Understanding Safety Hazards and Scale-up of Chemical Processes

Houston Info Day, June 28, 2017

Simon Rea

Senior Technology &

Applications Consultant

Mettler-Toledo

Agenda

1 Mettler-Toledo AutoChem

2 Calorimetry Review

3 Safe Scale-up of Chemical Processes

4 Introduction to RC1e

5 Questions?

2

Our Solutions Across the Value Chain

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3

Platforms for the Most Productive Researchers 4

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Continuous measurement of chemistry provides critical

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Provides confidence that a

process is safe and scaleable

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Take the best possible sample to characterize

reaction events with offline data

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■ Dosing

Kinetics

One software platform to easily extract, share,

and store key findings

Time

Do

sin

g

Re

actio

n

Agenda

1 Mettler-Toledo AutoChem

2 Calorimetry Review

3 Safe Scale-up of Chemical Processes

4 Introduction to RC1e

5 Questions?

6

Introduction: the First Calorimeter

Ice calorimeter (Lavoisier and LaPlace, 1782–83)

Measurement of heat through melting of ice

( Latent Heat)

Used to study simple chemical processes

(e.g. burning of oil) or metabolism of mammals

Relationship between the amount of oil burned

and the amount of ice that melted

7

TrQr

Tj

Isothermal operation- constant reaction temperature during reactions

- no heat accumulation during exothermic reaction

Exothermic Reaction

Tr ramp

T

t

Tj

TrQr

Tr

Tj

Q

t

t

T

Isothermal Operation 8

Tj

Isoperibolic operation- constant surrounding temperature

- heat of reaction is accumulated first and subsequently dissipated into jacket

Tr

Tj

Qr

Tj ramp

Tr

TjT

t

TrTj

Qr

T

t

tQ

Exothermic Reaction

Isoperibolic Operation 9

Adiabatic behavior- no heat exchange to the surroundings

- heat of reaction is accumulated

- DTadiab is proportional to conversion

Tr

Tj

Qr

DTadiab

Exothermic Reaction

t

t

T

Q

Tj

Tr

Qr

Adiabatic Operation 10

Calorimetric Methods

Heat Flow Trending

Heat Flow Calorimetry

Heat Balance Calorimetry

Power Compensation Calorimetry

Combinations of the above

RTCal™

Differential Scanning Calorimetry (DSC)

Accelerated Rate Calorimetry (Bomb Calorimeters)

…

11

Heat Flow Trending

Simplest approach

Principle: Heat can only flow from hotter to cooler areas

Meaningful results when temperature control and measurement is accurate and precise

Indication of heat flow and reaction power

T1 T2

Heat Flow = f(T2-T1)

12

Q flow

Tjacket

Treactor Qcal

)TT(UAQ jrflow

Qflow: Heat flow through reactor wall [W]

UA: Calibration factor [W/K]

U: Heat transfer coefficient [W/m2K]

A: Heat exchange area [m2]

Heat Flow Calorimetry 13

Heat flow across reactor wall into jacket

Highly accurate and simple method of measurement

UA dependence (requires calibrations, Ta model)

Heat Balance Calorimetry

Simple method

Need for perfect insulation of vessel

Additional heat is counted against

heat of reaction, e.g. stirring, mixing,

dissolution

All losses are counted as heat

consumed

Good accuracy requires low velocity

of oil

Small signal levels

Difficult to get reliable results

Problematic on liter scale

14

oiloiljinjoutr dm/dtcp)TT(Q

Power Compensation

Constant background cooling

Constant input of energy is applied via an

electrical heater to compensate for the

background cooling

During reaction, the heater power is reduced

enthalpy signal

Does not work for endothermic reactions, or

non-isothermal reactions (i.e. during T-ramps)

Maximum reaction power is limited by the

power of the heater

Hot spot unwanted effect, e.g. local

decompositions, secondary reactions …

Qcooling

Treactor Qheater

15

coolingheater r QQQ

Real heat flow trend (qr = qflow + qaccu) with

compensation of heat effects due to heat

accumulation

METTLER TOLEDO reaction calorimeters

with non-isothermal calorimetry

Enthalpy qflow = 14.48 kJ

Enthalpy qflow + qaccu = 14.39 kJ

qr = qflow (purely isothermal with no

compensation of heat effects due to heat

accumulation)

