Reactors

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Title: Reactors
:Authors
Sean Cabaniss, David Park, Maxim Slivinsky, and Julianne Wagoner [Winter 2014]
Neil Dalvie, KC Anderson, Natalia Majewska [Winter 2016]
Steward: David Chen, Fengqi You
Date Presented: February 4, 2014

Contents

1Introduction 
1.1Ideal Reactors o
1.1.1Batch Reactors 
1.1.2Plug Flow Reactor 
(PFR)
1.1.3Continuously Stirred 
Tank Reactor (CSTR)
2General Reactor Design 
2.1Step 1: Collect Required Data o
2.1.1Enthalpy of Reaction 
2.1.2Equilibrium Constant 
and Gibbs Free Energy
2.1.3Reaction Mechanisms, 
Rate Equations, and Rate
Constants
2.1.4Heat and Mass 
Transfer Properties
2.1.4.1Heat 
Transfer
2.1.4.2Diffusio 
n Coefficients
2.1.4.3Mass 
Transfer
2.2Step 2: Select Reaction Conditions o
2.2.1Chemical or 
Biochemical Reaction
2.2.2Catalyst 
2.2.3Temperature 
2.2.4Pressure 
2.2.5Reaction Phase 
2.2.6Solvent 
2.2.7Concentrations 
2.3Step 3: Determine Materials of o
Construction
2.4Step 4: Determine Rate-Limiting Step o
and Critical Sizing Parameters
2.5Step 5: Preliminary Sizing, Layout, and o
Costing of Reactor
2.6Step 6: Estimate Reactor Performance o
2.7Step 7: Optimize the Design o
3Mixing in Industrial Reactors 
3.1Gas Mixing o
3.2Liquid Mixing o
3.3Gas-Liquid Mixing o
3.4Solid-Liquid Mixing o
4Types of Reactors 
4.1Vapor-Liquid Reactors o
4.2Catalytic Processes o
4.2.1Homogeneous 
Catalysis
4.2.2Heterogeneous 
Catalysis
4.3Bioreactors o
4.3.1Enzyme Catalysis 
4.3.2Microorganism Design 
and Selection
4.3.2.1Fermen 
tation Goals

4.3.2.
1
.
1
C
o
s
t,
Y
i
e
l
d
,
a
n
d
P
r
o
d
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c
ti
vi
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y

4.3.2.
1
.
2
P
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o
l
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n
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P
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fi
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
4.3.2.
1
.
3
O
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C
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4.3.2.2Challen 
ges in
Microorganism
Design
4.3.2.3Case 
Studies

4.3.2.
3
.
1
P
e
n
ic
ill
i
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P
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
4.3.2.
3
.
2
A
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is
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P
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o
d
u
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ti
o
n
4.3.3Cell Growth 
4.3.4Batch or Continuous 
4.3.5Mass Transfer for 
Bioreactors
4.3.6Types of Bioreactors 
4.3.7Preventing 
Contamination
4.3.7.1Death 
Kinetics
4.3.7.2Steriliza 
tion of Liquids

4.3.7.
2
.
1
B
a
t
c
h

4.3.7.
2
.
2
C
o
n
ti
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u
o
u
s

4.3.7.
2
.
3
E
x
a
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C
a
lc
u
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a
ti
o
n
s
4.3.7.3Steriliza 
tion of Gases
4.3.7.4Sterile 
Sampling
4.3.7.5Cleanin 
g
5Heating and Cooling of Reacting Systems 
5.1Stirred Tank Reactors o
5.2Catalytic Reactors o
5.2.1Slurry Reactors 
5.2.2Fixed-bed Reactors 
5.2.3Fluidized-bed Reactors 
5.3Heat Exchangers as Reactors o
5.3.1Homogenous 
Reactions
5.3.2Heterogenous 
Reactions
6Safety Considerations in Reactor Design 
7Capital Cost of Reactors 
8Conclusions 
9References 

Introduction
The center of any chemical process is the reactor, where chemical reactions
are carried out to transform feeds into products. Reactor design is a vital step
in the overall design of a process. It is important to ensure that the equipment
.specified will be capable of achieving the desired yields and selectivity

