Enhanced Dissolution and Stability of Lansoprazole by Cyclodextrin Inclusion Complexation: Preparation, Characterization, and Molecular Modeling

In this study, lansoprazole (LSP)/cyclodextrin (CD) inclusion complexes were prepared using a fluid bed coating technique, with β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HPCD) as the host molecules, respectively, to simultaneously improve the dissolution and stability of LSP. The dissolution rate and stability of LSP was dramatically enhanced by inclusion complexation regardless of CD type. LSP/HPCD inclusion complex was more stable under illumination than LSP/β-CD inclusion complex. Differential scanning calorimetry and powder X-ray diffractometry proved the absence of crystallinity in both LSP/CD inclusion complexes. Fourier transform infrared spectroscopy together with molecular modeling indicated that the benzimidazole of LSP was included in the cavity of both CDs, while LSP was more deeply included in HPCD than β-CD. The enhanced photostability was due to the inclusion of the sulfinyl moiety into the HPCD cavity. CD inclusion complexation could improve the dissolution and stability of LSP.KEY WORDS: cyclodextrin, dissolution, inclusion complex, lansoprazole, molecular modeling, stability     

Host-guest complex formation in cyclotrikis-(1-->6)

The possibility that cyclotrikis-(1-->6)-[alpha-D-glucopyranosyl-(1-->4)-beta-D-glucopyranosyl] (CGM6) forms inclusion complexes, like cycloamyloses (cyclodextrins), was investigated by means of electrospray mass spectrometry and fluorescence spectroscopy. The complexing ability of both 1-anilinonaphthalene-8-sulfonate (ANS) and 2-p-toluidinylnaphthalene-6-sulfonate (TNS), which were already used with cyclodextrins, was investigated. The former showed very little or no tendency to be complexed by CGM6, while the latter produced detectable adducts with CGM6. Fixed 90 degree angle light scattering experiments supported the findings obtained by molecular modelling calculations, which indicated a polar character for the CGM6 internal cavity. CGM6-TNS complexes were probably formed throughout interaction of the polar regions of the two molecules.     

Hydroxymethylnitrofurazone:Dimethyl-β-cyclodextrin Inclusion Complex: A Physical–Chemistry Characterization

Hydroxymethylnitrofurazone (NFOH) is active against Trypanosoma cruzi; however, its low solubility and high toxicity precludes its current use in treatment of parasitosis. Cyclodextrin can be used as a drug carrier system, as it is able to form inclusion (host–guest) complexes with a wide variety of organic (guest) molecules. Several reports have shown the interesting use of modified β-cyclodextrins in pharmaceutical formulation, to improve the bioavailability of drugs and to decrease their toxicity. The aim of this work was to characterize inclusion complexes formed between NFOH and dimethyl-β-cyclodextrin (DM-β-CD) by complexation/release kinetics and solubility isotherm experiments using ultraviolet (UV)-visible spectrophotometry and by the measurement of the dynamics information obtained from T ₁ relaxation times and diffusion (DOSY) experiments using nuclear magnetic resonance (NMR) spectroscopy. The complex was prepared at different NFOH and DM-β-CD molar ratios. The UV-visible measurements were recorded in a spectrophotometer, and NMR experiments were recorded at 20°C on a NMR spectrometer (Varian Inova) operating at 500 MHz. Longitudinal relaxation times were obtained by the conventional inversion-recovery method and the DOSY experiments were carried out using the BPPSTE sequence. The kinetics of complexation revealed that 30 h is enough for stabilization of the NFOH absorbance in presence of cyclodextrin. Solubility isotherm studies show a favorable complexation and increase in solubility when NFOH interacts with cyclodextrin. The analysis of the NMR-derived diffusion coefficients and T ₁ relaxation times shows that in the presence of DM-β-CD, NFOH decreases its mobility in solution, indicating that this antichagasic compound interacts with the cyclodextrin cavity. The release kinetics assays showed that NFOH changes its release profile when in the presence of cyclodextrin due to complexation. This study was focused on the physicochemical characterization of drug-delivery formulations that may serve as potentially new therapeutic options for the treatment of Chagas’ disease.     

