NOTES ON LESSON-BT 2353-III YEAR A&B

DEPARTMENT OF BIOTECHNOLOGY
RAJALAKSHMI ENGINEERING COLLEGE,THANDALAM
CHENNAI

Prepared by

Kavitha Vijayaraghavan
Lecturer, Department of Biotechnology,
Rajalakshmi Engineering College,Thandalam
BT 2353 BIOPROCESS ENGINEERING

AIM
This course aims to develop the skills of the students in the area of Bioprocess
Engineering. This will be a pre-requisite for a few elective courses and for project in
Bioprocess Technology.
OBJECTIVES
 At the end of the course, the student would have learnt about stirred Tank
reactors and configuration of various reaches, and how to model and similar a
Bio process. This will help the student to undertake project in the area of Bio
process Technology.
UNIT I ANALYSIS OF STR 8
Stirred tank reactor - non-ideality, RTD and stability analysis, tanks in series and
dispersion models – application to design of continuous sterilizer.
UNIT II ANALYSIS OF OTHER CONFIGURATIONS 8
Packed bed reactor, airlift reactor, fluidized bed reactor bubble column reactors –
nonideality,
RTD and stability analysis.
UNIT III BIOREACTOR SCALE – UP 9
Regime analysis of bioreactor processes, oxygen mass transfer in bioreactors -
microbial oxygen demands; methods for the determination of mass transfer coefficients;
mass transfer correlations. Scale up criteria for bioreactors based on oxygen transfer,
power consumption and impeller tip speed.

UNIT IV MODELLING AND SIMULATION OF BIOPROCESSES 12

Study of structured models for analysis of various bioprocess – compartmental models,
models of cellular energetics and metabolism, single cell models, plasmid replication and
plasmid stability model. Dynamic simulation of batch, fed batch, steady and transient
culture metabolism.
UNIT V BIOREACTOR CONSIDERATION IN ENZYME SYSTEMS 8
Analysis of film and pore diffusion effects on kinetics of immobilized enzyme reactions;
formulation of dimensionless groups and calculation of effectiveness factors. Design of
immobilized enzyme reactors – packed bed, fluidized bed and membrane reactors.
TOTAL : 45 PERIODS
TEXT BOOKS
1. Anton Moser, “Bioprocess Technology”, Kinetics and Reactors”, Springer Verlag.
2. James E. Bailey & David F. Ollis, “Biochemical Engineering Fundamentals”,
McGraw-Hill.
3. Shuler and Kargl,Bioprocess Engineering, Prentice Hall , 1992.
REFERENCES
1. James M. Lee, “Biochemical Engineering”, PHI, USA.
2. EMT.EL-Mansi.CFA.Bryce, A.L.Demain, AR.Allman: Fermentation Microbiology
and
Biotechnology, Second Edition 2007.
3. Harvey W. Blanch, Douglas S. Clark, “Biochemical Engineering”, Marcel Decker Inc.
 UNIT I ANALYSIS OF STR 8
Stirred tank reactor - non-ideality, RTD and stability analysis, tanks in series and
dispersion models – application to design of continuous sterilizer.
Continuous Stirred Tank Reactors (CSTRs)
Characteristics

Typ
e of Reactor

Continuously Stirred Run at steady state with continuous flow of reactants and
Tank Reactor (CSTR) products; the feed assumes a uniform composition throughout
the reactor, exit stream has the same composition as in the
tank

Kinds of Usage Advantages Disadvantages

Phases
Present

1. Liquid 1. When 1. Continuous 1. Lowest

phase agitation is operation conversion per
required unit volume
2. Gas-liquid 2. Good
rxns 2. Series temperature 2. By-passing
configurations control and channeling
3. Solid-liquid for different possible with
rxns concentration 3. Easily poor agitation
streams adapts to two
phase runs

4. Good
control

5. Simplicity
of
construction

6 Low
operating
 (labor) cost

7. Easy to
clean

General Mole Balance Equation

Assumptions

1) Steady state therefore

2) Well mixed therefore rA is the same throughout the reactor

Rearranging the generation

In terms of conversion
Reactor Sizing

Given –rA as a function of conversion, –rA = f(X), one can size any type of
reactor. The volume of a CSTR can be represented as the shaded areas in the
Levenspiel Plot shown below:

Reactors in Series

Given –rA as a function of conversion, , –rA = f(X), one can also design any
sequence of reactors in series provided there are no side streams by defining the
overall conversion at any point.

Mole Balance on Reactor 1

Mole Balance on Reactor 2

Given –rA = f(X) the Levenspiel Plot can be used to find the reactor volume

For a PFR between two CSTRs

Problems with a straight-forward calculation.

The following reaction takes place in a CSTR:

Pure A is fed to the reactor under the following conditions:

FAo = 10 mol/min

CAo = 2 mol/dm3

X=?

V= 500 dm3 and k=0.1/min

Rate Law: -rA = kCA

What is the conversion in the CSTR?

The design equation for a CSTR is:

Derive Equation

Because the reaction is elementary, the combined mole balance and rate law
becomes:

From stoichiometry, this equation becomes:

Solving for X, we get the following equation:

then we substitute numerical values for our variables and calculate a conversion
of:

Problems that require intermediate calculations or manipulations.

The following reaction takes place in a CSTR:

Pure A is fed to the reactor under the following conditions:

FAo = 10 mol/min

CAo = 2 mol/dm3

At T=350 K
 X=0.75

V= ? and k=?

Rate Law: -rA = kCA

The activation energy: E=20 kcal/mol

What is the conversion in a PFR at 325 K with the same volume?

Problems that require intermediate calculations or manipulations.

In this problem we have to find a way to relate these two reactors. At first, this
question looks unsolvable, but then we recall the following relationship
between k1 and k2:

Derive Equation

In the Homogeneous Example 1 Solution, we derived the following equation

for a CSTR:
Our next step is to group our unknowns on one side of the equation and solve
for their product:

Then, we use our relationship between k1 and k2:

k2V=3.3

Next, we look at our PFR design equation:

Derive Equation

We integrate this equation over our limits:

and solve for X:

Recalling our result for k2V that we determined above, we get:

X=0.72
Problems that are over-specified.

The following irreversible reaction takes place in a CSTR:

It takes place under the following conditions:

FTo = 40 mol/min

CAo = 2 mol/dm3

The feed is 75 mol% A

 X=?
& 25 mol% inerts.

k(400 K) = 0.1/min

V = 500 dm3 and T = 400 K

This reaction follows the first order rate law: -rA = kCA

The activation energy (E) is 10 kcal/mol & the Arrhenius constant (A) is
3*104/min

What is the conversion?

Problems that are over-specified.

This problem might confuse the student with excess information about the rate
constant, but there is a straight-forward solution.

We begin with the design equation for a CSTR is:

Derive Equation

Following the calculations in the Homogeneous Example 1 Solution, we get the

equation for the conversion:
The problem gave us every variable except for FAo. FAo is just the mole fraction
of A (xA) multiplied by the total initial flow rate (FTo).

Then, we substitute for our variables and calculate a conversion of:

Stirred Tank Reactor

A batch stirred tank reactor is the simplest type of reactor. It is composed of a

reactor and a mixer such as a stirrer, a turbine wing or a propeller. The batch stirred tank
reactor is illustrated below:

This reactor is useful for substrate solutions of high viscosity and for immobilized
enzymes with relatively low activity. However, a problem that arises is that an
immobilized enzyme tends to decompose upon physical stirring. The batch system is
generally suitable for the production of rather small amounts of chemicals.

A continuous stirred tank reactor is shown below:

The continuous stirred tank reactor is more efficient than a batch stirred tank reactor
but the equipment is slightly more complicated.

Continuous Sterilization

Batch sterilization wastes energy and can overcook the medium

Batch sterilization uses steam or direct firing to elevate the temperature, and then cooling
water stops the process and brings the material back toward room temperature. Both the
heat and the cooling water are spent with no opportunity for energy recovery. Large
volumes should be passed continuously through heat exchangers for energy economy
with the hot, treated fluid heating the cold, incoming feed.

One method of continuous sterilization injects steam into the medium (no heat
exchanger). The medium stays in a loop for a predetermined holding time until the entire
medium is sterile.

Better heat economy comes from substituting heat exchangers for direct steam injection.
Instead of having a cold water stream to cool the sterile media, the lower temperature
unsterile media stream absorbs heat from the warm stream, cooling the sterile media.

A system for continuous sterilization has a holding coil for detention long enough to kill
all of the microorganisms. The medium from a make up vessel flows through the
exchanger, is held in the coil, and passes back through the heat exchanger, heating more
unsterile medium while becoming cool itself, as it is collected in a sterile fermenter.

This design would work only with an exchanger with infinite heat transfer area because
there is no driving force for heat transfer as the temperatures for the two streams
approach closely. A real design would have another small exchanger to raise the
temperature to the setpoint after the main exchanger has done all it can do. There is no
need for a cooler before entering the fermenter because it has a jacket or coils for
temperature control that can easily handle this load.

Heat economy is not important for a small pilot plant unit for continuous sterilization, so
direct steam injection is simpler. A heat exchanger is then needed with cooling water to
bring the medium back down quickly to a temperature at which it is not over cooked.

Advantages:
 Uniform steam requirements throughout the duration of the sterilization
 Simplified process control
 Shorter sterilization time means less thermal degradation of medium

Disadvantages:
 High demand for steam in a shorter period of time than batch
 Concentration of media becomes dilute due to steam condensation
 Since steam is actually dispersed in media, steam must be clean to avoid
contamination

High temperatures for short times are used in preparing nutrient media for industrial
fermentations and in pasteurizing milk, because this causes less damage to biochemicals
than more prolonged times at lower temperatures. This exploits the temperature effects
on activation energies because bacterial killing is affected by a temperature change more
than is heat destruction of biochemicals.

Shell and Tube Exchangers

When the flow in a heat exchanger is countercurrent, the outlet temperature of the stream
being heated can approach the temperature of the hot stream to be cooled. There is an
attempt to show this in the sketch. There are gradients on the shell side as well.

The Shell and tube exchanger is not as well-suited to continuous sterilization as the plate-
and-frame type of exchanger.

Sandwich of Plates. This sketch did not turn out well. Much better sketch by Lawrence
Bernstone, 1995 The idea is that the countercurrent flow in alternate sections gives a
gradient from coolest to hottest in each plate of the sandwich. In chemical processing, a
packed bed is a hollow tube, pipe, or other vessel that is filled with a packing material.
The packing can be randomly filled with small objects like Raschig rings or else it can be
a specifically designed structured packing.

UNIT II ANALYSIS OF OTHER CONFIGURATIONS 8

Packed bed reactor, airlift reactor, fluidized bed reactor bubble column reactors –
nonideality,RTD and stability analysis

Packed bed reactor

The purpose of a packed bed is typically to improve contact between two phases in a
chemical or similar process. Packed beds can be used in a chemical reactor, a distillation
process, or a scrubber, but packed beds have also been used to store heat in chemical
plants. In this case, hot gases are allowed to escape through a vessel that is packed with a
refractory material until the packing is hot. Air or other cool gas is then fed back to the
plant through the hot bed, thereby pre-heating the air or gas feed.

