GOALI: Modeling and Control of Fluid Dynamics and Ice Formation in Pharmaceutical Freeze-Drying

Alexeenko冷冻干燥广泛用于制药生产，以延长医用药品的保质期，并提供方便的运输和储存。冷冻干燥的目的是以一种使药物活性物质的敏感分子结构受到最小干扰的方式去除溶剂，并提供一种无菌粉末，只要加水就能迅速完全复水。这是通过快速冻结，然后升华完成的。冷冻干燥是一种既耗时又耗能的制造工艺。例如，冷冻干燥50毫升的实验性蛋白质药物需要长达3天的时间和超过200万BTU的能量。目前，冷冻干燥设备的设计，无论是实验室规模的还是工业规模的，都主要基于经验知识。PI将对冷冻干燥室中的蒸汽和不凝性气体的传输进行数值模拟，并开发冷凝器中的蒸汽/冰的相间传输模型。这些大规模的模拟将使用计算流体力学和直接模拟蒙特卡罗方法来模拟冷冻干燥中的蒸汽和不凝性气体流动以及冰的形成。数值模拟将为生物制药冷冻干燥过程的控制和紧凑型冷凝器的设计提供洞察。实验研究将通过比较受控辐射和传导条件下冷冻干燥室内升华速率与位置的关系、利用可调谐二极管激光吸收光谱分析冷凝室-冷凝器连接器中的水蒸气流速、不同冷凝面配置和温度下冷凝器内的结冰速率和几何形状以及大范围的冷凝室与冷凝器压力比来验证所开发的模型。经过验证的模型和模拟方法将形成一个知识库，据此将以物理方法而不是经验方法指导未来的冷冻干燥系统和工艺的设计。了解冻干机中水蒸气和不凝性气体的流体动力学以及蒸汽/冰界面的动力学，将加速冻干产品的开发，降低药品制造成本，具有很高的社会影响。

0829047Alexeenko Freeze-drying is widely used in pharmaceutical manufacturing to extend the shelf life of medical drugs and to provide easy shipping and storage. The goal of freeze-drying is to remove the solvent in such a way that the sensitive molecular structure of the active substance of a drug is least disturbed, and to provide a sterile powder that is quickly and completely rehydrated upon the addition of water. This is done by fast freezing followed by sublimation. Freeze-drying is both a time- and energy-intensive manufacturing process. For example, freeze-drying of 50 milliliters of an experimental protein drug takes up to three days and more than 2,000,000 BTU of energy. Currently, the design of freeze-drying equipment, both laboratory-scale and industrial, is based largely on empirical knowledge. The PIs will apply numerical simulations of vapor and non-condensable gas transport in a freeze-dryer chamber and develop models of vapor/ice interphase transport in a condenser. These large-scale simulations will model vapor and noncondensable gas flow and ice formation in freeze-drying using computational fluid dynamics and the direct simulation Monte Carlo method. Numerical modeling will provide insight into the control of the biopharmaceutical freeze-drying process and the design of compact condensers. Experimental studies will validate the developed models by comparison position dependence of sublimation rates in a freeze-dryer chamber under controlled radiative and conductive heat transfer conditions; water vapor flow rates in the chamber-condenser connector by tunable diode laser absorption spectroscopy; ice formation rates and geometric shapes in the condenser for various condensing surface configurations and temperatures; and a wide range of chamber-to-condenser pressure ratios. The validated models and simulation approaches will form a knowledge base by which future designs of freeze-drying systems and processes will be guided in a physics-based as opposed to an empirical approach. Understanding the fluid dynamics of the water vapor and non-condensable gas as well as the dynamics of vapor/ice interface in freeze-dryers will accelerate the development of freeze-dried products and decrease drug manufacturing costs, which will have a very high societal impact.