1、Optimization of the Lyophilization or Freeze Drying Process 冻干工艺的优化冻干工艺的优化Definition of Lyophilization冻干的定义冻干的定义lA 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 biol
2、ogical 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减少到不足以支持生物生长和发生化学反应的程度 Definition of Freeze Drying冷冻干燥的定义冷冻干燥的定义lFreeze drying is a stabilizing process in which there is first crystallization
3、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，然后靠升华和解溶剂先结晶，在产品中形
4、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。学反应的程度。Basic Difference基本差别基本差别lLyophilization product remains frozen during the drying process 冻干-干燥过程中产品保持冷冻lFreeze Drying product may not remain frozen during the drying process 冷冻干燥冷冻干燥-冻干过程中产品可能不是冷冻状态冻干过程中产品可能不是冷冻状态lKey poin
5、t is the term frozen “冻干冻干”这个词是关键点这个词是关键点Most Important Step最重要的步骤最重要的步骤lFormulation配方配方Why is the Formulation so Important?为何配方如此重要为何配方如此重要lDefines the freezing process 限定冷冻过程限定冷冻过程lDefines the drying process parameters限定干限定干燥过程参数燥过程参数lDefines the freeze drying equipment requirements 限定冷冻干燥设备要求限定冷冻
6、干燥设备要求lDefines the shelf-life of the product 限定产品的货架寿命限定产品的货架寿命lDefines if the process is going to be lyophilized or freeze dried 限定产品是冻干还是冷冻干燥限定产品是冻干还是冷冻干燥Key Properties of the Formulation配方的关键性质配方的关键性质lComposition 组成组成lStability 稳定性稳定性l Thermal Properties热性质热性质Key Thermal Properties主要的热性质主要的热性质lDe
7、gree of Supercooling过冷度过冷度lEutectic or Collapse Temperature共晶或塌陷温度共晶或塌陷温度lDegree of Crystallization结晶度结晶度Supercooling过冷度过冷度 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过冷度是指低于冰开始形成时的冷冻平衡
8、温度的度数度数Key Thermal Properties主要的热性质主要的热性质lDegree of Supercooling过冷度过冷度lEutectic or Collapse Temperature共晶或塌陷温度共晶或塌陷温度lDegree of Crystallization结晶度结晶度Basic Definition of a Eutectic共晶点的基本定义共晶点的基本定义lThat temperature at which the number of degrees of freedom in a system during freezing is zero.(f=0)冷冻过程
9、中，该温度下系统的自由度为零冷冻过程中，该温度下系统的自由度为零lThe 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饱和溶液的溶解曲线和溶剂结冰点凹陷的交点Key Thermal Properties主要热性质主要热性质lDegree of Supercooling过冷度过冷度lEutectic or Collapse Temperat
10、ure共晶和塌陷温度共晶和塌陷温度lDegree of Crystallization结晶度结晶度Collapse Temperature塌陷温度塌陷温度lThe 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塌陷温度是指脉间区的水的流动性为零时温度Key Thermal Properties主要热性质主要热性质lDegree of Super
11、cooling过冷度过冷度lEutectic or Collapse Temperature共晶或塌陷温度共晶或塌陷温度lDegree of Crystallization结晶度结晶度Degree of Crystallization结晶度结晶度lThe 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结晶度是指产品中形成的冰的量和等量水形成的冰的
12、量的比率冰的量的比率 主要工艺步骤主要工艺步骤 Freezing 冷冻What to consider before the Freezing Process冷冻开始前需要考虑的因素冷冻开始前需要考虑的因素lStability of the liquid formulation 液体配方的稳定性液体配方的稳定性lMolded vial,tubing vial or tray 模制西林瓶，管制西林瓶或托模制西林瓶，管制西林瓶或托盘盘lDimensions and composition of the container 容器的尺寸和成分容器的尺寸和成分lFill volume and aspec
13、t ratio(w/h)1 装料体积和长宽比装料体积和长宽比（w/h）1What to consider for the Freezing Process冷冻过程中需要考虑的问题冷冻过程中需要考虑的问题lInitial 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）搁板表面的初始温度（配方，装料体积，稳定性）lInitial shelf surface temperature(ambient,4-8 oC,0 oC)搁板表面的初始温度（室温搁板表面的初始温度（室温，4-8 oC
14、,100 mTorr to prevent backstreaming Pc 100 mTorr以阻止气体回流以阻止气体回流Example of Primary Drying第一次干燥举例第一次干燥举例lTc=-23 oClTp=-28 oClPp =340 mTorrlPc=100 mTorrlTi =-40 oClTs=10 oC?l(Tp Ti)=12 oCKey Process Steps主要冻干步骤主要冻干步骤lFreezing冷冻冷冻lPrimary Drying第一次干燥第一次干燥 lSecondary Drying第二次干燥第二次干燥Secondary Drying第二次干燥第
15、二次干燥lDependent on adsorption isotherms(formulation and cake structure)取决于吸收温度曲线（配取决于吸收温度曲线（配方和饼状物结构）方和饼状物结构）lKey parameters partial pressure of water vapor in the vial(Pw)and Tp 主要参数西林瓶中蒸气分主要参数西林瓶中蒸气分压压Example of Secondary Drying第二次干燥的例子第二次干燥的例子lShelf temperature ramp Ts Tp 10 oC 搁板温度斜面搁板温度斜面Ts Tp 1
16、0 oClHow long when Tp=Ts?达到达到T Tp p=T=Ts s时要多长时时要多长时间？间？End of Secondary Drying第二次干燥的终点第二次干燥的终点Final Product Properties最重产品性质lCosmetic 化妆品化妆品Final Product Properties最重产品性质lCosmetic化妆品化妆品lReconsitution复水复水Reconstitution复水复水lTime less than 3 minutes 时间时间-不超过不超过3 3分钟分钟lCheck assay of the formulation 配方
17、的检查化验配方的检查化验lCheck the pH pH的检查的检查lCheck for turbidity 混浊度的检查混浊度的检查Final Product Properties最终产品的性质lCosmetic化妆品化妆品lReconstitution复水复水lMoisture水分水分Moisture水分水分lMethod Karl Fischer or Loss on Drying(product dependent)方法方法-Karl Fischer 法或失重法（依产品而定）法或失重法（依产品而定）lEstablish the acceptable range of moisture
18、values(based on stability)建立可接受的水分值范围（根据稳定性）建立可接受的水分值范围（根据稳定性）lHow many samples?有多少样品？有多少样品？Final Product Properties最终产品性质lCosmetic化妆品化妆品lReconstitution复水复水lMoisture水分水分lStability稳定性稳定性Summary for Optimization关于优化的小结关于优化的小结lFormulation(most important)配方（很重要）配方（很重要）lThermal properties(must have)热性质（必
19、须有）热性质（必须有）lFreezing(formulation,thermal properties,fill volume and container)冷冻（配方、热性质、装料体积和容器）冷冻（配方、热性质、装料体积和容器）lPrimary Drying(Collapse and phase diagram of water,pressure control)第一次干燥（塌陷和水的相图，压力控制）第一次干燥（塌陷和水的相图，压力控制）lSecondary(desorption isotherms,time)第一次干燥（解吸附曲线，时间）第一次干燥（解吸附曲线，时间）lFinal Product Properties 最终产品性质最终产品性质