Applications

In industry, a packed column is a type of packed bed used to perform separation

processes, such as absorption, stripping, and distillation. A packed column is a pressure
vessel that has a packed section.[1] The column can be filled with random dumped
packing or structured packing sections, which are arranged or stacked. In the column,
liquids tend to wet the surface of the packing and the vapors pass across this wetted
surface, where mass transfer takes place. Packing material can be used instead of trays to
improve separation in distillation columns. Packing offers the advantage of a lower
pressure drop across the column (when compared to plates or trays), which is beneficial
while operating under vacuum. Differently shaped packing materials have different
surface areas and void space between the packing. Both of these factors affect packing
performance.

Another factor in performance, in addition to the packing shape and surface area, is the
liquid and vapor distribution that enters the packed bed. The number of theoretical stages
required to make a given separation is calculated using a specific vapor to liquid ratio. If
the liquid and vapor are not evenly distributed across the superficial tower area as it
enters the packed bed, the liquid to vapor ratio will not be correct and the required
separation will not be achieved. The packing will appear to not be working properly. The
height equivalent to a theoretical plate (HETP) will be greater than expected. The
problem is not the packing itself but the mal-distribution of the fluids entering the packed
bed. These columns can contain liquid distributors and redistributors which help to
distribute the liquid evenly over a section of packing, increasing the efficiency of the
mass transfer.[1] The design of the liquid distributors used to introduce the feed and reflux
to a packed bed is critical to making the packing perform at maximum efficiency.

Packed columns have a continuous vapor-equilibrium curve, unlike conventional tray

distillation in which every tray represents a separate point of vapor-liquid equilibrium.
However, when modeling packed columns it is useful to compute a number of theoretical
plates to denote the separation efficiency of the packed column with respect to more
traditional trays. In design, the number of necessary theoretical equilibrium stages is first
determined and then the packing height equivalent to a theoretical equilibrium stage,
known as the height equivalent to a theoretical plate (HETP), is also determined. The
total packing height required is the number theoretical stages multiplied by the HETP.

Columns used in certain types of chromatography consisting of a tube filled with packing
material can also be called packed columns and their structure has similarities to packed
beds.
Packed bed reactors

Packed bed reactors can be used in chemical reaction. These reactors are tubular and are
filled with solid catalyst particles, most often used to catalyze gas reactions. [2] The
chemical reaction takes place on the surface of the catalyst. The advantage of using a
packed bed reactor is the higher conversion per weight of catalyst than other catalytic
reactors. The reaction rate is based on the amount of the solid catalyst rather than the
volume of the reactor

THREE PHASE FLUIDIZED BED REACTOR

 A method of suspending solid particles is to fluidize the bed using upward flow
of the liquid.

 If gas is introduced at the bottom of the bed three phase contacting is achieved.

 As in bubble columns,agitated tank contacters hydrodynamic interaction

between the bubbles and particles occur.
 Large particles can cause break up of large bubbles.
 At present time 3 phase fluidised bed are not often chosen for gas – liquid –solid
reactions despite their advantages of good heat and mass transfer,the reason being
development of three phase fluidised bed reactor for the new process would
necessarily require extensive experimental work.
 Also scale up from pilot to large scale is uncertain due to insufficient knowledge.

 In contrast the scale up of trickle bed reactors is easy and might be chosen for a
process inspite of the advantages of the 3 phase fluidized bed reactor.
 The 3 phase fluidized bed reactors so far developed commercially for processes
such as hydrogenation of petroleum residues using bed of particles of various
sizes.
 Reactors with small molecules tend to produce large bubbles.These are similar to
bubble column
slurry reactors.
 A three phase fluidised bed using large particles requires high liquid flow rates in
order to maintain the particles in the fluidised state but have the advantage of
producing smaller bubbles and hence
large interfacial area for mass transfer.
 One of the areas of uncertainity in 3 phase design is the mixing that occurs in gas
and liquid phases.
 As particle size increases flow approximates to plug flow
 The overall rate of the reaction calculated from the 3 phase fluidised bed reactor is
approximately one tenth of the rate calculated for agitated slurry reactor.
 The main reasons are very poor effectiveness factor,
relatively smaller external surface area for mass
transfer caused by using larger particles.
  Although the three phase reactor does not appear to perform favorably compared
to agitated tank sluury
reactor it should be remembered that fluidised bed does not have a sealing or other
mechanical complications associated with agitators.

RESISTANCES
 The various resistances active in a 3 phase fluidised bed reactor are

1. Gas liquid mass transfer resistance ( 1/kla).

2. Liquid solid mass transfer resistance ( 1/ksapεp).
3. Reaction within particle ( 1/k1ηεp).

The overall rate Rt = 1/ (1/kla+ 1/ksapεp+ 1/k1ηεp)

A fluidized-bed reactor is a combination of the two most common, packed-bed and

stirred tank, continuous flow reactors. It is very important to chemical engineering
because of its excellent heat and mass transfer characteristics. The fluidized-bed reactor
can be seen below:

In a fluidized-bed reactor, the substrate is passed upward through the immobilized

enzyme bed at a high enough velocity to lift the particles. However, the velocity must not
be so high that the enzymes are swept away from the reactor entirely. This causes some
mixing, more than the piston-flow model in the packed-bed reactor, but complete mixing
as in the CSTR model. This type of reactor is ideal for highly exothermic reactions
because it eliminates local hot-spots, due to its mass and heat transfer characteristics
mentioned before. It is most often applied in immobilized-enzyme catalysis where
viscous, particulate substrates are to be handled.
FLUIDIZED BED REACTOR

 The first commercial use of a fluidized-bed reactor, in the 1920s was for the
gasification of coal to supply CO and H, for the production of synthetic
chemicals.

 The technology has been developed also for a number of other processes,
including other catalytic reactions for the production of chemicals and synthetic
gasoline by the Fischer-Tropsch process, and noncatalytic processes for the
roasting of sulfide ores, and the incineration of solid waste.

 Fluidized-bed and similar technology has also been used for nonchemical
operations in heat exchange, drying of solids, and coating processes analogous to
chemical vapor deposition.

 Consider a bed of solid particles initially fixed in a vessel, and the upward flow
through the bed of a fluid introduced at many points below the bed, as indicated
schematically . The rate of flow of fluid is characterized by the superficial linear
velocity us, that is, the velocity calculated as though the vessel were empty. At
relatively low values of us, the bed remains a fixed bed of particles, although it
expands somewhat as us, increases.
 As u, increases further, a point is reached at which the bed begins to “lift”.
Beyond this point, over a range of increasing us, the action of the multiphase fluid
+ solid region (bed) may resemble that of a vigorously boiling liquid with an
apparent upper surface from which rising fluid disengages.
 This action is referred to in general as fluidization of the bed (in the case above, a
“bubbling fluidized bed”.
 As U, increases still further, solid particles become elutriated from the fluidized
region by entrainment in the rising fluid.
 At sufficiently high values of us, the entire bed of particles may be entrained with
the fluid and carried overhead out of the vessel. Other types of intermediate
behavior occur, usually undesirable, and we have simplified the picture
considerably.
 When a chemical reaction occurs in the system, each of these types of behavior
gives rise to a corresponding type of reactor. These range from a fixed-bed
reactor, to a fluidized-bed reactor without significant carryover of solid particles,
to a fast-fluidized-bed reactor with significant carryover of particles, and
ultimately a pneumatic-transport or transport-riser reactor in which solid particles
are completely entrained in the rising fluid. (BFB)
(Pneumatic Conveying) (Fast Fluidized)

 At higher gas velocities the BFB transforms into TB-no distinct bubbles,much
churning and violent solid movement.The surface of the dense bed fades and
solids are increasingly found in the lean region above the bed.The flow of gas is
between PF and BFB.The concentration of solids in the upper lean region can be
represented by exponential decay function.
 In a fast-fluidized bed, the fluidization velocity is very high, resulting in
significant entrainment of solid particles. Consequently, there is a concentration
gradient of solid particles through both the bed and freeboard regions.Continuous
addition of fresh solid particles may be required for some operations(e.g., coal
gasification).
 The performance is typically described using both a fluidized bed model and a
freeboard-reaction model. Applications of fast-fluidized beds are in fluidized-bed
combustion and Fischer-Tropsch synthesis of hydrocarbons from CO and H2.
  In pneumatic flow, fluid velocities are considerably greater than the terminal
velocities of the particles, so that virtually all of the particles are entrained. The
vessel may be extremely tall, with no solid recirculation (e.g., coal combustion),
or it may provide for solid recirculation with external cyclones.
 The process stream is extremely dilute in solid particles because of the high
volumeof gas passing through the “bed.” Fluid-catalyzed cracking of gasoil is an
important example of pneumatic transport with external recirculation (and
regeneration) of catalyst pellets.
 A spouted bed is characterized by a high-velocity spout of gas moving up the
center of the bed, carrying particles to the top. This action induces particle
circulation, with particle motion toward the wall and downward around the spout
and toward the center. The particles in a spouted bed are relatively large and
uniformly sized.

