Inclusion Complexes In Solution Research Articles

Cyclodextrin Inclusion Complexes for Improved Drug Bioavailability and Activity: Synthetic and Analytical Aspects.

Many active pharmaceutical ingredients show low oral bioavailability due to factors such as poor solubility and physical and chemical instability. The formation of inclusion complexes with cyclodextrins, as well as cyclodextrin-based polymers, nanosponges, and nanofibers, is a valuable tool to improve the oral bioavailability of many drugs. The microencapsulation process modifies key properties of the included drugs including volatility, dissolution rate, bioavailability, and bioactivity. In this context, we present relevant examples of the stabilization of labile drugs through the encapsulation in cyclodextrins. The formation of inclusion complexes with drugs belonging to class IV in the biopharmaceutical classification system as an effective solution to increase their bioavailability is also discussed. The stabilization and improvement in nutraceuticals used as food supplements, which often have low intestinal absorption due to their poor solubility, is also considered. Cyclodextrin-based nanofibers, which are polymer-free and can be generated using environmentally friendly technologies, lead to dramatic bioavailability enhancements. The synthesis of chemically modified cyclodextrins, polymers, and nanosponges based on cyclodextrins is discussed. Analytical techniques that allow the characterization and verification of the formation of true inclusion complexes are also considered, taking into account the differences in the procedures for the formation of inclusion complexes in solution and in the solid state.

From Induced-Fit Assemblies to Ternary Inclusion Complexes with Fullerenes in Corannulene-Based Molecular Tweezers.

The participation of the tether moiety in fullerene recognition of corannulene-based molecular tweezers is known to be an important factor. In the present work, we describe the synthesis of a set of fullerene receptors bearing two corannulene units located at a suitable distance to effectively interact with C60 and C70. The tether comprises a fluorene-like scaffold where an assortment of different groups with variable electronic properties has been grafted. The photophysical and electrochemical properties of all final compounds have been unveiled and correlated to the donor/acceptor (DA) nature of the tether. Despite these strong variations, their affinity toward fullerenes cannot be correlated in any way to simple DA behavior as the main contribution to the interaction correspond to London dispersion forces. We found, however, that the sulfur-derived subfamily is able to adapt better to the fullerene outer surface slightly increasing the charge transfer and electrostatic attractive interactions being the most outstanding example the case of thiophene 4-S with C70 as it is capable of forming a ternary 2:1 inclusion complex in solution with an electronic binding energy that offsets entropy and desolvation penalties typically associated with higher-order inclusion complexes.

A Dinuclear Metallobridged Super Aryl‐Extended Calix[4]pyrrole Cavitand

AbstractA super aryl‐extended calix[4]pyrrole equipped with four oxazolo[4,5‐b]pyrazinyl units at its upper rim is reported. Its PtII/PdII‐metallobridged cavitand counterparts were obtained by treatment with 2 equiv of cis‐protected metal corners, [M(dppp)(OTf)2] (dppp=1,3‐(bis‐diphenylphosphino)propane). The metal corners arranged their axial phenyl substituents near the aromatic walls of the cavitand leading to the formation of inclusion complexes as single conformers. We characterized the inclusion complexes in solution using NMR spectroscopy. Selected complexes were also characterized in the gas‐phase and in the solid‐state using mass spectrometry and X‐ray diffraction analysis. The dimensions of the open portals of the dinuclear complexes were found to be dependent on the included guest. The results of DFT calculations served to explain the dissimilar complexation‐induced shifts observed in the dinuclear inclusion complexes with mono‐ and bis‐formamide guests.

A Dinuclear Metallobridged Super Aryl-Extended Calix[4]pyrrole Cavitand.

