Design and Scaling Up of Microchemical Systems: A Review.

The past two decades have witnessed a rapid development of microreactors. A substantial number of reactions have been tested in microchemical systems, revealing the advantages of controlled residence time, enhanced transport efficiency, high product yield, and inherent safety. This review defines the microchemical system and describes its components and applications as well as the basic structures of micromixers. We focus on mixing, flow dynamics, and mass and heat transfer in microreactors along with three strategies for scaling up microreactors: parallel numbering-up, consecutive numbering-up, and scale-out. We also propose a possible methodology to design microchemical systems. Finally, we provide a summary and future prospects.

[1]  Manish Sharma,et al.  Mass transfer in packed liquid—liquid extraction columns , 1975 .

[2]  J. Charpentier,et al.  Mass-Transfer Rates in Gas-Liquid Absorbers and Reactors , 1981 .

[3]  Laurent Falk,et al.  A new parallel competing reaction system for assessing micromixing efficiency—Determination of micromixing time by a simple mixing model , 1996 .

[4]  Laurent Falk,et al.  A new parallel competing reaction system for assessing micromixing efficiency—Experimental approach , 1996 .

[5]  P. Umbanhowar,et al.  Monodisperse Emulsion Generation via Drop Break Off in a Coflowing Stream , 2000 .

[6]  Holger Krummradt,et al.  Experiences with the use of microreactors in organic synthesis , 2000 .

[7]  Klavs F. Jensen,et al.  Microfabricated multiphase packed-bed reactors : Characterization of mass transfer and reactions , 2001 .

[8]  S. Quake,et al.  Dynamic pattern formation in a vesicle-generating microfluidic device. , 2001, Physical review letters.

[9]  J. Santiago,et al.  Electrokinetic instability micromixing. , 2001, Analytical chemistry.

[10]  L. Proctor,et al.  Development of a Continuous Process for the Industrial Generation of Diazomethane1 , 2002 .

[11]  John R. Bourne,et al.  Mixing and the Selectivity of Chemical Reactions , 2003 .

[12]  Slobodan Panić,et al.  Experimental approaches to a better understanding of mixing performance of microfluidic devices , 2004 .

[13]  Ch. Wille,et al.  Synthesis of pigments in a three-stage microreactor pilot plant—an experimental technical report , 2004 .

[14]  Nam-Trung Nguyen,et al.  Micromixers?a review , 2005 .

[15]  V. Hessel,et al.  Micromixers—a review on passive and active mixing principles , 2005 .

[16]  Helmut Pennemann,et al.  Micromixer Based Liquid/Liquid Dispersion , 2005 .

[17]  J. Moulijn,et al.  Scaling down trickle bed reactors , 2005 .

[18]  P. Woias,et al.  Convective mixing and chemical reactions in microchannels with high flow rates , 2006 .

[19]  M. Schlüter,et al.  Experimental investigation of liquid–liquid mixing in T-shaped micro-mixers using μ-LIF and μ-PIV , 2006 .

[20]  K. Jensen,et al.  Multiphase microfluidics: from flow characteristics to chemical and materials synthesis. , 2006, Lab on a chip.

[21]  K. Jensen,et al.  Multistep continuous-flow microchemical synthesis involving multiple reactions and separations. , 2007, Angewandte Chemie.

[22]  L. Luo,et al.  Hydrodynamics and mass transfer characteristics in gas–liquid flow through a rectangular microchannel , 2007 .

[23]  David W. Agar,et al.  Liquid−Liquid Slug Flow in a Capillary: An Alternative to Suspended Drop or Film Contactors , 2007 .

[24]  Helen Song,et al.  Reactions in Droplets in Microfluidic Channels , 2007 .

[25]  Jianhong Xu,et al.  Correlations of droplet formation in T-junction microfluidic devices: from squeezing to dripping , 2008 .

[26]  Croon de Mhjm,et al.  Beckmann rearrangement of cyclohexanone oxime to ??-caprolactam in microreactors , 2009 .

[27]  Jianhong Xu,et al.  Liquid–liquid two‐phase flow in pore array microstructured devices for scaling‐up of nanoparticle preparation , 2009 .

[28]  Steven V. Ley,et al.  Development of fluorination methods using continuous-flow microreactors , 2009 .

[29]  Ryan L Hartman,et al.  Microchemical systems for continuous-flow synthesis. , 2009, Lab on a chip.

[30]  Kai Wang,et al.  Gas–liquid flow in T-junction microfluidic devices with a new perpendicular rupturing flow route , 2009 .

[31]  Elena Castro-Hernández,et al.  Scaling the drop size in coflow experiments , 2009 .

