Industry/University Cooperative Research: Microspherical Polymer Matrix Formation by Rapid Expansion of SupercriticalSolutions (RESS) and Mathematical Modelling of RESS.

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This project is an investigation of the rapid expansion of supercritical solutions (RESS) as a means of producing monodisperse polymer microspheres and of incorporating low molecular weight compounds into the polymer matrix. Polymers studied include polylactic and polyglycolic acids and their copolymers, polystyrene, and polymethacrylates. Low molecular weight co-precipitates studied include the model compounds naphthalene and phenanthrene, as well as progesterone, a contraceptive steroid. The mathematical modeling of the RESS process constitutes the theoretical component of this project. The goal is to understand quantitatively how process variables influence the size distribution of RESS powders. Precipitation in RESS occurs as a result of a sudden expansion which propagates at the speed of sound. This leads to essentially uniform supersaturation in the nucleating medium, giving rise to particles with narrow size distributions. The nonideality of supercritical solutions gives rise to exceptionally high supersaturation ratios upon expansion, and hence to very small particles. To date, the idea of applying this novel process to the production of polymer microspheres for sustained drug release, combining into one step particle production, low molecular weight drug incorporation and size reduction has not been explored. No quantitative treatment of the RESS process exists to date. The proposed model accounts for nonidealities peculiar to supercritical mixtures, such as endothermic solute condensation, and high solvent compressibility. Polymer microspheres are used as chromatography packings, calibration standards, and sustained drug delivery devices. Problems associated with current methods for the production of polymeric microsphere powders include the need for solvent and surfactant elimination, poor control of particle size distribution, and, for drug delivery applications, the difficulty of incorporating drugs into the carrier particles uniformly and at high concentration. For micron or sub-micron particles, which can be made monodisperse but are colloidally stable, purification and drying are especially difficult steps. The RESS process has the potential for unifying particle production, incorporation of low molecular weight drugs, purification, and size reduction in a single step leading to solvent-free microspheres with a narrow size distribution. The resulting reduction in sample loss and contamination is especially important in drug delivery applications.