凍干工藝的優(yōu)化培訓(xùn)課程(共42頁(yè)).ppt

1、Optimization of the Lyophilization or Freeze Drying Process 凍干工藝的優(yōu)化凍干工藝的優(yōu)化Definition of Lyophilization凍干的定義凍干的定義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 凍凍干是一個(gè)使物干是一個(gè)使物質(zhì)穩(wěn)質(zhì)穩(wěn)定化的定化的過(guò)過(guò)程，在程，在該過(guò)該過(guò)程中，首先使程中，首先使產(chǎn)產(chǎn)品冷品冷凍凍，然后將溶，然后將溶劑劑升升華華和解吸附，使和解吸附，使產(chǎn)產(chǎn)品中的含水量品中的含水量減少到缺乏以支持生物生減少到缺乏以支持生物生長(zhǎng)長(zhǎng)和和發(fā)發(fā)生化學(xué)反響的程度生化學(xué)反響的程度 Definition of Freeze Drying冷凍枯燥的定義冷凍枯燥的定義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 冷凍枯燥是一個(gè)是物質(zhì)穩(wěn)定的過(guò)程，在該過(guò)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缺乏以維持生物生長(zhǎng)和發(fā)生化學(xué)反響的

4、程度。l Basic Difference根本差異根本差異Lyophilization product remains frozen during the drying process 凍干-枯燥過(guò)程中產(chǎn)品保持冷凍Freeze Drying product may not remain frozen during the drying process 冷凍枯燥-凍干過(guò)程中產(chǎn)品可能不是冷凍狀態(tài)Key point is the term frozen “凍干這個(gè)詞是關(guān)鍵點(diǎn)Most Important Step最重要的步驟最重要的步驟lFormulation配方配方Why is the Formul

5、ation so Important?為何配方如此重要為何配方如此重要lDefines the freezing process 限定冷凍過(guò)程限定冷凍過(guò)程lDefines the drying process parameters限定枯限定枯燥過(guò)程參數(shù)燥過(guò)程參數(shù)lDefines the freeze drying equipment requirementsl 限定冷凍枯燥設(shè)備要求限定冷凍枯燥設(shè)備要求lDefines the shelf-life of the productl 限定產(chǎn)品的貨架壽命限定產(chǎn)品的貨架壽命lDefines if the process is going to be l

6、yophilized or freeze driedl 限定產(chǎn)品是凍干還是冷凍枯燥限定產(chǎn)品是凍干還是冷凍枯燥Key Properties of the Formulation配方的關(guān)鍵性質(zhì)配方的關(guān)鍵性質(zhì)lComposition 組成組成lStability 穩(wěn)定性穩(wěn)定性l Thermal Properties熱性質(zhì)熱性質(zhì)Key Thermal Properties主要的熱性質(zhì)主要的熱性質(zhì)lDegree of Supercooling過(guò)冷度過(guò)冷度lEutectic or Collapse Temperature共晶或塌陷溫度共晶或塌陷溫度lDegree of Crystallization結(jié)晶度

7、結(jié)晶度Supercooling過(guò)冷度過(guò)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(guò)冷度是指低于冰開(kāi)始形成時(shí)的冷凍平衡溫度的過(guò)冷度是指低于冰開(kāi)始形成時(shí)的冷凍平衡溫度的度數(shù)度數(shù)Key Thermal Properties主要的熱性質(zhì)主要的熱性質(zhì)lDegree of Supercooling過(guò)冷度過(guò)冷度lEutectic or Collapse Temperatu

8、re共晶或塌陷溫度共晶或塌陷溫度lDegree of Crystallization結(jié)晶度結(jié)晶度Basic Definition of a Eutectic共晶點(diǎn)的根本定義共晶點(diǎn)的根本定義lThat temperature at which the number of degrees of freedom in a system during freezing is zero. (f = 0) 冷凍過(guò)程中，該溫度下系統(tǒng)的自由度為零冷凍過(guò)程中，該溫度下系統(tǒng)的自由度為零lThe point of intersection between the solubility curve for a sat

9、urated solution and the depression of the freezing point of the solvent 飽和溶液的溶解曲線(xiàn)和溶劑結(jié)冰點(diǎn)凹陷的交點(diǎn)飽和溶液的溶解曲線(xiàn)和溶劑結(jié)冰點(diǎn)凹陷的交點(diǎn)Key Thermal Properties主要熱性質(zhì)主要熱性質(zhì)lDegree of Supercooling過(guò)冷度過(guò)冷度lEutectic or Collapse Temperature共晶和塌陷溫度共晶和塌陷溫度lDegree of Crystallization結(jié)晶度結(jié)晶度Collapse Temperature塌陷溫度塌陷溫度lThe collapse temper

