Avoid Batch Failures via Scale Down Simulation of Exothermic Reactions in the Lab

Avoid Batch Failures via Scale Down Simulation of Exothermic Reactions in the Lab Leen Schellekens Applications & Technology Consultants Manager Americas VisiMix - The Influence of Mixing In Your Process July 13th 15th, 2011 Boston MA, USA Outline Introduction: Scale Up of exothermic processes Design of a safe & scalable process Heat Transfer & Mixing Scale Up Case study I: Scale Down Dosing Time Simulation for Plant Recipe of an Oxidation Reaction Safety Case Study II: Design of a Safe Plant Recipe for a Nitroalkane Process Conclusions 1 1

Process Scale Up? Determine effect of scale on chemical process Avoid batch failures: Different impurity profile, selectivity (quality) Different physical characteristics (physical property) Incomplete conversion (yield) Different safety -> runaway 2 Process Scale Up? Small lab reactor - high A/V => high heat removal rate Plant reactor low A/V => low heat removal rate 2

Process Scale Up What controls the rate of our process? What is the smallest rate constant? - Kinetics/chemistry or physics (scale independent) Rate of chemical or physical reaction Function of concentration, temperature: reaction system - Mixing (scale dependent) Mixing rate = speeding up the transport of molecules: macro, meso, micro Function of equipment + reaction system - Mass transfer (scale dependent) Rate of diffusion process of a molecule in or between Liquid phase(s) Function of concentration, pressure and kla: equipment + reaction system - - Heat transfer (scale dependent) Rate of energy transfer in form of heat: heat generation (reaction) Heat removal rate = function of Tr,Tj, U: equipment + reaction system Process-rate determines yield, quality, safety! 4 Process Scale-up From Lab process to Plant process Route Translation of lab recipe to plant recipe by respecting physical rates Recipe in lab equipment + chemistry Scale-up Recipe in plant equipment + chemistry Physical rates in lab equipment Scale down Physical rates in plant equipment 5 Yield Yield Quality Quality Safety Safety Yield Yield Quality Safety Safety GMP 3

What controls the rate of an exothermic process? Calorimetry is used to determine exothermicity of a process and can be used directly to follow reaction progress, start, end Basis for scale up strategy and safe & successful process design Batch Kinetically controlled Qr,W Mass,kg R low, R high Qr,W Mass,kg Non kinetically controlled Semi-batch (dosing) Kinetically controlled Qr,W Mass,kg Qr,W Mass,kg Dosing controlled 6 Scale up - Heat Balance of a reactor The heat produced by the chemical reaction has to be removed by the jacket at any time - heat balance of a reactor Heat accumulation = Heat production - Heat removal or dissipation SCALE UP QUALITY: Batch failures due to unexpected temperature increase outside range of recipe occur when no sufficient heat removal vs heat production SAFTEY: Runaway reactions occur when there is no sufficient heat removal versus heat production Q reaction Tr Q removal = Q flow Tj 7 4

RC1e - Generation 2008: Overview RTCal calorimetry icontrol RC1e software Mixing guidelines ic Safety Universal Control Box (UCB) Outline Introduction: Scale Up of exothermic processes Design of a safe & scalable process Heat Transfer & Mixing Scale Up Case study I: Scale Down Dosing Time Simulation for Plant Recipe of an Oxidation Reaction Safety Case Study II: Design of a Safe Plant Recipe for a Nitroalkane Process Conclusions 9 5

Design of a safe & scalable exothermic process 1. Can the plant reactor control the process during normal operating conditions? (SCALE UP) a) Heat transfer: Characterize exotherm of the process Characterize heat transfer changes due to physical property changes Design recipe to fit plant heat removal capacity b) Mixing: Is process mixing controlled: lab plant? Design recipe according appropriate mixing scale up rules 2. What happens in case of a failure such as cooling failure or stirrer failure? (SAFETY) i.e. abnormal operating conditions What is the adiabatic temperature rise of exothermic process? Can a thermal runaway be triggered? 10 Step 1 to safe process design scale up of process 1. Can your scale-up reactor provide sufficient cooling capacity and maintain a constant reactor temperature? Start by determining the heat generated by the desired reaction. This can be easily determined by running experiments in an RC1/RTCal for scale down simulation of plant reactor run in lab. In desired reaction, Temperature is controlled at set-point,tp, until reaction completion RC1e for heat characterization & scale up RC1 and RTCal for scale down 11 6