[32]  K. Sotowa,et al.  Flow Uniformity in Deep Microchannel Reactor under High Throughput Conditions , 2009 .

[33]  Klavs F. Jensen,et al.  Overcoming the Challenges of Solid Bridging and Constriction during Pd-Catalyzed C−N Bond Formation in Microreactors , 2010 .

[34]  Yuchao Zhao,et al.  Liquid-liquid two-phase flow and mass transfer characteristics in packed microchannels , 2010 .

[35]  Ryan L Hartman,et al.  Multistep microchemical synthesis enabled by microfluidic distillation. , 2010, Angewandte Chemie.

[36]  Drop production and tip-streaming phenomenon in a microfluidic flow-focusing device via an interfacial chemical reaction. , 2010, Langmuir : the ACS journal of surfaces and colloids.

[37]  A. Tonkovich,et al.  Microreaction Systems for Large‐Scale Production , 2010 .

[38]  Jonathan P. McMullen,et al.  An Automated Microfluidic System for Online Optimization in Chemical Synthesis , 2010 .

[39]  Laurent Falk,et al.  Performance comparison of micromixers , 2010 .

[40]  Kai Wang,et al.  Characterization and modeling of micromixing performance in micropore dispersion reactors , 2010 .

[41]  J. Aubin,et al.  Current methods for characterising mixing and flow in microchannels , 2010 .

[42]  Chun-Xia Zhao,et al.  Two-phase microfluidic flows , 2011 .

[43]  Albert Renken,et al.  Influence of Flow Regime on Mass Transfer in Different Types of Microchannels , 2011 .

[44]  Norbert Kockmann,et al.  Scale-up concept of single-channel microreactors from process development to industrial production , 2011 .

[45]  Norbert Kockmann,et al.  Scale-up concept for modular microstructured reactors based on mixing, heat transfer, and reactor safety , 2011 .

[46]  Klavs F. Jensen,et al.  Kinetic and Scale-Up Investigations of Epoxide Aminolysis in Microreactors at High Temperatures and Pressures , 2011 .

[47]  Ryan L. Hartman,et al.  Deciding Whether to Go with the Flow: Evaluating the Merits of Flow Reactors for Synthesis , 2011 .

[48]  C. Oliver Kappe,et al.  A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-butanones , 2011 .

[49]  Gary S. Calabrese,et al.  From batch to continuous flow processing in chemicals manufacturing , 2011 .

[50]  M.H.J.M. de Croon,et al.  Novel process windows – Concept, proposition and evaluation methodology, and intensified superheated processing , 2011 .

[51]  Thomas Wirth,et al.  A practical microreactor for electrochemistry in flow , 2011, Beilstein journal of organic chemistry.

[52]  Albert Renken,et al.  Gas–liquid and liquid–liquid mass transfer in microstructured reactors , 2011 .

[53]  Kai Wang,et al.  Droplet generation in micro-sieve dispersion device , 2011 .

[54]  Christophe A. Serra,et al.  Micromixer-assisted polymerization processes , 2011 .

[55]  Kai Wang,et al.  An Experimental Study of Liquid-Liquid Microflow Pattern Maps Accompanied with Mass Transfer , 2012 .

[56]  Cyril Aymonier,et al.  Supercritical microfluidics: Opportunities in flow-through chemistry and materials science , 2012 .

[57]  Ryan L. Hartman.  Managing Solids in Microreactors for the Upstream Continuous Processing of Fine Chemicals , 2012 .

[58]  Steven V Ley,et al.  A prototype continuous-flow liquid-liquid extraction system using open-source technology. , 2012, Organic & biomolecular chemistry.

[59]  Peter H Seeberger,et al.  Continuous-flow synthesis of the anti-malaria drug artemisinin. , 2012, Angewandte Chemie.

[60]  Klavs F. Jensen,et al.  Automated Multitrajectory Method for Reaction Optimization in a Microfluidic System using Online IR Analysis , 2012 .

[61]  K. Gernaey,et al.  Monitoring and Control of a Continuous Grignard Reaction for the Synthesis of an Active Pharmaceutical Ingredient Intermediate Using Inline NIR spectroscopy , 2012 .

[62]  Thorsten Röder,et al.  Application-Oriented Analysis of Mixing Performance in Microreactors , 2012 .

[63]  María José Nieves-Remacha,et al.  Hydrodynamics of Liquid–Liquid Dispersion in an Advanced-Flow Reactor , 2012 .

[64]  Yangcheng Lu,et al.  Process intensification of catalytic hydrogenation of ethylanthraquinone with gas‐liquid microdispersion , 2012 .

[65]  Kevin D. Nagy,et al.  Mixing and Dispersion in Small-Scale Flow Systems , 2012 .

