應(yīng)用PAT工具快速開發(fā)和優(yōu)化顆粒工藝副本

1、PAT工具快速開發(fā)和優(yōu)化顆粒工藝2013-托利多銷售顧問 陳斌Bin.22目錄梅特勒-托利多 實(shí)時(shí)在線顆粒分析技術(shù)介紹PVM 顆粒錄影顯微鏡FBRM 聚焦光束反射測(cè)量?jī)x實(shí)時(shí)在線顆粒分析技術(shù)優(yōu)化顆粒工藝3過程分析技術(shù)（PAT） 已經(jīng)成為趨勢(shì)3質(zhì)量源于設(shè)計(jì) QbD（Quality by Design）過程分析技術(shù) PAT（Process Analytical Technology）4質(zhì)量源于設(shè)計(jì)（QbD）和過程分析技術(shù)（ PAT）Implementing Quality by Design (Sept. 2007), Helen N. Winkle, Director, Office of Pha

2、rmaceutical Science, CDER-FDAThe PAT Guidance is part of the ongoing Pharmaceutical Quality for the 21st Century : A Risk-Based Approach 首先，徹底了解工藝過程其次，通過監(jiān)測(cè)關(guān)鍵工藝參數(shù)實(shí)時(shí)預(yù)測(cè)產(chǎn)品質(zhì)量最后，在“第一時(shí)間”就能對(duì)工藝過程進(jìn)行控制和把握梅特勒-托利多 實(shí)時(shí)在線顆粒分析技術(shù)梅特勒-托利多是原位條件下監(jiān)控和測(cè)量顆粒和液滴的世界領(lǐng)導(dǎo)者梅特勒-托利多在顆粒體系表征方面擁有超過25年的革新技術(shù)我們?nèi)虻膽?yīng)用顧問團(tuán)隊(duì)具有超過3000臺(tái)的實(shí)際安裝應(yīng)用經(jīng)驗(yàn)，主要

3、支持結(jié)晶、乳化、懸浮等多方面的顆粒及多相體系的應(yīng)用全世界超過 5000 名的科學(xué)家和工程師使用了該項(xiàng)技術(shù)Redmond, Washington, USA從實(shí)驗(yàn)室到工廠的安裝基于探頭的技術(shù)，不需要取樣，不需要樣品制備針對(duì)顆粒體系瞬間實(shí)時(shí)響應(yīng)工藝的變化安裝于10mL 至 20,000 L，管道、高壓、危險(xiǎn)的環(huán)境中實(shí)時(shí)在線顆粒分析技術(shù)FBRM TechnologyFocused Beam Reflectance Measurement PVM 技術(shù)Particle Video Microscopy顆粒錄影顯微鏡技術(shù)FBRM 技術(shù)Focused Beam Reflectance Measurement

4、聚焦光束反射測(cè)量技術(shù) 10 m dropletsTemperatureG400 #/sec 0-20mTimeChord Length (m)FBRM在當(dāng)前工藝條件下，實(shí)時(shí)原位在線追蹤顆粒和顆粒結(jié)構(gòu)的變化程度和變化比率- 規(guī)格參數(shù)和測(cè)量方法請(qǐng)參考 - PVM 在當(dāng)前工藝條件下，觀測(cè)顆粒和顆粒結(jié)構(gòu)的變化-規(guī)格參數(shù)和測(cè)量方法請(qǐng)參考- ISO 9001 CE8顆粒錄影顯微鏡技術(shù) Particle Video MicroscopePVM 是一種探頭式的觀測(cè)工具，能提供瞬間的豐富信息，幫助深入了解顆粒和液滴體系PVM 幫助用戶篩選實(shí)驗(yàn)參數(shù)，并在早期確定工藝可放大性和產(chǎn)品質(zhì)量每次試驗(yàn)捕捉上千張圖片精度2微

5、米快速表征小顆粒，形狀，聚結(jié)等不需要取樣，不需要制樣，不需要稀釋在整個(gè)工藝濃度范圍內(nèi)，透明或者不透明的體系了解原先未知的顆粒體系情況10 m 液滴PVM Website PVM 顆粒錄影顯微鏡PVM 技術(shù)沒有額外照明的要求探頭由耐化學(xué)腐蝕的材料制成 （哈氏合金Alloy C22及藍(lán)寶石窗口）緊密的焦平面所獲得高精度的圖片，將背景顆粒的影響減到最少即使在快速移動(dòng)的流體中，也能獲得清晰的圖片而不會(huì)產(chǎn)生模糊藍(lán)寶石窗口照明透鏡系統(tǒng)物鏡CCD導(dǎo)管CCD Camera在極端條件下高精度的圖像PVM 能在極端條件下獲得高精度的圖像信息:在特別粘稠或不透明的體系下，或者在極端低或者非常高的溫度和壓力下此時(shí)，不

