Posaconazole/hydroxypropyl-β-cyclodextrin host–guest system: Improving dissolution while maintaining antifungal activity

An alternative cyclodextrin based formulation for oral anticancer drug exemestane: In vitro and cell culture studies

The study was designed to investigate the effect of cyclodextrins (CDs) on the solubility, dissolution rate, and bioavailability of cilostazol by forming inclusion complexes. Natural CDs like beta-CD, gamma-CD, and the hydrophilic beta-CD derivatives, DM-beta-CD and HP-beta-CD, were used to prepare inclusion complexes with cilostazol. Phase solubility study was carried out and the stability constants were calculated assuming a 1:1 stoichiometry. Solid cilostazol complexes were prepared by coprecipitation and kneading methods and compared with physical mixtures of cilostazol and cyclodextrins. Prepared inclusion complexes were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. In vitro dissolution study was performed using phosphate buffer pH 6.4, distilled water, and HCl buffer pH 1.2 as dissolution medium. The optimized inclusion complex was studied for its bioavailability in rabbit and the results were compared with those of pure cilostazol and Pletoz-50. Phase solubility study showed dramatic improvement in the solubility of drug by formation of complexes, which was further increased by pH adjustment. The dissolution rate of cilostazol was markedly augmented by the complexation with DM-beta-CD. DSC and XRD curves showed sharp endothermic peaks indicating the reduction in the microcrystallinity of cilostazol. Selected inclusion complex was also stable at ambient temperature up to 6 months. The in vivo study revealed that DM-beta-CD increased the bioavailability of cilostazol with low variability in the absorption. Among all cilostazol-cyclodextrins complexes, cilostazol-DM-beta-CD inclusion complex (1:3) prepared by coprecipitation method showed 1.53-fold and 4.11-fold increase in absorption along with 2.1-fold and 2.97-fold increase in dissolution rate in comparison with Pletoz-50 and pure cilostazol, respectively.

Cyclodextrin, an efficient tool for trans-anethole encapsulation: Chromatographic, spectroscopic, thermal and structural studies

This study aimed to improve the solubility of ezetimibe (EZT), which has low aqueous solubility, by preparing complexes using β-cyclodextrin (β-CD) derivatives. Phase solubility studies and Job's plot confirmed a high apparent stability constant for EZT with β-CD and even higher constants with its derivatives, establishing a 1:1 stoichiometric ratio. The composites were prepared using spray drying over a range of molar ratios, and their physicochemical properties were evaluated using techniques such as scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FT-IR). Saturation solubility and in vitro dissolution tests revealed that solubility increased with higher CD molar ratios. EZT/RM-β-CD inclusion complexes (ICs) and EZT/DM-β-CD ICs exhibited a similar solubility, which was greater than that of EZT/HP-β-CD ICs and EZT/SBE-β-CD ICs (where RM, DM, HP, and SEB represent H, CH3, -CH2-CHOH-CH3 and -(CH2)4-SO3Na synthetic derivatives, respectively). Most complexes, except for EZT/SBE-β-CD at 1:2 or higher ratios, showed superior solubility compared with EZT powder and commercial products. Molecular docking simulations confirmed EZT inclusion within the CD, revealing hydrogen bonds and binding energies that aligned with solubility trends. These findings suggest that EZT complexes with β-CD derivatives significantly improve solubility, highlighting their potential for developing more effective oral solid formulations for hyperlipidemia treatment.

Encapsulation of hyperoside with acyclic cucurbiturils: Supramolecular binding behavior, water solubility and in vitro antioxidant activity

This study aimed to investigate the effect of hydroxypropyl methylcellulose on the complexation of fenofibrate and hydroxypropyl-β-cyclodextrin (HP-β-CD). Initially, phase solubility studies with an excess amount of drug in the HP-β-CD solutions with and without hydroxypropyl methylcellulose (HPMC) were investigated. Both of the binary and ternary complexes were prepared by ball-milling. The complexes were characterized by Fourier transform infrared spectroscopy (FI-IR), X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC) and nuclear magnetic resonance spectroscopy (1H-NMR). The AL type phase-solubility diagram revealed that the complexes of fenofibrate and HP-β-CD were formed with molecular ratio of 1:1. The results of FT-IR, XPRD, DSC and 1H NMR analysis show the formulation of inclusion complexes. In conclusion, the interaction occurrs between fenofibrate and HP-β-CD in the complexes, and the existence of HPMC effectively improves the complexation efficiency and stability constant. The in vitro dissolution test suggests ternary complex is superior to binary complex in terms of the release of fenofibrate.

