Chemical Engineering Science 189 (2018) 431–448

Contents lists available at ScienceDirect

Chemical Engineering Science

journal homepage: www.elsevier.com/locate/ces

Review

A review on microreactors: Reactor fabrication, design, and cutting-edge

applications
Prashant L. Suryawanshi a, Sarang P. Gumfekar b,⇑, Bharat A. Bhanvase c, Shirish H. Sonawane a,⇑,
Makarand S. Pimplapure d
a
Department of Chemical Engineering, National Institute of Technology, Warangal, India
b
Department of Chemical and Materials Engineering, University of Alberta, AB, Canada
c
Department of Chemical Engineering, Laxminarayan Institute of Technology, Nagpur, India
d
Corning Technologies, India Pvt. Ltd., Pune 410501, India

h i g h l i g h t s

Materials for microreactor fabrication, fabrication methods, and design principles are presented.

Challenges in microreactor commercialization and need for integrated process is highlighted.

Applications of microreactors in the field of nanoparticles, polymers, organic chemicals, and medicines are presented.

a r t i c l e i n f o a b s t r a c t

Article history: This review focuses on the latest trends and advancements in microstructured reactors. With the recent
Received 26 February 2017 drive towards the production of miniaturized systems, microstructured reactors have gained significant
Received in revised form 9 March 2018 prominence in the chemical and process industries. Herein, we describe the fabrication, commercial
Accepted 15 March 2018
aspects, design principles, and cutting-edge applications of microreactors. An overview of the significant
Available online 16 March 2018
areas of application under broad categories such as biological and pharmaceutical applications, inorganic
and noble metal nanoparticles, and organic chemicals and polymers is also included. Finally, the article
Keywords:
discusses future research prospects and key issues on microstructured reactors.
Microreactor
Fabrication
Ó 2018 Elsevier Ltd. All rights reserved.
Micromixing
Nanoparticles
Lab-on-chip microreactor

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
2. Fabrication of microreactors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
2.1. Materials for fabrication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
2.2. Fabrication processes/techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
2.2.1. Micromachining . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
2.2.2. Lithographie, Galvanoformung, und Abformung (LIGA) technique . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
2.2.3. Etching . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 436
3. Design principles and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437
4. Cutting-edge applications of microreactors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
4.1. Biological and pharmaceutical applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438
4.2. Synthesis of nanoparticles in microreactors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
4.2.1. Synthesis of inorganic nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439
4.2.2. Synthesis of noble metal nanoparticles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
4.3. Synthesis of organic chemicals and polymers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442

⇑ Corresponding authors.
E-mail addresses: gumfekar@ualberta.ca (S.P. Gumfekar), shirish@nitw.ac.in (S.H. Sonawane).

https://doi.org/10.1016/j.ces.2018.03.026
0009-2509/Ó 2018 Elsevier Ltd. All rights reserved.
432 P.L. Suryawanshi et al. / Chemical Engineering Science 189 (2018) 431–448
5. Conclusions and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 444
1. Introduction
Advancements in science and technology have resulted in sig-
nificant developments in microreactors and microreactor-based
devices. Microreactor applications have expanded rapidly over
the last few decades, displaying the effectiveness of microreactors
over batch processes and existing large-size continuous reactors.
(Jorda and Vizza, 2012; Lavric and Cerato-noyerie, 2012; Phillips
et al., 2014; Yoshida et al., 2013; Zhang et al., 2011) Besides being
the ‘‘micro” form of a large-size reactor, a microreactor can also be
employed to improve various unit operations and reactions in
microspace. These miniaturized chemical reactors mainly offer
controllable and high-throughput methods for the synthesis of
chemicals with high yield, stability, selectivity, less energy con-
sumption, improved sample consistency, low reaction volume,
and homogeneity. (Capretto et al., 2013; Fanelli et al., 2017;
Fitzpatrick and Ley, in press; Liu et al., 2015a,b; Martínez-
cisneros et al., 2012; Movsisyan et al., 2016; Newman and
Jensen, 2013; Phillips et al., 2014; Wegner et al., 2012; Yoshida
et al., 2013) The simplest microreactors comprise a micrometer-
sized capillary tube (diameter < 1 mm) or a network of channels
fabricated into a substrate. In 1959, Professor Feynman brought
micromachining into the limelight by proposing the concept of a
micron-sized motor. Today, the field of microreactor technology
has grown out of micromachining into a discipline with its own
concepts. Hence, the keywords ‘‘MEMS,” ‘‘BioMEMS,” ‘‘Lab-On-
Chip,” ‘‘mTAS” (Micro Total Analysis Systems), and ‘‘microreactors”
have become synonymous to advanced microfluidic devices used
in a variety of cutting-edge applications. The work cited in this
review illustrates that compared to counterpart bulk reactions,
synthetic procedures carried out in microreactors invariably gener-
ate purer products in a much shorter time. The use of microreac-
tors has seen significant enhancement from its roots in analytical
systems to the high-throughput production of chemicals, efficient
screening of cells and proteins, fabrication of portable devices,
and the study of reaction kinetics. Thus, microreactors have gained
attention from academics as well as the chemical and pharmaceu-
tical industries. (Feng et al., 2015; Porta et al., 2016) To date, most
of the research has highlighted on the use of individual microreac-
tors; this has made it challenging to determine how best to utilize
their key characteristics. These include the fabrication methods
needed to achieve the desired resolution and size; determination
of length-scale for commercial use; and the possible fields to which
these microreactors can be applied. This work reviews recent
works carried out to address these key characteristics. However,
there is a need to develop microreactors with controlled surface
features for which, fabrication technologies must go beyond con-
ventional micromachining and MEMS techniques. To progress
beyond the laboratory into commercial production, microreactors
must be integrated with various types of sensors and actuators,
specific to the type of industry. This integration can possibly be
implemented on the same chip or via a hybrid integration scheme.
The packaging of multiple reactors and processes poses various
challenges in fluid handling and individual reactor control that
are absent in the traditional design of chemical plants. Wohlge-
muth et al. reported similar challenges for the biocatalytic pro-
cesses and subsequent product recovery of microfluidic devices.
(Wohlgemuth et al., 2015) Notably, research in this area has been
increasing exponentially, reflecting the growing importance of this
field. This review presents various aspects of microreactor
technology ranging from fabrication to cutting-edge applications.
Though we have described the basic design principles of microre-
actors, mathematical modeling and related issues are not discussed
herein; these have already been described by Hardt (Hardt, 2006).
2. Fabrication of microreactors
In 2013, microfluidic-based devices were valued at $1.6 billion
and the market is estimated to hit $5.7 billion by 2018. (Volpatti
and Yetisen, 2014) Advancements include the miniaturization of
reactors as well as enhancement in functionality. This milestone
will be reached through the development of novel materials for
microreactor fabrication, innovative and efficient designs, and inte-
gration of multiple unit operations into one device. To date,
microreactors are fabricated using a variety of materials including
polymers, silicon, metals, stainless steel, glass, and ceramics.
Nowadays, advantages in microfluidics technology have simplified
the fabrication of complex structures so that microreactors can be
fabricated as microcapillaries and chips. Microcapillary reactors
are fabricated from suitable tubing of desired length and material,
while chip-based reactors employ glass, silicon, or plastics that are
fabricated by micromachining, wet etching, and soft lithography
techniques. (Krishna et al., 2013; Phillips et al., 2014) Fig. 1
illustrates both forms of microreactors.
Microcapillary reactors are mainly used for chemical reactions to
attain high yields and conversions. (Jolliffe and Gerogiorgis, 2015;
Rossetti and Compagnoni, 2016) Such microreactors offer better
control on heat and mass transfer within the reaction. Yen et al.
recently synthesized CdSe colloidal nanocrystals in a continuous
flow microcapillary reactor comprising a convective mixer and a
heated glass reaction channel in the form of a capillary. (Yen et al.,
2003) Their results provided an insight into the kinetics of nanocrys-
tal nucleation and growth. Fig. 1A presents the schematic of a micro-
capillary reactor for the synthesis of CdSe nanocrystals.
A microreactor can also be fabricated as a chip that offers easy
control of microfluidics and integration of many processes into a
single device. Such microreactors contain a series of miniature
channels connected in a specific geometry to control the spatial
and temporal alteration of a small volume of fluid. Multistep chem-
ical syntheses have become possible due to miniaturized reaction
networks fabricated onto a chip. (Fitzpatrick and Ley, 2016;
Jensen et al., 2014) Kralj et al. fabricated a device capable of mixing
and separating several organic-aqueous and fluorous-aqueous
liquid-liquid systems. (Kralj et al., 2007) Fig. 1B presents the design
schematic of a multiprocess microreactor capable of mixing,
extraction, and phase separation; the extraction is reported to be
equivalent to one equilibrium extraction stage.
The broad range of literature on microreactors may appear
intimidating to chemical engineers and chemists more familiar
with conventional batch and stirred continuous reactors. Addition-
ally, techniques used for the fabrication of microreactors are fre-
quently adopted from the well-established microelectronics and
semiconductor industries. Herein, we systematically discuss the
fabrication and flow behavior of customized reactors for specific
applications.
2.1. Materials for fabrication
Microreactors can be fabricated using a broad range of materials
such as glass, ceramics, perfluoroalkoxy (PFA), silicon, polymers,
 P.L. Suryawanshi et al. / Chemical Engineering Science 189 (2018) 431–448 433

Fig. 1. (A) Schematic of a capillary-type microreactor for the synthesis of CdSe nanocrystals (Yen et al., 2003) and (B) chip-type multiprocess microreactor capable of mixing,
extraction, and phase separation (Kralj et al., 2007).

