The document discusses using DynoChem software to model and optimize distillation processes. It presents two case studies:
1) Modeling an azeotropic distillation of MTBE and methanol to determine the endpoint. The model accurately predicted the distillation time.
2) Modeling a batch concentration distillation to assess premature crystallization. The model was used to reproduce a manufacturing process, determine the optimal operating pressure to avoid crystallization, and predict batch properties over time. The optimized process incorporated additional solvent charges to control temperature and maintain solubility.
2. 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
3. DynoChem at Amgen
Small 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
4. DynoChem Calculations
Antoine Equation
– Relates saturated vapor pressure of pure components to
Temperature
B
ln(Pvap) = A -
C+T
UNIFAC
– UNIversal Functional Activity Coefficients
– Provides a method for calculating activity coefficients
based on component functional groups
– Account for non-ideality of solvent mixtures
6. 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
9. Evaluation of Distillation Rates
Rate decreases with decreasing Pressure: More Driving Force!
Rate varies minimally with Fill Volume
Pressure Time Mode Final Batch
Temp
350 mbar 36.6 hr Constant Volume 40°C
300 mbar 11.4 hr Constant Volume 36°C
250 mbar 6.7 hr Constant Volume 32°C
200 mbar 4.6 hr Constant Volume 28°C
150 mbar 3.0 hr Constant Volume 22°C
150 mbar 3.0 hr Put and Take: 90% 22°C
150 mbar 3.4 hr Put and Take: 50% 22°C
150 mbar 3.7 hr Put and Take: 25% 22°C
10. Distillation Rates with Variable Fill Volume
Fill Volume does not effect overall distillation time, provided Vinital = Vfinal
Model Output: 150 mbar
30
e
t Volum
onstan
MeOH: C
25
MeO
H: P
ut &
Tak
e 50 %
20
Component Mass (kg)
MeO
15 H: Put &
Take
25 %
10
5
MTBE
0
0 0.5 1 1.5 2 2.5 3 3.5 4
Time (hrs)
11. Distillation Rates with Variable Fill Volume
Fill Volume does not effect overall distillation time, provided Vinital = Vfinal
Model Output: 150 mbar
30
e
t Volum
onstan
MeOH: C
25
MeO
H: P
ut &
Tak
e 50 %
20 V i = Vf
Component Mass (kg)
MeO
15 H: Put &
Take
25 %
10
5
MTBE
0
0 0.5 1 1.5 2 2.5 3 3.5 4
Time (hrs)
12. 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
16. 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
17. 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
19. DynoChem Model of Executed Batch
Good Agreement
Lot 79233-71 Dynochem Model
Vessel 250L Reactor
Initial Composition 80% IPAc in Anisole
Pressure 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
20. DynoChem Model Of Executed Batch
Distillation 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:
Dynochem Generated User Calculated
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
21. Distillation of Executed Batch
Solubility Curve in IPAc -Anisole
>300 mg/mL
300
250
200
Solubility mg/mL
150
100
55 mg/mL
58 mg/mL
50
0 8
20 60 70
30 40 50
50 60 40
70 20 30
80 90 10
Temperature °C % IPAc in Anisole
22. 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
Boilint Point of Anisole - Isopropyl Acetate Mixtures
150
1000 mbar
500 mbar
125 300 mbar
200 mbar
Boiling Point °C
100
75
50
25
0 20 40 60 80 100
% Anisole
23. 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
24. DynoChem 300 mbar model
‘Hottest’ Scenario that will achieve 20% IPAc Target
Solubility Curve in IPAc -Anisole
300
Time = 8 hr, 292 mg/mL
250
200
Solubility mg/mL
150
100
Time = 0, 55 mg/mL
50
0 80
20 70
30 60
40 50
50 40
60 70 30
80 20
90 10 % IPAc in Anisole
Temperature °C
25. 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
26. DynoChem 200 mbar Model
Solubility Curv in IPAc -Anisole
e
300
322 mg/mL
250
219 mg/mL
200
Solubility mg/mL
150
154 mg/mL
100
55 mg/mL
50 53 mg/mL
48 mg/mL
0 80
20 60 70
30 40 50
50 60 30 40
70 80 20
90 10
Temperature °C % IPAc in Anisole
28. 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
29. Dynochem 200 mbar Model
Initial Concentration = 48.3 mg/mL
Solubility vs. Time for 200 mbar Model
250
i mit
200
lit y L
Product Concentration (mg/mL)
bi
n= Solu
cen tratio
h Con
Batc
150
100
50
Solubility Limit
Batch Concentration
0
0 0.5 1 1.5 2 2.5 3 3.5
Time (hrs)
30. Dynochem 200 mbar Model
Initial Concentration = 45.5 mg/mL
Solubility vs. Time for 200 mbar Model
250
Initial Concentration = 45.5 mg/mL
rgin
200
fet y Ma
Product Concentration (mg/mL)
mb ar Sa
/ 40
5°C
150
100
50 Solubility Limit
Solubility Limit (5°C Cooler)
Batch
0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Time (hrs)
33. 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 2
Scale 10kg; 400L 20kg; 800L
Yield 79% 90%
Purity 97.1A% 99.3A%