6、能取樣PVM 增強(qiáng)型視窗下原油中的水PVM 測(cè)量原油中的氣體水合物水中的煤油1112有機(jī)晶體13意外形狀（由PVM，而不是 Raman）PVM 對(duì)顆粒數(shù)很少，意外形成的多晶體進(jìn)行探測(cè)/記錄P. Fernandez, Merck, Lasentec Users Conference 2001 PVM 探測(cè)意外晶體On-Line Monitoring of Crystallization of a Polymorphic Compound Using Lasentec-PVM -Raman P. Fernandez, Merck, Lasentec Users Conference 2002PVM

7、 在一次實(shí)驗(yàn)中觀測(cè)到的信息，用傳統(tǒng)的實(shí)驗(yàn)方法需要花幾周的時(shí)間?！皩?duì)于不同形狀的多晶型，PVM比Raman更靈敏地檢測(cè)到1)存在不同的晶型 2）轉(zhuǎn)變的終點(diǎn)14PVM 立刻揭示聚結(jié)過程在線 PVM 圖像：:離線顯微鏡圖像：之后：過濾干燥制樣The Use of In Situ Analytics for Crystallization Process Development Brian OSullivan, Ph.D. Thesis, University College Dublin, 2005Crystallization endpointCrystallization midpoint151

8、5FBRM聚焦光束反射測(cè)量?jī)xFBRM 是一個(gè)定量化的測(cè)量工具，使化學(xué)家或工程師迅速將顆粒體系的動(dòng)態(tài)變化同工藝條件和最終產(chǎn)品質(zhì)量相聯(lián)系。 在原位工藝條件下，追蹤顆粒及液滴的變化程度和變化速率FBRM 能直接測(cè)量顆粒的粒徑、形狀及數(shù)量運(yùn)用在線數(shù)據(jù)能幫助理解并優(yōu)化動(dòng)態(tài)過程無需取樣實(shí)驗(yàn)室或者工廠環(huán)境透明或者不透明的料液中從亞微米至毫米實(shí)驗(yàn)室中試及工廠管道FBRM 測(cè)量方法FBRM探頭導(dǎo)管電子光束分裂器旋轉(zhuǎn)棱鏡組合成藍(lán)寶石窗口聚焦光束監(jiān)測(cè)光纖激光光源光纖FBRM 在線探頭的剖視圖PVM 圖像說明 FBRM 探頭窗口看到的情況安裝于流體中的探頭17FBRM 測(cè)量方法PVM 圖片表示 FBRM 探頭窗口觀測(cè)

9、到的情況探頭監(jiān)測(cè)脈沖式的反射散射光并記錄所測(cè)量的弦長(zhǎng)聚焦光束經(jīng)過路線放大視圖FBRM 測(cè)量方法Path of Focused BeamEnlarged viewFBRM 每秒鐘測(cè)量數(shù)千個(gè)弦長(zhǎng)，從而形成弦長(zhǎng)分布放大圖聚焦光束的路徑19FBRM 測(cè)量原理Path of Focused BeamEnlarged view每秒測(cè)量上千個(gè)弦長(zhǎng)以獲得FBRM 弦長(zhǎng)分布 計(jì)算某個(gè)特定區(qū)間范圍的粒數(shù)分布或者總體統(tǒng)計(jì)分布如平均分布，隨著時(shí)間的變化趨勢(shì)在線顆粒分布以及趨勢(shì)變化不加權(quán)分布#/s 50 m#/s 50-1000 m2121目錄梅特勒-托利多 實(shí)時(shí)在線顆粒分析技術(shù)介紹PVM 顆粒錄影顯微鏡FBRM 聚焦

10、光束反射測(cè)量?jī)x實(shí)時(shí)在線顆粒分析技術(shù)優(yōu)化顆粒工藝應(yīng)用領(lǐng)域制藥結(jié)晶制藥液態(tài)懸浮生物結(jié)晶精細(xì)及特種化學(xué)石油學(xué)術(shù)大化工結(jié)晶大化工配方食品以及 助劑化學(xué)消費(fèi)產(chǎn)品吸入劑，混懸劑，乳化劑，一定劑量的吸入劑，口服混懸劑，溶解與崩解，乳劑結(jié)晶，濕法研磨API 原料藥的開發(fā)、放大和生產(chǎn)結(jié)晶，濕法研磨API原料藥的開發(fā)、放大和生產(chǎn)流動(dòng)保障，瀝青質(zhì)沉淀，石蠟結(jié)晶，油-水分離，破乳化，油-固分離上游油工藝過程結(jié)晶，催化劑沉淀，聚合 精細(xì)化學(xué)，特種聚合物，催化劑結(jié)晶，沉淀，聚合化工，化學(xué)，生物，石油，顆粒研究結(jié)晶，沉淀無機(jī)礦物懸浮液，乳化液，聚合物封裝的農(nóng)藥, 聚合，香精香料，農(nóng)產(chǎn)品乳液，懸浮液，均質(zhì)化護(hù)膚乳液，化妝品，