Fig. 2. Materials for the fabrication of microreactors for complex and challenging reactions: (A) silicon microreactor for the ignition study of propellants (Floyd et al., 2000);
(B) thin-walled microreactor for highly exothermic gas-phase reactions (Srinivasan et al., 1997); (C) energy-efficient chip-type microreactor that works on EOF (Tiggelaar
et al., 2007); and (D) polydimethylsiloxane (PDMS)-glass hybrid microreactor for protein synthesis (Fujii, 2002).

and steel. (Jensen, 2017; Dongfei Liu et al., 2015a,b; Martínez-
cisneros et al., 2012; Ren et al., 2014; Shang et al., 2017) The
selection of the material depends on various factors including the
operating conditions (pressure and temperature), physical properties
of the reaction mixture (pH, viscosity, phase, and reactivity), cost, the
ability of mass production, and ease of fabrication. Silicon is widely
available, relatively inexpensive, and very well characterized and
thus, is one of the most frequently used materials in microreactors.
Although it has been extensively used in microelectronic chip
applications, it is only in recent years that its use for microreactor
fabrication has expanded dramatically. Various industrially impor-
tant liquid and gas phase reactions can be realized using silicon
microreactors. Saksena et al. studied the ignition of hypergolic pro-
pellants (fuel-oxidizer pair) in a silicon microreactor. (Saksena
et al., 2015) These silicon microreactors can achieve excellent lam-
inar flow even in the presence of interfacial reactions. Floyd et al.
fabricated a microreactor (Fig. 2A) to carry out liquid phase reac-
tions that integrated laminar mixing, hydrodynamic focusing,
rapid heat transfer, and temperature sensing. (Floyd et al., 2000)
Thin-walled silicon microreactors can handle exothermic gas
phase reactions and allow the integration of heaters as well as flow
and temperature sensors on the external side of the reaction
region. (Srinivasan et al., 1997) These reactions can be performed
very rapidly in high conversion to enable the preparation of com-
binatorial libraries of various compounds (Fig. 2B). Nowadays, var-
ious types of polymers are attracting much attention as potential
materials for the fabrication of microreactors. Polymeric microre-
actors exhibit several advantages including tunable properties,
elastic flexibility, cost, ease of fabrication, and use as disposable
chips. The vast array of polymers available on the market makes
it difficult to provide a generalized discussion. Polymers used to
fabricate microfluidic devices can be broadly divided into two cat-
egories: polydimethylsiloxane (PDMS) and its modified versions
and thermoplastic polymers such as polyvinyl chloride (PVC), poly-
styrene (PS), polycarbonate (PC), poly(methyl methacrylate)
(PMMA), polyimide (PI), and olefin-based polymers. (Azouz et al.,
434 P.L. Suryawanshi et al. / Chemical Engineering Science 189 (2018) 431–448
Fig. 3. Typical process flow for the fabrication of polymeric microreactors. The blue line is assigned to the polydimethylsiloxane (PDMS)-based procedure, while the red line is
assigned to the thermoplastic-based procedure. (Tsao, 2016). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of
this article.)
2014; Fouillet et al., 2017; Halldorsson et al., 2015; Kucuk and
Edirisinghe, 2014; Zilio et al., 2014) Fig. 3 illustrates a typical strat-
egy for the fabrication of a polymeric microreactor. (Tsao, 2016)
PDMS is one of the most frequently used elastomers in the fabrica-
tion of microreactors since PDMS microchips can be fabricated
simply through microscale molding processes (Fig. 2D). Shah
et al. fabricated a PDMS microreactor for a proton exchange mem-
brane (PEM) fuel cell where all the cell components were vertically
stacked on the PDMS microreactor. (Shah et al., 2003) Hosokawa
et al. fabricated a high-performance low-cost micro total analysis
system (lTAS) using PDMS. (Hosokawa et al., 1999) PDMS-based
micro-devices are now capable of handling microliter to picoliter
scale volumes for various sensitive analyses. (Cooper et al., 2014;
Goyal et al., 2014; Liu et al., 2007) Numerous recent publications
have focused on PDMS as a promising material for the construction
of microreactors; however, its cost-effectiveness and compatibility
with existing process instrumentation has not been explored to
date. (Berthier et al., 2012) Therefore, from a commercialization
point of view, research efforts should be directed towards the scal-
able manufacture of PDMS-based microfluidic devices and other
low-cost materials. Recently, Azouz et al. fabricated a microfluidic
Table 1
Advantages and disadvantages of typical materials used for microreactor fabrication.
Material Advantages
Silicon
Cheaper

Well-characterized material

High-precision fabrication
Glass
Visualization of reaction and flow

Electroosmotic flow (EOF) possible

Withstands high operating pressures
Polymer
Low cost

Various fabrication techniques

Tunable properties

Disposable microreactors possible
Metal
No clean-room required

Durable materials

Well-established fabrication techniques
device using cyclic olefin copolymer (COC) films and the xurogra-
phy technique. (Azouz et al., 2014) They performed back-end poly-
mer bonding using a solvent vapor bonding technique. A complete
PVC-based microreactor for organic chemical synthesis was fabri-
cated by Quevedo et al. (Quevedo et al., 2005). This system only
requires a few minutes to construct while offering great flexibility
in the positioning of fluid junctions. Although polymers are poten-
tial candidates for the fabrication of microreactors, they can only
be used in applications where they are compatible. In many pro-
cesses, for example microreactor-based fuel cells, the temperature
is intrinsically maintained by the system by transferring the energy
consumed by a device to the environment. Thus, thermal load
management within small volumes of polymeric microreactors is
challenging.
Glass microreactors offer the benefit of visualizing the reaction
progress but are limited in reactor design due to the difficulty of
creating high aspect ratio structures. Still, they are a popular choice
for organic syntheses since they allow electroosmotic flow (EOF)
with various common polar solvents. In such reactors, pumping
is achieved by placing the electrodes in a reservoir and applying
voltages to enable EOF. (Hunter, 1981) Tiggelar et al. fabricated a
Disadvantages

