1. Crystallisation improvement driven by Dynochem
process modelling
Flavien Susanne Chemical Engineer
Moussa Boukerche, Thomas Dupont
Pfizer Confidential

2. Introduction
Crystallisation is a critical stage in the manufacture of an Active
Pharmaceutical Ingredient (API) where key attributes such as purity
together with physical and mechanical properties of the crystals are set.
Particle size distribution, polymorphic form and crystal habit, have a
direct impact on downstream processing (e.g. filtration, drying and
powder processing) and ultimately on the performance of the drug
product
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3. Outline
2 case studies to illustrate the use of Dynochem to
Improve API crystallisation
1. Distillation/crystallisation process by constant anti-solvent addition
Original process performed by strip and replace cycles
Limitation and physical property issues
Improvement by control of crystallisation parameters
2. Continuous crystallisation by distillation and anti-solvent addition
Original process performed by anti-solvent crystallisation
Limitation and physical property issues
Principle, Advantage and Improvement
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4. Case study 1: original process
Main issue: reliability of particle size distribution
Multiple Strip and Replace cycles (7-9 cycles)
80:20 % w/w THF:water to >95% acetonitrile
Large volume of solvent required
Long cycle time, potential decomposition of API
Concentration Addition of
by distillation anti-solvent
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5. Limitation of the process
For each addition
Variation of composition and temperature
Sudden drop of solubility and increase of supersaturation when
addition is done
Uncontrolled increased of number of particle = uncontrolled
crystallisation
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6. Results
Batch to batch variability
Crystallisation highly dependant to the process variability
Different particle size distribution and physical property
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7. Crystallisation by continuous distillation/addition
Transfer from Strip and Replace addition to constant addition
Control of solubility evolution by avoiding sudden changes
80
g/L
70
1st event of crystallisation
triggered by aliquot addition 60 batch Solubility g/L
50
cst Solubility g/L
40
2nd event of crystallisation 30
triggered by aliquot addition 20
10
0
0 100 200 300 400 500
mins
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8. Approach and principal
Addition of Addition of
Concentration anti-solvent anti-solvent distillation
by distillation
Improve efficiency
Better control of anti-solvent addition, less disruption of
temperature and composition
Better control of solubility and supersaturation
Benefit
Improvement of physical property
Additional benefit
Minimise solvent use
Cycle time
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9. Equipment for POC: RC1-MP06
RC1MP06: Reactor for
distillation
Constant feed
Weight of distillate
recorded Weight of solvent
measured
Concentration of solvents and
component monitored by IR
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10. RC1-MP06 Characterisation
Specific to reactor
Geometry, material of construction, HTF used (flow rate, Cp)
First use of the UA Dynochem estimation
Series of calibration run at different volume followed by heat up, cool
down and distillation experiments for validation
Prediction based on heat transfer and heat loss of the reactor used
90 35
80 30
% resistance
70
Temperature
25
60
50 20
0.085 40 15
30
10
20
10 5
0 0
Wall
Process
Lining
fouling
Outside
Outside
Inside
Service
Inside
fouling
film
fluid
fluid
film
Height (m)
0.035 10
8
UA (W/K)
6
4
-0.1 -0.05 0 0.05 0.1 2
0
0 0.5 1 1.5
Volume (user units)
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11. Model in Dynochem and prediction
Temperature prediction
Liquid phase
Composition prediction
gas phase composition
prediction
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12. Control of crystallisation parameters
Calculation and prediction of solubility and supersaturation
The solubility of the mixture THF:water:acetonitrile as a function
of temperature was determined experimentally using 13-run D-
optimal design
The supersaturation was calculated from the solubility
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13. POC Results
Prediction of solvent evolution
Validation of the Proof Of Concept
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14. POC Results
Repeatability from batch to batch
Similar mono modal
1.40
1.35
1.30
1.25
1.20
1.15
1.10
1.05
1.00
0.95
0.90
Density distribution q3*
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0.4 0.6 0.8 1.0 2 4 6 8 10 20 40 60 80 100 200
particle size / µm
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15. Transfer to Large Scale
POC demonstrated in the lab using the RC1
reactor
automated 0.8L calorimeter reactor
Transfer to the Pilot Plant reactor, conical
250L type reactor with twin jacket.
Transfer to manufacture reactor, 1500L
bottom dish reactor
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16. Model in Dynochem and prediction
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17. Large scale reactor Characterisation
Extract mathematical description of heat transfer using Dynochem
1 1 1 1 1 1 1
     
