Process Intensification Tools in the Small‐Scale Pharmaceutical Manufacturing of Small Molecules

The chemical process industry is paying significant attention to the intensification of processes with the main aim of achieving increased productivity, improved economic status, and enhanced sustainability. The pharmaceutical industry is moving in the same direction and, therefore, dozens of processes are in a state of change. However, it is important to note that not all processes can be intensified easily, such as slow chemical reactions, processes with solids, slurries, and on the like. This review summarizes applications of promising tools for achieving process intensification in the small-scale pharmaceutical manufacturing of so-called small molecules. The focus is on microwave radiation, microreactors, ultrasounds, and meso-scale tubular reactors.

[1]  Barry M. Trost,et al.  Applications of transition metal catalysis in drug discovery and development : an industrial perspective , 2012 .

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

[3]  Dusan Boskovic,et al.  Novel multifunctional microreaction unit for chemical engineering , 2004 .

[4]  Timothy J. Mason,et al.  Industrial sonochemistry: potential and practicality , 1992 .

[5]  Wei Ge,et al.  From Multiscale Modeling to Meso-Science: A Chemical Engineering Perspective , 2013 .

[6]  H. Löwe,et al.  Chemistry in microstructured reactors. , 2004, Angewandte Chemie.

[7]  Lukas Küpper,et al.  An Ozonolysis−Reduction Sequence for the Synthesis of Pharmaceutical Intermediates in Microstructured Devices , 2009 .

[8]  Klavs F Jensen,et al.  An integrated microreactor system for self-optimization of a Heck reaction: from micro- to mesoscale flow systems. , 2010, Angewandte Chemie.

[9]  K. Prasad,et al.  The Art of Meeting Palladium Specifications in Active Pharmaceutical Ingredients Produced by Pd-Catalyzed Reactions , 2004 .

[10]  Angel Díaz-Ortiz,et al.  Microwaves in organic synthesis. Thermal and non-thermal microwave effects. , 2005, Chemical Society reviews.

[11]  Gjalt W Huisman,et al.  On the development of new biocatalytic processes for practical pharmaceutical synthesis. , 2013, Current opinion in chemical biology.

[12]  Atsushi Urakawa,et al.  On-chip Raman analysis of heterogeneous catalytic reaction in supercritical CO2: phase behaviour monitoring and activity profiling. , 2008, The Analyst.

[13]  A. Manz,et al.  Miniaturized total chemical analysis systems: A novel concept for chemical sensing , 1990 .

[14]  Matthew B. Kerby,et al.  Measurements of kinetic parameters in a microfluidic reactor. , 2006, Analytical chemistry.

[15]  Steven V Ley,et al.  Microwave-assisted Suzuki coupling reactions with an encapsulated palladium catalyst for batch and continuous-flow transformations. , 2006, Chemistry.

[16]  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 .

[17]  C. Kappe,et al.  Controlled microwave heating in modern organic synthesis. , 2004, Angewandte Chemie.

[18]  Shahriyar Taghavi-Moghadam,et al.  Microreaction Technology as a Novel Approach to Drug Design, Process Development and Reliability , 2001 .

[19]  K. Savin,et al.  A study of the synthesis of triazoles using microwave irradiation , 2004, Molecular Diversity.

[20]  Rob C. Wheeler,et al.  Continuous Flow Microwave-Assisted Reaction Optimization and Scale-Up Using Fluorous Spacer Technology , 2008 .

[21]  K. Suslick,et al.  Applications of Ultrasound to the Synthesis of Nanostructured Materials , 2010, Advanced materials.

[22]  C. R. Strauss,et al.  Toward rapid, "green", predictable microwave-assisted synthesis. , 2005, Accounts of chemical research.

[23]  Gjergji Shore,et al.  Propargyl amine synthesis catalysed by gold and copper thin films by using microwave-assisted continuous-flow organic synthesis (MACOS). , 2010, Chemistry.

