Complex Formation Of Cyclodextrins Research Articles

Effect of Cyclodextrin Complex Formation on Solubility Changes of Each Drug Due to Intermolecular Interactions between Acidic NSAIDs and Basic H2 Blockers.

One of the solubilization of poorly water-soluble drugs is the use of cyclodextrin (CD)-based inclusion complexes. On the other hand, few studies have investigated how CD functions on the solubility of drugs in the presence of multiple drugs that interact with each other. In this study, we used indomethacin (IND) and diclofenac (DIC) as acidic drugs, famotidine (FAM) and cimetidine (CIM) as basic drugs, and imidazole (IMZ), histidine (HIS), and arginine (ARG) as compounds structurally similar to basic drugs. We attempted to clarify the effect of β-CD on the solubility change of each drug in the presence of multiple drugs. IND and DIC formed a eutectic mixture in the presence of CIM, IMZ, and ARG, which greatly increased the intrinsic solubility of the drugs as well as their affinity for β-CD. Furthermore, the addition of high concentrations of β-CD to the DIC-FAM combination, which causes a decrease in solubility due to the interaction, improved the solubility of FAM, which was decreased in the presence of DIC. These results indicate that β-CD synergistically improves the solubility of drugs in drug-drug combinations, where the solubility is improved, whereas it effectively improves the dissolution rate of drugs in situations where the solubility is reduced by drug-drug interactions, such as FAM-DIC. This indicates that β-CD can be used to improve the physicochemical properties of drugs, even when they are administered in combination with drugs that interact with each other.

A Systematic Review on Cyclodextrin: A Versatile Tool for Enhanced Formulations and Diverse Applications

Cyclodextrins (CDs) are cyclic oligosaccharides that have gained significant attention in various industries due to their unique structural properties and versatile applications. This study aims to provide a comprehensive overview of the types, formulation techniques, and wide-ranging applications of cyclodextrins. It explores the formulation techniques used to incorporate cyclodextrins into different matrices. Cyclodextrin Complex Formation, Cyclodextrin-Based Nanostructures involves the encapsulation of guest molecules within the hydrophobic cavity of cyclodextrins. The study presents a broad range of applications where cyclodextrins have demonstrated their utility. The pharmaceutical industry extensively employs cyclodextrins as excipients to enhance drug solubility, stability, bioavailability, and taste masking. Additionally, CDs find applications in the food and beverage industry for flavor encapsulation, preservation, and controlled release of bioactive compounds. They also play a vital role in various fields, including agriculture, cosmetics, environmental remediation, and separation sciences.

Optimizing ophthalmic delivery of a poorly water soluble drug from an aqueous in situ gelling system

Poorly soluble drugs are often unsuitable to incorporate in ocular in situ gelling systems due to the aqueous based gelling formulations and low volumes administered. For such formulations to be successful, the administered drug must have sufficient solubility to diffuse from the formulation to the eye and should not affect the gelation of the in situ gelling material. Drug salt forms can improve the solubility of poorly soluble drugs, however, as in situ gel forming formulations are often designed to be crosslinked by salts (present the lacrimal fluid) it can make salt forms difficult to formulate. The aim of this study was to develop an in situ gel forming ophthalmic formulation of a poorly soluble drug flurbiprofen (FBP) through cyclodextrin complex formation and to analyse the impact on gelation, release and permeation through the cornea. Hydroxypropyl-beta-cyclodextrin (HβCD) was used as a complexing agent and low acyl gellan gum was added to the FBP- HβCD complex as a water soluble in situ gelling polymer. Measurements were performed using rheo-dissolution, which utilises a rheometer with a modified lower plate that has the unique ability to allow rheological measurement and analysis of drug release simultaneously. An ex-vivo permeation study was also performed using porcine cornea. Rheological measurements in terms of elastic (Gʹ) and viscous (G″) modulus showed rapid gelation of the formulation upon contact with simulated lacrimal fluid (SLF). Approximately, 97% FBP was released when 10% HβCD was used and release was decreased to 79% when the amount of HβCD was increased to 20%. The percentage of drug permeation through the cornea was 55% in 300 min whereas the marketed non gelling eye drop formulation containing FBP sodium showed only 37% permeation. The data presented here, revealed that not only could a poorly soluble drug be complexed with cyclodextrin and loaded into an in situ gelling system without interfering with the gelation, but also permeability the of the drug improved.

