Aristides Docoslis

Effect of physical state and particle size distribution on dissolution enhancement of nimodipine/PEG solid dispersions prepared by melt mixing and solvent evaporation.

The physical structure and polymorphism of nimodipine were studied by means of micro-Raman, WAXD, DSC, and SEM for cases of the pure drug and its solid dispersions in PEG 4000, prepared by both the hot-melt and solvent evaporation methods. The dissolution rates of nimodipine/PEG 4000 solid dispersions were also measured and discussed in terms of their physicochemical characteristics. Micro-Raman and WAXD revealed a significant amorphous portion of the drug in the samples prepared by the hot-melt method, and that saturation resulted in local crystallization of nimodipine forming, almost exclusively, modification I crystals (racemic compound). On the other hand, mainly modification II crystals (conglomerate) were observed in the solid dispersions prepared by the solvent evaporation method. However, in general, both drug forms may appear in the solid dispersions. SEM and HSM microscopy studies indicated that the drug particle size increased with drug content. The dissolution rates were substantially improved for nimodipine from its solid dispersions compared with the pure drug or physical mixtures. Among solid dispersions, those resulting from solvent coevaporation exhibited a little faster drug release at drug concentrations lower than 20 wt%. Drug amorphization is the main reason for this behavior. At higher drug content the dissolution rates became lower compared with the samples from melt, due to the drug crystallization in modification II, which results in higher crystallinity and increased particle size. Overall, the best results were found for low drug content, for which lower drug crystallinity and smaller particle size were observed.

Influence of the water–air interface on the apparent surface tension of aqueous solutions of hydrophilic solutes

Abstract It is well known that sugars such as sucrose and glucose, when dissolved in water, cause an increase in its measured surface tension. We determined however that polymers of sucrose and glucose, i.e. ficoll and dextran, both cause a decrease in the measured surface tension of their aqueous solutions. From the surface tension properties of solid layers of dried sucrose and glucose, and from the aqueous solubilities of these two sugars, their surface tension components and parameters in the dissolved state could be determined. From these it follows that the surface tension of these sugars in the dissolved state is about twice as high as that of water. From the surface tension data of both sugars it also follows, however, that their molecules are repelled by the water–air interface, which leaves a thin zone inside the water–air interface that is depleted of sugar molecules, thus giving rise to an apparent measured surface tension for these aqueous sugar solutions that is only a few mJ/m2 higher than that of water. The cause of the high polar components of the surface tensions of sugars in the dissolved state lies in the elevated free energy of cohesion between the electron-acceptor and electron-donor sites of molecularly dissolved sugar molecules, as manifested by a very elevated Lewis acid-base (AB) surface tension component, γAB, of about double that of water. In polymers of these sugars the strong electron-acceptor/electron-donor interactions between sugar monomers is no longer possible, or much attenuated, which lends ficoll and dextran a γAB value of only above 40% of that of water. These polymer molecules are also repelled by the water–air interface, so that the decrease in surface tension they cause in aqueous solution, is relatively modest. Hydrophilic solutes are repelled by the water–air interface and although they homogeneously pervade almost the whole volume of the aqueous solvent at very low to very high concentrations, they are absent from the depletion layer, which, for relatively low molecular weight solutes, typically is slightly thinner than 1.0 nm, closest to the air interface. Partly hydrophilic/partly hydrophobic solutes orient their hydrophobic sites to the water–air interface. The bulk solution has a (usually rather dilute) concentration of solute, not surpassing its solubility, however the solute concentration at the water–air interface can be much more concentrated than the solubility limit, e.g. by having the amphipathic solute molecules form micelle-like structures, with their hydrophilic sites directed to the water-phase, and their hydrophobic moieties protruding into the air, usually with loss of water of hydration. This causes a drastic apparent decrease in the measured surface tension of the aqueous solvent, generally already noticeable at fairly low to very low solute concentrations. Thus, whether solutes are repelled by the water–air interface (e.g. sugars and their polymers, and salts), or attracted to that interface, the measured apparent surface tension of all such aqueous solutions is not proportional to the free energy of cohesion of the bulk liquid. In general, therefore, contact angle measurements using non-homogeneous liquids, such as solutions or mixtures of liquids, are best avoided.

