Aut CG4017 Part+b

CG4017
Bioprocess Engineering 2
Course Notes, Autumn 2014, Part 2 of 2
Dr Denise Croker, BM-028
Denise.Croker@ul.ie
Office Hours, Wednesday 11- 1.
6. HEAT TRANSFER
6. Heat Transfer
6.1 Heat transfer equipment
Two major applications of heat transfer (ht) equipment in bioprocessing, are for
bioreactor temperature control (usually removal of heat by cooling water), and for
the thermal sterilisation (by addition of heat using steam) of substrate media prior
to fermentation.
The rate (and hence efficiency) at which heat is transferred is primarily determined by
two key parameters:
1.
2.
The temperature difference between the hot and cold bodies

The surface area available for heat exchange
These in turn are influenced by a number of variables, including:
HT system physical size

HT system geometry
HT system materials used
Fluid flow conditions within the HT system
As seen in section 5, energy balance calculations allow us to evaluate the energy

requirement (HT rate) for a particular process/unit. Once this is known, estimating the
heat transfer surface area is the central objective in HT equipment design.
The HT requirements of bioreactors can be quite different depending on their scale of

operation: large fermenters usually require heat removal, whereas small systems lose
heat more easily (higher surface:volume ratio) and may require heating to maintain
operating temperature.
Heat transfer
configurations for
bioreactors: (a) jacketed
vessel; (b) external coil;
(c) internal coil; (d)
baffle-type coil; (e)
external heat exchanger
(a) & (b): Dont interfere with mixing in vessel, easy to maintain sterility, but low HT area
only really suitable for small/lab-scale vessels.
(c) & (d): High HT area hence good for large reactors, but may have mixing, sterility,
and/or cleaning issues.
(e):
Excellent HT area, may have problems with sterility or pumping mechanical
shear degradation of cells. Heat exchanger residence time must be small in
aerobic fermentations to ensure minimal depletion of liquid phase oxygen.
From Bioprocess Engineering Principles by Pauline M. Doran
The variation of cooling water temperature with distance through the coil in internal coiltype HT equipment (c) and (d) can be seen below:
The coolant temperature rises as it passes through the coil and takes up heat, whereas
the fermenter temperature remains fairly constant since the contents are well mixed.
The simplest form of HT

equipment for small-scale
external (to the reactor)
operation is the doublepipe heat exchanger:
Used for HT area <15m2

applications.
Countercurrent
Cocurrent
Shell and tube heat exchangers are used for HT area applications >15m2:
Single pass shell and tube heat exchanger
Large HT surface area in a small volume.

Shell-side baffles used to decrease flow cross-sectional area (increase linear velocity)
and to promote transverse rather than parallel flow over the pipes.
For increased HT area, without excessively long pipes, multiple pass shell & tube
heat exchangers are used.
Double pass shell and

tube heat exchanger
Temperature profiles for

different shell side entry
positions
Arrangement (a) is best since it

avoids temperature cross-over of
the heating and cooling fluids, as
seen in (b)
6.2 Heat transfer between fluids

The situation at the heat transfer surface of a heat exchanger pipe wall can be shown:
The stagnant liquid films on both sides of the
solid surface result in the formation of
thermal boundary layers, similar to the
situation for mass transfer at a solid surface.
In general thermal boundary layers are thinner

than the corresponding hydrodynamic
boundary layers for mass transfer.
Heat transfer rate, Qb, across a thermal
boundary layer is given by:
Qb h A T
(93)
Heat transfer across a solid

heat transfer surface
Where h is the boundary layer heat transfer

coefficient, A is the HT area normal to the
direction of heat flow, and T is the temperature difference between the wall and the
bulk fluid. Here Th = Th-Thw at the hot surface, and Tc = Tcw-Tc at the cold surface.
h values must normally be determined from correlations based on experimental data.
Thermal boundary layer heat transfer coefficients for

industrial heat exchange fluids
The rate of heat transfer by conduction through the pipe wall, Qw, can be obtained from
Fouriers law:
dT
Qw kA
(94)
dy
where k = wall thermal conductivity and y = distance from the hot side.
In this case, integrating eq. (94), with limits of: T=Thw at y=0, and T= Tcw at y=B gives:
Qw
kA
Thw Tcw kA Tw
B
B
Eq. (95) can be rewritten as:
Qw
(95)
Tw
Rw
where Rw is the wall thermal resistance:
(96)
Rw
B
kA
(97)
In a similar way, we can define the thermal boundary layer resistances:

Rh
1
hh A
(98) and
Rc
1
hc A
(99)
When a system, such as our heat exchanger pipe, contains a number of different heat
transfer resistances in series (thermal boundary layers + pipe wall), the overall
resistance is equal to the sum of the individual resistances.
Thus for the overall heat transfer rate, Q, we have:

Q
In eq. (100):
T
T
RT Rh Rw Rc
(100)
T Th Tc
and from eqs. (97)-(99):
RT
1
B
1
hh A kA hc A
or
where U = overall heat transfer coefficient. Thus:
RT
1 1 B 1 1

A hh k hc UA
Q UAT
(101)
(102)
Eq. (102) allows quantification of Q knowing U, A and with easily measureable hot and
cold bulk fluid temperatures.
From eq. (101) we can see that the major factors that govern the value of U are the
fluid hydrodynamics at the thermal boundary layers and the thermal conductivity and
thickness of the pipe wall.
6.3 Heat exchanger fouling factors

HT surfaces in process heat exchangers are almost always subject to dirt and scale
deposition during normal operation. The latter contribute additional resistance to heat
flow and reduce the value of U. Thus:
1
1
1 B 1
1