Interaction of cyclodextrins with fluorescent probes and its application to kinetic studies of amylase.

It was found that 6-p-toluidinylnaphthalene-2-sulfonate (TNS) showed pronounced fluorescence enhancement when it was added to alpha-, beta-, and gamma-cyclodextrin solutions. 2. The following results were obtained by quantitative study of the interactions of three kinds of cyclodextrins with TNS by following TNS fluorescence at pH5.3. and 25 degrees. i) alpha-Cyclodextrin forms a l : l complex with TNS. ii) beta- and gamma-Cyclodextrins form 1 : 1 and also 2 : 1 complexes; in the latter two cyclodextrin molecules bind to one TNS molecule. iii) The dissociation constants of cyclodextrin-TNS complexes were determined to be 54.9 mM for alpha-cyclodextrin, 0.65 mM for beta-cyclodextrin and 0.66 mM for gamma-cyclodextrin in the 1 : 1 complex, and the secondary dissociation constants in the 2 : 1 complex were 71.4 mM for beta-cyclodextrin in the 1 : 1 complex, and the secondary dissociation constants in the 2 : 1 complex were 71.4 mM for beta-cyclodextrin and 32.6 mM for gamma-cyclodextrin. iv)...     

NMR spectroscopic study of cyclodextrin inclusion complexes with A-007 prodrugs

One- and two-dimensional NMR spectroscopy was used to demonstrate the formation of inclusion cyclodextrin complexes with several A-007 prodrugs. These complexes are comprised from the encapsulation of the two phenol moieties of the A-007 prodrugs within the cyclodextrin cavity. Considering the size of the two phenol moieties of the A-007 prodrugs compared to the sizes of alpha-, beta-, and gamma-cyclodextrin cavities, we observed complementary binding of the A-007 prodrug with only beta-cyclodextrin, which was also demonstrated spectroscopically. The beta-cyclodextrin inclusion complexes increased the prodrug solubility and modified the prodrug half-life in water. Therefore, beta-cyclodextrin inclusion complexes can be used as an essential form of A-007 prodrug delivery.     

Complex formation of chlorhexidine gluconate with hydroxypropyl-β-cyclodextrin (HPβCD) by proton nuclear magnetic resonance spectroscopy ((1)H NMR)

The complex formation of chlorhexidine digluconate (CHX-G(2)) with hydroxypropyl-β-cyclodextrin (HPβCD) was studied using NMR spectroscopy. The results revealed that this surfactant agent shows an monomer/aggregate equilibrium, which is dependent on the concentration of this drug. This equilibrium can be modified by the presence of HPβCD, which reduces the aggregation of the CHX-G(2) molecules. An inclusion process of the CHX-G(2) aromatic residue within the cyclodextrin cavity was confirmed by 2D ROESY spectroscopy. (1)H NMR titration studies of CHX-G(2) with HPβCD in D(2)O confirmed the formation of higher order complexes between CHX-G(2) and HPβCD. Moreover, the addition of HPβCD into CHX-G(2) solutions forms insoluble aggregates. Such insoluble aggregates may result in the stacking of CHX-G(2) molecules on the surface of the CHX-G(2):HPβCD complexes.     

Evidence for covalent binding between copper ions and cyclodextrin cavity: a vibrational circular dichroism study

Vibrational absorption and circular dichroism (VCD) spectra were obtained for parent cyclodextrins, hydroxyl deuterated alpha-cyclodextrin, cyclodextrin-copper complexes, and for the cyclodextrin inclusion complexes with Methyl Orange, methyloxirane, 1-propanol, and substituted cyclohexanones, in the solution phase. Changes in the VCD spectra, reflecting perturbations of cyclodextrin cavity, were found in the case of an inclusion complex with Methyl Orange, but for the remaining inclusion complexes measurable changes in VCD were not found. Significant changes observed in the VCD spectra of cyclodextrin-copper complexes suggest that the covalent binding of copper ions to the hydroxyl groups of cyclodextrin is involved.     