11、膏狀物，護(hù)發(fā)產(chǎn)品，牙膏懸浮液，結(jié)晶，均質(zhì)化乳糖，糖，蛋白質(zhì)，維生素，氨基酸類，棕櫚油結(jié)晶ParticleTrack G400-G600溶劑體積, 30mL to 20,000LParticleTrack E25水溶液體積, 2 to 20,000L222323242425252626272728282929Batch 1 had the Lowest Number of Coarse Particles3030Good BatchFailed Specification31313232Investigating bauxite residue flocculation by hydroxama

12、te and polyacrylate flocculats utilizing the focused beam reflectance measurement probe33Cathy ZhengMarch. 2013Luke J.KirwanInt. J. Miner. Process. 90 (2009) 7480利用FBRM探頭研究加入異羥肟酸和聚丙烯酸酯絮凝劑鋁土礦殘?jiān)男跄^程Introduction: Bauxite residue flocculationExtraction of alumina from bauxite generates large volumes of

13、 residue (red mud). In gravity thickenerKey performance factors: underflow density底流密度, throughput, and overflow clarity 溢流澄清度.34Flocculants(a) Schematic representation of the repeat monomer unit within polyacrylate聚丙烯酸酯 flocculant (b) the incorporation of the hydroxamate異羥肟酸 functionality into an a

14、nionic polyacrylamide 陰離子聚丙烯酰胺 flocculant.35Introduction: FBRMSettling tests, measure: 1) the rate of decent of the mudline formed泥水分界線形成的速度; 2) the clarity of the supernatant liquor in batch cylinder 母液澄清度From this measurement, properties of the aggregates formed can be inferredFBRM: offers the pot

15、ential to measure aggregate size directlyFBRM is the only tool that will give a real-time, in situ indication, be shown to be a very useful tool in the study of mineral and process flocculation (e.g. Hecker et al., 1999; De Clercq et al., 2004).Chord Length Distribution differs from Particle Size Di

16、stributionSquare-weighted distribution is a more accurate representation of volume-weighting (Heath et al., 2002). Conventional sizing instruments, such as the Malvern Mastersizer.36Introduction: FBRMAfter flocculant addition there is an increase, followed by a peak, and then a gradual decay. The me

17、an square-weighted chord length achieved from flocculation is proportional to the measured settling rate (Heath et al., 2006).The decay behaviour is indicative of aggregate break-up caused by the continually applied mixing to the system.The rate of decay has been found to be inversely proportional t

18、o the resistance of the aggregates to breakage. A very small rate of decay indicates strong aggregates, or additionally a high rate of dynamic re-flocculation (Blanco et al., 2002).FBRM has been integrated into this flocculation study to examine the comparative performance of process hydroxamate and

19、 polyacrylate flocculants on Bayer process bauxite residue slurry. The study has focussed on clarity and aggregate strength as key performance indicators.37FBRM Data focused on aggregate strengthAfter flocculant addition there is an increase, followed by a peak, and then a gradual decay. the mean sq

20、uare-weighted chord length achieved from flocculation is proportional to the measured settling rate (Heath et al., 2006).38The decay shows aggregate break-up caused by mixing.The decay is an exponential function (Alfano et al., 1999). The rate of decay is inversely proportional to the resistance of

21、the aggregates to breakage. A very small rate of decay indicating strong aggregates, or additionally a high rate of dynamic reflocculation.(Blanco et al., 2002).MethodsWith settling test: 250ml, equilibrate 3 min, flocculant dose, stop stirrer; After 5min, 20ml sample determined gravimetrically With

22、out settling test: 150ml, 95C, equilibrate 10 min, flocculant dose for a further 10min. If add starch, added 7.5 min after experiment started.39Viscosity-concentrationHydroxamate flocculant: HX300 Polyacrylate flocculant: 977940At a 9779 concentration of 0.06 % and a HX300 concentration of 0.13 %, e

23、quivalent viscosities.Viscosity and hence mixing issues are not a concern for the starch solution, therefore in experiments where starch was used, it was added undiluted.FBRM41The decay shows aggregate break-up caused by mixing.The decay is an exponential function (Alfano et al., 1999). The rate of

24、decay is inversely proportional to the resistance of the aggregates to breakage. A very small rate of decay indicating strong aggregates, or additionally a high rate of dynamic reflocculation.(Blanco et al., 2002).Flocculation Studythere is an increase in the max. size with increasing flocculant dos