Expensive fabrication techniques

Clean-room required

Difficulty in creating high aspect ratio structures

Chemical compatibility

Thermal stability

Replacement with noble metals possible

Issues with variable pressure drop
 P.L. Suryawanshi et al. / Chemical Engineering Science 189 (2018) 431–448
chip-type microreactor (Fig. 2C) using glass to synthesize carbamic
acid. (Tiggelaar et al., 2007) Yen et al. also demonstrated the repro-
ducible synthesis of CdSe nanocrystals in a glass microcapillary
reactor; however, due to design limitations, a convective mixer
was necessary to achieve the desired mixing. (Yen et al., 2003) Var-
ious studies have demonstrated that glass microreactors can suc-
cessfully handle operating pressures  4  107 Pa. (Andersson
et al., 2016; Martin et al., 2016).
Reacting systems that involve consistent high temperatures,
especially for power generation application, require a suitable
material to withstand the high enthalpy of the reaction mixtures.
Virgin polymeric materials may not be suitable candidates for such
reactions at this stage of innovation; however, organic-inorganic
(polymer-filler) composites have emerged as promising materials
for microreactor fabrication. Vican et al. utilized the highly concen-
trated dispersion of alumina powder in a UV-curable polymer to
convert fuel into electric power for commercial thermoelectric sys-
tems. (Vican et al., 2002) Researchers have successfully used vari-
ous types of metals to fabricate microreactors; however, it is
difficult to achieve surfaces with low roughness in metals. In our
recent work, we have synthesized palladium nanoparticles in
copper-based continuous flow microreactors for fuel cell applica-
tions. (Sharada et al., 2016) At optimum reaction conditions, we
produced nanoparticles 5 nm. Moreover, we discovered that
rapid mass transfer associated with intense mixing could signifi-
cantly improve the physical and chemical properties of the Pd
nanoparticles. We also demonstrated the synthesis of ultra-small
nanoparticles of platinum in a continuous flow microreactor at
room temperature (25–30 °C). (Suryawanshi et al., 2016) Table 1
lists the advantages and disadvantages of some common materials
used for microreactor fabrication.
Although significant attention has been given to the fabrication
methods of microreactors, literature on the effect of the construc-
tion material on the reaction mixture is scarce. This is mainly
because inertness between the microreactor surface and the react-
ing mixture is assumed. However, it is essential to consider the
molecular transformations of the reactants and the catalyzing
effect of the inner surface of the microreactor to avoid substantial
generation of undesirable by-products. Chemical syntheses in
microreactors typically involve various unit operations, presenting
challenges in terms of choice of method and material of fabrication,
mixing, handling of multiple phases, synthetic procedures, and
separation. Microreactors must be fabricated from chemically
compatible materials and designed to realize the fluid contacting
advantages inherent in microfluidics. Mills and Nicole studied
the effect of various microreactor materials on the oxidation of 1,
3-butadiene to furan. (Mills and Nicole, 2005) They demonstrated
that type 316 stainless steel, titanium, and iron could act as cata-
lysts for O2 conversion (1–10%) depending on the construction
material. This confirmed that the development of inert surfaces
in microreactors is necessary, especially where radicals are gener-
ated as part of the reaction.
To determine the effect of scale on the performance of a
microreactor, the surface area to volume ratio of the microchannel
needs to be considered. This varies inversely with channel dimen-
sion so that a reduction in channel length, from 5 mm to 0.05 mm,
results in a hundredfold increase in the surface area to volume
ratio. Thus, if the oxidation of 1, 3-butadiene to furan is carried
out in a channel of such reduced dimensions, wall catalysis will
play a significant role on the conversion of the reactant. The more
practical way to gauge the sensitivity of a reaction towards the
wall-catalysis effect is to carry out that reaction in microreactors
of different surface area to volume ratios and subsequently mea-
sure the reaction rate for each dimension. This approach can lead
to conclusions on the potential contribution of the scale effect
435
towards the performance of reactions performed in microreactors
(Savago and Benke, 2014).
2.2. Fabrication processes/techniques
A number of fabrication techniques meet the general require-
ments for the construction of an efficient and compact microreac-
tor. Thus, depending on the desired complexity, common methods
such as micromachining, wet etching, injection molding, laser
ablation microforming, soft lithography, photolithography, hot
embossing, nanoimprinting, electroforming, and micro-electro-
discharge machining can be used to fabricate microreactors.
(Acikgoz et al., 2011; Jena et al., 2012; Konstantinou et al., 2016;
Marre and Jensen, 2010; Vladisavljevic et al., 2013; Wilson et al.,
2011; Zhao et al., 2011) Some of the most commonly used methods
for the fabrication of advanced microreactors are described below
(Sections 2.2.1–2.2.3).
2.2.1. Micromachining
Generally, micromachining is a broad term that includes vari-
ous processes such as the fabrication, production, and manufactur-
ing of the MEMS. Developments in MEMS technology have focused
on the widespread promotion of microreactors for chemical analy-
sis and the production of hazardous and expensive specialty chem-
icals. (Guckenberger et al., 2015; Hashimoto et al., 2013; Jivani
et al., 2016; Ley, 2012; Roberge, 2012) Ultra-precision milling,
turning, and grinding processes can be used independently or in
combination to fabricate the microreactors. The quality of the sur-
face afforded from these processes is broad and depends on the
material employed and the machining parameters. Though these
are simple processes, the features generated by these techniques
are not as small as those afforded by advanced cutting-edge tech-
niques. The most common procedure is to remove the material by
melting, evaporation, decomposition, photoablation, or a combina-
tion of these techniques. Precision machining can be performed by
spark erosion (wire and countersunk), laser machining, and
mechanical precision machining depending on the material.
(Muhler et al., 1987) When brass or copper is used as the structural
material, mechanical precision machining is one of the most suit-
able techniques to achieve the best surface quality. (Madou,
2002) Laser radiation can be used to remove the material or in
some cases, to build up the microreactor material. The tool may
vary depending on the microreactor material. Thus, a natural dia-
mond cutter is used for metals such as brass and copper, while a
hard metal tool is used for steel and nickel-based alloys. Fig. 4 illus-
trates a natural diamond cutter and hard-metal drill used for the
micromachining of various metals (Brandner, 2008).
2.2.2. Lithographie, Galvanoformung, und Abformung (LIGA)
technique
LIGA was first developed by German researchers and is the Ger-
man acronym for Lithographie, Galvanoformung, und Abformung
(lithography, electrodeposition, and molding). The use of this tech-
nique is becoming more popular because it readily allows the fab-
rication of microreactors from a variety of materials such as metals,
polymers, and plastics. Typically, this process is employed in com-
bination with other processes such as X-ray radiation, electroform-
ing, and molding. LIGA generally involves three steps: the first step
is the pattern transfer from a mask to a photoresist that is typically
a photosensitive epoxy resin. In the second step, the mask and any
undesirable materials are removed and a relief structure is formed
by electroplating onto the substrate area. Finally, in the third step,
the photoresist or epoxy is removed after the metallic structure is
formed. Sometimes, injection molding, casting, or embossing fol-
low the third step. Effenhauser et al. fabricated a microdevice for
436 P.L. Suryawanshi et al. / Chemical Engineering Science 189 (2018) 431–448

Fig. 4. (A) Natural diamond cutter and (B) hard-metal micro-drill used for the micromachining of various metals. (Brandner, 2008).

Fig. 5. Fundamental steps of the Lithographie, Galvanoformung, und Abformung (LIGA) fabrication technique for microreactors (Hormes et al., 2003).

the slab was placed on a PDMS block to form a complete device.

Fig. 5 depicts the basic steps involved in the LIGA process.