A noncovalent compatibilization approach to improve the filler dispersion and properties of polyethylene/graphene composites.

Graphene was prepared by low temperature vacuum-assisted thermal exfoliation of graphite oxide. The resulting thermally reduced graphene oxide (TRGO) had a specific surface area of 586 m(2)/g and consisted of a mixture of single-layered and multilayered graphene. The TRGO was added to maleated linear low-density polyethylene LLDPE and to its derivatives with pyridine aromatic groups by melt compounding. The LLDPE/TRGO composites exhibited very low electrical percolation thresholds, between 0.5 and 0.9 vol %, depending on the matrix viscosity and the type of functional groups. The dispersion of the TRGO in the compatibilized composites was improved significantly, due to enhanced noncovalent interactions between the aromatic moieties grafted onto the polymer matrix and the filler. Better dispersion resulted in a slight increase in the rheological and electrical percolation thresholds, and to significant improvements in mechanical properties and thermal conductivity, compared to the noncompatibilized composites. The presence of high surface area nanoplatelets within the polymer also resulted in a substantially improved thermal stability. Compared to their counterparts containing multiwalled carbon nanotubes, LLDPE/TRGO composites had lower percolation thresholds. Therefore, lower amounts of TRGO were sufficient to impart electrical conductivity and modulus improvements, without compromising the ductility of the composites.

Characterization of the distribution, polymorphism, and stability of nimodipine in its solid dispersions in polyethylene glycol by micro-Raman spectroscopy and powder x-ray diffraction

In the present study, a series of solid dispersions of the drug nimodipine using polyethylene glycol as carrier were prepared following the hot-melt method. Micro-Raman spectroscopy in conjunction with X-ray powder diffractometry was used for the characterization of the solid structure, including spatial distribution, physical state, and presence of polymorphs, as well as storage stability of nimodipine in its solid formulations. The effect of storage time on drug stability was investigated by examination of the samples 6 months and 18 months after preparation. Confocal micro-Raman mapping performed on the samples showed that the drug was not uniformly distributed on a microscopic level. The presence of crystals of nimodipine with sizes varying between one and several micrometers was detected, and the crystal size seemed to increase with overall drug content. In samples examined 6 months after preparation it was found that the crystals existed mainly as the racemic compound, whereas after 18 months of storage mainly crystal conglomerates were observed.

One-, two-, and three-dimensional organization of colloidal particles using nonuniform alternating current electric fields

We demonstrate here the use of nonuniform alternating current (AC) electric fields, generated by planar electrodes, for the organization of νm‐sized particles into one‐, two‐, and three‐dimensional assemblies. The electrodes, with separations that vary from 35 to 300 νm, are made of gold deposited on glass substrata. Latex, silica and graphite particles have been examined inside organic or aqueous media in order to illustrate the general applicability of the technique. Theoretical predictions of the particle response under the electric fields are experimentally confirmed for all the above particle/media combinations and can thus be used as a valuable design tool. The size and shape of the final structures are mainly dependent on the electrode shape and dimensions, but are also subject to the particle type and operating conditions. Particle organization in one dimension (strings) is achieved under conditions of positive or negative dielectrophoresis in the space between two energized electrodes. Two‐dimensional particle organization (ordered, planar particles assemblies) was observed under conditions of negative dielectrophoresis, when quadrupole electrodes were employed. Moreover, when negative dielectrophoresis and stronger electric fields are applied (of the order of 50 kVrms m–1), three‐dimensional, pyramid‐like structures with a vertical dimension 1000‐fold higher than that of the corresponding (planar) electrodes can be assembled. These 3‐D structures can grow as free‐standing assemblies, or inside templates etched in the substratum. The dielectrophoresis (DEP)‐organized particle assemblies can subsequently be rendered permanent via the in situ fixing (cross‐linking) of the individual particles.

