Chemical Engineering Journal 167 (2011) 718–726

Contents lists available at ScienceDirect

Chemical Engineering Journal

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

Scale-up concept of single-channel microreactors from process development to

industrial production
Norbert Kockmann ∗ , Michael Gottsponer, Dominique M. Roberge
Lonza AG, Exclusive Synthesis, Process Research, 3930 Visp, Switzerland

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

Article history: Microreactors can perform chemical reactions in tiny channels using continuous-flow processes. The
Received 16 April 2010 microreactor team at Lonza has designed and tested a series of microstructured devices in continuous-
Received in revised form 1 August 2010 flow plants, and performed lab studies of pharmaceutical reactions with successful transfer to commercial
Accepted 4 August 2010
production. Microreactor design and scale-up concept is guided by simple correlations, which are
described here and displayed in comprehensive diagrams for hydraulic diameter over typical range of flow
Keywords:
rate. This leads to a consistent and straightforward scale-up pathway for single-channel microreactors
Process development
avoiding parallelization from lab development to pilot-scale production.
Scale-up
Pilot-scale production © 2010 Elsevier B.V. All rights reserved.
Microstructured reactors
Microchannel flow
Pressure loss
Energy dissipation rate
Mixing time
Heat transfer
Reaction kinetics
Flow reactor
Reactor safety
Reactor design

1. Introduction chemical reaction works. Typical reactions are rapid or hazardous

Biology is a paradigm for many technical systems, since nature
has generated many efficient, perfectly adapted systems, contin-
uously improving them through evolution. Organisms use tiny
channels to transport fluids to supply cells and limbs or to perform
chemical reactions and separations [1]. Microreactors constitute a
similar system, where complex chemical reactions are performed
in tiny, highly adapted channels for improved process conditions
[2].
Microreactor technology is a new field in chemical engineering
and organic synthesis that embodies the principles of Green Chem-
istry [3,4]. In tiny channels smaller than a millimeter in diameter,
chemical and biochemical transformations can be carried out that
dramatically enhance mixing and heat transfer. The small internal
volume also lowers the consumption of energy and raw materials,
thereby increasing safety and economy. To achieve optimal perfor-
mance of the microreactors, engineers and chemists have to know
exactly how the interplay between flow, mixing, heat transfer and
∗ Corresponding author. Tel.: +41 027 948 65 80; fax: +41 027 947 65 80.
E-mail address: norbert.kockmann@lonza.com (N. Kockmann).
[5] or with unstable intermediates, but can be safely operated under
intensified process conditions [6].
This contribution describes a modular, multipurpose microre-
actor platform and the consistent design for scale-up from process
development to ton-scale production of pharmaceuticals. The reac-
tor consists of modular, microstructured plates in close contact
with the heat transfer medium. The microstructured plates ensure
the closed handling of hazardous reagents in a single pass with
defined mixing and residence time conditions. Only one single
channel is employed due to better flow and process control of
meta-stable reagents, which can precipitate and plug the reac-
tor [7]. The flow rate through the single channel determines flow
velocity, Reynolds number, flow regimes, and pressure loss in the
system. The pressure loss in the channel elements is a measure for
the energy dissipation rate and the typical mixing time for con-
vective mixing. Heat transfer in the reactor setup is composed of
contributions from the reactor channel, cooling channel, and wall
resistance and has to be correlated to the energy release from the
reaction [8]. Here, only two typical cases are discussed, the reac-
tion runaway in case of stopped flow, and the internal heat transfer
coefficient due to convective flow. The derived correlations are dis-
played in design diagrams indicating reactor size for typical flow

1385-8947/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.cej.2010.08.089
 N. Kockmann et al. / Chemical Engineering Journal 167 (2011) 718–726 719

Together with the small internal volume, microreactors allow for

Nomenclature safer process conditions compared to batch processes.
The above described characteristics indicate what kind of chem-
af temperature conductivity of the fluid (m2 s−1 ) ical reactions are suitable for continuous flow, microstructured
AC cross-sectional area (m2 ) reactors. The reagents have to flow through the tiny channels
AS wetted surface area (m2 ) without precipitation. Hence, starting material, intermediates, side
b channel width (m) products and products have to be soluble in the working fluid. Reac-
cp heat capacity (J kg−1 K−1 ) tion kinetics and enthalpy determine characteristic reaction time
CA concentration of key component (mol m−3 ) and adiabatic temperature rise of the reagents. Competitive reac-
Cf friction coefficient tions such as consecutive or parallel reactions lead to side product
Ch heat transfer constant formation, which lowers the yield and may complicate work-up
Cm mixing coefficient processes. Based on the characteristic reaction time, the following
EA activation energy (J mol−1 ) classification was set up to facilitate the reactor design [9].
d post or column diameter (m)
dh hydraulic diameter (m)
• Type A reactions have a characteristic reaction time below 1 s
(−Hr ) reaction enthalpy (J mol−1 )
and are mixing controlled. The generated reaction heat has to
h channel height (m)
be removed to avoid hot spot formation and side products from
k0 reaction rate coefficient (s−1 )
parallel-competitive reactions. Rapid mixing and correct con-
L channel length (m)
trol of the stoichiometry also avoids consecutive-competitive
m fluid mass (kg)
reactions. Typical reactions are of cryogenic type such as organo-
n exponent
metallic reactions [10–14].
N number of mixing channel elements
• Type B reactions are rapid in the range of several min-
Nu Nußelt number
utes (<10 min), but mixing in microchannels is always faster.
p pressure difference (Pa)
Enhanced heat exchange over the entire reaction period leads to
P wetted perimeter (m)
good yield in temperature sensitive reactions. Proper control over
Pr Prandtl number
the stoichiometry leads to high yield and low side product forma-
q̇ specific heat flux (W m−3 )
tion in consecutive reactions. Examples are coupling reactions or
r reaction rate (mol m−3 s−1 )
Simmons–Smith reactions [15].
R universal gas constant (J mol−1 K−1 )
• Type C reactions are slow and show hazardous tendency. Auto-
Re Reynolds number
catalytic reactions or decomposition potential of intermediates
Sc Schmidt number
or product belong to this class. The excellent temperature con-
tm mixing time scale (s)
trol in microchannels as well as the low internal volume gives
tR reaction time scale (s)
higher process safety [16].
TW temperature at the wall (K)
• Type D reactions are all reactions not belonging to the above
T temperature difference (K m−1 )
described classes. These reactions can be accelerated by harsh
Tad adiabatic temperature increase (K)
process conditions [17], such as high reaction temperature, high
V̇ volumetric flow rate (m3 s−1 )
pressure, enhanced reaction activation, or high active reagents.
w mean (fluid) velocity (m s−1 )

