凍干工藝的優(yōu)化.ppt

1、Optimization of the Lyophilization or Freeze Drying Process 凍干工藝的優(yōu)化,Definition of Lyophilization凍干的定義,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 grow

2、th or chemical reactions. 凍干是一個使物質(zhì)穩(wěn)定化的過程，在該過程中，首先使產(chǎn)品冷凍，然后將溶劑升華和解吸附，使產(chǎn)品中的含水量減少到不足以支持生物生長和發(fā)生化學(xué)反應(yīng)的程度,Definition of Freeze Drying冷凍干燥的定義,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 remo

3、ved first by sublimation and then by desorption to values that will no longer support biological growth or chemical reactions. 冷凍干燥是一個是物質(zhì)穩(wěn)定的過程，在該過程中，凍干的溶劑先結(jié)晶，在產(chǎn)品中形成一定的結(jié)構(gòu)，然后靠升華和解吸附作用將溶劑的量減少至不足以維持生物生長和發(fā)生化學(xué)反應(yīng)的程度。,Basic Difference基本差別,Lyophilization product remains frozen during the drying process 凍干-干燥

4、過程中產(chǎn)品保持冷凍 Freeze Drying product may not remain frozen during the drying process 冷凍干燥-凍干過程中產(chǎn)品可能不是冷凍狀態(tài) Key point is the term frozen “凍干”這個詞是關(guān)鍵點,Most Important Step最重要的步驟,Formulation 配方,Why is the Formulation so Important?為何配方如此重要,Defines the freezing process 限定冷凍過程 Defines the drying process parameter

5、s限定干燥過程參數(shù) Defines the freeze drying equipment requirements 限定冷凍干燥設(shè)備要求 Defines the shelf-life of the product 限定產(chǎn)品的貨架壽命 Defines if the process is going to be lyophilized or freeze dried 限定產(chǎn)品是凍干還是冷凍干燥,Key Properties of the Formulation配方的關(guān)鍵性質(zhì),Composition 組成 Stability 穩(wěn)定性 Thermal Properties熱性質(zhì),Key Therma

6、l Properties主要的熱性質(zhì),Degree of Supercooling 過冷度 Eutectic or Collapse Temperature 共晶或塌陷溫度 Degree of Crystallization 結(jié)晶度,Supercooling過冷度,The degree of supercooling is defined as the number of degrees below the equilibrium freezing temperature where ice first starts to form. 過冷度是指低于冰開始形成時的冷凍平衡溫度的度數(shù),Key T

7、hermal Properties主要的熱性質(zhì),Degree of Supercooling 過冷度 Eutectic or Collapse Temperature 共晶或塌陷溫度 Degree of Crystallization 結(jié)晶度,Basic Definition of a Eutectic共晶點的基本定義,That temperature at which the number of degrees of freedom in a system during freezing is zero. (f = 0) 冷凍過程中，該溫度下系統(tǒng)的自由度為零 The point of int

8、ersection between the solubility curve for a saturated solution and the depression of the freezing point of the solvent 飽和溶液的溶解曲線和溶劑結(jié)冰點凹陷的交點,Key Thermal Properties主要熱性質(zhì),Degree of Supercooling 過冷度 Eutectic or Collapse Temperature 共晶和塌陷溫度 Degree of Crystallization 結(jié)晶度,Collapse Temperature塌陷溫度,The coll

9、apse temperature is defined as that temperature at which the mobility of the water in the interstitial region approaches zero. 塌陷溫度是指脈間區(qū)的水的流動性為零時溫度,Key Thermal Properties主要熱性質(zhì),Degree of Supercooling 過冷度 Eutectic or Collapse Temperature 共晶或塌陷溫度 Degree of Crystallization 結(jié)晶度,Degree of Crystallization結(jié)

10、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. 結(jié)晶度是指產(chǎn)品中形成的冰的量和等量水形成的冰的量的比率,Key Process Steps 主要工藝步驟,Freezing 冷凍,What to consider before the Freezing Process冷凍開始前需要考慮的因素,Stability of the liquid formulation 液體配方的穩(wěn)

11、定性 Molded vial, tubing vial or tray 模制西林瓶，管制西林瓶或托盤 Dimensions and composition of the container 容器的尺寸和成分 Fill volume and aspect ratio (w/h) 1 裝料體積和長寬比（w/h）1,What to consider for the Freezing Process冷凍過程中需要考慮的問題,Initial shelf surface temperature (formulation, fill volume, stability) 擱板表面的初始溫度（配方，裝料體積，