Fluorescence sensing of Al3+ by an anthracene appended piperidone. Hindrance in excimer formation offered by β-cyclodextrin complexation

Development of fluorescence based chemosensors for aluminum ions is essential as aluminium causes several environmental issues. Herein, we report a piperidone based Al3+ ion sensor with anthracene as the fluorescent signalling unit. The compound shows aluminum ion selectivity through fluorescence enhancement. The compound also forms a 1:2 inclusion complex with β-cyclodextrin. The excimer fluorescence is quenched on cyclodextrin complex formation. Al3+ ions are not selectively bound by the chemosensor in the host–guest complex as the excimer is disintegrated in the presence of the host molecule. We report the range of sensing of Al3+ ions by the chemosensor in aqueous medium.

Solvophobically Driven Complexation of Adamantyl Mannoside with β-Cyclodextrin in Water and Structured Organic Solvents.

The effects of solvent and temperature on the complexation of adamantyl mannoside with β-cyclodextrin and 6-O-monotosyl-6-deoxy-β-cyclodextrin were explored experimentally and by means of molecular dynamics simulations. Efficient binding was observed only in hydrogen-bonded solvents, which indicated solvophobically driven complexation. The stability of the inclusion complex was considerably higher in aqueous media. A pronounced temperature dependence of Δr H○ and Δr S○ , resulting in perfect enthalpy-entropy compensation, was observed in water. The complexation thermodynamics was in line with classical rationale for the hydrophobic effect at lower temperatures and the nonclassical explanation at higher temperatures. This finding linked cyclodextrin complexation thermodynamics with insights regarding the effect of temperature on the hydration water structure. The complexation enthalpies and entropies were weakly dependent on temperature in organic media. The signs of Δr H○ and Δr S○ were in accordance with the nonclassical hydrophobic (solvophobic) effect. The structures of the optimized product corresponded to those deduced spectroscopically, and the calculated and experimentally obtained values of Δr G○ were in very good agreement. This investigation clearly demonstrated that solvophobically driven formation of cyclodextrin complexes could be anticipated in structured solvents in general. However, unlike in water, adamantane and the host cavity behaved solely as structure breakers in the organic media explored so far.

Machine Learning Approach for Determining the Formation of β-Lactam Antibiotic Complexes with Cyclodextrins Using Multispectral Analysis.

The problem of determining the formation of complexes of β-lactam antibiotics with cyclodextrins (CDs) and the interactions involved in this process were addressed by machine learning on multispectral images. Complexes of β-lactam antibiotics, including cefuroxime axetil, cefetamet pivoxil, and pivampicillin, as well as CDs, including αCD, βCD, γCD, hydroxypropyl-αCD, methyl-βCD, hydroxypropyl-βCD, and hydroxypropyl-γCD, were prepared in all combinations. Thermograms confirming the formation of cyclodextrin complexes were obtained using differential scanning calorimetry. Transmission Fourier-transform infrared (tFTIR) and complementary attenuated total reflectance FTIR (ATR) coupled with machine learning were techniques chosen as a nondestructive alternative. The machine learning algorithm was used to determine the formation of complexes in samples using solely their tFTIR and ATR spectra at the prediction stage. Parameterized method 7 (PM7) was used to support the analysis by molecular modeling of the complexes. The model developed through machine learning properly distinguished samples with formed complexes form noncomplexed samples with a cross-validation accuracy of 90.4%. Analysis of the contribution of spectral bands to the model indicated interactions of ester groups of β-lactam antibiotics with CDs, as well as some interactions of cephem ring in cefetamet pivoxil and penam moiety in pivampicillin. Molecular modeling with PM7 helped to explain experimental results and allowed to propose possible binding modes.