Heat Transfer Scale-up For exothermic processes: quick practical approach = make dosing controlled process Heat production exothermic reaction? = = = Heat removal (transfer) by jacket Q / V U. A/V. (Tr - Tj) 12 Dosing time (dosing controlled heat release profile) Heat Transfer Coefficient Temperature mode Temperature coolant Vessel choice Heat Transfer Scale-up Qr / V {W/L} = U A /V (ΔT) = U A/V (Tr-Tj) T Tj Tr Q reaction = 30 W/l (isothermal dosing controlled reaction) What is the required cooling temperature for the same reaction? t Reactor heat transfer specific cooling specific DT needed on jacket coëfficiënt area heat transfer to cool 30 W/L U (W/m 2 K) A / V (m 2 /m 3 ) U. A / V (W/lK) 500 ml ballon 200 86 17.2 2 RC1 150 40 6 5 250 liter 250 6,8 1,70 16 1000 liter 250 4,6 1,15 26 6300 liter 250 2,6 0,65 44 13 7

Heat release [W] Heat release [W] Temp - C Heat Transfer - Heat Removal Batch Reactor Example - Acetic Anhydride Hydrolysis Jacket Temperature Comparisions (1liter RC1, 1000 liter, 6300 liter vessel) 60 40 20 0-20 -40-60 Tr - RC1 Ta - RC1-80 Tj - Ideal 1000 liters Tj - Ideal 6300 liters -100 7600 7700 7800 7900 8000 8100 8200 8300 8400 8500 8600 8700 Run Time 14 Classic Batch Scale up - example Plant vessel: Max 35 W/l heat removal (fixed cooling medium temperature, scale) How to fit in a process with 140 W/l reaction heat release? 160 140 120 100 80 60 40 Reaction temperature = 17.5 C 1/2 hr feed 20 0-0.1 0.1 0.3 0.5 0.7 0.9 1.1 1.3 1.5-20 Time [h] Instantaneous reaction at 17.5 C No accumulation 1 L reaction calorimeter Max. heat flow: 140 W ½ hour feed Total reaction heat = 40 kj/mole 40 35 35W 30 25 20 15 10 5 0 0.0-5 -10-15 Reaction temperature = 17.5 C 0.5 2-hr feed 1.0 Time [h] 1.5 2.0 2.5 Instantaneous reaction at 17.5 C No accumulation 1 L reaction calorimeter Max. heat flow: 35 W 2 hour feed Total reaction heat = 40 kj/mole Time consuming 15 8

RC1 - Real Time Calorimetry: RTCal RTCal real time heat measurement, without calibrations, tedious evaluations = as simple as ph sensor! Heat flow calorimetry RTCal TM calorimetry Automatic, real time: (virtual) volume measurement, U measurement Accurate calorimetry even with UA changes during reaction Non isothermal accurate calorimetry without need for expert * Isothermal process Real Time HTC and volume measurement RC1 measures Overall Heat Transfer Coefficient - Discrete time points via calibrations (standard Heat flow Calorimetry) - Real Time (Real Time heat flux Calorimetry) U changes mainly with: - Reactor content (viscosity, V) 1/hr - Reactor cooling specifics f RC1 also measures Volume Vv RTC 9

Heat Transfer changes U reactor content Determination of f and 1/hr in the RC1 via Wilson plot experiments to understand how the reactor content changes the Overall HTC Scale Up: 1. Determine U Plant for solvent for # R 2. Plot Wilson Plot => f plant = Max Heat Transfer 3. Measure unknown reaction mixture in RC1, determine 1/hr 4. Once f lab and f plant are determined and 1/hr is measured in the RC1lab, the Plant U can be predicted for unknown mixtures U determines heating & cooling power : U. A. (Tr-Tj) Example of solvent study in RC1 f = Max cooling power (reactor specific) 1/hr reduces cooling power due to reactor content Heat Transfer - Scale Down For exothermic processes: quick practical approach = make dosing controlled process Real Time Calorimetry Dosing controlled heat release? Change of Heat Transfer Coefficient? Scale down: simulate dosing time in RC1 for plant cooling 10

