喷雾冷冻干燥制备微粒的结构形成机理研究

Structure characteristics of spray freeze dried (SFD) microparticles, including size, density, pore structure and specific surface area, determines the particle functionalities. The SFD microparticle structure is resulted from mesoscopic dynamic process of ice nucleation and growth, precursor migration and phase separation with dependence on both precursor properties and spray freezing conditions. Therefore, understanding formation mechanisms of microparticle structure is one of the key issues in spray freeze drying related research and product quality control. This project proposes to utilize a novel micro-fluidic jet spray freezing tower capable of producing microparticles with uniform characteristics, which facilitates precisely correlating processing parameters with particle structure characteristics owe to overcoming the disadvantages rendered by varied particle properties and functionalities in a single sample batch. To avoid the uncertainty caused by the multivariate difference in the properties of each component, three groups of precursors, i.e. those with obvious size difference, those in similar hydrodynamic size but with large solubility difference, and those with surface activity but large size difference, are selected to configure into one-component and binary precursor liquid, respectively. Under accurately tuning the initial droplet size and temperature inside the tower, the effects of precursor hydrodynamic size, concentration, solubility and surface activity on SFD microparticle structure will be studied, aiming at setting-up a theory model for the formation mechanisms of microparticle structure. The outcome of this project is expected to provide guidance for the rational design and control over structure characteristics of SFD products.

喷雾冷冻干燥微粒的结构，包括尺寸、密度、孔结构、比表面积、表面组成，是决定产品性能的核心因素，其取决于液滴中冰晶生长、前驱物组分迁移及相分离的介观动态过程的结果，受前驱物性质和喷雾冷冻条件的共同作用。因此，微粒结构的形成机理是喷雾冷冻干燥技术研究及产品质量控制中的关键问题。本项目拟使用一种新型微流控喷雾冷冻塔，其具有能够制备均一微粒的优势，将克服由于同批样品微粒的性质差异化所造成的弊端，从而建立过程参数与微粒结构之间的直接对应关系；为避免各组分性质的多变量差异所造成的不确定性，选择具有明显尺寸差别、分子尺寸相似而具有较大溶解度差别以及同样具有表面活性而尺寸差别较大的前驱物，分别配置成单组分或二元体系前驱液，调节初始液滴大小和冷冻塔内温度，研究前驱物尺寸、浓度、溶解度、表面活性、在不同喷雾冷冻条件下对微粒结构的影响规律，以构建影响微粒结构的理论模型，进而指导喷雾冷冻干燥微粒结构的设计与调控。

喷雾冷冻干燥是把液态物料干燥成粉末产品的重要技术之一，已被广泛应用于诸如医药、食品、吸附剂、催化剂等多种类型产粉状品的生产和加工领域。为进一步提升喷雾冷冻干燥产品的质量及附加值，尤为重要的是如何通过配方筛选和工艺参数调节，有效调控产品颗粒的物化性质，以实现最优产品功能。然而，在液滴快速冷冻过程中，配方物质的迁移行为及多尺度组装成粒过程极其复杂，这也是高质量喷雾冷冻干燥产品的研发和生产所面临的关键挑战。.本项目利用一种原创的微流控喷雾冷冻干燥设备，借助其制备微粒的物化性质均一可控的优势，避免了传统喷雾冷冻干燥技术中同批样品微粒性质差异化的弊端，能够有效建立过程工艺参数与微粒物化性质间的直接对应关系，为研究喷雾冷冻干燥颗粒结构的形成机理与调控机制提供了有力支撑。在基础理论方面，探究了配方物质的分子尺寸、溶解度、表面活性等性质，以及喷雾冷冻干燥条件对颗粒微纳结构的影响机理，并构建了一套独特的多尺度数值模拟方法，能够较为准确的预测产品颗粒特性，为实现喷雾冷冻干燥颗粒结构的精准设计与调控建立了良好的理论基础。在应用基础研究方面，围绕肺部吸入粉雾剂和鼻用粉雾剂领域，通过有效调节喷雾冷冻干燥颗粒的微纳结构，并与之相关的性能指标进行了系统性对比，揭示了决定产品颗粒功能的关键构效关系，将十分有助于高质量喷雾冷冻干燥产品的研发和生产。