Precision Macromolecular Chemistry group (PMC)
Charles Sadron Institute - UPR 22 CNRS
European Engineering School of Chemistry, Polymers and Materials Science
University of Strasbourg
Intensification of NMP and ATRP
(co)polymer syntheses by
microreaction technologies
Prof. Christophe A. Serra
Caine Rosenfeld, Florence Bally, Dambarudhar Parida, Dhiraj Garg
http://ics-cnrs.unistra.fr/caserra
Atelier de Prospective du GFP, Paris, Dec. 4th, 2014
Outline
 1. Context
 2. Microprocess overview
 3. Results
 Synthesis of linear, block and branched (co)polymers
– Influence of micromixing
– Influence of microreactor geometry
– Influence of pressure
 CFD Analysis
 4. Conclusion
2
Outline
 1. Context
 2. Microprocess overview
 3. Results
 Synthesis of linear, block and branched (co)polymers
– Influence of micromixing
– Influence of microreactor geometry
– Influence of pressure
 CFD Analysis
 4. Conclusion
3
1. Context
 Motivation
 Synthesis of architecture-controlled (co)polymers
– Block, linear or branched architectures
• low PDI, defined MW
– Applications in drug delivery, photoresist
 Two-fold strategy
– Chemistry
• Rely on controlled/”Living” polymerization techniques
» ATRP, NMP
» Intrinsically “slow” reactions
– Process
• Development of an intensified and integrated continuous-flow
microprocess
4
Outline
 1. Context
 2. Microprocess overview
 3. Results
 Synthesis of linear, block and branched (co)polymers
– Influence of micromixing
– Influence of microreactor geometry
– Influence of pressure
 CFD Analysis
 4. Conclusion
5
2. Overview
 Polymerization microprocess
Synthesis
(CMS)
Monomer A
Solvent
Initiator
Pump
µreactor 1
µmixer
Monomer B
µreactor 2
Copolymer
Pump
Rosenfeld et al., React. Eng., 1 (5) (2007) 547-552; Bally et al., React. Eng., 5 (11-12) (2011) 542–547
6
2. Overview
 Polymerization microprocess
Synthesis
(CMS)
Monomer A
Solvent
Pump
Initiator
µreactor 1
µmixer
Monomer B
µreactor 2
Copolymer
Pump
Analysis
(COA)
Solvent
Eluate
Injection
RI
GPC Column
Viscosimeter
UV
LSD
ELSD
Dilution
Waste
Train of detectors
Rosenfeld et al., React. Eng., 1 (5) (2007) 547-552; Bally et al., React. Eng., 5 (11-12) (2011) 542–547
7
2. Overview
 Polymerization microprocess
Synthesis
(CMS)
Monomer A
Solvent
Pump
Initiator
Recovery
(IPR)
µmixer
Monomer B
nanoparticles
solvent
µreactor 1
µreactor 2
µmixer
Copolymer
µmixer
Non solvent
Pump
Analysis
(COA)
Solvent
Eluate
Injection
RI
GPC Column
Viscosimeter
UV
LSD
ELSD
Dilution
Waste
Train of detectors
Rosenfeld et al., React. Eng., 1 (5) (2007) 547-552; Bally et al., React. Eng., 5 (11-12) (2011) 542–547
8
2. Synthesis (CMS)
 Continuous-microflow synthesis unit
To COA
9
2. Synthesis (CMS)
 Microreactors
 Microtubular reactors (ID 876 µm)
– Coiled tube (CT)
10
2. Synthesis (CMS)
 Microreactors (cont’d)
 Microtubular reactors (ID 876 µm)
– Coiled tube (CT)
End of the
helix
– Coil flow inverter (CFI)
• Better mixing
• Lower RTD
After
bend
1st
Inlet
A.K. Saxena and K.D.P. Nigam, AIChE J., 1984, 30, 363-368
After
2nd bend
11
2. Microprocess features
 Screening
 Operating conditions
– Flow rate, temperature, pressure, residence time, monomer
concentration
 Polymerization methods
– FRP, CRP (NMP, ATRP, RAFT)
 Rapid measurements
 Analysis every 12 minutes
 Libraries
 Homopolymers
 Copolymers
12
2. Microprocess features
 Fully automated
 Software controlled
 Over night experiments
– Pressure sensors
– Temperature probes
 Modular
 New reaction blocks
 New detectors
– Raman
– NIR
 Inline polymer recovery
 Colloidal suspension
13
Outline
 1. Context
 2. Microprocess overview
 3. Results
 Synthesis of linear, block and branched (co)polymers
