Host–guest interactions of 6-benzyladenine with normal and modified cucurbituril: 1H NMR,UV absorption spectroscopy and phase solubility methods

Guest–host inclusion complexes between 6-benzyladenine (6-BA), cucurbit[7]uril (Q[7]), symmetrical tetramethylcucurbit[6]uril (TMeQ[6]) and meta-hexamethyl-substituted cucurbit[6]uril (HMeQ[6]) in aqueous solution were investigated by ¹H NMR, UV absorption spectroscopy and phase solubility studies. The ¹H NMR spectra analysis revealed that the hosts selectively bound the phenyl moiety of the guests. Absorption spectroscopic analysis defined the stability of the host–guest inclusion complexes. A host:guest ratio of 1:1 was measured quantitatively as (5.63 ± 0.26) × 10⁴, (1.94 ± 0.17) × 10³ and (2.89 ± 0.23) × 10³ mol L^? 1 for the Q[7]-6-BA, TMeQ[6]-6-BA and HMeQ[6]-6-BA systems, respectively. Phase solubility diagrams were analysed through rigorous procedures to obtain estimates of the complex formation constants for Q[n]-6-BA complexation. The formation constants were (1.29 ± 0.24) × 10⁴ L mol^? 1 for Q[7]-6-BA, (3.20 ± 0.17) × 10³ L mol^? 1 for TMeQ[6]-6-BA and (3.52 ± 1.01) × 10³ L mol^? 1 for TMeQ[6]-6-BA. Furthermore, phase solubility studies showed that 6-BA solubility increased as a function of Q[7], TMeQ[6] and HMeQ[6] concentrations. The thermodynamic parameters of the complex formation were also determined. The formation of inclusion complexes between 6-BA and Q[7] was enthalpy controlled, suggesting that hydrophobic and van der Waals interactions were the main driving forces. Our results demonstrated that the complexation of 6-BA with Q[n] could be used to improve the solubility of 6-BA.     

Host–guest interactions between dapsone and β-cyclodextrin (Part II): thermal analysis, spectroscopic characterization, and solubility studies

The complex of dapsone with β-cyclodextrin was prepared by the co-precipitation/freeze–drying method. The physical–chemical characteristics of the complex were investigated by different methods and compared with those of the physical mixture and of the isolated compounds. The methods used were infrared spectroscopy, X-ray diffractometry and differential scanning calorimetry. The stability constant was calculated from phase solubility diagram (Higuchi–Connors) and fluorescence spectroscopy. The stoichiometry of the complex was confirmed by Job’s plot. Fluorescence measurements at different temperatures provided the thermodynamic parameters of the complexation. The infrared spectrum showed the disappearance of the SO₂ asymmetric stretching band of the drug at 1275?cm^?1 after complexation. The amorphization of the samples, as revealed by the X-ray diffraction patterns, was an indirect proof of the inclusion complex. The thermal analysis showed that the curves of the physical mixture are combination of the curves of both constituents (dapsone and β-cyclodextrin) while the absence of the melting peak of the drug in the DSC curve of the complex suggests the inclusion of the drug molecule in the host cavity as a 1:1 complex as indicated by Job’s plot. There was a linear increase in its solubility with the increase of the cyclodextrin concentration and the complex was classified as an A_L-type. The value of the stability constant was 3,998?L?mol^?1 calculated by the Higuchi–Connors diagram and around 18,100?L?mol^?1 from the fluorescence method indicating a strong interaction between the host and the guest. Complex formation was a spontaneous and enthalpy directed process.     

Encapsulation of vortioxetine with cyclodextrins via host–guest inclusion complex: Synthesis,characterization, solubility,and in vitro dissolution studies

Drug solubility plays a significant role in the development of drug formulation. The objectives of this work are to improve the solubility and dissolution rate of vortioxetine (VT) by preparing its inclusion complexes (ICs) with β-Cyclodextrin (β-CD) and γ-Cyclodextrin (γ-CD). The ICs were prepared in 1:1 M ratio via recrystallization method and characterized by P-XRD, FT-IR, ¹H NMR, 2D NOESY, and DSC. Further, the crystal structure of VT-β-CD was analyzed by SC-XRD. P-XRD data obtained for ICs describe the crystalline pattern. The DSC analysis shows change in the thermal behavior of VT, CDs and ICs. FT-IR analysis shows shifting of frequencies in ICs when compared with the pristine VT drug and CDs. The 2D NOESY in DMSO-d⁶ indicates weak interaction between the VT and CD molecules. The crystal structure of VT-β-CD consists of one guest VT, one host CD, and nine water molecules in the crystal lattice. The solubility of ICs was significantly improved in distilled water, pH 1.2 acidic, and phosphate buffer pH 6.8 medium, as compared with the solubility of the pristine VT drug. The in vitro dissolution rate of ICs in different dissolution media was investigated, which was higher than that of the commercial product of VT.     