U h fh hh k hc h fc
(103)
where hfh and hfc are the respective

hot- and cold-side fouling factors.
Increasing 1/U obviously decreases U,
and hence HT efficiency decreases with
fouling
It is very difficult to accurately estimate
fouling factors, due to the disparate
nature of such deposits and their
physical properties, as well as their timeand temperature-dependant nature.
Heat transfer across a solid heat transfer

surface with fouling of both surfaces
Fouling factors for typical scale deposits from

industrial heat exchange fluids
6.4 Heat transfer equipment design equations

Q UAT
(102)
Calculation of the heat transfer area, A, required for a particular heat exchanger, from
eq. (102), requires that Q, T, and U are known. The former two may be obtained from
energy balance calculations, whilst U is estimated from empirical correlations based on
experimental data.
6.4.1 HT system design: energy balance calculations
For double pipe or shell and tube heat exchangers, the general energy balance
equation (83), under steady-state conditions and in the absence of shaft work,
becomes:
M i Et i M o Et o Q 0
(104)
where M = mass flow rate, Et = specific enthalpy, i = in, o = out.

Applying eq. (104) separately to the hot and cold HT fluids, noting M is the same at
inlets and outlets:
M h Et hi Et ho Qh and M c Et ci Et co Qc
(105)
where h denotes the hot fluid, and c the cold fluid.
When there is no heat lost by the heat exchanger, all heat removed from the hot stream
is transferred to the cold stream, thus Qh = Qc = Q , and:
M h Et hi Et ho M c Et co Et ci Q
(106)
If sensible heat only is exchanged between the fluids, then the enthalpy differences can
be given in terms of heat capacity, Cp, and temperature change:
M hCph Thi Tho M cCpc Tco Tci Q
(107)
Eq. (107) is used in heat exchanger design to determine Q and inlet and outlet
temperatures of the fluid streams. It can also be used to evaluate the heat removal
requirement from a bioreactor, to maintain a desired reactor temperature. In this case,
at steady state the temperature of the hot fluid (i.e. the fermenter broth) is constant, so
the left hand side of eq. (107) is zero, and:
M cCpc Tco Tci Q
(108)
Q in eq. (108) can be determined from the energy balance equation for cell bioreactors:
Q = -Hr
Mv.hv - Q + Ws
(92)
Use of the heat exchanger design eq. (102) requires knowledge of T, the difference in
temperature between the hot and cold heat exchange fluids. As we have seen however
in section 6.1, fluid temperatures, and thus the rate of heat exchange, vary with position
in heat exchangers, even under steady state operation. This problem may be resolved
by including temperature as a positional variable, and subsequently solving the coupled
differential design equations that result, or more often by the use of an average T.
When the temperature of both hot and cold fluids vary in either co- or countercurrent flow, the average taken is the logarithmic mean temperature difference (LMTD),
TL. In eq. (109) T1 and T2 are the
temperature differences between the hot and
T2 T1
L
the cold fluids at the ends of the exchanger.
(109)
ln( T2 / T1 )
These are calculated using the values of Thi,
Tho, Tci, and Tco from the energy balance eq. (108).
Assumptions made in eq. (109): U and Cps are constant; negligible heat loss; steady
state operation. Corrections must be applied to eq. (109) for multi-pass exchangers.
When one fluid remains at constant temperature, e.g. in fermenters, the arithmetic
mean temperature difference, TA is used. In
eq. (110), TF is the fermenter temperature, and
2TF (T1 T2 ) (110)
T1 and T2 are the inlet and exit temperatures of
TA
2
the heat exchange fluid.
6.4.2 Evaluation of U, the overall heat transfer coefficient

Eq. (103) shows the constituent components of U, the overall heat transfer coefficient:
1
1
1 B 1
1

U h fh hh k hc h fc
(103)
The wall resistance term can be calculated knowing the thickness (B) and thermal
conductivity (k) of the wall material. Fouling factors (hfh and hfc) (if applicable) can be
estimated from typical literature data, as already seen.
Determination of the thermal boundary layer HT coefficients (hh and hc) is more
problematic however, since they are dependent on flow hydrodynamics and fluid
properties adjacent to the wall surfaces. These are normally evaluated using
experimentally determined empirical correlations, expressed in terms of dimensionless
numbers. This is similar to the situation for liquid-solid (external) mass transfer
coefficients (see section 4.3.1).
The Nusselt number, Nu, is the primary means by which hh or hc is calculated:
This dimensionless number represents the ratio of
hD
convective to conductive heat transfer rates.
Nu
k fb
where D = pipe or tank diameter and kfb =bulk fluid thermal conductivity.
(111)
Many empirical correlations exist that allow the determination of the Nu for different
heat exchange situations. These involve other, experimentally-measureable
dimensionless numbers or physical parameters, including:
Pipe Reynolds number, Re
Du
Impeller Reynolds number, Rei

Prandl number, Pr
(112)
b
N i Di2
C p b
k fb
(113)
(114)
(Pr represents the ratio of momentum to heat transfer)

D = pipe or tank diameter Di = impeller diameter u = fluid linear velocity
Ni = impeller rotational speed L = pipe length Cp = average heat capacity of fluid
b = bulk fluid viscosity
w = wall fluid viscosity = fluid average density
Some examples of these correlations are given below.

Turbulent flow inside tubes without phase change:
Nu 0.023Re 0.8 Pr 0.4
(low viscosity fluids)
(115)
when 104 Re 1.2 x 105 and 0.7 Pr 120 and L/D 60.

Nu 0.027 Re 0.8 Pr 0.33 b
w
0.14
(high viscosity fluids)
(116)
Turbulent flow outside tubes without phase change:

0.6
Nu C Remax
Pr 0.33
when Remax 6 x 103
(117)
Remax = Re with D = outside pipe diameter and u = maximum linear flow velocity
through the pipe bundle. C = 0.33 for staggered and C = 0.26 for in-line tubes.
Stirred tanks:
0.62
0.33 b
Nu 0.87 Rei Pr
w
Helical coil hx
0.14
(118)
0.62
0.33 b
Nu 0.36 Rei Pr
w
Jacket hx
0.14
(119)
7. DOWNSTREAM
SEPARATION PROCESS - 2
What is downstream processing?