Scale down of plant mcpba oxidation run in RC1 Determination and optimization of dosing rate for plant cooling in RC1 Dosing control based on real time heat release adjusted to cooling capacity of plant vessel: RC1 simulates plant vessel cooling => you can predict your batch output! One experiment: 1. Optimised dosing time for plant reactor (in temperature range) 2. Kinetics of plant run - impurity profile, yield, quality prediction of plant run 3. Heat of reaction 4. Safety parameters: Ad temp rise, accumulation for plant run! 20 Scale down of plant mcpba oxidation run in RC1 Process X -> Y = mcpba oxidation Heat to 60 C Cyril Benhaim, PhD, Senior Research Scientist I, Wyeth Research, Canada Dose 20g mcpba and keep Tr at 60 C Goal: find optimal dosing time for plant reactor with 50W/L cooling capacity in RC1 and simulate process of plant in lab (100 ml scale experiment => 5 W is limit) One experiment - set up via PID loop dosing based on Qr RTC: 11

Scale down of plant mcpba oxidation run in RC1 Results of one experiment: 1. Dosing time 2 X 15 minutes - for plant reactor cooling of 50W/L 2. Reaction is quasi dosing controlled, but slows down towards the end Total mass - Dosings of mcpba Heat release 5W equals 50W/l plant Cyril Benhaim, PhD, Senior Research Scientist I, Wyeth Research, Canada Scale down of plant mcpba oxidation run in RC1 Results of one experiment: 3. Total heat of this oxidation process (10 kj / 20 g mcpba) 4. Ad. Temp rise = 42K, almost no thermal accumulation Fast reaction => check scale up for mixing sensitivity! Total mass - Dosings of mcpba Heat release Cyril Benhaim, PhD, Senior Research Scientist I, Wyeth Research, Canada 12

Mixing Scale-up / Down For exothermic processes: Real Time Calorimetry Dosing controlled heat release? Change of Heat Transfer Coefficient? Scale down: simulate dosing time in RC1 for plant cooling For fast reactions (dosing controlled) Scale up is mixing critical? Ensure sufficient mixing at plant scale Test in RC1 via lower stirrer speed or via mixing guidelines scale up rules Study of Mixing Effects via Calorimetry Lab Protocol (Bourne) YES Agitation Rate NO YES Addition Rate No mixing effects NO YES Addition Point NO Micro-mixing control Meso-mixing control Macro-mixing control 25 13

RC1 - icontrol - Mixing Guidelines Mixing guidelines - Reactor + mixing set up optimized for 500 ml reactor - Extended mixing guidelines for understanding and scale up - Full mixing characterization of RC1 500 ml reactor via mixing numbers (Re, P/V, N js, ) and over 200 embedded mixing videos icontrol - Mixing Guidelines Extended mixing guidelines written by one of the leading mixing experts: how to identify and scale-up mixing sensitive processes Full mixing characterization of RC1 500 ml Lab Reactor Video s - provide you a visual understanding of the effect of different mixing set ups before run f.ex. Visualization: 20% polystyrene particles (1 mm) in 400cc isopropanol Numbers allowing you to simulate the exact mixing performance in lab as in your plant vessel mixing, without calculating or determining the mixing performance of your lab reactor 14

Recommended lab set up AP01-0.5 Power curves for the AP01-0.5 3 N D N P = P 2 ND Re = 5 N P 1000 100 10 K N = Re P N P,turbulent Re Re* Re 3 impellers 2 impellers 1 impeller model 3 imp. K=180, Np,turb.=5.55, Re*=36 model 2 imp. K=137, Np,turb.=3.70; Re*=36 model 1 imp. K=107, Np,turb.=1.85, Re*=36 1 1 10 100 1000 10000 Re 15

