Application of combined thermoanalytical techniques in the investigation of cyclodextrin inclusion complexes

Citronellol and citronellyl acetate have been entrapped with α-, β- and γ-cyclodextrin (CD). Evolved gas detection and TG-MS coupling was applied to prove the actual inclusion complex formation between monoterpens and CDs. The terpene content was determined by UV-VIS specrophotometry and RP-HPLC and the effect of storage time on the terpene content was also investigated. The α- and γ-cyclodextrin inclusion complexes showed higher thermal stabilities vs. dynamic heating compared to the β-CD complexes. On the contray, the retention of guest using β-cyclodextrin even after 10 years of storage was much more pronounced. Experimental data other than 1:1 complex compositions are assumed. Molecular modeling experiments also suggested multiple complex compositions.     

Investigation of Cyclodextrin Complexes of Mandelic acid

The inclusion complexes of both optically active and racemic mandelic acids with α-, (β- and γ-cyclodextrins were prepared by using a liophylisation technique. The compounds formed were investigated by thermoanalytical methods (TG, DSC and EGD) which were completed with FT-IR spectroscopic measurements, scanning electron microscopic observations, and dissolution rate determinations. The inclusion complex formation between all guests and hosts were proven using the thermoanalytical and FT-IR spectroscopic methods.     

β-环糊精与有机胺之间包合作用的理论与实验研究

通过实验和理论计算方法研究了β-环糊精(CD)与乙二胺1及它的三个类似物: 二乙烯三胺2、三乙胺3和乙二胺四乙酸4之间的包合作用. 利用旋光法确定了β-CD与客体分子形成1:1型主–客体包合物, 在298.2 K下测定了包合物在水中的稳定常数(K). 采用半经验PM3方法考察了β-CD与短链脂肪胺1~7、环状脂肪胺8~11以及芳香胺12~13的分子间结合能力, 报道了β-CD与这些客体分子间的包合络合过程并讨论了这些包合体系之间的包合差异性. 变形能和水合能对包合体系的相互作用能的贡献均相当小. β-CD包合物的稳定性取决于主、客体分子之间的尺寸匹配. 对于β-CD与客体1~4形成的包合物而言, 旋光法测定的包合物的K值的顺序与PM3计算得到的包合物络合能绝对值的排序有很好的一致性.     

Investigation of the cyclodextrin complexes of mandelic acid derivatives

Racemic free mandelic acid and its methyl, ethyl, isoamyl and benzyl esters were found to form inclusion complexes with all the three studied natural cyclodextrins proved by thermoanalytical results. Differences between the solid state stability of guests were detected mainly by evolved gas analysis. Even signs of an eventual optical resolution by molecular inclusion were observed in several cases, but still not sufficiently proven. Due to the rather high volatility and low melting points of the majority of guest substances DSC technique was found to be suitable for studying the cyclodextrin complexes of mandelic acid. Dedicated to Prof. József Szejtli on the occasion of his 60^th birthday     

环糊精及其衍生物在手性识别中的应用

详细地论述了环糊精及其衍生物在手性识别中的应用,并对环糊精超分子体系手性识别中的进一步研究提供了依据。     

Solid state studies on molecular inclusions of <Emphasis Type="Italic">Lippia sidoides</Emphasis> essential oil obtained by spray drying

Inclusion complexes of Lippia sidoides essential oil and β-cyclodextrin were obtained by slurry method and its solid powdered form was prepared using spray drying. The influence of the spray drying, as well as the different essential oil:β-cyclodextrin ratio on the characteristics of the final product was investigated. With regard to the total oil retention 1:10 mass/mass ratio as optimal was found between the essential oil and β-cyclodextrin. Thermoanalytical techniques (TG, EGD, TG-MS) were used to support the formation of inclusion complex and to examine their physicochemical properties after accelerated storage conditions. It may be assumed that the thermal properties of the complexes were influenced not only by the different essential oil/ β-cyclodextrin ratio but also by the storage conditions. In the aspect of their thermal stabilities, complex prepared with 1:10 m/m ratio (essential oil:β-cyclodextrin) was the most stable one.     

