Preparation and characterization of the crystalline inclusion complexes between cyclodextrins and poly(1,3-dioxolane)

The preparation and characterization of the crystalline inclusion complexes between a polymeric guest, poly(1,3-dioxolane) (PDXL), and small-molecular hosts, cyclodextrins (CDs) are reported. It is observed that the polymer guest can form crystalline inclusion complexes with three kinds of cyclodextrins, which may be attributed to the high oxygen atom density in PDXL chain. The crystalline inclusion complexes were characterized with FTIR , TGA, X-ray diffraction, SEM, 1H NMR and 13C CP/MAS NMR spectroscopes. It was found that the crystalline inclusion complexes have higher temperature stability than the pure CDs. The X-ray powder diffraction patterns of the crystalline inclusion complexes proved that they have columnar structures. 13C CP/MAS NMR spectra of the crystalline inclusion complexes indicate that CDs adopt a more symmetrical conformation in the complexes, while pure CDs assume a less symmetrical conformation in the crystal without a guest inside their cavities. The morphology of the crystal was     

Inclusion complexes of dihydroartemisinin with cyclodextrin and its derivatives: characterization,solubilization and inclusion mode

The characterization, inclusion complexation behavior and binding ability of the inclusion complexes of dihydroartemisinin with β-cyclodextrin and its derivatives, sulfobutyl ether β-cyclodextrin (SBE-β-CD), mono[6-(2-aminoethylamino)-6-deoxy]-β-cyclodextrin (en-β-CD) and mono{6-[2-(2-aminoethylamino)ethylamino]-6-deoxy}-β-cyclodextrin (dien-β-CD), were studied using phenolphthalein as a spectral probe. Spectral titration was performed in aqueous buffer solution (pH ca. 10.5) at 25 °C to determine the binding constants. The inclusion complexation behaviors were investigated in both solution and solid state by means of NMR, TG, XRD. The results showed that the water solubility and thermal stability of dihydroartemisinin were significantly increased in the inclusion complex with cyclodextrins (CDs). According to ¹H NMR and 2D NMR spectroscopy (ROESY), the A, B rings of dihydroartemisinin can be included into the cavity of CDs. The enhanced binding ability of CDs towards dihydroartemisinin was discussed from the viewpoint of the size/shape-fit concept and multiple recognition mechanism between host and guest.     

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.     

Preparation and characterization of inclusion complexes of pefloxacin mesylate with three kinds of cyclodextrins

The ability of alpha-cyclodextrin, beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin (alpha-CD, beta-CD and HP-beta-CD) to break pefloxacin mesylate (PM) aggregates by forming inclusion complexes has been studied using 1H NMR (nuclear magnetic resonance spectroscopy), 13C NMR and fluorescence spectra. The inclusion constants are determined to compare the corresponding inclusion capacity. Solid-inclusion complexes of PM with CDs are synthesized by coprecipitation method, and all the inclusion ratios are found to be 1:1. Additionally, spatial characterization of complexes has been proposed based on two-dimensional nuclear magnetic resonance technique (2D NMR) and spatial conformation is also investigated to propose two possible models between PM and CDs.     

H NMR titration and quantum calculation for the inclusion complexes of styrene and α-methyl styrene with α, β and γ-cyclodextrins

The inclusion behavior between styrene (α-methyl styrene) and cyclodextrins (CDs) was studied by using ¹H NMR titration in solution. The results indicate that 1:1 inclusion complexes were formed. The association constants of the inclusion complexes were determined by nonlinear least-square method. The inclusion process was also studied by using PM3 quantum-mechanical semi-empirical method. The calculated results are in agreed with the experimental data.     

Preparation and study on the inclusion complexes of two tanshinone compounds with beta-cyclodextrin

Solid inclusion complexes of two tanshinones (Tans): tanshinone IIA (Tan IIA), tanshinone I (Tan I) with beta-cyclodextrin (beta-CD) were synthesized by coprecipitation method. The solid inclusion complexes were characterized by using several analytical techniques: (1)H NMR spectra, IR spectra and thermal analysis. Stoichiometry of the inclusion complexes of Tans with beta-CD or HP-beta-CD is 1:1 which was investigated in solution. The formation constants of the complexes were determined by UV spectrophotometry. For same kind of CD, the stability was in the order: Tan IIA > Tan I; for same guest, the stability was in the order: HP-beta-CD > beta-CD. The effect of temperature on the inclusion interaction was examined and the thermodynamic parameters of inclusion process, Delta G, Delta H, Delta S were determined as well. The experimental results indicate that the inclusion process was an exothermic and enthalpy-driven process accompanied with a negative entropic contribution. The inclusion interaction between CD and Tans satisfied the law of enthalpy-entropy compensation.     