25、age and this corresponds with a decreasing trend in the 1 5 m fine counts.However, it can also be seen that several experiments have been repeated and reproducibility was often poor.However, such variations are inevitable with plant slurries involving digestion and supersaturation.42FBRM From Table

26、1on the same general curve, regardless of flocculant added, agitation intensity, and whether starch was added or not.the addition of starch would appear to improve the performance of the 9779 polyacrylate flocculant.43Settling testFigure 5: The relationship between the gravimetric solids left behind

27、 in the supernatant after settling for 5 mins with(a) the FBRM 1 5 m fine counts/s and; (b) the maximum mean square-weighted chord length.HX gave visibly much larger aggregates, which exhibited faster settling, and better fines capture in comparison to 9779HX offer a greater capture efficiency44Supe

28、rnatant SolidsHX300 flocculation were much harder to and appeared more red in coloured compared to those from 9779 flocculation.encouraging45SEM imagesFigure 6: (a) SEM image of the thickener overflow solids from the thickener utilising HX300 feedwell flocculation and (b) the thickener using 9779 fe

29、edwell flocculation.46DifferentHydroxamatePolyacrylateAfter flocculationFiner and more iron richMore coarse particlesEDX能量色散X射線光譜儀47Figure 7 shows that the solids from the HX300 treated thickener have relatively much higher amounts of iron, but relatively less amounts of titanium, calcium, and silic

30、on.Aggregate Strength48This aggregate breakage has been examined by fitting an exponentialy = Co + A.exp(-x/Tb)Co is the final size;A + Co the initial size;1/Tb the rate of decay.Tb indicates a robust aggregate structureAggregate Strength49The aggregates formed are more robustThe use of starch with

31、9779 did not appear to have an influenceAggregate Strength50Industrial ApplicationThe key difference was found to be the way the aggregates developed post-shear, with hydroxamate flocculation exhibiting a greater degree of post-shear flocculation 后剪切絮凝.51DifferentHydroxamatePolyacrylateAggregatesGre

32、ater fines captureMore dense 密度Lower solids in the supernatant 上清液More shear resistantAfter flocculationFiner and more iron richMore coarse particles剪切絮凝是利用對(duì)礦漿進(jìn)行較強(qiáng)烈攪拌而產(chǎn)生的剪切力和捕收劑在礦粒表面吸附所產(chǎn)生的疏水鍵合力，使微細(xì)礦粒形成絮團(tuán)，進(jìn)行分離回收的浮選方法。Co-flocculation of bauxite residue with polyacrylate and hydroxamate flocculants is

33、to be examined in further detail in a subsequent publication.ConclusionFBRM has proved to be a very powerful tool for investigating and comparing the flocculation performance of process hydroxamate and polyacrylate flocculants with Bayer process bauxite residue slurry.The key difference in polyacryl

34、ate and hydroxamate flocculation is the way the aggregates develop post-shear, with hydroxamate aggregates exhibiting a greater degree of post-shear aggregation.52FBRM&PVM在尾礦處理中的應(yīng)用礦石經(jīng)過選別之后，將有大量尾礦產(chǎn)生，尾礦顆粒極細(xì)，多為泥漿狀，難以沉淀，難以脫水。53尾礦沉淀池使尾礦水在池中進(jìn)行沉淀，以達(dá)到澄清的目的。尾礦水往往呈膠狀，為了使尾礦水很快地澄清，可加入凝聚劑，以加速顆粒的沉淀。優(yōu)化尾礦沉降工藝54在線監(jiān)測(cè)

35、不同粒徑顆粒的凝聚過程提高沉淀分離的效率優(yōu)化工藝適用最少的絮凝劑降低設(shè)備規(guī)模Luke Kirwan, Aughinish Alumina Limited高嶺土作為凝聚劑尾礦泥漿中加入規(guī)格為2% wt/V的高嶺土作為凝聚劑。不同加入量的PVM圖像558 g t-115 g t-130 g t-1100 m 沒有加入高嶺土高嶺土作為凝聚劑尾礦泥漿中加入4.5wt%高嶺土懸濁液為凝聚劑。FBRM監(jiān)測(cè)加入不同量的高嶺土的結(jié)果對(duì)照?qǐng)D。56精細(xì)及特種化學(xué)懸浮液和乳化液利用ParticleTrack過程分析技術(shù)（PAT）促進(jìn)更快的開發(fā)、提高工藝信心、在生產(chǎn)過程中控制批次間的一致性。案例：聚烯烴的聚合聚苯乙烯