Ideal Reactors
Batch Reactors
In a batch reactor, the reagents are added together and allowed to react for a
given amount of time. The compositions change with time, but there is no flow
through the process. Additional reagents may be added as the reaction
proceeds, and changes in temperature may also be made. Products are
.removed from the reactor after the reaction has proceeded to completion
Batch processes are suitable for small-scale production (less than 1,000,000
lb/yr) and for processes where several different products or grades are to be
produced in the same equipment (Douglas, 1988). When production volumes
are relatively small and/or the chemistry is relatively complex, batch
.processing provides an important means of quality control
Plug Flow Reactor (PFR)
A PFR with tubular geometry has perfect radial mixing but no axial mixing. All
materials hav the same residence time, τ, and experience the same
temperature and concentration profiles along the reactor. Equation for PFR is
:given by
where M = molar flow rate, dV is the incremental volume, and  is the rate of
.reaction per unit volume
This equation can be integrated along the length of the reactor to yield
.relationships between reactor resident time and concentration or conversion
Continuously Stirred Tank Reactor (CSTR)
The stirred tank reactor models a large scale conventional laboratory flask
and can be considered to be the basic chemical reactor. In a CSTR, shown in
Figure 1, there is no spatial variation- the entire vessel contents are at the
same temperature, pressure, and concentration. Therefore the fluid leaving
the reactor is at the same temperature and concentration as the fluid inside
.the reactor
:The material balance across the CSTR is given by
Some of the material the enters the reactor can leave immediately, while
some leaves much later, so there is a broad distribution in residence time as
.shown in Figure 1

Figure 1. Continuously Stirred Tank Reactor (Towler and Sinnott, 2013)

.More information on stirred tanks can be found in the Mixing section

General Reactor Design

The design of the reactor should not be carried out separately from the overall
process design due to the significant impact on capital and operating costs on
.other parts of the process (Towler and Sinnott, 2013)

Step 1: Collect Required Data

Out of all process equipment, reactor design requires the most process input
data: reaction enthalpies, phase-equilibrium constants, heat and mass
transfer coefficients, as well as reaction rate constants. All of the
aforementioned parameters can be estimated using simulation models or
literature correlations except for reaction rate constant constants, which need
.to be determined experimentally (Towler and Sinnott, 2013)
Enthalpy of Reaction
The heat given out in a chemical reaction is
based on the enthalpies of the component
chemical reactions, which are given for
standard temperature and pressure (1 atm, 25
C). Values for standard heats of reaction can
be found tabulated in literature, or can be
calculated from heats of formation or
combustion. Care must be taken to quote the
basis for the heat of reaction and the states of
.reactants and products
The following equation is used to convert
enthalpies from standard conditions to the
:process conditions

If the effect from pressure is not significant

and only Temperature needs to be accounted
:for, the following equation should be used

