crystallization process improvement driven by dynochem process modeling. flavien susanne
TRANSCRIPT
Pfizer Confidential
Crystallisation improvement driven by Dynochem
process modelling
Flavien Susanne Chemical Engineer
Moussa Boukerche, Thomas Dupont
Pfizer Confidential
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
Pfizer Confidential
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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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
by distillationAddition of
anti-solvent
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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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Results
Batch to batch variability
Crystallisation highly dependant to the process variability
Different particle size distribution and physical property
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Crystallisation by continuous distillation/addition
Transfer from Strip and Replace addition to constant addition
Control of solubility evolution by avoiding sudden changes
0
10
20
30
40
50
60
70
80
0 100 200 300 400 500
g/L
mins
batch Solubility g/L
cst Solubility g/L
1st event of crystallisation
triggered by aliquot addition
2nd event of crystallisation
triggered by aliquot addition
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Approach and principal
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
Concentration
by distillation
Addition of
anti-solvent
Addition of
anti-solvent distillation
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Concentration of solvents and
component monitored by IR
RC1MP06: Reactor for
distillation
Weight of solvent
measured
Weight of distillate
recorded
Constant feed
Equipment for POC: RC1-MP06
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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
0
2
4
6
8
10
0 0.5 1 1.5
UA
(W
/K)
Volume (user units)
0.085
0.035
-0.1 -0.05 0 0.05 0.1
Heig
ht (m
)
0
5
10
15
20
25
30
35
0
10
20
30
40
50
60
70
80
90
Pro
ce
ss
fluid
Insid
e
film
Insid
e
fou
ling
Lin
ing
Wa
ll
Ou
tsid
e
fou
ling
Ou
tsid
e
film
Se
rvice
flu
id
Te
mp
era
ture
% r
esis
tan
ce
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Temperature prediction
Liquid phase
Composition prediction
gas phase composition
prediction
Model in Dynochem and prediction
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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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POC Results
Prediction of solvent evolution
Validation of the Proof Of Concept
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POC Results
Repeatability from batch to batch
Similar mono modal
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
0.75
0.80
0.85
0.90
0.95
1.00
1.05
1.10
1.15
1.20
1.25
1.30
1.35
1.40
Density
dis
trib
utio
nq3*
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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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
Transfer to Large Scale
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Model in Dynochem and prediction
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Extract mathematical description of heat transfer using Dynochem
Jacket Reactor
TC
r (m)outside film
wall
lining inside film
oofwlifi hhhhhhU
1111111
Large scale reactor Characterisation
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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
Large scale reactor Characterisation
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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
Jacket.Temperature (Imp) (C)
Bulk liquid.Temperature (Exp) (C)
Bulk liquid.Temperature (C)
exp1 95kg Tj=60°C
Time (mins)
Pro
cess p
rofil
e (
see le
gend)
0.0 43.527 87.053 130.58 174.107 217.6330.0
14.0
28.0
42.0
56.0
70.0
Jacket.Temperature (Imp) (C)
Bulk liquid.Temperature (Exp) (C)
Bulk liquid.Temperature (C)
exp6 166.2kg Tj=60°C
Time (mins)
Pro
cess p
rofil
e (
see le
gend)