Determination of the structure of quinolone-γ-cyclodextrin complexes and their binding constants by means of UV–Vis and <Superscript>1</Superscript>H NMR

The host–guest inclusion complex structure and binding ability of two different quinolones with γ-cyclodextrin (γ-CD) were investigated in solution by means of UV–Vis and ¹H NMR spectroscopy. Competition of oxolinic and nalidixic acid molecules for the γ-CD cavity was evaluated by determination of association constants. Both quinolones form 1:1 inclusion complexes, their binding constants at room temperature (25 °C) under acidic and basic conditions were calculated using Benesi–Hildebrand equation. The stability of the complexes was dependent on the structure of the quinolone. In general, the weaker binding constants were observed for oxolinic acid-γ-CD complexes (1616 and 1765 M^?1) and the larger binding constants were obtained for nalidixic acid-γ-CD complexes (3760 and 3840 M^?1). ¹H NMR studies in D₂O were performed to elucidate the structure of each inclusion complex, nalidixic acid molecule penetrates more deeply into the γ-CD cavity and an intermolecular hydrogen bond is formed. Knowledge about structure and relative stability of quinolone-γ-CD complexes will be useful for future applications of these antimicrobial agents in medicinal chemistry.     

Study of the retention of aroma components by cyclodextrins by static headspace gas chromatography

The process of encapsulation is widely employed in the flavour industry to protect volatile and/or labile flavouring materials during storage. A variety of commercial practices are currently followed, but those involving the formation of flavour/cyclodextrin (CD) molecular inclusion complexes afford some of the greatest potential for increased product shelf life. The determination of the stability of inclusion complexes is of critical importance to take advantage of the complexation potential of CDs. Hence, we investigated the interactions between five CDs and thirteen aroma components. Relevant for, the retention of these compounds in presence of different CDs has been determined. The stability constants of the inclusion compounds have been calculated by static headspace gas chromatography in aqueous solution at 30 °C. The results indicate the formation of 1:1 inclusion complex for all the studied compounds. The binding between CDs and the aroma compounds depends on both hydrophobicity of the guest molecule and their geometric accommodation into the CD cavity. The results show that β-CDs are the most versatile CDs for the inclusion of the studied molecules.     

Theoretical and experimental study of the inclusion complexes of ferulic acid with cyclodextrins

The inclusion complexation behaviour of ferulic acid (FA) with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) was investigated by UV–vis, fluorescence and ¹H NMR spectroscopy. Since the guest may exist in either anionic or neutral form, the experiments were performed at different pH values. The stoichiometry and association constants of the complexes were determined by nonlinear regression analysis. The phase-solubility studies indicated that the water solubility of FA was improved through complexation with β-CD and HP-β-CD. An increase in the antioxidant reactivity was observed when inclusion complexes that FA formed with CDs were studied. Based on the NMR data, the spatial configurations of FA/β-CD and FA/HP-β-CD complexes were proposed, which suggested that FA entered into the cavity of β-CD from the narrow side, with the lipophilic aromatic ring and ethylenic moieties inside the CD cavity, and the –COOH group was close to the wider rim and exposed outside the cavity. A theoretical study of the complexes using molecular modelling gives the results in good agreement with the NMR data.     

Ternary β-Cyclodextrin Complexes as Models of Allosteric Effects

Two guests reacting with cyclodextrins (CDs) may form ternary complexes, in addition to the common competition of 1:1 complexes. One of the guests can really be included into the cavity of the CD, while the second guest molecule is either inserted close to the first one or attached to the outer surface of the supramolecule by H-bonding. There is a further possibility when the included guest bears a substituent outside the cavity and the second guest can interact with it. The properties of the ternary species formed are highly influenced by the solely (or primarily) included guest. The changes are attributed to the altered properties of the hydrophilic domain of the CD. The phenomena can be proved by NMR data obtained for some binary systems of -CD inclusion complexes and acetic acid and by the stability constants of the ternary complexes formed. Allosteric effects as well as coenzyme/apoenzyme/substrate interactions could be well modelled by these types of CD complexes.     