Equilibrium Constant and

Gibbs Free Energy
Where  is the change in Gibbs free energy
from the reaction at temperature ,  is the ideal
gas constant, and  is the reaction equilibrium
:constant, given by
where  is the activity of component i,  is the
stoichiometric coefficient of component ,
.and  is the total number of components
Equilibrium constants can be found in the
literature and are useful for evaluating the
rates of forward and reverse reactions. Care
must be taken to the experimental design
used for the literature equilibrium constants to
make sure they are consistent with the
conditions of the actual process reactor. For
more complicated reactions consisting of
several sequential or simultaneous reactions,
the equilibrium is found by minimizing the
Gibbs free energy (Towler and Sinnott, 2013).
Commercial process simulation programs use
.the Gibbs reactor model in this way
Reaction
Mechanisms,
Rate
Equations,
and Rate
Constants
In most cases the main process reaction rate
equations and rate constants cannot be
predicted from first principles and must be
approximated (Towler and Sinnott, 2013). This
:is due to the following
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As a result the main process reaction is
usually approximated as first- or second-order
over a narrow range of process conditions
(temperature, pressure, species
concentrations) to estimate the residence time
required for a target conversion. Rate
equations are always a fit for experimental
data and should thus be used for interpolation
within the data. It is important to collect more
data when extrapolating, especially for
exothermic reactions which have the potential
.for runaway (Towler and Sinnott, 2013)
Heat
and
Mass
Transfe
r
Propert
ies
Heat
Transfer
The design of internal heating or cooling
devices can be found in Heat Transfer
Equipment. Correlations for tube-side heat-
transfer coefficients for catalyst-packed tubes
:of a heat exchanger are given below
For heating: 
and for cooling: 
where  is the tube-side heat transfer
coefficient for a packed tube,  is the tube
diameter,  is the fluid thermal conductivity,  is
the fluid density,  is the superficial velocity,  is
the effective particle diameter, and  is the fluid
.viscosity
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Diffusion coefficients are necessary when
mass transfer can limit the rate of reaction,
such as in catalytic reactions or reactions
involving mass transfer processes such as
gas absorption, distillation, and liquid-liquid
.extraction
The diffusivity for gases can be estimated by
the following correlation (Fuller, Schettler,
:Giddings)
where  is the diffusivity,  is temperature,  are
the molecular masses of
components  and ,  is the total pressure,
and  are the summation of special diffusion
volume coefficients for components  and ,
:given in the table below
)volume coefficient table from towler (
Wilke and Chang developed a correlation for
estimating the diffusivity of components in the
:liquid phase
where  is the liquid diffusivity,  is an
association factor for the solvent,  is the
molecular mass of the solvent,  is the solvent
viscosity,  is the temperature, and  is the
molar volume of the solute at its boiling point.
This correlation holds for organic compounds
.in water but not for water in organic solvents
M
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For multiphase reactors it is necessary to
.estimate the mass transfer coefficient
The equation of Gupta and Thodos predicts
the mass transfer coefficient for a packed bed
:of particles
where  is the mass transfer coefficient,  is the
particle diameter,  is the diffusivity,  is the
Reynolds number calculated using the
superficial velocity through the bed,  is the
.Schmidt number, and  is the bed void fraction
Mass transfer between vapor and liquid in an
agitated vessel can be described by the Van't
:Riet equations
For air-water: 
and for air-water-electrolyte: 
where  is the mass transfer coefficient,  is the
interfacial area per unit volume,  is the gas
volumetric flow rate,  is the liquid volume,
.and  is the agitator power input
Fair's method for calculating the mass transfer
coefficient for low viscosity systems is given
:by
.where  is the liquid phase diffusivity
Mass transfer correlations for vapor-liquid
systems should be used with caution when
there are surfactants (Towler and Sinnott,
.2013)

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(c) annular (Towler and Sinnott, 2013)
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Homogeneous catalysis can be conducted in
the basic batch reactors, PFRs, or CSTRs that
have already been discussed. However, when
the catalyst is in the same phase as the
reagent, recovering this catalyst after the
reaction can be difficult and expensive,
particularly if the catalyst is sensitive to high
temperatures (Towler, 2012). Providing
adequate interfacial area is also a challenge
of homogeneous catalysis. A reaction often
only occurs at the interface or in the boundary
layer between the catalyst and the reagents.
Increased mixing can increase the rate and
selectivity of the reaction, but this can require
detailed and expensive mixing equipment
(Towler, 2012). For these reasons, reactions
requiring homogenous catalysts are not
usually used unless an easy separation can
.be found to recover the catalyst
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Catalyst recovery in processes involving
heterogeneous catalysis is much easier.
However, the rate of reaction is limited by the
available inter-phase surface area and the
mass transfer of reagents and products to and
from the interface (Towler, 2012). Therefore,
reactors for these processes are design to
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In a fixed-bed reactor, the reagent flows over
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and Sinnott, 2013). This is the most common
type of reactor used for heterogeneous
catalysis as long as the catalyst does not
require continuous regeneration and the
reaction mixture does not require high
agitation (Towler, 2012). The amount of
catalyst necessary can be found using the
:following equations

The ratio of the bed height (L) to the diameter

(D) determines the distribution of reagents
and the pressure drop across the bed. An
increased L/D ratio creates a more even
distribution and less change of localized
deactivation or "hot spots." However,
increasing the L/D ratio increases the
pressure drop, requiring higher compression
and pumping costs (Towler, 2012). The Ergun
equation can be used to calculate the
.pressure drop in packed beds

Where V is the superficial velocity (volume

flowrate divided by cross-sectional area), μ is
the viscosity, Dp is the particle diameter and ε
is the porosity of the packed bed (Towler,
2012). Given these trade-offs, it may make
sense to split the catalyst over several beds
.(Towler, 2012)

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available, the L/D ratio must be much less that
one (Towler, 2012). A common solution to this
is to use a radial flow reactor with the catalyst
contained in an annulus between vertical
perforated or slotted screens. The fluid flows
radially through the bed and the direction of
flow can be either inwards or outwards
(Towler and Sinnott, 2013). An example of a
.radial flow reactor is shown in Figure 12
Figure 12. Radial flow reactor (Towler, 2012)