Unit operations that take place after
the product has been synthesised with
the objective of:
-
Recovering the product

Improving quality and
concentration of the product
(formulating the product into final
form) not covered here
Post Reaction/Fermentation
Steps
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Downstream Separation Processes 1 (CG4003)

Application
Unit operation
Isolation of solids and cellular agglomerates
Regular filtration
Cell isolation
Centrifugation
Separation of intracellular products
Cell disruption
Isolation of cells and macromolecular species
Microfiltration/ultrafiltration
Isolation of macromolecular species and

soluble products
Dialysis/reverse osmosis
Isolation of soluble products
Liquid-liquid extraction
Adsorption
Chromatography
Final purification
Crystallisation
Final purification
Drying
7.5 Liquid-Liquid Extraction

This separation method relies on the different solubility's of mixture components
between two immiscible liquid phases, as a means of isolating the different soluble
components present in the mixture.
7.5.1 Aqueous-Organic Solvent Extraction

This is the conventional type of extraction system used in an organic chemistry lab, for
example when using diethyl ether to extract an organic product from an aqueous
reaction mixture. The basic process involves three parts, done on the lab scale in a
separating funnel:
1.Vigorous mixing of the aqueous and the organic phases to allow transfer of the
product between the phases
2.Settling of the mixture to allow phase separation to occur
3.Removal of heavier, spent aqueous phase (raffinate) from the bottom of the
separating funnel, to leave the lighter, organic, product-containing phase (extract).
Industrially, extractions are usually carried out in some sort of mixer-settler equipment.
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http://www.halwachs.de/solvent-extraction.htm
http://www.cheresources.com/liquid_extractor_design5.gif
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Aqueous-organic solvent extractions are used to isolate many pharmaceutical and

biopharmaceutical products:
Product
Extractive solvent
Antibiotics
Penicillin
Erythromycin
Butyl acetate, amyl acetate, or methyl isobutyl ketone

Pentyl acetate or amyl acetate
Steroids
N-hexane, pentane, or heptane
Vitamins
Vitamin B12
Isopropanol
Alkaloids
Morphine
Codeine
Butanol or benzene
Trichloroethylene
Organic solvents are not suitable however for the isolation of proteins and other
sensitive biopolymers, since denaturation can occur.
36
Aqueous Two-Phase Extraction

Aqueous solutions that form two distinct phases can provide favourable conditions for
separation of proteins, polysaccharides, nucleic acids, cell fragments, and organelles,
with protection of their structure and biological activity.
These two-phase aqueous systems comprise two incompatible polymers or a polymer
and a salt dissolved in water above certain concentrations. These liquid mixtures
partition into two immiscible phases, each containing more than 75% water.
37
Ficoll = hydrophilic polysaccharide

Dextran = branched glucose polysaccharide
38
Aqueous Two-Phase Extraction

Aqueous solutions that form two distinct phases can provide favourable conditions for
separation of proteins, polysaccharides, nucleic acids, cell fragments, and organelles,
with protection of their structure and biological activity.
These two-phase aqueous systems comprise two incompatible polymers or a polymer
and a salt dissolved in water above certain concentrations. These liquid mixtures
partition into two immiscible phases, each containing more than 75% water.
Cell fragments and biomolecules, when added to these systems, partition between the
two phases. By choosing appropriate conditions, it is possible, for example, to confine
cell fragments to one phase, while a product protein partitions to the other phase.
This is particularly useful as a product isolation step from cell debris produced by cell
disruption.
39
Quantification of Liquid-Liquid Extraction

The extent of partitioning of a solute component, i, between the two phases is
determined by the phase equilibrium or partition coefficient for the system, K:
[i ]L
[i ]H
(17)
where L and H refer to the light and heavy phases respectively.
If K>1, then component i favours the light phase, and vice versa.
In many systems K is constant over a wide range of solute concentrations, provided
that the molecular nature of the solvent phases are not changed. There are many
factors that determine the value of K for a particular system, including:
Size, electric charge, and hydrophobicity of the solute molecules/particles
Biospecific affinity of the solute for one of the solvent phases
Surface free energy and ionic composition of the solvent phases
For these reasons it is not possible to predict K from molecular properties. In some
cases it is possible to produce an empirical correlation (from lab-scale experiments)
that allows quantification of K for a particular system.
40
For example for extraction of soluble proteins with some polyethylene glycol (PEG)
containing aqueous two phase systems, the following empirical correlation can be
used:
K e
A. M
T
(18)
where M = protein molecular weight, T = absolute temperature, and A is an empirically

determined constant for the aqueous two phase solvent system used.
For a single stage extraction, K should be 3, otherwise multiple stage extraction must
be performed.
The product recovery or % yield, Y, of a solute component can be defined as:
YL
and:
VL
V
VL H
K
(19) for the light phase
YH
VH
VL K VH
(20) for the heavy phase
where V refers to the respective phase liquid volumes.
Thus it is possible to increase the product recovery by using a large volume of 41

the
preferred (extracting) phase.
Partition coefficient
increases with
potassium phosphate conc. ,
resulting in
more efficient separation of
enzyme A
42
From Bioprocess Engineering by M. L. Shuler & F. Kargi
The concentration or purification factor, c, is also used to characterise two phase

partitioning. This is defined as the ratio of product concentration in the preferred phase
to that in the extractor feed liquid, [i]o:
[i ]L
c
[i ]o
[i ]H
[i ]o
(21) (when the product partitions to the light phase)
(22) (when the product partitions to the heavy phase)
In the PEG-salt two phase aqueous system, proteins can be effectively separated from
cell debris, with the proteins partitioning into the light phase and the debris into the
heavy phase. It is only usually necessary to use a single mixer-settler stage since the
partition coefficient, K, is high for this system.
In many cases however phase separation equilibrium is not achieved in a single stage
and multistage operation is required.
43
Industrial Applications of Liquid-Liquid Extraction