36、的聚合結(jié)晶和沉淀實(shí)時(shí)在線顆粒分析技術(shù)ParticleTrack作為有用的工具幫助用戶快速評(píng)估工藝條件，確保結(jié)晶過程的最優(yōu)化。案例：混合和溶劑添加混合和磨損優(yōu)化冷卻以改進(jìn)過濾聚合聚烯烴的顆粒生長(zhǎng)介紹在催化乙烯油漿聚合過程利用FBRM和PVM技術(shù)監(jiān)控聚合物顆粒的生長(zhǎng)實(shí)驗(yàn)結(jié)果ParticleTrack實(shí)時(shí)在線顆粒分析技術(shù)在線監(jiān)控顆粒的粒數(shù)和粒徑。趨勢(shì)分析提供豐富的信息針對(duì)顆粒生長(zhǎng)過程方面的參數(shù)。“在聚合過程中利用PVM和ParticleTrack在線測(cè)定顆粒粒徑分布數(shù)據(jù)與相應(yīng)的標(biāo)準(zhǔn)離線分析方法獲得的數(shù)據(jù)非常吻合。”PVM是ParticleTrack數(shù)據(jù)的補(bǔ)充，它能觀察到聚烯烴生長(zhǎng)的過程。Online

37、 Monitoring of Polyolefin ParticleGrowth in Catalytic Olefin Slurry: Polymerization by Means of FBRM and PVM Probes; FMF Institute, University Freiburg, Germany.R. Xalter, R. Mlhaupt, Macromolecular Reaction Engineering 4, 2010, 25-39.58總結(jié)“這兩個(gè)探頭FBRM和PVM是強(qiáng)大的分析工具，能直接在線監(jiān)控催化烯烴油漿聚合中聚合物顆粒的生長(zhǎng)過程。” ParticleT

38、rack的數(shù)據(jù)結(jié)合乙烯質(zhì)量流的測(cè)量幫助區(qū)分理想的顆粒生長(zhǎng)和更加復(fù)雜的生長(zhǎng)過程例如破碎和聚結(jié)?！翱傊?，PVM和ParticleTrack探頭有助于研究和開發(fā)新型催化劑以提高多形態(tài)烯烴聚合的控制過程。”O(jiān)nline Monitoring of Polyolefin ParticleGrowth in Catalytic Olefin SlurryPolymerization by Means of FBRM and PVM Probes FMF Institute, University Freiburg, Germany.59聚合聚烯烴的顆粒生長(zhǎng)R. Xalter, R. Mlhaupt, Ma

39、cromolecular Reaction Engineering 4, 2010, 25-39.精細(xì)及特種化學(xué)懸浮液和乳化液利用ParticleTrack過程分析技術(shù)（PAT）促進(jìn)更快的開發(fā)、提高工藝信心、在生產(chǎn)過程中控制批次間的一致性。案例：聚烯烴的聚合聚苯乙烯的聚合結(jié)晶和沉淀實(shí)時(shí)在線顆粒分析技術(shù)ParticleTrack作為有用的工具幫助用戶快速評(píng)估工藝條件，確保結(jié)晶過程的最優(yōu)化。案例：混合和溶劑添加混合和磨損優(yōu)化冷卻以改進(jìn)過濾反溶劑添加過程中的介穩(wěn)區(qū)反溶劑的添加降低了溶質(zhì)在溶液中的溶解度添加速率會(huì)影響過飽和度，因此會(huì)影響成核和生長(zhǎng)C61滴加速率，過飽和度，反溶劑溶質(zhì)苯甲酸溶劑乙醇反溶劑

40、水相同質(zhì)量的反溶劑加入飽和溶液中，但是加料速率不同F(xiàn)astSlow在不好的加料位置確保一致性縮小加料管的直徑提高混合范圍，降低靠近加料位置的局部過飽和度在放大階段是有幫助的，但是此時(shí)改變反溶劑的加料位置不可行Barrett, M., OGrady, D., Casey, E., & Glennon, B. (2011). The role of meso-mixing in anti-solvent crystallization processes. Chemical Engineering Science, 66(12), 2523-2534. Elsevier. doi:10.1016/

41、j.ces.2011.02.042小顆粒的粒數(shù)與混合相關(guān)聯(lián)加料管的直徑與小顆粒的變化速率以及最終小顆粒粒數(shù)相關(guān)聯(lián)0.78mm0.3mmAdditional nucleation eventsFines reducedNucleation rate minimized and consistent over timeBarrett, M., OGrady, D., Casey, E., & Glennon, B. (2011). The role of meso-mixing in anti-solvent crystallization processes. Chemical Engineer

