Spectroscopic characterisation of the inclusion complexes between the antifungal drugs naftifine and terbinafine and cyclodextrins

The complexation of naftifine (NF) and terbinafine (TB) with cyclodextrins (CDs) has been investigated by UV/visible and ¹H NMR spectroscopy, ROESY techniques and also ESI-MS. Both drugs form 1:1 inclusion complexes with all the CDs tested except with α-CD, as deduced from the Benesi–Hildebrand plots and confirmed by ESI-MS and NMR spectroscopy (Job plot method). The K ₁₁ values for NF decrease in the order β-CD > methylated β-CD > 2-hydroxypropyl-β-CD >γ-CD. The determination of the enthalpy and entropy provides information about the main driving forces in the process. The stability constants of the complexes NF–β-CD, TB–β-CD and TB–γ-CD determined by ¹H NMR spectroscopy are in agreement with the values obtained by UV. For TB–β-CD, the value is higher, due to the fact that the length of the TB aliphatic chain allows a deeper inclusion of the naphthalene group inside the corresponding β-CD molecule, according to the 2D ROESY experiments.     

Interaction of 1-methyl-1-({2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl) piperidinium chloride with β-CD: spectroscopic,calorimetric and molecular modeling approaches

Spectroscopic investigation supported by molecular modeling methods has been used to describe the inclusion complex of β-cyclodextrin (β-CD) with 1-Methyl-1-({2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methyl) piperidinium chloride (1MPTMPC) in solution and in solid state. The formation of inclusion complex between the β-CD and the 1MPTMPC has been investigated both in solution and in the solid state. Solution-state complexation between the 1MPTMPC and β-CD was established using ¹H NMR spectroscopy and isothermal titration calorimetry (ITC). From the ¹H NMR spectroscopic studies, 1:1 complex stoichiometry was deduced with an association constant (K) of 925 M^?1. Using an independent binding model, the ITC technique provides a K value of the same order with the one determined by NMR and the thermodynamic parameters ΔH, ΔS and ΔG which reveals driving forces involved during complex formation. The formation of the solid inclusion compound was confirmed by X-ray powder diffraction and differential scanning calorimetry. The most probable conformation of the inclusion complex obtained through a molecular docking investigation corroborates well to ROESY experiment.     

Studies on α-, β-, and γ-cyclodextrin inclusion complexes of isoquinoline alkaloids berberine, palmatine and coralyne

The complexation of three isoquinoline alkaloids berberine, palmatine and coralyne with α-, β-, and γ-CDs were studied by absorption, fluorescence, circular dichroism, NMR spectroscopy and microcalorimetric assay techniques. Their binding constant (K _BH) values were determined by Benesi–Hildebrand equation. All the alkaloids formed 1:1 stoichiometry complexes with the cyclodextrins (CDs). The binding affinity is largest in β-CD followed by γ-, and α-CD for coralyne, followed by berberine and then palmatine. The thermodynamic parameters of the complexation were determined by calorimetry. The stoichiometry of complex formation and the variation of the apparent binding constant from spectroscopic studies were confirmed by calorimetry. The formation of the inclusion complexes was entropy driven in almost all the systems. Coralyne formed the strongest complex with all the CDs, followed by berberine and palmatine in that order. Coralyne-β-CD complex was studied through NMR, indicating more than one interaction mode.     

A comparative study of inclusion complexes of flunarizine with alpha (α-CD) and beta-cyclodextrin (β-CD)

A detailed NMR (¹H, COSY, and ROESY) spectroscopic study of complexation of Flunarazine (FL) with α- and β-CD was carried out. ¹H NMR titration studies confirmed the formation of FL/α-CD and FL/β-CD complexes as evidenced by chemical shift variations of the proton resonances of both the CDs and FL. The stoichiometry of the complexes was determined to be 1:2 (FL/α-CD) and 1:1 (FL/β-CD) and overall binding constants were also calculated. It was confirmed with the help of ROESY spectral data that only one of the F-substituted aromatic ring and phenyl ring penetrate the α-CD cavity while both F-substituted aromatic rings as well as phenyl ring penetrates the β-CD cavity during complexation. The binding modes of FL/CD cavity interactions derived from ROESY experimental data show that the resulting complex of FL with β-CD possesses better induced fit interaction as compared to α-CD, which is responsible for the enhanced molecular stability with β-CD in comparison to α-CD. The mode of penetration of guest into the CD cavity and structures of the complexes has been established.     