Encapsulation of ciprofloxacin,sparfloxacin, and ofloxacin drugs with α- and β-cyclodextrins: spectral and molecular modelling studies

Inclusion complexation of ciprofloxacin (CIP), sparfloxacin (SPA), and ofloxacin (OFL) drugs with α-CD and β-CD was studied by UV-visible, fluorescence, time-resolved fluorescence, Fourier transform infrared spectroscopy (FTIR), hydrogen nuclear magnetic resonance (¹HNMR), scanning electron microscopy (SEM), and molecular modelling techniques. Changes in the absorbance and fluorescence intensities and fluorescence lifetime of the drugs in the cyclodextrin (CD) solutions suggest the formation of inclusion complexes. Carbonyl stretching frequency moved to higher wave numbers and broadening of the N–H stretching band indicated the formation of inclusion complex. Cyclohexane ring protons of the drugs show remarkable upfield or downfield shift in the ¹HNMR spectrum, indicating that the cyclohexane part of the guest molecule is entrapped inside CD cavities. SEM images of CIP/CD, SPA/CD, and OFL/CD complexes have a crystal structure with different morphology from the isolated CIP, SPA, OFL, and CDs. Investigations of the energetic, thermodynamic, and electronic properties of parametric model number 3 computational calculations confirmed the stability of the inclusion complex.     

Thermal characterization of natural and modified cyclodextrins using TG-MS combined technique

Summary Thermoanalytical techniques (TG, DSC) are frequently used in the investigation of the thermal properties of cyclodextrins and their inclusion complexes. However, the above techniques do not provide information on the chemical composition of the evolved fragments upon the thermal decomposition. In this study &agr;-, &bgr;- and &ggr;-cyclodextrins and 4 methylated and 3 ethylated &bgr;-CD derivatives were investigated with a TG-MS combined thermoanalytical technique in order to get information about their fragmentation behaviour. By comparison of the TG/DTA curves, a different thermal behaviour was found for each of the native and the chemically modified cyclodextrins. Except for the water loss profiles and the solid-solid phase transformations, the thermal behaviour of the (investigated) native CDs do not show remarkable differences. However, the chemical modification of the native &bgr;-CD resulting in a new compound may change the strength of interactions between host and guest causing differences in the thermal stabilities of the derivatives. The mass spectrometry results supported the observed thermal differences and showed significant alterations in the fragmentation of ethylated and methylated compounds. The investigated natural CDs possess a very similar fragmentation profile, due to the common &agr;-D-glucopyranose building units. In the case of modified CDs characteristic signals of the substituents are present.     

Reactive desorption electrospray ionization for rapid screening of guests for supramolecular inclusion complexes

Reactive desorption electrospray ionization (DESI), an ambient technique, has been explored as a tool for the development of a fast screening approach for supramolecular complexes capitalizing on the specificity of mass spectrometric detection. A library of twelve potential guests for inclusion by a β‐cyclodextrin host was initially screened via DESI using a spray solution incorporating the host directed toward an array of deposited guests. The steroid nortestosterone was used to verify the applicability of reactive DESI for complexation experiments with β‐cyclodextrin. Results from the DESI experiment and results from an analogous electrospray ionization (ESI) mass spectral screen were compared with solution‐phase data obtained by nuclear magnetic resonance (NMR) spectroscopy. The complexes detected using DESI were identical to those determined using NMR, validating the applicability of the technique to supramolecular applications, but the ESI data exhibited significant disparities, predominantly due to the interference of nonspecific artifacts. Copyright © 2008 John Wiley & Sons, Ltd.     

Mesoporous silica and chitosan based pH-sensitive smart nanoparticles for tumor targeted drug delivery

This study investigated inclusion formation and the physicochemical properties of naringin/cyclodextrin through a combined computational and experimental approach. Molecular dynamics simulations were applied to investigate the thermodynamics and geometry of naringin/cyclodextrin cavity docking. The complexes were investigated by UV, FT-IR, DSC, XRD, SEM, 2D-NOSEY and ¹H-NMR analyses. Clearly visible protons belonging to naringin and chemical shift displacements of the H3 and H5 protons in cyclodextrin were anticipated in the formation of an inclusion complex. Naringin solubility increased linearly with increasing cyclodextrin concentration (displaying an A_L profile). The simulations indicated that the phenyl group of naringin was located deep within the cyclodextrin cavity, while the glycoside group of naringin was on the plane of the wider rim of cyclodextrin. The simulation and molecular modeling results indicate that (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) provided the more stable inclusion complex. This result was also in good concordance with the stability constants that had been determined by the phase solubility method. The consistency of the computational and experimental results indicates their reliability.     

