High throughput research and evaporation rate modeling for solvent screening for ethylcellulose barrier membranes in pharmaceutical applications.

CONTEXT: Ethylcellulose is commonly dissolved in a solvent or formed into an aqueous dispersion and sprayed onto various dosage forms to form a barrier membrane to provide controlled release in pharmaceutical formulations. Due to the variety of solvents utilized in the pharmaceutical industry and the importance solvent can play on film formation and film strength it is critical to understand how solvent can influence these parameters. OBJECTIVE: To systematically study a variety of solvent blends and how these solvent blends influence ethylcellulose film formation, physical and mechanical film properties and solution properties such as clarity and viscosity. MATERIALS AND METHODS: Using high throughput capabilities and evaporation rate modeling, thirty-one different solvent blends composed of ethanol, isopropanol, acetone, methanol, and/or water were formulated, analyzed for viscosity and clarity, and narrowed down to four solvent blends. Brookfield viscosity, film casting, mechanical film testing and water permeation were also completed. RESULTS AND DISCUSSION: High throughput analysis identified isopropanol/water, ethanol, ethanol/water and methanol/acetone/water as solvent blends with unique clarity and viscosity values. Evaporation rate modeling further rank ordered these candidates from excellent to poor interaction with ethylcellulose. Isopropanol/water was identified as the most suitable solvent blend for ethylcellulose due to azeotrope formation during evaporation, which resulted in a solvent-rich phase allowing the ethylcellulose polymer chains to remain maximally extended during film formation. Consequently, the highest clarity and most ductile films were formed. CONCLUSION: Employing high throughput capabilities paired with evaporation rate modeling allowed strong predictions between solvent interaction with ethylcellulose and mechanical film properties.

How to dip-coat and spin-coat nanoporous double-gyroid silica films with EO19-PO43-EO19 surfactant (Pluronic P84) and know it using a powder X-ray diffractometer.

Previously, the synthesis of highly oriented pure double-gyroid nanoporous silica films has been demonstrated using evaporation-induced self-assembly (EISA) and dip-coating with a specialty triblock surfactant (PEO-PPO-alkyl) as the template. For these films, grazing-incidence small-angle X-ray scattering (GISAXS) was used to determine orientation and structure. However, GISAXS is not widely available, and we have observed significant batch-to-batch variability in the PEO-PPO-alkyl surfactants used. Here, we show for the first time: (1) synthesis of highly oriented pure double-gyroid nanoporous silica films using freely available EO(19)-PO(43)-EO(19) surfactant (Pluronic-P84) as the nanostructure-directing agent, (2) the use of spin-coating and dip-coating EISA to fabricate the double-gyroid films, and (3) the use of theta-theta X-ray diffractometers (commonly available and typically used for powder X-ray diffraction, PXRD) to identify the double-gyroid phase. Processing diagrams for P84 using dip-coating and spin-coating are shown in order to map the dependency of the nanostructure on solution composition, relative humidity, and solution aging time. In addition, an effect of the rate of evaporation during EISA is observed via dependence on the angular velocity in spin-coating. Also, through quantitative comparison of the GISAXS patterns with corresponding PXRD patterns, previously unexplained diffraction peaks in the PXRD patterns are shown to result from diffraction from crystallographic planes that are not parallel to the substrate (typically not observed in PXRD) due to the small angles involved and the nonzero acceptance angle of the PXRD Soller slits. These peaks provide a means to distinctly identify the double-gyroid phase using PXRD. The same trends relating aging-time-before-coating to the phase that forms via EISA are observed with EO(19)-PO(43)-EO(19) as was the case in previous studies using EO(17)-PO(14)-C(12). This shows the generality of use of aging time to synthesize nanoporous silica films with nonionic surfactants. Finally, a list of "tips and tricks" is provided to facilitate easy reproducible synthesis of double-gyroid nanoporous silica thin films in other laboratories.

An electrochemical fabrication process for the assembly of anisotropically oriented collagen bundles.