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A moving bed reactor is similar to a radial flow
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If the fluid flow is up through the catalyst bed
then the bed can become fluidized if the
pressure drop is high enough to support the
weight of the catalyst. Fluidized beds usually
have a lower pressure drop than down flow at
high flow rates (Towler, 2012). In addition,
fluidizing the catalyst eases the transition from
.one reaction zone to another
The catalyst bed is fluidized using a distributor
to inject fluidization fluid, which is not
necessarily the feed. Fluidization occurs when
the bed pressure drop balances the weight of
the particles, or

Where ∆P is the pressure drop, ρp and ρg are

the densities of the particle and gas
respectively, εm is the porosity at minimum
fluidization, and L is the height of the bed
(Towler, 2012). Fluidization can only be used
with relatively small sized particles (<300
micrometers with gases). The solid material
must be strong enough to withstand attrition in
the fluidized bed and cheap enough to allow
for make-up to replace attrition losses (Towler
and Sinnott, 2013). A fluidized-bed reactors
must also make allowance for separating the
fluid-phase product from entrained solids so
that solids are not carried out of the reactor
.(Towler and Sinnott, 2013)

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Trickle bed reactors are used when all three
phases are involved in the reaction. They
must ensure good distribution of both the
vapor and the liquid, without channeling of
either phase (Towler, 2012). In a trickle bed
reactor, the liquid flows down over the surface
of a stationary bed of solids. The gas phase
usually also flows downwards with the liquid,
but countercurrent flow is feasible as long as
flooding conditions are avoided (Towler and
Sinnott, 2013). This requires a more
sophisticated distributor like those used for
packed distillation columns (Towler, 2012). An
example of a trickle bed reactor is shown in
.Figure 13

Figure 13. Example of trickle bed reactor

(Towler, 2012)

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Liquid is mixed up in the liquid in slurry phase
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of the solids, caused by pumping or agitation
of the liquid (Towler and Sinnott, 2013).
Slurry-phase operation is usually not preferred
for processes that use heterogeneous
catalysts because the catalyst tends to
become eroded and can be difficult to recover
.from the liquid (Towler and Sinnott, 2013)

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The stirred tank fermenter is the most
common reactor used for biological reactions
(Towler, 2012) and is similar to the stirred
tanks discussed previously. It can be used in
both batch and continuous mode. Figure 14
.shows a stirred tank fermenter
Figure 14. Fermentation reactor (Towler and
Sinnott, 2013)

Shaftless Bioreactors 
Shaftless bioreactors are used when the
pump shaft seal is considered a non-
permissible source of contamination. These
reactors use gas flow to provide agitation of
the liquid. The design requires careful
attention to hydraulics (Towler, 2012).
Examples of shaftless bioreactors are shown
.in Figure 15

Figure 15. Examples of shaftless bioreactors

(Towler, 2012)

WAVE Bioreactors 
WAVE bioreactors represent an alternative to
standard stainless steel bioreactors. These
reactors are flexible and single-use, cutting
down time between batches and allow for a
more sterile environment. These disposable
reactors are mostly used in mammalian cell
culture. Three layers of plastic are the
minimum necessary for construction. The first
is a structural layer, followed by a barrier layer
that allows for permeability. The last layer, the
fluid contact layer, is designed to take into
account inertness and maintain a good seal
.(Bioprocess, 2013)

Figure 16. Example of a WAVE bioreactor

.(GE Health, 2016)

Packed Bed Bioreactors 

Packed Bed Bioreactors are structured so that
the cells are immobilized and placed on large
particles. Although they are relatively simple
to construct, they can have blockage issues or
poor oxygen transfer. There are three types of
flow: downward flow, upward flow and the
recycling method. In industry, upward flow is
preferred, especially when there is gas
production during the fermentation (Prieto,
.2003)
Figure 17. Example of a packed bed
.bioreactor (Kang, 2000)