Cyclodextrin inclusion of four phenylurea herbicides: determination of complex stoichiometries and stability constants using solution 1H NMR spectroscopy

An inclusion complex formation between α- and β-cyclodextrin and four phenylurea analogues, namely metobromuron, monolinuron, monuron and fenuron, is reported. Complex formation was established using solution ¹H NMR spectroscopy. Complex stoichiometries were determined by the method of continuous variation using the chemically induced shifts of both the host and guest protons. An analysis of the spectroscopic data revealed the stoichiometry as 1:1 in all cases while a further analysis of the same data yielded values for the association constant K ranging from 208 to 2749 M^? 1. From the observed chemical shifts it was deduced that in all cases, only the guest aromatic ring enters the host cavities, the substituted urea moiety protruding from the secondary rim in the case of α-cyclodextrin, but from the primary rim in the case of β-cyclodextrin.     

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.     

Physicochemical properties,antioxidant action and practical application in fresh cheese of the solid inclusion compound γ-cyclodextrin·quercetin,in comparison with β-cyclodextrin·quercetin

Quercetin is an antioxidant flavonol very sensible to light and oxidants that can benefit from stabilisation by encapsulation into cyclodextrins. In this work we study the solid inclusion compounds of quercetin with β- and γ-cyclodextrins (β-CD and γ-CD) obtained by freeze-drying. Combined results from microanalysis, FT-IR, powder X-ray diffraction, ¹³C{¹H} CP/MAS NMR spectroscopy and thermogravimetry demonstrating that γ-CD, having a larger cavity, is the most adequate host to form a stable inclusion complex with quercetin. The anti-peroxidation capacity of the compounds was determined and followed the order β-CD·quercetin ≫ quercetin > γ-CD·quercetin. Both γ-CD·quercetin and β-CD·quercetin are able to inhibit DPPH radicals at a rate three times faster than pure quercetin, but their EC₅₀ is higher (50 μM vs 17 μM for quercetin). The practical applicability of the two CD·quercetin adducts as nutraceutical additives in fresh cheese was established. Fortified fresh cheese had a firmer texture and yellowish colour, but no significant changes in the overall sensorial qualities were found by a panel of non-trained tasters when compared with the control (non-treated fresh cheese).     

Kinetic studies on the thermal dissociation of β-cyclodextrin-cinnamyl alcohol inclusion complex

The stability of β-cyclodextrin-cinnamyl alcohol inclusion complex (β-CD·C₉H₁₀·8H₂O) was investigated using TG and DSC. The mass loss took place in three stages: the dehydration occurred between 50–120°C; the dissociation of β-CD·C₉H₁₀O occurred in the range of 210–260°C; and the decomposition of β-CD began at 280°C. The dissociation of β-CD·C₉H₁₀O was studied by means of thermogravimetry, and the results showed: the dissociation of β-CD·C₉H₁₀O was dominated by a two-dimensional diffusion process (D₂). The activation energyE was 161.2 kJ mol^?1, the pre-exponential factorA was 4.5×10¹³ min^?1. Cyclodextrin is able to form inclusion complexes with a great variety of guest molecules, and the interesting of studies focussed on the energy binding cyclodextrin and the guest molecule. In this paper, β-cyclodextrin-cinnamyl alcohol inclusion complex was studied by fluorescence spectrophotometry and infrared absorption spectroscopy, and the results show: the stable energy of inclusion complexes of β-CD with weakly polar guest molecules consists mainly of Van der Waals interaction.     

Investigation on Non-covalent Complexes of Cyclodextrins with Li+ in Gas Phase by Mass Spectrometry