 Spouted beds have been used for drying and low-temperature chemical-treatment.
Examples are the low-temperature roasting of agricultural products, and particle-
coating and crystal-growth operations.
EXAMPLES OF REACTIONS
 Reactions in moving-particle reactors in general, and in fluidized-bed reactors in
particular, may be catalytic or noncatalytic. That is, the particles may be catalyst
particles or reactant particles.
 Catalytic cracking of gasoil: an impetus for the development of fluidized-bed
reactorsover 50 years ago was the desire to make the catalytic cracking of
gasoil(to gasoline) a continuous process, in spite of the rapid deactivation of the
catalyst particles by coke and tarry deposits. Originally, both the catalytic-
cracking reactor (“cracker”) itself and the catalyst regenerator were fluidized-bed
reactors,with solid particles moving continuously between the two in an overall
continuous process, but more recently the cracker is made a pneumatic-transport
reactor.
 Production of acrylonitrile by ammoxidation of propylene (SOHIO process):
2NH3+ 3O2 + 2C2H2 -> 2C2H2N + 6H2O.The fluidized-bed process for this
reaction has several advantages over a fixedbed process. First, the process is
highly exothermic, and the selectivity to C,H,N is temperature dependent. The
improved temperature control of the fluidized bed operation enhances the
selectivity to acrylonitrile, and substantially extends the life of the catalyst, which
readily sinters at temperatures in excess of 800 K.
 Oxidation of napthalene to produce phthalic anhydride:
C10H10 + 02 à C10H10O3 à CO + H2
Proper control of temperature is required to limit
napthaquinone production and avoid the runaway (and
possibly explosive) reaction which leads to theproduction of CO, and H,O. A
fluidized-bed is thus preferred over a fixed-bed process.
 Production of synthetic gasoline by the Fischer-Tropsch process:
nCO + 2nH2 à (C,H,) + nH2O
This is another example of a highly exothermic process which requires strict
temperature control to ensure appropriate selectivity to gasoline, while limiting the
production of lighter hydrocarbons. Again, the enhanced temperature control provided by
a fluidized-bed system greatly improves the feasibility of this process.
 Noncatalytic roasting of ores such as zinc and copper concentrates:
2ZnS + 302 à 2ZnO + 2S02
The fluidized-bed process replaced rotary kilns and hearths; its primary advantages
are its higher capacity and its lower air requirement, which leads to a product gas richer
in SO, for use in a sulfuric acid plant.
 Noncatalytic complete or partial combustion of coal or coke in fluidized-bed
combustors:
C + O2 à CO2
C+1/2O2 àCO
These reactions may serve as a means of regeneration of coked catalysts. Both
reactions are exothermic, and the improved temperature control provided by a fluidized
bed is critical for regeneration of catalysts prone to
sintering.
 The advantages and disadvantages of moving-particle reactors may be considered
relativeto the characteristics and operating conditions of fixed-bed reactor.
Advantages
(i) Mode of operation: operation can be made continuous with respect to both the
processing fluid and the solid; this allows, for example, for the continuous regeneration
of a deactivating catalyst.
(ii) Thermal: there is near-uniformity of T throughout the bed, which allows for better
control of T and avoidance of hot spots in highly exothermic reactions;the uniformity of
T is due to such things as the high degree of turbulence(resulting in relatively high heat
transfer coefficients), and the large
interfacial area between fluid and small particles.
(iii) Chemical performance: the use of relatively small particles (e.g., 0.1 to 0.3 mm) can
result in lower pore-diffusion resistance in solid particles and an effectiveness factor (q)
much closer to 1; by itself, this, in turn, results in a smaller catalyst holdup.
Disadvantages
(i) Mechanical: abrasion causes erosion of pipes and internal parts (e.g., heat transfer
surface); attrition of particles leads to greater entrainment and elutriation,requiring
equipment (cyclones) for recovery; these mechanical features lead to higher operating
and maintenance costs, as well as greater complexity.
(ii) Fluid-mechanical: There is a larger (-AP), requiring greater energy consumption;the
complex flow and contacting patterns are difficult to treat rationally, and create
difficulties of scale-up from small-diameter, shallow beds to large-diameter, deep beds.
(iii) Chemical performance: in fluidized-beds, there is a “bypassing effect” which leads to
inefficient contacting; fluid in large bubbles tends to avoid contact with solid particles;
this leads to a larger catalyst holdup and/or lower conversion,which may even be lower
than that predicted on the basis of BMF,which in turn is lower than that based on PF, the
turbulence and resulting backmixing may result in adverse effects on selectivity, for
example, depressing the intermediate in a series reaction.
DESIGN
 Typical design requirements include calculations of catalyst or reactant solid
holdup for a given fractional conversion and production rate (or vice versa),
  The bed depth, the vessel diameter and height, and heat transfer requirements.
 The reactor model may also need to account for conversion in regions of the
vessel above(“freeboard” region) and below (“distributor” region) the bed, if there
is a significant fraction of the solid in these regions, and/or the reaction is very
rapid.
 The overall design must consider special features related to the superficial
velocity, and the flow characteristics of the solid and fluid phases within the
vessel.

The following regimes of (- ΔP), somewhat idealized for simplification, corresponding to

different conditions of the bed may be distinguished:

 AB: (- ΔP) increases with increasing u, , as the bed retains the character of a fixed
bed, with l g increasing somewhat.
 BC: (- ΔP) is relatively constant, as the bed becomes fluidized; B is the point of
incipient fluidization at urnf.
  CD: (- ΔP) decreases with increasing us, from C, at which elutriation begins, to
D, at which point the particles may be said to be entrained (at ut).

Umf2 + 150 umf( 1-εmf)μf/1.75ρfdp’ – g(ρg –ρf ) εmf3dp’/1.75 ρf=0

 A hydrodynamic model of fluidization attempts to account for several essential

features of fluidization: mixing and distribution of solids and fluid in a so-called
“emulsion region,” the formation and motion of bubbles through the bed (the
“bubbleregion”), the nature of the bubbles (including their size) and how they
affect particle motion/distribution, and the exchange of material between the
bubbles (with little solidcontent) and the predominantly solid emulsion. Models
fall into one of three classes(Yates, 1983, pp. 74-78):
 (1) two-region models, which take into account a bubble region and an emulsion
region, with very little variation in properties within each region;
(2) bubble models, which are based upon a mean bubble size; all system propertiesare
functions of this bubble size;
(3) bubble-growth models, which also endeavor to account for bubble coalescence
and bubble splitting.
K-L MODEL FOR BFB
Pass an excess of gas upwards through a bed of fine particles.As simplifications we
assume the following :
 The bubbles are all spherical of same size ds.The bed contains bubbles
surrounded by thin clouds rising through the emulsion.
 The emulsion stays at minimum fluidization conditions.Hence the relative G/S
velocity stays constant.
 Each bubble drags a wake of solids behind it.This generates a ciruculation of
solids in the bed,upflow behind bubbles and downflow everywhere else in the
bubble.This occurs when
uo > ( 3 to 11)umf
uo Superficial gas velocity in the bed.

MATERIAL BALANCE FOR GAS AND SOLIDS

 Ubr = 0.711(gdb)1/2 Rise velocity of a single bubble
 ub = uo - umf + ubr Rise velocity of bubbles
 ∂ Bed fraction in bubbles
 ∂ = (uo – umf)/ub = 1 – ubr/ub
 Hm(1-εm) = Hmf(1- εmf) = Hf(1- εf)
1 - ∂ = (1- εf) /(1- εmf) =Hmf /Hf
 Us = α ∂ub / 1- ∂ - α ∂ Down flow of emulsion solids
 Ue = Umf/ εmf – Us Down flow of emulsion gas
 Using Davidson’s theoritical expression for bubble cloud circulation the
interchange of gas between bubble and cloud is found to be
Kbc = 4.5( umf/db) + 5.85 (D1/2g1/4 / db5/4)
 Between cloud and emulsion
Kce = 6.77 (εmf Dubr/db3)1/2
  fb = 0.001 – 0.01 Volume of solid in bubble
 fc = ∂(1- εmf) [ 3umf/ εmf + α] Volume of solid in cloud
-----------
ubr - umf/ εmf
 fe = ( 1- ∂)(1- εmf ) - fb -fc Volume of solids in emulsion
 Hbfb = W / ρs A ( 1- εmf )

FIRST ORDER REACTION

A à R ra’’’ = k’’’Ca

ln Cao/Ca = k’’’τ’’’ = [fbk’’’ + 1

----------------------------------
1/ ∂Kbc + 1
------------------
fck’’’ + 1
-------------
1/ ∂Kce +1/fek’’’ ]ftotxHbfb
----------
ftot x uo

lnCao /Ca = k Lfl/Ub H = W/ρp(1-εmf)A

q = Fao RT/P
D = ( 4q / π uo)1/2
Wcat = (ρpq( 1- εmf )ubr/kuo) ln (Cao/Ca)
 As gas bubbles reach the upper surface of a fluidized bed, they burst, releasing
gas and ejecting particles into the freeboard region above the bed. The solid
particles thrown into the freeboard originate from the bubble wakes, and cover the
entire range of particle sizes present within the bed.
 Several models have been proposed to account for reaction in the freeboard. Yates
and Rowe (1977) developed a simple model based upon complete mixing of
particles in the freeboard, coupled with either BMF or PF of the freeboard gas.
 Experiments have shown that the following design features influence the extent of
particle entrainment, and, by extension, the likelihood of reaction in the freeboard
region:
(1) Vertical internals do not affect entrainment in small-particle beds, but may increase
entrainment in large-particle beds.
(2) Horizontal louvers placed near the bed surface can significantly decrease entrainment
in large-particle systems.
(3) Entrainment increases markedly at high pressure.
(4) Stirrers or bed internals which reduce the size of the bubbles bursting at the surface
can significantly reduce entrainment (reducing the number of particles ejected into the
freeboard).
MEMBRANE BIOREACTORS
• They are mainly a combination of a membrane process like micro filtration or
ultra filtration with a suspended growth bioreactor
• They are mainly used in industrial wastewater treatments
• There are two types of configurations
Internal(The membrane is inside the reactor and is an integral part of the
reactor)
External(The membrane is a separate unit)
• In the internal type of membrane bioreactors the membrane used is a hollow
fibre
• The hollow fibre are of different types.
Asymmetric
Symmetric
Flat sheet
• One of the reasons that hollow fibre is used is to mix liquor and to treat
the effluent obtained from liquor
• Membrane reactors combine a catalyst filled reaction chamber with a
membrane to add reactants or remove products of the reaction
• One of the important factor that has to be considered in a membrane
bioreactor is
MEMBRANE FOULING
• It affects the system performance
• This leads to a increase in the transmembrane pressure
• Membrane cleaning is hence required,this leads to the increase in the
operating costs
• In the case of a submerged reactor(Internal) air induced cross flow can
efficiently remove or atleast reduce the fouling layer on membrane
surface
• Aeration plays a major role in reducing membrane fouling
• Membranes with high pore size may foul rapidly due to clogging
• The membrane pore size should be about0.02 to0.5mum
• Two main ways to reduce fouling is
Membrane Backwashing
Air backwashing
• Intensive cleaning can also be carried out
• The frequently used cleaning agents are sodium hypochlorite and
citric acid
• Nutrient removal can also be done by nitrification and
denitrification processes combined
APPLICATIONS OF MEMBRANE BIOREACTORS:
• Waste water treatments
• To remove pathogens like (cryptspordium)
• Produce high quality of effluent
• Water reclamation
• Mico pollutant removal
 ADVANTAGES AND DISADVANTAGES
INTERNAL(ADVANTAGES)
• Lower flux
• Less frequent cleaning required
• Lower operating cost
• Very low liquid pumping cost
DISADVANTAGES
• Aeration cost is high
• High capital cost
EXTERNAL(ADVANTAGES)
• Aeration cost is low
• Low capital cost
DISADVANTAGES
• High pumping cost
• High flux
• More frequent cleaning required
• High operating cost
•

Derive the Design equation for a packed bed reactor.(Also give the design
considerations).

In addition to flow, thermal, and bed arrangements, an important design consideration

is the amount of catalyst required (W), and its possible distribution over two or more
stages. This is a measure of the size of the reactor. The depth (L) and diameter (D)
of each stage must also be determined. In addition to the usual tools provided by kinetics,
and material and energy balances, we must take into account matters peculiar
to individual particles, collections of particles, and fluid-particle interactions, as well as
any matters peculiar to the nature of the reaction, such as reversibility. Process design
aspects of catalytic reactors are described by Lywood (1996).

Characteristics of a catalyst particle include its chemical composition, which primarily

determines its catalytic activity, and its physical properties, such as size, shape,
density,and porosity or voidage, which determine its diffusion characteristics. We do not
consider in this book the design of catalyst particles as such, but we need to know these
characteristics to establish rate of reaction at the surface and particle levels
(corresponding to levels (1) and (2) in Section 1.3). This is treated in Section 8.5 for
catalyst particles. Equations 8.5-1 to -3 relate particle density pp and intraparticle
voidage or porosity  p .
The shape of a particle may be one of many that can be formed by extrusion or tabletting.
As in Chapter 8, we restrict attention to three shapes: (solid) cylinder, sphere, and flat
plate. The size for use in a packed bed is relatively small: usually about a few mm.At the
bed level (corresponding to level (3) in Section 1.3) we also use characteristics of density
and voidage. The volume of the bed for a cylindrical vessel is
V = πD2L/4

The bulk density, ρb, of the bed is the ratio of the total mass W to the total volume V:

ρb = W/V

The bed voidage, s, is the ratio of the interparticle void space to the total volume V:

εb =(V - volume of particles )/V= (V - V ρb/ ρp),/V = 1 - ρb /ρp

where ρp is the density of the particle, equation 8.5-1. From equations 21.3-2 and 8.5-3,

ρb= ρp(1- εb) = ρs(1- εb) (1- εp)

where is the true density of the solid (no intraparticle voidage).

