Cyclodextrin Inclusion Complex Formation Research Articles

Prediction and design of cyclodextrin inclusion complexes formation via machine learning-based strategies

This study reports a machine-learning (ML) method to develop multi-purpose prediction strategies for the formation of cyclodextrin inclusion complexes (ICs) in aqueous solutions. A balanced dataset of pharmaceutically relevant molecules was constructed using experimental verification. Three ML models (artificial neural network, support vector machine, and logistic regression) were established and optimized to predict IC formation. To provide more reliable approaches for different prediction requirements, ML-based linear, recall-first, and precision-first strategies were further established based on the ML models for the maximum recall or precision values. The proposed recall-first strategy identified all positive samples to avoid missing data in the prediction, and the precision-first strategy accurately identified positive samples to reduce the number of validation experiments. The ML-based prediction strategies for IC formation were first established and showed high accuracy and reliability. These strategies provide higher efficiency and lower processing cost solutions for IC screening.

Encapsulation of Carotenoids as Food Colorants via Formation of Cyclodextrin Inclusion Complexes: A Review

The use of natural carotenoids as food colorants is an important trend of innovation in the industry due to their low toxicity, their potential as bio-functional ingredients, and the increasing demand for natural and organic foods. Despite these benefits, their inclusion in food matrices presents multiple challenges related to their low stability and low water solubility. The present review covers the main concepts and background of carotenoid inclusion complex formation in cyclodextrins as a strategy for their stabilization, and subsequent inclusion in food products as color additives. The review includes the key aspects of the molecular and physicochemical properties of cyclodextrins as complexing agents, and a detailed review of the published evidence on complex formation with natural carotenoids from different sources in cyclodextrins, comparing complex formation methodologies, recovery, inclusion efficiency, and instrumental characterization techniques. Moreover, process flow diagrams (PFD), based on the most promising carotenoid-cyclodextrin complex formation methodologies reported in literature, are proposed, and discussed as a potential tool for their future scale-up. This review shows that the inclusion of carotenoids in complexes with cyclodextrins constitutes a promising technology for the stabilization of these pigments, with possible advantages in terms of their stability in food matrices.

Thermodynamics of antibiotics: natural cyclodextrin inclusion complex formation and covering of nano-metric calcite with these substances

Isothermal titration calorimetry (ITC) has been used to characterize inclusion complex formation of natural (α-, β-, γ-)cyclodextrins with antibiotics (ampicillin—sodium, penicillin G—sodium, streptomycin sulfate) in aqueous solutions. ITC measurements were taken at 298.15 K on Isothermal Titration Calorimeter Nano ITC. The experimental data were analyzed on the basis of the independent site model. Based on the experimental values of equilibrium constant (K) and enthalpy of complex formation (ΔH), the Gibbs energy of complex formation (ΔG) and the entropy of complex formation (ΔS) have been calculated. The analysis of the obtained inclusion complexes show that independently of the kind of cyclodextrin and antibiotics the obtained equilibrium constants are almost the same, but it is a difference between the changes in enthalpies of complex formation for the investigated systems. The stoichiometry of complexes formed both by ampicillin—sodium and by penicillin G—sodium with all the natural cyclodextrins is the same and equal to 1:1 and the complex formation is entropy driven. Three antibiotics (ampicillin—sodium, penicillin G—sodium and streptomycin sulfate) have been used further for covering of the monodisperse calcium carbonate nanoparticles obtained in the reactor (three-phase reaction) with rotating disks. Three series of experiments have been performed. First was connected with adsorption of the antibiotics on the surface on nano-calcite and two others with intercalation of the drugs into nano-metric CaCO3 structure (aggregates). An intercalation has been performed in two ways: one where the antibiotic was added to the reactor chamber at the beginning of the precipitation reaction and second where it was added just after the end of the reaction. Both pure CaCO3 nanoparticle and antibiotic-coated CaCO3 powders were deeply analyzed by the use of the thermogravimetric and the differential scanning calorimetry method. The performed investigations showed that all the antibiotics used can be both adsorbed and intercalated into the nano-metric CaCO3 obtained in the reactor with rotating disks. The different adsorption obtained by different antibiotics was caused by the different interaction between them and nano-calcite, caused by their different structure. The experimental data have allowed also for distinction between the antibiotics molecules present on calcite surface (adsorption) or antibiotics molecules intercalated into the nano-calcite structure. The conducted research shows that both approaches, i.e., formation of inclusion complexes with natural cyclodextrins and covering (adsorption and intercalation) of nano-metric CaCO3, can be successfully implemented for their pharmaceutical applications.