Complex Formation of Cyclodextrins with Sulfasalazine in Buffer Solutions

Complex formation of α-, β-, and γ-cyclodextrins with sulfasalazine in biologically relevant buffer solutions (pH 1.2 and 7.4) was studied. Formation of inclusion complexes of 1 : 1 stoichiometry between the drug and cyclodextrins was revealed. The ionization state of sulfasalazine more strongly affects the complex formation than does the structure of cyclodextrins. Compared with a neutral molecule, sulfasalazine anionic species forms with cyclodextrins more stable complexes, which are essentially stabilized by possible surface interactions.

A new fluorescent chemosensor for cadmium(II) based on a pyrene-appended piperidone derivative and its β-cyclodextrin complex.

We report, in this article, a piperidin-4-one derivative carrying pyrenyl fluorescent reporter groups which acts as a Cd2+ ion sensor. The compound is synthesized and characterized using IR and NMR spectral techniques. The compound forms an inclusion complex with β-cyclodextrin. It selectively binds to Cd2+ ions in water and aqueous β-cyclodextrin media. The stoichiometry of the host-guest complex of the compound with β-cyclodextrin is 1:2. The ligand-metal ion binding stoichiometry is 1:1 both in water and in β-cyclodextrin. The linear concentration range of detection of the metal ion is reported. Cyclodextrin complex formation does not affect the metal ion selectivity of the compound.

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.

Calorimetric study of the complex formation of cyclodextrins with nicotinic and niflumic acids in aqueous solutions

Thermodynamic parameters of the inclusion complex formation of native and hydroxypropylated cyclodextrins with pharmacologically active niflumic and nicotinic acids were obtained and analyzed. It was shown that cyclodextrins selectively react with these acids and display a higher binding affinity to niflumic acid which is more hydrophobic and less hydrated compared to nicotinic acid. An influence of the cyclodextrin cavity size and accessibility of the hydroxypropyl substituent on the thermodynamics of the reactions and the binding mode of the acids was revealed and discussed in this work.

Thermodynamics and binding mode of novel structurally related 1,2,4-thiadiazole derivatives with native and modified cyclodextrins

Study of complex formation of cyclodextrins with 1,2,4-thiadiazole derivatives intended for Alzheimer's disease treatment was carried out using 1H NMR, ITC and phase solubility methods. Structure of cyclodextrins and thiadiazoles affects the binding mode and thermodynamics of complexation. The larger cavity of β- and γ-cyclodextrins is more appropriate for deeper insertion of 1,2,4-thiadiazole derivatives which is accompanied by intensive dehydration and solvent reorganization. Benzene ring of the thiadiazoles is located inside macrocyclic cavity while piperidine ring is placed outside the cavity and can form H-bonds with cyclodextrin exterior. Complexation with cyclodextrins induces the enhancement of aqueous solubility of 1,2,4-thiadiazole derivatives.

Inclusion complex formation of cyclodextrin with its guest and their applications

Inclusion complex formation of cyclodextrin with its guest and their applications

Complex formation of cyclodextrins with some pharmacologically active 1,2,4-thiadiazole derivatives

Previously synthesized 1,2,4-thiadiazole derivatives displayed an activity in the treatment of Alzheimer’s disease; however, these compounds are poorly soluble in aqueous solutions. Inclusion complex formation with cyclodextrins is proposed for the development of water-soluble dosage forms of 1,2,4-thiadiazoles under study. To this end, binding of 1,2,4-thiadiazole derivatives with α-, β- and γ-cyclodextrins as well as with modified β-cyclodextrins was investigated by isothermal titration calorimetry, 1H NMR and UV–Vis spectroscopy in aqueous buffered solution (pH = 7.4) at 298.15 K. The detailed analysis of the thermodynamic parameters of complex formation is presented. The structure of 1,2,4-thiadiazole/cyclodextrin complexes was evaluated on the basis of 2D 1NMR (ROESY) experiments. The influence of structural factor (dimensions of macrocyclic cavity, modification of the host external surface, structure of guest molecules) on the thermodynamics and binding mode was discussed.