Greek symbols From the above classification, the question arises, how to design
˛ heat transfer coefficient (W m−2 K−1 ) continuous-flow systems with microreactors, which fulfils the
ˇ eigenvalue following purposes: proper control of stoichiometry, robust to
ε energy dissipation rate (m2 s−3 ) plugging or at least fast plugging detection, modular for different
 pressure loss coefficient reaction types, rapid mixing and volume providing, modular for dif-
 dynamic viscosity (N s m−2 ) ferent phases involving gas/liquid and liquid/liquid. The answer to
 heat conductivity (W m−1 K−1 ) these requirements is partially included in problem formulation: a
f friction factor of channel flow modular reactor plate setup with single microstructured channel
 kinematic viscosity (m2 s−1 ) for excellent mixing and proper flow control. It has to be flexi-
 density (kg m−3 ) ble for process development in the lab, reactor development, and
production on different scales with a consistent scale-up approach.

rates leading to a consistent scale-up procedure. Together with
the modular concept of pumps, heat exchangers, Lonza reactors
allow flexible and versatile set-up for laboratory development up
to pilot plant production. In one such Lonza plant, a multi-ton
campaign for a pharmaceutical intermediate was carried out in
2009.
2. Microreactor characteristics
Complex microstructured channels with meandering curves,
corrugated walls, or repeated contracting and diverging channel
elements generate secondary flow structures at high flow veloci-
ties, which lead to efficient and fast mixing. Large internal specific
surface enables enhanced heat transfer and good temperature con-
trol leading to good control of reaction rates and heat release.
3. Equipment overview for single channel microreactor
The microstructured reactor plates are made from corrosion
resistive material and can fulfill various task in modular set up.
Plates are designed for heat exchange to bring the reagents to
reaction temperature. Mixing plates include a mixing channel as
well as wider channel elements to provide reactor volume for resi-
dence time. Finally, reactor plates have only wide channels for heat
exchange and residence time. In an approach to standardize Lonza’s
reactor design, the sizes chosen for the production plates are based
on the European paper sheet format DIN A4, A5, and A6 standard.
The plate area is doubled by each size step with the result that also
heat exchange area and reactor volume are doubled. The scale-up
concept becomes apparent and is related to the reaction classes.
Thus, for Type A reactions, the aim will be:
720 N. Kockmann et al. / Chemical Engineering Journal 167 (2011) 718–726

Fig. 1. Left hand side: details of a typical mixing channel with contacting element, here a nozzle type, and succeeding tangential mixing elements. The characteristic channel
diameter is taken at the narrowest element. Right hand side: mixing channel with test reaction in the Lab-Plate reactor.

Fig. 2. Details of Lab-Plate reactor for development purposes. Left hand side: DN50 flange with view glass for optical access, cooling tube connections point to bottom side;
right hand side: explosive sketch with cover plate, cooling block, microchannel plate, view glass and flange (from left).