U hi hif hl hw ho f ho
TC
Jacket wall Reactor
r (m)
outside film lining inside film
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18. Large scale reactor Characterisation
Measure heat up and cool down curves for different volumes and stirring
speeds
Analyze dynamics of reactors with respect to heat transfer
Calculation of resistance contribution for different reactors
From lab to
large scale
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19. Large scale reactor Characterisation
Prediction heat transfer model specific to Pilot Plant reactor
Geometry, material of construction, HTF (flow rate and Cp)
Heat up and cool down experiment  UA and Uloss
exp1 95kg Tj=60°C
70.0
exp5 130.4kg DT=30°C Jacket.Temperature (Imp) (C)
Bulk liquid.Temperature (Exp) (C)
Jacket.Temperature (Imp) (C) 150.0 Bulk liquid.Temperature (C)
Bulk liquid.Temperature (Exp) (C)
Bulk liquid.Temperature (C)
56.0
120.0
Process profile (see legend)
exp4 130.4kg Tj=20°C Jacket.Temperature (Imp) (C)
Bulk liquid.Temperature (Exp) (C)
42.0 70.0 Bulk liquid.Temperature (C)
90.0
28.0 56.0
60.0
Process profile (see legend)
42.0 30.0
14.0
28.0 0.0
0.0 0.0 21.97 43.94 65.91 87.88 109.85
0.0 43.527 87.053 130.58 174.107 217.633
exp6 166.2kg Tj=60°CTime (mins) Jacket.Temperature (Imp) (C)
Bulk liquid.Temperature (Exp) (C)
exp7 166.2kg Tj=20°CTime (mins) Jacket.Temperature (Imp) (C)
Bulk liquid.Temperature (Exp) (C)
75.0 Bulk liquid.Temperature (C) 70.0 Bulk liquid.Temperature (C)
14.0
60.0 56.0
0.0
Process profile (see legend)
0.0 41.03 82.06 123.09 164.12 205.15
Time (mins)
45.0 42.0
30.0
28.0
15.0
14.0
0.0
0.0 33.873 67.747 101.62 135.493 169.367 0.0
0.0 35.707 71.413 107.12 142.827 178.533
Time (mins)
Time (mins)
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20. Large scale reactor Characterisation
Predictive model specific to the Pilot Plant reactor
Distillation trials  partial reflux and N2 sweep effect
constant level trial
150.0
sumof f gasv olume (Exp) (L)
Bulk liquid.Temperature (Exp) (C)
Jacket.Temperature (Exp) (C)
v apour.THF (kg)
120.0 Jacket.Temperature (C)
Bulk liquid.Temperature (C)
sumof f gasv olume (L)
90.0
exp11 distillation from batch exp
150.0
sumof f gas (Exp) (kg)
Bulk liquid.Temperature (Exp) (C)
60.0 Jacket.Temperature (Exp) (C)
sumof f gas (kg)
120.0 Jacket.Temperature (C)
Process profile (see legend)
Bulk liquid.Temperature (C)
30.0
90.0
0.0
0.0 30.0 60.0 90.0 120.0 150.0 exp10 distillation test
60.0 250.0
Time (mins) sumof f gas (Exp) (kg)
Bulk liquid.Temperature (Exp) (C)
Jacket.Temperature (Exp) (C)
sumof f gas (kg)
30.0 200.0 Jacket.Temperature (C)
Process profile (see legend)
Bulk liquid.Temperature (C)
150.0
0.0
0.0 24.347 48.693 73.04 97.387 121.733
Time (mins)
100.0
Different distillation conditions 50.0
Match between experimental data and prediction 0.0
0.0 32.0 64.0 96.0 128.0 160.0
Time (mins)
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21. Process transfer
Constant feed of MeCN : Flow rate between 32L/hour
Volume contained at 150L ± 10%
Variation of Cp and density affecting variation of volume
Distillation time 13h
10h time saving compare to batch for same end point
>10% solvent saving
More accurate control of solubility and supersaturation
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22. Case study 1: Results and Conclusions
Prediction of solvent evolution
Validation of the model on large scale
t 100
n d
e
e t
v
l a
l
l
o i
t
s s
i
s d
s e
a m
m 80 u
l
o
% v
60 THFmassratio (Exp)
watermassratio (Exp)
acetonitrilemassratio
40 (Exp)
watermassratio
acetonitrilemassratio
THFmassratio
20
sumoffgasvolume
sumoffgasvolume
(Exp)
0
0 200 400 600 800
mins
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23. Case study 1: Results and Conclusions
Repeatability from batch to batch
Process conducted in 250L and 1500L reactors
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24. Outline
2 case studies to illustrate the use of Dynochem to
Improve API crystallisation
1. Distillation/crystallisation process by constant anti-solvent addition
Original process performed by strip and replace cycles
Limitation and physical property issues
Improvement by control of crystallisation parameters
2. Continuous crystallisation by distillation and anti-solvent addition
Original process performed by anti-solvent crystallisation
Limitation and physical property issues
Principle, Advantage and Improvement
Pfizer Confidential