The time required for mass transfer to occur and the ease of mechanical separation of
the two phases are important considerations when performing liquid-liquid extraction
on an industrial scale. Each of these ultimately determine the respective sizes of the
mixer and the settler.
Interphase mass transfer depends on the interfacial surface area available for
exchange between the phases, which in turn is maximised by efficient mixing.
Phase separation in the settler is dependent on having a high interfacial surface
tension between the phases, and is best achieved under calm conditions with no
mixing.
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http://www.halwachs.de/mixersettler.gif
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http://www.rousselet-robatel.com/images/products/Mixer-Settler-pic-3lg.jpg
Rousselet Robatel 8 stage mixer-settler

http://www.rousselet-robatel.com/products/laboratory-mixer-settlers.php
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Tower extractors: general design
http://images.vertmarkets.com/crlive/files/Images/92F9B851C50C-11D3-9A82-00A0C9C83AFB/pod2.jpg
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Types of tower extractors with mechanical agitation
(a)
(b)
(c)
(d)
(a) Oldshue-Rushton extractor; (b) Scheibel-York extractor ; (c) Rotating-disk extractor ; (d) Pulsed extractor
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http://accessscience.proxy.mpcc.edu/content.aspx?id=636100
Industrial Applications of Liquid-Liquid Extraction

The time required for mass transfer to occur and the ease of mechanical separation of
the two phases are important considerations when performing liquid-liquid extraction
on an industrial scale. Each of these ultimately determine the respective sizes of the
mixer and the settler.
Interphase mass transfer depends on the interfacial surface area available for
exchange between the phases, which in turn is maximised by efficient mixing.
Phase separation in the settler is dependent on having a high interfacial surface
tension between the phases, and is best achieved under calm conditions with no
mixing.
Fast mixing and settling can be combined in centrifugal liquid-liquid separators such as
the Pod (Podbielniak). This equipment is very important in fermentation product
separations, such as in penicillin production. Speed of extraction is important in such
cases as the product is unstable in the pH-adjusted broth. A Pod separator can
achieve extraction and separation within minutes, with rapid return of the product into
another more stable aqueous phase (e.g. a phosphate buffer).
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Podbielniak (Pod) centrifugal L-L extractor
http://images.vertmarkets.com/crlive/files/Images/92F9B851-C50C-11D3-9A8200A0C9C83AFB/pod2.jpg
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7.2 Adsorption
This involves the concentration of component(s) of a fluid phase (in bioprocessing,
usually a liquid) on the surface or in the pores of a solid adsorbent material. The
adsorbed fluid component is called the adsorbate.
Adsorption serves to isolate products from dilute fermentation liquors or to remove

trace liquid phase impurities during product purification.
The adsorbate-adsorbent interaction is caused by attractive sorption forces between
the liquid component and the solid surface/pore. These can include:
Electrostatic forces
Van de Waals (weak physical)
Chemical bonding
Three main types of adsorption can be distinguished:

1.Ion exchange (involves electrostatic forces)
2.Physisorption (involves surface weak physical interactions)
3.Chemisorption (involves surface chemical bond formation)
All three are found in bioprocessing applications of adsorption.
52
Packed bed adsorber

Liquid mixture
containing
adsorbate, A
Step 2
A-free liquid
Adsorption
site
Catalyst pore
Adsorbent pellet
cross-section
Internal mass transfer

(pore diffusion)
Step 1
Adsorbent surface
stagnant liquid film
(external boundary layer)
A (liq)
Step 3
External mass transfer
A (ads)
Adsorption site surface
Adsorption (and desorption)
Mass transfer and adsorption steps during adsorption of a liquid phase adsorbate, A
53
Sequence of steps during adsorption/desorption of a fluid phase component

1.
Mass transfer (external diffusion) of adsorbate from the bulk fluid to the
external surface of the adsorbent pellet
2.
Mass transfer (internal diffusion) of adsorbate from the external pellet

surface through the pores to the adsorption site
3.
Adsorption of adsorbate onto the adsorption site
4.
Desorption of concentrated adsorbate from the adsorption site
5.
Internal diffusion of concentrated adsorbate through the pores to the external

surface of the adsorbent pellet
6.
External diffusion of concentrated adsorbate from the pellet surface into the bulk
fluid
54
Adsorbents
High surface area porous materials. Typical surface areas: 1 to 1000 m2/g.
Typical pore diameters: 1 to 50 nm. Pore size chosen to accommodate

adsorbate component molecular/ionic size.
Activated carbons, synthetic polymeric resins based on styrene, divinylbenzene

or acrylamide:
\\\\\\
Styrene
DVB
Acrylamide
55
Applications in bioprocessing
Ion exchange adsorption is widely used for the recovery from fermentation
broths of: amino acids, proteins, antibiotics, and vitamins.
Removal of coloured impurities e.g. during citric acid production.
Removal of organic chemicals during water purification and wastewater

treatment.
Adsorption generally has higher removal selectivity but smaller removal capacity
than liquid-liquid extraction methods.
56
Industrial Adsorption
Operation steps
1.
Contacting/adsorbing: removal of target solute from the liquid phase.
2.
Washing: to remove any residual unadsorbed material from the adsorbent.
3.
Desorption/elution of the concentrated adsorbate with a suitable solvent, e.g. of

different ionic strength or pH.
4.
Washing to remove residual eluant.
5.
Regeneration of the adsorbent to its original, active condition (inevitably this is

never 100% effective, and as a result most adsorbents must be replaced after a
limited number of adsorption/desorption cycles).
Equipment types
Adsorption operations are normally carried out in fixed, packed adsorbent beds.
Other equipment types sometimes found include moving beds, fluidised beds and
stirred-tank contactors.
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Moving bed adsorber
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http://www.cee-environmental.com/public/data/companyProduct1231011370.jpg
Quantification of Adsorption
Adsorption/desorption is an equilibrium process and the extent of adsorption of a
component on a solid surface is determined by the adsorption equilibrium
relationship. Since a number of different driving forces and types of adsorption may
be involved in a given adsorbate-adsorbent system, no single quantification model is
universally applicable.
Adsorption equilibrium relationships are usually expressed as adsorption isotherms