Anaerobic Bioreactors 
Anaerobic reactions are used in ethanol
production, winemaking, beer brewing, and
wastewater treatment. Due to its long standing
history, these processes have become well
established and improvements include
decreasing cost of production due to new
technology. Although continuous production
for beer has been patented on a large scale,
most investment is still focused on batch
.production (William, 2002)
Preventing Contamination
Since cells are easily affected by both unwanted chemicals and other species in the reactor, bio
Since they are meant to ensure survival of bacteria in times of environmental stress, they are he
.most common method, as it is the most economical method for large scale reactors. Chemical a
Death Kinetics
The death kinetics involved in sterilization can
usually be described by first order kinetics, but
since essentially all contaminants need to be
removed, it is usually described in probabilistic
terms (Towler 2013). The specific death rate
of an organism for thermal inactivation can be
described as
where  is the specific death rate,  is the Pre-
Arrhenius constant,  is the activation energy
for individual death, and T is the temperature.
Sterilization is usually designed for Bacillus
stearothermophilus since it is one of the most
heat resistant potential contaminants. The
death rate for the vitamins in the media must
also be considered when designing
sterilization, since the nutritional value of the
media can be damaged. Short time, high
temperature treatment to sterilize media can
ensure that the nutritional value is not
damaged, but the spores are killed. Typical
values for the pre-Arrhenius constant are
1*10^36 and 1*10^4 min^-1 for spores and
vitamins respectively. Typical values for the
activation energy for individual death are 65
and 10kcal/mol for spores and vitamins
.respectively (Jewett 2016)
The number of viable individuals after
sterilization can then be described as
where N is the number of viable individuals,  is
the number of contaminants initially present,
and t is time. The probability of having a
contaminated culture can then be described
as
This probability can also be determined with a
sterilization chart, using the spore challenge ()
and , as shown in Fig. 16. The same
equations are used for both batch and
continuous sterilization, but the spore
challenge will be calculated differently, which
will be discussed in further sections (Shuler
.2002)
.Fig. 18. Sterilization chart (Shuler 2002)
Sterilization of Liquids
Batch
Batch sterilization is used for smaller
fermenters (Biegler 1997). It is usually
performed at 121˚C. This is the more widely
used technique, since it is a simpler operation
than continuous sterilization and no additional
materials are added to the media. The
disadvantages of batch sterilization are
thermal lags and incomplete mixing. Heating
requirements are also greater. (DiLeo 2000).
The heat up and cool down times from 121˚C
to 37˚C are usually longer than the time at the
sterilization temperature and can damage the
vitamins and protein in the media (Shuelr
2002). The spore challenge for batch
sterilization can be calculated with the
following equation
where  is the concentration of spores in the
media initially and  is the total volume of
.media (Shuler 2002)
Continuous
The short-exposure and high temperature of
continuous sterilization is easier to control,
does less damage to the medium, and
reduces fermenter downtime. It is also more
efficient since it heats small portions of the
inlet stream at a time rather than using energy
to heat, hold, and cool the entire volume of
media at the same time. (DiLeo 2000). The
disadvantages, however, are dilution of the
medium with steam injection and foaming.
(Shuler 2002). A common process for
continuous sterilization consists of steam
injected into the medium in order to heat it,
passing the medium through a holding section
to achieve the desired residence time, and
then flash cooling the medium. Flash cooling
prevents contamination from cooling water
(Towler 2013). Diagrams and temperature
profiles of batch and continuous sterilization is
shown in Fig. 19. The spore challenge for
continuous sterilization can be calculated with
the following equation
where  is the hold up volume in the reactor,  is
the residence time, and t is the time spent in
.continuous mode (Jewett 2016)
Fig. 19. Diagrams and temperature profiles of
batch and continuous sterilization (Shuler
.2002)
Problems involved in sterilization increase
greatly with scale-up, as sterilization methods
used for lab-bench scale reactions are not
acceptable for industry-scale reactions. Given
the same medium, a sterilization temperature
and time may be enough for a small scale
reactor but not for a larger scale. For example,
given a  of 15 and  of 10^4 spores/L, the
probability of contamination in a 1L reactor will
be 0.003, and in a 10,000 L reactor will be
.about 1
Other considerations
Since spores will germinate in a moist
environment, making them easier to kill as
vegetative cells, moist heat is preferred for
sterilization. Connections in sterilization
equipment must be steam sterilized and
trapped air pockets should be avoided. Pipes
should be sloped in order to avoid condensate
pools and equipment should be pressure
tested for leaks. It should be ensured that no
viable host cells are in the waste streams and
escape to the environment, and exit gas
streams also need to be filtered to prevent the
escape of microbes to the environment
.(Jewett 2016)
If the medium being sterilized contains heat-
sensitive materials, filter sterilization must be
used instead of steam. Filtration is also used
to sterilize the process air used in the system.
Microporous filters are used, so the medium
must be prefiltered for larger particulates so
that the microporous filter does not get
clogged. However, filtration is not as reliable
as steam sterilization, as any defects in the
membrane can lead to contamination, and
viruses can often pass through the filter
.(Shuler 2002)
Example Calculations
A continuous culture is ran in a 1,000L fermentor, and it is desired to have only one in one thous
.140C is used.  for the spores is 1*10^36 min^-1, and  is 67kcal/mol. There is a key temperature