[66]  Peter H Seeberger,et al.  Applying flow chemistry: methods, materials, and multistep synthesis. , 2013, The Journal of organic chemistry.

[67]  Kai Wang,et al.  Generating microbubbles in a co-flowing microfluidic device , 2013 .

[68]  Norbert Kockmann,et al.  Liquid–Liquid Test Reactions to Characterize Two-Phase Mixing in Microchannels , 2013 .

[69]  John R. Thome,et al.  Infrared imaging of temperature profiles in microreactors for fast and exothermic reactions , 2013 .

[70]  Klavs F. Jensen,et al.  Membrane-Based, Liquid–Liquid Separator with Integrated Pressure Control , 2013 .

[71]  Steven V Ley,et al.  An expeditious synthesis of imatinib and analogues utilising flow chemistry methods. , 2013, Organic & biomolecular chemistry.

[72]  A. Ewinger,et al.  In situ measurement of the temperature of water in microchannels using laser Raman spectroscopy , 2013 .

[73]  Volker Hessel,et al.  Novel process windows for enabling, accelerating, and uplifting flow chemistry. , 2013, ChemSusChem.

[74]  Duncan Guthrie,et al.  Continuous Flow-Processing of Organometallic Reagents Using an Advanced Peristaltic Pumping System and the Telescoped Flow Synthesis of (E/Z)-Tamoxifen , 2013 .

[75]  A. deMello,et al.  The past, present and potential for microfluidic reactor technology in chemical synthesis. , 2013, Nature chemistry.

[76]  D. T. McQuade,et al.  Continuous synthesis and use of N-heterocyclic carbene copper(I) complexes from insoluble Cu2O. , 2013, Organic letters.

[77]  Eugeny Y. Kenig,et al.  Micro-separation of fluid systems: A state-of-the-art review , 2013 .

[78]  T. A. Nijhuis,et al.  Phenylacetylene Hydrogenation over [Rh(NBD)(PPh3)2]BF4 Catalyst in a Numbered-Up Microchannels Reactor , 2013 .

[79]  D. Sauer,et al.  Continuous-Flow Microfluidic Electrochemical Synthesis: Investigating a New Tool for Oxidative Chemistry , 2013, Journal of Flow Chemistry.

[80]  Faïçal Larachi,et al.  Hydrodynamics of gas–liquid micro-fixed beds – Measurement approaches and technical challenges , 2013 .

[81]  María José Nieves-Remacha,et al.  Gas–Liquid Flow and Mass Transfer in an Advanced-Flow Reactor , 2013 .

[82]  Klavs F. Jensen,et al.  The Role of Flow in Green Chemistry and Engineering , 2013 .

[83]  Steven V Ley,et al.  Flow chemistry syntheses of natural products. , 2013, Chemical Society reviews.

[84]  Ankit Bansal,et al.  Chemometrics tools used in analytical chemistry: an overview. , 2014, Talanta.

[85]  F. Larachi,et al.  Two-phase flow hydrodynamic study in micro-packed beds – Effect of bed geometry and particle size , 2014 .

[86]  Kai Wang,et al.  Strategy for Scaling‐up of a Microsieve Dispersion Reactor , 2014 .

[87]  Kai Wang,et al.  Liquid–liquid microflows and mass transfer performance in slit-like microchannels , 2014 .

[88]  K. Jensen,et al.  9.03 Organic Synthesis in Small Scale Continuous Flow: Flow Chemistry , 2014 .

[89]  Klavs F. Jensen,et al.  Scalability of mass transfer in liquid-liquid flow , 2014 .

[90]  A. Kulkarni.  Continuous flow nitration in miniaturized devices , 2014, Beilstein journal of organic chemistry.

[91]  Norbert Kockmann,et al.  Novel three-dimensional microfluidic device for process intensification , 2014 .

[92]  John R. Thome,et al.  Intensification of highly exothermic fast reaction by multi-injection microstructured reactor , 2014 .

[93]  Kai Wang,et al.  Mass transfer characteristics of bubbly flow in microchannels , 2014 .

[94]  Kai Wang,et al.  Intensification of fast exothermic reaction by gas agitation in a microchemical system , 2014 .

[95]  Klavs F Jensen,et al.  Tools for chemical synthesis in microsystems. , 2014, Lab on a chip.

[96]  Claude de Bellefon,et al.  Milli-channel with metal foams under an applied gas–liquid periodic flow: Flow patterns, residence time distribution and pulsing properties , 2015 .

[97]  Volker Hessel,et al.  2- and 3-Stage temperature ramping for the direct synthesis of adipic acid in micro-flow packed-bed reactors , 2015 .