Complexation of ferrocene derivatives by the cucurbit[7]uril host: a comparative study of the cucurbituril and cyclodextrin host families

The formation of inclusion complexes between cucurbit[7]uril (CB[7]) and ferrocene and its derivatives has been investigated. The X-ray crystal structure of the 1:1 inclusion complex between ferrocene and CB[7] revealed that the guest molecule resides in the host cavity with two different orientations. Inclusion of a set of five water-soluble ferrocene derivatives in CB[7] was investigated by 1H NMR spectroscopy and calorimetric and voltammetric techniques. Our data indicate that all neutral and cationic guests form highly stable inclusion complexes with CB[7], with binding constants in the 10(9)-10(10) M(-)(1) and 10(12)-10(13) M(-1) ranges, respectively. However, the anionic ferrocenecarboxylate, the only negatively charged guest among those surveyed, was not bound by CB[7] at all. These results are in sharp contrast to the known binding behavior of the same guests to beta-cyclodextrin (beta-CD), since all the guests form stable inclusion complexes with beta-CD, with binding constants in the range 10(3)-10(4) M(-1). The electrostatic surface potentials of CB[6], CB[7], and CB[8] and their size-equivalent CDs were calculated and compared. The CD portals and cavities exhibit low surface potential values, whereas the regions around the carbonyl oxygens in CBs are significantly negative, which explains the strong affinity of CBs for positively charged guests and also provides a rationalization for the rejection of anionic guests. Taken together, our data suggest that cucurbiturils may form very stable complexes. However, the host-guest interactions are very sensitive to some structural features, such as a negatively charged carboxylate group attached to the ferrocene residue, which may completely disrupt the stability of the complexes.     

Inclusion complexes of cyclodextrins with hydrophobic ionic liquids

Two imidazolium-based hexafluorophosphate ionic liquids (ILs), 1-butyl-3-methylimidazolium hexafluorophosphate and 1-dodecyl-3-methylimidazolium hexafluorophosphate, were used to form inclusion complexes (ICs) with α- and β-cyclodextrins (CDs). Formation of the ICs of each CD with each IL was confirmed by the appearance of a characteristic peak in the UV region. Characterisation of the ICs by NMR and FT-IR spectroscopy provided information about the interactions between the host and guest molecules and the structure of the ICs. Temperature-dependent particle size analysis by dynamic light scattering suggested that the size of the host and the guest governs their stability.     

Complexation of sodium picosulphate with beta cyclodextrin: NMR spectroscopic study in solution

Sodium Picosulphate (SPL) is a synthetic drug, widely used for thorough evacuation of the bowel, usually for patients who are preparing to undergo a colonoscopy. Cyclodextrins (CDs) are chiral, truncated cone shaped, cyclic oligosaccharides that can encapsulate a variety of drug molecules into inclusion complexes, thereby increasing their stability and solubility. ¹H NMR spectroscopic studies showed the inclusion complexation between β-CD and SPL, based on the upfield shift changes in the β-CD cavity protons (H-3′ and H-5′) and downfield shift changes in the guest (SPL) protons. The structure of inclusion complexes was determined by 2D ROESY spectral data. The 1:1 stoichiometry and overall association constant (Ka) were determined by using Scott’s plot method to be 450 M^?1.     

Study on inclusion interaction of piroxicam with beta-cyclodextrin derivatives

The inclusion behavior of piroxicam (PX) with beta-cyclodextrin (beta-CD), hydroxypropyl-beta-cyclodextrin (HP-beta-CD), and carboxymethyl-beta-cyclodextrin (CM-beta-CD) was investigated by using steady-state fluorescence and nuclear magnetic resonance (NMR) technique. The various factors affecting the inclusion process were examined in detail. The remarkable fluorescence emission enhancement upon addition of CDs suggested that cyclodextrins (CDs) were most suitable for inclusion of the uncharged species of PX. The stoichiometry of the PX-CDs inclusion complexes was 1:1, except for beta-CD where a 1:2 inclusion complex was formed. The formation constants showed the strongest inclusion capacity of beta-CD. NMR showed the inclusion mode of PX with CDs.     

Binding behaviors of scutellarin with α-, β-, γ-cyclodextrins and their derivatives

A series of cyclodextrin/scutellarin inclusion complexes were prepared from α-cyclodextrin, β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin with scutellarin (SCU), and their inclusion complexation behaviors, such as stoichiometry, complex stability constants and inclusion mode, were investigated by means of UV/Vis spectroscopy, ¹H NMR and 2D NMR. The results showed that the SCU could be efficiently encapsulated in the cyclodextrin cavity in aqueous solution to produce complexes that were more soluble than free SCU. The enhanced binding ability of cyclodextrins towards SCU was discussed from the viewpoint of the size/shape-fit and multiple recognition mechanism between host and guest.     

