Physicochemical characterization and molecular modeling study of host–guest systems of aripiprazole and functionalized cyclodextrins

Journal of Thermal Analysis and Calorimetry - Aripiprazole (ARP), an innovative atypical antipsychotic drug, exhibits very low aqueous solubility, affecting its dissolution and absorption and high...     

Host–guest complexation of omeprazole, pantoprazole and rabeprazole sodium salts with cyclodextrins: an NMR study on solution structures and enantiodiscrimination power

The application of different cyclodextrins (CDs) as NMR chiral solvating agents (CSAs) for the sodium salts of the proton-pump inhibitors omeprazole, pantoprazole (sesquihydrate) and rabeprazole was investigated. It was proved that the formation of diastereomeric host–guest complexes in D₂O solution between the CDs and those substrates permitted the direct ¹H NMR discrimination of the enantiomers of the sodium salts of these compounds without the need of previous working-up. Rotating frame nuclear overhauser effect spectroscopy (ROESY) was used to ascertain the solution geometries of the host–guest complexes. The results suggested a preferential binding of the benzimidazole moiety of the guest molecules within the macrocyclic cavity of α-CD, whereas the higher dimensions of β- and γ-CD also permitted the inclusion of the highly substituted pyridine moieties. Moreover, the solution stoichiometries and the binding constants of the complexes formed with pantoprazole at room temperature were determined by ¹H and ¹⁹F NMR titration. Diffusion-filtered Spectroscopy was applied to obtain clean spectra without the interference of the HOD signal.     

Host–guest complexation of antioxidative caffeic and ferulic acid amides with a functionalized cyclophane

Host?guest complexation has been studied by ¹H NMR on the benzyl and phenethyl amides of ferulic and caffeic acids as the guests in chloroform and acetonitrile; the counter host is a cyclophane which integrates four phenylene rings, amino and amide groups in the macrocyclic framework and bears four pendant methyl acetate ester arms. CAPE, one of the best known natural antioxidants, also has been studied for comparison. Among the guests studied, ferulic acid benzyl amide shows NMR shifts due to the formation of a host?guest complex in chloroform. The complexation occurs in two steps with the formation constants K ₁?=?[HG]/[H][G]?=?6?M^?1 and β ₂?=?[HG₂]/[H][G]²?=?87?M^?2. Two guest molecules are bound on the surface of the macrocyclic framework of a host molecule by two hydrogen bonds, NH(host amide)···O=C(guest amide) and C=O(host ester)···HO(guest phenol). The latter hydrogen bond may protect the bioactive site, i.e., phenol OH, of guest molecules captured in the complex against undesirable oxidation. This feature is observed only for ferulic acid benzyl amide in chloroform; the cyclophane ester interacts with this amide, distinctively from the other hydroxycinnamic acid derivatives.     

Host–guest system of 4-nerolidylcatechol in 2-hydroxypropyl-β-cyclodextrin: preparation, characterization and molecular modeling

The interaction of 4-nerolidylcatechol (4-NRC), a potent antioxidant agent, and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) was investigated by the solubility method using Fourier transform infrared (FTIR) methods in addition to UV–Vis, ¹H-nuclear magnetic resonance (NMR) spectroscopy and molecular modeling. The inclusion complexes were prepared using grinding, kneading and freeze-drying methods. According to phase solubility studies in water a B_S-type diagram was found, displaying a stoichiometry complexation of 2:1 (drug:host) and stability constant of 6494 ± 837 M^?1. Stoichiometry was established by the UV spectrophotometer using Job’s plot method and, also confirmed by molecular modeling. Data from ¹H-NMR, and FTIR, experiments also provided formation evidence of an inclusion complex between 4-NRC and HP-β-CD. 4-NRC complexation indeed led to higher drug solubility and stability which could probably be useful to improve its biological properties and make it available to oral administration and topical formulations.     

