Practical Applications of Distillation Modeling in DynoChemCarolyn Cummings5.13.09

Presentation Outline

Background

Case Studies– Distillation Utility as an Operations Tool

• Determining Endpoint of an Azeotropic Distillation in MTBE- Methanol

– Distillation Utility as a Development Tool• Assess Premature Crystallization during Distillation• Process Improvements Enabled by Dynochem

DynoChem at AmgenSmall Molecule Process Engineering & Development Group

– Software has been in use for 1 year by 4 Engineers– Group meets Phase 1 and Phase II deliveries in-house– Coordinates Tech Transfer to large-scale production

Distillation Utility an Instant Favorite– Distillation among most time consuming of unit operations– Typically, little quantification around distillation completed at time of first GMP

delivery– D.C. generates of high quality data very quickly & with minimal effort

Role of Dynochem in Operations and Development– Answering the Immediate Questions: How long? How much?– Optimization– Process Characterization

DynoChem Calculations

Antoine Equation– Relates saturated vapor pressure of pure components to

Temperature

UNIFAC– UNIversal Functional Activity Coefficients– Provides a method for calculating activity coefficients

based on component functional groups– Account for non-ideality of solvent mixtures

TCB -A )Pln( vap+

=

Case Study 1Case Study 1

Azeotropic DistillationAzeotropic Distillation MTBE MTBE Methanol Solvent SwapMethanol Solvent Swap

MTBE-Methanol Solvent Swap

Model Input Parameters – Equipment Specific

• Vessel UA• Heat Transfer Fluid Supply Rate

– Process Specific • Jacket Temperature Upper Limit 40°C• Initial Batch Composition 100% MTBE• Endpoint Concentration of MTBE <1% MTBE• Minimum / Maximum Fill Volume 5L / 100L• Pressure as necessary

Model Output– Batch profile as a function of time

• Composition• Temperature• Volume

Mixture Boiling Point from Tx-y UtilityBoiling Point of MTBE‐MeOH Mixtures

0

10

20

30

40

50

60

70

0 10 20 30 40 50 60 70 80 90 100

% MTBE

Temp (°C)

1000 mbar

750 mbar

500 mbar

250 mbar

X-Y Diagram from Tx-y Utilityx-y diagram for MTBE-MeOH System

0

10

20

30

40

50

60

70

80

90

100

0 10 20 30 40 50 60 70 80 90 100

Liquid wt% MTBE in MeOH

Vap

our w

t% M

TBE

1000 mbar750 mbar500 mbar250 mbar

Evaluation of Distillation Rates

PressurePressure TimeTime ModeMode Final Batch Final Batch TempTemp

350 mbar 36.6 hr Constant Volume 40°C300 mbar 11.4 hr Constant Volume 36°C250 mbar 6.7 hr Constant Volume 32°C200 mbar 4.6 hr Constant Volume 28°C150 mbar 3.0 hr Constant Volume 22°C150 mbar 3.0 hr Put and Take: 90% 22°C

150 mbar 3.4 hr Put and Take: 50% 22°C150 mbar 3.7 hr Put and Take: 25% 22°C

Rate decreases with decreasing Pressure: More Driving Force!Rate varies minimally with Fill Volume

Distillation Rates with Variable Fill VolumeFill Volume does not effect overall distillation time, provided Vinital = Vfinal

Model Output: 150 mbar

0

5

10

15

20

25

30

0 0.5 1 1.5 2 2.5 3 3.5 4

Time (hrs)

Com

pone

nt M

ass

(kg)

MeOH: Constant Volume

MeOH: Put & Take 50%

MeOH: Put & Take 25%

MTBE

Distillation Rates with Variable Fill VolumeFill Volume does not effect overall distillation time, provided Vinital = Vfinal

Model Output: 150 mbar

0

5

10

15

20

25

30

0 0.5 1 1.5 2 2.5 3 3.5 4

Time (hrs)

Com

pone

nt M

ass

(kg)

MeOH: Constant Volume

MeOH: Put & Take 50%

MeOH: Put & Take 25%

MTBE

Vi = Vf

Real World Execution

100L Vessel, 40°C Jacket Temperature– Operating Pressure: As low as possible

Results– Total Distillation Time 5.5 hr– Endpoint Concentration 0.3% MTBE

Did the Model Fit?– Model our operating Conditions

• Pressure Ramp 354-214 mbar• Put & Take Volume 50%• Final MTBE Concentration 0.3%