Reactor T, (Top-Bottom), O C T/ Tmax Determination k mix in RC1 Example mixing rate determination in RC1 (R. Machado, MTAC User forum 2004) Macro mixing Temp. Bottom Heater Temp. Top Hot Temperature Zone Procedure agitation off heater on heater off agitator on record temperature T(top) - T(bottom) 6 4 2 2 Liter Lab Reactor, T =10 cm; Marine Propeller, D =6.9 cm; Fluid =985 cp, =1.25 gm/cc 400 rpm Re = 40 300 rpm Re = 30 500 rpm Re = 50 0 0.0 0.5 1.0 1.5 2.0 2.5 Time, minutes 30 1 0.1 N = 500 rpm, k mix = 2.6 1/min N = 300 rpm, k mix = 0.63 1/min N = 400 rpm k mix = 1.6 1/min k mix = -2.303* Slope 0.01 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Time, minutes Mixing time: k mix and t 95 for the AP01-0.5 1000 data, 3 impellers, 400ml Eqn 1.11-13, 3 impellers, 400ml Eqn 1.11-13, 2 impellers, 400ml Eqn 1.11-13, 1 impeller, 100 ml 0.1 t 95*N 100 k mix/n 0.01 data, 3 impellers, 400ml Eqn 1.11-13, 3 impellers, 400ml Eqn 1.11-13, 2 impellers, 400ml Eqn 1.11-13, 1 impeller, 100 ml 10 10 100 1000 10000 Re 0.001 10 100 1000 10000 Re 16

Scale down for Mixing Sensitive Semi-batch Reactions Simulate plant mixing in RC1 - rules of thumb for semi-batch scale-up Homogeneous Phase with fast Reaction Rates in turbulent regimes Outline Introduction: Scale Up of exothermic processes Design of a safe & scalable process Heat Transfer & Mixing Scale Up Case study I: Scale Down Dosing Time Simulation for Plant Recipe of an Oxidation Reaction Safety Case Study II: Design of a Safe Plant Recipe for a Nitroalkane Process Conclusions 33 17

Build runaway scenario Step 2 to safe process design safety of desired process 2. What is the severity of the potential energy release? In the case of cooling failure, what is the Maximum Temperature of a Synthesis Reaction (MTSR) that can be reached? This is answered with the calculated Adiabatic Temperature Rise ( T ad ) If Severity is low, no significant thermal risks. If high, then one should consider ways to control the process to reduce thermal accumulation and lower the MTSR. RC1e - Delta T Adiabatic ic Safety TM - MTSR With complete loss of cooling capacity, Temperature increases to MTSR 34 Step 2 safety of desired process - criteria Criteria Severity HIGH T ad > 200 C Medium 50 < T ad < 200 Low T ad < 50 C and no pressure build up Process presents no thermal risks Ref.: Thermal Safety of Chemical Processes: Risk Assessment and Process Design by Francis Stoessel 18

Step 3 to safe process design safety desired & decomposition 3. Is there a potential runaway scenario? If the reactor reaches the MTSR, will that trigger a decomposition reaction? The decomposition reaction can be characterized with DSC. ic Safety TM Ref.: Thermal Safety of Chemical Processes: 36 Risk Assessment and Process Design by Francis Stoessel ic Safety - One Click to Safety Assessment click to assess safety assessment desired r Assessment 19

Tcf MTSR Safe Process Design - ic Safety Safe Process Design - ic Safety Example: effect of feed rate on MTSR: Feed rate 4, 6 and 8 hours at 80 C 130 125 120 115 110 105 100 95 90 85 0 2 4 Max (Tcf) = MTSR actual process 6 8 10 12 TIME How to get from high MTSR worst case to low MTSR for actual process? 1. Batch => Semi-Batch 2. Decrease thermal accumulation (increase temperature, increase feed rate, ) 20