Nanosuspensions Containing Oridonin/HP-β-Cyclodextrin Inclusion Complexes for Oral Bioavailability Enhancement via Improved Dissolution and Permeability

Chemotherapy via oral route of anticancer drugs offers much convenience and compliance to patients. However, oral chemotherapy has been challenged by limited absorption due to poor drug solubility and intestinal efflux. In this study, we aimed to develop a nanosuspension formulation of oridonin (Odn) using its cyclodextrin inclusion complexes to enhance oral bioavailability. Nanosuspensions containing Odn/2 hydroxypropyl-β-cyclodextrin inclusion complexes (Odn-CICs) were prepared by a solvent evaporation followed by wet media milling technique. The nanosuspensions were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), and dissolution. The resulting nanosuspensions were approximately 313.8 nm in particle size and presented a microcrystal morphology. Nanosuspensions loading Odn-CICs dramatically enhanced the dissolution of Odn. Further, the intestinal effective permeability of Odn was markedly enhanced in the presence of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and poloxamer. Bioavailability studies showed that nanosuspensions with Odn-CICs can significantly promote the oral absorption of Odn with a relative bioavailability of 213.99% (Odn suspensions as reference). Odn itself possesses a moderate permeability and marginal intestinal metabolism. Thus, the enhanced bioavailability for Odn-CIC nanosuspensions can be attributed to improved dissolution and permeability by interaction with absorptive epithelia and anti-drug efflux. Nanosuspensions prepared from inclusion complexes may be a promising approach for the oral delivery of anticancer agents.     

Complex formation of chlorhexidine gluconate with hydroxypropyl-β-cyclodextrin (HPβCD) by proton nuclear magnetic resonance spectroscopy (H NMR)

The complex formation of chlorhexidine digluconate (CHX-G₂) with hydroxypropyl-β-cyclodextrin (HPβCD) was studied using NMR spectroscopy. The results revealed that this surfactant agent shows an monomer/aggregate equilibrium, which is dependent on the concentration of this drug. This equilibrium can be modified by the presence of HPβCD, which reduces the aggregation of the CHX-G₂ molecules. An inclusion process of the CHX-G₂ aromatic residue within the cyclodextrin cavity was confirmed by 2D ROESY spectroscopy. ¹H NMR titration studies of CHX-G₂ with HPβCD in D₂O confirmed the formation of higher order complexes between CHX-G₂ and HPβCD. Moreover, the addition of HPβCD into CHX-G₂ solutions forms insoluble aggregates. Such insoluble aggregates may result in the stacking of CHX-G₂ molecules on the surface of the CHX-G₂:HPβCD complexes.     

Formation of inclusion complexes between cyclodextrins and aromatic compounds under pressurized carbon dioxide

The effects of moisture content, pressure and temperature on the formation of inclusion complexes with cyclodextrins under pressurized carbon dioxide (CO₂) were studied to determine the optimal conditions for the recovery of aromatic compounds after extraction with supercritical or liquid CO₂. The presence of water in the cyclodextrin was essential for the formation of inclusion complex. However, an excess of water lowered the amount of inclusion complex due to inhibition of contact with CO₂. As the pressure increased under a constant temperature, the amount of inclusion complex increased until CO₂ became liquid, where the formation of inclusion complex started to decline. The amount of inclusion complex for modified cyclodextrins was very little, because the cyclodextrins became paste- or candy-like by the addition of a small amount of water.     

