Rational Design of Biodegradable Polymer Particles Using Carbon Dioxide

美国国家科学基金会-化学与运输系统分部-颗粒与多相过程项目（1415）摘要项目编号：0553659首席研究员：Shine， Annette d .合作单位：特拉华大学利用二氧化碳合理设计可生物降解聚合物颗粒在这项拟议的研究中，开发了一种合理的设计方法，用于生产适合肺部给药应用的精细可生物降解聚合物颗粒。该过程被称为PLUSS（使用超临界溶剂的聚合物液化），使用压缩二氧化碳液化聚合物，然后快速减压沉淀聚合物，不含残留溶剂。与以前的建模有很大不同的是，这项工作假设沉淀聚合物的形态主要由两相流流体动力学控制。实验观察到的颗粒形态（球体，多孔不规则颗粒，纤维等）的多样性归因于聚合物在两相流图的不同区域的凝固（例如，分散的液滴，环形或段塞流）。将使用实验和过程建模来检查PLUSS过程。建模将使用富聚合物和纯CO2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，确定聚合物凝固时相分离流体的结构。将构建一个实验PLUSS装置，该装置允许独立控制组分通量和CO2密度，减压发生在毛细管上。颗粒形态、尺寸分布和孔隙度将通过实验确定结晶（聚己内酯、聚乙二醇）和无定形聚（乳酸-共乙醇酸）聚合物在制药应用中的应用，并与两相PLUSS模型的性能预测进行比较。必要时，将确定粘度、熔点（或玻璃化转变）下降和界面张力，以便做出可靠的模型预测。如果成功的话，这种实验和建模工作的结合将首次使使用超临界二氧化碳处理的粒子的理论设计成为可能。如果两相流占优势的假设得到证实，则建议创新设备设计，例如弯头以增强二次流并促进小颗粒。该项目的一个主要成果将是通过两相流流体动力学的定量应用统一超临界流体颗粒形成过程的描述。更广泛的影响该项目的更广泛的影响包括：通过对本科生和研究生研究人员的培训，以及通过向中学生和教师的推广，在药物输送方面的应用潜力，以及未来科学家和工程师的发展。高中科学教师将进行暑期研究，开发一种廉价的、对学生友好的粘度测量系统，这种系统可以在其他教室复制。使用该设备，学生可以直接和协作地参与与糖尿病患者血糖监测仪开发相关的研究数据的获取，同时满足国家科学课程标准，并享受乐趣

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