ray structure and thermal stability of a -cyclodextrin inclusion complex of the antidepressant paroxetine [(3S-trans)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine], with the formula ( -cyclodextrin)₂...paroxetine...28H₂O, are reported. On heating, the crystals dehydrate in two stages and begin to decompose from approximately 270 °C. An X-ray diffraction study at 173K showed that the complex crystallizes in the monoclinic system, space group P2₁ with a = 15.2262(3), b = 31.4771(1), c = 15.6739(1) Å, = 104.320(1)° and Z = 2 formula units. Refinement on F² converged at R1 = 0.066, wR₂ = 0.182 (21478 reflections). On encapsulation within a head-to-head -cyclodextrin dimer, the paroxetine molecule adopts an unusual `hairpin' conformation, stabilised by intramolecular ... interaction between the phenyl rings. The guest piperidine ring is located at the primary face of one host molecule of the dimer while the fluorophenyl and benzodioxole moieties respectively occupy the dimer interfacial region and the cavity of the second host molecule. Experimental and computed X-ray powder diffraction patterns for the complex are also reported. The mode of stacking of the dimeric complex units is shown to be one of at least three distinct variants which can be identified for -cyclodextrin complexes with similar unit cell dimensions and crystallizing in the same space group.     

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.     

Host-guest complex of nabumetone: β-cyclodextrin: quantum chemical study and QTAIM analysis

The aim of the present work is the investigation of the inclusion complex of nabumetone (NAB) and β-cyclodextrin (β-CD) using PM3, DFT, DFT-D and ONIOM2 methods. The results indicate that the most energetically favorable structure predicts a preference of the methoxy group to enter the cavity of β-CD from its wide rim. Consequently, the butanone moiety is positioned outside the cavity on the side of the secondary hydroxyls, with a total insertion of naphthalene group. The semi-empirical PM3 results are in good agreement with those obtained by the DFT optimization (with and without dispersion correction). The donor–acceptor interactions between drug and the cavity wall of the host, studied on the basis of natural bonding orbital (NBO) analysis, show the presence of weak intermolecular hydrogen bonds in addition to the most important van der Waals interactions. Furthermore, it is revealed that among the DFT and DFT-D techniques selected to quantify these interactions, WB97X-D functional provides the greatest values of stabilization energies E⁽²⁾. Finally, a detailed topological charge density analysis based on the quantum theory of atoms in molecules (QTAIM), developed by Bader and co-workers, has been accomplished using the WB97X-D and B3LYP methods on the most favorable complexes. A good correlation between the structural parameters and the electronic density is found.     

Inclusion of the Niflumic Acid Anion in β-cyclodextrin: A Solution NMR and X-ray Structural Investigation

We report parallel solution and solid state studies of the inclusion of the anionic form of the non-steroidal anti-inflammatory drug niflumic acid (2-[[3-(trifluoromethyl)phenyl]-amino]-3-pyridinecarboxylic acid) in the host g -cyclodextrin ( g -CD). 1 H NMR data for the interaction between host and guest in aqueous solution recorded at 300 MHz indicated a strong preference for insertion of the trifluoromethylphenyl residue, rather than the pyridinecarboxylate moiety, in the host cavity. A 1:1 complex stoichiometry was determined by the continuous variation method utilising chemical shifts of both host and guest protons. Analysis of the data using a new flexible program developed for this purpose yielded an overall association constant K of 336 M m 1 at 298 K. The NMR data indicate a dynamic equilibrium between complexed and uncomplexed species but do not distinguish guest entry from the primary and secondary sides of the host. Reaction between the Cs + salt of niflumic acid and g -CD yielded the crystalline complex ( g -CD) 2 ·(Cs + niflumate m ) 4 ·22H 2 O whose single crystal X-ray structure was determined. A novel inclusion mode for this host, namely entry of guest trifluoromethylphenyl residues from both the primary and secondary sides, was revealed by the X-ray analysis.