Safe scale up of Nitro-alkane chemistry MT Webinar April 2009 - Kevin J. Drost, WeylChem, USA X + N O - O H H CHO Base/Solvent + R NO 2 R H R CHO X = Cl, Br R = alkyl X + O N - O H + Salt + Acetone oxime Salts of Nitro Propane are Unstable- JACS, 77, 1114-6 (1955) In-situ Formation of Potassium Nitro propane? Bromo vs Chloro Derivatives Temperature of reaction? Conditions? Safe scale up of Nitro-alkane chemistry MT Webinar April 2009 - Kevin J. Drost, WeylChem, USA 21

Safe scale up of Nitro-alkane chemistry Modify process to make it safe? MT Webinar April 2009 - Kevin J. Drost, WeylCh Start temperature undesired (runaway reaction) Safe scale up of Nitro-alkane chemistry MT Webinar April 2009 - Kevin J. Drost, WeylChem, USA 22

Safe scale up of Nitro-alkane chemistry MT Webinar April 2009 - Kevin J. Drost, WeylChem, USA Total heat simulation of batch process conditions 3 Start temperature undesired (runaway reaction) Safe Scale-up of Nitroalkane Chemistry RC1 results: Standard Data for 3 reactions performed over 2-week period KOH feed time U Cp Hr (mole SM) T adiabatic 60 145 W/m 2 K 3.4 J/kgK 465 kj/mole 77C 90 143 W/m 2 K 3.3 J/kgK 467 kj/mole 78C 180 144 W/m 2 K 3.4 J/kgK 472 kj/mole 77C METTLER TOLEDO Webinar April 2009 - Kevin J. Drost, WeylChem, USA 23

Safe Scale-up of Nitroalkane Chemistry ic Safety results: trends Thermal Accumulations Thermal Conversions Increase in dosing time from 60 to 90 to 180 minutes, decreases Max Thermal accumulations from 52 to 48 to 38 to 31 %. METTLER TOLEDO Webinar April 2009 - Kevin J. Drost, WeylChem, USA Safe Scale-up of Nitroalkane Chemistry ic Safety results: trends Tcf = Temperature in Case of Cooling Failure, with Max (Tcf) = MTSR Increase in dosing time from 60 to 90 to 180 minutes, decreases MTSR from 84 to 82 to 74 C. METTLER TOLEDO Webinar April 2009 - Kevin J. Drost, WeylChem, USA 24

Safe Scale-up of Nitroalkane Chemistry ic Safety Desired Reaction: from one RC1 run (Dosing time of 180minutes) ) ic Safety Secondary Reaction: from 2 dynamic DSC runs TD24 = Temperature at which time to Max rate under adiabatic conditions or time to explosion = 24 h MTT = Max Technical Temperature (Bp) Safe Scale-up of Nitroalkane Chemistry ic Safety Secundary reaction TD24 from 2 Dynamic DSC runs 25

KOH Feed (gm) Safe Scale-up of Nitroalkane Chemistry ic Safety results - Real process conditions = semi-batch dosing process Max Tcf = MTSR < 80C Temperature @ Cooling Failure (TCF) Max desired temperature after Heat-up TCF ( o C) KOH Feed TCF Max desired temperature during feed - Instantaneous simulation of Tcf (temperature in case of cooling failure) - This reaction is sensitive to temperature both during the feed and digest» More coupling products after heat-up» More hydrolysis products during feed - No issues with safety: criticality class 1» MTSR decreased to 80C vs lowest DSC 167C => Large safety margin! METTLER TOLEDO Webinar April 2009 - Kevin J. Drost, WeylChem, USA Safe Scale-up of Nitroalkane Chemistry Simulation of batch addition, MAT = 147C dosing time 180 minutes, MTSR = 74C dosing time 60 minutes, MTSR = 84C dosing time 60 minutes, MTSR = 82C 26