Dielectrophoretic forces can be safely used to retain viable cells in perfusion cultures of animal cells

Dielectrophoresis is a well established and effective means for the manipulation of viable cells. However, its effectiveness greatly depends upon the utilization of very low electrical conductivity media. High conductivity media, as in the case of cell culture media, result only in the induction of weaker repulsive forces (negative dielectrophoresis) and excessive medium heating. A dielectrophoresis-based cell separation device (DEP-filter) has been recently developed for perfusion cultures that successfully overcomes these obstacles and provides a very high degree of viable cell separation while most of the nonviable cells are removed from the bioreactor by the effluent stream. The latter results in high viabilities throughout the culture period and minimization of lysed cell proteases in the bioreactor. However, an important question that remains to be answered is whether we have any adverse effects by exposing the cultured cells to high frequency electric fields for extended periods of time. A special chamber was constructed to quantitate the effect under several operational conditions. Cell growth, glucose uptake, lactate and monoclonal antibody production data suggest that there is no appreciable effect and hence, operation over long periods of time of the DEP-filter should not have any adverse effect on the cultured cells.

Measurements of the kinetic constants of protein adsorption onto silica particles

Abstract The early events pertaining to protein (human serum albumin: HSA) adsorption and desorption onto silica particles were studied employing real time, in situ measurements. The experimental method involved continuous measurements of the outflowing concentration of HSA with a fluorimeter, based on the natural fluorescence of the protein molecules. The adsorption (desorption) took place inside a well-stirred compartment, where particles were brought into contact by injection into a stream of a protein solution of known concentration. Intense mixing and sufficient protein supply rate allowed the process to take place solely under kinetic control. The acquired data were interpreted, according to a kinetic model, in terms of protein binding rates. From the latter, the kinetic association ( k a ) and dissociation ( k d ) constants were determined. To avoid the influence of steric hindrance, only data points obtained within the first 0.5 s of the initialization of the experiments were used. The experiments were performed at different protein concentrations, ranging from 7.25 nM to 14.5 μM. The real kinetic constants were determined by extrapolating the data obtained to zero protein concentration. Protein concentration effects were found to be pronounced in the determination of the kinetic association constant, producing values underestimated by as much as 30-fold for a 14.5 μM concentration. The concentration effect on the kinetic dissociation constant was not very significant: it was only of the order of a factor 2. The ratio of favorable to unfavorable protein orientations, also known as von Smoluchowski’s factor ( f ), was found to be 0.064 for the system of silica and HSA. For HSA adsorbing onto silica particles, the following values were found: k a =4.529×10 6 l mol −1 s −1 ; k d =0.21 s −1 . To convert from stirred to stationary conditions, both kinetic constants should be reduced by a factor 62.5, decreasing von Smoluchowski’s f factor to 0.001.

Influence of macroscopic and microscopic interactions on kinetic rate constants: I. Role of the extended DLVO theory in determining the kinetic adsorption constant of proteins in aqueous media, using von Smoluchowski’s approach

Abstract In the case of adsorption in an aqueous medium of a hydrophilic protein (e.g. human serum albumin (HSA)) onto a hydrophilic solid substratum such as a clean glass surface, one has to deal with a macroscopic-level repulsion between HSA and glass at (generally) the majority of orientations of the protein molecules, and also a microscopic-level attraction between HSA and glass at (generally) the minority of orientations of the protein molecules. The first phenomenon represents von Smoluchowski’s improbability of adhesion or adsorption and the second represents the probability of adhesion or adsorption [1] . Both contingencies have to be taken into account in determining von Smoluchowski’s net probability factor, f of the kinetic association constant, ka, pertaining to protein adsorption. In the exceptional case where both the protein and the solid substratum are hydrophobically/hydrophilically and electrostatically neutral, f=1, and the ka-value is only proportional to the diffusion coefficient of the protein [2] . In order to determine the contributions of both the macroscopic repulsion and the microscopic attraction pertaining to the kinetics of protein adsorption, an extended DLVO analysis (XDLVO) needs to be done on these interactions at all distances and at all protein orientations. The XDLVO analysis comprises the Lewis acid–base interaction energies as a function of distance, in addition to the Lifshitz–van der Waals and the electrokinetic interaction energies [2] , [3] , [4] , [5] .