Typical JLR calorimetry systems

Addition

Minimal change of Tr

Importance of Understanding Heat Accumulation

While the total enthalpy stays the same, the real heat trend of a reaction is

obtained only when the accumulation is accounted for

16

Why Calorimetry Brings Value: an Example

Esterification of propionic anhydride with

2-butanol

Tr = 40 °C, rpm = 500

First fill: 2-butanol

Addition of propionic anhydride

over 15 min

Catalyst addition at the endof propionic dosing

17

mr

DT

Tr

Catalyst addBasic information that

represents the reaction

18

mr

DT

Tr

qflow

qflow = energy flow across the reactor wall

qflow = UA*(Tr - Tj)DHr = qflow = 123.1 kJ

qflow represents the total heat that flows across the reactor wall, but does not represent the

way the heat is released

Why Calorimetry Brings Value: an Example

Specific Heat and Accumulation are Key 19

DHr = qaccu = 0 kJ

mr

DT

Tr

qaccu

qaccu = energy that is accumulated over

time due to changing temperature

qaccu = dTr/dt *(m*cp)

qaccu = increasing qaccu = decreasing

Whenever temperature is changing heat is accumulated and released with a delay over

time

Max. heat output

= 400W

Knowing the True Heat Release Pattern 20

mr

DT

Tr

qr

qr = qflow + qaccu = UA*(Tr - Tj) + dTr/dt *(m*cp)

qr = representing the true heat

release of the reaction

DHr = qflow = 123.0 kJ

Only when knowing the accumulated heat it becomes transparent HOW the heat was

released

Max. heat output

= 1,300W

Agenda

1 Mettler-Toledo AutoChem

2 Calorimetry Review

3 Safe Scale-up of Chemical Processes

4 Introduction to RC1e

5 Questions?

21

© Reinaldo M.Machado, rm2technologies LLC, 2008

Numerous physical and chemical processes interact during a manufacturing or

synthesis process

Reaction kinetics

Heat transfer

Thermodynamics

Physical property changes

Mass transfer between phases

Mixing to disperse multiple phases; homogenize a single phase with semi-batch feed

Chemical Development and Scale-up 22

What Controls the Process?

Kinetics

- Rate of chemical or physical reaction

- Function of concentration, temperature, catalyst (= reacting system)

scale independent

Mixing

- Transport of molecules (macro, meso, micro)

- Function of equipment (reactor, inserts, stirrer type, speed, reacting system)

scale dependent

Mass transfer

- Rate of diffusion process of a molecule in or between liquid phase(s)

- Function of concentration, pressure and kLa (equipment, mixing, reacting system)

scale dependent

Heat transfer

- Rate of energy transfer in form of heat: heat generation (reaction)

- Heat removal rate = function of Tr,Tj, U: (equipment + reaction system)

scale dependent

23

Comparing mixing rates with conversion profiles

Acetic anhydride hydrolysis in water at 50°C has mass transfer limitations due to the two

reagents being immiscible – increasing stirrer speed should improve this

Conversion profile trends show reaction progression as measured by heat flow calorimetry

The reaction rate is faster at 250 rpm than 100 rpm for same dosing profile

24

250/500 rpm

100 rpm

Specific Cooling Area for Different Size Reactors

Specific heat transfer A/V decreases exponentially with scale increase

meaning less specific cooling area available for bigger reactors

Data source: Pilot Plant Real Book

25

Jacket Temperature Comparisions (1liter RC1,

1000 liter, 6300 liter vessel)

-100

-80

-60

-40

-20

0

20

40

60

7600 7700 7800 7900 8000 8100 8200 8300 8400 8500 8600 8700

Run Time

Te

mp

- C

Tr - RC1

Ta - RC1

Tj - Ideal 1000 liters

Tj - Ideal 6300 liters

26

Heat Transfer - Heat Removal Batch Reactor 26

27

Xacc = fraction of the total heat of reaction which has not yet been

released

=> depends on Process "addition" design

Max. Thermal Accumulation => Safety

Thermal Accumulation

Qr

QrQr Qr

Reaction temperature = 17.5°C

Time [h]

160

140

120

100

80

60

40

20

-20-0.1

0

0.70.1 0.3 0.5 1.10.9 1.3 1.5

1/2 hrfeed

Heat re

lease [W

]

Scale-up of Dosing Controlled Reaction

Plant vessel: Max 35 W/l heat removal (fixed cooling medium temperature, scale)

How to fit in 140 W/l reaction heat release?