Kinetic and thermodynamic analysis of the cyclodextrin-allyl isothiocyanate inclusion complex in an aqueous solution

The decomposition of allyl isothiocyanate (AITC) in an aqueous solution was depressed in the presence of cyclodextrin (CD), it's suppression effect increasing in the order of none < beta-CD < alpha-CD. The results of kinetic and thermodynamic analysis of the CD-AITC inclusion complexes showed that the inclusion process was mostly governed by an enthalpy change (delta H degree) rather than by an entrophy change (delta S degree), and that Van der Waals forces played a primary role int he inclusion. Steric factors were important for the reaction activity of AITC inclusion into the CD cavity, especially significant being the stereospecificity between the size of the CD cavity and the AITC molecule which is the main factor concerning it's activity. Our results suggest that the association stability and activity of the included AITC molecule are important factors in the suppression mechanism for CDs. Therefore, both these factors would make an alpha-CD-AITC system more advantageous than a beta-CD-AITC system, and the marked suppression effect of alpha-CD on the decomposition of AITC can be attributed to the formation of inclusion complexes in an aqueous solution.     

Differential effects of alpha-, beta- and gamma-cyclodextrins on human erythrocytes

Alpha-, beta- and gamma-cyclodextrins are cyclic hexamers, heptamers, and octamers of glucose, respectively, and thus are hydrophilic; nevertheless, they have the ability to solubilize lipids through the formation of molecular inclusion complexes. The volume of lipophilic space involved in the solubilization process increases with the number of glucose units in the cyclodextrin molecule and, consequently, cyclodextrins were found to have different effects on human erythrocytes: (a) in the induction of shape change from discocyte to spherocyte the potency was observed to be alpha greater than gamma, but with beta-cyclodextrin hemolysis occurred before the change was complete; (b) in the increase of fluorescence intensity of 1-anilinonaphthalene-8-sulfonate in cyclodextrin-pretreated membranes, the observed potency was beta much greater than gamma greater than alpha; (c) in the release of potassium and hemoglobin, the potency was beta greater than alpha greater than gamma. The potencies of cyclodextrin for solubilizing various components of erythrocytes were alpha greater than beta much greater than gamma for phospholipids, beta much greater than gamma greater than alpha for cholesterol and beta much greater than gamma greater than alpha for proteins. The solubilization potencies were derived from concentration/final-effect curves. The above processes occurred without entry of solubilizer into the membrane, since (a) beta-[14C]cyclodextrin did not bind to erythrocytes and (b) cyclodextrins did not enter the cholesterol monolayer. A study of the [3H]cholesterol in erythrocytes indicated that beta-cyclodextrin extracted this lipid from membrane into a new compartment located in the aqueous phase which could equilibrate rapidly with additional erythrocytes. Therefore, the effects of cyclodextrins differ from those of detergents which first incorporate themselves into membranes then extract membrane components into supramolecular micelles.     

Spectral study on inclusion interaction and enantiorecognition of 2-aryl carboxylic acids with hydroxypropyl-β-cyclodextrin

The inclusion interaction between hydroxypropyl-β-cyclodextrin (HP-β-CD) and 21 2-aryl carboxylic acids was investigated by UV (ultraviolet) spectrophotometer. The inclusion constant of each 2-aryl carboxylic acids with HP-β-CD was determined by Benesi–Hildebrand's equation. According to our previous work, it was found that a high inclusion constant for inclusion complex formed by a racemate and cyclodextrin was always observed with the fact that a high enantioseparation factor was achieved for the racemate in enantioseparation by liquid–liquid chromatography, which suggested that high binding combination between racemate and cyclodextrin is very important for a successful enantioseparation in enantioselective liquid–liquid extraction. Among all the studied subjects, mandelic acid enantiomer, 2,3-diphenylpropionic acid enantiomer, and naproxen enantiomer were selected for the further study. The inclusion constants of enantiomers of these three subjects were determined by UV spectra, which indicated that a necessary difference in inclusion constants between enantiomer and cyclodextrin was also essential. It was found in UV spectra that the absorbance of the analytes with the addition of cyclodextrin would increase or decrease, which was determined by the type of electron excitation. The conformation changes of small molecules can lead to the changes of chromophore valence electron clouds distribution, causing the HOMO-LUMO energy difference decreased. Thus, a red shift of the wavelength of the maximum absorption was produced indicating that the possibility of the molecular interaction of enantiomers with HP-β-CD exists.     

