Block copolymers of ethylene oxide and phenyl glycidyl ether: micellization, gelation, and drug solubilization

Three triblock copolymers of ethylene oxide and phenyl glycidyl ether, type E(m)G(n)E(m), where G = OCH2-CH(CH2OC6H5) and E = OCH2CH2, were synthesized and characterized by gel-permeation chromatography, matrix-assisted laser desorption ionization time-of-flight mass spectrometry, and NMR spectroscopy. Their association properties in aqueous solution were investigated by surface tensiometry and light scattering, yielding values of the critical micelle concentration (cmc), the hydrodynamic radius, and the association number. Gel boundaries in concentrated micellar solution were investigated by tube inversion, and for one copolymer, the temperature and frequency dependence of the dynamic moduli served to confirm and extend the phase diagram and to highlight gel properties. Small-angle X-ray scattering was used to investigate gel structure. The overall aim of the work was to define a block copolymer micellar system with better solubilization capacity for poorly soluble aromatic drugs than had been achieved so far by use of block copoly(oxyalkylene)s. Judged by the solubilization of griseofulvin in aqueous solutions of the E(m)G(n)E(m) copolymers, this aim was achieved.

Recovery of astaxanthin using colloidal gas aphrons (CGA): a mechanistic study

The aim of this study is to investigate the mechanism responsible for the recovery of astaxanthin using Colloidal Gas Aphrons (CGA), which are surfactant stabilised microbubbles. The latter were produced using different surfactant solutions (Cetyl Trimethyl Ammonium Bromide (CTAB)-cationic, Sodium Dodecyl Sulfate (SDS)-anionic, TWEEN 60-non-ionic and mixtures of TWEEN 60-SPAN 80- non-ionic with varying hydrophobicity) at stirring speed 8000 rpm and stirring time 5 min. Experiments were carried out at varying pH and volumetric ratios of astaxanthin to CGA, and with two different astaxanthin standard suspensions: (i) astaxanthin dispersed in aqueous solutions and (ii) astaxanthin dispersed in ethanolic/aqueous solutions with different compositions of ethanol (20/80 (v/v) and 40/60 (v/v)). When astaxanthin is dispersed in aqueous solutions the separation seems to occur mainly by electrostatic interactions. Therefore the recoveries are higher in the case of the cationic surfactant when astaxanthin particles are strongly negatively charged, as shown by the zeta potential measurements. When ethanol is present, highest recoveries are achieved with CGA produced from the non-ionic surfactant, which indicates that, under these conditions, separation is driven mainly by hydrophobic interactions. In experiments with ethanolic/aqueous suspensions, when the hydrophobicity of the surfactant was increased by increasing volumes of SPAN 80, the CGA produced were less stable; thus higher recoveries of astaxanthin under conditions that favour hydrophobic interactions were not observed. (C) 2008 Elsevier B.V All rights reserved.

Albumin causes a synergistic increase in the antioxidant activity of green tea catechins in oil-in-water emulsions

Model oil-in-water emulsions containing epicatechin (EC) and epigallocatechin gallate (EGCG) showed a synergistic increase in stability in emulsions containing added albumin. EGCG showed a stronger synergy (35%) with ovalbumin than did EC. Oxidation of the oil was monitored by determining peroxide values and hexanal contents. The effect of bovine serum albumin (BSA) on model oil-in-water emulsions containing each of the green tea catechins [epicatechin gallate (ECG), EGCG, EC and epigallocatechin (EGC)] was studied during storage at 30 degrees C. The green tea catechins showed moderate antioxidant activity in the emulsions with the order of activity being ECG approximate to EGCG > EC > EGC. Although BSA had very little antioxidant activity in the absence of phenolic antioxidants, the combination of BSA with each of the catechins showed strong antioxidant activity. BSA, in combination with EC, EGCG or EGC, showing the strongest antioxidant activity with good stability after 45 days storage. Model experiments with the catechins stored with BSA in aqueous solutions confirmed that protein-catechin adducts with antioxidant activity were formed between the catechins and protein. The antioxidant activity of the separated protein-catechin adducts increased strongly with storage time and was stronger for EGCG and ECG than for EC or EGC. (c) 2006 Elsevier Ltd. All rights reserved.

