The effect of β-cyclodextrin on the solubility and dissolution rate of meloxicam and investigation of the driving force for complexation using molecular modeling

The aim of this study was to investigate the effect of β-cyclodextrin (β-CD) on the solubility and dissolution rate of meloxicam. The methods that were employed to prepare meloxicam–β-cyclodextrin complexes were physical mixture, kneaded dispersion, and spray drying. Spray drying method was found to be the best to form a true inclusion complex. Complexes were characterized by thermal analysis, X-ray diffractometry (XRD), and Fourier transform infrared (FT-IR) spectroscopy. The apparent stability constant of the complex, K _c, calculated from the slope and intercept of the A_L solubility diagram was found to be 429.73, 259.96, 183.31, and 36.50 L mol^?1 at pH 2, 3, 6.5, and 10.3, respectively. The dissolution rate of meloxicam from the complexes was higher than from meloxicam alone. Molecular modeling was also used to investigate the interaction between meloxicam and β-CD. The dominant driving force for the complexation was evidently Van der Waals force with very little electrostatic contribution.     

Self-assembled amorphous drug-polyelectrolyte nanoparticle complex with enhanced dissolution rate and saturation solubility

The dissolution rate and solubility of poorly soluble drugs can be enhanced by formulating them into stable amorphous nanoparticle complex (nanoplex). For this purpose, a highly sustainable self-assembly drug-polyelectrolyte complexation process is developed, with ciprofloxacin and dextran sulfate as the drug and polyelectrolyte models, respectively. The nanoplex are prepared by mixing two aqueous salt solutions - one containing the drug and the other containing the oppositely charged polyelectrolyte. The nanoplex suspension is transformed into stable dry-powder form by freeze-drying. The effects of drug concentration, drug-to-polyelectrolyte charge ratio, and salt concentration on the complexation efficiency, yield, drug loading, and nanoplex morphology are examined. The dissolution rates and solubility of the nanoplex are characterized and compared to raw drug crystals. Nearly spherical amorphous nanoplex having fairly uniform sizes in the range of 200-400 nm and 80% drug loading are successfully produced at ≥80% complexation efficiency and yield. The complexation efficiency is governed by the drug concentration and its ratio to the salt concentration. The nanoplex powders exhibit approximately twice higher dissolution rate and solubility than raw drug crystals and remain stable after one-month storage. Overall, amorphous nanoplex represent a promising bioavailability-enhanced formulation of poorly soluble drugs owed to their superior characteristics and ease of preparation.     

Preparation and characterization of cyclodextrin inclusion complex of naringenin and critical comparison with phospholipid complexation for improving solubility and dissolution

Naringenin, a flavonoid specific to citrus fruits shows a variety of therapeutic effects like anti-inflammatory, anticarcinogenic, and antitumour effects. But it is associated with some limitations like poor water solubility, poor dissolution, lower half-life, and rapid clearance from the body. With the aim of improving amorphous nature, water solubility, and dissolution profile of naringenin and its complexes were prepared with β-cyclodextrin in three different molar ratios (1:1, 1:2, and 1:3) by solvent evaporation method. These complexes were characterized for solubility, drug content, chemical interaction (using FTIR), phase transition behavior (using DSC), crystallinity (using XRPD), surface morphology (using SEM), and in vitro dissolution study. The results were also critically compared with the results obtained from naringenin-phospholipid complexes (from author’s previous study). The prepared complexes showed high drug content (ranging from 69.53 to 84.38 %) and about two fold improvement in water solubility (from 41.81 to 76.31 μg mL^?1 in the complex with 1:3 ratio). SEM of the complexes showed irregular and rough surface morphology. FTIR, DSC, and XRPD data confirmed the formation of the complex. Unlike the free naringenin which showed a total of only 48.78 % drug release at the end of 60 min, the complex showed 98.0–100 % in dissolution study. Thus it was concluded that the β-cyclodextrin of naringenin may be of potential use for improving bioavailability of poorly soluble phytoconstituents/herbal drugs. On critical comparison with the phospholipid complex of naringenin both the techniques were found almost equally effective in improving the solubility and the dissolution performance of naringenin in the complex form.     

Increasing the solubility of drugs through cyclodextrin complexation

The bioavailability of pharmaca which dissolve in water only with difficulty is very limited. The cyclodextrins /CDs/, and primarily -CD and -CD, were successfully applied to increase the dissolution characteristics and hence the bioavailability of drugs: furosemide, hydrochlorothiazide, mebendazole, metronidazole, spironolactone, tofisopam, vinpocetine base, etc. From these pharmaca, products were made by mixing, kneading, grinding, freeze-drying, spray-embedding and precipitation.The more important factors on which the dissolution and bioavailability of the drugs depend are concluded.     