– Influence of micromixing
– Influence of microreactor geometry
– Influence of pressure
 CFD Analysis
 4. Conclusion
14
3. Copolymers (CMS)
 Continuous one-step statistical copolymerization
 Atom Transfer Radical Polymerization (ATRP)
– Librairies of poly(DMAEMA-BzMA) / Influence of micromixer
15
3. Copolymers (CMS)
 Continuous one-step statistical copolymerization
 Continuous-flow setup
Nitrogen generator
Solvent
Catalyst
Ligand
Monomer
Comonomer
Initiator
HPLC Pump
HPLC Pump
Micromixer
P
Pressure sensor
Microreactor
T
Temperature Regulator
75°C
Online GPC Analysis
(CORSEMP)
Waste
NMR Analysis
16
3. Copolymers (CMS)
 Continuous one-step statistical copolymerization (cont’d)
 Micromixers
Micromixers
Name
Principle
Number of
channels/
Inlet
TJunction
Bilamination
1
450
micron
HPIMM
Digital
Multilamination
15
45
micron
KM CC-2
Impact mixing
5
100
micron
Parida et al., Green. Proc. Synt., 6 (1) (2012) 525-532
Channel
width
17
3. Copolymers (CMS)
 Continuous one-step statistical copolymerization (cont’d)
100
Conversion %
90
80
70
60
+35%
50
40
30
20
10
0
0
50
100
150
200
250
Time in minute
Batch 20%
T-Junc 20%
HPIMM 20%
Parida et al., Green. Proc. Synt., 6 (1) (2012) 525-532
KM 20%
18
3. Copolymers (CMS)
 Continuous one-step statistical copolymerization (cont’d)
25000
20000
+6,000
Mn
15000
10000
-50%
5000
0
0
50
100
150
200
250
Time in min.
Batch 20%
T-Junc. 20%
HPIMM 20%
Parida et al., Green. Proc. Synt., 6 (1) (2012) 525-532
KM 20%
19
3. Copolymers (CMS)
 Continuous one-step statistical copolymerization (cont’d)
2.2
a
PDI
1.9
1.6
1.3
Batch
T-J
HPIMM
KM
1
0
5000
10000
15000
20000
25000
X100
Mn (g/mol)
Parida et al., Green. Proc. Synt., 6 (1) (2012) 525-532
20
3. Copolymers (CMS)
 Continuous two-step block copolymerization PBA-b-PS
 Nitroxide-Mediated Polymerization (NMP)
– PBA-b-PS with low polydispersity index (PDI)
• Mixing between viscous and liquid fluids by
means of microstructured mixers
1) Homopolymerization
2) Block copolymerization
1st monomer
Pump 1
Solvent
Initiator
Pump 2
1st block
T1
1
Micromixer
2nd monomer
(solvent)
T2
2
Copolymer
Microtube reactor (µR1)
Microtube reactor (µR2)
900 µm ID / 2.9 m length
900 µm ID / 5.7 m length
21
3. Copolymers (CMS)
 Micromixers
Fluid B
Fluid B
Fluid A
Fluid A
Fluid B
Fluid A
Mixing by …
Bilamination
Multilamination
Multilamination
CF
ML45
ML20
ML50
Number of
microchannels
1
16
15
10
Film thickness
450µm
45µm
20µm
50µm
22
3. Copolymers (CMS)
 Sorting by form factor (F)
 Multilamination
 Bilamination
R
Re 
ρVD h

2  πR
Dh 
(  2)
Re CF
h
w
2 w  h
Dh 
(w  h)
ρ Q 
 
η  R π  2
Re ML 
F
ρ  2Q 
η  n w  h 
2 R (π  2)
n(w  h)
23
3. Copolymers (CMS)
 Micromixers
Fluid B
Fluid B
Fluid A
Fluid A
Fluid B
Fluid A
Mixing by …
Bilamination
Multilamination
Multilamination
CF
ML45
ML20
ML50
Number of
microchannels
1
16
15
10
Film thickness
450µm
45µm
20µm
50µm
F
1
2.8
3.9
4.6
24
3. Copolymers (CMS)
 Continuous two-step block copolymerization (cont’d)
 1st block
Microtube
Batch
T1 = 140°C
1 = 190 min
- 3:1 vol. BA/Toluene
- "High" [AX]0
Not purified
- 5% mol. free TIPNO
- 2 equiv. Acetic
BA Conversion (%)
91
95
Theoretical Mn
(g/mol)
33600
34900
Experimental Mn
(g/mol)
26600
29700
PDI
1.44
1.80
Rosenfeld et al., Chem. Eng. Sci., 62 (2007) 5245-5250.
anhydride
25
3. Copolymers (CMS)
 Continuous two-step block copolymerization (cont’d)
 Copolymer
Batch process
Continuous process
T2 = 125°C
2 = 190 min
Not purified
ML50
BA/S Conversions
ML20
CF
BR
93% / 44%
96% / 50%
99% / 36%
99% / 50%
Th. Mn (g/mol)
37100
40100
37800
43300
Exp. Mn (g/mol)
34700
36600
26600
33600
PDI
1.28
1.40
1.73
1.74
(1H NMR)
(PS equiv.)