5.6 hrs

Case Study 2:Case Study 2: Batch Concentration Batch Concentration

Distillation + Crystallization Procedure

1.) Initial Composition– 55 mg/mL Sulfonamide– 80% IPAc, 20% Anisole

2.) Initiate Distillation– Jacket 90°C– Adjust Vacuum as necessary

3.) Final Batch Composition– 20% IPAc, 80% Anisole

4.) Crystallization– Cooling Ramp 80°C 15°C– Charge Antisolvent (Heptane)

IPAc Heptane

Distillation + Crystallization Process

1.) Initial Composition– 55 mg/mL Sulfonamide– 80% IPAc, 20% Anisole

2.) Initiate Distillation– Jacket 90°C– Adjust Vacuum as necessary

3.) Final Batch Composition– 11% IPAc, 89% Anisole

4.) Crystallization– Slow Cooling Ramp to 60°C– Charge Antisolvent (Heptane)

IPAc Heptane

Uncontrolled Crystallization

Heavy Fouling – A Foamy distillation compounded the problem by depositing

solids above the liquid level– Large amount of material adhered to Reactor surfaces

• Estimated 10-15% Yield Loss

Reduced Impurity Rejection– Expected Material Purity: 99.9 wt%, 99.7 A%– Actual Material Purity: 92.0 wt%, 97.1 A%– Re-crystallization procedure developed and performed in

order to improve product purity

Evaluating & Improving the Process

Goal– Redesign Process to maintain homogenous solution

throughout distillation• Heating up the batch post-distillation may not entirely prevent

losses to sidewalls due to foaming.

Characterize Product Solubility Profile– Quantify Solubility = f(Temperature, Solvent Composition)

Leverage Dynochem– Reproduce the executed Manufacturing Procedure to assess

model for accuracy– Determine Optimal Operating Pressure– Predict Batch Temperature, Batch Composition

20 30 40 50 60 70 80 90 10 20 30 40 50 60 70 800

50

100

150

200

250

300

% IPAc in Anisole

Solubility Curve in IPAc -Anisole

Temperature °C

Sol

ubili

ty m

g/m

LProduct Solubility Curve

Solubility = f(Temp, %IPAc)

DynoChem Model of Executed Batch

Lot 79233-71 Dynochem Model

Vessel 250L ReactorInitial Composition 80% IPAc in AnisolePressure 275 136 mbar

Jacket Temp 90°C

Final IPAc Conc. 11%

Final Batch Temp 71°C 75°C

Distillate Volume 152 L 168 L

Distillation Time 4.5 hr 4.2 hr

Good Agreement

DynoChem Model Of Executed BatchDistillation Pathway– Determine Batch Temperature & Composition over Time– Calculate ‘Instantaneous’ Product Concentration for a given

Temperature, % IPAc– Calculate Maximum Solubility Concentration for a given

Temperature, % IPAc– Dynochem Output:

Bulk liquid Bulk liquid Bulk liquid Variables Variables Product Conc. Product Conc.

Time IPAc Anisole Temperature Volume WtPc_IPAc ACTUAL MAXIMUM

h kg kg C L % mg/mL mg/mL

0 144 41.3 63.0 207 77.7 54.9 134.1

0.0816 144 41.3 63.5 207 77.7 54.9 136.1

0.1633 136.614 41.031 63.5 198 76.9 57.3 135.6

0.2449 129.469 40.76 63.7 190 76.1 59.8 135.8

0.3265 122.686 40.491 64.0 182 75.2 62.4 136.1

0.4082 116.248 40.224 64.2 174 74.3 65.1 136.3

0.4898 110.137 39.96 64.4 167 73.4 67.8 136.7

0.5714 104.338 39.697 64.7 161 72.4 70.7 137.0

0.6531 98.838 39.436 64.9 154 71.5 73.6 137.4

Dynochem Generated User Calculated

Distillation of Executed Batch

>300 mg/mL

20 30 40 50 60 70 80 90 10 20 30 40 50 60 70 80

50

100

150

200

250

300

58 mg/mL

% IPAc in Anisole

Solubility Curve in IPAc -Anisole

Temperature °C

Sol

ubili

ty m

g/m

L

55 mg/mL

Boilint Point of Anisole - Isopropyl Acetate Mixtures

25

50

75

100

125

150

0 20 40 60 80 100% Anisole

Boi

ling

Poin

t °C

1000 mbar

500 mbar

300 mbar

200 mbar

Mixture Boiling Point from Tx-y Utility

With Jacket constrained at 90°C, Distillation must be performed at <300 mbar to maintain adequate driving force