Fig. 6. Wet etched channels in Pyrex glass. The channels are covered with a layer of
silicon that is anodic bonded to the glass. (Wagner et al., 2004).
the separation of DNA on a PDMS silicon elastomer. (Effenhauser
et al., 1997) The process comprised the creation of channels from
a silicon master wafer with a positive surface relief followed by
the removal of the cured slab. After the reservoirs were prepared,
2.2.3. Etching
In its simplest form, etching is the removal of materials from a
substrate. This technique is categorized into wet and dry etching.
Wet etching can be easily performed with lab glassware and suit-
able chemicals, whereas dry etching involves significant invest-
ment and maintenance costs. A typical etching process comprises
the application of a photosensitive mask onto the metal to be
etched. Further, a primary mask containing structural layers is
used to expose the photosensitive mask to light; various photosen-
sitive mask materials and light exposure methods have been
explored. Finally, the parts that are not exposed to light are poly-
merized so that they become insoluble in the solvent used to dis-
solve the rest of the polymer. The optimum aspect ratio (width
to depth of structure ratio) of the wet etching process is considered
 P.L. Suryawanshi et al. / Chemical Engineering Science 189 (2018) 431–448
Fig. 7. Schematic of isotropic and anisotropic etching demonstrating the selectivity
of the vertical and horizontal etching technique. (Hierlemann and Baltes, 2003).
as <0.5. This limitation is not applicable to dry etching and is one of
the most expensive techniques available. An important feature of
wet etching is the formation of semicircular structures due to the
isotropic etching of the wet solvent. Fig. 6 illustrates the wet
etched channels in Pyrex glass. On the contrary, dry etching can
afford various structural geometries with varying aspect ratios.
Pattekar and Kothare demonstrated the fabrication of microchan-
nels having a width of 1000 mm and a depth range of 200–400 m
m (Pattekar and Kothare, 2004).
Selectivity is an important consideration in etching processes
that affects the difference in the etching rates of the desired and
undesired materials. In wet etching, there can be infinite selectivity
between the photoresist and the substrate (Cheemalapati et al.,
2014; Miyawaki et al., 2013) Additionally, in wet etching, the
material is etched horizontally and vertically at the same rate. In
contrast, in the dry etching process (e.g., plasma etching) anisotro-
pic etching can be performed using a particular location of the
Fig. 8. Comparison of the different microreactor flow systems (Cabeza, 2016).
437
plasma in the etching chamber. Fig. 7 presents the schematic of
isotropic and anisotropic etching and demonstrates the selectivity
of the vertical and horizontal etching technique.
3. Design principles and methods
The scale-up of microreactors varies, depending on the pro-
cesses in the microreactor and the product economics. Addition-
ally, acceptance of such continuous microreactors for chemical
synthesis is rather challenging. Process designs using batch infor-
mation must often overcome both reactor design and scale-up
challenges to meet industrial requirements. One of the greatest
advantages exhibited by microreactors is their ability to carry
out complex reactions with superior control on kinetics and pro-
duct properties by improving the synthetic conditions. These com-
plex reactions often involve multiple phases and are immiscible
with each other. Broadly, these reacting systems can be catego-
rized as aqueous-organic liquids (Schouten, 2012; Woitalka et al.,
2014) and gas-liquid reactions; (Wang et al., 2013a) other multiple
systems have also been reported (Doku et al., 2003). However, mix-
ing mainly occurs by chaotic advection in microchannels of small
volume and involves laminar flow. Different designs of mixing ele-
ments can improve the mixing efficiency in microreactors. These
mixers can be categorized as either active or passive, according
to the existence of mechanical agitation and external forces. Active
micromixers often involve perturbation energy in the form of
electrokinetic, dielectrophoretic, acoustic/ultrasound, and magneto-
hydrodynamic (MHD) energy; however, they require special fabrica-
tion techniques. (Gambhire et al., 2016; Ober et al., 2015; Ward and
Fan, 2016) Passive mixing simply creates lamination of multiple fluid
streams, increasing the interfacial area for diffusion. (Farshchian
et al., 2017; Ward and Fan, 2016) Although micromixing by multi-
lamination is effective, the narrow microchannels can lead to high
pressure drops. The majority of the multiphase flow systems involve
passive mixing and reduce the tendency to foul after extended oper-
ation. Fig. 8 displays continuous flow and continuous flow with pas-
sive mixing profiles. The flow in microreactors can also be classified
as continuous or segmented flow. Further, segmented flow can be
438 P.L. Suryawanshi et al. / Chemical Engineering Science 189 (2018) 431–448
categorized as gas-liquid segmented and liquid-liquid segmented
flow. (Yue et al., 2013) A comparison of these flow profiles is pre-
sented systematically in Fig. 8. Compared to batch reactors, continu-
ous flow without passive mixing allows the facile change of
experimental conditions within microseconds and usually improves
the homogeneity of the solution during the synthetic process. How-
ever, because the fluid often flows within the laminar region, mixing
is achieved via molecular diffusion of the species. The flow profile in
continuous flow systems depends on the position within the cross-
section and can promote a wide residence time distribution depend-
ing on the flow conditions. In gas-liquid segmented flow systems,
flow patterns depend on the gas and liquid superficial velocities.
When gas bubbles are located between two liquid segments, the
drag force at the walls promotes convective mixing within each slug,
ensuring a narrower residence time and chemical homogeneity. The
co-current gas and liquid flows often involve a continuous gas flow
in the same direction as that of the pulsating liquid. Ganan-Calvo
et al. generated microbubbles of diameter ranging from 5 to 20 mm
by fine-tuning the relative gas and liquid flow rates and liquid vis-
cosities. (Ganan-Calvo and Gordillo, 2001) In liquid-liquid systems,
segmentation is created by the difference in the surface tension of
the two immiscible liquids. A large specific interfacial area for
immiscible systems yields a short molecular diffusion distance and
prevents undesirable side-reactions. Multiple pulses of one liquid,
while maintaining a continuous flow of the other, allows diffusion
and reaction to occur at multiple transverse interfaces.
Nowadays, the performance analysis of processes to be carried
out in microreactors is accomplished by a wide variety of
computer-based tools. Development of various advanced software
has enabled the solutions of complex multi-physics problems over
the length scales of microreactors. One of the main aims behind
these simulations is to save money and time when fabricating a
microreactor of the desired characteristics. Once the desired char-
acteristics for the required microreactor are conceptualized, a
software-based prototype can be developed to the level at which
it can be fabricated. This process requires that the heat, mass and
momentum transfer, and kinetic equations be defined. Further, ini-
tial and boundary conditions need to be specified and subse-
quently converted into a computer-based code. A method needs
to be developed to visualize and analyze the results. Finally, the
process needs to be optimized and accordingly, an implementation
scheme should be devised. Some software can perform these pro-
cesses to yield a numerical prototype. (Erickson, 2005) Usually,
finite difference, volume, and element methods, as well as the
boundary element method are used to solve the fundamental
transport and kinetic equations necessary for the mathematical
Fig. 9. Integration of a microreactor with a biological assay system. (Fletcher et al., 2002).
modeling of microreactors. These approaches are preferred
because they are based on fundamental phenomena and avoid
heuristic problems. Ferziger and Peric have provided a comprehen-
sive description for each of these methods and have reported their
detailed analysis. (Ferziger and Peric, 2002) The finite element
method is widely used; however, numerous difficulties may arise
if the geometry is highly curved or contains very high aspect ratios.
In contrast, the finite volume method is used when viscous terms
are absent; however, in this case, most of the microreactors oper-
ate at a lower Reynold’s number, i.e., a laminar flow regime.
Despite this drawback, the latter system is widely employed
because it can handle the geometries of more complex microreac-
tor systems.
Nowadays, various commercial software is used to solve the
numerical equations that describe microreactor systems. Examples
of such software are COMSOL Multiphysics, Fluent, CFD-ACE+, and
CoventorWare. Various components can be used for studying flu-
idics, generating the geometrical features of the microreactors,
analyzing the fluid flows, and optimizing a system by combing
all the models. Erickson has provided a comprehensive review of
the applications of numerical simulations for microfluidic systems.
(Erickson, 2005) Though this review was published a decade ago
and mainly focuses on lab-on-chip systems, it can be applied to
single and multiphase flow systems in microreactors. The task of
designing integrated microreactors with functional components
for research and small-scale production is still in the developing
stage.
4. Cutting-edge applications of microreactors
Applications of microstructured reactors have been diversified
in recent years due to their inherent safety, sustainability, com-
pactness, significant waste reduction, cost-effectiveness, low oper-
ating and capital costs, and reduced energy demand. The
significant areas of application with emphasis on recent research
are discussed below (Sections 4.1–4.3).
4.1. Biological and pharmaceutical applications
Biological and pharmaceutical applications of microreactors
mainly include biosynthesis and biochemical processes, enzyme
assays, biological screening assays, protein folding, and analytical
assays. (Dong-mei Liu et al., 2015a; 2015b; Yao et al., 2015)
Typical synthetic procedures in microreactors include complex
reaction processes and the production of molecules relevant to
 P.L. Suryawanshi et al. / Chemical Engineering Science 189 (2018) 431–448
pharmaceutical and medicinal chemistry. Further, it is possible to
integrate microreactors to highly sensitive microchannel-based
biological assay systems that can address some of the potential
industrial requirements. Fig. 9 illustrates the integration of a
microreactor with a biological assay system.
Recently, Daktari Diagnostics demonstrated a microfluidic tool
that combined sample preparation and analysis within a single
device. The device can quantify the CD4+ and CD8+ immune cells
in a blood sample. (Watkins et al., 2013) Another company, Diag-
nostics For All (DFA), has developed paper-based microfluidic
devices that utilize capillary forces for fluid movement in low-
cost medical diagnostics. (Yetisen et al., 2013) At laboratory scale,
Marques et al. have assessed the production of cholestenone by
bio-oxidation of cholesterol in a microchannel reactor. (Marques
et al., 2012) Food flavors are also synthesized in microreactors to
precisely control the composition of the product. Gumel and
Annuar synthesized flavor esters (methyl butanoate and methyl
benzoate) by esterification of the acids with methanol in a
microfluidic system. (Gumel and Annuar, 2017) They catalyzed
the reaction using Thermomyces lanuginosus lipase. Biological
assays and similar applications are also considered suitable for
microreactors. Wu et al. developed a thin, transparent, and flexible
polyurethane-based microfluidic device for blood contacting appli-
cations. Microreactors have also been used for DNA ligation since
they require less processing time than processes conducted in a
general laboratory where it takes several hours. (Wu et al., 2012)
Point-of-care diagnostics is one of the areas that has commercially
benefited from microreactor-based devices. (Sebastián and Jensen,
2016) Through their research and development department, large
companies, have introduced miniaturized devices for point-of-
care diagnostics. A start-up company from George Whitesides’ lab-
oratory at Harvard, Claros Diagnostics Inc., has developed a bench-
top microfluidic analysis system that can read a credit card-sized
disposable cassette containing a blood sample and perform various
tests for urology and infectious diseases. (Volpatti and Yetisen,
2014) Later, this company was acquired by OPKO Inc. that used
the Claros technology in combination with its biomarkers for early
diagnosis of Alzheimer and Parkinson’s diseases. Microreactors can
be explored in the field of carbanion chemistry, one of the most
common methods for CAC bond formation used in the pharmaceu-
tical industry. (Porta et al., 2016) In these reactions, the reaction
temperature often governs the stereochemistry of the product.
Hence, microreactors have gained considerable attention as they
enable excellent temperature control. Similarly, the synthesis of
monodispersed nanoparticles for pharmaceutical applications has
always been a challenge. In this regard, efficient mixing is a key
advantage for synthesizing monodispersed nanoparticles in
microreactors. (Khodashenas et al., 2015) Recently, Su demon-
strated the synthesis of monodispersed colloidal spheres of silica
under a continuous flow of inert gas. (Su, 2016) Bolivar et al. com-
prehensively reviewed the benefits, existing problems, and future
research requirements for biocatalysis in microreactors. (Bolivar
et al., 2011) They highlighted that the potential for intensification
is only significant if the actual chemical transformation is relatively
fast. Notably, biotransformations are often slow, implying that only
selected cases of enzyme-catalyzed reactions can be miniaturized
by process intensification.
4.2. Synthesis of nanoparticles in microreactors
Research on the synthesis and applications of nanomaterials
has increased dramatically over the past two decades. The advent
of microreactors has enabled potential alternatives for the large-
scale production of nanoparticles. (Chiu et al., 2017; Nakamura,
2014; Nightingale and DeMello, 2013; Phillips et al., 2014) This
section reviews recent developments in the synthesis of inorganic
439
and noble metal nanoparticles. Several review articles have
attempted to describe the synthesis of various types of nanoparti-
cles. However, this section focuses on technologically important
developments in inorganic and noble nanoparticle synthesis to
provide readers with a better understanding of the cutting-edge
developments in this field.
4.2.1. Synthesis of inorganic nanoparticles
Over the past few years, the synthesis and modification of var-
ious nanoparticles to impart multi-functionality has been an emer-
gent area of research and scientific interest. However, their
complex and expensive synthesis is a critical barrier to their rou-
tine use. (Kharissova et al., 2013) Recently, Nightingale and
deMello demonstrated the continuous production of nanomateri-
als in a microreactor that has the potential to become mainstream
technology. (Nightingale and DeMello, 2013) Their technique can
be extended for the synthesis of ZnS, CdS, PbS, ZnSe, CdSe, SiO2,
and TiO2. Most nanoparticles are synthesized under continuous
or segmented flow atmospheric pressure. The use of elevated pres-
sures is one avenue that enables the use of high boiling solvents.
However, at the adequately high pressures and temperatures
required for nanomaterial synthesis, nearly all common solvents,
precursors, and ligands are either in the liquid or supercritical
phase. (Marre and Jensen, 2010) Because of this barrier, microreac-
tors have attracted significant interest towards their application to
the continuous flow synthesis of various inorganic nanoparticles
such as nickel, silica, and copper (Howes et al., 2014) The critical
element in the semiconductor industry is the semiconducting
material, namely, semiconducting nanoparticles and quantum
dots. Researchers have recently synthesized these technologically
important materials in microfluidic reactors. (Cabeza, 2016;
Elvira et al., 2013; Feng et al., 2015; Makgwane and Ray, 2014;
Mcquade and Seeberger, 2013) In addition, commercially impor-
tant pigments are synthesized in microreactors due to the ease of
synthesis and homogeneity of the pigment composition. Synthesis
of unstable nanoparticle shapes and compositions is made possible
in microreactors. The SyrrisÒ glass microreactor is one example
that produces Ni nanoparticle spheres, cubes, pyramids, and tetra-
pods. (Shviro and Zitoun, 2013) Various stable shapes were pro-
duced due to the ability of the microreactors to control growth
parameters such as growth rate and surface energy by simply con-
trolling the mass flow and temperature. (Boken et al., 2015; Singh
et al., 2010; Zhao et al., 2011) In the conventional synthesis of
nanoparticles, a polymer coating is often used to stabilize the
nanoparticles, control polydispersity, and reduce the particle size
and size distribution. However, the use of polymers in microreac-
tors is not the preferred route to stabilize nanoparticles. Recently,
He et al. demonstrated the synthesis of silica nanoparticles in the
presence of a polyethyleneimine (PEI) polymer at room tempera-
ture without encountering any operational problems. (He et al.,
2011) The microreactor comprised ethylene tetrafluoroethylene
(ETFE) channels connected in series, in which only the flow rate
and residence time were used to control the properties of the silica
nanoparticles. Though scaling down the reactor to sub-millimeter
level offers numerous advantages, the synthesis of nanoparticles
in a microreactor must overcome the low volumetric flow rate
due to a low flow velocity and small microchannel radius. Recently,
our research team has explored the use of a Corning advanced
flowTM reactor (AFRTM) with heart-shaped channels for the synthesis
of various nanoparticles and compared it to different spiral
capillary-based microreactors. (Sharada et al., 2016; Suryawanshi
et al., 2017; 2016) We concluded that the AFRTM can operate at a
flow rate 200 mL/h at an economically viable reducing agent to
precursor molar ratio of 2.75. Using these conditions, we repro-
ducibly attained 270-nm colloidal copper nanoparticles. (Kumar
et al. (2015a,b)) A simple micromixer with short-mixing-length
440 P.L. Suryawanshi et al. / Chemical Engineering Science 189 (2018) 431–448