Rosenfeld et al., Chem. Eng. J., 15 (S1) (2008) S242-S246
26
3. Copolymers (CMS)
 Continuous two-step block copolymerization (cont’d)
 Influence of the micromixer geometry
2
- Most efficient
micromixer
tested: wider and
fewer
microchannels
ML20
 Mainly
controlled by the
velocity
CF
1.8
PDI Ip
Q2=9.3 µL/min
ML45
1.6
1.4
ML50
1.2
0.5
1.5
2.5
Re'
F
3.5
4.5
Rosenfeld et al., Lab. Chip., 8 (2008) 1682-1687
5.5
27
Outline
 1. Context
 2. Microprocess overview
 3. Results
 Synthesis of linear, block and branched (co)polymers
– Influence of micromixing
– Influence of microreactor geometry
– Influence of pressure
 CFD Analysis
 4. Conclusion
28
3. Microreactor geometry (CMS)
PDI
 Recall one-step statistical copolymerization in CT
5000
10000
15000
Mn
20000
25000
 Microreactor with internal mixing to overcome diffusion limitations
29
3. Microreactor geometry (CMS)
 Linear polymers
 Atom Transfer Radical Polymerization (ATRP)
– Librairies of poly(DMAEMA) / CT vs. CFI
Nitrogen generator
Solvent
Catalyst
Ligand
Monomer
Comonomer
Initiator
HPLC Pump
HPLC Pump
Micromixer
P
Pressure sensor
Microreactor
Online GPC Analysis
(CORSEMP)
T
Temperature Regulator
Waste
NMR Analysis
30
3. Microreactor geometry (CMS)
 Linear polymers (cont’d)
ID= 876 µm
Conversion (%)
80
60
CT, 3 m
40
20
CT
CFI
0
0
30
60
90
120
CFI, 3 m
Time (min.)
 No significant increase in conversion between CT and CFI
Parida et al., Macromolecules, 47 (10) (2014) 3282–3287.
31
3. Microreactor geometry (CMS)
25000
2
20000
1.8
15000
1.6
10000
ID= 876 µm
PDI
Mn (g/mol)
 Linear polymers (cont’d)
CT, 3 m
1.4
5000
CT
1.2
CFI
0
1
0
20
40
60
80
Conversion (%)
CFI, 3 m
 Mn is higher in case of CFI (avg. +2000 g/mol)
 Significant reduction in PDI for CFI (-0.13)
Parida et al., Macromolecules, 47 (10) (2014) 3282–3287.
32
3. Microreactor geometry (CMS)
 RTD measurements
1,4E-03
1,2E-03
1,0E-03
E(t)
8,0E-04
6,0E-04
4,0E-04
2,0E-04
0,0E+00
0
50
100
150
200
t(min)
Reactor
Variance (s²)
Pe (-)
Dax (m²/s)
CT
605
286
2.5 x 10-5
CFI
322
1004
7.14 x 10-6
 RTD is narrower in CFI compared to CT
 High Pe in case of both reactors indicates low axial dispersion
Parida et al., Macromolecules, 47 (10) (2014) 3282–3287.
33
3. Microreactor geometry (CMS)
 Branched polymers
 Self-Condensing vinyl coPolymerization, adapted to ATRP
Inimer = Monomer + Initiator
m
a- b
2-(2-bromoisobutyryloxy)ethyl
methacrylate (BIEM)
Matyjaszewskiet al., Macromolecules 1997, 30, 5192
34
3. Microreactor geometry (CMS)
 Branched polymers (cont’d)
35
3. Microreactor geometry (CMS)
 Branched polymers (cont’d)
 DMAEMA and BIEM conversions
Inimer Conversion (%)
80
+ 7.5%
60
40
Batch
20
CT
CFI
0
0
30
60
90
120
Time (min.)
 Higher BIEM conversion for CFI
Parida et al., Macromolecules, 47 (10) (2014) 3282–3287.
36
3. Microreactor geometry (CMS)
 Branched polymers (cont’d)
 GPC traces – Batch reactor
 Presence of BIEM-initiated macromonomers/oligomers
Parida et al., Macromolecules, 47 (10) (2014) 3282–3287.
37
3. Microreactor geometry (CMS)
 Branched polymers (cont’d)
 GPC traces (2 hrs)
10 %
Normalized Intensity (a.u.)
Normalised Intensity (a.u.)
5%
Batch
6
CT
Batch
CFI
7
8
Elution time (min.)
9
6
CT
7
8
Elution time (min.)