:To calculate the time needed to sterilize the medium 

Use the sterilization chart (Fig. 18), with  and ,
to get 
,To find k_d
Using
 and 
 find

,To find the concentration of active vitamin after sterilization 

First find
,
,Then use the equation
Sterilization of Gases
Almost all biopharmaceutical production
processes involve aeration and therefore
require huge volumes of air. For a
fermentation lasting five days, up to
200,000,000L of air could be required, and
since it is being pumped into the medium, the
air must be completely sterile. Air typically has
a concentration of microbes of about 1-10
.microbes per liter
Compressors are required for such large
volumes of air, and the adiabatic compression
of the air increases the temperature to about
150-220C, and in order to kill spores, the air
needs to be at about 220C for about thirty
seconds. Therefore, the compression helps to
sterilize the air, but since the air cools rapidly
as it exits the compressor, and the pipes are
hard to maintain as sterile, filtration is
necessary to ensure that the entering air is
still sterile after it exits the compressor and
.enters the reactor
Filtration of gases is done by either depth or
surface filters. In the past, carbon beds with
glass wool was used as a depth filter, but if
the filter became wet, it would no longer
function, as the wet filter provided an easy
path for contaminant penetration. The
contaminant also needed to come into contact
with the glass wool and stick to be stopped.
These filters are damaged by steam
sterilization, as they show hardening and
shrinkage over time. Membrane cartridge
filters as surface filters are now more
commonly used in industry, as they can get
wet and continue to stop contaminants. These
filters utilize a sieving effect to remove
particles, as membranes have a uniformly
small pores that prevent the passage of
particles with a larger radius. These filters can
also be steam-sterilized without being
damaged. Both types of filters increase the
pressure drop in the reactor, since the price of
energy needed for compressed air for these
processes is large, and air treatment can
account for a quarter of production costs.
However, since high costs are associated with
the loss of a batch to contamination, one has
to balance the sterility provided from a given
filter with minimizing the pressure drop in the
.reactor (Shuler 2002)
Sterile Sampling
Sampling the medium in the reactor is
necessary to ensure product quality, but it
also carries the risk of introducing
contamination into the medium. Sampling is
usually done about five time a day for a
bioreactor. A typical sampling device is shown
in Fig. 20. The sampling valve on the reactor
is connected to a steam trap to maintain a
steam barrier between the reactor and the
environment. A sterilized sampling device is
attached to the reactor and a valve is attached
to the sampling device. Steam runs through
the system for about thirty minutes, and then
the valves on the reactor and the sampling
device are opened to remove the sample
.(Chisti 1992)

Figure 20. Diagram of typical sampling device

.with filter (Chisti 1992)
Cleaning
Cleaning the fermentation vessel at the end of
the production run is necessary in order to
remove residual substrates that could lead to
contamination of future batches. Cleaning
:consists of the following wash steps
Wash with high-pressure water jets .1
Wash with an alkaline cleaning solution, .2
usually 1M NaOH
Rinse with tap water .3
Wash with an acidic cleaning solution, .4
usually 1M nitric or phosphoric acid
Rinse with tap water .5
Rinse with deionized water .6
The vessel is drained after each of these
steps. For this reason, the vessel should have
no internal dead spots where material could
accumulate. Also, due to the repeated
emptying and filling of the vessel, cleaning
leads to significant down time between
batches (Towler 2013). A clean-in-place (CIP)
system with a transfer flow plate can make
cleaning easier, as it connects all the
bioreactors and transfer pipes in a plant to
one cleaning system, as seen in Figure 21
and 22. The transfer plate has removable pipe
sections, providing assurance against mixing
.of different bioreactor contents (Chisti 1994)
Figure 21. Example of a clean-in-place system
with three bioreactors and a CIP tank (Chisti
.1992)