Synthesis of cationic water-soluble copolymers and hydrogels based on [2-(methacryloyloxy)ethyl]trimethylammonium cloride and 2-hydroxyethylacrylate and their complex formation with poly(acrylic acid)

Water-soluble cationic copolymers and hydrogels were synthesized by radical copolymerization of [2-(methacryloyloxy)ethyl]trimetilylammonium chloride (MADQUAT) and 2-hydroxyethylacrylate (HEA). The kinetics of copolymerization has been studied and the reactivity ratios were determined. It was found that MADQUAT exhibits higher reactivity in copolymerization. The complexation between linear MADQUAT-HEA and linear poly(acrylic acid) (PAA) has been studied in aqueous solutions at different pH. It results in the formation of insoluble polyelectrolyte complexes, whose composition and stability to aggregate depends on MADQUAT content in copolymers and pH. The hydrogels were synthesized by three-dimensional radical copolymerization of MADQUAT and HEA in the presence of a crosslinker. The effects of the feed mixture composition on yield and swelling properties of the hydrogels were studied. The interactions of these hydrogels with linear PAA result in formation of gel-polyelectrolyte complexes and contraction of the samples. It was found that the contraction depends on copolymer composition, PAA molecular weight, and solution pH. (c) 2006 Wiley Periodicals, Inc.

pH effects on the complexation, miscibility and radiation-induced crosslinking in poly(acrylic acid)-poly (vinyl alcohol) blends

The effect of pH on the complexation of poly(acrylic acid) with poly(vinyl alcohol) in aqueous solution, the miscibility of these polymers in the solid state and the possibility for crosslinking the blends using gamma radiation has been studied. It is demonstrated that the complexation ability of poly(vinyl alcohol) with respect to poly(acrylic acid) is relatively low in comparison with some other synthetic non-ionic polymers. The precipitation of interpolymer complexes was observed below the critical pH of complexation (pH(crit1)), which characterizes the transition between a compact hydrophobic polycomplex and an extended hydrophilic interpolymer associate. Films prepared by casting from aqueous solutions at different pH values exhibited a transition from miscibility to immiscibility at a certain critical pH, pH(crit2), above which hydrogen bonding is prevented. It is shown here that gamma radiation crosslinking of solid blends is efficient and only results in the formation of hydrogel films for blends prepared between pH(crit1), and pH(crit2). The yield of the gel fraction and the swelling properties of the films depended on the absorbed radiation dose and the polymer ratio.

Temperature-responsive water-soluble copolymers based on 2-hydroxyethyl acrylate and butyl acrylate

Amphiphilic copolymers have been synthesised by free radical copolymerisation of 2-hydroxyethyl acrylate with butyl acrylate, the reactivity ratios of which indicate practically equal reactivity. The copolymers containing less than 30 mol-% of BA were soluble in water and exhibited a LCST in aqueous solutions. It was found that the interaction between these copolymers and poly(acrylic acid) in aqueous solutions resulted in the formation of interpolymer complexes stabilised by hydrogen bonds and hydrophobic interactions. This interaction was significantly affected by solution I pH and led to modification of the temperature-responsive behaviour of the copolymers.

Novel temperature-responsive water-soluble copolymers based on 2-hydroxyethylacrylate and vinyl butyl ether and their interactions with poly(carboxylic acids)

Novel water-soluble amphiphilic copolymers have been synthesized by free radical copolymerization of 2-hydroxyethylacrylate with vinyl butyl ether. In water these copolymers exhibit lower critical solution temperature, which depends on the content of hydrophobic vinyl butyl ether units. The interaction between these copolymers and poly(acrylic acid) or poly(methacrylic acid) in aqueous solutions results in formation of interpolymer complexes stabilized by hydrogen bonds and hydrophobic interactions. An increase in hydrophobicity of the copolymers leads to the enhancement of their complex formation ability with respect to poly(acrylic acid) and poly(methacrylic acid). Poly(methacrylic acid) forms stronger complexes with the copolymers when compared with poly(acrylic acid). The complexes exhibit dual sensitivity to pH- and temperature and this property may be easily adjusted regulating the strength of interaction. (c) 2005 Wiley Periodicals, Inc.

pH-mediated interactions between poly(acrylic acid) and methylcellulose in the formation of ultrathin multilayered hydrogels and spherical nanoparticles

Poly(acrylic acid) forms insoluble hydrogen-bonded interpolymer complexes with methylcellulose in aqueous solutions under acidic conditions. In this work the reaction heats and binding constants were determined for the complexation between poly(acrylic acid) and methylcellulose by isothermal titration calorimetry at different pH and findings are correlated with the aggregation processes occurring in this system. The principal contribution to the complexation heat results from primary polycomplex particle aggregation. Transmission electron microscopy of nanoparticles produced at pH 1.4 and 2.4 demonstrated that they are spherical and dense structures. The nanoparticles ranged from 80 to 200 nm, whereas particles formed at pH 3.2 were 20-30 nm and were stabilized against aggregation by a network of uncomplexed macromolecules. For the first time, multilayered materials were developed on the basis of hydrogen-bonded complexes of poly(acrylic acid) and methylcellulose using layer-by-layer deposition on a glass surface. The thickness of these films was a linear function of the number of deposition cycles. The materials were subsequently cross-linked by thermal treatment, resulting in ultrathin hydrogels which detached from the glass substrate upon swelling. The swelling capacity of ultrathin hydrogels differed from the swelling of the thicker films of a similar chemical composition.