Controlled assembly of collagen molecules in vitro remains a major challenge for fabricating the next generation of engineered tissues. Here we present a novel electrochemical alignment technique to control the assembly of type-I collagen molecules into highly oriented and densely packed elongated bundles at the macroscale. The process involves application of electric currents to collagen solutions which in turn generate a pH gradient. Through an isoelectric focusing process, the molecules migrate and congregate within a plane. It was possible to fabricate collagen bundles with 50-400 microm diameter and several inches length via this process. The current study assessed the orientational order, and the presence of fibrillar assembly in such electrochemically oriented constructs by polarized optical microscopy, small angle X-ray scattering, second harmonic generation, and electron microscopy. The mechanical strength of the aligned crosslinked collagen bundles was 30-fold greater than its randomly oriented-crosslinked counterpart. Aligned crosslinked collagen bundles had about half the strength of the native tendon. Tendon-derived fibroblast cells were able to migrate and populate multiple macroscopic bundles at a rate of 0.5mm/day. The anisotropic order within biocompatible collagenous constructs was conferred upon the nuclear morphology of cells as well. These results indicate that the electrochemically oriented collagen scaffolds carry baseline characteristics to be considered for tendon/ligament repair.

Simulation and interpretation of 2D diffraction patterns from self-assembled nanostructured films at arbitrary angles of incidence: from grazing incidence (above the critical angle) to transmission perpendicular to the substrate.

A method to calculate the location of all Bragg diffraction peaks from nanostructured thin films for arbitrary angles of incidence from just above the critical angle to transmission perpendicular to the film is reported. At grazing angles, the positions are calculated using the distorted wave Born approximation (DWBA), whereas for larger angles where the diffracted beams are transmitted though the substrate, the Born approximation (BA) is used. This method has been incorporated into simulation code (called NANOCELL) and may be used to overlay simulated spot patterns directly onto two-dimensional (2D) grazing angle of incidence small-angle X-ray scattering (GISAXS) patterns and 2D SAXS patterns. The GISAXS simulations are limited to the case where the angle of incidence is greater than the critical angle (alpha(i) > alpha(c)) and the diffraction occurs above the critical angle (alpha(f) > alpha(c)). For cases of surfactant self-assembled films, the limitations are not restrictive because, typically, the critical angle is around 0.2 degrees but the largest d spacings occur around 0.8 degrees 2theta. For these materials, one finds that the DWBA predicts that the spot positions from the transmitted main beam deviate only slightly from the BA and only for diffraction peaks close the critical angle. Additional diffraction peaks from the reflected main beam are observed in GISAXS geometry but are much less intense. Using these simulations, 2D spot patterns may be used to identify space group, identify the orientation, and quantitatively fit the lattice constants for SAXS data from any angle of incidence. Characteristic patterns for 2D GISAXS and 2D low-angle transmission SAXS patterns are generated for the most common thin film structures, and as a result, GISAXS and SAXS patterns that were previously difficult to interpret are now relatively straightforward. The simulation code (NANOCELL) is written in Mathematica and is available from the author upon request.

Tricontinuous Cubic Nanostructure and Pore Size Patterning in Mesostructured Silica Films Templated with Glycerol Monooleate.

The fabrication of nanostructured films possessing tricontinuous minimal surface mesophases with well-defined framework and pore connectivity remains a difficult task. As a new route to these structures, we introduce glycerol monooleate (GMO) as a template for evaporation-induced self-assembly. As deposited, a nanostructured double gyroid phase is formed, as indicated by analysis of grazing-incidence small-angle x-ray scattering data. Removal of GMO by UV/O(3) treatment or acid extraction induces a phase change to a nanoporous body-centered structure which we tentatively identify as based on the IW-P surface. To improve film quality, we add a co-surfactant to the GMO in a mass ratio of 1:10; when this co-surfactant is cetyltrimethylammonium bromide, we find an unusually large pore size (8-12 nm) in acid extracted films, while UV/O(3) treated films yield pores of only ca. 4 nm. Using this pore size dependence on film processing procedure, we create a simple method for patterning pore size in nanoporous films, demonstrating spatially-defined size-selective molecular adsorption.

Characterization of lipid-templated silica and hybrid thin film mesophases by grazing incidence small-angle X-ray scattering.

The nanostructure of silica and hybrid thin film mesophases templated by phospholipids via an evaporation-induced self-assembly (EISA) process was investigated by grazing-incidence small-angle X-ray scattering (GISAXS). Diacyl phosphatidylcholines with two tails of 6 or 8 carbons were found to template 2D hexagonal mesophases, with the removal of lipid from these lipid/silica films by thermal or UV/O3 processing resulting in a complete collapse of the pore volume. Monoacyl phosphatidylcholines with single tails of 10-14 carbons formed 3D micellular mesophases; the lipid was found to be extractable from these 3D materials, yielding a porous material. In contrast to pure lipid/silica thin film mesophases, films formed from the hybrid bridged silsesquioxane precursor bis(triethoxysilyl)ethane exhibited greater stability toward (both diacyl and monoacyl) lipid removal. Ellipsometric, FTIR, and NMR studies show that the presence of phospholipid suppresses siloxane network formation, while actually promoting condensation reactions in the hybrid material. 1D X-ray scattering and FTIR data were found to be consistent with strong interactions between lipid headgroups and the silica framework.

