Inclusion Complexation Process Research Articles

IN-VITRO STUDIES OF BETAMETHASONE/CYCLODEXTRIN INCLUSION COMPLEXES

The interaction of Betamethasone with different types of CDs was investigated. The effects of the types and concentration of CDs, as well as temperature on the inclusion behavior were also investigated. Different techniques were used in this investigation including PSD, DSC, SEM, 1H-NMR and MM. PSD results indicated
 that the tendency of BMTZ to bind to CDs follows the order g-CD?a-CD<HP-b-CD<b-CD. This provides indications that size fit plays an important role on the inclusion complexation process. The thermodynamic parameters of the inclusion complexes under investigation were calculated. The negative entropy change indicated that conformational changes were the dominant compared to the release of water solubility for the CD cavity and these formed an ice-burg structure around the BMTZ. MM study revealed that the dominant driving force of the inclusion complexation is the electrostatic energy. The DSC and SEM confirmed the formation of inclusion complex in the solid state.

Effective Treatment of Knee Osteoarthritis Using a Nano-Enabled Drug Acupuncture Technology in Mice.

A nano-enabled drug delivery acupuncture technology (nd-Acu) is developed that is based on traditional acupuncture needles where the stainless-steel surface is designed to deliver various payload molecules. To create the nd-Acu platform, an electrochemistry procedure is used to attach methyl salicylate-modified cyclodextrin in which the sugar rings allow the encapsulation of structurally defined single or multiple payload molecules via an inclusion complexation process. Drug loading and release profile are first studied using fluorescent dyes abiotically and at intact animal level. nd-Acu allows more efficient dye loading and time-dependent release compared to pristine needles without cyclodextrin modification. Subsequently, a proof-of-principle efficacy study is conducted using the platform to load a local anesthetic, lidocaine, for the treatment of knee osteoarthritis (KOA) in mice. It is demonstrated that lidocaine-laden nd-Acu can effectively alleviate pain, reduce inflammation, and slow down KOA development biochemically and histologically. Hypothesis-driven and proteomic approaches are utilized to investigate the working mechanisms of lidocaine nd-Acu, indicating that the therapeutic outcome is attributed to the in vivo modulation of the HMGB1/TLR4 signaling pathway. The study also obtained preliminary evidence suggesting the involvement of mitochondria as well as small GTPase such as cdc42 during the treatment by lidocaine nd-Acu.

In-vitro dissolution and microbial inhibition studies on anticancer drug etoposide with β-cyclodextrin

In this article, we have reported the inclusion complex behaviors and their pharmaceutical application of anticancer drug property of Etoposide with β-cyclodextrin. The inclusion complex is used to improve the poor aqueous solubility of the anticancer drug Etoposide. The aqueous solubility and in-vitro dissolution studies support to the anticancer drug Etoposide with β-cyclodextrin complex is significantly improves the aqueous solubility. Etoposide:β-cyclodextrin solid-state complexes were prepared by Physical mixture, kneading and solvent evaporation methods, and were characterized by FT-IR, 1HNMR, XRD, DSC and SEM techniques. In addition, the in-vitro antimicrobial and antibiofilm study of Etoposide drug is a sensible microorganism was significantly increased by an inclusion complexation process. The antibiofilm of anticancer drug Etoposide with β-cyclodextrin studies have been analyzed by confocal laser scanning microscopy.

Experimental investigations, cytotoxicity and cellular uptake outcomes of physically modified duloxetine HCl inclusion complexes

Duloxetine HCl, an antidepressive drug, has poor water solubility and poor oral absorption leading to low bioavailability of the drug. The drug is also found to be acid labile, resulting in degradation in gastric environment. To overcome such drawbacks, inclusion complexation process was explored to improve the solubility and dissolution rate of duloxetine HCl by formulating its complexes with beta-cyclodextrin using different complexation techniques. Equimolar complexes of the drug with β-CD (1:1 molar) were prepared based on phase solubility analysis. Behaviour of complexes was characterized both in solution state and in solid state using DSC, FTIR, SEM, 1H NMR and PXRD techniques. Molecular docking studies were also carried out to investigate mode of inclusion and stability. Also, the cell culture studies, viz. MTT assay and cellular uptake, were investigated. Apparent stability or association constant (Ks) was predicted to be 165.64 M−1. Results of characterization techniques indicate the drug to be completely included in the hydrophobic cavity of β-CD, and hence, the physicochemical properties of the drug differ from parent molecule. Cytotoxicity studies indicated low IC50 value for complexes in comparison with native drug moiety, and cellular uptake of the complex was also found to be improved in case of complexed drug at different time points. Enhanced solubility and improved drug release was observed for physically characterized less crystalline complexes. Cellular uptake is also reported to be appreciably enhanced in complexed form. Thus, the process has logistic approach in reducing the dose of drug and related side effects.

Evidences for Inclusion and Encapsulation of an Ionic liquid with β-CD and 18-C-6 in Aqueous Environments by Physicochemical Investigation.