Treating an old disease with new tricks: strategies based on host–guest chemistry for leishmaniasis therapy

This critical mini-review is focused on leishmaniasis, namely on the factors causing the re-emergence of the disease, the available therapies and their limitations. It then looks into the tools available within the field of host–guest chemistry and that are now arising as innovative solutions for the treatment of infections caused by different species of the Leishmania genus. These include the use of cyclodextrins as medicinal agents per se, as well as the formation of cyclodextrin inclusion complexes for the amelioration of biophysical properties and in vivo activities of leishmanicidal drugs. A focus is given on the practical utility of the results reported in the literature, evaluating their potencial of transition from the bench to the market.

A review on thermal analyses of cyclodextrins and cyclodextrin complexes

Cyclodextrins are valuable natural or synthetically modified cyclic oligosaccharides that are widely used for ameliorating properties of biologically active compounds such as food additives and ingredients or medicinal compounds. They protect these compounds against light and oxidative degradation and provide host–guest supramolecular complexes having controlled release properties by molecular encapsulation, enhancing the water solubility and bioavailability. Among many characterization methods that are applicable in both solution and solid state, thermal techniques were widely used for analysis and stability evaluation of cyclodextrins and cyclodextrin complexes. This updated review deals with the use of thermal methods for analysis of cyclodextrins and cyclodextrin complexes. Classical and modern thermal techniques used for evaluation of inclusion compound formation were reviewed. Special attention was gave for thermogravimetry–differential thermogravimetry, differential thermal analysis, differential scanning calorimetry, hot stage microscopy, as well as for the more recent techniques thermogravimetry–mass spectrometry, gas chromatography-time-of-flight-mass spectrometry and isothermal titration calorimetry. In order to evaluate the cyclodextrin complexation capability by thermal methods, we grouped for the first time the guest compound as drugs by anatomical therapeutic chemical classification (ATC), as well as odorants, essential oils and vegetable extracts, antioxidants, fatty acids, oils, fatty acid-based derivatives, other organic, organometallic and inorganic compounds. The formation of cyclodextrin inclusion complexes was emphasized by disappearance of the signal corresponding to the melting or boiling points of the guest compound and the behavior of the hydration water molecules in the complex in comparison with the raw host and guest compounds. The thermal stability of the guest compound after cyclodextrin complexation was also discussed. It was emphasized that thermal methods are some of the most valuable techniques for analyzing cyclodextrin complexes and together with other methods can complete the information related to the host–guest molecular inclusion process and the specific properties of these cyclodextrin complexes.

Advances in the use of functional composites of β-cyclodextrin in electrochemical sensors.

β-Cyclodextrin (β-CD) possess a hydrophobic inner cavity and a hydrophilic exterior surface. They exhibit excellent inclusion properties with the guest molecules that match cavity size, and β-CD-based materials drew widespread attention in electrochemical sensors. The hydroxy groups at the edge of the cavity can form hydrogen bonds and undergo electrostatic and dipole-dipole interactions with other molecules. This review (with 109 refs.) reveals β-CD-based detection mechanisms from the viewpoint of the size/shape-fit concept, and summarizes the current state of multiple electrochemical sensors based on the use of β-CD and functionalized β-CD such as carboxymethyl-β-CD, mono-(6-ethanediamine-6-deoxy)-β-CD, hydroxypropyl-β-CD, thio-β-cyclodextrin,and others. Graphical abstract Schematic diagram of cyclodextrin inclusion complex formation in aqueous solution, represents water molecules, represents guest molecule.

