Tang Xiaolin, Nail Steven L, Pikal Michael J
Formulation Development, Centocor Inc, 145 King of Prussia Road, R-1-2, 19087, Radnor, PA.
Department of Industrial and Physical Pharmacy, Purdue University, 47907, West Lafayette, IN.
AAPS PharmSciTech. 2006 Mar;7(1):E95-E103. doi: 10.1208/pt070114. Epub 2017 Mar 8.
This study examines the factors that may cause systematic errors in the manometric temperature measurement (MTM) procedure used to evaluate product temperature during primary drying. MTM was conducted during primary drying using different vial loads, and the MTM product temperatures were compared with temperatures directly measured by thermocouples. To clarify the impact of freeze-drying load on MTM product temperatures, simulation of the MTM vapor pressure rise was performed, and the results were compared with the experimental results. The effect of product temperature heterogeneity in MTM product temperature determination was investigated by comparing the MTM product temperatures with directly measured thermocouple product temperatures in systems differing in temperature heterogeneity. Both the simulated and experimental results showed that at least 50 vials (5 mL) were needed to give sufficiently rapid pressure rise during the MTM data collection period (25 seconds) in the freeze dryer, to allow accurate determination of the product temperature. The product temperature is location dependent, with higher temperature for vials on the edge of the array and lower temperature for the vials in the center of the array. The product temperature heterogeneity is also dependent upon the freeze-drying conditions. In product temperature heterogeneous systems, MTM measures a temperature close to the coldest product temperature, even, if only a small fraction of the samples have the coldest product temperature. The MTM method is valid even at very low product temperature (-45°C).
本研究考察了在用于评估一次干燥过程中产品温度的测压温度测量（MTM）程序中可能导致系统误差的因素。在一次干燥过程中，使用不同的瓶载量进行MTM，并将MTM产品温度与热电偶直接测量的温度进行比较。为了阐明冷冻干燥载量对MTM产品温度的影响，对MTM蒸气压上升进行了模拟，并将结果与实验结果进行比较。通过在温度不均匀性不同的系统中比较MTM产品温度与直接测量的热电偶产品温度，研究了MTM产品温度测定中产品温度不均匀性的影响。模拟和实验结果均表明，在冷冻干燥机的MTM数据采集期（25秒）内，至少需要50个小瓶（5毫升）才能使压力上升足够快，以便准确测定产品温度。产品温度与位置有关，阵列边缘的小瓶温度较高，阵列中心的小瓶温度较低。产品温度不均匀性也取决于冷冻干燥条件。在产品温度不均匀的系统中，即使只有一小部分样品具有最低产品温度，MTM测量的温度也接近最低产品温度。即使在非常低的产品温度（-45°C）下，MTM方法也是有效的。
