1 Control of Size and Shape Distribution in Continuous Crystallisation Systems Zoltan K. NAGY 1,2 , Aniruddha MAJUMDER 2 , Ali SALEEMI 2 1 School of Chemical Engineering , Purdue University, West Lafayette, IN, USA 2 Chemical Engineering Department, Loughborough University, UK September 13, 2012 EPSRC Centre in Continuous Manufacturing and Crystallisation Open Day University of Strathclyde, Glasgow 2 Acknowledgments Dr. Aniruddha Majumder Dr. Ali Saleemi European Research Council Grant No. 280106-CrySys CrySys
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Control of Size and Shape Distribution in Continuous Crystallisation Systems · 2012-11-26 · Continuous real-time monitoring of crystallization processes CSD control via tailored
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1
McMaster University
Control of Size and Shape Distribution in Continuous
Crystallisation Systems
Zoltan K. NAGY1,2, Aniruddha MAJUMDER2, Ali SALEEMI2
1School of Chemical Engineering , Purdue University,
West Lafayette, IN, USA2Chemical Engineering Department, Loughborough University, UK
September 13, 2012
EPSRC Centre in Continuous Manufacturing and Crystallisation Open Day
University of Strathclyde, Glasgow
2
Acknowledgments
Dr. Aniruddha Majumder
Dr. Ali Saleemi
European Research Council Grant No. 280106-CrySys
CrySys
2
3
Introduction
Composite-PAT array (CPA) and CryPRINS
Continuous real-time monitoring of crystallization processes
CSD control via tailored dissolution in batch crystallisation (model-based and model-free)
Model-based control of CSD in continuous crystallizers
Control of shape distribution using growth modifiers
Conclusions
Overview
4
Monitoring and Control of CrystallisationProcesses - Motivation
Many technology and economic drivers
70% of all solid products & 90% of APIs involve a crystallization step
Control of crystal properties important Efficient downstream operations (filtration, drying)
Strict regulatory requirements related to variation of quality
High economic penalty of producing off-spec product (£1-2 million/batch)
Quality-by-design, fast scale up and product consistency
3
5
Continuous Crystallisation
Has been identified as a key paradigm shift with high potential of improving pharmaceutical production [1]
Continuous processing has the advantages:
– Consistency in product quality
– Reduction of cost by asset utilization
– Shorter down time
– Ease of scale up
– Achieve operating conditions unattainable in batch processes
Continuous processing is impossible without suitable control strategies
[1] Chen et al., Cryst. Growth Des., 2011, 11, 887-895
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New generation of integrated, intensified & intelligent crystallization systems with drastically improved flexibility, predictability, stability & controllability.
New generation of integrated, intensified & intelligent crystallization systems with drastically improved flexibility, predictability, stability & controllability.
• Seed addition
• Cooling profile
• Antisolvent
• Growth/nucleation modifiers
Manipulated inputs:
Key role of monitoring and control in process intensification and integration
Plant-wide PRINS
Integrated, intensified & reconfigurable plant
Batch versus continuous manufacturingNagy&Braatz, Handbook of Ind. Cryst., 2012; Nagy&Braatz, Annu. Rev. Chem. Biomol. Eng., 2012
CrySys
4
7
Crystallization product engineering via real-time feedback control
. . .
Composite PAT array
...
Continuous real-time monitoring
Full characterisation of crystallisation state in the phase diagram using CPA
Complementarity & redundancy in measurements robust control
Automated/adaptive operation to design particles with tailored made properties
Model-based and model-free crystallization design & control approaches
Automated Intelligent Decision Support and
Control System
Real-time control
CryPRINS
RAMANFBRM
PVMATR-
UV/Vis, FTIR
8
Introduction
Composite-PAT array (CPA) and CryPRINS
Continuous real-time monitoring of crystallization processes
CSD control via tailored dissolution in batch crystallisation (model-based and model-free)
Model-based control of CSD in continuous crystallizers