– to ensure sufficient cooling between the reactor plates and mix- necessary. The modular set up allows the integration of several
ing channel, microstructured plates as well as reactor integration into other flow
– to provide short mixing times in tiny, complex channels with equipment.
comparable high pressure drop. Mainly for Type B reactions, a plate stack reactor was developed
by Lonza [18], see Fig. 3. The reactor was initially based on the
For Type B reactions, the aim is different and will be: multi-scale approach, where differently sized plates are used and
adapted to the reaction needs [7]. For example a tiny channel may
– to maintain volume for sufficient residence time for the reaction be used at reaction start (when heat generation is strong) followed
and the same area-to-volume ratio for enhanced heat transfer, by a gradual size increase of the plates to accommodate slower
– to optimize mixing quality by choosing a pressure drop as low as reaction rates (less heat evolution). With such a design, heat trans-
possible. fer is optimized, while pressure drop is minimized coupled with a
large gain in volume (up to several mL). In addition, the reactor may
Type C reactions can be performed in conventional equipment be combined with conventional heat exchangers and tube equip-
such as static mixers. However, for Type A reactions, all the reac- ment to gain volume of several liters for residence times of several
tor plates will be microstructured as mixing and heat exchange are minutes.
the dominant factors, while for Type B reactions the same plate
depth will be used for the different plate format keeping constant
the surface-to-volume ratio. The gradual size increase of reactor
plates (multi-scale approach) and appropriate channel geometry
allow operating the microreactor at very high flow rates up to
600 mL/min.
A small, compact plate device called the Lab-Plate reactor has
been realized to visualize the flow inside the microstructured chan-
nel. It enables reactor channel design and process development
with low flow rates, when reagent availability is still limited. Con-
ditions are similar to capillary chemistry as well as in larger reactor
devices with the advantage that the reaction zone can be inspected
and viewed.
The fluid entering the microchannel within reactor plate passes
through the entrance, contacting element, several mixing and resi-
dence channel elements, each with individual design, see Fig. 1. The
entire reactor consists of cooling block with cover plate, microstruc-
tured plate, view glass, and flange housing, see Fig. 2. The fluids
Fig. 3. Typical setup of plate stack reactor with A6 and A5 size. The reagents are
are sealed by conventional O-rings against the environment, no precooled or preheated, contacted with the correct stoichiometry, completely mixed
direct sealing between reagents and heat exchange medium is and hold on cooling temperature for a certain time.
 N. Kockmann et al. / Chemical Engineering Journal 167 (2011) 718–726 721

The modularity and versatility of the single plate approach allow 5. Convective flow
the development of plates appropriate to any kind of application.
Plates for rapid mixing, gas–liquid dispersion, and multi-injection In a single channel with rectangular cross-section, the volumet-
applications were designed and manufactured demonstrating the ric flow rate determines the flow velocity in a given geometry with
multipurpose character of this technology. In Fig. 3, the individual nominal diameter, hydraulic diameter, and cross-sectional area.
reactor plates made from Hastelloy are sandwiched between alu- Microchannels typically have rectangular shaped cross-sections
minum plates with high thermal conductivity for the thermal fluid with a width b and a depth h. The hydraulic diameter indicates the
passage leading to a very compact reactor. In this way, the thermal characteristic length for the flow through this cross-section AC = bh
fluid layer is not directly fixed onto the reactor plates allowing a and is determined for a rectangular cross-section with perimeter P
cost effective manufacture as well as quick and easy adaptation to to
different reaction conditions. The overall reactor is robust, allows 4AC 2bh
high flow rates of the heat exchange fluid, and can sustain pressures dh = = (1)
P b+h
above 100 bar on the reaction side.
For a circular cross-section, the hydraulic diameter equals the geo-
In many cases, especially with viscous systems and low temper-
metric diameter, for an infinite wide slit (b → ∞) the hydraulic
ature applications, the pressure drop may become very important
diameter is twice the depth of the channel.
at high flow rates. In addition, the mixing zone is often the plate
The cross-sectional area of the rectangular channel AC = bh can
section that consumes the larger pressure drop. Consequently an
be approximated by the square of the hydraulic diameter.
enlargement of mixer elements at higher flow rates drastically
reduces the overall pressure drop. In general, no loss of perfor- Ac ≈ dh2 (2)
mance is observed as long as the same energy dissipation rate in
the mixing zone is maintained (Watt per liter). Thus, the mixing The equality holds for square shaped channels, and the error is less
zone becomes the only scaled factor that is considered in this reac- than 10% for aspect ratios b/h from 0.52 to 1.92. For larger aspect
tor technology and it must be properly designed and adapted. The ratios the approximation has to be replaced by the correct corre-
operation of a microreactor with one single channel and complete lation. To show some trends, we will work with this correlation in
avoidance of device parallelization is a must for successful scale-up the following.
of processes during their development from lab to pilot scale. The mean flow velocity in a cross-section is determined by the
The main goal in lab development is to achieve a robust pro- volumetric flow rate V̇ and the cross-sectional area
cess as chemical systems are often meta-stable and tend to form V̇ = AC w (3)
deposits that are more or less stable over time. Precipitation or
fouling creates an unpredictable pressure drop behavior. The reac- Using the approximation in Eq. (2) the hydraulic diameter dh
tor technology must facilitate timeliness and flexibility in process can be correlated with the volumetric flow rate and the mean flow
development and keep the chemical engineering aspects to a min- velocity.
imum. At this project stage the reactor should not be design and  1/2
V̇
fabricated, but chosen out of few standard equipment for good dh = (4)
mixing and heat transfer in a certain range of flow rate and liquid w
viscosities. The necessary residence time for the chemical reaction The Reynolds number determines the flow regimes in the mix-
is provided by enough process volume in the reactor and succeeding ing channel and is defined as the ratio of momentum forces to
tubes. The modularity of the equipment plays the major role, plate viscous forces.
and tube elements must be simply added in series to gain the nec-
dh w d w
essary volume for the reaction. Here the use of one single channel Re = = h (5)
together with robust, pulsation-free high pressure pumps always  
ensures correct feed balance and stoichiometry, as well as ability to With Eq. (3) follows
clean during and after operation. In the following, channel design
V̇
correlations for mixing and heat transfer are derived from volumet- dh = (6)
ric flow rate considering flow velocity, pressure drop, mixing time,  Re
and heat transfer. Eqs. (4) and (6) are displayed in Fig. 4 with typical flow veloci-
ties of water, 20 ◦ C, in the microchannel of 0.1, 1.0, 5.0, and 30 m/s
4. Design pathway from flow to kinetics