The interface between pyrrolidinium-based ionic liquid, i.e., 1-ethyl-1-methylpyrrolidinium bromide, with β-cyclodextrin and 18-crown-6 solution have been compared and explored by means of density, viscosity, refractive index, electrical conductance and surface tension, FTIR, 1H nuclear magnetic resonance, 2D ROESY NMR, and high resolution mass spectroscopy studies. Limiting apparent molar volumes (ϕV0), experimental slopes (SV*) interpreted in terms of inclusion and interaction (ion-solvent, ion-ion). Establishment of binding affinity were discussed in molecular terms supported this inclusion complexation and encapsulation interaction process. The result shows that the stability of the resulting complexes of β-cyclodextrin:[EMPyrr]+ and 18-crown-6:[EMPyrr]+ is based on the geometrical and spectrometric data. Host guest chemistry of the five-membered nitrogen containing cation with two different macro cyclic hosts is supported by studying NMR. HRMS has been used to support the complexation process with the proper stoichiometry ratio. The solid complex formations were established by Fourier transform infrared study.

Investigation on inter molecular complexation between 4,4′-methylene-bis(N,N-dimethylaniline) and β-cyclodextrin: Preparation and characterization in aqueous medium and solid state

The purpose of this research was to investigate the inclusion complex formation between 4,4′-methylene-bis(N,N-dimethylaniline) (MBDA) and β-cyclodextrin (β-CD). The inclusion complex of MBDA and β-CD was characterized both in solution and solid state by UV–Visible spectroscopy, fluorescence spectroscopy, Differential Scanning Calorimetry (DSC), Fourier Transform Infra-red spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), Powder X-ray diffractometry (XRD) and Atomic Force Microscopy (AFM). The solid inclusion complex was prepared by co-precipitation method. The 1:1 stoichiometry of inclusion complex and binding constant were determined by Benesi–Hildebrand plot and was confirmed by Jobs continuous variation method. The spectral shifts revealed that only a part of MBDA molecule is entrapped in the β-CD cavity. Nanosecond time resolved fluorescence study revealed that MBDA exhibits single exponential decay in aqueous medium and bi-exponential decay in β-CD medium indicating the formation of 1:1 inclusion complex. The Gibbs free energy change of the complexation process was determined and it was found that the inclusion complexation process was spontaneous. The most probable structure of the inclusion complex of MBDA and β-CD was proposed based on the molecular docking study.

Microencapsulation of herbicide MCPA with native β-cyclodextrin and its methyl and hydroxypropyl derivatives: An experimental and theoretical investigation

When a pesticide is released into the environment, most of it is lost before it reaches its target. An effective way to reduce environmental losses of pesticides is by using controlled release technology. Microencapsulation becomes a promising technique for the production of controlled release agricultural formulations. In this work, the microencapsulation of chlorophenoxy herbicide MCPA with native β-cyclodextrin and its methyl and hydroxypropyl derivatives was investigated. The phase solubility study showed that both native and β-CD derivatives increased the water solubility of the herbicide and inclusion complexes are formed in a stoichiometric ratio of 1:1. The stability constants describing the extent of formation of the complexes have been determined by phase solubility studies. 1H NMR experiments were also accomplished for the prepared solid systems and the data gathered confirm the formation of the inclusion complexes. 1H NMR data obtained for the MCPA/CDs complexes disclosed noticeable proton shift displacements for OCH2 group and H6 aromatic proton of MCPA provided clear evidence of inclusion complexation process, suggesting that the phenyl moiety of the herbicide was included in the hydrophobic cavity of CDs. Free energy molecular mechanics calculations confirm all these findings.The gathered results can be regarded as an essential step to the development of controlled release agricultural formulations containing herbicide MCPA.

Supramolecular architecture of tetrathiafulvalene-bridged bis(β-cyclodextrin) with porphyrin and its electron transfer behaviors

A bridged bis(β-cyclodextrin) 3 with a tetrathiafulvalene (TTF) linker was synthesized by an electrophilic reaction of mono-6-deoxy-6-iodo-β-cyclodextrin 1 with 6,7-bis(methylsulfanyl)-2,3- bis(2-cycanoethylsulfanyl)tetrathiafulvalene 2 under the alkaline condition. Benefiting from the good solubilizing ability of the β-cyclodextrin unit, the solubility limit of 3 in water could reach 1.0 × 10(-3) M, i.e. 0.4 mg mL(-1) calculated as TTF residue. The conformational changes during the inclusion complexation process of 3 with 5,10,15,20-tetrakis(4-sulfonatophenyl)-porphyrin 4 were investigated by UV/Vis and 2D NMR spectroscopy. Significantly, the photo-induced electron transfer (PET) process between the TTF moiety in 3 and the porphyrin unit in 4 would take place within the 3/4 supramolecular complex under the light irradiation, leading to the highly efficient quenching of the fluorescence of 4, and could then be recovered by the formation of TTF cations in the presence of H(2)O(2). Furthermore, taking advantage of the high affinity between 3 and 4, the linear nanoarchitectures were achieved and comprehensively characterized by using transmission electron microscopy (TEM) and atomic force microscopy (AFM). These observations indicated that the strong complexation was a crucial and basic factor to achieve the PET process in the non-covalently constructed assemblies.