The effect of humic acid on mercury solubility and complexation

Utilization of mercury in gold mining in the tropics has contributed to large inputs of the metal into the aquatic environment. Although in this activity mercury is utilized in its elemental state, which is relatively immobile and inert, transformations to methylmercury occurring in natural systems lead to mercury contamination of aquatic organisms and the food chain. We investigated the effectiveness and mechanisms involved in the solubilization of mercury in the presence of humic acid, which is an important component of dark river waters in the tropics. Results showed that the solubility of elemental mercury was enhanced due to the presence of humic acid through a solubilization–complexation mechanism, which was attributed to the presence of acid sites on the humic acid molecule, mainly the carboxyl group. Calcium ions in solution prevent humic‐acid‐induced elemental mercury solubility. Although it was demonstrated that the mercury complex formed is more mobile in the presence of humic acid, preliminary results indicated that this mercury complex seem absorbed by fish. Copyright © 2000 John Wiley & Sons, Ltd.     

Polymeric composites of 1,2,4-thiadiazole: solubility,dissolution and permeability assay

Journal of Thermal Analysis and Calorimetry - The derivative of 1,2,4-thiadiazole (TDZ) can be considered as a perspective agent for the Alzheimer’s disease prevention. Due to a highly...     

Solubility and dissolution enhancement of saquinavir mesylate by inclusion complexation technique

The objective of the present study was to formulate inclusion complex of saquinavir mesylate to improve the aqueous solubility and dissolution rate. Saquinavir mesylate is a BCS class II drug having low aqueous solubility and therefore low oral bioavailability. In the present study, inclusion complex of saquinavir mesylate with hydroxypropyl-β-cyclodextrin were prepared by kneading method. Inclusion complex were characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), ¹H NMR studies, and Fourier transform infrared spectroscopy and evaluated for in vitro dissolution, and phase solubility studies. DSC and XRD study demonstrated that there was a significant decrease in crystallinity of pure drug present in inclusion complex, which resulted in an increased dissolution rate of saquinavir mesylate and ¹H NMR studies strongly, confirmed that the inclusion complex has formed. Inclusion complexation results in improvement in solubility and dissolution rate. The inclusion complexation would be suitable method for dissolution and bioavailability enhancement of saquinavir mesylate.     

Kinetic justification of the solubility product: application of a general kinetic dissolution model

Using a simple, feldspar-like model and the crystal-based reaction mechanism for water-rock kinetics being developed before, we show directly how the dissolution of euhedral faces of crystals are governed by the nonlinear quantity represented by the solubility product. The kinetic approach requires recognition of the essential role played by the correlation of the dynamics of neighboring sites in a crystal, the statistical dynamics of steps, the coupling of the various kink sites on the surface by the crystal structure, and the inclusion of bond formation as well as bond rupture into the kinetic reaction mechanism. The same kinetic approach, which accounts for the role of the solubility product (or DeltaG) in the overall rate, is then shown also to explain the observed inhibition behavior in feldspars as well as the often-written phenomenological rate law, involving a product of a pH term, an activation energy term, and a DeltaG term.     

Enhanced solubility of galangin based on the complexation with methylated microbial cyclosophoraoses

Methylated cyclosophoraoses (M-Cys) were synthesized by reaction using dimethyl sulfate with native Cys (unbranched cyclic β-1,2-d-glucans) isolated from Rhizobium leguminosarum biovar viciae VF-39. Its structure was proven using nuclear magnetic resonance (¹H NMR) spectroscopy, Fourier-transform infrared (FT-IR) spectroscopy, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Based on the enhanced hydrophobicity by methylation of Cys, we investigated the inclusion property with the water-insoluble flavonoid, galangin, through a phase solubility study using ultraviolet–visible spectroscopy. The solubility of galangin was enhanced 5.6-fold according to the added concentrations (1 mM) of M-Cys, compared to the 1.9-fold and 3.4-fold enhancements by β-Cyclodextrin (β-CD) and heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD), respectively. M-Cys was also shown to have the highest binding constant (5,534 M^?1) with galangin among the tested host molecules (β-CD, DM-β-CD, Cys, and M-Cys). From this result, we can infer that the complex of galangin with M-Cys is more stable than any of the other host molecules. The continuous variation method showed that the galangin/M-Cys complex was suitable for 1:1 stoichiometry. The formation of the complex was confirmed with ¹H NMR, FT-IR, differential scanning calorimetry, and scanning electron microscopy. Furthermore, the hypothetical molecular model of 1:1 galangin/M-Cys complex was suggested by molecular docking simulations. The cytotoxicity to the human cervical adenocarcinoma cell lines was enhanced by the galangin/M-Cys complex compared with free galangin. The obtained results indicate that M-Cys can be utilized as an effective complexing agent for galangin.     