When a fluid flows through a bed of particles, interactions between fluid and particles
lead to a frictional pressure drop, (- AP). Calculation of (- AP) enables determination
of both L and D, for a given W (or V). This calculation is done by means of the
momentum balance, which results in the pressure gradient given by

dP/dx + fu2ρf /dp’ = 0

where x is the bed-depth coordinate in the direction of flow, f is the friction factor, u is
the superficial linear velocity, pf is the density of the fluid, and d; is an effective particle
diameter. Integration of equation 21.3-4 on the assumption that the second term on the
left is constant results in the pressure drop equation: -

-ΔP/L = fu2ρf /dp’

where L is the depth of the bed (L = x at the outlet); note that ΔP = P(outlet) -
P(inlet) is negative. In equation 21.3-5,dp; is the effective particle diameter, which
accounts
for shape, defined as
dp = 6 X volume of particle/external surface area of particle
For a spherical particle of diameter dP, dp’ = dP, and for a solid cylindrical particle,
dh = 3d,l(2 + d,lL,) or 1.5d,, if dp/Lp << 2, where L, is the length of the particle.
For the friction factor, we use the correlation of Ergun

f = [1.75 + 150(1-εp) /Re’ ] ( 1- εb)/ εb3 )

where εb is the bed voidage, and Re’ is a Reynolds number defined by

Re’ = dp’uρf / μf

Re’ = dp’G / μf

where μf is the viscosity of the fluid, and G is the mass velocity:

G = 4 m /πD2

where m is the mass flow rate, and A, is the cross-sectional area of the bed.
If D or L is specified (for a given W), (-ΔP) may be calculated from above 5 equations.
Alternatively, we may use these equations to determine D (and L) for a specified
allowable value of (-ΔP ). The equations may be solved explicitly for D (or L):

D6 –βКD2 – К = 0

β = 150 π μf( 1- εb)/4 x1.75 dpm =67.32 μf( 1- εb)/dpm

К = 64 αm2W/ π3 ρf dp(-ΔP) ρb

α = 1.75( 1- εb)/ εb3

Above Equation provides the value of the bed diameter D for a given allowable pressure
drop, (-ΔP), a value of W calculated as described later, and known
values of the other quantities. Since (α,β, and К are all positive, from the Descartes rule
of signs there is only one positive real root of the above equation . If the
equations are solved for L instead of D, a cubic equation results.
In the choice of a value for the allowable (-ΔP) on the one hand, or for D (or L)
on the other (given W), there is a trade-off between the cost of the vessel and the cost
of pumping or compressing the fluid. The smaller D, the greater the L/D ratio and the
greater (-ΔP); thus, the cost of the vessel is less, but the cost of pumping is greater, and
conversely.

The process design of an FBCR involves exploiting the continuity (material-balance)

and energy equations to determine, among other things, the amount of a specified
catalyst required for a given feed composition, fractional conversion, and throughput;
concentration and temperature profiles; and the thermal mode of operation
to achieve the objectives. The appropriate forms of these equations, together with
rate equations for reaction and heat transfer, constitute the main working equations
of a reactor model. Before using any particular model for calculations, we
describe a classification as a basis for consideration of models in general for an
FBCR.
The basis for a classification is shown in Figure below, and control volumes are shown
in Figure below for axial flow. These diagrams could apply to catalyst packed inside a
vessel or inside a tube in a multitubular arrangement

PACKED BED REACTORS

Gas can be made to contact the solid in many ways giving many contacting patterns.
These may be divided into two categories.
 Fixed Bed Reactors
 Fluidized Bed Reactors

The moving bed reactor is the intermediate

case which embodies the merits and demerits
of fixed and fluidized bed reactors.

MERITS AND DEMERITS

 In passing through the fixed beds gases approximate to plug flow whereas the
flow is complicated for fluidized beds.
This behavior leads to ineffective contacting and
requirement of more catalyst for high conversion. For effective contacting fixed bed
reactor is favored.

 Effective temperature control of large fixed beds is difficult.

In contrast rapid mixing of solids in a fluidized bed allow isothermal operations. If
operations are restricted to a narrow temperature range, fluidized bed reactor is preferred.

 Fixed beds cannot use very small size particles because of plugging whereas
fluidized bed can use small size particles.

 If catalyst is to be regenerated frequently then fluidized bed allows it to be

pumped from unit to unit.This feature of fluidzed bed offers overwhelming
advantage over fixed bed.

DESIGN
Many factors must be considered for optimum design and the
best design is the one which uses two different reactor types
in series.

The main difficulties in design of catalytic reactors is

 How to account for the non isothermal behavior for packed beds.
 How to account for non ideal flow of gas in the fluidized beds.
STAGED ADIABATIC PACKED BED REACTORS
 With proper interchange of heat and proper gas flow,staged adiabatic packed bed
systems become a versatile system which is able to approximate any desired
temperature progression.
 The reacting conditions should follow optimal temperature progression.
 For any preset number of stages the optimizing operations reduces to minimizing
the total catalyst for a given conversion.
OPTIMUM TWO STAGE PACKED BED REACTOR

In searching for the optimum we have three variables to set ; the

incoming temperature ( point Ta),the amount of catalyst used in the
first stage(locates point b along adiabatic),the amount of intercooling
(locates point c along bc line).

We are able to reduce this 3-d search to 1-d search where Ta alone
is guessed.

The procedure is as follows.

 Guess Ta
 Move along the adiabatic line till the following condition is satisfied.
out
∫ ∂/∂T (1/-ra’)dXa = 0
in
 Cool to point c which has the same rate of reaction as point b thus,
(-ra’ )leaving the reactor = ( -ra’)entering next reactor
  Move along the adiabatic from point c till the criterion given in second point is
satisfied giving point d.

 If point d is at desired conversion then Ta guessed is correct

 Else guess another value of Ta and repeat the above steps.

 For three or more stages just extend the above procedure.

CHOICE OF CONTACTING SYSTEM
 For endothermic reaction rate always decreases with conversion and hence we
should always use plug flow with no recycle.

 All else being equal cold shot cooling has the advantage of lower cost since heat
exchangers are not required.Cold shot cooling is practical only when feed
temperature is very much below the reaction temperature.

 For exothermic reactions if the slope of adiabatic line is low it is advantageous to

avoid low temperature regime.Thus high recycle approaching mixed flow is
favored.If slope is high plug flow should be used.

 For exothermic reactions

For pure gas use high recycle rate.
For dilute gas requiring no large preheating use plug flow.
For dilute gas requiring large preheating use cold shot operation.

Packed (fixed) bed reactors:

Packed towers are tubular reactors which are filled with packing and are used for
continuous contact of liquid and gas in both countercurrent and co-current flow. The
purpose of a packed bed is typically to improve contact between two phases in a chemical
process. Packed beds can be used in a chemical reactor (distillation process) or in
bioreactors where immobilized enzymes are used.
Packings are of two types:
1. Random/unstructured – Random packings are simply dumped into the tower
during installation and allowed to fall at random. They are inexpensive and offer
large surface area but lead to high pressure drops. Example: raschig ring, berl
saddle.

2. Regular/structured- They are arranged in a uniform manner. They are expensive

but offer the advantage of low pressure drop. Example: raschig rings stacked
uniformly, metal sheets or gauzes.

Packing supports: The support must be sufficiently strong to carry the weight of a
reasonable height of packing and it must have ample free area to allow for flow of
liquid and gas with a minimum of restriction.
Packing restrainers: These are necessary when gas velocities are high and they guard
against the lifting of packing during a sudden gas purge. Heavy screens or bars may
be used.

Immobilized enzymes in packed bed reactors(PBR):

Enzyme (biocatalyst) immobilization is done so that their activity can be retained and
they can be reused in the bioreactors. Various methods such as gel entrapment, cross
linking, covalent binding etc are used for immobilization. Like other bio reactors
immobilized enzymes are used in packed bed reactors for processes like glucose
isomerization, selective penicillin hydrolysis, and for selective reactive separation of
racemic mixture of amino acids. Generally enzymes are immobilized in calcium
alginate and then packed into the bioreactors.
In the PBR, the feed (fluid) is allowed to flow through these packings consisting of
the immobilized biocatalysts. Metabolites and products are released into the fluid and
removed in the outflow. The feed velocity (superficial velocity) is below the
minimum fluidization velocity.

The flow might be upwards or downwards, but upflow is more desirable as the fluid
will contact/wet the packing uniformly (avoids short circuiting/channeling) and also
the contact time will be more than that of downflow.
The PBR follows the plugged flow pattern, thereby only radial mixing will occur and
there won’t be any axial mixing (/backmixing) inside the reactor. Hence the residence
time distribution will be uniform as all the fluid particles literally travel the same path
length inside the reactor.
The substrate concentration will be more near the fluid inlet and the product
concentration will be less. As the reaction progresses the product concentration
increases and hence near the outlet the substrate concentration will be less and the
product concentration will be more. This important characteristic makes the PBR
useful for carrying out product inhibition reactions.
In product inhibition reactions, there will be competitive inhibition as the product
present initially competes with the substrate for binding with the enzyme. However,
as only a small portion of product will initially compete with the substate in the PBR,
the product inhibition reactions can successfully be carried out in these reactors.
Pressure drop:
It is the decrease in pressure from one point to another point along the length of the
reactor.
Tube convergence, divergence, turns and the flow rates affect the pressure drop.
It is given by the Ergun equation:
High flow rates in small tubes give larger pressure drop, low flow rates in large tubes
give lower pressure drops.
High pressure drops are undesirable because it will result in both high pumping
energy costs and non-uniform pressure of the gas reactant, affecting the overall
reactor performance.
The pressure drop in the reactor can be reduced by using larger catalyst particles.
However smaller particles will increase the surface area of contact. So the diameter of
the particle used should be optimum favouring a low pressure drop as well as giving a
good surface area for contact.