The aim of this part is to describe the design parameters of the

single channel microreactor in terms of hydraulic diameter and
volumetric flow rate. Together with channel geometry and fluid
properties, the mean flow velocity and Reynolds number Re can
be determined in the channel. Both give an indication for the flow
regime, pressure drop, and energy dissipation rate in the mixing
channel. Together with the diffusivity of the reacting species, the
energy dissipation rate is the measure for the mixing time in the
mixing channel. Temperature control of the reagents by enhanced
heat transfer is the second important design parameter. Kinetic
data for reaction rate as well as thermodynamic data for reaction
enthalpy have to be compared with the typical transport charac-
teristics of species and heat. Simple correlations are used to show
trends and general design characteristics. Important is to note,
that the following generic correlations have to be adjusted to spe-
Fig. 4. Typical flow velocities (m/s) and Reynolds numbers in rectangular channels
cific microchannels with data from literature or own experimental with water at 20 ◦ C as working fluid. The horizontal bar indicates the typical flow
investigations. rate range for a channel with a diameter of 0.5 mm as orientation.
722 N. Kockmann et al. / Chemical Engineering Journal 167 (2011) 718–726

Table 1 diameter dh and length l. The ratio of both length scales should be
Properties of organic solvents in relation to water properties at 295 K.
kept constant during scale up or down to have similar flow con-
solv
water 20 ◦ C
solv Prsolv
Prwater 20 ◦ C
ditions. For mixing channel, the pressure loss coefficient  can be
water 20 ◦ C
expressed with the following correlation
Toluene 295 K 0.24 0.22 0.38
235 K 0.89 0.25 1.23
Cf Li
Ethanol 295 K 1.63 0.28 2.50 =N (8)
Ren dh,i
235 K 6.56 0.31 7.44

THF 295 K 0.55 0.23 1.29 The exponent n of the Re number in the dominator depends
235 K 1.14 0.45 1.35 on the flow regime in the channel. For straight laminar flow and
fully turbulent flow, n is 1 or 0, respectively. In complex channel
and typical Re numbers of 200, 2000, 10,000, and 100,000, respec- elements, transition flow between straight laminar and fully tur-
tively. For orientation, the horizontal bar indicates the typical flow bulent flow is often dominant, leading to non-integer number of n.
range in a channel with 0.5 mm internal diameter. This bar of typ- For this flow regime with Re number from 100 to 1000 [21], the
ical flow range at 0.5 mm diameter is also shown in the following exponent was determined to 1/3 in a T-shaped micromixer, while
three figures. Majumdar et al. [22] found a value of 1/4, which correlates with
In Fig. 4 and in the following diagrams, water at 20 ◦ C is taken the well-known Blasius equation. With a pressure loss coefficient
as reference fluid for the properties. However, other fluids than for N channel elements, the correlation for the pressure loss in the
water are often used in chemical synthesis as well as for heating mixing channel is simplified to
or cooling purposes. In Table 1, the property ratio of further typical
Li Cf 
organic solvents such as toluene, ethanol or tetrahydrofurane (THF) p = N · w2 (9)
dh,i Ren 2
are listed to the properties of water at 20 ◦ C. The kinematic viscosity,
heat conductivity and Prandtl number (Pr = /a) are main properties
Using the approximation in Eq. (2) gives the following correla-
in the trend correlations given in this contribution. The ratios are
tion
given at two different temperature levels of 295 K and 235 K with
data from [19]. The maximum ratio is given by 7.44 for Pr number  1/(5−n)
NLi Cf n 2−n
ratio of ethanol to water at 235 K, the minimum ratio with a value dh =  V̇ (10)
2p
0.22 for heat conductivity at room temperature. All ratios are less
than one order of magnitude, hence, trends are also valid for the
mentioned fluids to a certain range. This correlation is depicted in Fig. 5 for n = 0.25 (transitional
The ratios in Table 1 can also be read in the following way: the Re flow) and a pressure loss of 1.0, 5.0, and 20 bar.
number, which is determined by the kinematic viscosity, is 4 times Mixing depends mainly on the local energy dissipation rate
higher for toluene at 295 K or 6.5 times lower for ethanol at 235 K as [23] and geometry of the channel. The channel shape guides the
water at 295 K, same flow velocity and hydraulic diameter assumed. flow and causes flow deflection. Besides shear forces, new flow-
The ratio of heat conductivity is always lower than unity indicating perpendicular forces act on the fluid and generate secondary flow
lower heat transfer in organic solvents compared to water. structures, vortices, and recirculation zones [8]. From the theory of
Due to the high velocities in complex winding and meander- chaotic advection, the center of vortex formation is called elliptic
ing structure of the channels, the flow is not laminar for Re > 100, point; intersection points of separation lines between two vor-
but shows transitional behavior to turbulent characteristics. Under tices with another separation line or with the channel wall are
these flow conditions, vortices appear in bend flow, which start to called hyperbolic points. The position of the interface between
fluctuate with increasing Re number and lead to chaotic flow struc- two components or two fluids in relation to vortex separation line
tures, see [20]. Flow characteristics are often determined by highest of characteristic points is a very important issue for the design
flow velocity in narrowest channel, hence smallest hydraulic diam- of efficient mixing channels. A rapid change of flow vortices by
eter. alternating channel elements or by repeated deflecting flow leads
to efficient flow mixing. To generate these flow structures and
vortices, the fluid needs mechanical energy consumed from the
6. Pressure loss and mixing time in microchannels
pressure of the fluid. Hence, the pressure drop per unit volume is
The pressure driven flow in microchannels needs mechanical
energy to drive fluids through the channel. This mechanical energy
is spent to the system by a pump ahead of the reactor and is dissi-
pated within the channel. The dissipation leads to shear flow, vortex
generation, and internal flow mixing, depending on the typical
channel geometry. The pressure loss is typically correlated with the
flow velocity and to the geometry related pressure loss coefficients.
Considering long straight channel elements with length L and
short elements, where the flow is turbulent, the pressure loss is rep-
resented by Bernoulli’s equation with kinetic energy and neglecting
potential energy. The pressure loss consists of long straight ele-
ments (i (Li /dh,i )) and short elements with  i .
 Li