Safe scale up of Nitro-alkane chemistry CONCLUSIONS Reaction Conditions - Feed rate >180 min to control cooling - Heat-up rate (Will allow to self heat) icontrol TM - Reproducibility of Data - Ability to Change Program on the Fly - Very nice graphics and easy to navigate - Exotherm not observed in the lab ic Safety TM - Accuracy of Data -Run to Run - Quick Calculations of Useful Data - More Data available to the Ordinary Chemist - Win RC Data vs. ic Safety TM Pilot Run - 750 Gallon Reactor w/30-35w/l Cooling Capacity - Feed completed in 120minutes - Used heat of reaction to aid heat-up - 90+ % yield MT Webinar April 2009 - Kevin J. Drost, WeylChem, USA Conclusions Scale Down Simulation of exothermic reactions in RC1 RTCal / RC1 enables quick and easy scale down of plant run in lab - Heat balance lab plant - Mixing lab plant - Safety Quality - QbD design space validation Mixing guidelines provides fully characterized 500 ml RC1 reactor for mixing ic Safety provides safety information from RC1 data in one click : - Thermal Accumulation and Temp. (cooling failure) for process recipe - Thermal Runaway scenario - Criticality class safety assessment 53 27

Acknowledgements Cyril Benhaim, Wyeth Research, Canada Simon Rea, Mettler-Toledo AutoChem Inc. Kevin J. Drost, WeylChem, USA Dominique Hebrault, Mettler-Toledo AutoChem Inc. Nilesh Shaw, Mettler-Toledo AutoChem Inc. Dr Reinaldo Machado, rm2 technologies Prof. Francis Stoessel, Swiss Institute of Safety 54 Thank You Questions? Remarks? 55 28

Conclusions 1. Early Identification of Thermal Risks - Chemical R&D The full process must be understood in detail for risk assessment: RC1 2. Ensure a safe & scalable process design Process Safety & Scale up Design of inherent safe & scalable processes at scale is critical New technologies & accurate instruments (RC1 scale down approach) help accelerate & simplify 3. Assurance of safe working conditions - Manufacturing Balance between risk / hazards & operational plant reactor performance is key skill: New software (ic Safety) allows for quick and visual understanding of different scenarios 56 Calorimetry Process Scale up/down: Heat release - Cooling capacity determination Process Safety Total heat => T adiabatic 29

Calorimetry 1. SAFETY assessment of chemical processes (safety) - Reaction enthalpy ( H) - Max heat (rate) output - Thermal conversion - thermal accumulation profile (max thermal accumulation point) - T Adiabatic => MTSR (assessment of safety criticality class) - Heat capacity (Cp) determination of reaction mixtures - Heat transfer coefficient (UA) determination of reaction mixtures - Induction periods 2. Scale up studies like mass transfer, heat transfer, mixing, material characterization ( chemical engineers) - Heat transfer measurement and Wilson plot heat transfer assessment - Measure impact of different kla on reaction rate - Determination of kla values - Measure impact of different mixing on reaction rate 58 Calorimetry 3. Calorimetry data gives great qualitative insight into chemical processes/rates ( process chemists) - Start/end points of reactions - reaction progress - induction periods - Measurement of heat: safety scale up SCREENING - Thermal conversion accumulation of process - Can be used directly to determine kinetics: kinetics in real time! - Identifies all thermodynamic effects very accurately in total process => up to 80 % of physical & chemical reactions are either exothermic or endothermic? 4. Physical phenomena can be identified and measured (crystallization - material characterization - fundamental research) - Detection of crystallization temperatures + measurement of crystallization heat - Measurement of solubility /MSZW data - Detection of gas evolution (endothermic signal) - Detection and measurement of heat of solution: usually endothermic - Detection and measurement of mixing heat, dosing heat, adsorption,vle, 59 30

What is an RC1? Thermostat - accurate and sensitive temperature control - heat flow trending for real time (no sampling) determination of start/end of reaction - Stirrer control & torque measurement Automated dosing - Gravimetric dosing - Volumetric dosing - ph control dosing - Distill control material removal RC1e ic software - 24/7 - easy to use - advanced controls - data logging - intuitive analysis - one click reporting - reproducible, traceable - Seamless integration of in-situ analysitcs Universal Control Box - ph - gas evolution - relay control - turbidity - dosing Calorimetry - Heat flow trending (Tr-Tj): EasyMax/MultiMax/LabMax - Heat flow calorimetry (kj/w): MultiMax/RC1 - Heat flux sensor for real time calorimetry : RC1 (without calibrations) (W in real time/kj) 60 Reactor - Cover - tank style, different sizes, pressure ranges - optimized mixing inserts (stirrers/baffles) - Optimized probe positions RC1e Calorimeter - Generation 2008 RTCal calorimetry icontrol RC1e software Mixing guidelines ic Safety Universal Control Box (UCB) 31