(adsorbed amount versus amount present in the fluid phase under equilibrium
conditions at constant temperature).
A typical scenario found is that amount adsorbed increases with increasing amount
present in the fluid phase, up to a maximum. At this loading no further adsorption can
occur and the adsorbent surface is essentially saturated with adsorbate.
The Langmuir adsorption isotherm has been used to quantify gas-solid adsorption:
*
AS
C ASm K AC A*
1 K AC A*
(23)
where: C*AS is the amount adsorbed per unit adsorbent, CASm is the maximum
amount adsorbed giving compete coverage of all adsorption sites with monolayer
coverage, C*A is the equilibrium concentration of adsorbate in the fluid phase, and
59 KA
is a constant.
Langmuir isotherm:
*
AS
C ASm K AC A*
1 K AC A*
Freundlich isotherm:
*
AS
KFC
*1
n
A
60
For liquid-solid systems, the Freundlich isotherm has been found to be more
applicable:
*1
*
C AS K F C A n
(24)
where KF and n are constants for a particular system. If adsorption is favourable n >1
and vice versa.
This adsorption isotherm applies well for the adsorption of many antibiotics,
hormones, and steroids.
There are many other adsorption isotherms, each applicable only to certain systems.
Since the exact adsorption mechanisms vary from system to system, adsorption data
cannot generally be predicted from theory, but must be determined by laboratory
experiment.
61
Fixed Bed Adsorber Characteristics

A fixed bed adsorber is in its simplest form, a vertical column packed with the
adsorbent particles.
These are normally operated industrially as unsteady-state processes, where:
1.
2.
3.
4.
The mixture containing the solute is continuously passed through the bed and
amount adsorbed increases with time.
Eventually the bed becomes fully loaded/saturated.
Desorption of concentrated solute is carried out.
Regeneration of the adsorbent is performed, prior to restarting the cycle.
When step 2 occurs, the unadsorbed solute breaks through the adsorbed bed, as
observed by an increase in the effluent solute concentration.
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63
Fixed Bed Adsorber Characteristics

A fixed bed adsorber is in its simplest form, a vertical column packed with the
adsorbent particles.
These are normally operated industrially as unsteady-state processes, where:
1.
2.
3.
4.
The mixture containing the solute is continuously passed through the bed and
amount adsorbed increases with time.
Eventually the bed becomes fully loaded/saturated.
Desorption of concentrated solute is carried out.
Regeneration of the adsorbent is performed, prior to restarting the cycle.
When step 2 occurs, the unadsorbed solute breaks through the adsorbed bed, as
observed by an increase in the effluent solute concentration.
Efficient operation of a fixed bed adsorber is greatly dependent on the shape of the
breakthrough curve and on the exact effluent solute concentration at which
adsorption operation is stopped:
Waiting until high effluent solute concentrations are reached means losing a
large amount of solute unadsorbed.
Stopping adsorption at too low effluent solute concentration means having a

large amount of the adsorbent bed unused.
64
65
From Bioprocess Engineering
Principles by Pauline M. Doran
7.3 Process Chromatography

This involves the separation of the components of a mixture by differential component
migration as the mixture (mobile phase) moves through a chromatography column
packed with a solid (stationary phase).
Component-stationary phase interactions can be of an adsorptive (surface adhesion)

or a partitionary (dissolution in an adsorbed solvent located on the stationary phase)
nature.
This product separation/purification method is widely used industrially in
bioprocessing:
Isolation of recombinant products from genetically engineered organisms
Recovery of high-purity theraputics and biopharmaceuticals
Purification of proteins, peptides, amino acids, nucleic acids, alkaloids,
vitamins, and steroids.
Like adsorption, this technique has high selectivity but relatively low capacity for
product isolation, compared to e.g. liquid-liquid extraction. Hence it is normally used for
low production volume/high value added biochemical products.
The theory and quantification of chromatography will be covered in analytical
chemistry modules and will not be covered here.
66
67
From Bioprocess Engineering
Principles by Pauline M. Doran
The following types of chromatographic separation methods are important industrially:
1.Adsorption chromatography (ADC): based on solute adsorption onto a porous solid

adsorbent (as in section 7.6).
2.Liquid-liquid partition chromatography (LLC): based on different partition coefficients
(solubility) of the solute molecules between a stationary adsorbed liquid phase and a
passing solution. The adsorbed liquid is often non-polar, e.g. wax-type materials.
3.Gel filtration chromatography (GFC): Based on the molecular sieving effect when
solute molecules penetrate into the small pores of column packing materials to
different extents. Separation occurs on the basis of solute molecular size and shape.
A.k.a size exclusion chromatography.
4.Ion exchange chromatography (IEC): Based on adsorption of ions or electrically
charged biomolecules on an ion exchange resin by electrostatic forces.
5.Hydrophobic chromatography (HC): Based on hydrophobic interactions between
solute molecules (e.g. proteins) and functional groups (e.g. alkyl residues) on the
column packing material surface.
6.Affinity chromatography (AFC): Based on specific chemical interactions between
solute molecules and packing material surface ligands. Ligand-solute interaction is
very specific and governed by solute molecule size, shape and polarity. Lock and key
type interaction akin to an enzyme-substrate binding.
7.High pressure liquid chromatography (HPLC): Can be any of the above, except high
liquid pressure through column gives fast separation with high resolution. Very
important in the pharma/biopharma industry, so get experience with it!! 68
Process Scale Chromatography Columns
7.4 Precipitation and Crystallisation