 2
p = i + i w (7)
dh,i 2 i
i

Typically, mixing happens in the first channel part with N iden-

tical channel elements with mean characteristic fluid velocity w. Fig. 5. Typical values of pressure loss in bar and mixing time in seconds together
The element can be characterized with a characteristic hydraulic with Re = 2000 and flow velocities of 1 and 5 m/s.
 N. Kockmann et al. / Chemical Engineering Journal 167 (2011) 718–726
the measure for mixing, expressed in the energy dissipation rate.
pV̇ pw
ε= = (11)
m L
The channel length, over which the pressure loss occurs, is equal
to the length of the sum of all mixing elements L = NLi . With
more energy dissipated in the mixing channel, the mixing time
gets shorter due to smaller fluid structures, where diffusion of the
species occurs as last measure of mixing [17,23,24]. The species
diffusion is represented by the Schmidt number, the ratio of the
kinematic viscosity to the diffusivity of the main species.
  1/2
tm = Cm Sc
ε
The mixing coefficient Cm was given by Bourne [23] as engulf-
ment rate to 17.3. With the approximation in Eq. (2) and the above
correlations, the hydraulic diameter can be correlated to the volu-
metric flow rate and the typical mixing time
 t 2/(7−n)  C 1/(7−n)
m f n−1 3−n
dh =  V̇
Cm Sc 2Li
Both Eqs. (10) and (13) are displayed in Fig. 5 for typical pres-
sure losses of 1.0, 5.0, and 20 bar and mixing times of 0.1, 0.01,
and 0.001 s. For many industrial applications, these values display
an appropriate range. The horizontal bar indicates the typical flow
rate range at 0.5 mm channel diameter, see also Fig. 4.
Fig. 5 shows for transitional flow (n = 0.25) in the mixing channel,
the pressure drop and the mixing time have nearly the same incline.
Hence, slightly higher pressure drop in larger channels will lead
to similar mixing times in these channels. In pure laminar flow
(n = 1.0), where the pressure loss is proportional to inverse of the
Re number, similar mixing time in reactors with larger diameter
consumes remarkable higher pressure loss. In turbulent flow (n = 0),
pressure drop and mixing times scale with the same incline with the
volumetric flow rate and depends only on channel geometry and
surface roughness. For most industrial applications, a mixing time
of 0.1 s is sufficient. Often, heat transfer will be the limiting step.
Only for analytical devices, rapid mixing below 1 ms is important
[22].
7. Heat transfer and reaction runaway in microchannels
Heat transfer and runaway of exothermic reactions are closely
related with the energy balance in a channel element. Two cases are
discussed here, the convective heat transfer in the microchannel
and the heat conduction in a case of stopped flow of the reacting
fluid to avoid reaction runaway. The latter case is important for
safety discussion in case of pump failure or similar event, when
the reaction should be under control. Because the convective heat
transfer in a channel is always higher than heat conduction in a
non-moving system, this case gives an upper limit of the channel
size [25]. Larger channels may lead to reaction runaway in case of
interrupted flow.
The internal convective heat transfer on the reaction side is
described by the heat transfer coefficient ˛i , in dimensionless form
with the Nußelt number Nu
Nu
˛i =
dh
Textbooks describe many ways to determine the heat transfer
coefficient or Nu number in channel flow. Here, we use the Lévêque
correlation [26]:
 1/3
dh
Nu = Ch total · Re2 Pr
L following characteristic parameter, also called Frank-Kamenetzkii
723
(12)
Fig. 6. Internal heat transfer coefficient (water, 20 ◦ C) with 10 and 50 kW/m2 K and
typical reaction conditions, adiabatic temperature rise of 50 and 150 K, typical char-
acteristic reaction time of 1 and 10 s, describing the difference between Type A and
Type B reactions.
(13)
The constant is Ch = 0.404, which is valid for complex geometries
such as fixed beds or tube bundles in cross flow with Re num-
bers above 1000 [26]. The pressure loss coefficient is introduced
from the transitional flow regime between laminar and turbulent
flow from Eq. (8). Combination of the correlations above yields for
the characteristic hydraulic diameter depending on flow rate and
internal heat transfer coefficient.
  2−n  3 1/(5−n)
V̇ Ch f
dh = Cf Pr (16)
 ˛i
Other pressure loss correlations as well as heat transfer corre-
lations can also be integrated into the above correlations to adjust
the correlations to other geometries or flow conditions. The pur-
pose here is to show trends of heat transfer scale-up characteristics
with increasing flow rate and increasing hydraulic diameter. Typi-
cal values of internal heat transfer coefficients for water 20 ◦ C with
10 kW/m2 K and 50 kW/m2 K are given in Fig. 6. The horizontal bar
indicates the typical flow rate range at 0.5 mm channel diameter,
see also Fig. 4.
In the second case we discuss the critical heat transfer to avoid
reaction runaway. Starting with the thermal energy balance for
an exothermic reacting flow in a channel, we have two issues to
consider, the reaction heat
 E 
A
q̇ = (−Hr )CA k0 exp − (17)
RT
and the cooling heat transfer by conduction within the fluid to the
channel wall during stopped flow with fluid thermal conductivity
 and temperature difference T between fluid and wall tempera-
ture.
q̇ = −T (18)
The wall often consists of metal; hence the main thermal resis-
tance presents the fluid itself. It is assumed, that half of the
hydraulic diameter is necessary to transfer the heat to the wall. Both
(14) equations above can be graphically analyzed in the Semenov curve,
because an analytical solution is hard to find due to the non-linear
behavior [17] of the Arrhenius term in Eq. (16). Here, we follow the
approach of Frank-Kamenetzkii [27], who derived the heat balance
and introduced dimensionless parameters for temperature and the
spatial coordinate. The solution for the dimensionless differential
equation in steady state can be given from the eigenvalues of the
(15)
724 N. Kockmann et al. / Chemical Engineering Journal 167 (2011) 718–726
parameter.
 2
(−Hr ) EA dh
 E 
A tm . The horizontal bars indicate the typical flow rates for a single
ı= k0 exp −
 RT02 2 RT0
The critical value of ıcrit is reached, when the vessel tempera-