Background: Stigmasterol possesses numerous physiological effects and is used as food supplements and behaves as a pharmaceutical agent. It exhibits anticancer effects against various cancers. The usefulness of the stigmasterol is restricted due to its poor solubility. To overcome this and enhance the solubility and bioavailability of this phytosterol, molecular encapsulation is utilized to augment the desirable properties of stigmasterol. This research work aims to investigate the interaction between stigmasterol and alpha-cyclodextrin (α-CD) in aqueous solution as well as in solid state and experimentally examined by spectral techniques. Methods: The liquid complexes are characterized by ultraviolet (UV)-visible spectroscopy and solid inclusion complexes are characterized by Fourier transformer infrared resonance and 1H nuclear magnetic resonance spectroscopy. The thermal behavior of the complex is analyzed by differential scanning calorimeter. Phase solubility studies are done to learn the solubility of the newly synthesized complex. Results: Formation constant from UV-visible analysis is found to be 569 M−1 by Benesi–Hildebrand equation. The solubility constant is calculated to be 52 M−1. The results obtained prove the inclusion which is confirmed through molecular docking studies. Conclusion: The newly synthesized inclusion complex is a potent pharmaceutical agent in drug formulation as stigmasterol solubility is enhanced when included in the cavity of α-CD.

Purpose: The aim of the paper was to develop the simple procedures for preparation of inclusion complexes of ellagic acid (EA) with cyclodextrins (CDs) and to investigate their antioxidant and antimicrobial activity.Methods: The structural characterization was carried out using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), and nuclear magnetic resonance (NMR) methods. The phase solubility technique was used to investigate the interactions between ‘host’ and ‘guest’ molecules and to estimate the molar ratio between them. The antioxidant and antimicrobial activity of EA and inclusion complexes were determined.Results: The apparent stability constants were found to be 117 dm3 mol−1 for the complex with β-CD and 161 dm3 mol−1 for the complex with (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD). The results of phase-solubility studies showed that EA formed the inclusion complexes with CDs in the molar ratio of 1:1. The calculated half-maximal inhibitory concentration was 41.18 μg cm−3 for butyl hydroxy toluene, 1.96 μg cm−3 for EA, 0.88 μg cm−3 for inclusion complex with HP-β-CD, and 1.27 μg cm−3 for inclusion complex with β-CD.Conclusion: The stability constants indicated the rapid release of EA from the inclusion complexes in the aqueous medium at 25 °C. The antioxidant activity of EA was increased, while the antimicrobial activity was preserved after complexation with CDs.

Characterisation of inclusion complex of trans-ferulic acid and hydroxypropyl-β-cyclodextrin

Preparation and characterization of spiro-acridine derivative and 2-hydroxypropyl-β-cyclodextrin inclusion complex

The aims of this study were to improve both the solubility of the amiodarone hydrochloride (AMD) and its controlled release from the inclusion complexes with 2-hydroxypropyl-\(\beta\)-cyclodextrin (HP-\(\beta\)-CD).The complexation with cyclodextrins (CDs) is a method to optimize the therapeutic performance of the insoluble drugs, including AMD. The inclusion complexes were prepared by co-precipitation and freeze-drying. The solubility enhancement of AMD/HP-\(\beta\)-CD inclusion complexes increase by 4–22 times was evaluated by the phase solubility method. The inclusion complexes were studied both in solution and in solid state by spectroscopic methods, dynamic light scattering (DLS), zeta-potential (ZP) analysis, scanning electron microscopy (SEM) and differential scanning calorimetry (DSC). The obtained inclusion complexes (AMD/HP-\(\beta\)-CD) showed an increase in solubility by more than 200%. Two kinds of formulations have been tested namely of AMD/HP-\(\beta\)-CD inclusion complexes both as powdered form and as matrix tablets containing Kollidon®SR (KOL), Chitosan (CHT) and one containing only pure AMD as a control sample. The kinetics of AMD release form the two kinds of formulations was evaluated by in vitro and in vivo studies. The active substance release was followed by in vitro release testing and the results were analyzed by fitting into four representative mathematical models for the modified release oral formulations. The release of the active substance from the matrix modified tablets is dependent on its solubility degree in the dissolution medium as well as on the composition of the matrix forming polymers. It was found that both formulations showed superior pharmacokinetic performance by improving both loading and release properties in respect with those of the pure low soluble AMD drug. In vitro kinetic study reveals a complex mechanism of release which occurred in three steps, the first one is attributed to a burst effect and the other two to different bondings existing in inclusion complexes. Two factors have been calculated to assess the release profile of amiodarone: f1 - the similarity factor and f2 - the difference factor. Akaike index and the correlation coefficient were the criteria used for selecting the model that most faithfully depicted the release profile of each studied formulation. In vivo tests on complexed aminodarone loaded in matrix tablets containing KOL and CHT revealed a multiple (at least two) peaks release diagram because of both structure of the inclusion complexes and also of different sites of absorption in biological media (digestive tract).