Inclusion complexation of chloropropham with β-cyclodextrin: preparation, characterization and molecular modeling

An inclusion complex between the agrochemical chloropropham (CIPC) and β-cyclodextrin (β-CD) was prepared. A 2:1 host-guest stoichiometry was conformed by elemental analysis. From the phase solubility studies, the calculated stepwise stability constants were K(1)=224.6L/mol and K(2)=939.2L/mol, respectively. FT-IR, thermoanalysis and (1)H NMR spectra were applied to characterize the complex. It was speculated that the inclusion mode was two β-CD cavities included the chlorophenyl and the isopropyl moiety of one CIPC molecule, which was in agreement with the most predominant configuration optimized by molecular modeling. By complexation with β-CD, the water solubility and the thermal stability of CIPC were prominently improved.     

Structure and molecular dynamics of host–guest complexes of TEMPO with cucurbituryl: An ESR and DFT study

Host–guest complexes are of interest as promising nanodevices for molecular recognition and chemosensors. In this work, the structure and molecular dynamics of complexes of the nitroxyl radical TEMPO (I), as models of indicator and analyte, with cucurbituril CB[7] in solution and in the solid phase have been studied by ESR and DFT methods. The kinetic accessibility of the NO group of I for water-soluble reagents has been determined. By simulation of the ESR spectra of the complex, the rotational diffusion coefficients and the anisotropy of its rotation have been determined. To study the rotational mobility of the guest in the CB[7] cavity, solid solutions of I@CB[7] in the CB[7] matrix have been obtained. The ESR spectra indicate rapid jump-like rotation of I about an axis oriented along the normal to the CB[7] portals. The formation energy and the spatial structure of the complex have been calculated by the DFT method; a change in the spin density on the NO group with changing the orientation of I in the CB[7] cavity has been found.     

NMR study of host–guest complexes of disulfonated derivatives of 9, 10-diphenylanthracene and corresponding endoperoxides with cyclodextrins

Disulfonated derivatives of 9,10-diphenyl anthracene (dsDPA) are known carriers of singlet oxygen. DsDPA and corresponding endoperoxides (dsDPAO₂) form host–guest complexes with native cyclodextrins (i.e. β-CD and γ-CD). The modes of host–guest interaction were studied by ¹H NMR and 2D-NMR (ROESY). Specific inclusions of phenyl groups of dsDPA/dsDPAO₂ into the cyclodextrin cavities were found for both β-CD and γ-CD. The mode of interaction depends on the size of the CD cavity and the position of the sulfonate group.     

Host–guest interaction of hemicucurbiturils with phenazine hydrochloride salt

The host–guest interactions between phenazine hydrochloride salt (PheH⁺) and hemicucurbit[n]uril (n = 6 or 12) (HemiQ[6 or 12]) have been studied by ¹H NMR, UV–vis, IR, mass spectrometry (MS) and quantum chemistry. In ¹H NMR spectra, the broadening of proton resonances of the hosts suggests the interactions of PheH⁺ with HemiQs. The quantitative stabilities of the host–guest systems have been obtained by UV–vis titration experiments, that is, the stoichiometric interactions of PheH⁺ with HemiQ[6] have been observed with an association constant of K_a = (2.5 ± 1.2) × 10⁶ L mol^? 1, while the 2:1 ratio complexes of PheH⁺ with HemiQ[12] are formed with stepwise association constants of K₁ = (9.2 ± 2.8) × 10⁴ L mol^? 1 and K₂ = (6.4 ± 0.9) × 10⁵ L mol^? 1, respectively, which induce a total association constant of K_a = 5.9 × 10¹⁰ L² mol^? 2. Both the 1:1 and 2:1 complexes have been detected by MS. Quantum chemistry calculations have been used to understand the static structures and thermodynamic stabilities of the supramolecular assemblies.     

The formation of host–guest complexes between surfactants and cyclodextrins

Cyclodextrins are able to act as host molecules in supramolecular chemistry with applications ranging from pharmaceutics to detergency. Among guest molecules surfactants play an important role with both fundamental and practical applications. The formation of cyclodextrin/surfactant host–guest compounds leads to an increase in the critical micelle concentration and in the solubility of surfactants. The possibility of changing the balance between several intermolecular forces, and thus allowing the study of, e.g., dehydration and steric hindrance effects upon association, makes surfactants ideal guest molecules for fundamental studies. Therefore, these systems allow for obtaining a deep insight into the host–guest association mechanism. In this paper, we review the influence on the thermodynamic properties of CD–surfactant association by highlighting the effect of different surfactant architectures (single tail, double-tailed, gemini and bolaform), with special emphasis on cationic surfactants. This is complemented with an assessment of the most common analytical techniques used to follow the association process. The applied methods for computation of the association stoichiometry and stability constants are also reviewed and discussed; this is an important point since there are significant discrepancies and scattered data for similar systems in the literature.     