ture holds a steady value and no reaction run away occurs. These
values are 2.00 and 3.32 for an infinite cylinder and spherical vessel,
respectively. Now we can define the critical diameter of a cylinder,
where internal heat conduction is not sufficient to remove heat
release from reaction.
 1/2
2
8af RTW
dh = tR
EA Tad
The characteristic reaction time tr is determined from the reac-
tion rate r, where the adiabatic temperature rise is determined by
the reaction enthalpy and initial concentration CA,0 .
CA,0 1 CA,0 (−Hr )  ditions. The flow velocity reaches several m/s and the Re number
tR = = m−1
; Tad = ; af =
r(TW ) k0 CA,0 cp cp
The last parameter af is the temperature conductivity of the
reacting fluid. In Eq. (20) we see no influence of the flow rate any-
more, because the heat transfer is only by thermal conduction. This
case occurs for example for pump failure, when the reacting fluid is
not moving anymore. No reaction runaway occurs in this case. For
a streaming reacting fluid, the internal heat transfer is much higher
than pure conduction and also no reaction runaway will occur.
In Fig. 6, the internal heat transfer coefficient is between 10 and
50 kW/m2 K in the displayed diameter and related range of flow
rate. For reactions with an adiabatic temperature rise below 150 K,
a reaction run away will not occur, if they are slower than 10 s.
For faster reactions, a more detailed analysis is necessary to guar-
anty safe operation. For example, one reagent can be split up in
several feed streams to individual injection points, forming the so-
called cross flow reactor [28]. Involving a second phase as well as
adjustment of concentration or component reactivity can trim the
transport characteristics and kinetics to coherent values.
8. Plate and reactor design
The above derived correlations in Eqs. (4), (6), (10), and (13)
guide the proper and consistent design of microchannel reactors
for flow velocity, Re number, pressure drop, and mixing time. The
internal channel size and channel cross-section area are also grow-
ing with plate size allowing higher flow rates through the reactor,
see Fig. 7.
The typical hydraulic diameter of the mixing channel is qual-
itatively displayed over the flow rate in double-logarithmic scale
Fig. 7. Plate size and channel diameter for different flow rates with comparable
mixing time.
for constant flow velocity w, constant Reynolds numbers, constant
pressure loss p over the mixing channel, and typical mixing time
(19)
channel diameter and size for necessary mixing time and allowable
pressure loss.
The reactor stacks were already displayed in Fig. 3. The reactor
size in Fig. 7 is named according to the outer dimensions of the
plates. For example, the A6 Lonza reactor corresponds to DIN A6
paper sheet format of 148 mm × 105 mm. The A5 reactor has dou-
ble the area of A6 reactor and also roughly twice the heat transfer
capacity. The stepwise scale-up of the plates is accompanied by
stepwise scale-up of the channel cross-section, leading to a scaling
(20)
factor of approx. 1.4 between each step. For example, the typical
hydraulic diameters of the mixing channel in the A6 reactor plate
are 0.35 and 0.5 mm, hence, the A5 reactor plate contains mixing
channel structures with typical diameters of 0.7 and 1.0 mm. Larger
plates are accordingly scaled up leading to comparable mixing con-
(21) indicates turbulent flow regime in the mixing channel. Heat trans-
fer area and internal volume to gain residence time are increased
in corresponding steps of connected plates in series. These mea-
sures result in a consistent, versatile, and flexible scale-up strategy
completely avoiding parallelization over a wide range of flow rates
[7,13].
Beside the reactors size, the operational conditions are changing
accordingly. Small reactors size of Lab-Plate and A6 Lonza reactor
are well suited for projects in process development. They fulfill the
needs of early phase studies in a highly consistent and straight-
forward manner. Once a project has survived and progressed to
commercial manufacture, the aim changes to detail engineering
and piloting of the process. More resources can be invested in
the project. Chemical engineering plays an important role and the
scale-up is performed using either conventional static mixers with
mini-heat exchangers, higher cross-sectional reactors (as small as
needed), or as a last measure numbering-up and equipment paral-
lelization.
9. Scale-up example
All reactor types displayed in Figs. 2 and 3 are frequently used
in Lonza’s laboratories and production environment. The Lab-Plate
and A6 reactor are suitable for early feasibility studies for given
chemical routes to check main parameters and precipitation poten-
tial. Process development is performed in A6 and A5 reactors, where
main influence parameters such as temperature, stoichiometry,
solvents, and reagents are investigated and optimized. Sample pro-
duction in the laboratory and large scale production are performed
in the A5 reactor. However, the A5 reactor can be operated for short
time in laboratory under simulated process conditions similar to
later production conditions.
As conclusion, we will demonstrate the scale up of microreactors
with a real-case example consisting of a two-steps organo-metallic
reaction (Li–H exchange and coupling) with three feeds having fol-
lowing composition: Feed-1 with substrate at 15 wt.%, Feed-2 with
first reagent at 30 wt.%, and Feed-3 with second reagent at 16 wt.%.
The reaction is stoichiometric and operated at two temperature
levels. Feed-1 and Feed-2 were precooled to the cryogenic reactor
temperature, while the second reaction could be performed with-
out cooling at room temperature. The flow diagram and reaction
scheme are depicted in Fig. 8.
The first reaction is of Type A with an adiabatic temperature
rise of more than 75 ◦ C. Three reactors were tested: a static mixer,
a glass microreactor, and the Lonza plate microreactor, see Table 2.
The second reaction is of Type B and less demanding in terms of
heat exchange (Tad < 25 ◦ C) and mixing. A microreactor and static
mixer were tested with identical performances. Mixing and heat
 N. Kockmann et al. / Chemical Engineering Journal 167 (2011) 718–726 725