A super aryl-extended calix[4]pyrrole equipped with four oxazolo[4,5-b]pyrazinyl units at its upper rim is reported. Its PtII /PdII -metallobridged cavitand counterparts were obtained by treatment with 2 equiv of cis-protected metal corners, [M(dppp)(OTf)2 ] (dppp=1,3-(bis-diphenylphosphino)propane). The metal corners arranged their axial phenyl substituents near the aromatic walls of the cavitand leading to the formation of inclusion complexes as single conformers. We characterized the inclusion complexes in solution using NMR spectroscopy. Selected complexes were also characterized in the gas-phase and in the solid-state using mass spectrometry and X-ray diffraction analysis. The dimensions of the open portals of the dinuclear complexes were found to be dependent on the included guest. The results of DFT calculations served to explain the dissimilar complexation-induced shifts observed in the dinuclear inclusion complexes with mono- and bis-formamide guests.

Changes in chemical stability and bioactivities of curcumin by forming inclusion complexes of beta- and Gama-cyclodextrins

In the present study investigated the effect of curcumin (CUR), beta (β) and gamma (γ) cyclodextrin (CD) complexes on its solubility, stability, antioxidating activity and bioavailability. CUR the active principle of turmeric is a natural antioxidant agent with potent anti-inflammatory activity along with chemotherapeutic and chemopreventive properties. Poor solubility and poor oral bioavailability are the main reasons which preclude CUR use in therapy. Curcumin/CD complex systems were prepared and characterized by FT-IR, UV-Vis and 1HNMR spectroscopies. The content, solubility, dissolution, and stability of the complexes were evaluated and compared with curcumin and their physical mixture. The phase solubility analysis indicated that the solubility of CUR was increased in the presence of CDs and revealed an A(L)-type diagram, suggesting the formation of a 1:1 inclusion complex. The estimated apparent stability constant (K1:1), according to the Higuchi and Connors method, is 1.87 × 105 M−1 and 5.99 × 105 M−1 for CUR/β-CD and CUR/γ-CD respectively. The results of this study confirm the formation of inclusion complexes in solution and suggest that the complexes formation between CUR and CDs could improve the bioavailability of the drug due to the enhancing absorption expected from increased drug solubility. Furthermore, the antioxidant activities of CUR and CDs inclusion complexes were determined by the 1,1-diphenyl-2-picryl-hydrazyl (DPPH) method. The experimental results confirmed the forming of CUR complexes with CDs also these indicated that the CUR/CDs inclusion complexes were the most reactive than its free form into antioxidant activity.

Gram-Scale Synthesis and Supramolecular Complex of Precursors of Clar's Hydrocarbon Triangulene.

We present to date the most efficient gram-scale synthesis of triangulene-4,8-dione and 12-hydroxytriangulene-4,8-dione, the precursors of Clar’s hydrocarbon, in overall yields >50%. The direct dihydroprecursors of triangulene, obtained upon reduction of triangulene-4,8-dione, were stabilized in a supramolecular complex with a tetracationic cyclophane ExBox4+ and characterized by single-crystal X-ray crystallography. This result represents the first step in an endeavor to stabilize the fragile core of triangulene in an inclusion complex in solution and solid state.

Effect of cyclodextrin additives on azithromycin in aqueous solution and insight into the stabilization mechanism by sulfobutyl ether-β-cyclodextrin

The stability of azithromycin in buffered aqueous solution at pH 6.7 was investigated in the presence of different cyclodextrin (CD) additives by HPLC monitoring of the drug concentration over time. In the presence of γ-CDs, either in native or derivatized form, the long-term stability of azithromycin was sensibly decreased with respect to the reference sample without any additives, whereas the opposite effect was observed with all the three tested β-CDs. The most effective stabilization of the drug was obtained by using sulfobutyl ether-β-cyclodextrin, which allowed a concentration of azithromycin in solution at 99% up to 6 months at room temperature. The positive action of sulfobutyl ether-β-cyclodextrin was mainly exerted through the suppression of a degradation pathway leading to the opening of lactone ring of azithromycin. The formation of dynamic inclusion complexes in solution was ruled out by NMR data and stabilization of azithromycin by the amphiphilic sulfobutyl ether-β-cyclodextrin through surfactant-like effects was proposed on the basis of the strict similarity, either in the degradation profiles and in the NMR data, with a solution of the drug in the presence of sodium hexylsulphonate as surfactant.

