Determination of End Point of Primary Drying in Freeze-Drying Process Control
Determination of End Point of Primary Drying in Freeze-Drying Process Control
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DOI：
10.1208/s12249-009-9362-7
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发表时间：
2010-03-01
影响因子：
3.3
通讯作者：
Pikal, Michael J.
中科院分区：
文献类型：
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作者：
Patel, Sajal M.;Doen, Takayuki;Pikal, Michael J.
冷冻干燥是一种相对昂贵的工艺，需要较长的加工时间，因此，冷冻干燥工艺开发期间的关键目标之一是尽量减少初级干燥时间，这是冷冻干燥三个步骤中最长的一个。然而，在从产品中去除所有冰之前增加搁板温度进入二次干燥可能会导致塌陷或共晶熔化。因此，从产品质量以及工艺经济的角度来看，检测初级干燥的结束是非常关键的。以5%甘露醇和5%蔗糖为模型体系进行实验。初级干燥的表观终点通过比较压力测量来确定（即，Pirani vs. MKS Baratron）、露点、Lyotrack（气体等离子体光谱法）、可调谐二极管激光吸收光谱法的水浓度、冷凝器压力、压力上升测试（测压温度测量或该方法的变体）和产品热电偶。在初级干燥后期和次级干燥早期，使用取样器从干燥室中取出小瓶，以重量分析法或卡尔费休法测定残留水分百分比，并在初级干燥的表观终点（即，起点、中点和偏移）。到目前为止，Pirani是用于评估初级干燥终点的测试方法的最佳选择。此外，它是一种批量技术，价格便宜，可蒸汽灭菌，易于安装，无需任何改装。现有的干燥机。
Freeze-drying is a relatively expensive process requiring long processing time, and hence one of the key objectives during freeze-drying process development is to minimize the primary drying time, which is the longest of the three steps in freeze-drying. However, increasing the shelf temperature into secondary drying before all of the ice is removed from the product will likely cause collapse or eutectic melt. Thus, from product quality as well as process economics standpoint, it is very critical to detect the end of primary drying. Experiments were conducted with 5% mannitol and 5% sucrose as model systems. The apparent end point of primary drying was determined by comparative pressure measurement (i.e., Pirani vs. MKS Baratron), dew point, Lyotrack (gas plasma spectroscopy), water concentration from tunable diode laser absorption spectroscopy, condenser pressure, pressure rise test (manometric temperature measurement or variations of this method), and product thermocouples. Vials were pulled out from the drying chamber using a sample thief during late primary and early secondary drying to determine percent residual moisture either gravimetrically or by Karl Fischer, and the cake structure was determined visually for melt-back, collapse, and retention of cake structure at the apparent end point of primary drying (i.e., onset, midpoint, and offset). By far, the Pirani is the best choice of the methods tested for evaluation of the end point of primary drying. Also, it is a batch technique, which is cheap, steam sterilizable, and easy to install without requiring any modi. cation to the existing dryer.