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.

Protonation and β-cyclodextrin complex formation equilibria of fluconazole

Fluconazole, the adequate antifungal agent in Candida infections was studied to quantify its acid–base and cyclodextrin-complex formation equilibria. 1H NMR-pH titrations revealed protonation steps in the highly basic region (log K1 = 11.96) and in the acidic region (log K2 = 1.48). The stability and structure of its complexes with β-cyclodextrin (2-hydroxy)propyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin were investigated by 1D and 2D solution NMR spectroscopic techniques. The cyclodextrin complexes of fluconazole are of moderate stability (1 < log K < 2). Peculiarly enough, two isomeric complexes of comparable stability are formed between the neutral fluconazole and β-cyclodextrin.

Changes in the anti-inflammatory activity of aurone and chalcone class flavonoids from Cotinus coggygria extracts after complexation with cyclodextrins

Aurones and chalcones are less studied flavonoid classes with emerging therapeutical potential. Using the heartwood of European smoke tree (Cotinus coggygria Scop. syn Rhus cotinus L.) which contains aurones (sulfuretin, S) and chalcones (butein, B) [1], the aim of the present research was to obtain cyclodextrin (CDX) derivatives with enhanced water solubility and improved biological activity. Following steps were performed: 1) A flavonoid-enriched extract was prepared and standardized to its content in S, B, fustin, 2,3-dihydroquercetagetin, and quercetin using an established HPLC method [1]; 2) C. coggygria extract, S and B were each complexed through kneading with hydroxypropyl-beta cyclodextrin (HPBCD) and randomely methylated beta-cyclodextrin (RAMEB). A molar ratio of CDX: flavonoid = 2:1 was employed; 3) Formation of CDX complexes was confirmed by DSC, FT-IR and Karl Fisher titration techniques; 4) Anti-inflammatory effects of C. coggygria extract, S, B, and their CDX complexes were assessed in the model of the mouse ear edema (SKH1 male mice). Corneometry was used to measure the hydration level of the stratum corneum, this level being inversely correlated with skin irritation. Results showed that the noncomplexed extract, B, and S reduced inflammation with 50%, 33% and 50%, respectively. They are as well capable to lessen (with 26%, 97% and 30%, respectively) the skin dehydration induced by TPA. Complexation with CDXs enhances the anti-inflammatory effect of B (maximal for HPBCD) and S (maximal for RAMEB), but reduces it in case of the extract. These findings encourage further development of S- and B-CDX derivatives with improved biological effects.

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.

BIOAVAILABILITY ENHANCDEMENT OF POORLY SOLUBLE DRUGS BY SMEDDS: A REVIEW

Oral route has always been the favorite route of drug administration in many diseases and till today it is the first way investigated in the development of new dosage forms. The major problem in oral drug formulations is low and erratic bioavailability, which mainly results from poor aqueous solubility, thereby pretense problems in their formulation. More than 40% of potential drug products suffer from poor water solubility. For the therapeutic delivery of lipophilic active moieties (BCS class II drugs), lipid based formulations are inviting increasing attention. Currently a number of technologies are available to deal with the poor solubility, dissolution rate and bioavailability of insoluble drugs such as micronization, solid dispersions or cyclodextrin complex formation and different technologies of drug delivery systems. One of the promising techniques is Self‐Micro Emulsifying Drug Delivery Systems (SMEDDS). Self emulsifying drug delivery system has gained more attention due to enhanced oral bio-availability enabling reduction in dose, more consistent temporal profiles of drug absorption, selective targeting of drug(s) toward specific absorption window in GIT, and protection of drug(s) from the unreceptive environment in gut. This article gives a complete overview of SMEDDS as a promising approach to effectively deal with the problem of poorly soluble molecules. Keywords: SMEDDS, surfactant, oil, co-surfactant, bioavailability