To investigate the non-covalent interaction between cyclodextrins (CD) and lithium ion, a stoichiometry of α-CD, β-CD, heptakis(2,6-di-O-methyl)-β-CD (DM-β-CD), or heptakis(2,3,6-tri-O-methyl)-β-CD (TM-β-CD) was mixed with lithium salt, respectively, and then incubated at room temperature for 10 min to reach the equilibrium. In posi-tive mode, the electrospray ionization mass spectrometry (ESI-MS) results demonstrated that lithium ion can conjugate to α-, β-, DM-β- or TM-β-CD and form 1:1 stoichiometric non-covalent complexes. The binding of the complexes was further confirmed by collision-induced dissociation. The dissociation constants K_d1 of four complexes (Li+α-CD, Li+β-CD, Li+DM-β-CD, and Li+TM-β-CD) were determined by mass spectrometric titration. The results showed K_d1 were 18.7, 26.7, 33.6, 30.5 μmol/L for the complexes of Li+ with α-CD, β-CD, DM-β-CD, and TM-β-CD, respectively. K_d1 for the Li⁺ complexes of β-CD is smaller than that of DM-β-CD due to its steric effect of the partial substituted -CH₃. The Kd1 for the Li⁺ complexes of DM-β-CD is nearly in agreement with that of TM-β-CD, indicating Li⁺ is more likely to locate in the small rim of DM-β-CD's hydrophobic cavity. The DFT results showed through electrostatic interaction, one Li+ can strongly conjugate to four neighboring oxygen atoms. For the (α-CD+Li)⁺ complex, one Li⁺ may also situate the small rim of α-CD's hydrophobic cavity to form a non-specific host-guest complex.     

Inclusion complexes of rosmarinic acid and cyclodextrins: stoichiometry,association constants,and antioxidant potential

The interaction between β-cyclodextrin (β-CD) and the polyphenol rosmarinic acid (RA) is here reported by ¹H NMR titration experiments. The formation of an aqueous soluble inclusion complex is confirmed and valuable information regarding mode of penetration of guest into β-CD, stoichiometry, and stability of the complex is obtained. The analysis by the continuous variation method shows the undoubted formation of 1:1 β-CD/RA complex. Additionally, the estimated apparent association constants reveal the importance of the asymmetry of the RA in the complexation; the incorporation of the catechol moiety closer to the carboxylic group is more favorable (K?=?2,028 M^?1) than from the other end of the RA molecule (K?=?1,184 M^?1). Finally, we have also investigated the antioxidant activity and storage stability of the β-CD/RA complexed system; the presence of β-CD was found to produce a remarkable enhancement on the antioxidant activity.     

Spectroscopic study and antioxidant activity of the inclusion complexes of cyclodextrins and amlodipine besylate drug

The aim of the study was to synthesize and characterization the inclusion complexes of amlodipine besylate (AML) drug with β-cyclodextrin (β-CD) and γ-cyclodextrin (γ-CD) which has antioxidating activity property. The guest/host interaction of AML with β-CD and γ-CD in order to complexation drug in β-CD and γ-CD were investigated. The interaction inclusion complexes was characterized by fourier transform infrared and ultraviolet–visible spectroscopies. The formation constant was calculated by using a modified Benesi–Hildebrand equation at 25 °C. The stoichiometry of inclusion complexes was found to be 1:1 for β-CD and γ-CD with AML drug. The antioxidant activity of AML drug and its inclusion complexes were determined by the scavenging of stable radical 2,2′-diphenyl-1-picrylhydrazyl (DPPH^·). Kinetic studies of DPPH^· with AML and CDs complexes were done. The experimental results confirmed the forming of AML complexes with CDs also these indicated that the AML/β-CD and AML/γ-CD inclusion complexes was the most reactive than its free form into antioxidant activity.     

Characterization of β-cyclodextrin inclusion complex with procaine hydrochloride by 1H NMR and ITC

The inclusion of local anesthetic drug procaine hydrochloride by β-cyclodextrin was investigated by 1D and 2D proton NMR spectroscopy and isothermal titration calorimetry (ITC) at 298 K. The stoichiometry of the complex was determinate by the method of continuous variation, using the chemical induced shift of both host and guest protons. The association constant K, of the obtained complex was calculated and found to be 293.17 M^?1. Rotating frame NOE spectroscopy, was used to ascertain the solution geometry of the host–guest complex. The result reveals that the procaine molecule penetrates into the β-cyclodextrin cavity with the aromatic ring. The energetics of complexation process is investigated by ITC technique. The analysis indicates that the complexation of procaine by β-CD is an exothermic process and show that both enthalpy and entropy contribute to the binding process. The obtained value for the association constant is in good agreement with that obtained from NMR.     