Fig. 8. Reaction scheme and process scheme with image of pilot-scale production setup.

Table 2 ting first chemical results. The question, how to transfer the lab
Comparison of different reactors and flow rates for scale-up of the lithiation reaction,
results to pilot plant and large commercial production is still a chal-
see Fig. 8.
lenging task. This contribution shows a consistent pathway from
Reactor ṁMR [g/min] Tout [◦ C] p [bar] Isolated yield [%] lab development to pilot plant production of continuous-flow pro-
Static mixer 3/8
33 9 0.3 88 cesses with microstructured devices. The key factor of the reactor is
Static mixer 3/8 148 41 1.6 84 that it has only one single channel, which characteristic dimension,
Glass MR 0.5 mm 33 −14 0.4 86 the hydraulic diameter, is scaled up in correlation with mixing time
Glass MR 0.5 mm 148 15 3.2 88
and heat transfer characteristics. Pressure drop in the mixing chan-
Lonza MR-A6 0.5 mm 33 −22 0.9 89
Lonza MR-A6 0.5 mm 140 −16 8.8 90 nel plays the key role to determine mixing time and heat transfer
Lonza MR-A5 0.7 mm 150 −20 3.4 90 rates. The reaction kinetics and enthalpy are correlated with the
Lonza MR-A5 1.0 mm 150 −21 2.0 88 above results and indicate the operability of the reactor. A modular
Lonza MR-A5 1.0 mm 237 −16 4.5 88
microreactor system developed at Lonza is presented, which can
be used for process research in the lab as well as for production
campaigns on pilot scale. The scale-up is shown for an industrial
transfer are not critical issues, only sufficient residence time has to example. With this approach, valuable laboratory experience can
be provided for the reagents. be easily transferred with success into production environment
Investigating the lithiation reaction (Table 2), no adequate tem- without the loss in productivity. Simple and robust scale up with
perature control was observed within the static mixer; more or less modularity for multipurpose applications will give new drive for
the complete adiabatic temperature rise was detected at medium microreactor development and applications.
flow rate (148 g/min). Un-wanted side products were formed to
large extend, visible also in a drop of yield (84% versus 89% on
average). Certain concentration of the critical byproduct leads to References
problems during workup. The results with the glass microreactor
show a loss of temperature control at higher flow rates, but not [1] G.A. Truskey, F. Yuan, D.F. Katz, Transport Phenomena in Biological Systems,
2nd ed., Pearson Prentice Hall, Boston, 2010.
yet reflected in the product yield. For lower flow rates, the mix- [2] N. Kockmann (Ed.), Micro Process Engineering, Wiley-VCH, Weinheim, 2006.
ing was not fast enough and led to higher byproduct formation. [3] S.J. Haswell, P. Watts, Green chemistry: synthesis in micro reactors, Green
Besides rapid mixing, a short residence time is also very important. Chem. 5 (2003) 240–249.
[4] J.-I. Yoshida, Microreactor synthesis in green chemistry, Chem. Ind. 57 (2006)
Nevertheless, the operational robustness of the glass reactor was
461–464.
not adequate for this particular reaction. The results with Lonza’s [5] V. Hessel, Novel process windows—gate to maximizing process intensification
reactor technology show a good equivalence of performance for via flow chemistry, Chem. Eng. Technol. 32 (2009) 1655–1681.
[6] J.-I. Yoshida, Flash Chemistry: Fast Organic Synthesis in Microsystems, Wiley,
the smaller (A6) and larger (A5) reactors. It was possible to operate
New York, 2008.
the A5 reactor with an internal mixing channel of 1 mm diame- [7] D.M. Roberge, M. Gottsponer, M. Eyholzer, N. Kockmann, Scale-up approach and
ter up to 237 g/min with a total flow rate over 700 g/min for the production of pharmaceuticals in microreactors, Chem. Today 27 (July–August)
second reaction by keeping the pressure drop well under control. (2009) 8–11.
[8] N. Kockmann, Transport Phenomena in Micro Process Engineering, Springer,