Table 2
Synthesis of metallic/inorganic nanomaterials in different microreactors.

Micromixer type Microreactor Flow rate Residence time (s) Material Size (nm) Reference
dimensions (mL/min)
Y-shaped Microchannel ID: 1.2 mm 4 29.35 Ag 5 Patil et al. (2012)
L: 1730 mm
Microchannel ID: 0.2 mm 0.16–0.5 – Ag 8–14 Xu et al. (2016)
L: 10 mm
H: 0.05 mm
Microchannel L: 20.9 mm 0.005–0.05 – Au 12 Wagner and Kohler (2005)
V: 2.3 lL
T- shaped Microchannel ID: 0.2 mm 0.005–0.05 35 Au 2 Rahman and Rebrov
L:1500 mm (2014)
Microchannel – 0.8–0.9 – Co 2.8–3.5 Song et al. (2008)
Y-shaped Microchannel ID: 0.8 mm 2–0.33 13.56–135.7 Cu 270–591 M. Kumar et al. (2015))
L:1500 mm
Y-shaped Microchannel ID: 0.8 mm 0.833 72.38 Cu2Cr2O5 69–263 Appalakutti et al. (2015)
L:2000 mm
Y-shaped Microchannel ID: 0.8 mm 0.5–0.833 8.77–14.73 Pd 5–200 Sharada et al. (2016)
L:1240 mm
Microchannel W: 0.7 mm – 12–195 Pd 1 Karim et al. (2015)
ծ: 0.27 mm
L: 800 mm
Microchannel W: 0.05 mm 0.33 – Pt 2 Hossain et al. (2016)
L: 25 mm
H: 0.15 mm
T-shaped Microchannel W: 0.4 mm 0.001–10 – Pt 3–4 Luty-Błocho et al. (2014)
L: 2509 mm
ծ: 0.25 mm
T-shaped Microchannel L: 225 mm 2–4 0.0372–0.0186 Pt 2–8 Luty-błocho et al. (2013)
Y-shaped Microchannel ID: 0.5 mm 0.85–1.67 4.42–8.83 Pt <5 Suryawanshi et al. (2016)
L: 1250 mm
X-shaped Microchannel ID: 0.85 mm 0.4 75 Pt 0.8–3.6 Baumgard et al. (2013)
L: 840 mm
S-shaped Microchannel ID: 0.2 mm 0.03–0.15 – Pt/C 3.3–2.5 Ran et al. (2015)
OD: 0.36 mm
Y-shaped Microchannel ID: 0.8 mm 2–30 – Fe3O4 10.5–25 Azimi et al. (2015)
L: 112.5 mm
Y-shaped Microchannel ID: 0.364 mm 0.583 10–40 CdSe 3.5 Yang et al. (2011)
Y-shaped Microchannel ID: 0.3 mm (Y-shape) 2–6 – ZnO 16 Wang et al. (2014)
with relay tube L: 3 mm
ID: 6.35 mm (relay
tube)
L: 1000 mm
Y-shaped Microchannel with ID: 0.8 mm 0.15–0.9 151.2–25.2 ZnO 2–3 Yang et al. (2016)
ultrasonics L: 1500 mm
Y-shaped Microchannel ID: 1.2 mm 5.5 & 2.75 600 or 1200 ZnO 3.6–5.2 Schejn et al. (2014)
L: 2500 mm
Y-shaped Microchannel ID: 0.8 mm 1.5–3 67.82–33.91 ZnS 5–10 Ansari et al. (2016)
L: 1500 mm
Microchannel L: 200 mm QM1 and QM2: 2–5 Janus 40,000– Nie et al. (2006)
0.000167 to 100,000
0.00167
QW: 0.00667 to 0.2
T-shaped Microchannel – 6 4.7–5 Ceria 23.5–26 Tseng et al. (2013)
T-shaped Microchannel W: 0.3 mm 0.01 6–24 Zn/Fe3O4 5 Simmons et al. (2015)
ծ: 0.06 mm
V: 10 lL
T-shaped Microchannel ID: 1.6 mm 0.75 6 Pb/Se 11.2–13.9 Hostetler et al. (2014)
L: 40 mm
T-shaped Microchannel W: 1 mm 0.00004 – BaSO4 10–40 Li et al. (2008)
H: 1 mm
Microchannel W: 2 mm 48, 64, 120 – BaSO4 40–60 Du et al. (2013)
L: 20 mm
H: 0.5 mm
T-shaped Microchannel W: 1 mm (channel 1) 20, 10, 5 – BaSO4 18 Ying et al. (2008)
ծ: 0.2 mm
L: 20 mm
W: 1 mm (channel 2) – – – –
ծ: 1 mm
L: 40 mm
T-shaped Microchannel ID: 2.5 mm (PVC) 3–9 For PVC 42.3– Fe3O4 3.7–300 Bari et al. (2015)
L: 1300 mm 127.8
ID: 1 mm (SS) – For SS – –
L: 1300 mm 6.6–20.4
 P.L. Suryawanshi et al. / Chemical Engineering Science 189 (2018) 431–448 441