28

Instantaneous reaction at 17.5°C

No accumulation

1L reaction calorimeter

Max. heat flow: 140W

½ hour feed

Total reaction heat

= 40 kJ/mole

Instantaneous reaction at 17.5°C

No accumulation

1L reaction calorimeter

Max. heat flow: 35W

2 hour feed

Total reaction heat

= 40 kJ/mole

Reaction temperature = 17.5°C

Time [h]

2-hr feed

0.5-5

-10

-15

35

30

25

20

15

10

50

2.01.51.0

40

2.50.0

35W

Heat re

lease [W

]

28

Ref.: Thermal Safety of Chemical Processes: Risk Assessment and Process Design by Francis Stoessel

Build

runaw

ay

scenario

Process presents

no thermal risks

Criterium Severity

HIGH DTad > 200°C

Medium 50 < DTad < 200

LowDTad < 50°C and

no pressure build up

Safety Criteria for Severity of Desired Reaction 29

∆Tad is scale independent and is

useful for comparing processes

Steps for a Safe Scale-up Process

1. Can the pilot plant/plant reactor provide sufficient cooling to maintain

constant reactor temperatures during the process?

2. What happens if you are not able to control reactor temperature

(severity of potential energy release → MTSR)?

3. Is there a potential runaway scenario if the process temperature

reaches MTSR (what is the size of your Safety Margin)?

- TD8 – Time to Decomposition for 8 hours → more realistic (one shift)

- TD24 – Time to Decomposition for 24 hours → more conservative (Prof.

Stoessel's recommendation)

30

Ref.: Thermal Safety of Chemical Processes: Risk Assessment and Process Design

by Francis Stoessel

Agenda

1 Mettler-Toledo AutoChem

2 Calorimetry Review

3 Safe Scale-up of Chemical Processes

4 Introduction to RC1e

5 Questions?

31

32Reaction Calorimetry at CIBA 1965 - 1981

1965 First prototype by Dr. Willy Regenass

1975 WFK75 (Wärme-Fluss-Kalorimeter 1975)

1981 BSC81 (Bench-Scale-Calorimeter 1981)

1985 RC1 (Reaction Calorimeter) 1st series

Reactor working volumes range from 80mL to 18L

RC1e for various volumes and pressures

33

Reactor working pressures range from ambient to 350 bar

80mL, ambient

pressure

18L, ambient

pressure

Glass 1L, 6

and 10 bar

SS, HC-22 and Ti

1.5L, 60 and 100 bar

SS, HC-22 and Ti 1L,

150 and 350 bar

33

34

Q = UA ● (Tr - Tj)

UA1, 2: calibration factor

Tr-Tj: driving force for heat exchange

Q = A ● qband

A: heat flux area RTCal™

Qband: heat flux through lower band

Heat Flow vs. RTCal™

Heat flow calorimetry

RTCal™

Method that allows you a real time measurement of

- heat flux through the reactor wall

- using sensors that are attached to the wall of the reactor

(inner wall, towards oil side)

- Horizontal sensor band

- Vertical sensor band

Real Time Heat Flow (W): Qrtc = A * qs0

RTCal™ – How it works

qs0 = the specific heat flow through

the lower band

A = the wetted reactor area as function

of the fill height measured through

vertical sensor band in the back

35

Initial Charge

Styrene

Toluene

AIBN

Polymerization

Quench

Hydro Quinone

Exp. Conditions

Polymerization: Batch

addition, 85°C, 6h

Quench: Batch, 25°C,

1h

SHE

Polymerization: DH to

be determined, max.

heat output

Process info

85°C, 6h Polymerization:

Reaction end point

RTCalTM Heat flow

n

Styrene Polystyrene

85°C, 6h

AIBN, toluene

Polymerization

Change of viscosity

Change of heat transfer coefficient (UA)

Real time data / no calibration

Automated wetted area determination

No sensitivity to viscosity change

versus

S

s

s

Example – Qr with major UA changes 36

Heat flow calorimetry conundrum- Wetted area / fill volume manual determination or “virtual volume”

- How to interpolate UA? Linear, based on torque or “virtual volume”

Example – Styrene polymerization

Addition of AIBN

Addition of HQ to stop polymerization

Heat of reaction

UA Calibration UA Calibration

Heat transfer coefficient UA (linear interpol.)

