量热法 安全化工工艺设计的必要工具

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1、Calorimetry:An Essential Tool in the Design of Safe Chemical ProcessesDesign of Safe Chemical ProcessesSteve Hallam,Process Safety,Supply Chain,y,pp y,Pharmaceutical Development,Macclesfield,UKOverviewnHistoryOverview010,XianEvaluation of the Initial ProcessChemistryTPCP 20yExperimental ResultsConcl

2、usionsrkshop STModified ProcessChemistryonal WorkyExperimental ResultsConclusionsInternatioOverall Conclusions3rdIHistorynProcess developed by external contractor.History010,XianNo development work or hazard assessment carried out within AstraZeneca.TPCP 20Process developed by the initial contractor

3、 given to a second contractor.rkshop STSecond contractor initially very keen,then lost interest very quickly.onal WorkQuestion for AZ.Why the loss of interest?.The answer was provided by Screening,InternatioIsothermal and Adiabatic Calorimetry.3rdIProcess Developed by First ContractornProcess Develo

4、ped by First ContractorYHXYHXO2Nnitric acid/acetic acid010,XianNitric acid(1.2 equiv)added to acetic acid,temperature 40-42oC.YXzYXz40-45degCTPCP 20Starting material(1.0 equiv)added in portions over 2 hours,temperature maintained at 40 45oC.rkshop STOn completion of addition,batch stirred for 10 min

5、utes at 45oC.Note:If cooling is lost the batch is drowned out into water.onal WorkWater added to the batch over 15 minutes.Cooled to 0 5oC and precipitated product filtered off.InternatioWashed with water until pH of filtrates is greater than 3.Pulled dry on the filter and stored as a wet paste(typi

6、cally 15%w/w).3rdINote:The presentation will not cover the water addition or final isolation.Addition of Nitric AcidnNitric acid added evenly to acetic acid over 20Addition of Nitric Acid010,XianNitric acid added evenly to acetic acid over 20 minutes,temperature maintained at 40oC.Looking at:TPCP 20

7、Looking at:Heat of ReactionThermal Stabilityrkshop STThermal StabilityGas Evolutiononal WorkInternatio3rdIAddition of Nitric Acid:Heat of Reaction/GEl tinGas Evolution010,XianTPCP 20rkshop STResultsReaction is exothermiconal WorkReaction is exothermic.No delayed onset and no accumulation.No gas evol

8、ution.Heat of reaction 17kJ/mol starting materialInternatioHeat of reaction-17kJ/mol starting material.Adiabatic temperature rise 18K.Maximum batch temperature 60oC.3rdIConclusionNo hazard during normal processingAddition of Nitric Acid:Thermal Stabilityn010,XianTPCP 20rkshop STResultsonal WorkLarge

9、 exotherm from 135oC,ie on the plant scale could be seen from as low as 75oC.Gas evolution indicated from around 100oCInternatioGas evolution indicated from around 100oCConclusionNo hazard during normal processing3rdIAddition of Nitric Acid:What Information has“Calorimetry”given us?nExothermic desir

10、ed reaction(Isothermal calorimetry)has“Calorimetry”given us?010,XianExothermic desired reaction(Isothermal calorimetry).Reaction is immediate and there is no accumulation(Isothermal calorimetry)TPCP 20calorimetry).Very exothermic decomposition reaction,generating lots of gas (Screening calorimetry)r

11、kshop ST(Screening calorimetry).On the plant scale the decomposition exotherm could be seen from as low 75oC,i.e.still above the proposed operating temperatureonal Worklow 75 C,i.e.still above the proposed operating temperature(Screening calorimetry).The adiabatic temperature rise associated with th

12、e desired reaction is Internatiopnot sufficient to raise the batch to temperatures where the decomposition reaction could be accessed(Isothermal Calorimetry)3rdIAddition of Starting MaterialnStarting material added in 24 equal aliquots over Addition of Starting Material010,Xiangqq65 minutes,temperat

13、ure maintained at 40oC.Looking at:TPCP 20Looking at:Heat of ReactionThermal Stabilityrkshop STThermal StabilityGas Evolutiononal WorkInternatio3rdIAddition of Starting Material:Heat of Reaction/GEl tinGas Evolution010,XianTPCP 20rkshop STResultsReaction is exothermiconal WorkReaction is exothermic.N