[24]  Paul Watts,et al.  Solution phase synthesis of β-peptides using micro reactors , 2002 .

[25]  Mary M. Kirchhoff,et al.  Catalysis as a foundational pillar of green chemistry , 2001 .

[26]  M. Larhed,et al.  Microwave methods in organic synthesis , 2006 .

[27]  N. Kockmann,et al.  Microreactor Technology and Continuous Processes in the Fine Chemical and Pharmaceutical Industry: Is the Revolution Underway? , 2008 .

[28]  Dominique M. Roberge,et al.  Microreactor Technology: A Revolution for the Fine Chemical and Pharmaceutical Industries? , 2005 .

[29]  Werner Bonrath,et al.  Microwave assisted synthesis – a critical technology overview , 2004 .

[30]  S. Haswell,et al.  Monitoring of chemical reactions within microreactors using an inverted Raman microscopic spectrometer , 2003, Electrophoresis.

[31]  E. B. Nauman,et al.  Static Mixers in the Process Industries—A Review , 2003 .

[32]  Andreas Kirschning,et al.  Ten key issues in modern flow chemistry. , 2011, Chemical communications.

[33]  B. W. Webb,et al.  Characterization of frictional pressure drop for liquid flows through microchannels , 2002 .

[34]  K. Jensen,et al.  Microreactor System for High-Pressure Continuous Flow Homogeneous Catalysis Measurements , 2011 .

[35]  Kwangbum Park,et al.  Design, fabrication and characterization of an integrated micro ammonia analysis system (IMAAS) with microreactor and in-plane type optical detector based on the Berthelot reaction , 2006 .

[36]  A. Wolf,et al.  Microreactors – A New Efficient Tool for Reactor Development , 2001 .

[37]  W. Little,et al.  Measurement of friction factors for the flow of gases in very fine channels used for microminiature Joule-Thomson refrigerators , 1983 .

[38]  Concepción Jiménez-González,et al.  Expanding GSK's solvent selection guide ― embedding sustainability into solvent selection starting at medicinal chemistry , 2011 .

[39]  Steven V Ley,et al.  Non-metal-catalysed intramolecular alkyne cyclotrimerization reactions promoted by focussed microwave heating in batch and flow modes. , 2005, Organic & biomolecular chemistry.

[40]  Rafiqul Gani,et al.  Process intensification: A perspective on process synthesis , 2010 .

[41]  Philip G. Jessop,et al.  Searching for green solvents , 2011 .

[42]  J. Yoshida,et al.  Grignard Exchange Reaction Using a Microflow System: From Bench to Pilot Plant , 2005 .

[43]  Simon J. F. Macdonald,et al.  Mesoscale Flow Chemistry: A Plug-Flow Approach to Reaction Optimisation , 2007 .

[44]  Paul Watts,et al.  Investigation of racemisation in peptide synthesis within a micro reactor. , 2002, Lab on a chip.

[45]  Y. Gonthier,et al.  Standing waves in a high frequency sonoreactor : Visualization and effects , 1998 .

[46]  C. Kappe,et al.  Microwaves in Organic and Medicinal Chemistry: KAPPE:MICROWAVES 2E O-BK , 2005 .

[47]  Paul Watts,et al.  Improving chemical synthesis using flow reactors , 2007, Expert opinion on drug discovery.

[48]  Timothy M. Braden,et al.  Improved Synthesis of 1-(Azidomethyl)-3,5-bis-(trifluoromethyl)benzene: Development of Batch and Microflow Azide Processes , 2009 .

[49]  P. Anastas,et al.  Green Chemistry , 2018, Environmental Science.

[50]  Eduardo Garcia-Egido,et al.  Synthesis and analysis of combinatorial libraries performed in an automated micro reactor system. , 2003, Lab on a chip.

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

[52]  William T. Richards,et al.  THE CHEMICAL EFFECTS OF HIGH FREQUENCY SOUND WAVES I. A PRELIMINARY SURVEY , 1927 .