Improvement of opipramol base solubility by complexation with β-cyclodextrin

Opipramol (OPI), a tricyclic antidepressant and anxiolytic compound, is administered orally in the form of a dihydrochloride. Salt form of the drug has a higher solubility in water and hence bioavailability and stability. A similar effect can be achieved by closing the hydrophobic part of the drug molecule in the cyclodextrin cavity. The paper presents opipramol inclusion complexes with beta-cyclodextrin (β-CD) in 1:1 molar ratio. Studies on the formation of inclusion complexes were carried out both in solution and in the solid state. The formation and physicochemical characterisation of the complexes were determined by UV spectroscopic measurement (UV–vis), Fourier Transform Infrared (FTIR) Spectroscopy, ¹H Nuclear Magnetic Resonance (¹H NMR, 2D NOESY NMR), thermoanalytical methods (TGA – Termogravimetric analysis, DSC – differential scanning calorimetry), X-ray diffractometry (XRD) and scanning electron microscopy (SEM). The phase solubility profile with β-CD was classified as the A_N- type, indicating the formation of the inclusion complex with a drug.     

Synthesis, thermal and other studies of 2,4'-bipyridine-dichloroacetato complexes of Mn(II), Co(II), Ni(II) and Cu(II)

Four new mixed ligand complexes were prepared by the reaction of title metal dichloroacetates and 2,4'-bipyridine. The general formulae of synthesized compounds are M(2,4'-bpy)₂(CCl₂HCOO)₂·nH₂O (where M(II)=Mn, Co, Ni, Cu; 2,4'-bpy=2,4'-bipyridine, n=2 or 4). The complexes have been isolated from aqueous media and characterized by chemical analysis, molar conductance (in MeOH, DMSO and DMF), magnetic, IR and VIS spectral studies. The nature of metal(II)-ligand coordination is discussed. The thermal behaviour of obtained complexes was studied by thermal analysis and TG-MS techniques in air. IR, X-ray powder diffraction and thermoanalytical data were used for the determination of solid intermediate products of the thermal decomposition. The principal volatile products of thermal decomposition of complexes were proved by mass spectroscopy: H₂O⁺, CO⁺ ₂, HCl⁺ ₂, Cl⁺ ₂, NO⁺ and other. This revised version was published online in July 2006 with corrections to the Cover Date.     

Study on Properties of Inclusion Complexation of Triclopyr Butoxy Ethyl Ester with Mixed Surfactant System

β‐cyclodextrin exhibits the property of forming inclusion complexes with various molecules. These complexes display improved properties in comparison with starting molecules in terms of their solubility and stability. In the present study, triclopyr butoxy ethyl ester, a selective systemic herbicide was utilized for forming inclusion complexes with β‐cyclodextrin in absence and presence of the nonionic: lauric acid monoethanolamide (C₁₂MEA)/anionic: α‐olefin sulfonate (AOS) mixed surfactant system. The objective of present work was to study the important physical properties like dissolution rate, dispersion stability and wettability in presence of mixed surfactant systems of inclusion complex of a herbicide. Coprecipitation method was used for inclusion complex formation, which was consequently characterized by analytical techniques such as x‐ray diffractometry (XRD), differential scanning calorimetry (DSC) and ultra‐violet spectroscopy (UV).     

Preparation of gamma cyclodextrin stabilized solid lipid nanoparticles (SLNS) using stearic acid–γ-cyclodextrin inclusion complex

The inclusion complexation behaviour of higher chain fatty acid, stearic acid (SA) with gamma cyclodextrin has been investigated. The inclusion complex was characterized by FT-IR, ¹H NMR, 2D NMR, XRD and DSC techniques. The results showed that the SA molecule was entrapped inside the gamma cyclodextrin cavity. Further, inclusion complex was treated with lopinavir at 85 °C and emulsified with hot water at 85 °C. The resulted nanoemulsion was cooled down to form solid lipid nanoparticles (SLNs) stabilized with gamma cyclodextrin. Prepared SLNs were having average particle size of 212.5 ± 4.8 nm, zeta potential of ?19.7 ± 0.66 mV and drug loading of 57.54 ± 0.62 %. The surface characteristics of SLNs were also observed with transmission electron microscopy and atomic force microscopy. Results indicate that inclusion complex of SA and gamma cyclodextrin can be used for SLNs preparation.     

