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

该项目是对超临界溶液快速膨胀（RESS）作为生产单分散聚合物微球和将低分子量化合物纳入聚合物基质的一种手段的研究。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，以及黄体酮，一种避孕类固醇。RESS过程的数学建模构成了本项目的理论组成部分。目的是定量地了解工艺变量如何影响RESS粉末的尺寸分布。RESS中的降水是由于以声速传播的突然膨胀而产生的。这导致在成核介质中基本均匀的过饱和，从而产生具有窄尺寸分布的颗粒。超临界溶液的非理想性在膨胀时产生异常高的过饱和比，因此产生非常小的颗粒。迄今为止，尚未探索将这种新工艺应用于聚合物微球的生产，用于药物缓释，将其结合为一步颗粒生产，低分子量药物掺入和缩小尺寸。迄今为止，还没有对RESS过程进行定量处理。提出的模型解释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性。聚合物微球可用作色谱填料、校准标准和持续给药装置。与目前生产聚合物微球粉末的方法相关的问题包括需要溶剂和表面活性剂的消除，粒度分布的控制不好，以及药物输送应用。难以将药物均匀且高浓度地结合到载体颗粒中。对于微米或亚微米颗粒，它们可以单分散但胶体稳定，纯化和干燥是特别困难的步骤。RESS工艺具有将颗粒生产、低分子量药物掺入、纯化和尺寸减小统一在一个步骤中的潜力，从而产生具有窄尺寸分布的无溶剂微球。由此产生的样品损失和污染的减少在药物输送应用中尤为重要。

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.