14、o delayed onset and no accumulation.Heat of reaction-83kJ/mol starting material.Adiabatic temperature rise 70KInternatioAdiabatic temperature rise 70K.Maximum batch temperature 110oC.No gas evolution.Conclusion3rdIConclusionNo hazard from heat of reaction/gas evolution during normal processing.Addit

15、ion of Starting Material:Thermal Stabilityngy010,XianTPCP 20rkshop STResultsLthf89oChi hthltlld bonal WorkLarge exotherm from 89oC which on the plant scale could be seen from as low as 29oC,that is below the proposed operating temperature of 40-45oC.Gas evolution indicated from around 78oC Residual

16、pressure ofInternatioGas evolution indicated from around 78oC.Residual pressure of 327psig indicates significant gas evolution.Conclusion3rdIConclusionFurther adiabatic thermal stability testing required.Addition of Starting Material:Thermal nBeca se all the nitric acid is added at the start the the

17、rmalStability Testing010,XianBecause all the nitric acid is added at the start,the thermal stability of reaction mixtures a)after 25%TPCP 20a)after 25%andb)after 100%rkshop STb)after 100%of the starting material had been added were looked at.Thitd tithtonal WorkThis was to determine the worst case.I

18、nternatio3rdIAddition of Starting Material:Carius Tube Testsn010,XianTPCP 20rkshop STAfter 25%of Starting material After 100%of starting materialResultsonal WorkLarge exotherm from 86oC.Large exotherm from 85oC.Gas from around 81oC.Gas from around 80oCInternatioConclusionEven though the decompositio

19、ns are different,there is no apparent significant 3rdIdifference in the heat and gas evolved.Therefore need to investigate both mixtures further.Addition of Starting Material:ARC Testsn010,XianTPCP 20rkshop STAfter 25%of Starting material After 100%of starting materialResultsonal WorkSelf heating fr

20、om 50oC,Self heating from 50oCreaching 59oC after 16.7 hours.reaching 60oC after 3 hours.Rapid gas evolution from 93oC.Rapid gas evolution from 91oC.InternatioResidual pressure 53 bar Residual pressure 33 bar.ConclusionNo apparent difference in exotherm and gas evolution onset temperatures However v

21、ery3rdINo apparent difference in exotherm and gas evolution onset temperatures.However very significant difference in the speed of the decompositions.With 100%of the starting material charged,the exotherm is much faster.This is therefore the worst case.Addition of Starting Material:What Informationh

22、“C lit”i?nVery exothermic desired reaction(Isothermal calorimetry).has“Calorimetry”given us?010,Xiany(y)Reaction is immediate and there is no accumulation(Isothermal calorimetry).TPCP 20Very exothermic decomposition reaction,generating lots of gas(Screening calorimetry).rkshop STThe reaction mixture

23、 is thermally unstable at the proposed operating temperature(Adiabatic calorimetry).onal WorkIf cooling is lost the batch will self-heat to its maximum temperature and pressure in less than 5 hours(Adiabatic Internatiocalorimetry).The decomposition reaction is un-ventable and would result in 3rdIdam

24、age to the plant(Adiabatic calorimetry).ConclusionsnWe have a process that is decomposing exothermicallyConclusions010,XianWe have a process that is decomposing exothermically at the proposed operating temperature and which will runaway in approximately 5 hours.TPCP 20The runaway reaction will cause

25、 significant damage to the plant.rkshop STThe process is not safe to operate on a significant scaleonal WorkInternatio3rdINext StepsnContacted original contractor to share our findings and Next Steps010,Xianggask:Why operate by charging all the nitric acid at thtt?TPCP 20the start?Why operate at a t

26、emperature where the reaction mixture is thermally unstable?rkshop STreaction mixture is thermally unstable?Contacted second contractor to share our findings and ask:onal Workask:Why they decided not to operate the process?Internatio3rdIAnswersnOriginal ContractorAnswers010,XianControlled addition o

27、f nitric acid had not really been evaluated.At lower operating temperatures the reaction would stop.They h dlllit th t tddbtlTPCP 20had a small scale experiment that stopped and subsequently restarted.This resulted in material being ejected from the flask.rkshop STSecond ContractorThey had had a sma