The formation of hydrochlorothiazide inclusion complexes has been carried out to improve the physicochemical properties and increase the dissolution rate of hydrochlorothiazide. Inclusion complexes were made by co-grinding using ß cyclodextrin at a ratio of 1:1 mol, with variations in milling time, namely 30 minutes (F1), 1 hour (F2), and 2 hours (F3). The inclusion complexes formed were characterized by X-ray diffraction analysis, differential scanning calorimetry (DSC), Fourier transforms infrared (FT-IR), scanning electron microscopy, and dissolution tests. X-ray diffraction results showed a decrease in hydrochlorothiazide intensity, the DSC thermogram showed a decrease in endothermic peaks and enthalpy values, and FT-IR spectrum analysis showed that there was a chemical interaction between hydrochlorothiazide and ß-cyclodextrin. All characterization checks carried out met the requirements and confirmed an increase in the dissolution rate. The dissolution yield of hydrochlorothiazide was 41.711%, the physical mixture was 57.135%, the F1 inclusion complex was 59.52%, the F2 inclusion complex was 79.17%, and the F3 inclusion complex was 103.62%. This proves that the formation of inclusion complexes with the addition of ß-cyclodextrin can significantly increase the dissolution

Idebenone is a high permeable drug with very slight water solubility that affects the dissolution rate in the biological fluids, causing an irregular and limited in vivo absorption after oral administration. Moreover, it is marketed in Europe as tablets equivalent to 150 mg, with the consequent administration of multiple dose of solid unit to obtain the correct dose, a deterrent for the patients’ compliance. According to these considerations, our goal was to develop spray-dried microparticles using a soluble β-cyclodextrin (CD) polymer and an enhancer of dissolution rate, such as carboxymethyl cellulose, to obtain a formulation easily dosable and soluble in water. The complex in solution was evaluated by phase solubility studies and the Idebenone/CD molar ratio selected was 1:1. According to Higuchi and Connors, adding carboxymethyl cellulose, a Bs-type profile was obtained. This result was due to the presence of carboxymethyl cellulose that competes with the CD in forming Idebenone microsystems, reducing of 10-fold the formulation bulk. UV–Vis absorption, 1H nuclear magnetic resonance and circular dichroism showed the formation of the CD/Idebenone inclusion complex confirmed also by differential scanning calorimetry, Fourier transform infrared spectroscopy and fluorescence microscope (FM). The water solubility data and the in vitro dissolution tests performed in simulated gastric fluid, showed an increase of the drug water interaction due to the presence of the CD and carboxymethyl cellulose, both able to improve drug wettability, water solubility and dissolution rate. This approach seems to be suitable to produce microsystems which are able to enhance the in vivo absorption of Idebenone after oral administration and to increase the patient compliance.

The purpose of this research was to evaluate the inclusion complex composed of osthole and hydroxypropyl-β-cyclodextrin (HP-β-CD) by using two preparative techniques, neutralization and high-pressure homogenization (HPH) method. The solid complexes were characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), particle size determination, and dissolution test. The DSC diagrams indicated that the solid complex from the HPH method led to more complete complexation than that of physical mixture and neutralization method. The formation of inclusion complex between drug and cyclodextrin (CD) was verified by FTIR analysis. The smallest mean particle size of solid complex was acquired from the HPH method. The results proved that the rate of drug release for the inclusion complex obtained from the HPH method was much faster than those of neutralization, physical mixture, HP-β-CD and osthole alone.

Context: Colchicine (CLC) causes cell death by destabilizing the tubulin unit. However, it ionizes at physiological pH resultant low bioavailability and therapeutic efficacy.Objectives: We have attempted to augment the bioavailability of CLC by fabricating the inclusion complex with hydroxypropyl-β-cyclodextrin (HP-β-CD).Materials and methods: CLC-HP-β-CD inclusion complex was prepared and evaluated with Fourier-transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy, 1H nuclear magnetic resonance (1H NMR) spectroscopy and rotating frame overhauser enhancement spectroscopy (ROESY). Oral bioavailability of CLC-HP-β-CD inclusion complex was analyzed using high performance liquid chromatography method.Results and discussion: Our phase-solubility data indicated the formation of a stable complex with Kc ~0.31 mM−1 at pH 7.4. 1H NMR ascertains that NHCOCH3 moiety of CLC enters in the HP-β-CD cavity and deshielded the H-3 and H-5 protons. ROESY also correlates the Hf and Hg of CLC with H-3 and H-5 protons of HP-β-CD and indicates that Hf and Hg protons of CLC are present either as cis and/or trans form in CLC-HP-β-CD inclusion complex. Pharmacokinetic studies showed a 1.82-fold increase in absolute bioavailability of CLC upon complexation.Conclusion: CLC-HP-β-CD inclusion complex may potentially be used as a viable formulation of CLC.