Performance equations:
These are also called as design equations as they are useful for reactor design.
Considering mass balance:
Rate of substrate diffusion out of bulk liquid = rate of substrate disappearance by
reaction within the pellet
4πR2ks(S-Ss) = (4/3) πR3η (Ss, Ps) v (Ss, Ps)
Where,
R= radius of pellet (biocatalyst)
ks = saturation constant
S = substrate concentration in bulk liquid
Ss = substrate concentration on the exterior surface of the pellet
η = effectiveness factor
v = intrinsic rate of product formation
Ps = product concentration on surface of pellet
Considering material balance on substrate:
u.ds/dz = - ((1-ε)/ε)η (Ss,Ps)v (Ss,Ps)
Where,
ε = void fraction
1-ε = fraction occupied by the solid particles in the packing
If η = 1, then Ss = S; i.e. no mass transfer resistance will be there between the liquid
and solid phase when effectiveness is 1.
 In design, the number of necessary theoretical equilibrium stages is first determined
and then the packing height equivalent to a theoretical equilibrium stage, known as
‘Height equivalent to a theoretical plate (HETP)’ is determined.
Total packing height = (number of theoretical stages) x (HETP)

Advantages:
1. High conversion per unit mass of catalyst

2. Low pressure drop

3. For processing product inhibition reactions

Disadvantages:
1. Poor temperature control

2. Poor pH control

3. Difficult to service and clean the packings.

Residence Time Distribution for Chemical Reactors

General Characteristics
The two major uses of the residence time distribution to characterize nonideal
reactors are
1. To diagnose problems of reactors in operation
2. To predict conversion or effluent concentrations in existing/available reactors
when
a new reaction is used in the reactor.
Three concepts were used to describe nonideal reactors: the distribution of
residence times in the system, the quality of mixing and the model used
to describe the system.

~The time the atoms have spent in the reactor is called the residence time
of the atoms in the reactor.
~In any reactor, the distribution of residence times can significantly affect
its performance.
~The residence-time distribution (RTD) of a reactor is a characteristic of
the mixing that occurs in the chemical reactor.
~Not all RTDs are unique to a particular reactor type; markedly different
reactors can display identical RTDs.
~The RTD exhibited by a given reactor type yields distinctive clues to the
type of mixing occurring within it and is one of the most informative
characterizations of the reactor.

Measurement of the RTD

The RTD is determined experimentally by injecting an inert chemical,
molecule,
or atom, called a tracer, into the reactor at some time t=0 and then
measuring
the tracer concentration, C, in the effluent stream as a function of time.
~In addition to being a nonreactive species that is easily detectable, the tracer
 should have physical properties similar to those of the reacting mixture and
be
completely soluble in the mixture.
~It also should not adsorb on the walls or other surfaces in the reactor. The
latter
requirements are needed so that the tracer’s behavior will honestly reflect
that
of the material flowing through the reactor.
~Colored and radioactive materials along with inert gases are the most
common
types of tracers.
Pulse Input Experiment
In a pulse input, an amount of tracer N0 is suddenly injected in one shot into
the feedstream entering the reactor in as short a time as possible.
We shall analyze the injection of a tracer pulse for a single-input and single-
output system in which only flow carries the tracer material across system
boundaries
First, we choose an increment of time ∆ t sufficiently small that the
concentration of tracer, C(t), exiting between time t and t+∆ t is essentially the
same. The amount of tracer material, ∆ N, leaving the reactor between
time t and t+∆ t is then

For pulse injection we define

The quantity E(t)dt is the fraction of fluid exiting the reactor that has spent between
time t and t+dt inside the reactor.
SLURRY REACTORS

SLURRY REACTORS
 The design of gas liquid solid reactor is very much dependent on the size of the
solid particles chosen for the reaction.

 Smaller the size of the particle the closer is the value of

effectiveness factor to 1.

 Particles smaller than 1 mm cannot be used in fixed beds.

 Small particles should only be used as suspensions in liquid.

TYPES OF REACTOR
 Three phase reactors can be mainly divided into 2 classes.

Three Phase reactor

Suspended Bed Fixed Bed

Reactors Reactors
Bubble Agitated
Columns Tanks
BUBBLE COLUMNS AND AGITATED TANKS
 If particles are very small they can be quite easily kept in suspension by bubbling
gas through liquid in a bubble column.

 Agitated tanks can be used for large size particles because of the high local
velocities produced by the impeller.

 The impeller needs to be properly designed and positioned at the bottom of the
tank so that it will keep the solids in
suspension and disperse the incoming gas.
 A slurry reactor is a multiphase flow reactor in which the reactant gas is bubbled
through a solution containing solid catalyst particles.

 The solution may be a reactant as in the case of methyl linoleate or an inert as in

the case of Fischer Tropsch synthesis of methane.

 In slurry reactor the catalyst is suspended in liquid and gas is bubbled through the
liquid.

 The slurry reactor may be operated either in semibatch or continuous mode.

 In addition constant overall catalytic activity can be maintained by addition of

small amount of catalyst with each reuse in the batch operation or constant
feeding in continuous opearation.

 In modelling slurry reactors we assume that the liquid phase is well mixed and the
catalyst particles are uniformly distributed and gas phase is in plug flow

SLURRY REACTOR - DIAGRAM

RATE EQUATION

 Let the gas consist of pure reactant A ( typically H2) and let
the reaction take place at the interior of the catalyst, the
reaction being pseudo first order with rate constant k1.

 In an agitated tank suspended bed reactor gas is dispersed

as bubbles and it is assumed that liquid phase is well mixed
and concentration of A in liquid CAL is uniform throughout.

 In this case the overall reaction rate Rt will be based on the

unit volume of the whole dispersion ( Gas + Liquid +Solid )

 Let
a : Gas liquid interfacial area per unit volume of the
dispersion.
εg = volume fraction of gas bubbles.
εl = volume fraction of liquid.
εs = volume fraction of solid.

εg + εl + εs = 1

 For particles external surface is given by

ap = External surface area per unit volume of particle

 The above quantities can be related to volume/surface or

 sauter mean bubble / particle diameters by the following
relations.

db = 6 εg /a for bubbles
dp = 6/ap for particles

 The surface area of the particles per unit volume is apεp

 The above quantities can be related to volume/surface or

sauter mean bubble / particle diameters by the following
relations.

db = 6 εg /a for bubbles
dp = 6/ap for particles

 The surface area of the particles per unit volume is apεp

The reactants in the gas phase participate in 5 reaction steps.

 Absorption from gas phase into liquid phase at bubble surface.

 Diffusion in the liquid phase from bubble surface to bulk liquid.

 Diffusion from bulk liquid to external surface of solid catalyst.

 Internal diffusion of reactants into the porous catalyst.

 Reaction within the porous catalyst.

 Each step may be thought as a resistance to the overall rate
of the reaction.
  The concentration in the liquid phase is related to gas phase
concentration by Henry’s law.
Ci = Pi H

 Consider hydrogenation of methyl linoleate to form methyl

oleate.
Methyl Linoleate + Hydrogen à Methyl Oleate
(L) (H2) (O)

 Hydrogen is absorbed in liquid methyl linoleate diffuses to the external surface of

the catalyst pellet,then diffuses into the catalyst pellet where it reacts with methyl
linoleate to form methyl oleate. Methyl oleate diffuses out of the pellet back to the
liquid.

 The steps 1 and 2 and 4 and 5 can be combined to single steps.

 The mass transfer and chemical reaction steps take place in series. Hence each
step should proceed at the same rate as the
overall process.

For gas-liquid mass transfer

Rt = Kla ( Cai –Cal)

For liquid-solid mass transfer

Rt = Ksap εp(Cal –Cas)

For rate of reaction within the particle

Rt = k1Casƞ εp

Since the rate of the reaction is the same the overall rate of the
reaction can be obtained as

Rt = CAi / ( 1/Kla + 1/ Ksapεp + 1/K1 ƞεp )

1/Kla - Resistance for gas-liq mass transfer step

1/ Ksapεp - Resistance for liq-solid mass transfer step
1/K1 ƞεp - Resistance for pore diffusion with reaction step
DESIGN OF SLURRY REACTOR

Thiele Modulus φ = (Vp /Sp )*√k/De

Vp /Sp = ro / 3
For spherical particles
ƞ = 3/ λro ( coth λro – 1/ λro ) λ = √k/De
STEPS

1. Calculate λro and ƞ.(From given k,De and ro)

2. The size of the bubbles produced in the reactor and gas volume fraction will depend
on agitation conditions and the rate at which gas is fed to impeller.

Typical values are db =0.8 mm and εg = 0.20

3. The mass transfer coefficients Kl and Ks depend on the
physical properties of the system such as viscosity of the
liquid and diffusivity of the dissolved gas.
The corrleations are
For no Shear : Ks = 2DA-B/dp
For Shear : Ksdp/DA-B = 2 + 0.6(Re)1/2(Sc)1/3
Ks α (U/dp)1/2
Typical values : Kl =1.23 x10-3 and Ks =0.54 x10-3

4. The most important parameter to be specified is catalyst

loading ie the ratio of catalyst to liquid to be charged into the

Reactor.A solid/liquid ratio of about 0.1 can be used.

5. The pressure of the gas in the reactor also needs to be fixed.
6. Using the equations , db = 6 εg /a for bubbles
dp = 6/ap for particles
we can calculate a and ap
7. Using εp / εl = 0.1 and εg + εl + εp =1 we can calculate
εl and εp.

8. We can calculate 1/Kla , 1/ Ksapεp and 1/K1 ƞεp and hence

the overall rate of the reaction can be determined.
9. Mixed flow of G and any flow of L
A material balance for A and B about the reactor as a whole
yields
Fao Xa= Fbo Xb/ b = (-ra’’’’ )Vr

Fao Xa - Rate of loss of A.

Fbo Xb/ b - Rate of loss of B
(-ra’’’’ )Vr - Rate of disappearance of A by reaction

The above equation is derived as follows.

Fao = Fa + (-ra’’’’ )Vr

Fao - Fa = (-ra’’’’ )Vr

Fao – Fao ( 1-Xa) = (-ra’’’’ )Vr
FaoXa = (-ra’’’’ )Vr
Similarly ,
FboXb = (-rb’’’’ )Vr
(-ra’’’’ ) = (-rb’’’’ )/b

FaoXa = FboXb/b = (-ra’’’’ )Vr

From the above equations the volume of the reactor can be found
out knowing the value of the rate of the reaction.
10. Mixed flow of G and batch L.
For component A
Input = Output + Disappearance
Fao = Fao(1- Xaexit) + (-ra’’’’)Vl

For component B
Input = Output + Disappearance + Accumulation
0 = 0 + dNb/dt + (-rb)Vr
(-rb)Vl = -dNb/dt
-rb = (1/ Vl ) -dNb/dt = -dCb/dt

- ra = -rb/ b
-rb = b(-ra) = -dCb/dt
-ra = 1/ b (-dCb/dt)
(-ra)Vl = (-ra’’’’)Vr
Thus
Vl/b (-dCb/dt) = (-ra’’’’)Vr = FaoXaexit
USES
 Hydrogenation of
1. Fatty acids over supported nickel catalyst.
2. 2-butyne-1,4-diol over pd-CaCO3 catalyst.
 Oxidation of
1. C2H4 in inert liquid over a pdCl2 –Carbon catalyst.
2. SO2 in inert water over activated carbon catalyst.
 Hydroformation
1.CO with high molecular weight olefins with cobalt complex bound polymers.
 Ethynylation
1. Reaction of acetylene with formaldehyde over a CaCl2 supported catalyst.

TANK REACTORS
 Tank reactors usually employ mechanical agitation to bring about more intimate
contact of the phases, with one phase being dispersed in the other as the
continuous phase.