25. Case study 2: original process
Main issue: reliability of particle size distribution
Anti-solvent crystallisation
65:35 % w/w heptanes:IPAc, 11mL/g
Long cycle time, low throughput
Physical property issues (high degree of secondary nucleation)
Addition of
anti-solvent
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26. Results: standard crystallisation
• Varying composition/volume/supersaturation
• Deliver small primary particles(<20m) that are prone to
agglomeration
• 92% yield of recovery in >600min
• Throughput ~9kg/m3.hour
0.925
0.900
0.875
0.850
Pfizer, Materials Science, Sympatec HELOS (H1258)
Primary particles
UK-453061
0.825
0.800 Batch No. % < 21.5 µm D[v,0.1] D[v,0.5] D[v,0.9] D[4,3]
agglomeration
0.775 %
703611/30 65.47
µm
1.61
µm
7.06
µm
328.29
µm
84.38
primary particles
0.750
0.725
703611/26 75.93
703611/27 80.31
1.43
1.53
5.38
6.11
357.17
107.04
73.46
43.41 agglomerated
0.700
0.675
Neil Dawson
21 JUL 2010 during drying
0.650
0.625
0.600
0.575
0.550
0.525
Density distribution q3*
0.500
0.475
0.450
0.425
0.400
0.375
0.350
0.325
0.300
0.275
0.250
0.225
0.200
Primary particles
0.175 Controlled by
0.150
0.125 crystallization
0.100
0.075
0.050
0.025
0.000
1 2 4 6 8 10 20 40 60 80 100 200 400 600 800
particle size / µm
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27. Continuous crystallisation
Concept
Design new process to enable better crystallisation
Increase the seed surface to promote rate of growth
Control the rate of nucleation Vs rate of growth
Starting volume with high seed concentration
The crystallisation is generated by addition of anti-solvent and distillation
to the right concentration solvent/anti-solvent
Continuous distillation of azeotropic solution
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28. Model in Dynochem and prediction
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29. Continuous crystallisation
P-8
Start
+++++++++++++++++++++++++++++++
No flow
Heptane
P-10
E-6 Preparation of seed bed
13g API in 65g heptanes and 32g
IPAc
solubility ~6g/L
IPAc
Composition and concentration
stay constant
Continuous Distillation/crystallisation
Large surface of seed
Promote growth
Liquors
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30. Continuous crystallisation
P-8
Flow in
+++++++++++++++++++++++++++++++
Start of flow in
7.5g/min Heptane
heptanes P-10
E-6 0.5g/min API
6g/min IPAc
7.5g/min heptanes
Solution of IPAc Start of vacuum at 80mbar
0.5g/min T= 25.5C
6g/min IPAC
Continuous Distillation/crystallisation
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Liquors
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31. Continuous crystallisation
P-8
Flow in
+++++++++++++++++++++++++++++++
Start of flow in
7.5g/min Heptane
heptanes
P-10
E-6 0.5g/min API
6g/min IPAc
7.5g/min heptanes
Solution of IPAc Start of vacuum at 80mbar
0.5g/min T= 25.5C
6g/min IPAC
Continuous Distillation/crystallisation
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Liquors
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32. Continuous crystallisation
P-8
Flow in
+++++++++++++++++++++++++++++++
Start of flow in
7.5g/min Heptane
heptanes P-10
E-6 0.5g/min API
6g/min IPAc
7.5g/min heptanes
Solution of IPAc Start of vacuum at 80mbar
0.5g/min T= 25.5C
6g/min IPAC
Continuous Distillation/crystallisation
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Liquors
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33. Continuous crystallisation
P-8
Flow in
+++++++++++++++++++++++++++++++
Start of flow in
7.5g/min Heptane
heptanes
P-10
E-6 0.5g/min API
6g/min IPAc
7.5g/min heptanes
Solution of IPAc Start of vacuum at 80mbar
0.5g/min P-9
T= 25.5C
6g/min IPAC
Continuous Distillation/crystallisation
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Liquors
Pfizer Confidential

34. Continuous crystallisation
P-8
Flow in
+++++++++++++++++++++++++++++++
Start of flow in
7.5g/min Heptane
heptanes P-10
E-6 0.5g/min API
6g/min IPAc
7.5g/min heptanes
Solution of IPAc Start of vacuum at 80mbar
0.5g/min P-9
T= 25.5C
6g/min IPAC
Continuous Distillation/crystallisation
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Liquors
Pfizer Confidential

35. Continuous crystallisation
P-8
Flow in
+++++++++++++++++++++++++++++++
Start of flow in
7.5g/min Heptane
heptanes P-10
E-6 0.5g/min API
6g/min IPAc
7.5g/min heptanes
Solution of IPAc Start of vacuum at 80mbar
0.5g/min P-9
T= 25.5C
6g/min IPAC
Continuous Distillation/crystallisation
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Liquors
Pfizer Confidential

