Kramer T, Kremer D M, Pikal M J, Petre W J, Shalaev E Y, Gatlin L A
Parenteral Center of Emphasis, Pfizer, Inc., Global Research and Development, Groton/New London Laboratories, Eastern Point Road, Groton, Connecticut 06340, USA.
J Pharm Sci. 2009 Jan;98(1):307-18. doi: 10.1002/jps.21430.
This article describes a procedure to facilitate scale-up for the primary drying phase of lyophilization using a combination of empirical testing and numerical modeling. Freeze dry microscopy is used to determine the temperature at which lyophile collapse occurs. A laboratory scale freeze-dryer equipped with manometric temperature measurement is utilized to characterize the formulation-dependent mass transfer resistance of the lyophile and develop an optimized laboratory scale primary drying phase of the freeze-drying cycle. Characterization of heat transfer at both lab and pilot scales has been ascertained from data collected during a lyophilization cycle involving surrogate material. Using the empirically derived mass transfer resistance and heat transfer data, a semi-empirical computational heat and mass transfer model originally developed by Mascarenhas et al. (Mascarenhas et al., 1997, Comput Methods Appl Mech Eng 148: 105-124) is demonstrated to provide predictive primary drying data at both the laboratory and pilot scale. Excellent agreement in both the sublimation interface temperature profiles and the time for completion of primary drying is obtained between the experimental cycles and the numerical model at both the laboratory and pilot scales. Further, the computational model predicts the optimum operational settings of the pilot scale lyophilizer, thus the procedure discussed here offers the potential to both reduce the time necessary to develop commercial freeze-drying cycles by eliminating experimentation and to minimize consumption of valuable pharmacologically active materials during process development.
本文介绍了一种通过结合经验测试和数值模拟来促进冻干一次干燥阶段放大的程序。采用冻干显微镜来确定冻干物塌陷发生时的温度。使用配备压力温度测量装置的实验室规模冻干机来表征冻干物与配方相关的传质阻力，并开发冻干循环的优化实验室规模一次干燥阶段。通过在涉及替代材料的冻干循环过程中收集的数据，已确定了实验室规模和中试规模的传热特性。利用经验得出的传质阻力和传热数据，证明最初由马斯卡雷尼亚斯等人开发的半经验计算传热传质模型（马斯卡雷尼亚斯等人，1997年，《计算方法与应用力学工程》148：105 - 124）能够在实验室规模和中试规模下提供预测性的一次干燥数据。在实验室规模和中试规模下，实验循环与数值模型在升华界面温度分布以及一次干燥完成时间方面都取得了极好的一致性。此外，计算模型预测了中试规模冻干机的最佳操作设置，因此这里讨论的程序有可能通过消除实验来减少开发商业冻干循环所需的时间，并在工艺开发过程中尽量减少宝贵的药理活性材料的消耗。