0.0 33.873 67.747 101.62 135.493 169.3670.0
15.0
30.0
45.0
60.0
75.0
Jacket.Temperature (Imp) (C)
Bulk liquid.Temperature (Exp) (C)
Bulk liquid.Temperature (C)
exp4 130.4kg Tj=20°C
Time (mins)
Pro
cess p
rofil
e (
see le
gend)
0.0 41.03 82.06 123.09 164.12 205.150.0
14.0
28.0
42.0
56.0
70.0
Jacket.Temperature (Imp) (C)
Bulk liquid.Temperature (Exp) (C)
Bulk liquid.Temperature (C)
exp5 130.4kg DT=30°C
Time (mins)
Pro
cess p
rofil
e (
see le
gend)
0.0 21.97 43.94 65.91 87.88 109.850.0
30.0
60.0
90.0
120.0
150.0
Jacket.Temperature (Imp) (C)
Bulk liquid.Temperature (Exp) (C)
Bulk liquid.Temperature (C)
exp7 166.2kg Tj=20°C
Time (mins)
Pro
cess p
rofil
e (
see le
gend)
0.0 35.707 71.413 107.12 142.827 178.5330.0
14.0
28.0
42.0
56.0
70.0
Large scale reactor Characterisation
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Predictive model specific to the Pilot Plant reactor
Distillation trials partial reflux and N2 sweep effect
sumof f gasv olume (Exp) (L)
Bulk liquid.Temperature (Exp) (C)
Jacket.Temperature (Exp) (C)
v apour.THF (kg)
Jacket.Temperature (C)
Bulk liquid.Temperature (C)
sumof f gasv olume (L)
constant level trial
Time (mins)
Pro
cess p
rofil
e (
see le
gend)
0.0 30.0 60.0 90.0 120.0 150.00.0
30.0
60.0
90.0
120.0
150.0
sumof f gas (Exp) (kg)
Bulk liquid.Temperature (Exp) (C)
Jacket.Temperature (Exp) (C)
sumof f gas (kg)
Jacket.Temperature (C)
Bulk liquid.Temperature (C)
exp11 distillation from batch exp
Time (mins)
Pro
cess p
rofil
e (
see le
gend)
0.0 24.347 48.693 73.04 97.387 121.7330.0
30.0
60.0
90.0
120.0
150.0
sumof f gas (Exp) (kg)
Bulk liquid.Temperature (Exp) (C)
Jacket.Temperature (Exp) (C)
sumof f gas (kg)
Jacket.Temperature (C)
Bulk liquid.Temperature (C)
exp10 distillation test
Time (mins)
Pro
cess p
rofil
e (
see le
gend)
0.0 32.0 64.0 96.0 128.0 160.00.0
50.0
100.0
150.0
200.0
250.0
Different distillation conditions
Match between experimental data and prediction
Large scale reactor Characterisation
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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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Prediction of solvent evolution
Validation of the model on large scale
0
20
40
60
80
100
0 200 400 600 800
% mass solvent
mins
THFmassratio (Exp)
watermassratio (Exp)
acetonitrilemassratio (Exp)watermassratio
acetonitrilemassratio
THFmassratio
sumoffgasvolume
sumoffgasvolume (Exp)
volume distillated
Case study 1: Results and Conclusions
Pfizer Confidential
Case study 1: Results and Conclusions
Repeatability from batch to batch
Process conducted in 250L and 1500L reactors
Pfizer Confidential
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
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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• Varying composition/volume/supersaturation
• Deliver small primary particles(<20m) that are prone to
agglomeration
• 92% yield of recovery in >600min
• Throughput ~9kg/m3.hour
Results: standard crystallisation
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0.175
0.200
0.225
0.250
0.275
0.300
0.325
0.350
0.375
0.400
0.425
0.450
0.475
0.500
0.525
0.550
0.575
0.600
0.625
0.650
0.675
0.700
0.725
0.750
0.775
0.800
0.825
0.850
0.875
0.900
0.925
De
nsity d
istr
ibu
tio
n q
3*
1 2 4 6 8 10 20 40 60 80 100 200 400 600 800
particle size / µm
Batch No.
703611/30
703611/26
703611/27
% < 21.5 µm
%
65.47
75.93
80.31
D[v,0.1]
µm
1.61
1.43
1.53
D[v,0.5]
µm
7.06
5.38
6.11
D[v,0.9]
µm
328.29
357.17
107.04
D[4,3]
µm
84.38
73.46
43.41
Pfizer, Materials Science, Sympatec HELOS (H1258)
UK-453061
Neil Dawson
21 JUL 2010
Primary particles
Controlled by
crystallization
primary particles
agglomerated
during drying
0.000
0.025
0.050
0.075
0.100
0.125
0.150
0.175
0.200
0.225
0.250
0.275
0.300
0.325
0.350
0.375
0.400
0.425
0.450
0.475
0.500
0.525
0.550
0.575
0.600
0.625
0.650
0.675
0.700
0.725
0.750
0.775
0.800
0.825
0.850
0.875
0.900
0.925
De
nsity d
istr
ibu
tio
n q
3*
1 2 4 6 8 10 20 40 60 80 100 200 400 600 800
particle size / µm
Batch No.