Multivalency in Heteroternary Complexes on Cucurbit[8]uril-Functionalized Surfaces: Self-assembly, Patterning, and Exchange Processes.

The spatial confinement of multivalent azopyridine guest molecules mediated by cucurbit[8]urils is described. Fluorescent dye-labelled multivalent azopyridine molecules were attached to preformed methyl viologen/cucurbit[8]uril inclusion complexes in solution and at surfaces. The formation of the resulting heteroternary host-guest complexes was verified in solution and on gold substrates. Surface binding constants of the multivalent ligands were two orders of magnitude higher than that of the monovalent one. Poly-l-lysine grafted with oligo(ethylene glycol) and maleimide moieties was deposited on cyclic olefin polymer surfaces and further modified with thiolated methyl viologen and cucurbit[8]uril. Defined micrometer-sized patterns were created by soft lithographic techniques. Supramolecular exchange experiments were performed on these surface-bound heterocomplexes, which allowed the creation of cross-patterns by taking advantage of the molecular valency, which led to the substitution of the monovalent guest by the multivalent guests but not vice versa.

Molecular recognition of flunarizine dihydrochloride and \u03b2-cyclodextrin inclusion complex by NMR and computational approaches

BackgroundFlunarizine dihydrochloride (FLN) is used in the prophylactic treatment of migraine, vertigo, occlusive peripheral vascular disease and epilepsy. Cyclodextrins (CDs) are chiral, truncated cone shaped macrocycles known for their inner hydrophobic and outer hydrophilic site. They form complexes with hydrophobic drug molecules and enhance the solubility and bioavailability of such compounds by enhancing drug permeability through mucosal tissues. NMR spectroscopy and computational docking have been recognized as an important tool for the interaction study of CDs-drug inclusion complexes in solution state.ResultsThe structural assignments of FLN and β-CD protons were determined by 1H NMR and 2D 1H-1H COSY NMR spectroscopy. 1H NMR spectroscopic studies of FLN, β-CD and their mixtures confirmed the formation of β-CD-FLN inclusion complex in solution. 1H NMR titration data for β-CD-FLN inclusion complex showed 1:1 stoichiometry, an association constant of Ka = 157 M−1 and change in Gibbs free energy of ∆G = − 12.65 kJ mol−1. The binding constant of the β-CD inclusion complex with two nearly similar structures, FLN and cetirizine dihydrochloride, were compared. Two-dimensional 1H-1H ROESY spectral data and molecular docking studies showed the modes of penetration of the aromatic rings from the wider rim side into the β-CD cavity. The possible geometrical structures of the β-CD-FLN inclusion complex have been proposed in which aromatic rings protrude close to the narrower rim of the β-CD truncated cone.ConclusionNMR spectroscopic studies of FLN, β-CD and FLN:β-CD mixtures confirmed the formation of 1:1 inclusion complex in solution at room temperature. Two-dimensional 1H-1H ROESY together with molecular docking study confirmed that the F-substituted aromatic ring of FLN penetrates into β-CD truncated cone and the tail of aromatic rings were proximal to narrower rim of β-CD. The splitting of aromatic signals of FLN in the presence of β-CD suggests chiral differentiation of the guest FLN by β-CD.

Structure of the β-cyclodextrin: acetamiprid insecticide inclusion complex in solution and solid state

The molecular microencapsulation process, through the formation of the inclusion complex with β-cyclodextrin (β-CD), shows numerous environmental and industrial cost advantages, such as, stability improvement of the active substance, synthesis of water-based products, option of commercializing the final product either in solid state or in solution and avoidance of the undesired side-effects derived from the use of insecticides. Furthermore, the inclusion complexes have other advantages that involve controlled and specific release of active component in the medium. In this work the synthesis of the inclusion complex formed by β-CD and the acetamiprid (ACET) nicotinoid insecticide ((E)-N1-[(6-chloro-3-pyridyl)methyl]-N2-cyano-N1-methyl-acetamidine) was done and their molecular structure was studied in solid state and in solution, by means of experimental techniques. The 2:2 stoichiometry found in solid state, a structure based on dimmers classified as a channel type, is similar to that found in solution (1:1 stoichiometry). In both cases, the nitrile and chloropyridine groups of the insecticide molecules are oriented toward primary rim and secondary rim of the β-CD molecule, respectively.