Characterisation of blends based on hydroxyethylcellulose and maleic acid-alt-methyl vinyl ether

Hydrophilic polymeric films based on blends of hydroxyethylcellulose and maleic acid-co-methyl vinyl ether were produced by casting from aqueous solutions. The physicochemical properties of the blends have been assessed using Fourier transform infrared spectroscopy, thermal gravimetric analysis, differential scanning calorimetry, dielectric spectroscopy, etc. The pristine films exhibit complete miscibility due to the formation of intermacromolecular hydrogen bonding. The thermal treatment of the blend films leads to cross-linking via intermacromolecular esterification and anhydride formation. The cross-linked materials are able to swell in water and their swelling degree can be easily controlled by temperature and thermal treatment time. The formation of the crosslinks is apparent in the dynamic properties of the blends as observed through the mechanical relaxation and dielectric relaxation spectra. The dielectric characteristics of the material are influenced by the effects of change in the local structure of the blend on the ionic conduction processes and the rate of dipolar relaxation. Separation of these processes is attempted using the dielectric modulus method. Significant deviations from a simple additive rule of mixing on the activation energy are observed consistent with hydrogen bonding and crosslinking of the matrix. This paper indicates a method for the creation of films with good mechanical and physical characteristics by exposing the blends to a relatively mild thermal treatment.

Mucoadhesive interactions of amphiphilic cationic copolymers based on [2-(methacryloyloxy)ethyl]trimethylammonium chloride

Three series of water-soluble cationic copolymers have been synthesised by free-radical copolymerisation of [2-(methacryloyloxy)ethyl]-trimethylammonium chloride (MADQUAT) with methyl acrylate (MA), butyl acrylate (BA) and butyl methacrylate (BMA). The interactions between these copolymers and porcine stomach mucin have been studied in aqueous solutions using dynamic light scattering, zeta-potential measurements, turbidimetric titration and transmission electron microscopy (TEM). It was demonstrated that mixing aqueous dispersions of mucin with solutions of the cationic copolymers results in significant changes in size distribution and zeta-potential of its particles. It was found that an increase in the content of hydrophobic groups in copolymers leads to more efficient adsorption of macromolecules on the surface of mucin particles, which evidences the importance of hydrophobic effects in mucoadhesion. The efficiency of mucoadhesive interactions was found to be significantly dependent on pH, which affects the surface charge and aggregation stability of mucin. (C) 2007 Elsevier B.V. All rights reserved.

Design of mucoadhesive polymeric films based on blends of poly(acrylic acid) and (hydroxypropyl)cellulose

Mixing of aqueous solutions of poly(acrylic acid) and (hydroxypropyl) cellulose results in formation of hydrogen-bonded interpolymer complexes, which precipitate and do not allow preparation of homogeneous polymeric films by casting. In the present work the effect of pH on the complexation between poly(acrylic acid) and (hydroxypropyl)cellulose in solutions and miscibility of these polymers in solid state has been studied. The pH-induced complexation-miscibility-immiscibility transitions in the polymer mixtures have been observed. The optimal conditions for preparation of homogeneous polymeric films based on blends of these polymers have been found, and the possibility of radiation cross-linking of these materials has been demonstrated. Although the gamma-radiation treatment of solid polymeric blends was found to be inefficient, successful cross-linking was achieved by addition of N, N'- methylenebis(acrylamide). The mucoadhesive potential of both soluble and cross-linked films toward porcine buccal mucosa is evaluated. Soluble films adhered to mucosal tissues undergo dissolution within 30-110 min depending on the polymer ratio in the blend. Cross-linked films are retained on the mucosal surface for 10-40 min and then detach.