Time

37

Heat flow calorimetry conundrum- How to interpolate UA? based on torque here:

Heat transfer coefficient UA (based on torque)

Heat of reaction

Time

Example – Styrene polymerization 38

Heat flow calorimetry- Determine heat of reaction Qr and reaction enthalpy

DHr interpolation

UA estimated value between two calibration

pointsReaction enthalpy ΔHr

Linear - 409 kJ

Virtual volume -291 kJ

Torque -372 kJ

39Example – Styrene polymerization

Real time calorimetry RTCalTM

- No calibration, real time data, no Vv challenge

Styrene polymerization

RTCalTM measured heat Reaction enthalpy ΔHr

Measured heat through

sensor-387 kJ (-372 kJ using heat flow/Torque)

40Example – Styrene polymerization

Safe Process Design - iC Safety™

Example: effect of feed rate on MTSR:

Feed rate 4, 6 and 8 hours at 80°C

TIME

MT

SR

How to get from high MTSR worst case to low MTSR for actual process?

1. Batch (MAT) => Semi-Batch (MTSR)

2. Decrease thermal accumulation

(increase temperature, decrease feed rate,…)

Tcf

Max (Tcf) = MTSR actual process

41

42

CH CHCH2 CH2 CH3 CH3

Hydrogenation is one of the most prevalent chemical reactions used because it allows to

form in one single step:

CH3 R

O

CH3 N

R

R

CH3 R

OH

CH3 N

R

H

CH3 N

H

H

or

or

alkenes and alkynes C-C simple bonds

ketones, aldehydes or estersC-O bonds (alcohols)

from imines C-N (amines)nitriles

CH2 N

H

or

Hydrogenations in Fine Chemicals Industry

… with different type of catalysts as example Pd, Pt, Ru, Co, Ni on Carbon, on

alumina, with special ligand and so on depending on the level of selectivity!

42

O

R

O

R

H2+

Pd/C

40° C5 bar

Catalyst: Pd/C 1%

Reagent: Substituted 2-cyclohexene-1-one

Pressure: 5 bar (H2 const.)

Temperature: 40°C (isotherm)

Stirrer speed: 1000-1500rpm

The reaction starts when the hydrogen is added in the reactor

Hydrogenation of a substituted 2-cyclohexene-1-one 43

Stirrer speed

1000rpm - 1500rpm

Gas uptake measurement

Agitation effect

occurs and causes

an increase in the

gas uptake rate

Reaction conditions: substrate: substituted 2-cycloesen-1-one; catalyst: Pd/C 5%;

pressure: 5 bar; temperature: 50°C; ratio catalyst/substrate = 0.8 g· mol-1.

Agitation effect 44

Heat Flow

Gas uptake

Heat Flow signal

correlates with gas

uptake signal and

can be used to

estimate heat output

for safety

considerations

Agitation effect

Reaction conditions: substrate: substituted 2-cycloesen-1-one; catalyst: Pd/C 5%

(~0.050 g); pressure: 5 bar; temperature: 50°C; ratio catalyst/substrate = 0,8 g· mol-1.

Gas Uptake / Heat flow 45

Process conclusions

- Very simple reaction to check the influence of the stirrer speed on the MT

- Mass transfer is a critical control parameter in this reaction, following investigations need to be

done:

- Define optimal mixing conditions: (different blades – stirring speeds)

- Define optimal catalyst species (contact area)

- Define optimal gas dispersion system

46Mass Transfer Limited Reactions

Agenda

1 Mettler-Toledo AutoChem

2 Calorimetry Review

3 Safe Scale-up of Chemical Processes

4 Introduction to RC1e

5 Questions?

47

Time for Questions?

www.mt.com/autochem

community.autochem.mt.com

48