[53]  A J de Mello,et al.  Microchip-based synthesis and analysis: control of multicomponent reaction products and intermediates. , 2001, The Analyst.

[54]  Daniele Vigo,et al.  Reaction of Grignard reagents with carbonyl compounds under continuous flow conditions , 2010 .

[55]  Charles A Nielsen,et al.  Novel tubing microreactor for monitoring chemical reactions. , 2002, Analytical chemistry.

[56]  Tapio Salmi,et al.  Utilization of electromagnetic and acoustic irradiation in enhancing heterogeneous catalytic reactions , 2005 .

[57]  T. Hatakeyama,et al.  Transition-metal-free electrophilic amination between aryl Grignard reagents and N-chloroamines. , 2010, Organic letters.

[58]  L. H. Thompson,et al.  Sonochemistry: Science and Engineering , 1999 .

[59]  Colin Ramshaw,et al.  Process intensification: laminar flow heat transfer , 1986 .

[60]  Jean-Louis Luche,et al.  Synthetic Organic Sonochemistry , 1998 .

[61]  Paul Watts,et al.  Green chemistry: synthesis in micro reactors , 2003 .

[62]  Tom Van Gerven,et al.  Structure, energy, synergy, time - the fundamentals of Process Intensification , 2009 .

[63]  Klavs F Jensen,et al.  Integrated microreactors for reaction automation: new approaches to reaction development. , 2010, Annual review of analytical chemistry.

[64]  Steven V Ley,et al.  Microwave reactions under continuous flow conditions. , 2007, Combinatorial chemistry & high throughput screening.

[65]  Johan Grievink,et al.  Process intensification and process systems engineering: A friendly symbiosis , 2008, Comput. Chem. Eng..

[66]  C. Leonelli,et al.  Microwave and ultrasonic processing: Now a realistic option for industry , 2010 .

[67]  P. Garstecki,et al.  Microfluidic Reactors for Polymer Particles: Kumacheva/Microfluidic Reactors for Polymer Particles , 2011 .

[68]  R. Bates.  Organic Synthesis Using Transition Metals: Bates/Organic Synthesis Using Transition Metals , 2012 .

[69]  Peter Styring,et al.  From discovery to production: Scale-out of continuous flow meso reactors , 2009, Beilstein journal of organic chemistry.

[70]  F. Liguori,et al.  Heterogenized Homogeneous Catalysts for Fine Chemicals Production , 2010 .

[71]  David Reay,et al.  Chapter 2 – Process Intensification – An Overview , 2013 .

[72]  Alan D. Curzons,et al.  Solvent selection guide: a guide to the integration of environmental, health and safety criteria into the selection of solvents , 1999 .

[73]  V. Hessel,et al.  Microstructured reactors for development and production in pharmaceutical and fine chemistry. , 2006, Ernst Schering Foundation symposium proceedings.

[74]  Steven V Ley,et al.  Flow and batch mode focused microwave synthesis of 5-amino-4-cyanopyrazoles and their further conversion to 4-aminopyrazolopyrimidines. , 2007, Organic & biomolecular chemistry.

[75]  Wenka Schweikert,et al.  Inline Analysis in Microreaction Technology: A Suitable Tool for Process Screening and Optimization , 2007 .

[76]  N. Leadbeater.  Microwave Heating As A Tool For Sustainable Chemistry , 2017 .

[77]  John M. Woodley,et al.  Reaction and Process Engineering , 2012 .

[78]  Se-Kwon Kim,et al.  Determination of kinetic parameters, Km and kcat, with a single experiment on a chip. , 2009, Analytical chemistry.

[79]  Wolfgang Ehrfeld,et al.  Microreactors: New Technology for Modern Chemistry , 2000 .

[80]  Ryan L. Hartman,et al.  Deciding whether to go with the flow: evaluating the merits of flow reactors for synthesis. , 2011, Angewandte Chemie.