Controlling interfacial curvature in nanoporous silica films formed by evaporation-induced self-assembly from nonionic surfactants. II. Effect of processing parameters on film structure.

The double-gyroid phase of nanoporous silica films has been shown to possess facile mass-transport properties and may be used as a mold to fabricate a variety of highly ordered inverse double-gyroid metal and semiconductor films. This phase exists only over a very small region of the binary phase diagram for most surfactants, and it has been very difficult to synthesize metal oxide films with this structure by evaporation-induced self-assembly (EISA). Here, we show the interplay of the key parameters needed to synthesize these structures reproducibly and show that the interfacial curvature may be systematically controlled. Grazing angle of incidence small-angle X-ray scattering (GISAXS) is used to determine the structure and orientation of nanostructured silica films formed by EISA from dilute silica/(poly(ethylene oxide)-b-poly(propylene oxide)-b-alkyl) surfactant solutions. Four different highly ordered film structures are observed by changing only the concentration of the surfactant, the relative humidity during dip-coating, and the aging time of the solution prior to coating. The highly ordered films progress from rhombohedral (Rm) to 2D rectangular (c2m) to double-gyroid (distorted Iad) to lamellar systematically as interfacial curvature decreases. Under all experimental conditions investigated, increasing the aging time of the coating solution was found to decrease the interfacial curvature. In particular, this parameter was critical to being able to synthesize highly ordered, pure-phase double-gyroid films. The key role of the aging time is shown via processing diagrams that map out the interplay between the aging time, composition, and relative humidity. 29Si nuclear magnetic resonance (NMR) spectroscopy and solution-phase small-angle X-ray scattering (SAXS) of the aged coating solutions presented in part I of this series are then used to interpret the effects of aging prior to dip-coating. Specifically, it was found that a predictive model based on volume fractions and the silica cluster stoichiometry obtained from 29Si NMR qualitatively explains the trends observed with composition and aging. However, apart from the effects of relative humidity, a quantitative comparison of the predicted phase with the experimental processing diagram suggests that less-condensed silica clusters are more effective at swelling the EO blocks at early aging times. This enhanced swelling decreases with aging time and results in lower-curvature nanostructures such as the double-gyroid. The decrease in swelling is attributed to the decreased thermodynamic driving force for the more-condensed silica clusters to mix with the EO block of the surfactant.

Order and orientation control of mesoporous silica films on conducting gold substrates formed by dip-coating and self-assembly: a grazing angle of incidence small-angle X-ray scattering and field emission scanning electron microscopy study.

Grazing-angle of incidence small-angle X-ray scattering (GISAXS) and high-resolution field emission scanning electron microscopy have been used to characterize the mesophase symmetry, orientation, and long-range order in PEO20-PPO70-PEO20 (Pluronic P123) templated mesoporous silica thin films on conducting gold substrates as a function of silica-to-ethylene oxide (Si/EO) block ratio and relative humidity (RH). The films are formed by dip-coating followed by evaporation-induced self-assembly under tightly controlled RH. The general evolution of the mesophase follows the trends that are expected based on shape factors due to swelling of the PEO block. However, changes in orientation of the nanostructure relative to the substrate and the degree of long-range order are found to depend on Si/EO ratio. These effects are likely due to the dynamics of evaporation and self-assembly. Generally, at Si/EO ratios lower than 3.29, the films contained regions where the nanostructure was not oriented relative to the plane of the substrate. However, for Si/EO ratios greater than 3.62, conditions were found where the nanostructure of the film was highly oriented relative to the plane of the substrate. This is true over the range of RH studied, independent of the nanostructure symmetry. For low Si/EO ratios at the highest RH levels, the films were composed of a mixture of spherical and cylindrical pores. At high Si/EO ratios and high RH levels, the films had a highly oriented R-3m nanostructure but displayed streaking perpendicular to the substrate in the Bragg spots on GISAXS patterns. This streaking is interpreted as faulting along planes parallel to the substrate.