Table 2 (continued)

Micromixer type Microreactor Flow rate Residence time (s) Material Size (nm) Reference
dimensions (mL/min)
Spiral SS and PEEK micromixer ID: 1.38 mm for 1, 0.1 & 10.5 Ag >10 Ravi Kumar et al. (2012)
SS, 0.5 for PEEK 0.035 105
W: 1 mm 300
ծ: 1 mm
Micromixer W: 3.2 mm 0.42–3.33 – Au 1 Tsunoyama et al. (2008)
ծ: 0.1 mm (region I)
ծ: 0.5 mm (region II)
Standard slit interdigital Micromixer ID: 1.3 mm – 900/1800/5400 SiO2 170 nm Gutierrez et al. (2011)
PTFE Microchannel capillary ID: 0.75 mm – 30–320 Au/Ag 4–7 Sun et al. (2012)
L: 1000 mm
ծ: 0.1 mm
Y-shaped and Capillary W: 0.15–0.4 mm 0.8–0.9 – Co 2.5–6.5 Song et al. (2006)
L: 480 mm
ծ: 0.3–0.7 mm
CorningÒ Advanced flowTM reactor V: 1 mL Heart-shaped 3.33–0.833 18–72 Cu 206–320 Kumar et al. (2015a,b)
Microchannel capillary ID: 0.15–0.32 mm 0.0025–0.5 – Pd 2–5 Torigoe et al. (2010)
L: 1500 mm
Capillary ID: 0.2 mm 0.0942 3–60 CdSe 2.25–4.3 Toyota et al. (2010)
L: 150–3000 mm
Microchannel droplet jet injector ID: 0.053 mm 0.001–0.00125 9.5–38 CdSe 3.4–3.8 Chan et al. (2005)
L: 0.3 mm
H: 0.045 mm
Y-shaped, capillary ID: 0.1 mm 0.1 12 CdSe- – Wang et al. (2004)
L: 300 mm ZnS
Capillary ID: 0.75 mm 0.20–0.85 210–810 Zeolite 278–426 Ju et al. (2006)
OD: 1.2 mm
L: 1500 mm
Capillary ID: 0.25 mm 0.05 (PbS) 6–11 PbS, 4–5 Lignos et al. (2015);
L: 100–150 mm 0.07 (PbSe) PbSe (2014))

*Abbreviations: ID: inner diameter, OD: outer diameter, W: width, L: length, H: height, V: volume, ծ: depth, QM1 and QM2: flow rates of monomers 1 and 2, Qw: flow rate of
surfactant, SS: stainless steel, PEEK: polyether ether ketone, PTFE: polytetrafluoroethylene, PVC: polyvinyl chloride.