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.     

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 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.     

NMR Studies of Host–guest Complexes Between Monocarboxylic Acids and Amide-based Cyclophanes in Chloroform

Formation of host–guest complexes with acetic acid and benzoic acid was studied by NMR for amide-based octaazacyclophanes having pendant methyl ester arms; the cyclophanes were tetramethyl 2,9,18,25-tetraoxo-1,4,7,10,17,20,23,26-octaaza[10.10]paracyclophane-4,7,20,23-tetraacetate, its meta-isomer and analogues. Amide NH proton and CH₂ proton adjacent to amide C = O in every cyclophane host showed down-field NMR shifts in the presence of the guest acids in CHCl₃-d, suggesting the formation of 1:1 complexes in which the carboxyl group of an acid molecule formed two hydrogen bonds with the amide NH and C = O moieties of a host molecule. Since the complex formation competed with the dimerization of the guest acids, the monomer–dimer equilibrium was restudied by NMR and the equilibrium constant was determined to be 330 M^? 1 for acetic acid and 518 M^? 1 for benzoic acid. By using these values, the formation constants of the host–guest complexes were determined to be 8–51 M^? 1. The close contact between the host and guest molecules via hydrogen bonding was consistently confirmed by NMR shifts due to the ring current of aromatic group.     

Host–guest interactions between niobocene dichloride and α-, β-, and γ-cyclodextrins: preparation and characterization

The possible inclusion complexes of Cp₂NbCl₂ into α-, β-, and γ-CD hosts have been investigated. The existence of a true inclusion complex in the solid state was confirmed by a combination of thermogravimetric analysis, FTIR, PXRD, and ¹³C CP-MAS NMR spectroscopies. The solid-state results demonstrated that α-cyclodextrin does not form inclusion complexes with Cp₂NbCl₂ whereas β- and γ-cyclodextrins do form such complexes. PXRD, NMR, and thermal analysis showed that the organometallic molecules of Cp₂NbCl₂OH are included in the cavities of β- and γ-cyclodextrins, possibly adopting a symmetrical conformation in the complex, with each glucose unit in a similar environment. In solution, ¹H NMR experiments suggest that niobocene has a shallow penetration on the β-CD leading to upfield shift on H-3 signal with a minor perturbation on the H-5 proton while for γ-CD, both H-3 and H-5 are shifted upfield substantially. This suggests that niobocene penetrates deeper into the γ-CD cavity than in the β-CD cavity, as a result of the cavity size. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

UV–vis,IR and 1H NMR spectroscopic studies and characterization of ionic-pair crystal violet–oxytetracycline

The present study shows the formation and characterization of the ionic-pair between the antibiotic oxytetracycline and the dye crystal violet in ammonia solution pH 9.0 ± 0.2 extracted into chloroform. The characterization was demonstrated using UV–vis spectrophotometry, ¹H NMR, measurement of relaxation times T₁ and IR spectroscopy, using a comparison between the signals of individual pure compounds with the signals with the mixture CV–OTC in different alkaline media. The formation of ionic-pair was also corroborated by new signals and chemical shifts. (2D) NMR spectroscopy experiments show that the interaction is electrostatic.     

Host–guest complexation of a nitroheterocyclic compound with cyclodextrins: a spectrofluorimetric and molecular modeling study

Nitroheterocyclic compounds (NC) were candidate drugs proposed for Chagas disease chemotherapy. In this study, we investigated the complexation of hydroxymethylnitrofurazone (NFOH), a potential antichagasic compound, with α-cyclodextrin (α-CD), β-cyclodextrin (β-CD), Hydroxypropyl-β-cyclodextrin (HP-β-CD), Dimethyl-β-cyclodextrin (DM-β-CD) and γ-cyclodextrin (γ-CD) by fluorescence spectroscopy and molecular modeling studies. Hildebrand–Benesi equation was used to calculate the formation constants of NFOH with cyclodextrins based on the fluorescence differences in the CDs solution. The complexing capacity of NFOH with different CDs was compared through the results of association constant according to the following order: DM-β-CD > β-CD > α-CD > HP-β-CD > γ-CD. Molecular modeling studies give support for the experimental assignments, in favor of the formation of an inclusion complex between cyclodextrins with NFOH. This is an important study to investigate the effects of different kinds of cyclodextrins on the inclusion complex formation with NFOH and to better characterize a potential formulations to be used as therapeutic options for the oral treatment of Chagas disease.     

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.     

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.     

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.     