 The gas phase may be introduced through a “sparger” located at the bottom of the
tank;this is a circular ring of closed-end pipe provided with a number of holes
along its length allowing multiple entry points for the gas.
  Tank reactors are well suited for a reaction requiring a large liquid holdup or a
long liquid-phase residence time. The operation may be continuous with respect
to both phases, or it may be semicontinuous (batch with respect to the liquid).
 The simplest flow pattern for each phase is BMF. The reactor may be single-stage
or multistage and the flow for the latter may be cocurrent or countercurrent.
 In the case of a liquid-liquid reaction, each stage typically consists of a mixer
(with agitation, for reaction) and a settler (without agitation, for separation by
gravity).
 Tank reactors equipped with agitators (stirrers, impellers, turbines, etc.) are used
extensively for gas-liquid reactions, both in the traditional chemical process
industries and in biotechnology.
 In comparison with nonagitated tank reactors equipped only with spargers,
mechanically agitated tank reactors have the advantage of providing a greater
interfacial area for more efficient mass transfer
 The enhanced mixing also ensures a nearly uniform temperature within the vessel,
an advantage for processing temperature-sensitive materials, and for control of
product yield and selectivity in complex systems.
 A major disadvantage is the cost of the energy required for agitation.
 Furthermore, since the mass transfer characteristics are related to agitation
characteristics (e.g., stirrer rate), there are difficulties of scale-up.

CHOICE OF TOWER OR TANK REACTOR

 The choice between a tower-type and a tank type reactor for a fluid-fluid reaction
is determined in part by the kinetics of the reaction.
 As described by the two-film model for gas-liquid reactions the rate of the overall
process is influenced by relative rates of mass transfer and of intrinsic reaction.
 The two extremes , for a nonvolatile liquid-phase reactant, are virtually
instantaneous reaction in the liquid-film, which is controlled by interphase mass
transfer and “very slow” reaction, which is controlled by reaction itself in the bulk
liquid

 Typical values of gas-liquid interfacial area (ai and ai’) for various types of
vessels

Tower(Spray,Plate) Tank
Agitated Sparger
ai 1000 200 20
ai’ 100 180 20
vl/vr 0.1 0.9 0.98

- ai interfacial area based on unit volume of liquid phase, m2 m-3 (liquid)

- ai’ interfacial area based on unit volume of vessel (occupied by fluids),m2 m-3 (vessel)
  The two quantities ai and ai’ are related by ai’ =(Vl/Vr)ai, = (1 – εg)ai where Vl,
= volume of liquid in the vessel, Vr, = volume of reactor (vessel) occupied by
fluid, and εg is the gas holdup, m3 gas (m3 reactor)-1.

 Values of the ratio Vl / Vr given in table emphasize that most of the volume in a
tower reactor is occupied by the gas phase, and conversely for a tank reactor.
This means that ai >> ai’ in a tower and ai= ai’ : in a tank.
 For a tank reactor the ideal flow pattern is BMF for each phase (gas and liquid).
Important considerations are the dispersion of gas bubbles within the liquid phase,
and the agitator power required for this.

 The h/D ratio is usually about 1, but this is exceeded if the stages in a multistage
arrangement are stacked vertically. Gas is usually fed to the reactor below the
agitator through a distributor which may be a perforated plate or pipe ring
(sparger).

 The type of agitator also can affect bubble size, and, thus, mass transfer
characteristics.
 The most common types are rotating flat paddle mixers, with straight or inclined
blades, and a turbine, with several flat blades attached to a disc (turbine).
 The diameter of the blades is usually about 35% of the vessel diameter (D).
Several vertical baffles, each with a width of up to 10% of D, are attached to the
wall of the vessel around its circumference.

CONTINUITY EQUATION
 Continuity equation for A in the gas phase (BMF).Since the gas phase is in BMF,
the continuity equation corresponding to and based on the entire vessel of
volume V=Ach = πd2/4 h
Rate of input = Rate of output + Rate of transfer
of A by bulk flow of A by bulk flow transfer of A to
liquid film
YainGAc = YaoutGAc + Naai’Ach

 Continuity equation for A in liquid phase

Rate of input + Rate of transfer of A = Rate of output
of A by bulk flow from liquid film of A by bulk flow +
Rate of reaction of A
in bulk liquid

Cainql +ai’NaV = Caoutql + (1-εg)(-raint)V

Overall material balance around tank

The overall material balance around the tank is again given by equation
G/P ( pain –paout ) = L/b ( Cbin –Cbout) + L(Caout-Cain)
CORRELATIONS FOR DESIGN PARAMETERS FOR TANK REACTORS
 Before we can apply the continuity or design equations for tank reactors
developed we must have the means of determining values of the parameters
involved. These include gas holdup, g, mass transfer coefficients, kAl , and kAs,
and gas-liquid interfacial area, ai or ai’.

 For a nonelectrolyte liquid phase, the correlation of Robinson. (1977) is

εg = 0.21( qgnimp2/σ)0.57
 Power Input Pl = 0.34nb,imp1/2 ( Plo nimpDimp3/qg)m

Plo Power Input without gas flowl

nb,imp Number of impeller blades
Nimp Rate of rotation of the impeller
Dimp Diameter of impeller
m =0.45 for non coalescing liquids
=0.33 for ionic liquids

 Chandrasekharan and Calderbank (1981) proposed the following correlation,

which shows a much stronger inverse dependence on vessel diameter:
kalai’ = 0.048 (Pl/vl)0.5 qg0.55D-0.5

 The correlation of Calderbank (1958) for ai’ is

ai’ = 22.8 ( Pl/Vl)0.4(usg/ubr) (ρl/σ)3

 L(D) = ql /Ac

 G(D) = Fain,/0.21Ac

 V(D) = (1 - εg)V

 Usg(D) = qg/Ac

UNIT III BIOREACTOR SCALE – UP 9

Regime analysis of bioreactor processes, oxygen mass transfer in bioreactors -
microbial oxygen demands; methods for the determination of mass transfer coefficients;
mass transfer correlations. Scale up criteria for bioreactors based on oxygen transfer,
power consumption and impeller tip speed.

Oxygen Transfer in Bioreactors

Oxygen is needed by cells for respiration. Oxygen used by cells in suspension must be
available as dissolved oxygen. Since oxygen solubility is quite small, about 6 to 7 mg/L
under normal cultivation conditions, metabolic oxygen requirement is supplied on a as
needed basis by continuous aeration of culture medium. Actively respiring yeast requires
about 0.15 g O2 (g cell)-1 h. At a cell concentration of 10 g L-1, medium saturated with air
can support less than 30 seconds worth of metabolic oxygen. That is, a continuous supply
of oxygen must be maintained in any viable aerobic manufacturing process. In this
Chapter, we will first get a quantitative appreciation for metabolic oxygen demand,
followed by methods used in calculating rates at which oxygen is transfered from sparged
air. We will then examine methods useful in characterizing oxygen mass transfer
coefficient. Finally we will evaluate bioreactor operation and design based on oxygen
transfer capability.

Metabolic Oxygen Demand

Metabolic oxygen demand of an organism depends on the biochemical nature of the cell
and cultivation conditions. Oxygen need is usually satisfied in most cells if the dissolved
oxygen concentraiton in the medium is kept at about 1 mg/L. If the oxygen level is
allowed to fall far below this value, oxygen consumption rate decreases with concomitant
decrease in biochemical energy production, and as a result cell growth rate also
decreases. We described this behavior in Section 4-4. The value of oxygen concentration
above which growth rate is at the maximum was described as the critical oxygen
concentration, . Characteristic values are summarized in Table 5-1.

Table 5-1 Critical Oxygen Concentration

Organism in mg L-1
E. coli at 37 C 0.26
S. cerevisiae at 30 C 0.13
Penicillium sp at 24 C 0.78

The oxygen requirement for growth is expressed best in the the parameter, yield
coefficient, YX/O2. It represents the amount of oxygen required to grow one gram of cells.
Typical values summarized in Table 5-2, show that approximately 0.7 to 1 g of oxygen is
needed to produce 1 g of cells. In the same table respiration quotient is also included.

Table 5-2 Stoichiometric Oxygen Demand &Respiration Rate

YX/O2 qO2
Organism Substrate
[g (g cell)-1 h] [g O2 (g cell)-1 h]
E. coli Glucose 1.1 0.20
S.cerevisae Glucose 0.98 0.30
Candida utilis Glucose 1.32
Pennicillium sp. Glucose 1.35 0.18
Hybridoma
CHO cell line

Volumetric Oxygen Mass Transfer Coefficient

In a typical aeration system, oxygen from the air bubble is transferred through the gas-
liquid interface followed by liquid phase diffusion/bulk transport to the cells. Although
this is a multi-step serial transport, in a well dispersed systems, the major resistance to
oxygen transfer is in the liquid film surrounding the gas bubble. Consider the oxygen
concentration profiles in the region near the interface illustrated in Figure 5-1.

Figure 5-1 Oxygen Concentration Profile at Air Bubble-Medium Interface

The transport of oxygen through the gas and liquid films are equal at steady state. They
can be expressed by

where subscript G and L refer to gas and liquid phases respectively. The terms, NO2G and
NO2L are oxygen transfer expressed in g O2 h-1, A is interfacial area and CDO is oxygen
concentration expressed in g O2 per unit volume. At the interface, equilibrium between
the liquid and gas phase oxygen is reached. That is

Because of low oxygen solubility and the fact that kG is much higher than kL,

Hence, Eq (5-1a) can be written as

The subscript L in NO2 has been dropped to note that the above represents overall transfer
of oxygen. The driving force in the above consists of the difference between bulk oxygen
concentrations in the two phases; the first term represents the concentration of oxygen in
the liquid which is in equilibrium with the bulk gas phase oxygen. If air is the gas
medium, this term will equal to 7 mg/L at 35 C.

When the above oxygen transfer is applied to an entire volume of a bioreactor, A will
represent the total interfacial area and kL will represent an average mass transfer
coefficient. The concentrations will be bulk gas and liquid phase oxygen concentrations.
If we divide the above equation by volume of liquid phase, V, the resulting term will
represent the amount of oxygen transfered per unit volume per unit time --- which is in
the same units as the rate expressions we saw in last chapter. Since the rate is due to a
physical phenomena, let us distinguish it by the symbol, RO2. That is,

The term, kL A represents the product of mass transfer coefficient and interfacial area
available for mass treansfer. In a bioreactor, air is sparged and the liquid is agitated to
break up the bubbles so that interfacial area can be kept high to enhance rate of oxygen
transfer. In such systems, the area, A, is not easily measured or estimated. But, the term
consisting of the product - mass transfer coefficient and interfacial area - is more readily
measured. Further more, it is convenient to use interfacial area per unit volume, a, rather
than total area, A because rate of oxygen transfer is expressed per unit volume of
bioreactor, similar to rate of cell growth, which is reported on a volumetric basis. Hence,
area per unit volume, a, is combined with the mass transfer coefficient, kL and is given by
the term, kLa. In Eq(5-5) the term, can be replaced by oxygen solubility at bioreactor
conditions, .

The above will be our working equation for describing transfer of oxygen from gas phase
to growth medium. In order for us to calculate oxygen transfer rate (OTR), we need the
mass transfer coefficient, kLa , solubility of oxygen in the medium, and the dissolved
oxygen concentration in the medium, CDOL. In the last chapter we had used the notation,
CDO to describe dissolved oxygen concentration. In the discussion above, there was a need
to make a distinction between gas and liquid phase concentration. In Eq (5-5), one notes
that both concentrations are expressed on the basis of liquid phase. Hence, from here on
we will drop the subscript L. In situations where we need to make a distinction between
the two phases, we will re-introduce the subscript L and G.