Precipitation is usually the first step in the purification of intracellular proteins after cell
disruption and refers to the transition of one component of a solution mixture from the
liquid phase to the solid phase. The resulting solid may be in a disordered form
(amorphous precipitate), or the molecules/ions may be in an ordered three
dimensional lattice (crystallised form).
Precipitation
In bioprocessing, there are three major methods used for precipitation.
1. Salting out by adding inorganic salts such as sodium sulphate at high ionic
strength. The added ions interact with the water more strongly, causing the
protein molecules to precipitate. The relationship between protein solubility, S,
and solution ionic strength, I, can be given by:
log
S
K S .I
So
(25)
where So is the protein solubility when I = 0, and KS is the salting out

coefficient, which is a function of temperature and pH, and
I 0.5[i].Zi2
71
where Z = ionic charge
72
From Bioprocess Engineering by M. L. Shuler & F. Kargi
2. Solubility reduction at reduced temperatures (<-5oC) by adding organic

solvents. Here precipitation is caused by a reduction in the dielectric constant
of the solution. This results in stronger electrostatic forces between the protein
molecules, reduces protein-water interactions and thus decreases protein
solubility and facilitates precipitation. Protein solubility as a function of
dielectric constant is given by:
log
S
K
2
So
Ds
(26)
where DS is the dielectric constant of the water-organic solvent solution.

In some cases, the use of organic solvents can cause protein denaturation.
3. Isoelectric precipitation. In this method, proteins are precipitated at their
isoelectric point. This is accomplished by adjusting the pH so that the protein
has no net charge (i.e. both the amino and carboxylate groups are uncharged).
Under such conditions protein molecules have little capability to interact with
the surrounding water molecules, and hence tend to precipitate out of solution.
This method is particularly useful for proteins that have high surface
hydrophobicity. It is relatively inexpensive, but the use of low pHs may cause
denaturation in some cases.
73
Lysine isoelectric point
74
http://upload.wikimedia.org/wikipedia/commons/7/7e/Lysine_pI.png
75
7.8.2.1 Nucleation & Growth
Nucleation first formation of a solid - nucleus

Growth subsequent size enlargement of that nucleus to the final crystal
product
Nucleation governs the final product size:

High nucleation rate lots of nuclei existing solute has a large surface
area to deposit upon resulting crystals will be small
Low nucleation rate few nuclei existing solute has less area to
deposit on resulting crystals will be larger
Driving force for nucleation/growth Supersaturation
76
The Solubility Curve
Supersaturation
Saturated Solution
Supersaturated
The amount of solute dissolved
in the solution is greater than
the solubility
Undersaturated
Generating Supersaturation
Supersaturation
The Metastable Zone

Nucleation
The Metastable Zone

Spontaneous
Nucleation
Possible
& Growth
can occur
No Nucleation
But
Growth is Possible
No Nucleation
No Growth
82
83
84
Crystal face
Bulk solution
cb
cb - ci
Concentration
ci
ci - cs
cs
85
7.8.2.2
86
Combining to eliminate ci:
(27)
(28)
87
(29)
88
Solubility
MX.yH2O (hydrated salt)
MX (anhydrous salt)
NaCl
KNO3
Temperature
89
7.8.2.3 Variation of solubility with temperature
Increasing temperature normally increases the solubility of a solute

(positive temperature coefficient) since dissolution is normally
endothermic.
However in some cases increasing temperature may have little effect on

solubility, or may even decrease the solubility (i.e. dissolution may be
exothermic).
Solutes with large temperature coefficients are easily crystallised by
cooling, whereas those with small coefficients must be crystallised by
evaporation.
Careful temperature control must be used with negative temperature
coefficient solutes. Thus for example the hydrated salt shown above
can only be crystallised out at low temperatures (by vacuum
crystallisation).
90
7.8.2.4 Industrial crystallisation equipment

Crystallisers can be classified in various ways: batch/continuous,
cooling/evaporative, linear/stirred. The most important feature is the method by
which crystal size is controlled, i.e. control of nucleation rate. Crystallisers are
generally simple in design, the only moving parts being agitators and/or scrapers.
Batch crystallisation
These most often take the form of an open tank with agitation, heating/cooling and
evaporation at the free surface. Agitation helps ensure uniform crystal size
distribution. The major difficulty with this type of unit is fouling of the heat exchange
surfaces by product crystals.
Vacuum crystallisers are commonly used for evaporative cooling where it is

necessary to achieve supersaturation by evaporation. These usually take the form of
tall vertical cylinders. Flash evaporation is used to cool the liquor and to increase the
solute concentration.
91
Continuous crystallisation equipment

Continuous crystallisation equipment
End view
Votator crystalliser
92
From: Chemical Engineering, vol. 2 Coulson & Richardson, p673-681
Votator crystalliser
93
http://www.labx.com/v2/adsearch/morepics.cfm?chpics=1&chback=
1&adzone=431000&pic=431030&cn=0&adnumber=431030
Supersaturation
Nucleation &
growth
Oslo cooler crystalliser
94
Vacuum
Supersaturation
Nucleation &
growth
Oslo evaporative crystalliser
95
8. BIOREACTOR DESIGN &

