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Process Intensification as Viewed by Synthetic Chemists

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Contributed by Tao Li, National Risk Management Research Laboratory, Office of Research and Development, US Environmental Protection Agency

The concept of “Process intensification (PI)” was introduced in the late 1970’s when Ramshaw and Mallison of ICI invented the rotating packed bed contactor to promote gas-liquid mass transfer. By then PI was narrowly defined as “The physical miniaturization of process equipment, while retaining throughput and performance[1]. In the same vein, different types of equipment and engineering technologies have been invented over the past four decades, to serve a more general purpose of developing clean, safe, efficient, and more robust processes. As such, PI is increasingly important in Green Synthesis as it offers more and more options to improve the sustainability of chemical processes.

Process development is a complex task that involves participants from different fields. As the primary stakeholders, synthetic chemists need to share an effective conceptual framework with engineers, so as to identify opportunities for PI early. The engagement of chemists and engineers starts from early development, when hazardous reactions or reagents are evaluated, and scale effects are studied. In full development, this collaboration expands to all aspects after a route is selected and the sequence of intermediates has been established. They take different roles to address the issues including safety, health and environment, quality and process control, production throughput, and economy.[2] To prioritize their efforts, it is critical to understand the limits of the technologies from both chemistry and engineering perspectives. Indeed, when classical process optimization cannot meet the expectation, the development team should look into PI for chemical engineering solutions, which involves maximizing the driving forces to overcome the limitation in conventional processes.[3]

To carry out a batch reaction, the reactants, solvents, and auxiliaries are mixed by a well-defined procedure until the entire starting material inventory ends up in the reactor. The evaluation of reaction scale up involves the study of many variables such as time to charge, charge method, sequence of addition, mixing time, mass transfer, and heat transfer. A set of critical process parameters (CPP, e.g., up to 10) are prescribed to control the course of reactions and energy exchange.[4] Systematic optimization of a large number of CPPs can be challenging and tedious, especially when discrete variables are involved. As the batch scale increases, energy exchange is slowed because the surface to volume ratio decreases.  Reaction selectivity will be reduced as side reactions become more significant in a prolonged operation scenario. For hazardous reactions, the batch scale is limited since a larger inventory increases process risk.

The issues in batch reactions can be simplified by decoupling the driving forces from scale-up factors with several functions that can be integrated in a design. One important example is microfluidic reactor. It uses configuration design and tuning of flow rate to meet the needs for mass and energy transport, thereby reducing the factors for consideration in scale up. The reactor is minimized with a high volume-to-surface ratio and a defined flow pattern to enhance mass transfer and energy transfer. In theory, this reactor also enables accurate application of additional forces (e.g. alternative energy) to the reaction mixture. Microfluidic reactors also use continuous mode of operation, thereby creating an ideal plug flow type reactor to carry out reactions at steady state under optimized conditions. When used for chemical preparation, microfluidic reactor can be used directly by numbering up (parallel use of multiple units); or scaled up with other flow reactors (meso-fluidic, tube, column, micro-channel, etc), which offer the same advantages for Green Chemistry. Such benefits can include:

  • Atom Economy: With better condition control and more efficient mixing, reaction selectivity is improved. As a result, reaction yield is increased and the process mass intensity (PMI) is reduced.

  • Less hazardous synthesis: Flow reactors have reduced reactant hold-up and rapid heat dissipation, which leads to reduced reaction risk.  Reactive reactants (e.g. hydrogen) or intermediates can be generated in situ to avoid risk associated to large inventory.

  • Design for energy efficiency: Smaller reactor volume (> 100 fold volume reduction from batch reactor), more accurate energy management, and increased process throughput all contribute to potential energy savings.

  • Catalysis: Catalyst immobilization is feasible (E.g. catalytic hydrogenation)

  • Real time analysis for in-process monitoring: Real time analyses, especially non-invasive analyses (e.g., IR, calorimetry), are simple and direct with flow reactor since the reaction is at steady state.

The microfluidic reactor is particularly suitable for reactions that are limited by mass or heat transfer in batch reactors. They also accelerate reactions by creating operation windows (i.e. conditions) unachievable in batch reactors.[5] For example, by using a pressure-resistant microstructure inline, the reaction can proceed at temperatures above the boiling point of the solvent and high pressure, thus creating conditions more forceful than that under reflux. This also allows for uniform application of alternative energy (e.g. electromagnetic radiation) to the reaction mixture.