Theoretical study of inclusion complex formation of cyclodextrin and single polymer chain

We study the inclusion complex formation of cyclodextrins and a single polymer chain by a grand canonical Monte Carlo simulation and by a statistical-mechanical theory. The filling ratio of the polymer chain by threaded cyclodextrins is calculated and shows good agreement with reported experimental results. The adsorption isotherm of the filling ratio is also derived by the statistical-mechanical theory. We confirm the significance of hydrogen bonds between cyclodextrins for the inclusion complex formation. When hydrogen bonds can be formed between cyclodextrins, the filling ratio drastically increases at a certain concentration of the cyclodextrins, and inclusion complexes are formed. However, inclusion complexes are rarely formed without hydrogen bonds. We also find the expansion of size of the polymer chain with the development of one-dimensional aggregates constructed by threaded cyclodextrins along the polymer chain.

Poly-cyclodextrin cryogels with aligned porous structure for removal of polycyclic aromatic hydrocarbons (PAHs) from water

Cyclodextrins (CDs) are sugar-based cyclic oligosaccharides, which form inclusion complexes with small guest molecules through their hydrophobic cavity. Here we successfully synthesized highly porous poly-cyclodextrin (poly-CD) cryogels, which were produced under cryogenic conditions by the cross-linking of amine-functional CDs with PEG-based diepoxide cross-linker. The poly-CD cryogels showed aligned porous network structures owing to the directional freezing of the matrix, of which the pore size and architecture exposed variations depending on the composition of the reactants. The cryogels were employed for the removal of genotoxic polycyclic aromatic hydrocarbons (PAHs) from aqueous solutions. They reached PAH sorption capacities as high as 1.25mg PAH per gram cryogel. This high sorption performance is due to interactions between PAHs and the complete swollen network, and thus, is not restricted by interfacial adsorption. Given that the hydrophilic nature of the components, the sorption performance could only be attributed to the inclusion complex formation of CDs with PAH molecules. The poly-CD cryogels could be recycled with an exposure to ethanol and reused without any significant loss in the sorption capacity of PAHs.

Inclusion of lycorine with natural cyclodextrins (α-, β- and γ-CD): Experimental and in vitro evaluation

The primary goal of this research was to investigate the effect of spatial compatibility in the inclusion complex formation of cyclodextrins with different cavity size on physicochemical and anticancer properties. For this purpose, the binding behaviors of the complex formations of α-, β- and γ-cyclodextrins with lycorine were observed by the use of UV, MS, XRD, DSC, TG, 1H, and 2D NMR spectroscopy and elemental analysis. The results displayed that the binding behavior was contrary to the size of the CDs, and the value of binding constant of lycorine/γ-CD was the smallest, while the value of binding constant of lycorine/α-CD was the greatest. In vitro study demonstrated that the lycorine-α-CD and lycorine-β-CD are valuable approaches to enhance lycorine bioavailability. The results deduced that using CDs with moderate cavities (such as α-CD or β-CD) as a cyclodextrin-based delivery system to form the lycorine-type inclusion complex could be more applicable, and further helps to improve the properties of lycorine-type therapeutic agent.

Thermodynamic study on salt effects on complex formation of α-, β- and γ-cyclodextrins with p-aminobenzoic acid

The aim of this work was to gain a deeper understanding of salt effects in the inclusion complex formation of cyclodextrins. For this purpose, thermodynamic study of complex formation of α-, β- and γ-cyclodextrins with p-aminobenzoic acid was carried out in water and solutions of KCl, KBr, KH2PO4 and K2SO4 (0.2mol/kg). Stability constants were calculated from the binding isotherms obtained on the basis of 1H NMR measurements. Enthalpy and entropy of complex formation were estimated from the van’t Hoff plots. It was found that effects of KCl, KH2PO4 and K2SO4 are insignificant, while the influence of KBr on complex formation of cyclodextrins with p-aminobenzoic acid is more pronounced and results in a decrease of the stability constants. Specific action of Br− is caused by the ability of these anions to penetrate into macrocyclic cavity. Coexistence of two complexation equilibria in KBr solution is accompanied by significant solvent reorganization originated from more intensive dehydration of the interacting species. This results in an increase of the enthalpy and entropy of complex formation. Manifestation of Br− effect was found to be the same in the binding of p-aminobenzoic acid with α-, β- and γ-cyclodextrins.