42、ing Science, 66(12), 2523-2534. Elsevier. doi:10.1016/j.ces.2011.02.042精細(xì)及特種化學(xué)懸浮液和乳化液利用ParticleTrack過程分析技術(shù)（PAT）促進(jìn)更快的開發(fā)、提高工藝信心、在生產(chǎn)過程中控制批次間的一致性。案例：聚烯烴的聚合聚苯乙烯的聚合結(jié)晶和沉淀實(shí)時(shí)在線顆粒分析技術(shù)ParticleTrack作為有用的工具幫助用戶快速評(píng)估工藝條件，確保結(jié)晶過程的最優(yōu)化。案例：混合和溶劑添加混合和磨損優(yōu)化冷卻以改進(jìn)過濾成核和生長(zhǎng)都受到過飽和度的控制500ml Scale 實(shí)驗(yàn)室70 L 中試規(guī)模 增大湍流混合的規(guī)模 濃度梯度 純度，產(chǎn)

43、量，顆粒粒徑都會(huì)受到影響 !4Mark Barrett, UCD Crystallization Research Group, SSPC Ireland 放大階段的挑戰(zhàn)一般的放大參數(shù)放大不是簡(jiǎn)單的線性的尺寸增加，而是存在幾何相似度1 L100L1LReferenceFrancis X. McConville, Impact Technology Consultants, Inc.一般的放大參數(shù)熱傳遞表面積和規(guī)模Reference: Francis X. McConville, Impact Technology Consultants, Inc.Factor of 20!介紹Particle

44、Track 用于在攪拌的結(jié)晶器中確定、追蹤和建立晶體破碎和磨損的模型，目的是為了預(yù)測(cè)放大的行為實(shí)驗(yàn)結(jié)果ParticleTrack 顯示主要機(jī)理是細(xì)微的磨損而不是晶體破碎“ParticleTrack 提供顯著優(yōu)勢(shì)在于它是一種實(shí)時(shí)在線監(jiān)控測(cè)量技術(shù)”結(jié)晶混合的影響Modeling Particle Disruption of an Organic Fine Chemical Compound Using FBRM in Agitated SuspensionGlaxoSmithKline, Stevenage, UKKougoulos et al, Powder Technology (2005)

45、153-158Fig. 6. Inline ParticleTrack monitoring attrition showing particle trends (square weight) over time for different particle size groups: (a) 0 10m (d) 100300m at an impeller speed of 300 rpm.Fig. 5. Population density distribution shift as the agitator speeds is increased.總結(jié)ParticleTrack 成功用于計(jì)

46、算磨損速率，并且為有機(jī)化合物的破裂核心建立一個(gè)模型“建立顆粒磨損和破裂的模型其重要意義在于，能夠在放大過程中精確預(yù)測(cè)結(jié)晶行為”Modeling Particle Disruption of an Organic Fine Chemical Compound Using FBRM in Agitated SuspensionGlaxoSmithKline, Stevenage, UKKougoulos et al, Powder Technology (2005) 153-158Fig. 7. Influence of power input on net attrition fragmenta

47、tion generation rate.Decrease in dimensionIncrease in population結(jié)晶混合的影響精細(xì)及特種化學(xué)懸浮液和乳化液利用ParticleTrack過程分析技術(shù)（PAT）促進(jìn)更快的開發(fā)、提高工藝信心、在生產(chǎn)過程中控制批次間的一致性。案例：聚烯烴的聚合聚苯乙烯的聚合結(jié)晶和沉淀實(shí)時(shí)在線顆粒分析技術(shù)ParticleTrack作為有用的工具幫助用戶快速評(píng)估工藝條件，確保結(jié)晶過程的最優(yōu)化。案例：混合和溶劑添加混合和磨損優(yōu)化冷卻以改進(jìn)過濾最適宜的冷卻晶種等溫階段控制冷卻最適宜的冷卻放大推論在工廠中，一系列的線性冷卻模擬了理想狀態(tài)TemperatureTi

48、me cooling curveThree linear cooling ramps73根據(jù)經(jīng)驗(yàn)確定最適合的冷卻不同的冷卻速率造成了目標(biāo)顆粒的行為快速冷卻導(dǎo)致小顆粒的成核可控的冷卻導(dǎo)致生長(zhǎng)Barrett, M. et al. (2011). In-Situ Monitoring of Supersaturation and Polymorphic Form of Piracetam during Batch Cooling Crystallization. Organic Process Research & Development, 15(3), 681-687ReactIRFBRMUnwe

49、ighted (a) and square weighted (b) FBRM chord length distributions resulting from cooling a saturated solution of piracetam in ethanol, as a function of cooling rate: (blue) crash cool, (red) fast cool, (black) slow cool.TimeSeedingTimeIsothermal AgeControl CoolingIncrease in Coarse: Growth Dominate