baffles is effective for mixing over a wide range of flow rates. Appa-
lakutti et al. synthesized bimetallic nanoparticles of copper chro-
mite using a continuous flow microreactor at a flow rate of 50
mL/h. (Appalakutti et al., 2015) Combinatorial synthesis optimizes
various significant parameters at the same instance. The continu-
ous synthesis of semiconducting CdSe nanoparticles is a recent
example that demonstrates the strong commercialization potential
of these nanoparticles. (Toyota et al., 2010) Various combinations
of temperature, residence time, and reagent concentrations were
mapped for this process and the effect of each parameter on the
nanoparticle properties was subsequently determined. Though
the combinatorial study of a process is often carried out in conven-
tional chemical process industries, it is novel in the field of nano-
material synthesis and thus, it can ease the technology transfer
process. Similarly, pigment quality is assessed based on its unifor-
mity in a set quantity because the quality of the pigments may dif-
fer in the scaled-up process. Therefore, the quality of the product
can be clearly maintained in lab-scale and pilot-scale microreac-
tors. In contrast, the quality of the composite materials in pilot-
scale microreactors can be significantly different from that
afforded by lab-scale microreactors. (Al-Rawashdeh et al., 2012;
Patil et al., 2012) Quantum dots are potential candidates for appli-
cation in fields including plasmonics, biomedicine, and electronic
displays. Though various types of quantum dots have been synthe-
sized, ‘‘bimetallic” quantum dots are gaining popularity as a tech-
nologically important new material for various cutting-edge
applications. The synthesis of CdS/CdSe, CdSe/ZnS, and CdSe/ZnO
bimetallic quantum dots in microreactors was attempted recently.
(Nightingale and DeMello, 2013; Rakgalakane and Moloto, 2011)
These bimetallic quantum dots are highly functional, displaying
semiconducting and luminescent properties. The synthesis of
quantum dots is independent of microreactor material and thus,
quantum dots have been synthesized in both silica/glass and PTFE
microreactors. (Yang et al., 2011) Further, deMello et al. probed the
early-time kinetics (<1 s) of PbS quantum dots using a novel
droplet-based microfluidic platform. (Lignos et al., 2015) A
microreactor combined with ultrasound is frequently being used
to produce quantum dots such as 2–3 nm colloidal ZnO. (Yang
et al., 2016) This synthetic method resulted in a quantum yield
of 64.7%, which is higher than those afforded by individual
microreactors and ultrasound reactors. Table 2 summarizes recent
works on the synthesis of nanomaterials in microreactors. The
table provides a quick outlook on the synthesis of nanomaterials
in various types of microreactors along with details on the micro-
mixer, microreactor dimensions, and product details.
4.2.2. Synthesis of noble metal nanoparticles
The context of noble metals arises from the chemical reactivity
of metals, which ultimately relates to the standard reduction
potential. Usually, metals are electropositive and exhibit a ten-
dency to donate electrons. Therefore, the reduction potential indi-
cates the extent of their electropositive nature. Based on their
reduction potentials, a few metals, such as cadmium and iron,
are moderately electropositive, while metals such as lithium and
sodium are extremely reducing in nature. Another category of met-
als that includes Ag, Au, Pt, and Pd is regarded as noble due to the
non-oxidative effects of these metals with water and oxygen.
(Kumar et al. (2015a,b); Maceiczyk et al., 2016; Sebastian et al.,
2016; Sebastián and Jensen, 2016) Noble metal nanoparticles have
attracted much attention due to their interesting optical, elec-
tronic, and chemical properties. These nanoparticles play a major
role in several electrochemical systems including fuel cells, batter-
ies, and corrosion. Nowadays, there are numerous synthetic meth-
ods for the preparation of noble metal nanoparticles. The
underlying mechanism behind these procedures is the reduction
of the corresponding metal ion precursors using a reducing agent.
(Baumgard et al., 2013; Hossain et al., 2016; Riche et al., 2016)
Often, surfactants, polymers, and stabilizing agents are employed
442 P.L. Suryawanshi et al. / Chemical Engineering Science 189 (2018) 431–448
to avoid nanoparticle agglomeration. Though noble metal nanopar-
ticles have been synthesized over the past several decades, it is
only recently that microreactors are being used for their produc-
tion. Microreactors can be advantageous if they can continuously
produce noble nanoparticles in various shapes. Carboni et al.
reported a continuous flow synthesis of triangular silver nanopr-
isms in a microfluidic device. This was achieved via the reduction
of AgNO3 by NaBH4 in the presence of the stabilizing agent triso-
dium citrate dehydrate (TSCD). (Carboni et al., 2013) Shave et al.
demonstrated the large-scale continuous production of quaternary
chalcogenide Cu2ZnSnS4 (CZTS) nanoparticles with controlled com-
position using a flow microreactor. (Shavel et al., 2012) The com-
position was controlled by adjusting the solution flow rate
through the reactor and by the proper choice of nominal precursor
concentration within the flowing solution. Similarly, Pacławski
et al. demonstrated a continuous flow microreactor system as a
valuable tool for the controlled synthesis of Au nanoparticles with
well-defined shape, size, and narrow size distribution. Moreover,
the diameter of the synthesized spherical Au nanoparticles could
be controlled precisely within 10–50 nm. (Pacławski et al., 2012)
Xu et al. created Ag nanoparticles <5 nm by using a sodium boro-
hydride reducing agent in the presence of polyvinylpyrrolidone
(PVP) as stabilizer. (Xu et al., 2016) Despite the successful synthe-
sis of monometallic noble nanoparticles in microreactors, the syn-
thesis of bimetallic metal alloys proved to be rather challenging.
However, recently, Sun et al. synthesized monodisperse Au–Ag
alloy nanoparticles via a one-step rapid injection method in a cap-
illary microreactor within a short residence time of <3 min. (Sun
et al., 2012) Though these nanoparticles can be synthesized in
microreactors with greater ease, reactor fouling is one of the key
issues that still needs to be addressed. This can be prevented by
coating the inner wall of the microreactor with a material that is
incompatible with the flowing fluid. This approach avoids unneces-
sary high flow rates to overcome fouling in the microreactor. Alter-
natively, the pH of the reaction mixture can be adjusted so that
interactions between the net charges on the particle surfaces and
the inner surface of the microreactor prevent the deposition of par-
ticles within the microreactor. As described earlier in this review
(Section 3), flow patterns and the subsequent mixing of the reac-
tants play an important role in determining the final particle size
within a given residence time. The pulsed flow mixing method
has emerged as a potential technique to control the optimum mass
transport of species within a microfluidic device. Microreactors can
also produce these nanoparticles in a variety of shapes. Suryawan-
shi et al. produced ultra-small Pt nanoparticles (<5 nm) in a contin-
uous flow microreactor. (Suryawanshi et al., 2016) Highly stable
(8–9 months) spherical clusters of Pt nanoparticles were reported
by Blocho et al., whereby vitamin C was employed as a reducing
agent for the chloride complex of a platinum (IV) precursor.
(Luty-Błocho et al., 2014) They also synthesized Pt nanoparticles
3.5 nm in a glass Syrris microreactor using polyvinyl alcohol as
a steric stabilizer. (Luty-Błocho et al., 2013) In their attempt to syn-
thesize an electrocatalyst, they deposited Pt nanoparticles on
active carbon fibers with an efficiency ranging between 81% and
95%. While various noble electrocatalysts can be synthesized in
microreactors, the microreactor itself can also be used as the
packed-bed of the electrocatalyst for various reactions. Using a
similar concept, methanol decomposition was achieved in a
packed-bed microreactor of Pt-cerium oxide (Pt-CeO2) and the pro-
cess was modeled in one and three dimensions. (Pohar et al., 2014).
Microreactors have also been employed as a tool for real-time
monitoring of the nucleation and growth of noble metal nanopar-
ticles 1 nm in combination with X-ray absorption fine-structure
(XAFS) and small-angle X-ray scattering (SAXS) analysis (Karim
et al., 2015).
4.3. Synthesis of organic chemicals and polymers
In chemical process engineering, microreactors are mainly used
for the synthesis of organic compounds, specialty chemicals, chem-
ical intermediates, and pharmaceutical products. (Fitzpatrick et al.,
2016; Fitzpatrick and Ley, in press; Junkers, 2016; Makarshin et al.,
2016) In these organic syntheses, researchers are often concerned
with the toxicity of chemicals, hazardous temperature and pres-
sure conditions, and reaction kinetics. Microreactors present the
advent of carrying such reactions more safely. (Cantillo and
Kappe, 2017; Movsisyan et al., 2016; Rossetti, 2016) Certain
microreactors have been commercialized with the possibility of
customization. Nettekoven et al. employed a commercial custom-
made meso-scale continuous flow microreactor for an intramolec-
ular cycloaddition reaction to afford a relatively larger yield (>5 g
larger). (Nettekoven et al., 2012) They attained a 48-g yield after
optimizing the system, demonstrating the robustness and reliabil-
ity of microreactor-based platforms. Microreactors combined with
an irradiation feature offer additional features to carry out chal-
lenging organic reactions. Aillet et al. demonstrated the use of a
0.81-mL microphotoreactor to synthesize a pentacyclic ‘‘cage”
compound and compared it to a 225-mL batch reactor. (Aillet
et al., 2013) This work featured the full conversion of highly con-
centrated solutions in a short irradiation time. Traditionally, ester-
ification reactions are known for their sluggish kinetics. A simple
Y-shaped microreactor can be effective to improve the esterifica-
tion kinetics. Zanati et al. used such a microreactor, without any
catalyst, for the esterification of the fatty acid 2- ethyl hexanoic
acid and reached  99.3% conversion after 30 s at 25 °C. (Zanati
et al., 2016) Complex chemical reactions that involve multiphase
reactants such as gas and liquid phase reagents and a solid phase
catalyst can be easily performed in microreactors. Inoue et al. car-
ried out the direct multiphase synthesis of hydrogen peroxide in a
glass microreactor using a Pd catalyst at room temperature. (Inoue
et al., 2013) The catalyst can also be coated onto the walls of the
microreactor to carry out such synthetic procedures. The direct
synthesis of hydrogen peroxide in the presence of Au-Pd and Au-
Pd/TiO2 catalysts coated onto the walls of the microchannel and
flow reactor can be similarly accomplished. Paunovic et al. and
Freakley et al. used this concept to synthesize hydrogen peroxide
using Au-Pd-coated microreactors. (Freakley et al., 2013;
Paunovic et al., 2015a,b) A decomposition study on hydrogen per-
oxide was also carried out in such a microreactor at high temper-
ature and concentration in the presence of sodium tungstate
catalyst, demonstrating the versatility of microreactors. (Shang