DynoChem 300 mbar Model

For Distillation Endpoint of 80% Anisole– Batch Temperature = Jacket Temperature

300mbar as Best Case Scenario– Highest Batch Temperature over course of distillation– Most likely procedure to maintain product in solution

300mbar as Worst Case Scenario– Longest process time

‘Hottest’ Scenario that will achieve 20% IPAc Target

DynoChem 300 mbar model

20 30 40 50 60 70 80 90 10 20 30 4050 60 70 800

50

100

150

200

250

300

% IPAc in Anisole

Time = 0, 55 mg/mL

Time = 8 hr, 292 mg/mL

Solubility Curve in IPAc -Anisole

Temperature °C

Sol

ubili

ty m

g/m

L

DynoChem 300 mbar model

A single batch concentration is not possible without crossing into the Metastable Zone

Path Forward– Incorporate additional charge of Anisole to lower the

product concentration:• Reduced concentration allows for

- Lower operating pressure- Lower batch temperature - Faster Distillation (greater ΔT)

• Optimally, minimize the Anisole Charge that will maintain product in solution

- Least perceived impact on Crystallization Procedure

DynoChem 200 mbar Model

20 30 40 50 60 70 80 90 10 20 30 40 50 60 70 800

50

100

150

200

250

300

% IPAc in Anisole

55 mg/mL53 mg/mL

48 mg/mL

322 mg/mL

Solubility Curve in IPAc -Anisole

219 mg/mL

154 mg/mL

Temperature °C

Sol

ubili

ty m

g/m

L

DynoChem 200 mbar Model

20 30 40 50 60 70 80 90 1020

3040

5060

7080

0

50

100

150

200

250

300

% IPAc in Anisole

154 mg/mL

48 mg/mL53 mg/mL55 mg/mL

219 mg/mL

322 mg/mL

Solubility Curve in IPAc -Anisole

Temperature °C

Sol

ubili

ty m

g/m

L

Assessing Process Robustness

Quantify process sensitivity to perturbations in– Operating Pressure– Batch Temperature– Charge Quantity of Anisole– Missed Concentration Endpoint

Utilize Dynochem to fine tune process– Determine Initial Concentration that will allow 5°C margin

between Batch Temperature and Solubility Limit– Ensure margins are within temperature / pressure control

limits of process equipment

Solubility vs. Time for 200 mbar Model

0

50

100

150

200

250

0 0.5 1 1.5 2 2.5 3 3.5

Time (hrs)

Prod

uct C

once

ntra

tion

(mg/

mL)

Solubility Limit

Batch Concentration

Dynochem 200 mbar Model Initial Concentration = 48.3 mg/mL

Batch Concentration = Solubility Limit

Batch Concentration = Solubility Limit

Solubility vs. Time for 200 mbar ModelInitial Concentration = 45.5 mg/mL

0

50

100

150

200

250

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Time (hrs)

Prod

uct C

once

ntra

tion

(mg/

mL)

Solubility Limit

Solubility Limit (5°C Cooler)

Batch

Dynochem 200 mbar Model Initial Concentration = 45.5 mg/mL

55°°C / 40 mbar Safety Margin

C / 40 mbar Safety Margin

Dynochem 200 mbar ModelInitial Concentration: 45.5 mg/mL

Elapsed Distillation Time: 2.0 hrsDynoChem Model Output

200 mbar, Initial Concentration = 45.5 mg/mL

0

20

40

60

80

100

120

140

160

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Time (hrs)

IPAc (kg)Anisole (kg)IPAc (%)Batch Temperature (°C)

Assessing Process Robustness

Parameter Operating Target Threshold Consequence

Batch Temperature 57-75°C

5°C Below Expected

Batch TempEnter MSZ

Vessel Pressure 200 mbar 160 mbar Enter MSZ

Anisole Undercharge

45.5 mg/mL 48.3 mg/mLEnter MSZ

5.0V 4.2V

Concentration Endpoint

20% IPAc 6% IPAc None

Batch Temp = 75°C Batch Temp = 90°C

Real World Execution of Improved Process

Small Scale Validation Run Completed– No Evidence of premature crystallization on 1L scale

Process Improvements successfully incorporated into Manufacturing Procedure– No premature crystallization observed– Side by Side comparison before and after development work

Campaign 1 Campaign 2Scale 10kg; 400L 20kg; 800LYield 79% 90%Purity 97.1A% 99.3A%

Acknowledgements

Jackie Milne Process Chemistry

Mina Seran Process Chemistry

Seth Huggins Process Engineering

Questions?Questions?