practical aspects of distillation modeling in dynochem. carolyn cummings
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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?