et al., 2017) Similarly, Grignard reactions (Cervera-padrell et al.,
2012), Diels-Alder reactions (Sachse et al., 2012), chlorination
(Fukuyama et al., 2016), oxygenation (Park et al., 2015), fluorina-
tion (Amii et al., 2013), hydrogenation (Feng et al., 2016), ammox-
idation (Dong et al., 2015), coupling reactions (Li et al., 2012),
tritylation reactions (Maralla et al., 2017), and nitration reactions
(Billaud et al., 2016) were carried out in microreactors more effec-
tively than in their conventional counterpart reactors. Typically,
these reactions are preferentially performed in microreactors due
to ease of temperature, flow rate, and pressure control; efficient
and fast mixing of the reactants; high heat and mass transfer rates,
narrow residence time distributions, and operational safety.
(Visaveliya and Koehler, 2014; Yao et al., 2015) Nitration reactions
are often problematic in large-scale processes due to the use of
excess quantities of nitric and sulfuric acid that makes them highly
exothermic. (Kulkarni, 2014) Microchannel reactors dissipate the
heat generated during the reaction more efficiently than conven-
tional jacketed stirred tank reactors due to their high heat transfer
coefficient. (Westermann and Mleczko, 2015) Riano and Zea mod-
eled the synthesis of propylene in a microreactor by propane
 P.L. Suryawanshi et al. / Chemical Engineering Science 189 (2018) 431–448
dehydrogenation using V2O5/TiO2 doped with Rb catalyst. (Riano
and Zea, 2014) They revealed that compared to the reactor pressure,
the inlet composition and wall temperature had a more significant
effect on selectivity and conversion. Microreactor technology has
enabled the nitration of various organic compounds such as toluene.
This reaction employs concentrated nitric acid as the nitrating agent
and a constant temperature water bath. (Kulkarni, 2014) Recent
studies have revealed that microreactors are capable of carrying
out the reactions at higher temperatures (260 °C). (Aida et al.,
2017; Reichart et al., 2013) Aida et al. formed peptides by reacting
bovine serum albumin at 260 °C with minimal amino acid and
ammonia formation, (Aida et al., 2017) whereas Reichart et al. pre-
pared n-alkyl chlorides (180 °C; backpressure @ 20 bar) by direct
uncatalyzed chlorodehydroxylation. (Reichart et al., 2013) However,
basic additives may be necessary to suppress the formation of by-
products, while the residence time significantly affects the conver-
sion of most of the reactants. Abahmane et al. used a two-step con-
tinuous flow assembly to synthesize polypyridine derivatives using
montmorillonite K-10 and Au nanoparticle-impregnated alumina
catalysts in two different packed-bed microreactors at different
temperatures (Abahmane et al., 2011).
Microreactors have also found application in the polymeriza-
tion of various monomers. Recent studies have reported that
microreactors help achieve narrow particle size and molecular
weight distributions of polymers due to effective control of various
steps that occur during polymerization. (Badilescu and
Packirisamy, 2012) Conventional polymerization reactors exhibit
a lack of reactant homogeneity and undesired heat removal. Effi-
cient micromixing is the key to controlling the molecular weight
and distribution, temperature, and uniformity of the reactant con-
centration. (Nagaki and Yoshida, 2012) Often, the polymer proper-
ties are correlated to their microstructures (linear, short-branched,
long-branched, and dendritic). The microstructures of polymers are
controlled mainly by the method of polymerization, namely free
radical, cationic, anionic, and condensation polymerization. Indus-
trially, polymers of styrene, butyl acrylate, and methyl methacry-
late have been systematically synthesized by Fukuyama et al. via
nitroxide-mediated radical polymerization. They compared the
polymerization performance in a microreactor and conventional
batch reactor under similar conditions and determined that the
former afforded higher conversions and produced polymers with
lower polydispersity indices. (Fukuyama et al., 2012) Block copoly-
mers were synthesized by connecting two microflow tubular reac-
tors through a T-junction. Polymers of vinyl ethers are widely used
in various fields and occupy a significant portion of the market.
These polymers are synthesized by cationic polymerization using
electrogenerated dendritic diarylcarbenium ions in a microreactor
(Nagaki et al., 2015) Furthermore, Natalello et al. studied the effect
of micromixing devices on living polymerization of homo- and di-
block copolymers of 2-vinylpyridine and styrene synthesized in a
microreactor (Natalello et al., 2014).
The polymers used in advanced applications such as medical
diagnostics, drug delivery, biometrics, cosmetics, and photonics
can also be synthesized in flow microreactors. This is an effective
strategy to produce highly monodisperse polymer colloids. Kucuk
and Edirisinghe prepared solid polymer nanospheres with tailored
surfaces for drug adhesion using a V-shaped microfluidic junction.
(Kucuk and Edirisinghe, 2014) Their polymer particles displayed
fine pores and cracks on the surface that could be used as drug
entrapment locations. Recently, ethylene glycol and lactide-based
polymers have gained attention due to their promising in vivo drug
delivery performance. Therefore, it is essential to reliably produce
these polymers without batch-to-batch variability for high-
throughput production. Min et al. synthesized poly(ethylene
glycol)-b-poly(lactide-co-glycolide) nanoparticles in a pressure-
tolerant (160 bar) 3D parallel polyimide film microreactor with
443
direct 3D flow focusing geometry. (Min et al., 2014) They coated
a polyimide microchannel with a hydrophobic non-stick fluo-
ropolymer. The resultant direct 3D hydrodynamic flow-focusing
geometry led to zero adsorption on the channel surface and no par-
ticle aggregation. Wang et al. demonstrated the continuous self-
assembly of polystyrene-b-poly(acrylic acid) and loading of probes
in gas–liquid segmented microfluidic reactors. (Wang et al., 2013a,
b) Continuous loading of drugs in carriers can be very effective for
patient-specific point-of-care drug preparation. However, control
of the multiscale structure of polymeric carriers is extremely
important for selectivity and effectiveness in nanomedicine. Mof-
fitt group have employed microreactors for systematic control of
the desired self-assembly of polymers, loading of the drug, and
delivery of drugs such as paclitaxel. (Bains et al., 2017, 2016,
2015) Molecular weight distribution (MWD) plays an important
role by imparting specific properties to the polymeric materials.
Polymers with a narrow polydispersity have a broad application
potential including chromatography, encapsulation of drugs,
resins, and optical data storage. Microreactors have greatly con-
tributed towards the synthesis of such monodispersed polymers
because the technique provides great control over particle size,
shape, and composition. Despite the recent progress in controlled
radical polymerization, the control of MWD has been highly chal-
lenging. Continuous flow microreactors can provide a solution by
tailoring the chemical concentration and residence time in
microreactors. Recently, Corrigan et al. developed a ‘‘greener” pro-
cess of photoinduced polymerization in a microreactor to control
the MWD of a range of polymers. (Corrigan et al., 2017) Their
microreactor-based photoinduced polymerization process used a
zinc tetraphenylporphyrin photoredox catalyst allowing the mono-
mer to be polymerized in open vessels (in the presence of oxygen).
They synthesized polyacrylamide with a polydispersity as low as
1.05. (Corrigan et al., 2016) Fig. 10 displays the various applications
of light-based microreactors such as water purification and synthe-
sis of polymers and nanoparticles. Over the past decade, water-
borne hybrid emulsions have been gaining interest due to an
increasing demand in the paint and coating industry. However,
the solid content of emulsions and clogging of continuous reactors
are major problems faced by the industry. Asua et al. have industri-
ally synthesized paclitaxel polyurethane, styrene/butyl acrylate,
and pressure sensitive adhesives in continuous flow microreactors.
(Daniloska et al., 2014, 2013, 2012; Tomovska et al., 2014) Their
methodology yielded a high solid content (20%) miniemulsion in
Fig. 10. Various photomicroreactor applications for water purification and polymer
and nanoparticle synthesis. (Cambie et al., 2016).
444 P.L. Suryawanshi et al. / Chemical Engineering Science 189 (2018) 431–448
water without clogging the microreactor. Despite the time-
consuming optimization of the reactor to avoid clogging, the tunable
characteristics of the system finally afforded the hybrid polymer
with a diverse polymerization rate and microstructure.
5. Conclusions and future prospects
The development of microreactors to produce fine chemicals,
polymers, and advanced materials are progressing rapidly. These
‘‘tiny” reactors are designed to customize products and their asso-
ciated processes. This review presents recent advancements in the
field of microreactors, specifically materials and processes, for the
fabrication of microreactors and their cutting-edge applications.
Novel fabrication techniques are being developed and commercial-
ized to manufacture these microreactor systems. This review also
describes commercial aspects and design principles of microreac-
tor technologies. As there are numerous techniques and materials
for the fabrication of microreactors, the complexity of the microre-
actor design to address the specific issues would increase accord-
ingly. To date, microreactor technology has been successful in
circumventing some of the problems faced by conventional batch
and large-size reactors for various materials ranging from organic
chemicals to nanoparticles. Apart from the use of microreactors
for synthetic processes, their integration with various measure-
ment techniques is also capturing a significant part of the market.
However, a paradigm of microreactor usage will be shifted towards
disposable, use-and-through devices for synthesis and integrated
analysis applications. Often, resources for high-end facilities are
limited in developing nations, thereby creating a major barrier
for the commercialization of advanced technologies. For integrated
microreactors to become viable, the study of individual steps, such
as synthesis, separation, detection, and analytical measurements, is
not sufficient. The performance of the overall system for a particu-
lar process needs to be reported to compete with a complete large-
scale plant for the same process. Studies are revealing the strong
potential of microreactor-based technologies, however, most have
focused on the innovation of the individual components such as
sample preparation, reactor, mixer, separator, and sensor, rather
than a ‘complete’ integrated device. Therefore, researchers and
technologists should redirect their efforts from proof-of-concept
demonstrations to marketable technology and benefits over con-
ventional technologies. Considering the rapid advancements taking
place in this field, the development of knowledge at the intersec-
tion of science and technology is foreseeable and will lead to more
exciting applications of this technology.
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