Naringenin Schiff base: antioxidant activity,acid–base profile,and interactions with DNA

A Schiff base derived from naringenin (NTSC) and its complex with Cu(II) ([Cu(H₃L)(OAc)]·H₂O, Cu(II)–NTSC) have been synthesized and characterized by physicochemical and spectroscopic methods. EPR studies confirmed that nitrogen, oxygen, and sulfur are the donor atoms bound to Cu(II) in the complex. The geometry of the complex has been modelled using DFT methods. Furthermore, naringenin and NTSC were used for the formation of Cu(II) complexes in solution, for comparison of biological activities. Antioxidant studies confirmed better radical scavenging activity of both NTSC and its Cu(II) complex compared to naringenin. The interaction of these compounds with calf thymus DNA was monitored by UV–Vis spectroscopy.     

Host–guest complexes of the antituberculosis drugs pyrazinamide and isoniazid with cucurbit[7]uril

The potential use of cucurbit[7]uril (CB[7]) as an excipient in oral formulations for improved drug physical stability or for improved drug delivery was examined with the antituberculosis drugs pyrazinamide (pyrazine-2-carboxamide) and isoniazid (isonicotinohydrazide). Both drugs form 1:1 host–guest complexes with CB[7] as determined by ¹H nuclear magnetic resonance spectrometry, electrospray ionisation mass spectrometry and molecular modelling. Drug binding is stabilised by hydrophobic effects between the pyridine and pyrazine rings of isoniazid and pyrazinamide, respectively, to the inside cavity of the CB[7] macrocycle as well as hydrogen bonds between the hydrazide and amide groups of each drug to the CB[7] carbonyl portals. At pH 1.5, isoniazid binds CB[7] with a binding constant of 5.6 × 10⁵ M^?1, whilst pyrazinamide binds CB[7] at pH 7 with a much smaller binding constant (4.8 × 10³ M^?1). Finally, CB[7] prevents drug melting through encapsulation. Where previously pyrazinamide displays a typical melting point of 189 °C and isoniazid 171 °C, by differential scanning calorimetry, no melting or degradation at temperatures up to 280 °C is observed for either drug once bound by CB[7].     

Determination of apparent binding constants by NSAIDs-βcyclodextrin complexes: HPLC, phase solubility diagrams and theoretical studies

The complexation of NSAIDs (nonsteroidal antiinflamatory drugs): Ibuprofen (Ibu), Ketoprofen (Ket) and Naproxen (Nap) with βcyclodextrin (βCD) has been studied from structural and thermodynamic points of view. The binding constants of NSAIDs-βCD complexes were determined by reversed phase liquid chromatography (RP-HPLC) and phase solubility diagrams using a UV–Vis spectrophotometric method varying the working temperature. The complexation efficiency (CE) values were determined: CE_Ibu ≈ CE_Nap < CE_Ket. Experimental measurements indicated that K_Nap-βCD > K_Ibu-βCD > K_Ket-βCD, and that the apparent stability constants decrease as the polarity of the solvent decreases. The changes of ?Hº (enthalpy), ?Sº (entropy) and ?Gº (Gibbs free energy) for the inclusion process were obtained by means of the van’t Hoff equation. In addition, semiempirical quantum mechanics calculations using the PM6 method were performed. The energetically favorable structures of the inclusion complexes were identified: the most favorable orientation was found to be the head down for all the complexes. Enthalpy for complexation processes was found to be favorable (?Hº < 0), entropy was found unfavorable (?Sº < 0) and Gibbs free energy was favorable (?Gº < 0). The theoretical results are in agreement with the experimental parameters associated with the encapsulation process.     

Structural connectivity of 18-Crown-6/H+/L-tryptophan noncovalent complexes in gas phase and in solution: Delineating host–guest–solvent interactions in solution from gas phase structures

We investigate the structural correlation of noncovalent crown ether/H⁺/L-tryptophan (CR/TrpH⁺) host–guest complexes in the solution phase with those in the gas phase generated through electrospray ionization/mass spectrometry (ESI/MS) techniques. We perform quantum chemical calculations to determine their structures, relative Gibbs free energies, and infrared spectra. We compare the calculated infrared (IR) spectra with the IR multiphoton dissociation (IRMPD) spectra observed for the 18-Crown-6/TrpH⁺ complex by Polfer and co-workers [J. Phys. Chem. A 2013, 117, 1181–1188] for assigning the IR bands. We observe that the carboxyl group remains “naked,” lacking hydrogen bonding with the CR unit in the gas phase, and that this most stable conformer originates from the corresponding lowest Gibbs free energy structure in solution. Based on these findings, we propose that gas phase host–guest complexes directly correlate with those in solution, reinforcing the possibility of obtaining invaluable information about host–guest–solvent interactions in solution from the structure of the host–guest pair in the gas phase.     

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.