Inclusion complexes of α‐cyclodextrin and (AB)n block copolymers

Cyclodextrins thread onto polymer chains to form inclusion complexes, especially when the polymer is hydrophobic relative to the solvent. Selective threading might occur when the polymer architecture contains both hydrophobic and hydrophilic segments. α‐Cyclodextrin formed crystalline inclusion complexes with (AB)_n microblock copolymers, where the A block was a linear alkyl segment containing a single double bond and the B block was an exact length segment of poly(ethylene oxide). The complexes were isolated and characterized by solution and solid‐state NMR, X‐ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. Each method confirmed complex formation and showed that the physical properties of the complexes were distinct from those of its individual components. The X‐ray data were consistent with known inclusion complexes having a channel or column crystal structure. The stoichiometry of the complex formation, 2.3 α‐cyclodextrin rings per polymer repeat unit, was determined by NMR analysis of the complexes and from an analysis of the inclusion complex yields. The data suggest that the inclusion complex stoichiometry is defined by the increasing insolubility of the polymer–cyclodextrin complex. Solid‐state NMR data were consistent with a preference for threading onto hydrophobic segments of the (AB)_n polymer. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 2731–2739, 2001     

Interaction between tetramethylcucurbit[6]uril and some pyridine derivates

Interaction between tetramethylcucurbit[6]uril (TMeQ[6], host) with hydrochloride salts of 2-phenylpridine (G1), 2-benzylpyridine (G2), and 4-benzylpyridine (G3) (guests) have been investigated by using 1H NMR spectroscopy and electronic absorption spectroscopy and theoretical calculations. The 1H NMR spectra analysis established an interaction model in which the host selectively included the phenyl moiety of the HCl salt of the above three guests, and formed inclusion complexes with a host-guest ratio of 1:1. Absorption spectrophotometric analysis allowed quantitative measurement of the stability of these host-guest inclusion complexes. Particularly, we have established a competitive interaction in which one host-guest inclusion complex pair is much more stable than another host-guest inclusion complex pair. The stability constants for the three host-guest inclusion complexes of TMeQ[6]-G1, TMeQ[6]-G2, and TMeQ[6]-G3 are approximately 2x10(6), 60.7, and 19.9 mol-1.L, respectively. To understand how subtle differences in the structure of the title guests lead to a significant difference in the stability of the corresponding host-guest inclusion complexes with the TMeQ[6], ab initio theoretical calculations have been performed, not only for the gas phase but also the solution phase (water as solvent) in all cases. The calculation results revealed that when the phenyl moiety of the three pyridine derivate guests was included, the host-guest complexation reached the minimum, and the corresponding energy differences for the formation of the title host-guest inclusion complexes are qualitatively consistent with the experimental results.     

Desorption of Water from CD/DRUG Inclusion Complexes

Thermogravimetric and differential scanning calorimetric traces were recorded for several crystalline hydrated cyclodextrin complexes containing drug substances (salts of diclofenac, meclofenamate sodium, (L)-menthol) as guests. It was possible to reconcile observed thermal events for complex dehydration with three dimensional hydration patterns deduced from available X-ray crystal structures of the complexes. For complexes containing drug salts, strong retention of water molecules is attributed to their coordination to metal ions.     

Supramolecular self-assembly of inclusion complexes of a multiarm hyperbranched polyether with cyclodextrins