In general, PI can break the limitation of conventional process by meeting the following four main objectives:[6]

  1. To maximize the effectiveness of intra- and intermolecular events
  2. To give each molecule the same processing experience
  3. To optimize the driving forces/maximize specific interfacial area
  4. To maximize the synergistic effects of partial processes

Table 1. Some PI technologies that have been used to serve synthetic chemistry

PI Table.png

In a survey of about 1000 patents and a search of scientific publications, The European Roadmap for Process Intensification has identified 72 of PI technologies.[7] They are organized into hardware (Equipment) and Software (Method) groups. They are further classified into subgroups based on their intended uses, and characterized by the benefit they offer and challenges to implement. For synthetic chemists, building awareness starts from understanding the basics of most popular PI technologies (Table 1).[8]

Typically, synthetic chemists conduct route scouting with lab glassware, which resembles batch reactors. These batch reactions offers several important advantages in early development. They are inexpensive, can be used for multiple products, flexible to handle reaction conditions, and more suitable for slow reactions which are not limited by mixing or heat transfer. In general, batch reactors can accommodate most reactions at small scale. They are also suitable for advanced process strategies such as concurrent reactions (e.g. dynamic kinetic resolutions, crystallization induced transformations, cascade reactions, etc.) or telescoping synthesis. When large scale production is needed, then scale-up limitation becomes critical, thus creating opportunities to retrofit the processes with PI technology by chemical engineers.

Direct translation of bench protocol to practical preparation employing PI technologies remains challenging to chemists. The most critical issue is the availability of plug-and-play, small scale PI equipment that is suitable for both process development research and practical preparation at gram-to-kilo scale. The equipment needs to be multipurpose, flexible to handle different reaction conditions, and suitable for systematic study with small quantity of reagent chemicals. This will enable chemists to better appreciate the benefit of PI technologies and identify opportunities for early application. It has been generally accepted that PI can be used to improve reaction efficiency and selectivity, break the limitation imposed by reaction equilibrium, mitigate scale-related risks, and reduce the variables in scale up optimization. For commercial manufacture, it can reduce the facility footprint and production lead time.

Flow chemistry is the most versatile PI technology for synthetic chemistry.[9] Currently, micro-scale flow reactors, including those for hydrogenation or ozonolysis, are available from multiple vendors.They allow chemists to simplify scale up by selectively studying the impact of mixing efficiency, temperature, stoichiometry, and other variables. The scale up is relatively straight forward as larger flow reactor (e.g. PLANTRIX®, tonnage scale) have similar operation range and flexibility. Ultimately, end-to-end synthesis can be built by integrating multiple flow reactions with work up and isolation modules.[10]

Disclaimer: This document has been reviewed in accordance with U.S. Environmental Protection Agency (EPA) policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.


1. W. T. Cross, and C. Ramshaw, Chem. Eng. Res. Des., 1986, 64, 293-301

2. D. J. Ager, in Process Understanding, ed. I. Houson, Wiley-VCH, Weinheim, Germany, 2011, pp. 17-58

3. S. Curcio, in Sustainable Development in Chemical Engineering: Innovative Technologies, ed V. Piemonte, M. De Falco, Wiley, Chichester, UK, 2013, pp 95-116

4. A. D. Bream, J. T. Sweeny, and J. W. Tom, in Chemical Engineering in the Pharmaceutical Industry: R&D to Manufacturing, ed D. J. am Ende. Wiley, US, 2011, pp 379-405

5. V. Hessel, D. Kralisch, N. Kockmann, T. Noel, and Q. Wang, ChemSusChem, 2013, 6, 746-789

6. A. Gòrak, and A. Stankiewicz, Annu. Rev. Chem. Biomol. Eng. 2011, 2, 431-451

7., accessed on Jan 4, 2015

8. (a) Process Intensification for Green Chemistry, ed. K. Boodhoo, and A. Harvey, Wiley Chichester, Sussex, UK 2013;

    (b) I. A. Sutherland, J. Chromatogr. A, 2007, 1151, 6-13

9. I. R. Baxendale, R. D. Braatz, B. K. Hodnett, K. F. Jensen, M. D Johnson, P. Sharratt, J-P. Sherlock,  and A. J. Florence, J. of Pharmaceut. Sci. 2014, DOI: 10.1002/jps.24252

10. S. Mascia, P. L. Heider, H. Zhang, R. Lakerveld, B. Benyahia, P. I. Barton, R. D. Braatz, C. L. Cooney, J. M. Evans, T. F. Jamison, K. F. Jensen, A. S. Myerson AS, B. L. Trout, Angew Chem Int Ed Engl. 2013, 52, 12359-12363

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