冻干工艺的优化培训课程(共42页).ppt

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.l l 冻冻干是一个使物干是一个使物质稳质稳定化的定化的过过程，在程，在该过该过程中，首先使程中，首先使产产品冷品冷冻冻，然后将溶，然后将溶剂剂升升华华和解吸附，使和解吸附，使产产品中的含水量品中的含水量减少到缺乏以支持生物生减少到缺乏以支持生物生长长和和发发生化学反响的程度生化学反响的程度 Definition of Freeze Drying冷冻枯燥的定义冷冻枯燥的定义lFreeze drying is a stabilizing process in which there is first crystallizat

3、ion 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. l 冷冻枯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缺乏以维持生物生长和发生化学反响的

4、程度。l Basic Difference根本差异根本差异Lyophilization product remains frozen during the drying process 冻干-枯燥过程中产品保持冷冻Freeze Drying product may not remain frozen during the drying process 冷冻枯燥-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Most Important Step最重要的步骤最重要的步骤lFormulation配方配方Why is the Formul

5、ation 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限定枯限定枯燥过程参数燥过程参数lDefines the freeze drying equipment requirementsl 限定冷冻枯燥设备要求限定冷冻枯燥设备要求lDefines the shelf-life of the productl 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 l

6、yophilized or freeze driedl 限定产品是冻干还是冷冻枯燥限定产品是冻干还是冷冻枯燥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

7、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 Temperatu

8、re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共晶点的根本定义共晶点的根本定义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 sat

9、urated 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 Temperature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 temper

10、ature 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 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Degr

11、ee 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

12、前需要考虑的因素lStability of the liquid formulationl 液体配方的稳定性液体配方的稳定性lMolded vial, tubing vial or trayl 模制西林瓶，管制西林瓶或模制西林瓶，管制西林瓶或托盘托盘lDimensions and composition of the containerl 容器的尺寸和成分容器的尺寸和成分lFill volume and aspect ratio (w/h) 1l 装料体积和长宽比装料体积和长宽比w/h1What to consider for the Freezing Process冷冻过程中需要考虑的问题冷

13、冻过程中需要考虑的问题lInitial shelf surface temperature (formulation, fill volume, stability)l 搁板外表的初始温度配方，装料体积，稳定性搁板外表的初始温度配方，装料体积，稳定性lInitial shelf surface temperature (ambient, 4 - 8 oC, 0 oC)l 搁板外表的初始温度室温，搁板外表的初始温度室温，4 - 8 oC, 100 mTorr to prevent backstreamingl Pc 100 mTorr以阻止气体回流以阻止气体回流Example of Primar

14、y Drying第一次枯燥举例第一次枯燥举例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lFreezingl冷冻冷冻lPrimary Dryingl第一次枯燥第一次枯燥 l lSecondary Dryingl第二次枯燥第二次枯燥Secondary Drying第二次枯燥第二次枯燥lDependent on adsorption isotherms (formulation and cak

15、e structure)l 取决于吸收温度曲线取决于吸收温度曲线配方和饼状物结构配方和饼状物结构lKey parameters partial pressure of water vapor in the vial (Pw ) and Tpl 主要参数西林瓶中蒸气主要参数西林瓶中蒸气分压分压Example of Secondary Drying第二次枯燥的例子第二次枯燥的例子lShelf temperature ramp Ts Tp 10 oCl 搁板温度斜面搁板温度斜面Ts Tp 10 oClHow long when Tp = Ts ?l 到达到达Tp = Ts时要多长时要多长时间？时间？

16、End of Secondary Drying第二次枯燥的终点第二次枯燥的终点Final Product Properties最重产品性质lCosmetic l化装品化装品Final Product Properties最重产品性质lCosmeticl化装品化装品lReconsitutionl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 配方的检查化验配方的检查化验lCheck the pH pH的检查的检查lCheck for turbid

17、ity 混浊度的检查混浊度的检查Final Product Properties最终产品的性质lCosmeticl化装品化装品lReconstitutionl复水复水lMoisturel水分水分Moisture水分水分lMethod Karl Fischer or Loss on Drying (product dependent)l 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 values (based on stability)l 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?l 有多少样品？有多少样品？Final Product Properties最终产品性质lCosmetic化装品化装品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 )l 配方很重要配方很重要lThermal properties (must have)l 热性质必须有热性质必须有lFreezing (formulation, thermal pr