10、ature is defined as that temperature at which the mobility of the water in the interstitial region approaches zero. 塌陷溫度是指脈間區(qū)的水的流動(dòng)性為零時(shí)溫度塌陷溫度是指脈間區(qū)的水的流動(dòng)性為零時(shí)溫度Key Thermal Properties主要熱性質(zhì)主要熱性質(zhì)lDegree of Supercooling過(guò)冷度過(guò)冷度lEutectic or Collapse Temperature共晶或塌陷溫度共晶或塌陷溫度lDegree of Crystallization結(jié)晶度結(jié)晶度Degr

11、ee of Crystallization結(jié)晶度結(jié)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. 結(jié)晶度是指產(chǎn)品中形成的冰的量和等量水形成的結(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冰的量的比率 主要工藝步驟主要工藝步驟 Freezing 冷凍What to consider before the Freezing Process冷凍開(kāi)始前需要考慮的因素冷凍開(kāi)始

12、前需要考慮的因素lStability of the liquid formulationl 液體配方的穩(wěn)定性液體配方的穩(wěn)定性lMolded vial, tubing vial or trayl 模制西林瓶，管制西林瓶或模制西林瓶，管制西林瓶或托盤(pán)托盤(pán)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 裝料體積和長(zhǎng)寬比裝料體積和長(zhǎng)寬比w/h1What to consider for the Freezing Process冷凍過(guò)程中需要考慮的問(wèn)題冷

13、凍過(guò)程中需要考慮的問(wèn)題lInitial shelf surface temperature (formulation, fill volume, stability)l 擱板外表的初始溫度配方，裝料體積，穩(wěn)定性擱板外表的初始溫度配方，裝料體積，穩(wěn)定性lInitial shelf surface temperature (ambient, 4 - 8 oC, 0 oC)l 擱板外表的初始溫度室溫，擱板外表的初始溫度室溫，4 - 8 oC, 100 mTorr to prevent backstreamingl Pc 100 mTorr以阻止氣體回流以阻止氣體回流Example of Primar

14、y Drying第一次枯燥舉例第一次枯燥舉例lTc = - 23 oClTp = -28 oClPp = 340 mTorrlPc = 100 mTorrlTi = - 40 oClTs = 10 oC ?l(Tp Ti) = 12 oCKey Process Steps主要凍干步驟主要凍干步驟lFreezingl冷凍冷凍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 取決于吸收溫度曲線(xiàn)取決于吸收溫度曲線(xiàn)配方和餅狀物結(jié)構(gòu)配方和餅狀物結(jié)構(gòu)lKey parameters partial pressure of water vapor in the vial (Pw ) and Tpl 主要參數(shù)西林瓶中蒸氣主要參數(shù)西林瓶中蒸氣分壓分壓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 擱板溫度斜面擱板溫度斜面Ts Tp 10 oClHow long when Tp = Ts ?l 到達(dá)到達(dá)Tp = Ts時(shí)要多長(zhǎng)時(shí)要多長(zhǎng)時(shí)間？時(shí)間？

16、End of Secondary Drying第二次枯燥的終點(diǎn)第二次枯燥的終點(diǎn)Final Product Properties最重產(chǎn)品性質(zhì)lCosmetic l化裝品化裝品Final Product Properties最重產(chǎn)品性質(zhì)lCosmeticl化裝品化裝品lReconsitutionl復(fù)水復(fù)水Reconstitution復(fù)水復(fù)水lTime less than 3 minutes 時(shí)間時(shí)間- -不超過(guò)不超過(guò)3 3分鐘分鐘lCheck assay of the formulation 配方的檢查化驗(yàn)配方的檢查化驗(yàn)lCheck the pH pH的檢查的檢查lCheck for turbid

17、ity 混濁度的檢查混濁度的檢查Final Product Properties最終產(chǎn)品的性質(zhì)lCosmeticl化裝品化裝品lReconstitutionl復(fù)水復(fù)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 法或失重法依產(chǎn)品而定法或失重法依產(chǎn)品而定lEstablish the acceptable range of moisture values (based on stability)l 建立可接受的水分值范圍根據(jù)穩(wěn)定性建立可接受的水分值范圍根據(jù)穩(wěn)定性lHow many samples?l 有多少樣品？有多少樣品？Final Product Properties最終產(chǎn)品性質(zhì)lCosmetic化裝品化裝品lReconstitution復(fù)水復(fù)水lMoisture水分水分lStability穩(wěn)定性穩(wěn)定性Summary for Optimization關(guān)于優(yōu)化的小結(jié)關(guān)于優(yōu)化的小結(jié)lFormulation (most important )l 配方很重要配方很重要lThermal properties (must have)l 熱性質(zhì)必須有熱性質(zhì)必須有l(wèi)Freezing (formulation, thermal pr