50、d增加冷卻使得生長(zhǎng)占主導(dǎo)地位增加冷卻使得成核占主導(dǎo)地位ParticleTrack 立刻表明二次冷卻曲線導(dǎo)致增加小顆粒的生成（二次成核）通過晶種和冷卻速率的優(yōu)化，產(chǎn)生顆粒分布，從而確保最有效的結(jié)晶工藝Increase cooling rateIncrease in fines generationMore fine countsParticleTrack 幫助用戶理解放大不一致的根本原因，從而改進(jìn)產(chǎn)品質(zhì)量工藝效率（過濾）增加冷卻使得成核占主導(dǎo)地位過濾顆粒數(shù)目、顆粒粒徑和顆粒形狀在過濾過程中都起到重要作用考慮到結(jié)晶過程是不一致的每次產(chǎn)生不同粒徑分布的晶體每次的過濾速率不同容易過濾難以過濾增大小顆粒

51、提高過濾速率Optimization of Pharmaceutical Batch Crystallization for Filtration and scale-upBrian K. Johnson, Carol Szeto, Omar Davidson and Art AndrewsAIChE Annual Meeting, Los Angeles, CA, November 1997優(yōu)化過濾速率特定的濾餅阻力同顆粒粒數(shù)和粒徑相關(guān)聯(lián)原位 ParticleTrack 測(cè)量方式能預(yù)測(cè)下游過濾速率ParticleTrack 能用于預(yù)測(cè)過濾效率由于它對(duì)小顆粒非常敏感優(yōu)化溫度循環(huán)溫度循環(huán)是一種有

52、用的方法，它能解決批次終點(diǎn)小晶體的問題而不會(huì)影響到產(chǎn)量根據(jù)Gibbs-Thomson效應(yīng)，小顆粒比大顆粒更容易溶解，因此在加熱循環(huán)過程中，更小的顆粒先溶解利用 ParticleTrack表征需要升高到多少溫度才能去除小顆粒然后，將溫度降低到初始值，使晶體生長(zhǎng)小顆粒溶解的在線優(yōu)化溫度循環(huán)過程能減少小顆粒到可以接受的水平并且確保批次的重現(xiàn)性Time小顆粒溶解的在線優(yōu)化所確定的批次終點(diǎn)表征“目標(biāo)”分布對(duì)應(yīng)于理想的批次終點(diǎn)能夠?qū)崟r(shí)追蹤分布根據(jù)目標(biāo)分布，確保一致性的下游過濾Dimension mAndre Ridder, PAT from Lab scale to Production, Excella

53、 Pharma, 2008Andre Ridder, PAT from Lab scale to Production, Excella Pharma, 2008Andre Ridder, PAT from Lab scale to Production, Excella Pharma, 2008制藥結(jié)晶結(jié)晶和沉淀制藥公司正面臨著如何以更快的速度、更低的成本和更高的質(zhì)量理解和開發(fā)可放大的結(jié)晶工藝。必須控制結(jié)晶條件以改進(jìn)循環(huán)時(shí)間、優(yōu)化產(chǎn)品產(chǎn)量和質(zhì)量。ParticleTrack 是一個(gè)有用的工具使用戶快速評(píng)估工藝條件以確保優(yōu)化的結(jié)晶過程。案例：結(jié)晶晶種多晶型溶解度和晶種我應(yīng)該在哪里加入晶種？Sol

54、ubilityCurveMSZWtemperaturesolubilitySeed hereSeed here基本原則晶種加入溶解度曲線和介穩(wěn)區(qū)一半的位置（但是表征他們的行為）晶種Solubility curveTemperatureSolubility20C22.5C25CMSZWCool研究目標(biāo)是為了理解過飽和度的變化對(duì)成核和生長(zhǎng)動(dòng)力學(xué)的影響這一點(diǎn)很重要，由于表面積對(duì)體積的比率有變化，在放大階段存在溫度梯度的差異時(shí)三次實(shí)驗(yàn)在不同的晶種溫度（過飽和度）和加入 0.2% wt 晶種晶種并且等溫，冷卻到 20CParticleTrack 和 PVM 用于監(jiān)控成核和生長(zhǎng)晶種Counts/sec 0

55、-20mTrack Nucleation Kinetics TimeCounts/second 0-20m在放大過程中晶種溫度的差異導(dǎo)致成核動(dòng)力學(xué)很大的不同。晶種20C Seeding22.5C Seeding25C SeedingChord Length (m)CountsEndpoint Images at 20C在20C下的終點(diǎn)分布分布的遷移顯示放大階段晶種溫度的重要性問題：批次不穩(wěn)定Christian Airiau, PAT & Chemometrics Team, Stevenage, UK.在中試過程中的8個(gè)批次獨(dú)立的粒徑分布有一些變化整個(gè)8個(gè)批次分布漂移（Sympatec儀器測(cè)量