Hyperhydrophobicity of the Water‐Air Interface

The air side of the water‐air interface is the most hydrophobic surface known. In quantitative terms the water‐air interface is about 30% more hydrophobic than the surfaces of nonpolar condensed‐phase compounds or materials such as octane or Teflon. The hyperhydrophobicity of the air side of the water‐air interface is the main cause of the large increase in contact angle of drops of water deposited upon rough surfaces of apolar materials, as compared with the water contact angle on smooth surfaces of the same materials. A water drop supported on a very porous fractal surface, encountering only about 1% solid support and 99% air, can reach a contact angle of 174°, which is exceedingly close to the (albeit unattainable) maximum of 180°. The water‐air interface hydrophobically attracts completely apolar molecules, as well as the apolar side of amphiphilic molecules (such as surfactants). Thus, for instance, dissolved surfactant molecules aggregate at a high concentration at the water‐air interface when dissolved in water. On the other hand, the water‐air interface repels dissolved hydrophilic (or near‐hydrophilic) solutes, such as sugars and polysaccharides, mainly via net repulsive van der Waals forces. Thus, the water‐air interface is depleted of such hydrophilic (or near‐hydrophilic) solutes, leaving a significantly higher concentration of these solutes in the bulk of the aqueous medium than at its air interface. As both of these contrasting phenomena result in strongly anisotropic concentration distributions in liquid drops and as contact angle determinations depend on a known and homogeneous free energy of cohesion of the liquid throughout the drop, one should never measure contact angles on solid surfaces for the purpose of measuring their surface thermodynamic properties by using aqueous solutions, mixtures, or solutions in or mixtures of other polar or partly polar liquids. Finally, the peculiar properties of the water‐air interface give rise to what at first sight appears to be paradoxical behavior of air bubbles in water: in pure deionized water, air bubbles attract one another and coalesce. On the other hand, upon the addition of salt (e.g., NaCl), air bubbles repel each other and thus do not coalesce, all in apparent contradiction of the classical rules governing the stability or instability of colloidal suspensions in water.

Macroscopic-scale surface properties of streptavidin and their influence on aspecific interactions between streptavidin and dissolved biopolymers

To avoid aspecific attractions between carrier surfaces for either ligand or receptor molecules in, e.g., immunoassays, or kinetic rate constant measurements, it has long been established that a background consisting of an aspecific, very hydrophilic carrier surface is generally quite effective. However, it is not often realized that one achieves such a non-reactive background, even with electrostatically neutral materials, at the price of creating a strong (polar) hydrophilic repulsion between dissolved biopolymer (e.g., protein) molecules and the non-adsorbing carrier surface. To investigate the quantitative effects of this type of repulsion in systems involving streptavidin, the surface properties of a streptavidin-coated glass plate were determined by contact angle measurements, from which the aspecific, macroscopic-scale free energies of repulsion between a streptavidin-coated surface and dissolved proteins such as immunoglobulin-G (IgG), and human serum albumin (HSA), could be derived. Streptavidin, even at neutral pH (at which it has virtually no electric surface charge as determined by electrophoresis) is very hydrophilic and strongly repels both IgG and HSA molecules. At neutral pH, molecules such as IgG and HSA, in aqueous solution, cannot approach a streptavidin layer more closely than to approximately 3.0 nm, which suffices to prevent IgG or HSA from any aspecific adherence to the streptavidin layer (as determined by extended DLVO analysis). This aspecific repulsion however also has the (usually unsuspected) effect of causing a decreased specific attachment between ligand and receptor molecules. In addition, it decreases the measured kinetic on-rate constants, often by about two decimal orders of magnitude. However, once the surface-thermodynamic properties of all the aspecific (macroscopic-scale) and specific (microscopic-scale) entities, as well as the specific equilibrium binding constant are known, the real kinetic on-rate constant between just the ligand and the receptor determinants can be determined, yielding the value it would have if the measurement of that constant were unhindered by the repulsive interactions exerted by the background of hydrophilic carrier molecules.