RC1 High Performance Thermostat Fast, powerful thermostat is the essential element for safe and accurate reaction control. - Measures Tr, Tj, Tc every 2 seconds - Oil circulation in jacket is up to 100 L/min (compared to 15 30 liter/minute for a cryostat) - Extremely fast response time - 6 liter of cold oil reservoir - Can remove 6000 W/L (6kJ/sec/L) - Heating power: 2 kw - Accurate temperature control - Max. error ( 0.5 C - 1.0 C) - Resolution: 10 mk for Tj; Tr: 0.2 mk (<100 C) - Noise: 0.2 W (1L water at 25 C) Why thermostat? 10 L Thermostat oil 4L pre-heated 6L pre-cooled Controlled via 3200 stepper motor Cooling of exotherms: 1) the HP thermostat has a container of 6 liter of cold oil ready to inject 2) at speed of open control valve = 60ml/sec 3) or even faster in emergency cooling, when safety valves opens too = 600ml/sec => system can remove up to 6000W/liter! Flow rate of thermostat oil = up to 1.2 L/s (up to 100 L/min) => fast and precise temperature control A variety of temperature control algorithms are > 20 years fine tuned for each reactor and proven! (no overshoot!) heating power: 2 kw or 4kW for HighTemp 63 6 L cryostat oil (Julabo LH85 - BIG) All at the same temperature, the same cooling oil Cooling of exotherms: 1) All the oil has to be cooled first, before the reactor can be cooled 3) In case of emergency, no additional pathway or faster cooling available Flow rate of cryostat oil = 0.25-0.5L/s ( about 15-30 L/min) => slower & less precise temperature control Limited temperature controls, PID controller still needs to be fine tuned for each reactor set up NO heating possible! 32

Why thermostat? RC1e example The High Performance Thermostat - measures Tr, Tj, Tc every 2 seconds - optimized PID temperature control/reactor - heating power: 2 kw or 4kW for HighTemp -sensitive temperature measurement - Calorimetry - resolution of Tr-Sensor = 0.0001 K internally in RC1 electronics, 0.001K visible in PC SW => essential for dtr/dt as a basis for Qaccu. - Noise: 0.2 W (1l water at 25C) - Max. error ( 0.5 C - 1.0 C) - precise temperature control due to extremely fast oil circulation in jacket is up to 100 L/min or 1.2 L/sec - extremely fast response time for exotherms: 1) the RC 1 thermostat has a container of 6 liter of cold oil ready to inject 2) at speed of open control valve = 60ml/sec 3) or even faster in emergency cooling, when safety valves opens too = 600ml/sec => system can remove up to 6000W/liter! 64 Ready to go reactor for Precise & sensitive Calorimetry Fast & precise temperature control SAFEST working environment HP thermostat - safety RC1e Commercial reactors 33

Process measurement & Control - Torque Torque is measure in real time (Rt) Rt is an indicator for viscosity changes Rt value can be used in expressions f.ex Cool until Rt < x After calibrating Rt for different viscosities, a true in situ & real time viscosity value may be obtained via expression Viscosity = f (Rt,T) Viscosity can be determined in situ & in real time via calibrating Rt Process measurement & Control ph and more Universal Control Box - Inputs - Outputs - ph - Relay - Balances For conductivity, turbidity, redox, ph, Add sensors on the fly Automatic ph control by: - Ramp by rate - Hold actual value - Change rate of current ramp - Pause running ramp - Continue paused ramp - Switch off FCE Acid (Pump) FCE Basic (Pump) Full flexibility in automation & measurements of your experiments 34