Specific and nonspecific effects of biologically active inorganic salts on inclusion complex formation of cyclodextrins with aromatic carboxylic acids

Inclusion complex formation of α- and β-cyclodextrins with zwitterionic nicotinic and m-aminobenzoic acids in water and 0.2M solutions of KCl, KBr, KH2PO4 and K2SO4 was studied by 1H NMR and UV-spectroscopy. We complemented the experiments with statistical mechanics calculations in the framework of the 3D-RISM approach to analyze the ion-binding between inorganic univalent anions and positively charged groups of the acids under study. It was detected that binding affinity of cyclodextrins to the acids is decreased in the presence of the salts. This is caused by specific and nonspecific action of the considered inorganic anions. The influence of the Cl− and SO42− was found to be nonspecific and insignificant. On the contrary, Br− and H2PO4− ions can considerably affect the inclusion complex formation. Insertion of Br− into the macrocyclic cavity and attraction between H2PO4− and the zwitterions are the main processes competing with cyclodextrin–acid binding. It has been demonstrated that the manifestation of the salt effects depends on the cyclodextrin cavity size, ionization state of the acid and other experimental conditions.

Microcoil NMR Study of the Interactions between Doxepin, β-Cyclodextrin, and Acetate during Capillary Isotachophoresis

The capillary isotachophoresis (cITP) separation of the isomers of the tricyclic antidepressant doxepin using β-cyclodextrin (β-CD) as a buffer additive is investigated by online microcoil NMR detection. Capillary electrophoresis (CE) is also used to determine the binding constant between the doxepin E and Z geometric isomers and β-CD. Although the doxepin isomers could be easily baseline resolved by CE, their separation by cITP was more challenging due in part to the high concentration of doxepin after cITP-focusing. The use of online (1)H NMR detection allows observation of changes in doxepin dynamics due to formation of the β-CD inclusion complex, changes in the fraction complexed and the intracapillary pH. It also provides novel experimental evidence that a weak complex between β-CD and acetate contributes to its active transport from the leading electrolyte through the sample band to the trailing electrolyte in this cationic cITP separation. The results of these cITP-NMR experiments provide new mechanistic details about the interactions of the buffer counterion acetate with various components of the separation system and have important implications for other analyses based on formation of cyclodextrin inclusion complexes.

Mechanical grinding effect on thermodynamics and inclusion efficiency of loratadine-cyclodextrin inclusion complex formation.

The interaction of poor water-soluble drug loratadine (LOR) with β-cyclodextrin (β-CD) or hydroxypropyl-β-cyclodextrin (HP-β-CD) in aqueous or solid state was investigated. Mechanical grinding effect on the inclusion steps, thermodynamic kinetics and inclusion efficiency of inclusion complex formation of LOR with β-CD or HP-β-CD was quantitatively investigated by DSC and FT-IR microspectroscopy with curve-fitting analysis. The phase solubility profiles of LOR with β-CD and HP-β-CD were classified as AL-type phase diagram. The grinding-induced reduction in LOR crystallinity in the presence of β-CD or HP-β-CD was found to be apparent zero-order kinetics. The inclusion efficiency of solid inclusion complex for LOR/β-CD or LOR/HP-β-CD was significantly correlated with the reduction in LOR crystallinity and the grinding time. The mechanism of inclusion complex formation for LOR/β-CD or LOR/HP-β-CD was proposed through the progressive reduction in LOR crystallinity, the promoted LOR amorphization, and molecular inclusion processes in the continuous energy input process of mechanical grinding.