28、ll scale reaction runaway.onal WorkThey had had a small scale reaction runaway.Internatio3rdIFurther Process Development within AstraZeneca nControlled Addition of Nitric Acidp010,XianResultsOne isothermal calorimetry experiment carried out.Same stoichiometry reaction temperature 40oCTPCP 20stoichio

29、metry,reaction temperature 40 CHeat of reaction determined as 15kJ/mol Starting Material.This is much lower than the heat of reaction measured previously,rkshop STThis is much lower than the heat of reaction measured previously,that is 83kJ/mol Starting Material but is very close to the value of 17k

30、J/mol measured for the addition of nitric acid to acetic acid.DSCf thil t ddt ll i dit d thdiddtonal WorkDSC of the isolated product clearly indicated the desired product had not been generated.ConclusionInternatioConclusionControlled addition of the nitric acid does not generate the desired product

31、.The reaction probably needs a high concentration of nitric id idtk3rdIacid in order to work.Further Process Development within AstraZenecanLower Reaction TemperatureFurther Process Development within AstraZeneca010,XianpResultsOne isothermal calorimetry experiment carried out.Same TPCP 20ypstoichio

32、metry,reaction temperature 20oC.Heat of reaction determined as 93kJ/mol Starting Material.This is very similar to the heat of reaction measured previously that isrkshop STvery similar to the heat of reaction measured previously,that is 83kJ mol Starting Material.Reaction was immediate and there was

33、no accumulation.onal WorkDSC of the isolated product clearly indicated the desired product had been generated.The yield has also been increased!ConclusionInternatioConclusionThe reaction does proceed at 25oC,generating an increased yield of the desired product.3rdIIs the Process,using a Lower Reacti

34、on Temperature Safe to Operate?nQuestion Hhthddtittfft dthTemperature,Safe to Operate?010,XianHow has the reduced reaction temperature affected the thermal stability of the reaction mixture?Carius Tube testsTPCP 20Carius Tube testsrkshop STonal WorkInternatioRM generated at 40oC RM generated at 20oC

35、 Exotherm from 89oCExotherm from 88oC3rdIExotherm from 89oC Exotherm from 88oCGas from ca 78oCGas from ca 79oC Is the Process,using a Lower Reaction Temperature Safe to Operate?nQuestion Temperature,Safe to Operate?010,XianHow has the reduced reaction temperature affected the thermal stability of th

36、e reaction mixture?TPCP 20ARC Test ExperimentSample charged to Ti bomb rkshop STpgand temperature raise to 30oC.Resultonal WorkReaction mixture self-heated from 30 to 36.4oC over 63.8 hours.Reaction temperature raised to 50oC.Reaction mixture self-heated to 224oC over the next 48.8hours.Internatio3r

37、dIIs the Process,using a Lower Reaction Temperature,Safe to Operate?:What Information has“Calorimetry”nSafe to Operate?:What Information has Calorimetry given us?010,XianHeat of reaction at 20oC is the same as at 40oC:Isothermal calorimetry.TPCP 20Reaction is immediate and there is no accumulation:I

38、sothermal calorimetry.The reaction mixture is thermally much more stable at therkshop STThe reaction mixture is thermally much more stable at the proposed operating temperature:Adiabatic calorimetry.The rate of self-heating is very slow at 30oC:Adiabaticonal WorkThe rate of self heating is very slow

39、 at 30 C:Adiabatic calorimetry.If cooling is lost the batch will self-heat from 30 to 36oC over Internatio60hours:Adiabatic calorimetry.3rdIConclusionsnIn order to operate a process safely we need to know:Conclusions010,XianIf heat is generated and if so how much,how fast and when.If gas is evolved

40、and if so how much,how fast and when.TPCP 20Whether the starting materials,mixtures and products,used and generated in the process,are thermally stable under the dtiditiithtf fiblrkshop STproposed operating conditions or in the event of feasible maloperationsCalorimetry can provide the heat generati

41、on and thermal stabilityonal WorkCalorimetry can provide the heat generation and thermal stability information and the addition of a gas measuring system to an isothermal calorimeter will provide the information relating to tiInternatiogas generation.It is hoped that this presentation has clearly shown the benefits of calorimetry in terms of both understanding why a process is3rdIcalorimetry in terms of both understanding why a process is not safe and in designing one that is.