SCALE-UP
8. Bioreactor Design, Scale-up & Operation

This section will comprise a review of key quantitative reactor design methods,
together with an overview of bioreactor control methodologies.
Many different types, most commonly used is the stirred tank bioreactor:
Major design challenges lie in achieving

adequate mixing/aeration
Typically 70-80% filled with liquid, rest is

headspace
Foam breaker or chemical antifoam agents

often used
Various aspect ratios (height:diameter) used:

low (1:1) for anaerobic, higher for aerobic
fermentations
Not used in plant and animal cell culture due to

high level of shear damage to sensitive cells
Most suitable type for viscous media

8.1 Bioreactor design

Fed batch (no external mass transfer limitations)
For single cell fermentation reactions, time dependence of
Reaction mixture volume, V:
Cell concentration:
Substrate concentration:
Product concentration:
dV
F
dt
(120)
dx
(121)
x( D)
dt

ds
qP
D si s
mS x
dt
YXS YPS
dp
q p x pD
dt
Fed batch
bioreactor
(122)
(123)
where F = volumetric feed rate, D = dilution rate(=F/V), other parameters as in section 2.
FB bioreactor, quasi-steady state* operation:
Total cell mass in reactor, Mx:
M x M x,o (YXS si F )t fb
(124)
where Mx,o = cell mass at start of substrate feeding and tfb = time from start of feeding
Reactor substrate concentration:
s0
(125)
p YPSsi
(126)
* Quasi-steady state operation involves operating the reactor in batch mode until a
high cell density is achieved and where substrate is virtually exhausted, and then
commencing substrate feeding. Under such conditions the large cell mass present
ensures that the substrate is consumed as fast as it is supplied in the feed, hence
giving s 0.
7.1.2 Chemostat / MFR / CSTR (anaerobic reactions, low viscosity media)

Here the reactor liquid volume is maintained constant by setting inlet and outlet flows
equal and constant. Steady state is achieved by the reactor concentrations adjusting
themselves to the feed rate. At steady state = D.
For enzymatic reactions,
Dsi s
max s
Km s
(127)
Effectiveness factor, = 1 for cell free enzymes in solution. Since [substrate] is

constant at steady state in continuous flow reactors, then is also normally constant
and can be calculated.
For single/suspended cell culture,

DK S
max D
x
Cell concentration:
(128)
p pi
qp x
D
Dsi s
qp
D
ms
YXS YPS
(129)
(130)
Cell washout: D > MAX
Steady state cell and substrate concentrations

as a function of dilution rate in a chemostat
From eq. (129), assuming no product formation or maintenance requirement:
x si s YXS
(131)
The critical dilution rate condition, Dcrit, for cell washout can now be obtained by
substituting from eq. (128) for s, letting x = 0, and solving for D:
Dcrit
Usually Ks << si , so Dcrit max.
max si
K S si
(132)
Biomass productivity, Qx, of a chemostat is the rate at which cells leave the reactor:
Qx
Fx
Dx
V
(133)
Substituting for x from eq. (129), again assuming no product formation or maintenance
requirement, gives:
DK S
YXS
Qx D si
max D
The relationship between D and QX can be shown graphically:
(134)
Cell washout: Dcrit
Dopt
Chemostat biomass productivity
The value of D for maximum Qx, Dopt, can be obtained by differentiating eq. (134) with
respect to D and equating to zero:
KS
Dopt max 1
(135)
K S si
Chemostat with immobilised cells.

Assuming:
No product formation
No maintenance requirement
Cells produced by immobilised cell reproduction are

released into the medium and ultimately removed in the
product flow. Immobilised cell particles stay in reactor.
Chemostat with
immobilised cell
particles
Steady state biomass balance:

Fxs xsV T ximV 0 (136)
where xS = released/suspended [cell], xim = immobilised [cell], and T = total

effectiveness factor from eq. (79).
Dividing by V and expressing F/V as dilution rate: D

1
T xim
xS
Steady state limiting substrate balance:
Fsi Fs
or
xs
YXS
Dsi s
YXS
T xim
YXS
V 0
xS T xim
(138)
(139)
(137)
Combining eqs. (137) and (139) and substituting the Monod equation (3) for gives:
max s
KS s
Dsi s YXS
si s YXS T xim
(140)
Eq. (140) graphically:
Immobilised cell
chemostat
Plug flow (packed bed) bioreactors

The major industrial application of this bioreactor type
is for immobilised enzyme reactions.
Differential steady-state substrate balance across a reactor section:
ds T max s A
(141)
dz
Km s F
A = reactor cross-sectional area

z = distance along reactor length from the entrance
Minimal attrition damage to biocatalyst particles c.f. stirred reactors.
Good liquid-solid mass transfer due to high flow rate in bed.

Liquid recycle also improves this.
Used commercially for immobilised cells and enzymes for

production of aspartate and fumarate, and for resolution of
amino acid isomers.
Plug flow
bioreactor with
immobilised
enzyme packing
For aerobic reactions, aeration is done in a separate vessel to avoid liquid

maldistribution in bed due to trapped air bubbles:
Plug flow bioreactor with external medium aeration
Unsuitable for processes that evolve large amounts of gas, e.g. CO2, since gas
bubbles can become trapped in bed.
Bubble column reactors
Do not require mechanical agitation for mixing and aeration:
Gas sparging causes aeration & mixing
Require less energy than mechanical

mixing
Aspect ratios from 2:1 to 6:1 common
Perforated horizontal plates sometimes

installed to break up/redistribute
coalesced bubbles
Few moving parts: low capital costs

Foaming can be a problem
Used industrially for production of:
bakers yeast, beer, & vinegar, and in
wastewater treatment.
Bubble column reactor

Flow regimes in bubble column reactors:
1.Homogeneous flow low gas flow rates, uniform

bubble size and velocity, poor gas and liquid mixing.
2.Heterogeneous flow high gas flow rates, large, chaotic
oscillatory liquid flow cells occur. Upward movement of
liquid & gas in centre of reactor, downflow of liquid at
walls. Good mixing of liquid & gas.
For non-viscous reaction media in heterogeneous flow, kLa
can be correlated with gas flow rate:
(142)
where uG = gas linear flow rate

Not suitable for high viscosity reaction media.
Heterogeneous flow
in a bubble column
Airlift reactors
Airlift reactors:
(a) and (b) internal
loop vessels,
and (c) external loop
Airlift reactors also do not require mechanical agitation for mixing and aeration:
Liquid flow pattern more defined c.f. bubble column reactor since there is physical
separation of the up-flowing and down-flowing streams.
Fewer gas bubbles entrained in the downcomer, so liquid flow is faster.

