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 Atelier de Prospective du GFP, Paris, Dec. 4 th, 2014

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 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

4 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

5 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

6 2. Overview Pump µreactor1 Pump µreactor2 MonomerA Solvent Initiator MonomerB Synthesis (CMS) µmixer Rosenfeld et al., React. Eng., 1 (5) (2007) ; Bally et al., React. Eng., 5 (11-12) (2011) 542–547 Copolymer  Polymerization microprocess

7 2. Overview Pump µreactor1 Pump µreactor2 MonomerA Solvent Initiator MonomerB Synthesis (CMS) GPC Column Waste SolventEluate Dilution Injection Analysis (COA) µmixer Train ofdetectors Copolymer  Polymerization microprocess Rosenfeld et al., React. Eng., 1 (5) (2007) ; Bally et al., React. Eng., 5 (11-12) (2011) 542–547

8 2. Overview Pump µreactor1 Pump µreactor2 MonomerA Solvent Initiator MonomerB Synthesis (CMS) GPC Column Waste SolventEluate Dilution Injection Analysis (COA) µmixer Train ofdetectors Copolymer Recovery (IPR) µmixer nanoparticles Non solvent µmixer solvent  Polymerization microprocess Rosenfeld et al., React. Eng., 1 (5) (2007) ; Bally et al., React. Eng., 5 (11-12) (2011) 542–547

9 To COA  Continuous-microflow synthesis unit 2. Synthesis (CMS)

10  Microreactors  Microtubular reactors (ID 876 µm) –Coiled tube (CT) 2. Synthesis (CMS)

11  Microreactors (cont’d)  Microtubular reactors (ID 876 µm) –Coiled tube (CT) –Coil flow inverter (CFI) Better mixing Lower RTD 2. Synthesis (CMS) Inlet Outlet End of the helix After 1 st bend After 2 nd bend A.K. Saxena and K.D.P. Nigam, AIChE J., 1984, 30,

12  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 2. Microprocess features

13  Fully automated  Software controlled  Over night experiments –Pressure sensors –Temperature probes  Modular  New reaction blocks  New detectors –Raman –NIR  Inline polymer recovery  Colloidal suspension 2. Microprocess features

14 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

15  Continuous one-step statistical copolymerization  Atom Transfer Radical Polymerization (ATRP) –Librairies of poly(DMAEMA-BzMA) / Influence of micromixer 3. Copolymers (CMS)

16  Continuous one-step statistical copolymerization  Continuous-flow setup 3. Copolymers (CMS) 75°C

17  Continuous one-step statistical copolymerization (cont’d)  Micromixers 3. Copolymers (CMS) Parida et al., Green. Proc. Synt., 6 (1) (2012) MicromixersNamePrinciple Number of channels/ Inlet Channel width T- Junction Bilamination1450 micron HPIMMDigital Multilamination 1545 micron KM CC-2Impact mixing5100 micron

18  Continuous one-step statistical copolymerization (cont’d) 3. Copolymers (CMS) Parida et al., Green. Proc. Synt., 6 (1) (2012) %

19  Continuous one-step statistical copolymerization (cont’d) 3. Copolymers (CMS) Parida et al., Green. Proc. Synt., 6 (1) (2012) , %

20  Continuous one-step statistical copolymerization (cont’d) 3. Copolymers (CMS) Parida et al., Green. Proc. Synt., 6 (1) (2012) X100

21  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 3. Copolymers (CMS)

22 Multilamination Fluid B Fluid A Number of microchannels Film thickness 450µm20µm50µm ML50 16 ML20 ML45 45µm CF Bilamination Fluid A Fluid B Mixing by … Fluid B Fluid A Multilamination  Micromixers 3. Copolymers (CMS)

23  Bilamination  Multilamination  Sorting by form factor (F) 3. Copolymers (CMS)

24 Multilamination Fluid B Fluid A Number of microchannels Film thickness 450µm20µm50µm ML50 16 ML20 ML45 45µm CF Bilamination Fluid A Fluid B Mixing by … Fluid B Fluid A Multilamination  Micromixers F Copolymers (CMS)

25 T 1 = 140°C  1 = 190 min Microtube Batch BA Conversion (%)9195 Theoretical M n (g/mol) Experimental M n (g/mol) PDI :1 vol. BA/Toluene - "High" [AX] 0 - 5% mol. free TIPNO - 2 equiv. Acetic anhydride Not purified  Continuous two-step block copolymerization (cont’d)  1 st block Rosenfeld et al., Chem. Eng. Sci., 62 (2007) Copolymers (CMS)

