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Practical Applications of Distillation
Modeling in DynoChem
Carolyn Cummings
5.13.09
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 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
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
Case Study 1

Azeotropic Distillation
MTBE    Methanol 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 Utility
                                      Boiling Point of MTBE‐MeOH Mixtures
            70




            60




            50




            40
Temp (°C)




            30




            20




            10       1000 mbar
                     750 mbar
                     500 mbar
                     250 mbar
             0
                 0        10     20      30     40      50      60      70   80   90   100
                                                      % MTBE
X-Y Diagram from Tx-y Utility
                                               x-y diagram for MTBE-MeOH System

                    100
                              1000 mbar
                              750 mbar
                     90
                              500 mbar
                              250 mbar
                     80



                     70



                     60
  Vapour wt% MTBE




                     50



                     40



                     30



                     20



                     10



                      0
                          0       10      20   30      40       50        60       70   80   90   100


                                                             Liquid wt% MTBE in MeOH
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
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)
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)
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:
Batch Concentration
Distillation + Crystallization Procedure
                                      IPAc   Heptane
  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)
Distillation + Crystallization Process
                                      IPAc   Heptane
  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)
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
Product Solubility Curve
                                                         Solubility Curve in IPAc -Anisole




                   300




                   250
                         Solubility = f(Temp, %IPAc)

                   200
Solubility mg/mL




                   150




                   100




                   50




                     0                                                                                                               80
                    20                                                                                                          70
                         30                                                                                              60
                              40                                                                               50
                                   50          60                                                      40
                                                    70                                            30
                                                                80                           20             % IPAc in Anisole
                                   Temperature °C                             90       10
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
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
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
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
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
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
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
                                                          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
DynoChem 200 mbar Model
                                                         Solubility Curve in IPAc -Anisole




                                                                                             322 mg/mL
                   300




                   250


                                                                                             219 mg/mL

                   200
Solubility mg/mL




                   150
                                                                                               154 mg/mL




                   100

                                                                                              55 mg/mL
                                                                                              53 mg/mL
                                                                                              48 mg/mL
                   50




                                                                                                                                                   80
                                                                                                                                             70
                                                                                                                                       60
                    0                                                                                                          50
                                                                                                                          40
                   20    30                                                                                          30             % IPAc in Anisole
                              40         50                                                                     20
                                                    60                70                80          90     10
                                   Temperature °C
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
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)
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)
Dynochem 200 mbar Model
 Initial Concentration: 45.5 mg/mL
 Elapsed Distillation Time: 2.0 hrs
                           DynoChem Model Output
                     200 mbar, Initial Concentration = 45.5 mg/mL
   160
                                                                    IPAc (kg)
                                                                    Anisole (kg)
   140                                                              IPAc (%)
                                                                    Batch Temperature (°C)

   120


   100


    80


    60


    40


    20


     0
         0.0   0.5   1.0           1.5                2.0   2.5           3.0                3.5
                                         Time (hrs)
Assessing Process Robustness


Parameter         Operating Target     Threshold        Consequence
                                           5°C
Batch
Temperature
                      57-75°C         Below Expected     Enter MSZ
                                       Batch Temp

Vessel Pressure      200 mbar           160 mbar         Enter MSZ

Anisole             45.5 mg/mL         48.3 mg/mL
Undercharge
                                                         Enter MSZ
                        5.0V              4.2V
Concentration        20% IPAc            6% IPAc
                                                           None
Endpoint          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 2
      Scale         10kg; 400L           20kg; 800L
      Yield            79%                  90%
      Purity          97.1A%              99.3A%
Acknowledgements
 Jackie Milne   Process Chemistry
 Mina Seran     Process Chemistry
 Seth Huggins   Process Engineering
Questions?

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Practical aspects of distillation modeling in DynoChem. Carolyn Cummings.

  • 1. Practical Applications of Distillation Modeling in DynoChem Carolyn Cummings 5.13.09
  • 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
  • 5. Case Study 1 Azeotropic Distillation MTBE Methanol Solvent Swap
  • 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
  • 7. Mixture Boiling Point from Tx-y Utility Boiling Point of MTBE‐MeOH Mixtures 70 60 50 40 Temp (°C) 30 20 10 1000 mbar 750 mbar 500 mbar 250 mbar 0 0 10 20 30 40 50 60 70 80 90 100 % MTBE
  • 8. X-Y Diagram from Tx-y Utility x-y diagram for MTBE-MeOH System 100 1000 mbar 750 mbar 90 500 mbar 250 mbar 80 70 60 Vapour wt% MTBE 50 40 30 20 10 0 0 10 20 30 40 50 60 70 80 90 100 Liquid wt% MTBE in MeOH
  • 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
  • 13. Case Study 2: Batch Concentration
  • 14. Distillation + Crystallization Procedure IPAc Heptane 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)
  • 15. Distillation + Crystallization Process IPAc Heptane 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)
  • 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
  • 18. Product Solubility Curve Solubility Curve in IPAc -Anisole 300 250 Solubility = f(Temp, %IPAc) 200 Solubility mg/mL 150 100 50 0 80 20 70 30 60 40 50 50 60 40 70 30 80 20 % IPAc in Anisole Temperature °C 90 10
  • 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
  • 27. DynoChem 200 mbar Model Solubility Curve in IPAc -Anisole 322 mg/mL 300 250 219 mg/mL 200 Solubility mg/mL 150 154 mg/mL 100 55 mg/mL 53 mg/mL 48 mg/mL 50 80 70 60 0 50 40 20 30 30 % IPAc in Anisole 40 50 20 60 70 80 90 10 Temperature °C
  • 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)
  • 31. Dynochem 200 mbar Model Initial Concentration: 45.5 mg/mL Elapsed Distillation Time: 2.0 hrs DynoChem Model Output 200 mbar, Initial Concentration = 45.5 mg/mL 160 IPAc (kg) Anisole (kg) 140 IPAc (%) Batch Temperature (°C) 120 100 80 60 40 20 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Time (hrs)
  • 32. Assessing Process Robustness Parameter Operating Target Threshold Consequence 5°C Batch Temperature 57-75°C Below Expected Enter MSZ Batch Temp Vessel Pressure 200 mbar 160 mbar Enter MSZ Anisole 45.5 mg/mL 48.3 mg/mL Undercharge Enter MSZ 5.0V 4.2V Concentration 20% IPAc 6% IPAc None Endpoint Batch Temp = 75°C Batch Temp = 90°C
  • 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%
  • 34. Acknowledgements Jackie Milne Process Chemistry Mina Seran Process Chemistry Seth Huggins Process Engineering