HPLC study of the host–guest complexation between fluorescent glutathione derivatives and β-cyclodextrin

RP-HPLC and the van’t Hoff law were used to study the association in which β-cyclodextrin forms inclusion complexes with aminothiol–phthaldialdehyde derivatives prepared from either glutathione (GSH) or γ-glutamylcysteine (γ-glucys) and either naphthalene-2,3-dicarboxaldehyde (NDA) or o-phthaldialdehyde (OPA). Elution was carried out at pH 8.5, the derivatization pH which gave the highest fluorescence signal during batch experiments. The variation of the retention factor (k) was monitored as a function of column temperature (10–35 °C) and β-cyclodextrin concentration (0–5 mM) in the mobile phase. Apparent binding constants, enthalpy and entropy were calculated from van’t Hoff plots for the complexation reaction. These data lay the groundwork for the improvement of high throughput GSH quantification methods using fluorimetry in biological and vegetal samples.     

Cisapride/β-cyclodextrin complexation: stability constants, thermodynamics, and guest–host interactions probed by 1H-NMR and molecular modeling studies

Phase solubility techniques were used to obtain the complexation parameters of cisapride (Cisp) with β-cyclodextrin (β-CD) in aqueous 0.05 M citrate buffer solutions. From the UV absorption spectra and the pH solubility profile, two basic pK _as were estimated: pK _a(1+) = 8.7 and pK _a(2+) < 2. The inherent solubility (S _o) of Cisp was found to increase as pH decreases, but is limited by the solubility product of the CispH⁺·citrate¹⁻ salt at low pH (pK _sp = 3.0). Cisp forms soluble 1:1 and 1:2 Cisp/β-CD complexes. A quantitative measure of the hydrophobic effect (desolvation) contribution to 1:1 complex formation was obtained from the linear variation of free energy of 1:1 Cisp/β-CD complex formation (ΔG ₁₁ = −RT ln K ₁₁ < 0) with that of the inherent solubility of Cisp . The results show that the hydrophobic character of Cisp contributes about 35% of the total driving force to 1:1 complex formation (slope = −0.35), while other factors, including specific interactions, contribute −10.6 kJ/mol (intercept). Protonated 1:1 Cisp/β-CD complex formation at pH 6.0 is driven by favorable enthalpy (ΔH° = −9 kJ/mol) and entropy (ΔS° = 51 J/mol K) changes. In contrast, inherent Cisp solubility is impeded by unfavorable enthalpy (ΔH° = 12 kJ/mol) and entropy (ΔS° = 90 J/mol K) changes. ¹H-NMR spectra in D₂O and molecular mechanical studies indicate the formation of inclusion complexes. The dominant driving force for neutral Cisp/β-CD complexation in vacuo was predominantly van der Waals with very little electrostatic contribution.     

Host–guest interactions between dapsone and β-cyclodextrin (part I): study of the inclusion compound by nuclear magnetic resonance techniques

Dapsone (4,4′diaminodiphenylsulfone) is a very effective drug to treat leprosy and a broad range of infectious conditions such as Pneumocystis carinii pneumonia, toxoplasmosis and tuberculosis. However, the oral administration of this drug generally is related to serious side effects and treatment failures. It is believed that the inclusion compound of this drug and cyclodextrins would increase the wettability and the solubility of the encapsulated drug for a supported and gradual release, maximizing its biodisponibility over time. The encapsulation of dapsone in β-cyclodextrin was investigated by five nuclear magnetic resonance spectroscopy techniques. The data obtained for the complex in aqueous solution and in solid-state revealed a strong interaction between host and guest, showing that the drug molecule is deeply inserted in the CD cavity. The diffusion experiments (diffusion ordered spectroscopy) showed a high percentage of complexation (86 %) and that the drug molecule is preferentially interacting with the large side of the β-cyclodextrin cavity.     

