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

该项目是研究超临界溶液(RESS)的快速膨胀，作为一种制备单分散聚合物微球和将低分子化合物加入到聚合物基质中的方法。所研究的聚合物包括聚乳酸和聚乙醇酸及其共聚物、聚苯乙烯和聚甲基丙烯酸酯。研究的低分子量共沉淀物包括模型化合物萘和菲，以及避孕类固醇黄体酮。RESS过程的数学建模构成了该项目的理论组成部分。目的是定量了解工艺变量如何影响RESS粉末的粒度分布。RESS中的降水是以音速传播的突然膨胀的结果。这导致成核介质中的过饱和基本上是均匀的，从而产生具有窄尺寸分布的颗粒。超临界溶液的非理想性导致了膨胀时极高的过饱和度，从而产生了非常小的颗粒。到目前为止，将这一新工艺应用于聚合物缓释微球的生产，将微粒生产、低分子药物掺入和尺寸减小一步到位，还没有人探索过。到目前为止，还没有对RESS过程进行定量处理。所提出的模型考虑了超临界混合物特有的非理想性，如吸热溶质冷凝和高溶剂压缩系数。聚合物微球被用作层析填充物、校准标准和持续给药装置。与当前生产聚合物微球粉末的方法相关的问题包括需要消除溶剂和表面活性剂，对颗粒大小分布的控制不佳，对于药物输送应用，难以在高浓度下将药物均匀地掺入载体颗粒中。对于可以单分散但胶体稳定的微米或亚微米颗粒来说，提纯和干燥是特别困难的步骤。RESS工艺有可能在单一步骤中统一颗粒生产、低分子药物的加入、纯化和尺寸减小，从而获得尺寸分布较窄的无溶剂微球。由此产生的样品损失和污染的减少在药物输送应用中尤其重要。

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.