Solubility, photostability and antifungal activity of phenylpropanoids encapsulated in cyclodextrins

Effects of the encapsulation in cyclodextrins (CDs) on the solubility, photostability and antifungal activities of some phenylpropanoids (PPs) were investigated. Solubility experiments were carried out to evaluate the effect of CDs on PPs aqueous solubility. Loading capacities and encapsulation efficiencies of freeze-dried inclusion complexes were determined. Moreover, photostability assays for both inclusion complexes in solution and solid state were performed. Finally, two of the most widespread phytopathogenic fungi, Fusarium oxysporum and Botrytis cinerea, were chosen to examine the antifungal activity of free and encapsulated PPs. Results showed that encapsulation in CDs significantly increased the solubility and photostability of studied PPs (by 2 to 17-fold and 2 to 44-fold, respectively). Free PPs revealed remarkable antifungal properties with isoeugenol showing the lowest half-maximal inhibitory concentration (IC50) values of mycelium growth and spore germination inhibition. Encapsulated PPs, despite their reduced antifungal activity, could be helpful to solve drawbacks such as solubility and stability.

Preparation, physicochemical analysis and molecular modeling investigation of 2,2′-Bipyridine: β-Cyclodextrin inclusion complex in solution and solid state

Supramolecular interaction between 2,2′-Bipyridine (BPY) and β-Cyclodextrin (β-CD) has been investigated in solution and solid state. Non-covalent interaction between BPY and β-CD was studied in solution using absorption and fluorescence spectroscopy. Inclusion complex of BPY and β-CD was prepared in solid state by co-precipitation method and it was characterized using Fourier Transform Infra-red spectroscopy (FT–IR), Thermal analysis, Scanning Electron Microscopy (SEM), Powder X-ray diffractometry (XRD) and Atomic Force Microscopy (AFM). Binding constant values and 1:1 stoichiometry of the inclusion complex were calculated using Benesi–Hildebrand plots at 303 K. Using continuous variation method the 1:1 stoichiometry has been confirmed for BPY: β-CD complex. Thermodynamic parameter, ΔG of inclusion complex formation was determined and the negative value indicated that the inclusion process was an exergonic and spontaneous process. The most probable model of BPY: β-CD inclusion complex suggested by molecular docking studies was in good agreement with the results obtained by experimental methods.

Masking the bitter taste of injectable lidocaine HCl formulation for dental procedures.

Several attempts have been made to mask the bitter taste of oral formulations, but none have been made for injectable formulations. This study aims to mask the bitter taste of dental lidocaine HCl (LID) injection using hydroxypropyl-β-cyclodextrin (HP-β-CD) and sodium saccharin. Inclusion complexes of LID and HP-β-CD were prepared by the solution method in 1:1 and 1:2 M ratios. Inclusion complexes in solution were studied using phase solubility in phosphate buffer solutions (pH 8, 9, and 10). Freeze-dried inclusion complexes were characterized using differential scanning calorimetry (DSC), X-ray, Fourier transform infrared (FT-IR), nuclear magnetic resonance (NMR), scanning electron microscopy (SEM), and in vitro release. Injectable formulations were prepared using inclusion complexes and characterized for stability and for taste using an Alpha MOS ASTREE electronic tongue (ETongue). The association constants of HP-β-CD with lidocaine-free base and its ionized form were found to be 26.23 ± 0.00025 and 0.8694 ± 0.00045 M(-1), respectively. Characterization studies confirmed the formation of stable inclusion complexes of LID and HP-β-CD. Injectable formulations were found to be stable for up to 6 months at 4°C, 25°C, and 40°C. The taste evaluation study indicated that HP-β-CD (1:1 and 1:2 M ratios) significantly improved the bitter taste of LID injectable formulation. In conclusion, inclusion complex in the 1:1 M ratio with 0.09% sodium saccharin was considered to be optimum in masking the bitter taste of LID.