Host–guest interactions of a twisted cucurbit[15]uril with paraquat derivatives and bispyridinium salts

Host–guest complexations of a twisted cucurbit[15]uril with some paraquat derivatives and bispyridinium salts in aqueous solution are investigated by nuclear magnetic resonance, UV–vis spectrometry and isothermal titration calorimetry. These complexations are mainly enthalpy-driven.     

Host–guest complexation between 5-aminoisoquinoline and β-cyclodextrin and its effect on spectral and prototropic characteristics

The effects of the addition of β-cyclodextrin (β-CDx) on the absorption and emission properties of the 5-aminoisoquinoline (5AIQ) have been investigated in aqueous media. The formation of host–guest inclusion complex with 1:1 stoichiometry was revealed by absorption, steady state and time-resolved emission spectroscopy. The complex formation has also been confirmed by FT-IR spectra and SEM image analysis of the solid inclusion complex between 5AIQ and β-CDx. No significant change was observed in the ground and excited state pKa values in β-CDx medium. Based on photophysical and prototropic characteristics of 5AIQ in β-CDx, the structure of the 1:1 inclusion complex is proposed.     

Toward a light-harvesting Hyperbranched Polyesteramine Host–guest Complex

A novel hyperbranched polyesteramine (PEA) architecture 1 was found to display light-harvesting properties by hosting anthracene-9-carboxylic acid guest 3. The light-harvesting ability has been studied by means of fluorescence spectroscopy. The binding behaviour has also been described by FT-IR and ¹H NMR spectroscopic methods. Hyperbranched host 1 also acts as the photon-harvesting chemosensor of the anthracenyl guest over the benzoic acid guest. Furthermore, the host loaded with the anthracenyl guest also exhibited ‘ON–OFF’ switching on protonation of amine sub-units with HCl, thereby making it of potential use as a pH-assisted photon-harvesting material.     

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.     

Electrochemical study of indapamide and its complexation with ��-cyclodextrin

Electrochemical oxidation of indapamide has been investigated at glassy carbon electrode using cyclic and differential pulse voltammetry (DPV). Indapamide exhibited two well resolved signals which attributed to the oxidation of indoline ring and benzamide moiety in phosphate buffers in the pH range of 2.7?C10.1. The oxidation processes have been shown to be irreversible and diffusion controlled. The formation of an inclusion complex of indapamide with ??-cyclodextrin (??-CD) has been investigated by cyclic, differential pulse voltammetry as well as UV?CVis spectrophotometry. The stability constant of the complex was determined to be 6199 and 2717 M^?1 using differential pulse voltammetry and UV?CVis spectrophotometry, respectively.     

Host–guest system of etodolac in native and modified β-cyclodextrins: preparation and physicochemical characterization

Etodolac, being a practically insoluble candidate, exhibits certain toxic effects and a limited bioavailability. Upon chronic use, it causes gastro-intestinal injury and increases the risk of ulcer complications. The approach of this study was to improve the physicochemical properties of the drug utilizing complexation phenomenon with β-, methyl-β- and hydroxypropyl-β-cyclodextrins, which may enhance the aqueous solubility and dissolution rate of etodolac, in an effort to increase oral bioavailability. In certain instances, this approach can be used to increase drug solubility, improve organoleptic properties and maximize the gastrointestinal tolerance by reducing drug irritation after oral administration. Differential UV measurements as well as continuous variation plots revealed the formation of equimolar complex with hydroxypropyl-β-cyclodextrin and 1:2 complexes with β-cyclodextrin and its methyl derivative. Differential scanning calorimetry (DSC), X-ray and FT-IR measurements were applied to prove inclusion complex formation and characterize the complexes. These results lend support to the idea that solubilization of etodolac is mainly related to inclusion complex formation and to a lesser extent to cyclodextrin aggregates. Understanding the factors that influence the performance of etodolac, will allow us to state that molecular encapsulation of the drug and other modifications with appropriate hydroxylation or methylation of parent β-cyclodextrin is able to overcome its problems and facilitate safe and efficient delivery of the drug.