Bioreactor Oxygen Balance

Let us now consider the case of oxygen balance within a bioreactor in which cells are
growing and in the process consuming oxygen. There is a continuous inflow of air at a
constant volumetric flow rate. The liquid broth is agitated by a Rushton agitator (flat
blade stirrer ). Le the metabolic oxygen uptake rate be qO2 and cell concentration is X. Let
us examine the reactor system over a sufficiently short period that we can treat X as a
constant. Consider oxygen balance over the liquid phase of the bioreactor.

O2 transfered from Gas Phase - O2 consumed by Cells = Accumulation

For constant liquid phase volume, the above can be simplified to

The concentration, CDO is readily measured using an dissolved oxygen electrode. A later
segment of the course on Biosensors, will deal with principle of measurement and
construction of DO electrodes.

If oxygen being supplied is in exact balance with the oxygen consumed by the cells, we
expect the dissolved oxygen concentration to remain constant; that is, the derivative in
Eq(5-7) will vanish. That is,

One useful application of the above is in estimating the maximum cell concentration a
particular bioreactor is capable of supporting in terms of oxygen supply. See the example
below.

Example 5-1.

A bioreactor has an oxygen mass transfer coefficient capability of 400 h-1. What is the
maximum concentration of E. coli that can be grown aerobically in this reactor.
Respiration rate of E. coli is 0.35 g O2 (g Cell)-1 h-1. Critical oxygen concentration is 0.2
mg/L. Assume oxygen saturation with air to be 6.7 mg/L.

Solution

From Eq(5-8), we have

The maximum oxygen concentration driving force that can be expected is

= ( 6.7 - 0.2) = 6.5 mg/L.

Therefore, maximum cell concentration that can be grown at maximum growth rate is

Factors Affecting KLa The mass transfer coefficient is strongly affected by agitation
speed and air flow rate. In general,

Note that the mass transfer coefficient increases with agitation speed and air flow rate.

Measurement of KLa

Most common method of measuring kLa is to conduct experiments in the bioreactor when
cells are absent, or cell concentration is low so that consumption by cells can be
neglected. The latter condition is present immediately after inoculating the bioreactor.
Consider Eq (5-7) under these conditions:

If we allow steady state to occur, the dissolved oxygen concentration will reach saturation
value, and the concentration-time profile will be flat, as shown in the diagram.

Fig 5-2 Oxygen Profile During a Transient. The responses will be exponential, rather
than straight lines.

If the oxygen source (air) is replaced by nitrogen, the resulting response of the system is
described by the above equation with the term, set to zero. That is,
The solution to the above is

If one plots the response on a semi-log plot, the slope will equal to the negative of mass
transfer coefficient. It is relatively a simple experiment and the data analysis is also easy
to do. When other type of transient mass transfer experiments are conducted, the above
equations should be suitably modified. For example for the case of nitrogen to air switch,
we should suitably modify the solution because the initial condition is now different.

Case Studies

You are part of a tech service team asked to evaluate if the available 10,000 liter
fermentor is adequate to produce 10 kg/day of a recombinant protein using a strain of E.
coli that expresses the protein as 20 % of cellular protein. In order to enhance plasmid
stability, the nutrients are manipulated to give a low specific growth rate is 0.2 h-1. The
oxygen demand is 0.15 g O2/g cell - h. Assume that the r-protein formation is cell growth
associated.

Data: The lag phase is 4 hours. Typical clean-up time following a fermentation batch and
preparation for the next batch is 8 hours. The plant runs three shifts. Cell yield on
substrate is 0.55 g cell/g substrate. Available support services can supply inoculum of a
maximum of 6 kg of cells every 24 hour period. Maximum KLa for the available
-
fermentor is 500 h 1. Fermentor accessories are capable of handling cell concentrations of
60 g/L. Assume any other parameters you need to complete the calculation.

Assumption: Critical oxygen conc. is 0.2 mg/L and DO at air saturation is 6.4 mg/L

Solution A: Lag phase and clean-up/ prep time is given as 12 h. If a batch is to

completed within each 24 h period, production is limited to 12 h per day. If this is not a
limitation, one can optimize production by varying batch time. Let us first evaluate
assuming 12 h batch times.
If max. cell concentration of 20.6 g/L is obtained, amount of r-protein produced is = (0.2)
(0.5) (20.6) = 2.06 g/L. 50% of cell dry matter was assumed to be protein. Hence in
10,000 liters, we will produce 20.6 kg.

Next to determine the inoculum level. The maximum batch growth phase is 12 h.
Substitute in growth eqn, and assuming nutrients are present to support exponential
growth during the 12 h period,

For 10,000 liters, we will need 18.7 kg every 12 h. Since only 6 kg is available, max.
protein that can be produced is

{(0.2)(0.5)[0.6 Exp((0.2)(12)] 10,000 = 6.61 kg

Solution B: Now let us allow batch times to be longer than 12 h, meaning that there
might not be a harvest every day. Since it is advantageous to use the max. inoculum
concentration, select X0 = 0.6 g/L. This value is obtained by diving 6 kg of cells in
10,000 L. Max. cell concentration is fixed due to aeration requirements. Use the batch
growth eqn to find the batch growth time of 17.7 h. Hence 20.6 kg or r-protein will be
produced every 29.7 h which gives a 24 h production rate of 16.6 kg.

What alternative way of running reactor would you recommend to achieve the production
target?

You are part of a tech service team asked to evaluate if the available 10,000 liter
fermentor is adequate to produce 10 kg/day of a recombinant protein using a strain of E.
coli that expresses the protein as 20 % of cellular protein. In order to enhance plasmid
stability, the nutrients are manipulated to give a low specific growth rate is 0.2 h-1. The
oxygen demand is 0.15 g O2/g cell - h. Assume that the r-protein formation is cell growth
associated.

Data: The lag phase is 4 hours. Typical clean-up time following a fermentation batch and
preparation for the next batch is 8 hours. The plant runs three shifts. Cell yield on
substrate is 0.55 g cell/g substrate. Available support services can supply inoculum of a
maximum of 6 kg of cells every 24 hour period. Maximum KLa for the available
-
fermentor is 500 h 1. Fermentor accessories are capable of handling cell concentrations of
60 g/L. Assume any other parameters you need to complete the calculation.

Assumption: Critical oxygen conc. is 0.2 mg/L and DO at air saturation is 6.4 mg/L
Solution A: Lag phase and clean-up/ prep time is given as 12 h. If a batch is to
completed within each 24 h period, production is limited to 12 h per day. If this is not a
limitation, one can optimize production by varying batch time. Let us first evaluate
assuming 12 h batch times.

If max. cell concentration of 20.6 g/L is obtained, amount of r-protein produced is = (0.2)
(0.5) (20.6) = 2.06 g/L. 50% of cell dry matter was assumed to be protein. Hence in
10,000 liters, we will produce 20.6 kg.

Next to determine the inoculum level. The maximum batch growth phase is 12 h.
Substitute in growth eqn, and assuming nutrients are present to support exponential
growth during the 12 h period,

For 10,000 liters, we will need 18.7 kg every 12 h. Since only 6 kg is available, max.
protein that can be produced is

{(0.2)(0.5)[0.6 Exp((0.2)(12)] 10,000 = 6.61 kg

Solution B: Now let us allow batch times to be longer than 12 h, meaning that there
might not be a harvest every day. Since it is advantageous to use the max. inoculum
concentration, select X0 = 0.6 g/L. This value is obtained by diving 6 kg of cells in
10,000 L. Max. cell concentration is fixed due to aeration requirements. Use the batch
growth eqn to find the batch growth time of 17.7 h. Hence 20.6 kg or r-protein will be
produced every 29.7 h which gives a 24 h production rate of 16.6 kg.

What alternative way of running reactor would you recommend to achieve the production
target?

UNIT IV MODELLING AND SIMULATION OF BIOPROCESSES 12

Study of structured models for analysis of various bioprocess – compartmental models,
models of cellular energetics and metabolism, single cell models, plasmid replication and
plasmid stability model. Dynamic simulation of batch, fed batch, steady and transient
culture metabolism.

Compartmental models

If metabolite corrected arterial blood curve and dynamic PET data are available from the
time of injection to the time where all important changes in tracer kinetics have been
seen, and the data is of sufficient quality, then it may be possible to estimate the
parameters of a complete model, including perfusion, blood volume in tissue vasculature,
transport, specific binding or reaction rate etc. In practice this can be done only in very
simple cases, e.g. with labeled water which just flushes in and out of tissue. As is
mentioned above, it is possible and desirable to either measure some of the parameters in
separate studies, e.g. blood volume using [15O]CO, or constrain them to literature values,
or to reduce the model. Most often there is no need to measure all the parameters, but just
one key parameter which correlates with the desired property in usual conditions.

Plasma compartment

To be precise, the plasma is not a compartment of the model. The concentration of tracer
in the plasma is measured, and applied to the compartment model as a known input
function. However, plasma compartment is still usually counted as one of the
compartments.

The metabolite corrected arterial plasma curve is the input to the compartment model. If
the intravascular activity is accounted for in the calculation, the whole blood
concentration, containing metabolites, should be used for that. If metabolite corrected
plasma curve is used instead of uncorrected whole blood curve to correct for vascular
blood volume fraction, blood contribution at late times is underestimated, which could
result in the artificial presence of an apparent additional tissue compartment
[Lammertsma 2002].

Two-compartment model (one-tissue compartment model)

Methods for quantitation of perfusion (blood flow, f) with freelydiffusable tracers are
based on Kety's analyses of the principles of inert gas exchange. Tracers such as
[15O]H2O, [15O]butanol, [11C]butanol and [18F]fluoromethane are used for this purpose.
Also a single breath inhalation of [15O]CO2 produces an arterial bolus of [15O]H2O.

Three-compartment model (two-tissue compartment model)

The kinetic model for measurement of glucose transport and phosphorylationrate in brain
is based on a three-compartment model.

Four-compartment model (three-tissue compartment model)

The description of the time course of the ligand in tissue rquires a modelthat accounts for
the different components contributing to the signal. These are free ligand in plasma, free
ligand in tissue, CF, ligand in tissue which is not specifically bound, CNS, and ligand
specifically bound to the receptor, CB [Schmidt and Turkheimer 2002]:
Use of 4-compartment model is not feasible given the large number of rate constants to
be estimated, and the kinetically undistinguishable compartments for specific and non-
specific binding. The model is simplified under the assumption of a rapid equilibrium
between free and non-specifically bound compartments that produces a single
compartment of free + non-specifically bound ligand:

Although for most ligands k3' and k4 cannot be estimated with a reasonable degree of
accuracy, their ratio is usually more stable.

UNIT V BIOREACTOR CONSIDERATION IN ENZYME SYSTEMS 8

Analysis of film and pore diffusion effects on kinetics of immobilized enzyme reactions;
formulation of dimensionless groups and calculation of effectiveness factors. Design of
immobilized enzyme reactors – packed bed, fluidized bed and membrane reactors.