Enhancing the dissolution of hydrophobic guests using solid state inclusion complexation: characterization and in vitro evaluation

The objectives of the present investigation were to prepare and characterize solid inclusion complexes of Etodolac (ETD) with β-cyclodextrin (β-CD) in order to study the effect of complexation on the dissolution rate of ETD, a hydrophobic guest molecule. Phase solubility curve was classified as a typical A_L-type for the cyclodextrins (CD’s), showing that soluble complex was formed. The inclusion complexes in the molar ratio of 1:1 and 1:2 (β-CD–ETD) were prepared by various methods such as kneading, co-evaporation and in molar ratio of 1:1 by spray dried technique respectively. The molecular behaviors of ETD in all samples were characterized by nuclear magnetic resonance (NMR) spectroscopy, fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies and Scanning Electron microscopy (SEM) analysis. The results of these studies indicated that complexes prepared by kneading, co-evaporation and spray drying techniques showed inclusion of the ETD molecule into the CD’s cavities. The highest improvement in in vitro dissolution profiles was observed in complexes prepared with spray dried technique. Mean in vitro dissolution time indicated significant difference between the release profiles of ETD from complexes and physical mixtures and from pure ETD.     

Molecular calculations and thermodynamical considerations on the solubility enhancement of triflumizole by cyclodextrin complexation

Complexation of pesticides (fungicides, herbicides, insecticides, etc.) with cyclodextrins results in advantageous modifications of their properties like e.g. enhanced solubility and therefore a better activity combined with a reduced application concentration. The activity of the fungicide Triflumizole encapsulated in -cyclodextrin was investigated and thermodynamical parameters of the association process were determined.     

Enhanced dissolution and oral bioavailability of α-tocopheryl esters by dimethyl-β-cyclodextrin complexation

Inclusion complexation of heptakis (2,6-di-O-methyl)--cyclodextrin (DM--CyD) with -tocopheryl acetate and -tocopheryl nicotinate in aqueous solution was studied by the solubility method. The aqueous solubilities of the esters were about 10⁵ times increased by DM--CyD complexation. The phase-solubility diagram of the tocopheryl ester-DM--CyD systems showed a typicalA _p type, and the stability constants (K) of high-order complexes were estimated by analyzing the upward curvature of the diagrams. The solid complex of -tocopheryl nicotinate with DM--CyD in a molar ratio of 12 was prepared by the kneading method. The dissolution rate of the solid complex was much greater than that of the drug itself, and the rapidly dissolving form of -tocopheryl nicotinate, as an example, showed a markedly increased bioavailability (about 70-fold) after oral administration to fasted dogs.     

Enhancement of solubility, dissolution and bioavailability of ibuprofen in solid dispersion systems

To improve its solubility, dissolution, and bioavailability; Ibuprofen-polyethylene glycol 8000 (PEG 8000) solid dispersions (SDs) with different drug loadings were prepared, characterized by scanning electron microscopy (SEM) and differential scanning calorimetry (DSC), and evaluated for solubility, in-vitro release, and oral bioavailability of ibuprofen in rats. Loss of individual surface properties during melting and solidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting towards the lower melting temperature of the drug peak in SDs and physical mixtures in DSC study indicated the possibilities of drug-polymer interactions. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C(max), and a significant decrease in T(max) over pure ibuprofen. Preliminary results of this study suggested that the preparation of ibuprofen SDs using PEG 8000 as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution and bioavailability of ibuprofen.     

Automated microfluidic platform for studies of carbon dioxide dissolution and solubility in physical solvents

We present an automated microfluidic (MF) approach for the systematic and rapid investigation of carbon dioxide (CO(2)) mass transfer and solubility in physical solvents. Uniformly sized bubbles of CO(2) with lengths exceeding the width of the microchannel (plugs) were isothermally generated in a co-flowing physical solvent within a gas-impermeable, silicon-based MF platform that is compatible with a wide range of solvents, temperatures and pressures. We dynamically determined the volume reduction of the plugs from images that were accommodated within a single field of view, six different downstream locations of the microchannel at any given flow condition. Evaluating plug sizes in real time allowed our automated strategy to suitably select inlet pressures and solvent flow rates such that otherwise dynamically self-selecting parameters (e.g., the plug size, the solvent segment size, and the plug velocity) could be either kept constant or systematically altered. Specifically, if a constant slug length was imposed, the volumetric dissolution rate of CO(2) could be deduced from the measured rate of plug shrinkage. The solubility of CO(2) in the physical solvent was obtained from a comparison between the terminal and the initial plug sizes. Solubility data were acquired every 5 min and were within 2-5% accuracy as compared to literature data. A parameter space consisting of the plug length, solvent slug length and plug velocity at the microchannel inlet was established for different CO(2)-solvent pairs with high and low gas solubilities. In a case study, we selected the gas-liquid pair CO(2)-dimethyl carbonate (DMC) and volumetric mass transfer coefficients 4-30 s(-1) (translating into mass transfer times between 0.25 s and 0.03 s), and Henry's constants, within the range of 6-12 MPa.     

