Rational Design of Biodegradable Polymer Particles Using Carbon Dioxide

美国国家科学基金会-化学和运输系统颗粒和多相工艺计划部门(1415)摘要建议编号：0553659主要调查者：Share，Annette D.从属关系：特拉华大学提案标题：使用二氧化碳合理设计可生物降解聚合物颗粒的智力价值在这项拟议的研究中，为一种工艺开发了一种合理的设计方法，以生产适合肺部药物输送应用的精细可生物降解聚合物颗粒。这一过程被称为PLUSS(超临界溶剂化聚合物液化)，使用压缩的二氧化碳液化聚合物，然后快速减压以沉淀聚合物，没有残留溶剂。与以前的模型有很大不同的是，这项工作假设沉淀聚合物的形态主要由两相流水动力学决定。实验观察到的各种颗粒形态(球形、多孔性、不规则形状的颗粒、纤维等)这归因于聚合物在两相流图的不同区域(例如分散液滴、环状或弹状流)的固化。将使用实验和过程建模来检查PLUSS过程。建模将使用富含聚合物的相和纯二氧化碳相之间的均匀平衡假设。建模的目的是通过将工艺条件映射到合适的两相流图上，识别聚合物凝固点的相分离流体的结构。将建造一个实验PLUSS装置，允许独立控制组分流量和二氧化碳浓度，并通过毛细管进行降压。将通过实验确定用于制药应用的结晶型(聚己内酯、聚乙二醇)和无定形聚(乳酸-乙醇酸)聚合物的颗粒形态、尺寸分布和孔隙率，并与两相PLUSS模型的性能预测进行比较。在必要的情况下，将确定粘度、熔点(或玻璃化转变)压降和界面张力，以便做出可靠的模型预测。如果成功，这种实验和建模工作的结合将首次能够使用超临界CO2工艺进行颗粒的理论设计。如果两相流占主导地位的假设得到证实，那么就会提出创新的设备设计，如弯头，以增强二次流并促进更小的颗粒。该项目的一个主要成果将是通过两相流水动力学的定量应用统一对超临界流体颗粒形成过程的描述。广泛的影响包括该项目在药物输送中的应用潜力，以及通过其对本科生和研究生研究人员的培训以及通过其对中学生和教师的外联，发展未来的科学家和工程师。高中科学教师将进行暑期研究，以开发一种廉价、学生友好的粘度测量系统，可以在其他教室复制。使用这种设备，学生可以直接和合作地获取与糖尿病患者血糖监测仪开发相关的研究数据，同时满足国家科学课程标准，并享受与

National Science Foundation - Division of Chemical &Transport Systems Particulate & Multiphase Processes Program (1415)ABSTRACTProposal Number: 0553659Principal Investigator: Shine, Annette D.Affiliation: University of Delaware Proposal Title: Rational Design of Biodegradable Polymer Particles Using Carbon DioxideIntellectual MeritIn this proposed research, a rational design methodology is developed for a process to produce finebiodegradable polymeric particles suitable for pulmonary drug delivery applications. The process, termed PLUSS (Polymer Liquefaction Using Supercritical Solvation, uses compressed carbon dioxide to liquefy the polymer, followed by rapid depressurization to precipitate the polymer, free of residual solvents. In a significant departure from previous modeling, this work postulates that the morphology of precipitated polymers is governed primarily by two-phase flow hydrodynamics. The variety of experimentally observed particulate morphologies (spheres, porous irregular-shaped particles, fibers, etc.) is attributed to the solidification of the polymer in different regions of the two-phase flow map (e.g., dispersed droplet, annular, or slug flow). The PLUSS process will be examined using both experiments and process modeling. Modeling will use the assumption of homogeneous equilibrium between polymer-rich and pure CO2 phases. The objective of the modeling is to identify the structure of the phase-separated fluid at the point of polymer solidification, by mapping process conditions onto a suitable two-phase flow diagram. An experimental PLUSS apparatus will be constructed which allows independent control of the component fluxes and CO2 density, with depressurization occurring across a capillary. Particle morphology, size distribution and porosity will be determined experimentally for crystalline (polycaprolactone, polyethylene glycol) and amorphous poly(lactic-co-glycolic acid) polymers of interest in pharmaceutical applications, and comparisons made with property predictions from the two-phase PLUSS modeling. Where necessary, viscosity, melting point (or glass transition) depression and interfacial tension will be determined so that reliable model predictions can be made.If successful, this combination of experimental and modeling work will enable, for the first time, therational design of particles using supercritical CO2 processing. If the hypothesis of two-phase flow dominance isconfirmed, then innovative equipment designs are suggested, such as elbows to enhance secondary flows andpromote smaller particles. A major outcome of the project will be unifying the description of supercritical fluidparticle formation processes through the quantitative application of two-phase flow hydrodynamics.Broader Impacts Broader impacts of the project include the potential for application in drug delivery together with the development of future scientists and engineers through its training of undergraduate and graduate student researchers, and through its outreach to secondary school students and teachers. High school science teachers will perform summer research to develop an inexpensive, student-friendly version of the viscosity-measurement system that can be replicated in other classrooms. Using this equipment, students can be directly and collaboratively involved in the acquisition of research data relevant to development of a glucose monitor for diabetics, while simultaneously meeting state science curriculum standards, and having fun with