Clawlike Tripodal Porphyrin Trimer: Ion-Controlled On–Off Fullerene Binding

A practical method for the preparation of novel tripodal tris(porphyrinato-urea) TP3 1 was readily achieved. Because of its appreciable preorganized triangular cone-shaped cavity resulting from the intramolecular hydrogen bonds of the tripodal tris-urea backbone, this porphyrin trimer host was found to have a high affinity toward fullerenes to form stable inclusion complexes in solution. A 120-fold binding selectivity toward C70 (Kassoc = 1.81 × 10(7) M(–1)) over C60 (Kassoc = 1.51 × 10(5) M(–1)) was further achieved in toluene. Moreover, the dissociation of such inclusion complexes can be easily realized by introducing H2PO4(–), and recapturing of the fullerene can be achieved after withdrawing H2PO4(–) by Ca(2+). A recyclable process for the inclusion and release of fullerene was therefore built by alternately feeding H2PO4(–) and Ca(2+). Benefiting from this approach, TP3 1 was sequentially applied to isolate C70 from the C60-enriched fullerene mixture successfully.

Enhanced Mineralization of Diuron Using a Cyclodextrin-Based Bioremediation Technology

The phenylurea herbicide diuron [N-(3,4-dichlorophenyl)-N,N-dimethylurea] is widely used in a broad range of herbicide formulations and, consequently, it is frequently detected as a major soil and water contaminant in areas where there is extensive use. Diuron has the unfortunate combination of being strongly adsorbed by soil organic matter particles and, hence, slowly degraded in the environment due to its reduced bioavailability. N-Phenylurea herbicides seem to be biodegraded in soil, but it must be kept in mind that this biotic or abiotic degradation could lead to accumulation of very toxic derived compounds, such as 3,4-dichloroaniline. Research was conducted to find procedures that might result in an increase in the bioavailability of diuron in contaminated soils, through solubility enhancement. For this purpose a double system composed of hydroxypropyl-β-cyclodextrin (HPBCD), which is capable of forming inclusion complexes in solution, and a two-member bacterial consortium formed by the diuron-degrading Arthrobacter sulfonivorans (Arthrobacter sp. N2) and the linuron-degrading Variovorax soli (Variovorax sp. SRS16) was used. This consortium can achieve a complete biodegradation of diuron to CO2 with regard to that observed in the absence of the CD solution, where only a 45% biodegradation was observed. The cyclodextrin-based bioremediation technology here described shows for the first time an almost complete mineralization of diuron in a soil system, in contrast to previous incomplete mineralization based on single or consortium bacterial degradation.

Crystallographic, UV spectroscopic and computational studies of the inclusion complex of α-cyclodextrin with p-aminobenzoic acid

Crystal structure of the cyclomaltohexaose (α-cyclodextrin, α-CD) inclusion complex with p-aminobenzoic acid (pABA) has been determined by X-ray diffraction. The host:guest stoichiometry is 1:1. The pABA molecule is included in the cavity with its axis coincident with the axis of α-CD; the benzoic group is inserted in the cavity, while the amino group sticks out from the cavity. Four water molecules are located near the cavity rims and in interstices between the molecules of α-CD participating in a dense network of intermolecular hydrogen bonds. UV–visible spectroscopy was applied to estimate the stability constant (K c) at different temperatures on the basis of the Benesi–Hildebrand equation. This allowed calculation of complexation and on the basis of the Van't Hoff equation. The results are in good agreement with the values obtained by other methods in the literature. Phase-solubility profiles indicate that the solubility of pABA is significantly increased in the presence of α-CD at different pH values, and it was classified as AL-type, indicating a 1:1 stoichiometric inclusion complex in solution. A theoretical investigation has also been carried out on the α-CD-pABA systems in order to search for other stable complexes. PM6 semi-empirical calculations were made to investigate equilibrium geometries of inclusion complexes formed between α-CD and neutral, anionic, cationic and zwitterionic forms of pABA. Two possible orientations were considered (A, with the carboxylic end inside the cavity and B, with the amino group inside the cavity). Preference between A and B orientations of each α-CD-pABA form results from different H-bond interaction patterns.