Cyclodextrin inclusion complex formation with butylated hydroxytoluene and its application in polyethylene film

AbstractThe phenolic antioxidant, butylated hydroxytoluene (BHT), is added during polymer processing to protect polymers from oxidative degradation. Because of its high‐volatility, it is susceptible to loss through volatilization in high‐temperature processing. Cyclodextrin (CD) inclusion complexation (IC) with volatile compounds can prevent losses of volatile compounds, because of volatilization. In this study, BHT was successfully included in β‐CD and its complex was confirmed using Wide‐Angle X‐ray Diffraction (WAXD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), and Nuclear Magnetic Resonance spectroscopy (NMR). Low‐density polyethylene (LDPE) films with BHT itself and BHT‐β‐CD‐IC were produced on a pilot plant scale. After extrusion, it was found that 44 and 78% BHT was lost from the BHT‐β‐CD‐IC LDPE and BHT LDPE films, respectively. Hence, the complex proved to be more efficient in preventing loss of BHT, because of encapsulation of volatile BHT. In addition, microscopy studies indicate that BHT‐β‐CD‐IC LDPE film shows small aggregates, uniformly distributed in the LDPE matrix over a large range. The BHT efficiency of the complex in the film was measured using DSC for determining the oxidation induction time. The oxidation induction time (OITtime) was 35 min for the BHT‐β‐CD‐IC LDPE film as compared with 16 min and 26 min values of LDPE and BHT LDPE films, respectively. Hence, the encapsulation of BHT in β‐CD maximizes the efficiency and stability to thermal degradation for BHT‐β‐CD‐IC LDPE film. The viscoelastic behavior of the films was also studied using dynamic mechanical analysis. The results indicate increases in storage modulus (El) and loss modulus (Ell) of the complex and a shift in the maxima of tan δ (Ell/El) to lower temperature in the LDPE films processed with BHT, β‐CD, and BHT‐β‐CD‐IC. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010

Cyclodextrin Inclusion Complex Formation and Solid-State Characterization of the Natural Antioxidants α-Tocopherol and Quercetin

Cyclodextrin (CD) complexation procedures are relatively simple processes, but these techniques often require very specific conditions for each individual guest molecule. Variations of the coprecipitation from aqueous solution technique were optimized for the CD complexation of the natural antioxidants alpha-tocopherol and quercetin. Solid inclusion complex products of alpha-tocopherol/beta-CD and quercetin/gamma-CD had molar ratios of 1.7:1, which were equivalent to 18.1% (w/w) alpha-tocopherol and 13.0% (w/w) quercetin. The molar reactant ratios of CD/antioxidant were optimized at 8:1 to improve the yield of complexation. The product yields of alpha-tocopherol/beta-CD and quercetin/gamma-CD complexes from their individual reactants were calculated as 24 and 21% (w/w), respectively. ATR/FT-IR, 13C CP/MAS NMR, TGA, and DSC provided evidence of antioxidant interaction with CD at the molecular level, which indicated true CD inclusion complexation in the solid state. Natural antioxidant/CD inclusion complexes may serve as novel additives in controlled-release active packaging to extend the oxidative stability of foods.

Cavity size effect on ICT-dual emission of p-(N,N-dimethylamino)-2-styrylquinoline: complexation with cyclodextrin derivatives

The effect of cyclodextrin inclusion complex formation on the intramolecular charge transfer (ICT) of the included 4-N,N-dimethylamino-2-strylquinoline (2-StQ-NMe2) has been studied in detail. 2-StQ-NMe2 in presence of α-, β-, γ- and HP-α- and Hp-β-CDs predominantly exhibits ICT fluorescence predominantly than the emission from locally excited state, whereas in presence of HP-γ-CD the later is observed. In presence of α-CD, 2:1 complexation of the 2-StQ-NMe2 is observed in addition to 1:1 complexation. The observed results are explained by the CD cavity size and an active role for the secondary hydroxyl groups present in the wider rim of the CD cavity and also which finds support from absorption, emission, lifetime and molecular modeling studies.

