School of Aeronautics and Astronautics, Purdue University, West Lafayette, IN 47907, USA; Birck Nanotechnology Center, Purdue University, West Lafayette, IN 47907.
Pharmaceutical Development, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
J Pharm Sci. 2021 Nov;110(11):3639-3647. doi: 10.1016/j.xphs.2021.07.011. Epub 2021 Jul 22.
Controlled ice nucleation offers several key benefits to the pharmaceutical lyophilization process, including reducing lyophilization cycle time, control of ice crystal morphology, and increased consistency of lyophilized product quality attributes. The rapid depressurization based controlled ice nucleation technique is one of the several demonstrated controlled ice nucleation technologies and relies on the rapid discharge of an inert pressurized gas to induce ice nucleation. In this work, a series of custom wireless gas pressure and temperature sensors were developed and applied to this process to better understand the mechanism of controlled ice nucleation by depressurization. The devices capture highly transient conditions both in the chamber near the vial and within the vial headspace throughout the entire process. The effects of ballast gas composition, initial charge pressure, and vial size on gas pressure and headspace/chamber temperature are explored individually. We model the depressurization as an isentropic process, allowing the influence of these parameters to be evaluated quantitatively. It is demonstrated that monatomic gases (e.g. argon) with low thermal conductivity produce the most favorable conditions for ice nucleation at the end of depressurization, based on temperature drop in the vial headspace. Experimental data also reveal a correlation between initial charge pressure and vial size with the temperature drop within the vial headspace, during depressurization. These findings ultimately provide deeper insight into the rapid depressurization based controlled ice nucleation process and help lay the foundation for a more robust process development and control.
控冰成核为药物冷冻干燥过程带来了几个关键的好处，包括缩短冷冻干燥周期、控制冰晶形态和提高冷冻干燥产品质量属性的一致性。基于快速减压的控冰成核技术是几种已证明的控冰成核技术之一，它依赖于快速排出惰性加压气体以诱导冰成核。在这项工作中，开发并应用了一系列定制的无线气体压力和温度传感器来更好地理解减压控冰成核的机制。这些设备在整个过程中，在靠近小瓶的腔室内以及小瓶的瓶头空间内，捕捉到高度瞬态的条件。研究了压载气体成分、初始装料压力和小瓶尺寸对气体压力和瓶头空间/腔室温度的单独影响。我们将减压过程建模为等熵过程，从而可以定量评估这些参数的影响。结果表明，基于瓶头空间的温度下降，导热系数低的单原子气体（例如氩气）在减压结束时最有利于成核。实验数据还揭示了初始装料压力和小瓶尺寸与减压过程中瓶头空间内温度下降之间的相关性。这些发现最终为基于快速减压的控冰成核过程提供了更深入的见解，并为更强大的工艺开发和控制奠定了基础。