[81]  C. R. Strauss,et al.  Development and Application of a Continuous Microwave Reactor for Organic Synthesis , 1994 .

[82]  A. Manz,et al.  Microstructure for efficient continuous flow mixing , 1999 .

[83]  N. Leadbeater,et al.  In situ Raman spectroscopy as a probe for the effect of power on microwave-promoted Suzuki coupling reactions. , 2007, Organic & biomolecular chemistry.

[84]  Wei Ge,et al.  Meso-scale oriented simulation towards virtual process engineering (VPE)-The EMMS Paradigm , 2011 .

[85]  Holger Löwe,et al.  Selectivity Gains and Energy Savings for the Industrial Phenyl Boronic Acid Process Using Micromixer/Tubular Reactors , 2004 .

[86]  F. Bonfils,et al.  Michael reactions carried out using a bench-top flow system. , 2006, Organic & biomolecular chemistry.

[87]  D. Mingos.  Theoretical Aspects of Microwave Dielectric Heating , 2009 .

[88]  Peter J. Dunn,et al.  Green chemistry tools to influence a medicinal chemistry and research chemistry based organisation , 2008 .

[89]  Catherine Boussard-Pledel,et al.  Remote analysis using IR glass fibers , 1999, Optics East.

[90]  Heterogeneous catalysts for clean technology:spectroscopy, design, and monitoring , 2013 .

[91]  Ignacio E. Grossmann,et al.  Research challenges in process systems engineering , 2000 .

[92]  M. de la Guardia,et al.  Green Analytical Chemistry , 2008 .

[93]  Frank J. Villani,et al.  Application of Microreactor Technology in Process Development , 2004 .

[94]  B. Maes,et al.  Microwave-assisted organic synthesis: scale-up of palladium-catalyzed aminations using single-mode and multi-mode microwave equipment , 2005 .

[95]  Roman Davis,et al.  Expedited Development through Parallel Reaction Screening: Application to PTC-Mediated Knoevenagel Condensation , 2010 .

[96]  Noel S. Wilson,et al.  Development and Applications of a Practical Continuous Flow Microwave Cell , 2004 .

[97]  Y. Nishihara.  Applied Cross-Coupling Reactions , 2013 .

[98]  Chin‐Fa Lee,et al.  Synthesis of aryl thioethers through the N-chlorosuccinimide-promoted cross-coupling reaction of thiols with Grignard reagents. , 2012, The Journal of organic chemistry.

[99]  C. Oliver Kappe,et al.  Translating High-Temperature Microwave Chemistry to Scalable Continuous Flow Processes , 2010 .

[100]  E. H Stitt.  Alternative multiphase reactors for fine chemicals: A world beyond stirred tanks? , 2002 .

[101]  E. Amis,et al.  Raman spectroscopic monitoring of droplet polymerization in a microfluidic device. , 2006, The Analyst.

[102]  Jens Geisler,et al.  Kinetics and Process Development for Deoxofluorination of a Steroid , 2008 .

[103]  C. Frech,et al.  Transition metal-free amination of aryl halides-A simple and reliable method for the efficient and high-yielding synthesis of N-arylated amines , 2009 .

[104]  Rafiqul Gani,et al.  Active pharmaceutical ingredient (API) production involving continuous processes--a process system engineering (PSE)-assisted design framework. , 2012, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[105]  M. J. Collins,et al.  Automated batch scale-up of microwave-promoted Suzuki and Heck coupling reactions in water using ultra-low metal catalyst concentrations , 2005 .

[106]  F. Dautzenberg,et al.  Process intensification using multifunctional reactors , 2001 .

[107]  Jeremy L. Steinbacher,et al.  Greener approaches to organic synthesis using microreactor technology. , 2007, Chemical reviews.

[108]  Volker Hessel,et al.  Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry , 2009 .