Control of shape distribution using growth modifiers
Conclusions
Overview
5
9
60 80 100 120 140 1600
20
40
60
80
Temperature (C)
Hea
t F
low
(W
/g) Melting point
60 80 100 120 140 1600
20
40
60
80
Temperature (C)
Hea
t F
low
(W
/g) Melting point
Form 1 to form 2 transformation
60 80 100 120 140 1600
20
40
60
80
Temperature (C)
He
at F
low
(W
/g)
Form 1 to form 2 transformation
Melting point
FBRM for detection of OABA polymorphism
9
60 80 100 120 140 1600
20
40
60
80
Temperature (C)
Hea
t F
low
(W
/g) Melting point
Form 1 to form 2 transformation
60 80 100 120 140 1600
20
40
60
80
100
Temperature (C)
Hea
t F
low
(W
/g)
Form 1 to form 2 transformation
Melting point
20
30
40
50
60
Tem
per
atu
re (C
)
0.02
0.04
0.06
0.08
Ab
sorb
ance
0 200 400 6000
5000
10000
15000
Time (min)
To
tal C
ou
nts
/s
Total Counts/sTemperature (C)Absorbance
Nucleation
1
2
Polymorphictransformation
3
4
5
Form 1 (raw) Form 2 (nucleation) Form 2 + 1 (starts) Form 2 + 1 Form 1
Surface roughness due to polymorphic transformation
Solubility difference between polymorphs
1010
Image analysis (IA) for monitoring polymorphic transformation of OABA
0.5
0.55
0.6
Cir
cula
rity
0.58
0.6
0.62
0.64
0.66
0.68
0.7
Rec
tan
gu
lari
ty
1.7
1.8
1.9
2
2.1
Fer
et A
spec
t R
atio
0 100 200 3000
1000
2000
3000
4000
Time (min)
To
tal C
ou
nts
/s
Total Counts/sCircularityRectangularityFeret Aspect Ratio
Phase 1 Phase 2 Phase 3
a
b
(a/b
)
Decrease in aspect ratio
Increase in circularity
Increase in rectangularity agglomeration
Form 1 Form 2
Form 2 nucleates Mixture of forms 2+1 Form 1
6
11
200 400 600 800 1000 1200 1400 1600 18000
5
10x 104
Raman Shift (1/cm)
Inte
nsi
ty
200 400 600 800 1000 1200 1400 1600 18000
5
10x 107
Raman Shift (1/cm)
Inte
nsi
ty
200 400 600 800 1000 1200 1400 1600 18000
5
10x 107
Raman Shift (1/cm)
Inte
nsi
ty
Monitoring polymorphic transformation OABA using process Raman Spectroscopy
11
Form 1 and 2 monitored using fingerprint regions
Nucleation of form 2 and transformation into form 1 is monitored
25
30
35
40
45
50
55
60
Tem
per
atu
re (C
)
2.6
2.8
3
3.2
3.4
x 104
Arb
itra
ry U
nit
s
0 150 300 450 600 750
0
5
10
15x 10
4
Time (min)
Arb
itra
ry U
nit
s
Form 1
Temperature(C)
Form 2
Nucleation of form 2
Transformation of form 2 in form 1
12
Introduction
Composite-PAT array (CPA) and CryPRINS
Continuous real-time monitoring of crystallization processes
CSD control via tailored dissolution in batch crystallisation (model-based and model-free)
Model-based control of CSD in continuous crystallizers
Control of shape distribution using growth modifiers
Conclusions
Overview
7
13
In situ fine removal via controlled dissolution
15
20
25
30
35
40
Te
mp
era
ture
(C
)0 50 100
-4
-2
0
2
4
6
8x 10
-3
time (min)
Sup
ersa
tura
tion
(g
/g)
0 200 400 6000
0.005
0.01
0.015
0.02
0.025
t = 0 min
Particle size (m)
Vol
ume
pdf
(m
-1)
Target CSDSimulated CSD
Seed CSD
0 200 400 6000
0.005
0.01
0.015
0.02
0.025
t = 12 min
Particle size (m)
Vol
ume
pdf
(m
-1)
Target CSDSimulated CSD
0 200 400 6000
0.005
0.01
0.015
0.02
0.025
t = 32 min
Particle size (m)
Vol
ume
pdf
(m
-1)
Target CSDSimulated CSD
0 200 400 6000
0.005
0.01
0.015
0.02
0.025
t = 39 min
Particle size (m)
Vol
ume
pdf
(m
-1)
Target CSDSimulated CSD
0 200 400 6000
0.005
0.01
0.015
0.02
0.025
t = 59 min
Particle size (m)
Vol
ume
pdf
(m
-1)
Target CSDSimulated CSD
0 200 400 6000
0.005
0.01
0.015
0.02
0.025
t = 65 min
Particle size (m)
Vol
ume
pdf
(m
-1)
Target CSDSimulated CSD
0 200 400 6000
0.005
0.01
0.015
0.02
0.025
t = 74 min
Particle size (m)
Vol
ume
pdf
(m
-1)
Target CSDSimulated CSD
0 200 400 6000
0.005
0.01
0.015
0.02
0.025
t = 90 min
Particle size (m)
Vol
ume
pdf
(m
-1)
Target CSDSimulated CSD
0 200 400 6000
0.005
0.01
0.015
0.02
0.025
t = 100 min
Particle size (m)
Vol
ume
pdf
(m
-1)
Target CSDSimulated CSD
Growth & nucleation
Dissolution
Optimal Temp ProfileOptimal Temp Profile
SupersaturationSupersaturation
0 200 400 600 8000
1
2
3
4
5
6
7
x 10-3
Particle Size (m)V
olum
e pd
f (m
-1)
CSD withoutDissolutionCSD withDissolution
15 20 25 30 35 400.04
0.05
0.06
0.07
0.08
0.09
0.1
Temperature (oC)
Co
ncen
tratio
n (w
t fra
ctio
n)
OptimisedTemperatureProfileSolubility Curve
Fines dissolutionFines dissolutionNucleationNucleation