26 T 2 = 125°C  2 = 190 min Continuous process Batch process BA/S Conversions ( 1 H NMR) 93% / 44%96% / 50%99% / 36%99% / 50% Th. M n (g/mol) Exp. M n (g/mol) (PS equiv.) PDI ML20CF BR Not purified ML50  Continuous two-step block copolymerization (cont’d)  Copolymer Rosenfeld et al., Chem. Eng. J., 15 (S1) (2008) S242-S Copolymers (CMS)

Re' I p Q 2 =9.3 µL/min CF ML50 ML20 ML45 PDI - Most efficient micromixer tested: wider and fewer microchannels  Mainly controlled by the velocity  Continuous two-step block copolymerization (cont’d)  Influence of the micromixer geometry F Rosenfeld et al., Lab. Chip., 8 (2008) Copolymers (CMS)

28 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

29 Viscosity  Microreactor with internal mixing to overcome diffusion limitations 3. Microreactor geometry (CMS)  Recall one-step statistical copolymerization in CT

30  Linear polymers  Atom Transfer Radical Polymerization (ATRP) –Librairies of poly(DMAEMA) / CT vs. CFI 3. Microreactor geometry (CMS)

31  Linear polymers (cont’d)  No significant increase in conversion between CT and CFI CT, 3 m CFI, 3 m ID= 876 µm 3. Microreactor geometry (CMS) Parida et al., Macromolecules, 47 (10) (2014) 3282–3287.

32  Linear polymers (cont’d) ID= 876 µm 3. Microreactor geometry (CMS) CT, 3 m  Significant reduction in PDI for CFI (-0.13)  Mn is higher in case of CFI (avg g/mol) CFI, 3 m Parida et al., Macromolecules, 47 (10) (2014) 3282–3287.

33  RTD measurements 3. Microreactor geometry (CMS)  RTD is narrower in CFI compared to CT  High Pe in case of both reactors indicates low axial dispersion ReactorVariance (s²)Pe (-)Dax (m²/s) CT x CFI x Parida et al., Macromolecules, 47 (10) (2014) 3282–3287.

34  Branched polymers  Self-Condensing vinyl coPolymerization, adapted to ATRP m I m m m b a m m m* m b m b a m m a- b a m m* Inimer = Monomer + Initiator 2-(2-bromoisobutyryloxy)ethyl methacrylate (BIEM) Matyjaszewskiet al., Macromolecules 1997, 30, Microreactor geometry (CMS)

35  Branched polymers (cont’d) 3. Microreactor geometry (CMS)

36  Branched polymers (cont’d)  DMAEMA and BIEM conversions  Higher BIEM conversion for CFI + 7.5% 3. Microreactor geometry (CMS) Parida et al., Macromolecules, 47 (10) (2014) 3282–3287.

37  Branched polymers (cont’d)  GPC traces – Batch reactor  Presence of BIEM-initiated macromonomers/oligomers 3. Microreactor geometry (CMS) Parida et al., Macromolecules, 47 (10) (2014) 3282–3287.

38  Branched polymers (cont’d)  GPC traces (2 hrs) Parida et al., Macromolecules, 47 (10) (2014) 3282– Microreactor geometry (CMS)  Highest oligomeric units in batch  Lowest in CFI 5 % 10 %

39  Branched polymers (cont’d)  Polymer characteristics (BIEM 2 hrs) Parida et al., Macromolecules, 47 (10) (20141)3282– Microreactor geometry (CMS)  Mn exhibits the following trend: batch < CT < CFI  PDI follows the opposite trend: batch > CT > CFI

40  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– Microreactor geometry (CMS)  Branched polymers (cont’d)  Impact of flow inversion on molecular characteristics

41 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

42 3. Operating parameters (CMS)  Effect of pressure  Chemical system

43 3. Pressure (CMS)  Effect of pressure  Procedure

44 Parida et al., J. Flow Chem., 4 (2) (2014) Pressure (CMS)  Effect of pressure (cont’d)  Polymer characteristics  Decrease in activation volume  Reduced termination  Increased density, thus increased residence time

45 Parida et al., J. Flow Chem., 4 (2) (2014) Pressure (CMS)  Effect of pressure (cont’d)  Microreactor dimension 576 µm 876 µm 1753 µm

46 Parida et al., J. Flow Chem., 4 (2) (2014)  Effect of pressure (cont’d)  Microreactor dimension  Reduced diffusion distance 3. Pressure (CMS)

47 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

48 Inlet

49 Inlet Outlet

50 Inlet Outlet

51 Inlet Position of two tracer particles

52 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

53  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 4. Conclusion

54 4. Acknowledgements  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  Faculty –C. Brochon –M. Bouquey –R. Muller –G. Hadziioannou  Staff –T. Djekrif –J. Quillé / S. Gallet –C. Mélart –C. Ngov –C. Sutter –C. Kientz  Collaborators –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

55 Thank you for your attention

56 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)