Synthesis and spectral investigation of Al(III) catechin/β-cyclodextrin and Al(III) quercetin/β-cyclodextrin inclusion compounds

Al-catechin/β-cyclodextrin and Al-quercetin/β-cyclodextrin (β-CD) inclusion compounds were synthesized and characterized by IR, UV–vis, 1H and 13C NMR and TG and DTA analyses. Because quercetin is sparingly soluble in water, the stability constants of the Al-quercetin/β-CD and Al-catechin/β-CD compounds were determined by phase solubility studies. The A L-type diagrams indicated the formation of 1:1 inclusion compounds and allowed calculation of the stability constants. The thermodynamic parameters were obtained from the dependence of the stability constants on temperature and results indicated that the formation of the inclusion compounds is an enthalpically driven process. The thermal decomposition of the solid Al-quercetin/β-CD and Al-catechin/β-CD inclusion compounds took place at different stages, compared with the respective precursors, proving that an inclusion complexation process really occurred.

Preference Prediction for the Stable Inclusion Complexes between Cyclodextrins and Monocyclic Insoluble Chemicals Based on Monte Carlo Docking Simulations

Cyclodextrins (CDs) are useful functional excipients, which are being used to camouflage undesirable pharmaceutical characteristics, especially poor aqueous solubility, through the inclusion complexation process with insoluble drugs. The selection of more efficient cyclodextrin is important to improve the bioavailability of drugs. In this study, the complexing and solubilizing abilities toward poorly water-soluble monocyclic molecules of natural CDs (α-CD, β-CD, and γ-CD) were investigated using Monte Carlo (MC) docking simulations studies. These theoretical results closely agree with the experimental observation of the complex stability in water of the various guests–CD complexes. Host preferences, based on the experimentally determined stability constants between host CDs and guest molecules, show excellent correlation with the calculated interaction energies of corresponding complexes. The inclusion complex with the lower MC docking interaction energy shows a higher value of stability constant than that of the other complex, and the prediction accuracy of the preferred complex for 21 host–guest pairs is 100%. This result indicates that the MC docking interaction energy could be employed as a useful parameter to select more efficient cyclodextrin as a host for the bioavailability of insoluble drugs. In this study, β-CD shows greater solubilizing efficacies toward guest molecules than those of α-CD and γ-CD, with the exception of one case due to the structure of a guest molecule containing one lipophilic cyclic moiety. The surface area change of CDs and hydrogen bonding between the host and guest also work as major factors for the formation of the stable complex.

Separation of m- and p-Ethylphenols, and of 2,4- and 2,5-Dimethylphenols by Inclusion Complexation with 1,1-Bis(p-hydroxyphenyl)cyclohexane as Host Compound

Separation of isomers with the same or similar boiling points is very difficult, since fractional distillation cannot be used. For example, separation of m- (bp 214°C) and p-ethylphenol (bp 219°C) and of 2,4- (bp 212°C) and 2,5-dimethylphenol (bp 212°C) by fractional distillation is almost impossible. However, when an inclusion complexation process with 1,1-bis( p-hydroxyphenyl)cyclohexane is applied, these isomers were easily separated. m- and p-Ethylphenols were separated on a ton scale by the inclusion complexation technique.

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

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.

Studies of cyclodextrin inclusion complexes. II. Molecular modelling and 1H-NMR evidence for the salbutamol-β-cyclodextrin complex

β-Cyclodextrin (β-CYD) has a hydrophobic cavity in which salbutamol may be clathrated. The ability of a guest molecule to penetrate the CYD host is determined by its size, stereochemistry and polarity. Intermolecular interactions such as the hydrophobic interaction, van der Waals forces, H bonding and other physical forces are involved in the inclusion complexation process. Proton-NMR was employed to assess the mode of inclusion of salbutamol within the β-CYD cavity. The technique is based on the shielding of the CYD and drug protons. If inclusion does occur, protons located within or near the CYD cavity should be strongly shielded. The spectra showed upfield shifts of the CYD protons in the presence of salbutamol and the salbutamol protons shifted downfield in the presence of β-CYD. The downfield shifts of the aromatic protons were greater than those of the aliphatic protons, suggesting that the aromatic ring of salbutamol interacts more strongly with the β-CYD. The interior protons of the CYD molecule were shielded as a result of the anisotropy of the guest aromatic moiety. The highest shifts of β-CYD protons occurred for a molar ratio of 1:1 (salbutamol:β-CYD) indicating the probable stoichiometry of the complex. Molecular graphical computation showed that the minimum van der Waals energy positioning of salbutamol relative to β-CYD occurs when the aromatic ring of salbutamol penetrates the cavity leaving the aliphatic chain externalised.