On the mechanisms of dissolution of montroydite [HgO(s)]: dependence of the dissolution rate on pH, temperature, and stirring rate

The dissolution behavior of montroydite (HgO) has been studied using a fully automated system. Dissolution data under equilibrium conditions are in agreement with previously published data and indicate that HgO solubility is relatively high and constant between pH 4 and 10.1 and increases markedly at pH<4. The dissolution rate also has similar behavior: it is relatively high and constant between pH 4 and 10.1 and increases sharply at pH<4. The dissolution process obeys a three-dimensional contraction or attrition mechanism. The dissolution rate increases with increasing temperature and stirring rate and is the result of mixed transport and reaction control. The rate of HgO dissolution is considerably higher than that of other divalent metal oxides at low pH. This high rate is due to the ability of Hg(II) to rapidly exchange its ligands. Data suggest that montroydite will only occur in nature in highly contaminated sites and indicate that Hg oxidation products that are formed at the liquid Hg/water interface may dissolve rapidly.     

A flavin analogue with improved solubility in organic solvents

We report the synthesis and initial electrochemical characterization of a benzene-soluble flavin analogue: N(10)-2,2-dibenzylethyl-7,8-dimethylisoalloxazine (DBF, 1). This analogue, which has an unmodified flavin headgroup, is intended for use in the spectroscopic examination of the electronic effects of flavin hydrogen bonding in simple model systems in aprotic, non-hydrogen bonding solvents. With future spectroscopic studies in mind, we have developed a synthetic route, which allows the incorporation of isotopic labels using inexpensive starting materials.     

Determination of the solubility, dissolution enthalpy and entropy of Deflazacort in different solvents

The solubility of Deflazacort in four solvents, acetone, ethyl acetate, ethanol and 2-propanol, was measured at temperatures ranging from 293.15 K to 348.15 K at atmospheric pressure using Laser Monitoring Technique. The solubility data were correlated by the modified Apelblat model. Then the dissolution enthalpy and entropy of Deflazacort were predicted from the solubility data using van’t Hoff equation. In this study, it should be concluded that the viscosity and surface tension of solvents affect the solubility behavior, dissolution enthalpy and entropy of Deflazacort in different solvents.     

PEGylation of chitosan for improved solubility and fiber formation via electrospinning

PEG-N-chitosan and PEG-N,O-chitosan were synthesized via reductive amination and acylation of chitosan, respectively. The structures were confirmed by FTIR and H¹NMR. The extents of PEGylation increased with reducing chain lengths of either chitosan (M _v = 137–400 kDa) or poly(ethyelene glycol) (PEG, M _n = 500–2 kDa). Water solubility were easily achieved at degree of substitution (DS) as low as 0.2 for either derivtive whereas the PEG-N,O-chitosan at DS = 1.5 was soluble in organic solvents, including CHCl₃, DMF, DMSO and THF. None of the aqueous solutions of PEG-N-chitosan or PEG-N,O-chitosan alone could be electrospun into fibers. Electrospinning of PEG550-N,O-chitosan145 at 25% in DMF produced fibrous structure intermixed with beads. The efficiency of fiber formation and the uniformity of fibers were improved by increasing the solution viscosity using a cosolvent or reducing the solution surface tensions with a non-ionic surfactant. Ultra-fine fibers with diameters ranging from 40 nm to 360 nm and an average diameter of 162 nm were efficiently generated from electrospinning of 15% PEG550-N,O-chitosan145 in 75/25 (v/v) THF/DMF cosolvents with 0.5% Triton X-100^TM.     

Beta-carotene/cyclodextrin-based inclusion complex: improved loading,solubility, stability,and cytotoxicity

Journal of Inclusion Phenomena and Macrocyclic Chemistry - Beta-carotene (BC) is a vitamin A precursor and has potential anticancer benefits, but the delivery of BC is hindered by its low...