Spectral modulation of a charge transfer reaction of 2-methoxy-4-(N,N-dimethylamino)benzaldehyde inside cyclodextrin nanocage

This article reports modulation of intramolecular charge transfer (ICT) reaction of 2-methoxy-4-(N,N-dimethylamino)benzaldehyde (2-MDMABA) encapsulated within the cyclodextrin nanocavities investigated by steady state and time resolved measurements. The ICT emission, absent in bulk water, originates in the presence of α-, β- and γ-CD with the huge enhancement of local emission. From the Benesi–Hildebrand plot, the stoichiometry of the host–guest inclusion complex is found to be 1:1 for β- and γ-CD whereas 1:1 and 1:2 guest to host complexation occur at low and high concentration of α-CD, respectively. The association constants of the inclusion complexes have also been estimated from the Benesi–Hildebrand plot. The greater binding capability of 2-MDMABA with β-CD than that of other two CDs is further supplemented by time resolved study.     

Inclusion of the allicin mimic S-p-tolyl t-butylthiosulphinate in β-cyclodextrin

Allicin, the active thiosulphinate present in freshly crushed garlic, has potent antimicrobial activity but is chemically labile. As part of a study aimed at producing stable allicin analogues as potential antimicrobial agents, the allicin mimic S-p-tolyl t-butylthiosulphinate was synthesised and complexed with β-cyclodextrin (β-CD). The inclusion complex, β-CD·S-p-tolyl t-butylthiosulphinate·12.5H₂O, was characterised by thermal analysis techniques (HSM, TG, DSC), powder X-ray diffraction and single-crystal X-ray diffraction. The inclusion complex is dimeric (space group C222₁) with the guest disordered over three positions. Within each β-CD molecule of the dimer, each disordered guest component is located in the host cavity with the t-butyl group protruding slightly from the primary hydroxyl side, while the phenyl ring is situated near the secondary hydroxyl side and the thiosulphinate moiety is centrally located within the host cavity. Stereoselectivity of guest inclusion is implicit in the disordered model, which reflects a 2:1 ratio of S- and R-enantiomers in the β-CD cavity.     

β-Cyclodextrin Inclusion Complexes of 2-Hydroxyfluorene and 2-Hydroxy-9-fluorenone: Differences in Stoichiometry and Excited State Prototropic Equilibrium

We report that 1:1 and 1:2 complexes are formed for 2-hydroxy-9-fluorenone with β-cyclodextrin (β-CD) and that there is an unusual red shift in emission at higher concentrations of β-CD. Between different stoichiometries of the complexes the titrimetric curves for the neutral–anionic equilibria for the guests differ drastically and so do the excited state pK values. The formation of an 1:1 inclusion complex with 2-hydroxy-9-fluorenone (2HFN) as the guest in β-CD with the binding constant (K) of 606.65 L·mol^?1 was determined. The ground and excited state pK _a values for the neutral–mono-anion equilibrium are not affected by β-CD. Hence the hydroxyl group is considered exposed in the aqueous environment. Two different types of inclusion complexes of 2HFN were observed in β-CD. The 1:2 complex of 2HFN shows a red shift from the 1:1 complex and is less fluorescent that the 1:1 complex. The red shift reveals that the 1:2 complex is more stabilized than the 1:1 complex. The excited state pK _a values in both complexes with β-CD are higher that those in aqueous solution. This shows that the complexation makes the molecule less acidic in the S1 state. The β-CD molecule is perceived as not able to encapsulate the 2HFN molecule fully, but the larger rim of the β-CD comes closer to the C=O group. The other half of the 2HFN molecule is encapsulated by the second β-CD molecule and thus there is formation of the 1:2 inclusion complex at higher concentrations of β-CD.     

Host–guest association of Morin with β-CD and C-hexylpyrogallol[4]arene: Structure of the complexes and the effect of pH

The study of the host–guest association of Morin hydrate (MO) with β-cyclodextrin (β-CD) and C-hexylpyrogllol[4]arene (C-HPA) is reported in this paper. The iInclusion complexation of MO is studied by ultraviolet-visible, steady-state fluorescence, time-resolved fluorescence, ¹H nuclear magnetic resonance (NMR), and two dimentional rotating-frame nuclear overhauser effect correlation (2D ROESY) spectroscopic techniques. The stoichiometry and the binding constant for the MO–β-CD complex are derived from the linearity of the Benesi–Hildebrand equation. The binding constant for the MO–C-HPA complex is calculated from the nonlinear curve fitting of fluorescence intensities. The effects of the acid strength on the absorption and fluorescence spectra of MO are studied in the absence and the presence of β-CD/C-HPA host molecules. The pK _a values of the ground and the excited states are reported.     