[98]  A. Shooshtari,et al.  Hydrodynamics and mass transfer performance of a microreactor for enhanced gas separation processes , 2015 .

[99]  V. Hessel,et al.  Beyond organometallic flow chemistry : the principles behind the use of continuous-flow reactors for synthesis , 2015 .

[100]  Connor W. Coley,et al.  Oscillatory Microprocessor for Growth and in Situ Characterization of Semiconductor Nanocrystals , 2015 .

[101]  Kai Wang,et al.  Liquid–liquid mixing enhancement rules by microbubbles in three typical micro-mixers , 2015 .

[102]  C. Oliver Kappe,et al.  Continuous-Flow Technology — A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients , 2015 .

[103]  Peter H Seeberger,et al.  Chemical assembly systems: layered control for divergent, continuous, multistep syntheses of active pharmaceutical ingredients. , 2014, Angewandte Chemie.

[104]  Claudio Battilocchio,et al.  Machine‐Assisted Organic Synthesis , 2015, Angewandte Chemie.

[105]  S. Kuhn,et al.  Hydrodynamic Study of Single- and Two-Phase Flow in an Advanced-Flow Reactor , 2015 .

[106]  Yong Jin,et al.  Simulation of liquid mixing inside micro-droplets by a lattice Boltzmann method , 2015 .

[107]  Richard J Ingham,et al.  Organic synthesis: march of the machines. , 2015, Angewandte Chemie.

[108]  Kai Wang,et al.  Bubble generation rules in microfluidic devices with microsieve array as dispersion medium , 2015 .

[109]  Peter H Seeberger,et al.  A concise flow synthesis of efavirenz. , 2015, Angewandte Chemie.

[110]  Kai Wang,et al.  Measurement of internal flow field during droplet formation process accompanied with mass transfer , 2015 .

[111]  K. Jensen,et al.  Characterization and modeling of multiphase flow in structured microreactors: a post microreactor case study. , 2015, Lab on a chip.

[112]  Volker Hessel,et al.  Accelerated gas-liquid visible light photoredox catalysis with continuous-flow photochemical microreactors , 2015, Nature Protocols.

[113]  R. Luque,et al.  Liquid phase oxidation chemistry in continuous-flow microreactors. , 2016, Chemical Society reviews.

[114]  Geoffrey R Akien,et al.  Online quantitative mass spectrometry for the rapid adaptive optimisation of automated flow reactors , 2016 .

[115]  Shuj Kobayashi,et al.  Flow “Fine” Synthesis: High Yielding and Selective Organic Synthesis by Flow Methods , 2015, Chemistry, an Asian journal.

[116]  Guangwen Chen,et al.  Hydrodynamics and mass transfer of oscillating gas‐liquid flow in ultrasonic microreactors , 2016 .

[117]  G. Luo,et al.  Kinetic Study and Intensification of Acetyl Guaiacol Nitration with Nitric Acid-Acetic Acid System in a Microreactor , 2016, Journal of Flow Chemistry.

[118]  Kai Wang,et al.  Determination of the Micromixing Scale in a Microdevice by Numerical Simulation and Experiments , 2016 .

[119]  V. Dua,et al.  Hydrodynamic effects on three phase micro-packed bed reactor performance – Gold–palladium catalysed benzyl alcohol oxidation , 2016 .

[120]  Jin Ho Jung,et al.  On-demand droplet splitting using surface acoustic waves. , 2016, Lab on a chip.

[121]  Jisong Zhang,et al.  Measuring enthalpy of fast exothermal reaction with infrared thermography in a microreactor , 2016 .

[122]  Klavs F Jensen,et al.  Feedback in Flow for Accelerated Reaction Development. , 2016, Accounts of chemical research.

[123]  Yung-Chiang Chung,et al.  Particles Sorting in Micro Channel Using Designed Micro Electromagnets of Magnetic Field Gradient , 2016 .

[124]  I. Rossetti,et al.  Chemical reaction engineering, process design and scale-up issues at the frontier of synthesis: Flow chemistry , 2016 .

[125]  Volker Hessel,et al.  Applications of Continuous-Flow Photochemistry in Organic Synthesis, Material Science, and Water Treatment. , 2016, Chemical reviews.

[126]  Leroy Cronin,et al.  Towards dial-a-molecule by integrating continuous flow, analytics and self-optimisation. , 2016, Chemical Society reviews.

[127]  S. Y. Wong,et al.  On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system , 2016, Science.

[128]  Marcus Baumann,et al.  The Synthesis of Active Pharmaceutical Ingredients (APIs) Using Continuous Flow Chemistry , 2016 .