A new class of crystalline inclusion complexes of a multiarm hyperbranched polyether combined with various cyclodextrins (CDs) was successfully prepared. Using self-condensing ring-opening polymerization, a kind of multiarm polyether with a hyperbranched poly(3-ethyl-3-oxetanemethanol) core and multiple linear poly(ethylene glycol) (PEG) arms was obtained. It has been found that this kind of hyperbranched polyether can be dissolved in water. Adding alpha-CDs to the multiarm hyperbranched polyether solution, molecular recognition results in the formation of crystalline inclusion complexes based on the noncovalent interactions between the linear PEG arms of the polyether particles and the alpha-CDs. These multiarm polyether inclusion complexes have been well characterized. Interestingly, quite different from inclusion complexes of CDs and linear polymeric guests, the complexes of the multiarm hyperbranched polyether with alpha-CDs show a novel lamellar morphology. The experimental results validate that the resultant lamellar crystals have a juxtaposed structure. In addition, the formation mechanism of these inclusion complexes of a multiarm polyether with alpha-CDs has also been well described. Besides the role of displacement of associated water molecules and the presence of hydrogen bonding between CDs in channel structure CD inclusion complexes, the noncovalent intermolecular forces between CDs and polymers also play an important role in the formation of complex architectures.     

Molecular Recognition Studies on Supramolecular Systems. 29. Anilino- and m-Toluidino-β-Cyclodextrins: Structural and Conformational Analyses and Molecular Recognition of Aliphatic Alcohols

Abstract

Mono(6-anilino-6-deoxy)-β-cyclodextrin (1) and mono[6-(m-toluidino)-6-deoxy]-β-cyclodextrin (2) were synthesized and characterized. Circular dichroism and fluorescence spectral studies and fluorescence lifetime measurements have been performed to elucidate the conformations of 1 and 2 in aqueous buffer solution. 1-D and 2-D NMR spectra of 2 have been measured in D₂O to deduce its structure and detailed conformation in solution. From the circular dichroism, fluorescence, and NMR spectroscopic studies, it was revealed that the substituents appended to 1 and 2 penetrate into the cyclodextrin cavity forming a stable self-inclusion complex in aqueous solution, and also that the short linkage between the m-toluidino and cyclodextrin moieties makes the cyclodextrin ring of 2 deformed to some extent. The complex stability constants (K _S) of 1 and 2 for a series of aliphatic alcohols have been determined by using spectropolarimetric titrations in aqueous phosphate buffer solution (pH 7.20) at 25°C to elucidate the role of introduced substituents and the weak interactions involved in inclusion complexation by the modified cyclodextrins. The results obtained indicate that the van der Waals and hydrophobic interactions mainly contribute to the formation of complexes between the cyclodextrins and aliphatic alcohols, and the inclusion complexation process involves the induced-fit mechanism. Modified β-cyclodextrin 2 can recognize not only the size, shape, and hydrophobicity of the guest molecules, but also chiral guests, affording a moderate enantioselectivity of 1.55 for (+)/(-)-borneol.     

Electrospray ionization mass spectrometry studies of cyclodextrin‐carboxylate ion inclusion complexes

Aqueous solutions containing simple model aliphatic and alicyclic carboxylic acids (surrogates 1–4) were studied using negative ion electrospray mass spectrometry (ESI‐MS) in the presence and absence of α‐, β‐, and γ‐cyclodextrin. Molecular ions were detected corresponding to the parent carboxylic acids and complexed forms of the carboxylic acids; the latter corresponding to non‐covalent inclusion complexes formed between carboxylic acid and cyclodextrin compounds (e.g., β‐CD, α‐CD, and γ‐CD). The formation of 1:1 non‐covalent inclusion cyclodextrin‐carboxylic complexes and non‐inclusion forms of the cellobiose‐carboxylic acid compounds was also observed. Aqueous solutions of Syncrude‐derived mixtures of aliphatic and alicyclic carboxylic acids (i.e. naphthenic acids; NAs) were similarly studied using ESI‐MS, as outlined above. Molecular ions corresponding to the formation of CD‐NAs inclusion complexes were observed whereas 1:1 non‐inclusion forms of the cellobiose‐NAs complexes were not detected. The ESI‐MS results provide evidence for some measure of inclusion selectivity according to the 'size‐fit' of the host and guest molecules (according to carbon number) and the hydrogen deficiency (z‐series) of the naphthenic acid compounds. The relative abundances of the molecular ions of the CD‐carboxylate anion adducts provide strong support for differing complex stability in aqueous solution. In general, the 1:1 complex stability according to hydrogen deficiency (z‐series) of naphthenic acids may be attributed to the nature of the cavity size of the cyclodextrin host compounds and the relative lipophilicity of the guest. Copyright © 2009 John Wiley & Sons, Ltd.