Figure 22. Delivery of CIP liquids to a

.bioreactor (Chisti 1994)

Heating and Cooling of Reacting Systems

Exothermic and endothermic reactions will require reactors with heat control systems to prevent
often limited by the ability to add or remove heat. Insufficient heat removal can cause runaway r
.2012). Before considering the design of a heating or cooling system to couple with a reactor, a
?Can the reaction be carried out adiabatically .1
Can the feeds provide the required heating or cooling? Staged addition of feed can help alleviate
.consider adding an inert diluent or hot/cold shots (Seider et al., 2004)
?Would it be more cost effective to carry out the heat exchange outside of the reactor .3
Would it be more effective to carry out the reaction inside of a heat transfer device? If a reaction
.to utilize a heat exchanger as a temperature controller and as a reaction location
?Does the proposed design allow the process to be started up and shut down smoothly .5
?Are there safety concerns with heating or cooling the reactor .6
After considering these aspects of the design, commercial design software such as HYSYS or U
.design of the heat exchange system can begin, with different reactor types and reactions requir

Stirred Tank Reactors

Heating and cooling of a stirred tank reactor is done to ensure a uniform reaction temperature, s
.affect selectivity (Towler and Sinnott, 2013)
For indirect heat transfer, there are three main alternatives: a heat transfer jacket, an internal co
sufficient heat transfer area for the heat exchange to take place. If this is not the case, coils are
volume and utility requirements, leading to a large increase in price for the reactor. External circ
and recycle this material to the reactor to control temperature. External circuits are useful becau
and heat exchangers will not fundamentally change the activity of the reactor. For any of these c
utility streams bleeding into the reactor can have a very negative impact on the selectivity of the
.2013)
Some direct heat transfer alternatives also exist, as long the reaction in question is compatible w
temperature, which will eliminate the need to design heat transfer surfaces. However, steam inje
utility costs. Additionally, vapor will be produced if it did not exist previously, so reactors will nee
.2013)

Catalytic Reactors
Slurry Reactors
Since slurry reactors already use a mix of solid catalyst and liquid reactants, any of the methods
.is not recommended to use internal coils in such a design, as reactor slurry will often corrode he
Fixed-bed Reactors
Indirect heat transfer is not often utilized to control the temperature in fixed-bed reactors, as it ha
cases where temperature control is required, the reactor will be split into smaller sections. After
.or cooled as necessary and returned to the next catalytic segment (Towler and Sinnott, 2013)
Fluidized-bed Reactors
Fluidized bed reactors have high heat-transfer coefficients, so indirect heat transfer is highly effe
transfer medium themselves; heated catalyst contains a reaction location and the necessary hea
.reactivation and recycle (Towler and Sinnott, 2013)

Heat Exchangers as Reactors

It is sometimes necessary to design a reactor as a heat transfer device, like when it is necessary
common situations include high-temperature endothermic reactions that quickly quench without
at constant temperature to maintain selectivity. The most common heat transfer equipment used
.Sinnott, 2013)
Homogenous Reactions
If the reaction does not required a catalyst, than the heat transfer design is the same as a conve
The usual heat exchanger equations will not apply to the design of a heat exchanger reactor due
these cases, the usual practice of conservative temperature estimations will not aid in heat trans
.reactor. Detailed kinetic models should be developed before designing the internals of the heat
Heterogenous Reactions
The problems of designing for homogenous reactions still hold for heterogenous ones, with the a
a shell and tube exchanger if the exchanger is mounted vertically and a suitable retaining screen
recycled and heat treated to reactivate the catalysts and reduce the presence of reactor hot spo
as their heat requirements often exceed the amount provided by a heated catalyst. In these case
simultaneously by an external fired heater. This can be done as long as thermal expansion does
The same concerns as detailed in homogenous reactions will still apply for any design utilized fo
.model before determining the amount of heat transfer required to maintain proper selectivity (To

Safety Considerations in Reactor Design

Reactors require much attention to safety details in the design process due to the hazards they
reaction may be released, and residence times can be long leading to a large inventory of chem
or reduce process hazards, limiting the impact of unforeseen events. These design methods sho
:they cannot be retroactively added by a process safety specialist. Some examples are given in
Some Applications of Inherently Safer Design Approaches in Reactor Design (Towler and Sinno