Process measurement & Control Dosing Gravimetric or volumetric dosing Simultaneous temperature measurement of addition reagent via T- glass ware & pt100 Fully automated controlled dosing actions: - Ramp by duration - Ramp by rate - Hold actual value - Change rate of current ramp - Pause running ramp - Continue paused ramp - Switch off RC1 Real Time calorimetry RTCal TM RTCal Real Time heat measurement, without calibrations, tedious evaluations Heat flow calorimetry* RTCal TM calorimetry Automatic, real time: (virtual) volume measurement, U measurement Accurate calorimetry even with UA changes during reaction (i.e. polymerizations) Accurate non-isothermal calorimetry without need for an expert * Isothermal process 35

RTCal - Real value Calorimetric data on-line in real time => save time, enable scale down Real time measurement of Qr RTC, no evaluation needed Optimization of your reaction in real time (dosing based on Qr RTC) No calibrations, no change to recipe No entry of Vv, fully automated experimentation Enable accurate calorimetry measurement in all process conditions Non isothermal Viscosity or UA changes Volume changes/ foaming Very exothermic & fast reactions Additional, orthogonal method to heat flow calorimetry 2 independent data sets from 1 experiment Gain confidence, time, and expensive material No uncertain evaluations, better & faster decisions RTCal The walk up tool / easy to use Makes calorimetry straightforward to handle, easy to use Short training times, more people can apply Fast & more accurate data collection & interpretation RC1 - RTCal and Synthesis RTCal brings a wealth of real-time data to organic synthesis. From one experiment, and in real time, it is possible to monitor start- and endpoints of reactions, measure the heat release, heat transfer coefficient and specific heat capacity. Online More accurate reaction start and end, delayed initiation Qr, max. heat output H (integrated Qr), - 487 kj/kg Heat transfer coefficient (UA) Reaction heat capacity (Cp) End of reaction T adiabatic 233 K MTSR (batch): 273 C Thermal accumulation 36

ic Safety ic Safety TM for Evaluation of Thermal Risks of a Chemical Reaction at Industrial Scale* MTSR semi-batch trend Integration of DSC data Criticality index analysis Source: Thermal Safety of Chemical Processes: Risk Assessment and Process Design, Francis Stoessel, 2008, ISBN 978-3527317127 Key features of ic Safety 5.0 ic Safety provides the ability to automatically: - Determine the heat of reaction and heat removal (w/wo dosing heat) - Determine if the dosing rate fit for plant heat removal limit or not - Calculate & trend thermal conversion - Calculate & trend the thermal accumulation - Calculate & trend Temperature in case of Cooling Failure (Tcf) - Display the safety runaway graph Calculate adiabatic temperature rise and MTSR (Maximum Temperature of the Synthesis Reaction) Calculate Max Achievable Temperature (MAT) - Display the criticality index Calculate TD24 form DSC or other data Calculate automatic Max Technical Temperature from lowest boiling point 37

What: Key Features of ic Safety 5.0 Automatically converts data into safety parameters ic Safety Features Summary of all reactions evaluated 38

ROI of ic Safety 5.0 Safety More robust & safe process = reduced risk at scale Identifies the potential of a runaway reaction and quantifies its severity Helps understanding how a thermal runaway is triggered and quantifies its probability Provides better understanding how losing the control of a reaction can be prevented Supports the design of control strategies to protect against the consequences of a thermal runaway Speed faster safety analysis and reporting = faster time to market ic Safety is a module that significantly shortens the data analysis time Provides essential information required for safety and risk assessment in an easy-to-understand graphical format Designed as a tool for novice and experienced users Conclusions why RC1? Why? RC1 for process understanding Increase personal productivity Speed development time RC1 for Process Scale Up Reduce batch failures / rework of exothermic processes Scale up cost reduction RC1 for Process Safety Avoid incidents/outsourcing costs Ensure personal safety in the lab 77 39

Conclusions ROI for RC1? Return On Investment can be quantified via ROI worksheet A general ROI for RC1 for Mid size Chemical Company example = Pay back in 6-12 months 78 Executive summary Why invest in safety? Conclusions Return On Investment can be calculated via ROI worksheet A general ROI for RC1 for Mid size Chemical Company example: = Pay back in 7 months 79 40