Formation and characterization of inclusion complexes of poly(butylene succinate) with alpha- and gamma-cyclodextrins

The inclusion complexes (ICs) of alpha- and gamma-cyclodextrins (CDs) with high-molecular-weight poly(butylene succinate) (PBS) were prepared and characterized by differential scanning calorimetry, Fourier-transform infrared spectroscopy (FT-IR), wide-angle X-ray diffraction, solid-state 13C nuclear magnetic resonance (NMR) spectroscopy, and solution 1H NMR spectroscopy. The resultant ICs were found to have channel structures. FT-IR data suggested that the ICs were stabilized by hydrogen bonds between the host CD molecules and the guest PBS chains. Through the formation of ICs, the PBS chain possibly adopts the kink conformation in the included state, as indicated by NMR analysis.     

The binding behavior of cyclodextrins toward a nitroxide spin probe in the presence of different alcohols as studied by EPR

Stability constants, rates of association and dissociation, and thermodynamic and activation parameters for the formation of inclusion complexes between the radical guest, N-benzyl- tert-butyl- d 9-nitroxide and beta- or 2,6- O-dimethyl-beta-cyclodextrin (CDs), have been determined by EPR spectroscopy in water in the presence of 14 different alcohols, differing in size and lipophilicity. In all cases, it was found that addition of alcohol, depending on its structure and concentration, causes a reduction of the stability of the paramagnetic complex. Global analysis of EPR data allowed us to explain the CDs binding behavior: we discarded the formation of a ternary complex, where alcohol and radical guest are coincluded into CD cavity, while data were found more consistent with the formation of a binary complex alcohol:CD competing with the monitored complex nitroxide:CD. Both kinetic and thermodynamic analysis of the experimental results have revealed that the presence of alcohols affects to a larger extent the dissociation rather then the association of radical probe and CD and that the former process is of greater importance in determining the stability of the complex, this confirming the reliability of the competition model proposed. This competition has been used for the indirect determination of the stability constants of complexes between CD and examined alcohols. By using a similar approach, we showed EPR spectroscopy can be considered a rapid and accurate technique to investigate the CDs binding behavior toward different nonradical guest.     

Physicochemical Study of Ribavirin Complexes with α-, β- and γ-Cyclodextrins

The aim of this work was to characterise interactions between ribavirin (RBV) and native cyclodextrins (CDs). The extent of complexation in solution has been evaluated by high performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR). Thermogravimetry (TG), differential scanning calorimetry (DSC) and infrared spectroscopy (FT-IR) were used to characterise the solid state of all the binary systems. Complexation of RBV with α-, β-, and γ-CDs was proved by FT-IR, HPLC and thermal analysis. The 1:1 stoichiometry for the complexes was obtained by HPLC. The stability constants for RBV with α-, β- and γ-CD were determined to be 1493, 2606, and 1179 M⁻¹, respectively. Consequently β-CD was the most suitable of the three complexing agents since it showed the highest stability constant. RBV appears not included inside the cavity of the CD because H-3 and H-5 protons were not shifted in the presence of the molecule as proved by NMR. The 2D ROESY spectra did not show any dipolar proton interaction of the RBV with the CDs. Thus the complexation does not seem to be a host–guest inclusion complex but an external intermolecular complex. FT-IR spectral changes due to the RBV carboxamide group vibrations with the CDs confirm this association.     

Crown ether-based cryptand/tropylium cation inclusion complexes

Host–guest complexation between crown ether-based cryptand hosts and a carbonium ion, tropylium hexafluorophosphate was studied. ¹H NMR, NOESY NMR, and electrospray ionization mass spectrometry were employed to characterize these inclusion complexes. The contrast tests of ¹H NMR and association constants indicated that cryptands are much better hosts for tropylium hexafluorophosphate than the corresponding simple crown ethers. C–H?O hydrogen bonding, face-to-face π-stacking interactions, and charge-transfer interactions are thought to be the main driving forces for the formation of these host–guest complexes. These multiple non-covalent interactions may jointly contribute to the complex formation and considerably reinforce the complex stability. Moreover, the complexation between dibenzo-24-crown-8-based cryptand 4 and tropylium hexafluorophosphate 7 can be reversibly controlled by adding KPF₆ and then DB18C6 in 1:1 acetonitrile/chloroform, providing a new cation-responsive host–guest recognition motif for supramolecular chemistry.     

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.