56、）在結(jié)晶過程中，是否可以用FBRM的數(shù)據(jù)進(jìn)行表征？在結(jié)晶工藝多早可以表征那個(gè)工藝步驟會(huì)造成物性參數(shù)的變化問題陳述利用 ParticleTrack 在線測(cè)量By measuring inline scientists identify the source of process variability將顆粒粒徑分布的數(shù)據(jù)同早期的FBRM數(shù)據(jù)相關(guān)聯(lián)整個(gè)結(jié)晶過程 利用前30分鐘的FBRM數(shù)據(jù) 重新安排數(shù)據(jù)同離線的顆粒粒徑分布作比較和關(guān)聯(lián)前30分鐘的FBRM數(shù)據(jù)同離線的顆粒粒徑分布的數(shù)據(jù)是否有關(guān)聯(lián)Inconsistency 8 Minutes After Seed is Added CLD = 弦長(zhǎng)分

57、布（通過 FBRM)FBRM Chord Length (m)在線 ParticleTrack 數(shù)量分布對(duì)晶種的分散和表面積很敏感利用 ParticleTrack 確定是否晶種不穩(wěn)定在前八分鐘的工藝過程中 ParticleTrack在一個(gè)15小時(shí)的批次中確定8分鐘有問題！ 離線激光衍射技術(shù)對(duì)晶種的變化不敏感放大的結(jié)論 表明能夠直接將離線的變量同在線的數(shù)據(jù)相關(guān)聯(lián) 確定工藝變化的變量來源：加入晶種的階段 使項(xiàng)目組關(guān)注根本原因分析加入晶種的策略 避免任何進(jìn)一步的工作在其他工藝步驟（分離/過濾、干燥） 幫助設(shè)定合適的來源，來解決進(jìn)一步的問題 研究結(jié)果表征粒徑的實(shí)時(shí)變化t=10mins確定設(shè)計(jì)空間的限制

58、能在自然存在條件下，理解顆粒和液滴的變化表征粒徑的實(shí)時(shí)變化t=25mins追蹤變化過程，并且表征必要的時(shí)間，以確保完全轉(zhuǎn)變t=45mins表征粒徑的實(shí)時(shí)變化由不同的工藝條件溫度、濃度、攪拌，計(jì)算轉(zhuǎn)換速率動(dòng)力學(xué)。懸浮和乳化懸浮和乳化在藥物產(chǎn)品的質(zhì)量方面起到重要的作用。對(duì)顆粒和液滴的優(yōu)化和控制能確保配方和工藝設(shè)計(jì)中的質(zhì)量源于設(shè)計(jì)（QbD）。利用 ParticleTrack 過程分析技術(shù)（PAT）促進(jìn)更快速的工藝開發(fā)、提高工藝信心，在生產(chǎn)中控制批次間的一致性。案例：高剪切研磨計(jì)量吸入器（MDI）的均勻化隨溫度變化計(jì)量吸入器（MDI） 懸浮液的穩(wěn)定性隨著表面活性劑的穩(wěn)定和再懸浮液-液乳化的生產(chǎn)（液-液

59、乳化的放大）制藥液體懸浮目標(biāo)一致性和高重現(xiàn)性的加料批次的一致性理解絮凝過程，評(píng)估API的分散、再懸浮的穩(wěn)定性藥物懸浮液快速定量的穩(wěn)定開發(fā)Charles Reichel, Pfizer, CT, AAPS 2005研究對(duì)象利用濕的作用劑、穩(wěn)定劑以及鹽類對(duì)藥物懸浮也進(jìn)行沉淀控制，并且理解絮凝過程材料：懸浮的API吐溫 80，濕的作用劑 嵌段共聚物，穩(wěn)定劑NaCl，控制絮凝表面活性劑的穩(wěn)定和再懸浮TimeChords/Sec階段1階段 2階段 3階段 4階段 5混合（均勻分散）)階段1：穩(wěn)定的攪拌狀態(tài)停止攪拌（開始聚集）階段2：停止攪拌階段3：絮體開始形成停止攪拌（開始沉淀）階段4：絮體形成的上限階

60、段5：最后階段，大的顆粒沉淀得快，小的顆粒沉淀的慢Charles Reichel, Pfizer, CT, AAPS 2005用表面活性劑進(jìn)行穩(wěn)定和再懸浮在懸浮開發(fā)過程中，停止攪拌進(jìn)行評(píng)估(10mgA/ml in 1% 吐溫 80, 1% 嵌段共聚物)在絮凝/團(tuán)聚過程中的實(shí)時(shí)圖像在線 PVM 顯微鏡圖像能優(yōu)化表面活性劑，穩(wěn)定絮體或者團(tuán)聚體的形成和再分散Time: 0minTime: 3minTime: 5min100mm100mm100mmChords/sec in the 1-5 um rangeChords/sec in the 29-86 um range當(dāng)嵌段共聚物的濃度增加，懸浮的小