CFI
9
 Highest oligomeric units in batch
 Lowest in CFI
Parida et al., Macromolecules, 47 (10) (2014) 3282–3287.
38
3. Microreactor geometry (CMS)
 Branched polymers (cont’d)
 Polymer characteristics (BIEM 5mol% @ 2 hrs)
3
3500
+700
2.5
2500
PDI
Mn (g/mol)
3000
2000
-0.28
2
Batch
1500
CT
CFI
1000
1.5
0
20
40
60
80
100
120
Time (min.)
 Mn exhibits the following trend: batch < CT < CFI
 PDI follows the opposite trend: batch > CT > CFI
Parida et al., Macromolecules, 47 (10) (20141)3282–3287
39
3. Microreactor geometry (CMS)
 Branched polymers (cont’d)
 Impact of flow inversion on molecular characteristics
 Highest branching efficiency in CFI and lowest in batch
 Controlled branched structure in microreactors especially in CFI
Parida et al., Macromolecules, 47 (10) (20141)3282–3287
40
Outline
 1. Context
 2. Microprocess overview
 3. Results
 Synthesis of linear, block and branched (co)polymers
–
–
–
–
Influence of micromixing
Influence of microreactor geometry
Influence of pressure
Scale-up
 CFD Analysis
 4. Conclusion
41
3. Operating parameters (CMS)
 Effect of pressure
 Chemical system
42
3. Pressure (CMS)
 Effect of pressure
 Procedure
43
3. Pressure (CMS)
 Effect of pressure (cont’d)
 Polymer characteristics
80
25000
20000
40
20
1 Bar
50 Bar
0
0
20
40
60
1.4
15000
1.3
10000
PDI
60
Mn (g/mol)
Conversion (%)
1.5
1.2
5000
1.1
1 Bar
50 Bar
0
1
0
20
Time (minute)
40
60
80
Conversion (%)
 Decrease in activation volume
 Reduced termination
 Increased density, thus increased residence time
Parida et al., J. Flow Chem., 4 (2) (2014) 92-96.
44
3. Pressure (CMS)
 Effect of pressure (cont’d)
 Microreactor dimension
576 µm
876 µm
1753 µm
Parida et al., J. Flow Chem., 4 (2) (2014) 92-96.
45
3. Pressure (CMS)
 Effect of pressure (cont’d)
 Microreactor dimension
 Reduced diffusion distance
Parida et al., J. Flow Chem., 4 (2) (2014) 92-96.
46
Outline
 1. Context
 2. Microprocess overview
 3. Results
 Synthesis of linear, block and branched (co)polymers
–
–
–
–
Influence of micromixing
Influence of microreactor geometry
Influence of pressure
Scale-up
 CFD Analysis
 4. Conclusion
47
Inlet
48
Inlet
Outlet
49
Inlet
Outlet
50
Inlet
Position of two
tracer particles
51
Outline
 1. Context
 2. Microprocess overview
 3. Results
 Synthesis of linear, block and branched (co)polymers
– Influence of micromixing
– Influence of microreactor geometry
– Influence of pressure
 CFD Analysis
 4. Conclusion
52
4. Conclusion
 NMP and ATRP processes can be intensified




Higher monomer conversion
Higher MW
Narrower MWD (lower PDI)
Better controlled architecture (higher branching rates)
 Microreactors and micromixers
 Efficient intensification tools
 New operating windows (Higher P, Higher T)
 CFI
– A chaotic mixer/reactor
• Better internal mixing
• Narrower RTD
– Smaller foot print than ST
53
4. Acknowledgements
 Faculty
 Students
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
N. Sary
M. Quentin
N. Berton
C. Rosenfeld
E. Godard
B. Reynard
A. Filliung
J. Quillé
C. Zhang
S. Trotzier
F. Bally
C. Kister
A. Ali
P. Gonzales
D.K. Garg
D. Parida
–
–
–
–
 Collaborators
C. Brochon
M. Bouquey
R. Muller
G. Hadziioannou
 Staff
–
–
–
–
–
–
T.
J.
C.
C.
C.
C.
Djekrif
Quillé / S. Gallet
Mélart
Ngov
Sutter
Kientz
–
–
–
T. Vandamme & N. Anton
(CAMB)
K. Nigam (IIT Dehli)
Y. Hoarau (IMFS)
 Industrial partners
–
–
S. O’Donohue (PL)
V. Hessel (IMM)
 Financial support
EAc 4379
« Ponts Couverts » in Strasbourg
54
Thank you for your attention
55
Increasing throughput
 Polymer in solution
8 microtube reactors in parallel for the production of
to 4 kg per week of PMMA
Yoshida and coll., Org. Process Res. Dev., 10 (2006) 1126-1131
56