Solvent influences on metastable polymorph lifetimes: real-time interconversions using energy dispersive X-ray diffractometry

Solvent influences on the crystallization of polymorph and hydrate forms of the nootropic drug piracetam (2-oxo-pyrrolidineacetamide) were investigated from water, methanol, 2-propanol, isobutanol, and nitromethane. Crystal growth profiles of piracetam polymorphs were constructed using time-resolved diffraction snapshots collected for each solvent system. Measurements were performed by in situ energy dispersive X-ray diffraction recorded in Station 16.4 at the synchrotron radiation source (SRS) at Daresbury Laboratory, CCLRC UK. Crystallizations from methanol, 2-propanol, isobutanol, and nitromethane progressed in a similar fashion with the initial formation of form I which then converted relatively quickly to form II with form III being generated upon further cooling. However, considerable differences were observed for the polymorphs lifetime and both the rate and temperature of conversion using the different solvents. The thermodynamically unstable form I was kinetically favored in isobutanol and nitromethane where traces of this polymorph were observed below 10 degrees C. In contrast, the transformation of form II and subsequent growth of form III were inhibited in 2-propanol and nitromethane solutions. Aqueous solutions produced hydrate forms of piracetam which are different from the reported monohydrate; this crystallization evolved through successive generation of transient structures which transformed upon exchange of intramolecular water between the liquid and crystalline phases. (c) 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96:1069-1078, 2007.

Alignment of a model amyloid peptide fragment in bulk and at a solid surface

The alignment of model amyloid peptide YYKLVFFC is investigated in bulk and at a solid surface using a range of spectroscopic methods employing polarized radiation. The peptide is based on a core sequence of the amyloid beta (A beta) peptide, KLVFF. The attached tyrosine and cysteine units are exploited to yield information on alignment and possible formation of disulfide or dityrosine links. Polarized Raman spectroscopy on aligned stalks provides information on tyrosine orientation, which complements data from linear dichroism (LD) on aqueous solutions subjected to shear in a Couette cell. LD provides a detailed picture of alignment of peptide strands and aromatic residues and was also used to probe the kinetics of self-assembly. This suggests initial association of phenylalanine residues, followed by subsequent registry of strands and orientation of tyrosine residues. X-ray diffraction (XRD) data from aligned stalks is used to extract orientational order parameters from the 0.48 nm reflection in the cross-beta pattern, from which an orientational distribution function is obtained. X-ray diffraction on solutions subject to capillary flow confirmed orientation in situ at the level of the cross-beta pattern. The information on fibril and tyrosine orientation from polarized Raman spectroscopy is compared with results from NEXAFS experiments on samples prepared as films on silicon. This indicates fibrils are aligned parallel to the surface, with phenyl ring normals perpendicular to the surface. Possible disulfide bridging leading to peptide dimer formation was excluded by Raman spectroscopy, whereas dityrosine formation was probed by fluorescence experiments and was found not to occur except under alkaline conditions. Congo red binding was found not to influence the cross-beta XRD pattern.

Influence of salt on the self-assembly of two model amyloid heptapeptides

We study the effects of NaCl on the self-assembly of AAKLVFF and beta A beta AKLVFF in solution. Both AAKLVFF and beta A beta AKLVFF self-assemble into twisted fibers in aqueous solution. The addition of NaCl to aqueous solutions of AAKLVFF produces large crystal-like nanotapes which eventually precipitate. In contrast, highly twisted fibrils were observed for beta A beta AKLVFF solutions at low salt concentration, while a coexistence of highly twisted fibers and nanotubes was observed for beta A beta AKLVFF at high salt concentration. The self-assembled structures observed for beta A beta AKLVFF in NaCl solutions were ascribed to the progressive screening of the beta A beta AKLVFF surface charge caused by the addition of salt.

Molecular dynamics simulations of threadlike cetyltrimethylammonium chloride micelles: effects of sodium chloride and sodium salicylate salts

We use atomistic molecular dynamics simulations to probe the effects of added sodium chloride (NaCl) and sodium salicylate (NaSal) salts on the spherical-to-threadlike micelle shape transition in aqueous solutions of cetyltrimethylammonium chloride (CTAC) surfactants. Long threadlike micelles are found to be unstable and break into spherical micelles at low concentrations or NaCl, but remain stable for 20 ns above a threshold value of [NaCl] approximate to 3.0 M, which is about 2.5 times larger than the experimental salt concentration at which the transition between spherical and rodlike micelles occurs. The chloride counterions associate weakly oil the surface of the CTAC micelles with the degree of counterion dissociation decreasing slightly with increasing [NaCl] on spherical micelles, but dropping significantly on the threadlike micelles tit high [NaCl]. This effect indicates that the electrolyte ions drive the micellar shape transition by screening the electrostatic repulsions between the micellar headgroups, The aromatic salicylate counterions, on the other hand, penetrate inside the micelle with their hydrophilic groups staying in the surfactant headgroup region and the hydrophobic groups partially embedded into the hydrophobic core of the micelle. The strong association of the salicylate ions with the surfactant headgroups leads to dense packing of the surfactant molecules, which effectively reduces the surface area per surfactant, and increases intramicellar ordering of the surfactant headgroups, favoring the formation of long threadlike micelles. Simulation predictions of the geometric and electrostatic properties of the spherical and threadlike micelles are in good agreement with experiments.