700 kg of isolated material were produced in a pilot campaign lead- Berlin, 2008.
ing to more than 10 m3 of processed solution through the reactor [9] D.M. Roberge, L. Ducry, N. Bieler, P. Cretton, B. Zimmermann, Microreactor tech-
setup. A second campaign was performed to produce more than nology: a revolution for the fine chemical and pharmaceutical industries, Chem.
Eng. Technol. 28 (2005) 318–323.
2 tons of isolated material in 2009. Both campaigns showed the [10] A. Nagaki, H. Kim, J.-I. Yoshida, Nitro-substituted aryl lithium compounds in
long-term robustness of the process and reliability of the installed microreactor synthesis: switch between kinetic and thermodynamic control,
reactor equipment. Angew. Chem. IE 48 (2009) 8063–8065.
[11] C. Wiles, P. Watts, Continuous flow reactors, a tool for the modern synthetic
chemist, Eur. J. Org. Chem. 10 (2008) 1655–1671.
[12] K. Geyer, J.D.C. Codee, P.H. Seeberger, Microreactors as tools for synthetic
10. Conclusion
chemists—the chemists’ round-bottom flask of the 21st century? Chem. Eur.
J. 12 (2006) 8434–8442.
Microreactors have found their place in research laboratories [13] N. Kockmann, M. Gottsponer, B. Zimmermann, D.M. Roberge, Enabling
in academia and industry for development and small scale pro- continuous-flow chemistry in microstructured devices for pharmaceutical and
fine-chemical production, Chem. Eur. J. 14 (2008) 7470–7477.
duction. Chemical and pharmaceutical companies are now starting [14] L. Ducry, D.M. Roberge, H. Dibal, Reduction of methyl butyrate into butyralde-
to invest more and more effort in setting up lab devices and get- hyde using microreactors, Org. Process Res. Dev. 12 (2008) 163–167.
726 N. Kockmann et al. / Chemical Engineering Journal 167 (2011) 718–726
[15] F. Rainone, N. Kockmann, B. Zimmermann, Industrial fine-chemical and phar-
maceutical production with microreactor technology (MRT), CPAC Satellite
Workshop, Rome, 2008, March 26–28.
[16] L. Ducry, D.M. Roberge, Controlled autocatalytic nitration of phenol in a
microreactor, Angew. Chem. IE 44 (2009) 7972–7975.
[17] N. Kockmann, D.M. Roberge, Harsh reaction conditions in continuous-flow
microreactors for pharmaceutical production, Chem. Eng. Technol. 32 (2009)
1682–1694.
[18] D.M. Roberge, N. Bieler, B. Zimmermann, R. Forbert, Micro-Reactor System
WO2007112945, 2007.
[19] H.G. Hirschberg, Handbuch Verfahrenstechnik und Anlagenbau. Chemie, Tech-
nik und Betriebswirtschaft, Springer, Berlin, 1999.
[20] N. Kockmann, D.M. Roberge, Transitional flow and related transport phenom-
ena in curved microchannels, Heat Transfer Eng (2011).
[21] N. Kockmann, Pressure loss and transfer rates in microstructured devices with
chemical reactions, Chem. Eng. Technol. 31 (2008) 1188–1195.
[22] Z.K. Majumdar, J.D. Sutin, R.M. Clegg, Microfabricated continuous-flow, turbu-
lent, microsecond mixer, Rev. Sci. Instrum. 76 (2005), 125103.
[23] J.R. Bourne, Mixing and selectivity of chemical reactions, Org. Process Res. Dev.
7 (2003) 471–508.
[24] L. Falk, J.-M. Commenge, Characterization of mixing and segregation in
homogenous flow systems, vol. 1, in: V. Hessel (Ed.), Micro Process Engineering,
Wiley-VCH, Weinheim, 2009, Chapter 6.
[25] M. Gödde, C. Liebner, H. Hieronymus, Sicherheit in der Mikroreaktionstechnik,
Chemie-Ing. Technik 81 (2009) 73–78.
[26] H. Martin, The generalized Lévêque equation and its practical use for the pre-
diction of heat and mass transfer rates from pressure drop, Chem. Eng. Sci. 57
(2002) 3217–3223.
[27] D.A. Frank-Kamenetskii, Diffusion and Heat Transfer in Chemical Kinet-
ics, Russian eds. 1947, 1967, 1987, German ed. 1959, English eds.
1969.
[28] D.M. Roberge, N. Bieler, M. Mathier, M. Eyholzer, B. Zimmermann, P. Barthe, C.
Guermeur, O. Lobet, M. Moreno, P. Woehl, Development of an industrial multi-
injection microreactor for fast and exothermic reactions—part II, Chem. Eng.
Technol. 31 (2008) 1155–1161.