12、穩(wěn)定性） Initial shelf surface temperature (ambient, 4 - 8 oC, 0 oC) 擱板表面的初始溫度（室溫，4 - 8 oC, 0 oC) Shelf cooling rate (supercooling and fill volume) 擱板冷卻速率（過冷河裝料體積） Freezing temperature (eutectic or collapse temperature 10 oC lower mobility of water is zero) 冷凍溫度（共晶和塌陷溫度10 oC更低-水的移動性為零 Time (fill volume)

13、/ 時間（裝料體積）,Effect of Freezing on the Product冷凍對產(chǎn)品的影響,Was there a change in the composition of the formulation?/ 配方的成分時候有變化 Any change in turbidity?/混濁度是否有變化 Nature of the frozen cake (uniform or crust or glaze) 冷凍餅狀物的性質(zhì)（均一或者硬殼或凍膠層）,Example of a Freezing Process凍干過程舉例,Degree of Supercooling = 7 oC 過冷

14、度= 7 oC Collapse temperature (Tc) = - 23 oC 塌陷溫度= - 23 oC Freezing temperature 35 oC 冷凍溫度 35 oC,Key Process Steps主要工藝步驟,Freezing 冷凍 Primary Drying 第一次干燥,Primary Drying第一次干燥,Sublimation of ice from the matrix according to the phase diagram of water 根據(jù)水的相圖使水從基質(zhì)中升華 Lyophilization frozen interstitial 凍干

15、-脈間區(qū)凍結(jié) Freeze Drying frozen or not frozen interstitial region. 冷凍干燥-脈間區(qū)凍結(jié)或不凍結(jié),Key Primary Drying Parameters第一次干燥主要參數(shù),Pc Ts Tp Pc = Chamber pressure/箱內(nèi)壓力 Ts = Shelf surface temperature/擱板表面溫度 Tp = Product temperature/產(chǎn)品溫度,Select the Chamber Pressure選擇箱內(nèi)壓力,Determine the vapor pressure of ice at 5 oC b

16、elow the collapse or eutectic temperature 在低于塌陷溫度或共晶點5 oC的溫度下確定冰的蒸氣壓,Select the Chamber Pressure選擇箱內(nèi)壓力,Select a lower chamber pressure (Pc ) 選擇較低的箱內(nèi)壓力(Pc ) A pressure that will give a difference in ice interface temperature (Ti ) (defined by the phase diagram of water) and the product temperature (T

17、p ) 箱內(nèi)壓力會使冰界面的溫度（Ti）（由水的相圖限定）和產(chǎn)品溫度不同(Tp ) q = KA(Tp Ti)/d cal./sec. Pc 100 mTorr to prevent backstreaming Pc 100 mTorr以阻止氣體回流,Example of Primary Drying第一次干燥舉例,Tc = - 23 oC Tp = -28 oC Pp = 340 mTorr Pc = 100 mTorr Ti = - 40 oC Ts = 10 oC ? (Tp Ti) = 12 oC,Key Process Steps主要凍干步驟,Freezing 冷凍 Primary

18、Drying 第一次干燥 Secondary Drying 第二次干燥,Secondary Drying第二次干燥,Dependent on adsorption isotherms (formulation and cake structure) 取決于吸收溫度曲線（配方和餅狀物結(jié)構(gòu)） Key parameters partial pressure of water vapor in the vial (Pw ) and Tp 主要參數(shù)西林瓶中蒸氣分壓,Example of Secondary Drying第二次干燥的例子,Shelf temperature ramp Ts Tp 10 oC

19、 擱板溫度斜面Ts Tp 10 oC How long when Tp = Ts ? 達到Tp = Ts時要多長時間？,End of Secondary Drying第二次干燥的終點,Final Product Properties最重產(chǎn)品性質(zhì),Cosmetic 化妝品,Final Product Properties最重產(chǎn)品性質(zhì),Cosmetic 化妝品 Reconsitution 復(fù)水,Reconstitution復(fù)水,Time less than 3 minutes 時間-不超過3分鐘 Check assay of the formulation 配方的檢查化驗 Check the pH pH的檢查 Check for turbidity 混濁度的檢查,Final Product Properties最終產(chǎn)品的性質(zhì),Cosmetic 化妝品 Reconstitution 復(fù)水 Moisture 水分,Moisture水分,Method Karl Fis