Exothermic reactions require special consideration due to their potential to runaway (temperatur
more heat, and so on). The reactor must be designed such that temperature can be precisely co
solvents or inert species also allows for temperature control by adjusting heat capacity flow rate
.allow the reactor to be flooded with cold solvent or diluent
.If there is a cooling system it should be designed to return the process to desired temperature if
Venting and relief of reactors is complicated by the potential to keep reacting if containment is lo
should be designed according to guidelines outlined in the Design Institute for Emergency Relie
.reaction mechanism and kinetics, including the role of any compounds which may accelerate th

Capital Cost of Reactors

Reactors are classified as pressure vessels, and as such the pressure vessel design methods c
costs come from reactor internals or other equipment. Jacketed stirred-tank reactors require mo
reaction vessel may be in compression due to the jacket. For preliminary cost estimating a corre
:used
where  is the purchased equipment cost on a U.S. Gulf Coast Basis,  are cost constants,  is the
:given in the table below
Purchased Equipment Cost Factors (Towler and Sinnott, 2013)

Conclusions
The conversion of feed to products is the essence of a chemical process and, thus, the reactor i
collect data about the chemical reaction and then select appropriate reaction conditions, which w
determine the rate-limiting step and, from this, the critical sizing parameter. Next, preliminary siz
and experiments can be conducted to verify that the proposed reactor will meet the desired spec
design process, it is important for the engineer to consider the most appropriate type of reactor t
.considerations

References
.Douglas JM. Conceptual Design of Chemical Processes. New York: McGraw-Hill; 1988
.Seider WD, Seader JD, Lewin DR. Process Design Principles: Synthesis, Analysis, and Evalua
.Towler G. Chemical Engineering Design. PowerPoint presentation; 2012
.Towler G, Sinnott R. Chemical Engineering Design: Principles, Practice and Economics of Plan
.Turton R, Bailie RC, Whiting WB, Shaewitz JA, Bhattacharyya D. Analysis, Synthesis, and Desi
.Westfall, Patrick J., and Timothy S. Gardner. "Industrial fermentation of renewable diesel fuels."
.Schmidt, F. R. "Optimization and scale up of industrial fermentation processes." Applied microb
Yurimoto, Hiroya, et al. "Regulation and evaluation of five methanol-inducible promoters in the m
.Structure and Expression 1493.1 (2000): 56-63
.Huang, Hua-Jiang, et al. "A review of separation technologies in current and future biorefineries
.Stephanopoulos, George, Aristos A. Aristidou, and Jens Nielsen. Metabolic engineering: princip
.Nothaft, Harald, and Christine M. Szymanski. "Protein glycosylation in bacteria: sweeter than ev
Shuler, ML, Kargi, F. Bioprocess Engineering Basic Concepts. 2nd ed. Upper Saddle River: Pre
.L.T. Biegler, I.E. Grossmann, A.W. Westerberg, Systematic Methods of Chemical ProcessDesig
.Shuler, Michael L., and Fikret Kargi. Bioprocess engineering. New York: Prentice Hall, 2002
Arsenault, Patrick R., Kristin K. Wobbe, and Pamela J. Weathers. "Recent advances in artemisin
.15.27 (2008): 2886
Karimi, Ali, Golbabei, Farideh, Pourmand, Mohammad. “Oxygen mass transfer in a stirred tank b
.Iranian Journal of Environmental Health, Science, and Engineering, 2013
.WAVE Bioreactor 500/1000 System.” Bioprocess Online, 2013 “
.WAVE Bioreactors.” GE Healthcare Life Sciences, 2016 “
.Prieto, G., Okumoto, M., Gay, C.R. “Nonthermal plasma reactors for the production of light hydr
.Kang, Xuezhen. “Packed Bed Bioreactor.” 2000
.Y. Chisti, Assure Bioreactor Sterility, Chemical Engineering Process. 1992: 88(9): 80-85
.M. Jewett. Media Design. ChBE 375: Biochemical Engineering Class Notes. January 12, 2016
.Y. Chisti, M. Moo-Young. Clean-in-place systems for industrial bioreactors: design, validation an
G. DiLeo and S. Ogoreuc. “Sterilization”. Rensselaer Polytechnic Institute. 2000. http://www.rpi.e
.February 20, 2016
Y. Bakri, Y. Akeed, P. Thonart. "Comparison between continuous and batch processing to produ
.Engineering, 2012
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