Molecular Tethering or Aggregation: Is the Existence of Charge‐Transfer Bands Indicative of the Formation of Blue‐Box/Tetrathiafulvalene Inclusion Complexes?

The interaction between tetrathiafulvalene and tetracation cyclobis(paraquat-p-phenylene) fragments-the key elements of many rotaxane systems-was investigated theoretically by using ab-initio second-order perturbation methods. In addition to the inclusion complex observed in the solid state, a thermodynamically stable "exterior" complex was identified. Calculation of the UV/Vis spectra for the inclusion and the exterior complexes indicated that the charge-transfer band that is often used to predict the formation of the inclusion complexes in solution is, in reality, due to the exterior mode of complexation. These results suggest that UV/Vis spectroscopy is not a reliable method for assigning the complexation modes in TTF:BB(4+) rotaxanes and related systems.

Hydrogen bonding of excited states in supramolecular host–guest inclusion complexes

Host-guest inclusion complexes represent an important type of supramolecular structure, one which finds widespread applications in diverse areas including separations science, the food industry, molecular sensors and optical devices. There are several driving forces for the formation of such inclusion complexes in solution; one of the most important is hydrogen bonding between the guest and host molecules. The nature or strength of the hydrogen bonding may change upon electronic excitation of the guest, for example during fluorescence studies or when the inclusion complex is used as an optical sensor. In this Perspective article, the impact of hydrogen bonding between excited state guests and their hosts is examined in detail, in terms of the impact on the formation and stability of such excited state complexes, the effects on guest fluorescence, changes in the stability of ground state guest complexes upon electronic excitation, the application of inclusion complexes as fluorescent sensors and materials, and the use of fluorescence spectroscopy for their study.

Hexahomotrioxacalix[3]arene derivatives as ionophores for molecular recognition of dopamine, serotonin and phenylethylamine

The lower rim functionalized hexahomotrioxacalix[3]arene derivatives cone-3 and cone-5 bearing three benzyl and three N,N-diethyl-2-aminoethoxy groups, respectively, were synthesized from triol 1. Their complexation with 2-(3,4-dihydroxyphenyl)ethylamine (dopamine), 5-hydroxytryptamine (serotonin), and 2-phenylethylamine (phenethylamine), which have biologically important activities, has been studied by (1)H-NMR spectroscopy. The chemical shifts of the aromatic protons of the host and guest molecules and the up-field shifts of the ethyl protons of the guest molecules strongly suggest the formation of inclusion complexes in solution. The formation of the host-guest complexes is assisted by a hydrogen bond and/or an electrostatic interaction between the host and ammonium ion (RNH(3)(+)) of the guest. The structures of receptors cone-3 and cone-5 have been determined by X-ray crystallography.

Studies on 6-chloro-5-(1-naphthyloxy)-2-(trifluoromethyl)-1H-benzimidazole/2-hydroxypropyl-β-cyclodextrin association: Characterization, molecular modeling studies, and in vivo anthelminthic activity

The purpose of this work is to study the molecular association that occurs between 2-hydroxypropyl-β-cyclodextrin (HPβCD) and 6-chloro-5-(1-naphthyloxy)-2-(trifluoromethyl)-1H-benzimidazole (RCB20), an antiparasitic compound recently found by our research group, with poor aqueous solubility. The complex stability constant and stoichiometric ratio determined by phase-solubility diagram and Job's plot provided evidence that HPβCD enhanced water solubility of RCB20 through inclusion complex formation. Two-dimensional ¹H NMR spectroscopy is used to study the molecular arrangement of inclusion complex in solution. These results are further supported using molecular modeling studies. In the solid state, the complexation is confirmed by differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy. Finally, RCB20/HPβCD complex has better activity than RCB20 against the adult and muscle larvae phase of Trichinella spiralis.