Formation of Cyclodextrin Inclusion Complexes with Doxycyclin-Hyclate: NMR Investigation of Their Characterisation and Stability

The solubility of cyclodextrin (CD) can be notably improved when it is included in a polymeric structure. CD was reacted with citric acid, yielding a water-soluble polymer whose inclusion properties towards doxycyclin-hyclate (DOX) as guest molecule were investigated by NMR. The new DOSY (Diffusion Ordered SpectroscopY) method, based on diffusion coefficient measurements is convenient study complexes made of large molecules and it was applied to determine the association constants between DOX and parent β and γ-CD and their polymerised forms. The association constant obtained by DOSY was compared with that determined more classically by the chemical shift variation measurement using Scott's plot.

Influence of cyclodextrins on the fluorescence, photostability and singlet oxygen quantum yields of zinc phthalocyanine and naphthalocyanine complexes

The effects of formation of cyclodextrin inclusion complexes on the photochemical and photophysical properties of zinc phthalocyanine ( ZnPc ) and various peripherally substituted zinc phthalocyanines as well as zinc naphthalocyanine ( ZnNPc ) are investigated. The cyclodextrins employed were the hydroxypropyl-γ-cyclodextrin and unsubstituted β-cyclodextrin. Job's plots were employed to confirm the stoichiometry of the inclusion complexes and showed 2:1 and 4:1 (cyclodextrin:phthalocyanine) inclusion behavior. The phthalocyanine inclusion complexes showed larger singlet oxygen quantum yield (ϕΔ) values when compared to the free phthalocyanines before inclusion, for complexes 1 (zinc naphthalocyanine), 2 (zinc tetranitrophthalocyanine) and 4 (zinc tetra-tert-butylphenoxyphthalocyanine). The fluorescence quantum yields generally remained unchanged following inclusion.

Near-Infrared Spectroscopic Investigation of Inclusion Complex Formation of Cyclodextrins in Room-Temperature Ionic Liquid

Near-infrared spectrometry has been successfully used to determine association binding constants between phenol and α-, β- and γ-cyclodextrin (CD) in [butylmethylimidazolium][chloride] room-temperature ionic liquid (RTIL). It was found that adding CD into the RTIL solution of phenol resulted in an enhancement in the absorption coefficient of the stretching overtone of the aromatic C–H groups. However, the enhancement induced by CDs in RTIL is much lower (order of magnitude) than those corresponding in D2O. The binding constants in RTIL are also much lower than those in D2O ((11 ± 2) M-1, (16 ± 2) M-1and(40 ± 6) M-1forphenol and α-, β- and γ-CD, respectively. compared to 87 M-1and 214 M-1for α- and β-CD in D2O). The results obtained seem to suggest that in ionic liquid, the main interaction between phenol and CDs may not be inclusion complex formation but rather external adsorption. A variety of reasons may be responsible for relatively weaker interactions and lower binding constants in ionic liquid including differences in the polarity and viscosity of RTIL and D2O. However, the main reason may be due to the fact that the cation of the ionic liquid (i.e., butylmethylimidazolium ion) may form inclusion complexes with the cyclodextrin, thereby preventing phenol from being included in cavity of CDs.

Calorimetric Study of Sodium n-Alkanoate−Modified Cyclodextrin−Water Ternary Systems

Enthalpies of dilution of sodium n-alkanoate and cyclodextrin aqueous solutions with water as functions of their concentration were measured at 298 K. The enthalpy of transfer (ΔHt) of cyclodextrin (≈0.02 mol kg-1) from water to the aqueous solutions of the substrates was determined as a function of the substrate concentration. The cyclodextrins are hydroxypropyl-α-cyclodextrin (HP-α-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), and hydroxypropyl-γ-cyclodextrin (HP-γ-CD). The substrates (CnCO2Na) are sodium acetate to sodium decanoate. From the experimental data of the binary systems, the apparent molar relative enthalpies were calculated. The trends of ΔHt versus substrate concentration in the premicellar region were rationalized in terms of the substrate−cyclodextrin inclusion complex formation. The latter was not evidenced for HP-γ-CD with C3CO2Na and C5CO2Na and for HP-β-CD with C3CO2Na. The standard free energy for the complex formation decreases with the number of carbon atoms in the alkyl chain. Bot...