冻干工艺的优化

Freeze Drying – product may not remain frozen during the drying process 冷冻干燥-冻干过程中产品可能不是冷冻状态 Key point is the term frozen “冻干”这个词是关键点
Copyright 2006 Phase Technologies, Inc
Most Important Step 最重要的步骤
Formulation 配方
Copyright 2006 Phase Technologies, Inc
Why is the Formulation so Important? 为何配方如此重要 Defines the freezing process 限定冷冻过程 Defines the drying process parameters限定干 燥过程参数 Defines the freeze drying equipment requirements 限定冷冻干燥设备要求 Defines the shelf-life of the product 限定产品的货架寿命 Defines if the process is going to be lyophilized or freeze dried 限定产品是冻干还是冷冻干燥
Copyright 2006 Phase Technologies, Inc
Example of a Freezing Process 冻干过程举例
Degree of Supercooling = 7 oC 过冷度= 7 oC
Collapse temperature (Tc) = - 23 oC 塌陷温wk.baidu.com= - 23 oC
Copyright 2006 Phase Technologies, Inc
Key Properties of the Formulation 配方的关键性质
Composition 组成
Stability 稳定性 Thermal Properties热性质
Copyright 2006 Phase Technologies, Inc
Copyright 2006 Phase Technologies, Inc
Degree of Crystallization 结晶度
The degree of crystallization is the ratio of the ice formed in the product to the amount of ice formed in an equal amount of water. 结晶度是指产品中形成的冰的量和等量水形成的 冰的量的比率
Freezing temperature – 35 oC 冷冻温度– 35 oC
Copyright 2006 Phase Technologies, Inc
Copyright 2006 Phase Technologies, Inc
Key Process Steps
主要工艺步骤
Freezing 冷冻
Copyright 2006 Phase Technologies, Inc
Degree of Crystallization 结晶度
Copyright 2006 Phase Technologies, Inc
Basic Definition of a Eutectic 共晶点的基本定义
That temperature at which the number of degrees of freedom in a system during freezing is zero. (f = 0) 冷冻过程中，该温度下系统的自由度为零
Copyright 2006 Phase Technologies, Inc
Copyright 2006 Phase Technologies, Inc
Key Thermal Properties 主要的热性质
Degree of Supercooling 过冷度
Eutectic or Collapse Temperature 共晶或塌陷温度
The point of intersection between the solubility curve for a saturated solution and the depression of the freezing point of the solvent 饱和溶液的溶解曲线和溶剂结冰点凹陷的交点
冻干是一个使物质稳定化的过程，在该过程中，首先使 产品冷冻，然后将溶剂升华和解吸附，使产品中的含水量 减少到不足以支持生物生长和发生化学反应的程度
Copyright 2006 Phase Technologies, Inc
Definition of Freeze Drying 冷冻干燥的定义
Freeze drying is a stabilizing process in which there is first crystallization of the solvent to form a structure in the product and then the amount of solvent is removed first by sublimation and then by desorption to values that will no longer support biological growth or chemical reactions.
What to consider for the Freezing Process 冷冻过程中需要考虑的问题
Initial shelf surface temperature (formulation, fill volume, stability) 搁板表面的初始温度（配方，装料体积，稳定性） Initial shelf surface temperature (ambient, 4 - 8 oC, << 0 oC) 搁板表面的初始温度（室温，4 - 8 oC, << 0 oC) Shelf cooling rate (supercooling and fill volume) 搁板冷却速率（过冷河装料体积） Freezing temperature (eutectic or collapse temperature 10 oC lower – mobility of water is zero) 冷冻温度（共晶和塌陷温度10 oC更低-水的移动性为零 Time (fill volume)/ 时间（装料体积）
Copyright 2006 Phase Technologies, Inc
Copyright 2006 Phase Technologies, Inc
Key Thermal Properties 主要热性质
Degree of Supercooling 过冷度
Eutectic or Collapse Temperature 共晶和塌陷温度 Degree of Crystallization 结晶度
Copyright 2006 Phase Technologies, Inc
Collapse Temperature 塌陷温度
The collapse temperature is defined as that temperature at which the mobility of the water in the interstitial region approaches zero. 塌陷温度是指脉间区的水的流动性为零时温度
冷冻干燥是一个是物质稳定的过程，在该过程中，冻干的 溶剂先结晶，在产品中形成一定的结构，然后靠升华和解 吸附作用将溶剂的量减少至不足以维持生物生长和发生化 学反应的程度。
Copyright 2006 Phase Technologies, Inc
Basic Difference 基本差别
Lyophilization – product remains frozen during the drying process 冻干-干燥过程中产品保持冷冻
Copyright 2006 Phase Technologies, Inc
Copyright 2006 Phase Technologies, Inc
Key Thermal Properties 主要热性质
Degree of Supercooling 过冷度
Eutectic or Collapse Temperature 共晶或塌陷温度 Degree of Crystallization 结晶度
Copyright 2006 Phase Technologies, Inc
Effect of Freezing on the Product 冷冻对产品的影响
Was there a change in the composition of the formulation?/ 配方的成分时候有变化 Any change in turbidity?/混浊度是否有变化 Nature of the frozen cake (uniform or crust or glaze) 冷冻饼状物的性质（均一或者硬壳或冻胶层）
Key Thermal Properties 主要的热性质
Degree of Supercooling 过冷度 Eutectic or Collapse Temperature 共晶或塌陷温度 Degree of Crystallization 结晶度
Copyright 2006 Phase Technologies, Inc
Optimization of the Lyophilization or Freeze Drying Process 冻干工艺的优化
Copyright 2006 Phase Technologies, Inc
Definition of Lyophilization 冻干的定义
A stabilizing process in which the product is first frozen and then the amount of solvent is removed first by sublimation and then by desorption to values that will no longer support biological growth or chemical reactions.
Supercooling 过冷度
The degree of supercooling is defined as the number of degrees below the equilibrium freezing temperature where ice first starts to form. 过冷度是指低于冰开始形成时的冷冻平衡温度的 度数
What to consider before the Freezing Process 冷冻开始前需要考虑的因素
Stability of the liquid formulation 液体配方的稳定性 Molded vial, tubing vial or tray 模制西林瓶，管制西林瓶或托 盘 Dimensions and composition of the container 容器的尺寸和成分 Fill volume and aspect ratio (w/h) >1 Copyright 2006 Phase Technologies, Inc 装料体积和长宽比（w/h）>1