Structural insights into the inclusion complexes between clomiphene citrate and β‐cyclodextrin: The mechanism of preferential isomeric selection

A major challenge in pharmaceuticals for clinical applications is to alter the solubility, stability, and toxicity of drug molecules in living systems. Cyclodextrins (CDs) have the ability to form host–guest inclusion complexes with pharmaceuticals for further development of new drug formulations. The inclusion complex of clomiphene citrate (CL), a poorly water‐soluble drug, with native β‐cyclodextrin (β‐CD) was characterized by a one and two‐dimensional nuclear magnetic resonance (NMR) spectroscopic approach and also by molecular docking techniques. Here we report NMR and a computational approach in preferential isomeric selection of CL, which exists in two stereochemical isomers, enclomiphene citrate (ENC; E isomer) and zuclomiphene citrate (ZNC; Z isomer) with β‐CD. β‐CD cavity protons, namely, H‐3′ and H‐5′, experienced shielding in the presence of CL. The aromatic ring protons of the CL molecule were observed to be deshielded in the presence of β‐CD. The stoichiometric ratio of the β‐CD:CL inclusion complex was observed by NMR and found to be 1:1. The overall binding constant of β‐CD:CL inclusion complexes was based on NMR chemical shifts and was calculated to be 50.21 M⁻¹. The change in Gibb's free energy (∆G) was calculated to be −9.80 KJ mol⁻¹. The orientation and structure of the β‐CD:CL inclusion complexes are proposed on the basis of NMR and molecular docking studies. 2D ¹H‐¹H ROESY confirmed the involvement of all three aromatic rings of CL in the inclusion complexation with β‐CD in the solution, confirming the multiple equilibria between β‐CD and CL. Molecular docking and 2D ¹H‐¹H ROESY provide insight into the inclusion complexation of two isomers of CL into the β‐CD cavity. A molecular docking technique further provided the different binding affinities of the E and Z isomers of CL with β‐CD and confirmed the preference of the Z isomer binding for β‐CD:CL inclusion complexes. The study indicates that the formation of a hydrogen bond between –O– of CL and the hydrogen atom of the hydroxyl group of β‐CD was the main factor for noncovalent β‐CD:CL inclusion complex formation and stabilization in the aqueous phase.     

Explaining cyclodextrin-mycotoxin interactions using a 'natural' force field

Docking techniques and the HINT (Hydropathic Interaction) program were used to explain interactions of aflatoxin B(1) and ochratoxin A with beta- and gamma-cyclodextrins. The work was aimed at designing a chemosensor to identify very low concentrations of these mycotoxins by exploiting the affinity of the cyclodextrin cavity for many small organic molecules. Actually, the inclusion of the fluorescent portion of these toxins into the cavity may lower the quenching effect of the solvent, thus enhancing the luminescence. HINT is a 'natural' force field, based on experimentally determined LogP(octanol/water) values, that is able to consider both enthalpic and entropic contributions to the binding free energy with an unified approach. HINT is normally applied to predict the DeltaG degrees of binding for protein-ligand, protein-protein, and protein-DNA interactions. The leading forces in biomolecular processes are the same as those involved in organic host-guest inclusion phenomena, therefore we applied this methodology for the first time to cyclodextrin complexes. The results allowed us to explain spectroscopic data in absence of available crystallographic or NMR structural data.     

Molecular dynamics simulation of cyclodextrin inclusion complexes in enzymatic lipid hydrolysis

Summary Cyclodextrin derivatives can increase the enzymatic hydrolysis of triolein in aqueous solution. Two types of cyclodextrin inclusion complexes could be responsible for this effect. In the present study, molecular dynamics simulations clearly suggest that cyclodextrin hosts only the liberated fatty acid thus accelerating lipolysis by decreasing product inhibition.     