703611/30
703611/26
703611/27
% < 21.5 µm
%
65.47
75.93
80.31
D[v,0.1]
µm
1.61
1.43
1.53
D[v,0.5]
µm
7.06
5.38
6.11
D[v,0.9]
µm
328.29
357.17
107.04
D[4,3]
µm
84.38
73.46
43.41
Pfizer, Materials Science, Sympatec HELOS (H1258)
UK-453061
Neil Dawson
21 JUL 2010
Primary particles
Controlled by
crystallization
primary particles
agglomerated
during drying
Primary particles
agglomeration
Pfizer Confidential
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
Continuous crystallisation
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Model in Dynochem and prediction
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
Continuous crystallisation
Start
No flow
Preparation of seed bed
13g API in 65g heptanes and 32g
IPAc
solubility ~6g/L
Composition and concentration
stay constant
Large surface of seed
Promote growth
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
Continuous crystallisation
Solution of
0.5g/min
6g/min IPAC
7.5g/min
heptanes
Flow in
Start of flow in
0.5g/min API
6g/min IPAc
7.5g/min heptanes
Start of vacuum at 80mbar
T= 25.5C
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
Continuous crystallisation
Solution of
0.5g/min
6g/min IPAC
7.5g/min
heptanes
Flow in
Start of flow in
0.5g/min API
6g/min IPAc
7.5g/min heptanes
Start of vacuum at 80mbar
T= 25.5C
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
Continuous crystallisation
Solution of
0.5g/min
6g/min IPAC
7.5g/min
heptanes
Flow in
Start of flow in
0.5g/min API
6g/min IPAc
7.5g/min heptanes
Start of vacuum at 80mbar
T= 25.5C
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
P-9
Continuous crystallisation
Solution of
0.5g/min
6g/min IPAC
7.5g/min
heptanes
Flow in
Start of flow in
0.5g/min API
6g/min IPAc
7.5g/min heptanes
Start of vacuum at 80mbar
T= 25.5C
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
P-9
Continuous crystallisation
Solution of
0.5g/min
6g/min IPAC
7.5g/min
heptanes
Flow in
Start of flow in
0.5g/min API
6g/min IPAc
7.5g/min heptanes
Start of vacuum at 80mbar
T= 25.5C
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
P-9
Continuous crystallisation
Solution of
0.5g/min
6g/min IPAC
7.5g/min
heptanes
Flow in
Start of flow in
0.5g/min API
6g/min IPAc
7.5g/min heptanes
Start of vacuum at 80mbar
T= 25.5C
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
P-9
Continuous crystallisation
Solution of
0.5g/min
6g/min IPAC
7.5g/min
heptanes
Flow in
Start of flow in
0.5g/min API
6g/min IPAc
7.5g/min heptanes
Start of vacuum at 80mbar
T= 25.5C
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
P-9
Continuous crystallisation
Solution of
0.5g/min
6g/min IPAC
7.5g/min
heptanes
Flow in
Start of flow in
0.5g/min API
6g/min IPAc
7.5g/min heptanes
Start of vacuum at 80mbar
T= 25.5C
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
P-9
Continuous crystallisation
Solution of
0.5g/min
6g/min IPAC
7.5g/min
heptanes
Flow in
Start of flow in
0.5g/min API
6g/min IPAc
7.5g/min heptanes
Start of vacuum at 80mbar
T= 25.5C
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
P-9
Continuous crystallisation
Solution of
0.5g/min
6g/min IPAC
7.5g/min
heptanes
Flow in
Start of flow in
0.5g/min API
6g/min IPAc
7.5g/min heptanes
Start of vacuum at 80mbar
T= 25.5C
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
Continuous crystallisation
Solution of
0.5g/min
6g/min IPAC
7.5g/min
heptanes
Flow in
Start of flow in
0.5g/min API
6g/min IPAc
7.5g/min heptanes
Start of vacuum at 80mbar
T= 25.5C
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
API
Continuous crystallisation
Solution of
0.5g/min
6g/min IPAC
7.5g/min
heptanes
Flow in
Start of flow in
0.5g/min API
6g/min IPAc
7.5g/min heptanes
Start of vacuum at 80mbar
T= 25.5C
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
API
Continuous crystallisation
Solution of
0.5g/min
6g/min IPAC
7.5g/min
heptanes
Flow in
Start of flow in
0.5g/min API
6g/min IPAc
7.5g/min heptanes
Start of vacuum at 80mbar
T= 25.5C
Distillation rate controlled by T
Heptanes: 4.1 – 6 g/min
IPAc: 3.65 – 5.3 g/min
Pfizer Confidential
Use of Dynochem prediction for distillation
Continuous crystallisation
API
API
Pfizer Confidential
Continuous Distillation/crystallisation
P-10
Liquors
E-6
Heptane
IPAc
Solid out
++
++
++
++
++
++
++
++
++
++
++
++
++
++
++
+
P-8
Advantage
Control of the crystallisation by modelling
Only one reactor required for the
crystallisation
Only half Heptane required for same
conditions
Green Chemistry approach
No additional investment
existing batch reactor can be used
4 plates columns
to recycle the
Heptane
API in
solution
Continuous crystallisation
Pfizer Confidential
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
0.75
0.80
0.85
0.90
0.95
1.00
1.05
1.10
1.15
1.20
1.25
De
nsity d
istr
ibu
tio
n q
3*
0.6 0.8 1.0 2 4 6 8 10 20 40 60 80 100 200 400
particle size / µm
Batch No.
120782/109/1
120782/103/3
D[v,0.1]
µm
2.24
2.71
D[v,0.5]
µm
9.06
9.84
D[v,0.9]
µm
21.95
25.31
D[4,3]
µm
10.96
12.97
UK-453,061 API - Particle size distribution
Comparison of continuous crystallisation batches isolated in an AFD
Neil Dawson
•Constant supersaturation and composition: optimisation of
crystal growth
•Bigger particles (~25m) 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
Results: continuous crystallisation
Pfizer Confidential
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!!!
Pfizer Confidential
Acknowledgment
Thomas Dupont
Moussa Boukerche
Andrew Derrick
Julian Smith
Wilfried Hoffmann
Garry O’Connor