Study of the interaction between modified cyclodextrin and octopriox : potential applications in drug delivery

Host–guest interactions between the antifungal agent Octopirox^® (Oc) and modified β-cyclodextrin-derivatives were studied using ¹H- and 2D-ROESY NMR spectroscopy, Job-Plot and isothermal titration calorimetry (ITC). In addition to β-cyclodextrin (β-CD) a number of derivatives, namely randomly methacrylated β-cyclodextrin (RM-β-CD), mono-methacrylated β-cyclodextrin (MM-β-CD), randomly methylated β-cyclodextrin (RAMEB), hydroxypropyl-β-cyclodextrin (HP-β-CD) and randomly methacrylated hydroxypropyl-β-cyclodextrin (RM-HP-β-CD) were used. NMR data suggests the formation of highly ordered complexes, while ITC measurements allowed the identification of their stoichiometries and the thermodynamic data. To evaluate the possibility of retarded drug release from complexes prepared from polymeric materials like artificial nails, the complexes were polymerized with comonomers and subjected to aqueous extraction followed by quantification of Oc release by means of UV-spectroscopy.     

Complexation of Fluvastatin Sodium with β-Cyclodextrin: NMR Spectroscopic Study in Solution

¹H NMR spectroscopic study of fluvastatin sodium (FLU), β-Cyclodextrin (β-CD) and their mixtures confirmed the formation of FLU/β-CD inclusion complex in solution. The stoichiometry of the complex was determined to be 1:1 and the overall binding constant (K _s) was calculated to be 340 M⁻¹. Two dimensional COSY, ROESY and DEPTO experiments were performed for the unambiguous assignment of aromatic proton resonances and it was found that two isomeric forms of FLU are present in solution. It was confirmed with the help of ROESY spectral data that only F-substituted aromatic ring penetrates the β-CD cavity and there is chiral differentiation by the β-CD as one of the isomer binds more strongly, which is indicated by the intensity of correlation peaks. The mode of penetration of the guest into the β-CD cavity was also established and structure of the complex has been proposed.     

Complexation of Ketoconazole by Native and Modified Cyclodextrins

Complexation of ketoconazole (KET), a broad-spectrum antifungal drug, with β- and γ-cyclodextrins (CDs), heptakis (2,6-di-O-methyl)-β-CD (2,6-DM-β-CD), heptakis (2,3,6-tri-O-methyl)-β-CD (TM-β-CD), 2-hydroxypropyl-β-CD (2HP-β-CD) and carboxymethyl-β-CD (CM-β-CD) was studied. The stability constants were determined by the solubility method at pH = 6 and for 2,6-DM-β-CD and CM-β-CD at pH = 5. At pH = 6, the stability constants increased in the order: TM-β-D < γ-CD < 2HP-β-CD < β-CD < CM-β-CD < 2,6-DM-β-CD. At pH = 5, due to the increased ionization of KET, the stability constant with CM-β-CD increased and with 2,6-DM-β-CD decreased. For complexes of KET with 2HP-β-CD and 2,6-DM-β-CD, the thermodynamic parameters of complexation were determined from the temperature dependence of the corresponding stability constants. For β–γ and TM-β-CD complexes, calculations using HyperChem 6 software by the Amber force field were carried out to gain some insight into the host–guest geometry.     

Formation of nanotubes and secondary assemblies of cyclodextrins induced by BBOT

The study of cyclodextrin nanotubes is a significant topic among the self-assembly behaviors of cyclodextrins. We report herein the interaction of 2,5-bis(5′-tert-butyl-2-benzoxazoyl)thiophene (BBOT) with α-, β-, γ-cyclodextrins (CDs). It has been discovered that the reaction patterns of BBOT with CDs are remarkably different. β-CD forms a simple inclusion complex with BBOT in a stoichiometry of 1:2 (guest:host). β-CD forms a 1:1 inclusion complex with BBOT at its low concentration. At higher concentration of BBOT, the nanotube and secondary assembly of β-CD are formed. As for γ-CD, the nanotube and secondary assembly are formed within the whole concentration range of BBOT studied. The structure of γ-CD nanotubes is different from that of β-CD nanotubes to a certain extent.