The Role of <Emphasis Type="SmallCaps">l</Emphasis>-arginine in Inclusion Complexes of Omeprazole with Cyclodextrins

In this study, we investigate how the effect of l-arginine (ARG) and cyclodextrins upon omeprazole (OME) stability and solubility. The effect of the presence of ARG on the apparent stability constants (K_1:1) of the inclusion complexes formed between OME and each cyclodextrin, β-cyclodextrin (βCD), and methyl-β-cyclodextrin (MβCD) is studied by phase solubility diagrams and nuclear magnetic resonance (NMR) spectroscopy. The interaction of OME with those cyclodextrins, in the presence of ARG, is characterized using NMR spectroscopy and molecular dynamics simulations. ARG significantly increases the drug solubility and complex stability, in comparison to inclusion complexes formed in its absence. The effect is more pronounced for the OME:βCD complex. ARG also contributes to a larger stability of OME when free in aqueous solution. The combination of ARG with cyclodextrins can represent an important tool to develop stable drug formulations.     

Characterization of beta-lapachone and methylated beta-cyclodextrin solid-state systems

The purpose of this research was to explore the utility of beta cyclodextrin (betaCD) and beta cyclodextrin derivatives (hydroxypropyl-beta-cyclodextrin [HPbetaCD], sulfobutylether-beta-CD [SBbetaCD], and a randomly methylated-beta-CD [RMbetaCD]) to form inclusion complexes with the antitumoral drug, beta-lapachone (betaLAP), in order to overcome the problem of its poor water solubility. RMbetaCD presented the highest efficiency for betaLAP solubilization and was selected to develop solid-state binary systems. Differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier transform infrared (FTIR) and optical and scanning electron microscopy results suggest the formation of inclusion complexes by both freeze-drying and kneading techniques with a dramatic improvement in drug dissolution efficiency at 20-minute dissolution efficiency (DE(20-minute) 67.15% and 88.22%, respectively) against the drug (DE(20-minute) 27.11%) or the betaCD/drug physical mixture (DE(20-minute) 27.22%). However, the kneading method gives a highly crystalline material that together with the adequate drug dissolution profile make it the best procedure in obtaining inclusion complexes of RMbetaCD/betaLAP convenient for different applications of betaLAP.     

Spray-dried voriconazole–cyclodextrin complexes: Solubility,dissolution rate and chemical stability

The present work investigates the effect of complexation with hydroxypropyl-beta-cyclodextrin (HPBCD) and 2-O-methyl-beta-cyclodextrin (2-O-MBCD), on voriconazole solubility, dissolution rate and chemical stability. Drug–cyclodextrin complexes were prepared as aqueous solutions, which were spray-dried, and their properties were compared to wet ground samples and physical mixtures. DSC analysis revealed absence of crystalline voriconazole from spray-dried complexes. FTIR spectroscopy indicated changes in the H-bonding network of the hydroxyl groups of cyclodextrin following drug inclusion. Dissolution rate of voriconazole was significantly higher from spray-dried complexes with either cyclodextrin in comparison with free drug, physical mixtures, or wet ground mixtures. However, two degradation impurities were found in aged samples, with slightly higher impurity level with HPBCD. Performed solubility studies suggested that 2-O-MBCD is more efficient solubilizer. Molecular docking simulations showed a difference in the 1:1 binding affinities and sites, with HPBCD surprisingly forming complexes of much lower energy, thus suggesting a multiple rather than a 1:1 complexation.     

Determination of binding constants of cyclodextrin inclusion complexes with amino acids and dipeptides by potentiometric titration

Cyclodextrins are well known for their ability to separate enantiomers of drugs, natural products, and other chiral substances using HPLC, GC, or CE. The resolution of the enantiomers is due to the formation of diastereomeric complexes between the cyclodextrin and the pairs of enantiomers. The aim of this study was to determine the binding constants of the complexes between alpha- and beta-cyclodextrin and the enantiomers of a series of aliphatic and aromatic amino acids, and dipeptides, using a potentiometric titration method. The results of this method are compared to other methods, and correlated to findings in cyclodextrin-modified capillary electrophoresis and possible complex structures. Potentiometric titration was found to be an appropriate tool to determine the binding constants of cyclodextrin inclusion complexes.