1,Optimization of the Lyophilization or Freeze Drying Process 冻干工艺的优化,2,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. 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,3,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. 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。,4,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 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,5,Most Important Step最重要的步骤,Formulation 配方,6,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,7,Key Properties of the Formulation配方的关键性质,Composition 组成 Stability 稳定性 Thermal Properties热性质,8,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,9,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,10,11,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,12,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 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,13,14,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,15,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,16,17,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,18,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,19,20,Key Process Steps 主要工艺步骤,Freezing 冷冻,21,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 装料体积和长宽比（w/h）1,22,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）,23,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）,24,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 塌陷温度= - 23 oC Freezing temperature 35 oC 冷冻温度 35 oC,25,Key Process Steps主要工艺步骤,Freezing 冷冻 Primary Drying 第一次干燥,26,Primary Drying第一次干燥,Sublimation of ice from the matrix according to the phase diagram of water 根据水的相图使水从基质中升华 Lyophilization frozen interstitial 冻干-脉间区冻结 Freeze Drying frozen or not frozen interstitial region. 冷冻干燥-脉间区冻结或不冻结,27,Key Primary Drying Parameters第一次干燥主要参数,Pc Ts Tp Pc = Chamber pressure/箱内压力 Ts = Shelf surface temperature/搁板表面温度 Tp = Product temperature/产品温度,28,Select the Chamber Pressure选择箱内压力,Determine the vapor pressure of ice at 5 oC below the collapse or eutectic temperature 在低于塌陷温度或共晶点5 oC的温度下确定冰的蒸气压,29,Select the Chamber Pressure选择箱内压力,Select a lower chamber pressure (Pc ) 选择较低的箱内压力(Pc ) A pressure that will give a difference in ice interface temperature (Ti ) (defined by the phase diagram of water) and the product temperature (Tp ) 箱内压力会使冰界面的温度（Ti）（由水的相图限定）和产品温度不同(Tp ) q = KA(Tp Ti)/d cal./sec. Pc 100 mTorr to pre