36. Continuous crystallisation
P-8
Flow in
+++++++++++++++++++++++++++++++
Start of flow in
7.5g/min Heptane
heptanes P-10
E-6 0.5g/min API
6g/min IPAc
7.5g/min heptanes
Solution of IPAc Start of vacuum at 80mbar
0.5g/min P-9
T= 25.5C
6g/min IPAC
Continuous Distillation/crystallisation
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Liquors
Pfizer Confidential

37. Continuous crystallisation
P-8
Flow in
+++++++++++++++++++++++++++++++
Start of flow in
7.5g/min Heptane
heptanes P-10
E-6 0.5g/min API
6g/min IPAc
7.5g/min heptanes
Solution of IPAc Start of vacuum at 80mbar
0.5g/min P-9
T= 25.5C
6g/min IPAC
Continuous Distillation/crystallisation
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Liquors
Pfizer Confidential

38. Continuous crystallisation
P-8
Flow in
+++++++++++++++++++++++++++++++
Start of flow in
7.5g/min Heptane
heptanes P-10
E-6 0.5g/min API
6g/min IPAc
7.5g/min heptanes
Solution of IPAc Start of vacuum at 80mbar
0.5g/min P-9
T= 25.5C
6g/min IPAC
Continuous Distillation/crystallisation
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Liquors
Pfizer Confidential

39. Continuous crystallisation
P-8
Flow in
+++++++++++++++++++++++++++++++
Start of flow in
7.5g/min Heptane
heptanes P-10
E-6 0.5g/min API
6g/min IPAc
7.5g/min heptanes
Solution of IPAc Start of vacuum at 80mbar
0.5g/min P-9
T= 25.5C
6g/min IPAC
Continuous Distillation/crystallisation
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Liquors
Pfizer Confidential

40. Continuous crystallisation
P-8
Flow in
+++++++++++++++++++++++++++++++
Start of flow in
7.5g/min Heptane
heptanes P-10
E-6 0.5g/min API
6g/min IPAc
7.5g/min heptanes
Solution of IPAc Start of vacuum at 80mbar
0.5g/min T= 25.5C
6g/min IPAC
Continuous Distillation/crystallisation
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Liquors
Pfizer Confidential

41. Continuous crystallisation
P-8
Flow in
+++++++++++++++++++++++++++++++
Start of flow in
7.5g/min Heptane
heptanes P-10
E-6 0.5g/min API
6g/min IPAc
7.5g/min heptanes
Solution of IPAc Start of vacuum at 80mbar
0.5g/min T= 25.5C
6g/min IPAC
Continuous Distillation/crystallisation
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
API Liquors
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42. Continuous crystallisation
P-8
Flow in
+++++++++++++++++++++++++++++++
Start of flow in
7.5g/min Heptane
heptanes P-10
E-6 0.5g/min API
6g/min IPAc
7.5g/min heptanes
Solution of IPAc Start of vacuum at 80mbar
0.5g/min T= 25.5C
6g/min IPAC
Continuous Distillation/crystallisation
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
API Liquors
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43. Continuous crystallisation
Use of Dynochem prediction for distillation
API
API
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44. Continuous crystallisation
Advantage
P-8
4 plates columns
to recycle the
+++++++++++++++++++++++++++++++
Control of the crystallisation by modelling Heptane
Heptane
Only one reactor required for the P-10
E-6
crystallisation
Only half Heptane required for same
conditions
Green Chemistry approach
API in IPAc
No additional investment
solution
existing batch reactor can be used Solid out
Continuous Distillation/crystallisation
Liquors
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45. Results: continuous crystallisation
•Constant supersaturation and composition: optimisation of
crystal growth
•Bigger particles (~25m) than typical batch size
•Particles can be grown bigger if processed longer
•Particles are not prone to agglomeration
•>90%yield of recovery
•Throughput : 36kg/m3.hour
1.25
UK-453,061 API - Particle size distribution
1.20
Comparison of continuous crystallisation batches isolated in an AFD
1.15
Batch No. D[v,0.1] D[v,0.5] D[v,0.9] D[4,3]
1.10 µm µm µm µm
1.05 120782/109/1 2.24 9.06 21.95 10.96
120782/103/3 2.71 9.84 25.31 12.97
1.00
0.95
Neil Dawson
0.90
0.85
0.80
0.75
Density distribution q3*
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0.00
0.6 0.8 1.0 2 4 6 8 10 20 40 60 80 100 200 400
particle size / µm
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46. Conclusion
Alternative to standard crystallisation process can be
developed
Dynochem was a fantastic tool to enable new
process crystallisation development
Dynochem makes innovative thinking possible and
easy!!!
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47. Acknowledgment
Thomas Dupont
Moussa Boukerche
Andrew Derrick
Julian Smith
Wilfried Hoffmann
Garry O’Connor
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