Enzyme reactors

An enzyme reactor consists of a vessel, or series of vessels, used to perform a desired

conversion by enzymic means. A number of important types of such reactor are shown
diagrammatically in Figure 5.1. There are several important factors that determine the
choice of reactor for a particular process. In general, the choice depends on the cost of a
predetermined productivity within the product's specifications. This must be inclusive of
the costs associated with substrate(s), downstream processing, labour, depreciation,
overheads and process development, in addition to the more obvious costs concerned
with building and running the enzyme reactor. Other contributing factors are the form of
the enzyme of choice (i.e. free or immobilised), the kinetics of the reaction and the
chemical and physical properties of an immobilisation support including whether it is
particulate, membranous or fibrous, and its density, compressibility, robustness, particle
size and regenerability. Attention must also be paid to the scale of operation, the possible
need for pH and temperature control, the supply and removal of gases and the stability of
the enzyme, substrate and product. These factors will be discussed in more detail with
respect to the different types of reactor.

Batch reactors generally consist of a tank containing a stirrer (stirred tank reactor, STR).
The tank is normally fitted with fixed baffles that improve the stirring efficiency. A batch
reactor is one in which all of the product is removed, as rapidly as is practically possible,
after a fixed time. Generally this means that the enzyme and substrate molecules have
identical residence times within the reactor, although in some circumstances there may be
a need for further additions of enzyme and/or substrate (i.e. fed -batch operation). The
operating costs of batch reactors are higher than for continuous processes due to the
necessity for the reactors to be emptied and refilled both regularly and often. This
procedure is not only expensive in itself but means that there are considerable periods
when such reactors are not productive; it also makes uneven demands on both labour and
services. STRs can be used for processes involving non-immobilised enzymes, if the
consequences of these contaminating the product are not severe. Batch reactors also
suffer from pronounced batch-to-batch variations, as the reaction conditions change with
time, and may be difficult to scale-up, due to the changing power requirements for
efficient fixing. They do, however, have a number of advantageous features. Primary
amongst these is their simplicity both in use and in process development. For this reason
they are preferred for small-scale production of highly priced products, especially where
the same equipment is to be used for a number of different conversions. They offer a
closely controllable environment that is useful for slow reactions, where the composition
may be accurately monitored, and conditions (e.g. temperature, pH, coenzyme
concentrations) varied throughout the reaction. They are also of use when continuous
operation of a process proves to be difficult due to the viscous or intractable nature of the
reaction mix.

Figure 5.1. Diagrams of various important enzyme reactor types.

 a. Stirred tank batch reactor (STR), which contains all of the enzyme and substrates)
until the conversion is complete;
b. batch membrane reactor (MR), where the enzyme is held within membrane tubes
which allow the substrate to diffuse in and the product to diffuse out. This reactor
may often be used in a semicontinuous manner, using the same enzyme solution
for several batches;
c. packed bed reactor (PBR), also called plug -flow reactor (PFR), containing a
settled bed of immobilised enzyme particles;
d. continuous flow stirred tank reactor (CSTR) which is a continuously operated
version of (a);
e. continuous flow membrane reactor (CMR) which is a continuously operated
version of (b);
f. fluidised bed reactor (FBR), where the flow of gas and/or substrate keeps the
immobilised enzyme particles in a fluidised state.

All reactors would additionally have heating/cooling coils (interior in reactors (a), and
(d), and exterior, generally, in reactors (b), (c), (e) and (f)) and the stirred reactors may
contain baffles in order to increase (reactors (a), (b), (d) and (e) or decrease (reactor (f))
the stirring efficiency. The continuous reactors ((c) -(f)) may all be used in a recycle
mode where some, or most, of the product stream is mixed with the incoming substrate
stream. All reactors may use immobilised enzymes. In addition, reactors (a), (b) and (e)
(plus reactors (d) and (f), if semipermeable membranes are used on their outlets) may be
used with the soluble enzyme.

The expected productivity of a batch reactor may be calculated by, assuming the validity
of the non -reversible Michaelis -Menten reaction scheme with no diffusional control,
inhibition or denaturation (see reaction scheme [1.7] and equation (1.7). The rate of
reaction (v) may be expressed in terms of the volume of substrate solution within the
reactor (VolS) and the time (t):

(5.1)

Therefore:

(5.2)

On integrating using the boundary condition that [S] = [S]0 at time (t) = 0:
 (5.3)

Let the fractional conversion be X, where:

(5.4)

Therefore;

(5.4a)

and

(5.4b)

Also

(5.4c)

Therefore substituting using (5.4c) and (5.4b) in (5.3):

(5.5)

The change in fractional conversion and concentrations of substrate and product with
time in a batch reactor is shown in Figure 5.2(a).
Figure 5.2. This figure shows two related behaviours.

(a) The change in substrate and product concentrations with time, in a batch reactor. The
reaction S P is assumed, with the initial condition [S]0/Km = 10. The
concentrations of substrate (??? and product (-----------) are both normalised with respect
to [S]0. The normalised time (i.e. t? = t Vmax/[S]0) is relative to the time (t? = 1) that would
be required to convert all the substrate if the enzyme acted at Vmax throughout, the actual
time for complete conversion being longer due to the reduction in the substrate
concentration at the reaction progresses. The dashed line also indicates the variation of
the fractional conversion (X) with t?.

(b) The change in substrate and product concentrations with reactor length for a PBR.
The reaction S P is assumed with the initial condition, [S]0/Km = 10. The
concentrations of substrate (???) and product (-----------) are both normalised with
respect to [S]". The normalised reactor length (i.e. I? = lVmax/F, where Vmax is the
maximum velocity for unit reactor length and I is the reactor length) is relative to the
length (i.e. when I? = 1) that contains sufficient enzyme to convert all the substrate at the
given flow rate if the enzyme acted at its maximum velocity throughout; the actual
reactor length necessary for complete conversion being longer due to the reduction in the
substrate concentration as the reaction progresses. P may be considered as the relative
position within a PBR or the reactor's absolute length.

Types of Reactors
 In an enzyme reactor, the highest specific enzyme activity is desirable. It is
considered an added bonus if the support that is used also aides in separation. One
approach is to use a molecular sieve as the support and pulse the reactor bed with the
alternating passage of substrate solution and water. The result is that bands of unused
substrate and product progress down the column. It so happens that the enzymes for
which this technique would be useful are also those which in some cases benefit in
having the enzyme immobilized on a porous support.

For an industrial reactor, it is preferable to use supports that are non-biodegradable

such as glass, silica, Celite, Bentonite, alumina, or titanium oxide, if possible. Even the
linkages between enzyme and support can be non-biodegradable, as they are in the case
of titanium. In some of these supports the physical nature of the surface becomes a major
problem. Thus, some supports that form excellent packed beds fail to do so when coated
with enzyme. Particles which ideally self-suspend in a fluid bed may form aggregates
during use which will require more power to pump through substrate. Many problems
were encountered using porous glass supports until someone realized that the glass itself
could dissolve. This problem has been eliminated by treatment of the glass surface with
zirconium.

Many types of reactors have been proposed including the following:

• Batch reactors may include:

o Stirred Tank for Soluble Enzymes
o Stirred Tank for Immobilized Enzymes
o Stirred Tank with Immobilized Enzyme Basket Paddles
o Stirred Tank with Immobilized Enzyme Basket Baffles
o Total Recycle Packed Bed Reactor
o Total Recycle Fluidized Bed Reactor

• Continuous reactors may include:

o Stirred Tank Reactor with Filtration Recovery
o Stirred Tank Reactor with Settling Tank Recovery
o Stirred Tank Reactor with Immobilized Enzyme Basket
Paddles
o Stirred Tank Reactor with Ultra filtration Recovery
o Packed Bed Reactor (same link as above)
o Packed bed with recycle
o Flat Bed Reactor
o Filter Bed Reactor
o Fluidized Bed Reactor, Same but better design (expanded
top section)
o Membrane Reactor using hollow fibers
Combined CSTR/UF Reactor

A combined CSTR/UF reactor is a combination of a continuously stirred tank

reactor and an Ultra Filtration Unit. This type of reactor begins as a typical CSTR.
However, the product passes through an Ultra Filtration Unit where the enzyme is
removed and recycled back into the reactor. An example of what this combination rector
can look like is shown below:

In a combined CSTR/UF reactor the enzymes are immobilized in that they can not
leave the reactor because of the filtration unit. This allows continuous processing with
free enzymes in the CSTR. The Ultra Filtration Unit contains a membrane which
provides a semipermeable barrier which allows products and unreacted substrate, if there
is any, to pass through while holding back the enzyme. There are other possibilities for
similar reactors, such as combined reactor-separators. However, the combined CSTR/UF
reactor has proven useful for several types of reactions where a typical immobilized
enzyme would not be as effective. One example of this is for the conversion of
benzylpenicillin to 6-aminopenicillanic acid by penicillin amidase.

Packed Bed Reactor

Continuous packed bed reactors are the most widely used reactors for immobilized
enzymes and immobilized microbial cells. In these systems, it is necessary to consider the
pressure drop across the packed bed or column, and the effect of the column dimensions
on the reaction rate. There are three substrate flow possibilities in a packed bed and they
are illustrated below:

1. Downward flow method

 2. Upward flow method
3. Recycling method

The recycling method is advantageous when the linear velocity of the substrate
solution affects the reaction flow rate. This is because the recycling method allows the
substrate solution to be passed through the column at a desired velocity.

For industrial applications, upward flow is generally preferred over downward flow
because it does not compress the beds in enzyme columns as downward flow does. When
gas is produced during an enzyme reaction, upward flow is preferred.

A continuous packed bed reactor has the following advantages over a batch packed
bed reactor:

1. Easy, automatic control and operation

2. Reduction of labor costs
3. Stabilization of operating conditions
4. Easy quality control of products

Recycle Reactor

A recycle reactor is a reactor that is not seen very often, but is very important to
consider when studying immobilized enzymes. It is very important to chemical
engineering because it allows some substrates to be processed, which could not be
processed using other reactor types. An example of a recycle reactor can be seen below:

In a recycle reactor, a portion of the product stream is recycled and mixed with the
inlet flow to the reactor. If the entire product stream is recycled back to the inlet stream,
then it is called a total recycle reactor. This can obviously only be used in a batch
process, because if the entire product stream is recycled back into the reactor in a
continuous reactor, the volume of the reactor would increase to infinity. Therefore, we
will only consider partial recycle streams in a continuous reactor on this page.

This type of rector is used when you have a substrate that cannot be completely
processed on a single pass, such as with an insoluble substrate. These reactors continue to
move the same substrate through the reactor so that the effective contact time is high
enough to allow the substrate to be processed. Recycle reactors also allow the reactor to
operate at high fluid velocities. This is important because it minimizes the bulk mass
transfer resistance to the transport of the substrate. It is important to remember that a
recycle reactor is simply a reactor, such as a CSTR or fluidized-bed reactor, with a
recycle stream.
 Ultrafiltration Membrane Devices

A continuous ultrafiltration membrane device is shown below:

This device is suitable for a substrate of high molecular weight and a product of low
molecular weight. Since the enzyme used here is soluble, no improvement in the stability
of the enzyme can be expected. A hollow fiber device can also be used and its
characteristics are essentially the same as those of an ultrafiltration membrane.