Better liquid mixing c.f. bubble columns, but gas hold-up (and hence gas-liquid
mass transfer) not as good:
kLa < 0.32uG0.7
(143)
External loop reactors have even greater gas-liquid disentrainment in the

downcomer, c.f. internal loop airlift vessels.
Performance is significantly affected by the details of the vessel internal

structure, e.g. size and position of the draft tube can drastically affect kLa.
Very large capacity (>1000m3 volume) airlift reactors have been built. Very tall
vessels (aspect ratios up to 100:1), called deep-shaft reactors have been built
underground. These have very good gas-liquid mass transfer.
Used for single cell protein production from methanol and gas oil, for plant and
animal cell culture, and in municipal/industrial waste treatment.
Fluidised bed reactors
Upward flow of liquid through a particulate biocatalyst bed is the basis of operation.
Particles must have a suitable size

and density in order to fluidise.
Constant motion of particles

avoids bed clogging and allows
direct air injection in aerobic
processes.
Particle damage by mechanical

attrition can be a problem.
Used in waste treatment (microbes

supported on sand particles) and
with microbial flocs for brewing and
vinegar production.
Fluidised bed reactor
for aerobic processes
Trickle bed reactors
Involve spraying the liquid onto the top of a packed bed:
Liquid trickles down over the bed

in small rivulets.
Suitable for aerobic processes: air

can be injected at the bottom of the
bed without significantly affecting
the liquid distribution.
Good gas-liquid mass transfer due

to large G-L interfacial area.
Liquid hold-up is low, so liquid

reaction capacity is relatively low.
Limited liquid flow rates: prone to

bed flooding at high liquid flows.
Widely used for aerobic wastewater
Trickle bed reactor for aerobic processes
treatment.
8.2 Scale-up
Overview of a complex and evolving field
From our discussions thus far, it is obvious that biochemical processes can involve
numerous mass transfer and biochemical reaction steps, depending on their exact
nature.
Whereas the latter (biochemical reaction) steps are intrinsically independent of
the scale of the process, mass transfer steps by their very nature, are very sensitive to
the physical scale and hydrodynamic environment of the process.
For these reasons, scale-up of a biochemical or chemical reaction is often a complex
and demanding task, yet one that is critical to the commercial success of any process.
Treatment of this topic in textbooks and the process engineering literature is often
limited, focussing on relatively isolated cases, with the lack of a comprehensive
overview of scale-up methods and their ranges of application. In part, this may be due
to the fact that scale-up methodologies are currently in the process of undergoing a
major evolution, with the advent of computational fluid dynamics (CFD) applied to
reaction systems.
This section attempts to give my overview of the field as it stands at the time of writing.
Biochemical & Chemical Reactor Scale-up Methods Overview

Method
Used for
Requires
Good points
Bad points
Scale-up from lab

data (recipe),
based on overall
reaction time.
Reactions in
low viscosity,
well mixed
media.
Throughput,
yield, and
reaction time or
space time (V/F).
Simple method.
No good for poorly

mixed/viscous reaction
media. Unreliable if reaction
conditions other than those of
the original recipe are
chosen.
Ideal reactor
design equations.
Reactions in
low viscosity,
well mixed
media.
Throughput and
reaction kinetic
data. i if
immobilised
/catalyst.
Accurate method.
Can be used for
various reaction
conditions.
No good for poorly

mixed/viscous reaction
media.
Scale-up based
on empirical
mass transfer
correlations.
Multiphase
reactions or
high viscosity,
poorly mixed
media.
Throughput,
medium rheology,
and empirical
mass transfer
correlation.
Relatively simple
to use.
Unreliable if reaction
conditions other than those of
the original mass transfer
correlation are chosen.
Non-ideal reactor
models.
Any type of
reaction.
Throughput,
medium rheology,
and reaction
kinetic data.
Powerful,
accurate method.
Works for
multiphase or
poorly mixed,
viscous reaction
media
Complex to use. Requires

use of CFD (computational
fluid dynamics) methods and
significant computational
power. New: only developed
post-2005.
Scale-up from lab (recipe) data

Simplistic approach, only really useful for low viscosity, homogeneous reactions with no
variation of reaction conditions. Only needs throughput and reaction time:
Reactor sizing example
A batch enzymatic reaction time has been found to be 3.0 hours. Given a required
processing rate of 240kg per day of S at [S]o = 100g/litre , and assuming 18 hours per
day reactor operation, then we can size the reactor volume V as follows:
1. Number of batches per day = 18/3 = 6

2. Mass S required to be processed per batch = 240/6 = 40kg = 40000g
3. Since there is 100g of S in each litre of reaction mixture,
then volume of solution containing 40000g of S
= 40000/100
= 400 litres = Reactor volume*
*Notes:
1. Normally 20% extra would be added to this to allow reactor headspace for stirring.
2. This calculation assumes no down time for filling/emptying/cleaning the reactor. If reactor down time is
significant, then it must be added to the reaction time for calculation purposes.
Ideal reactor design equations

Use of equations from sections 7.1.1-7.1.3 (or CG4003 section 5.5.1 for batch reactor)
to get reaction time, tR, or space time, (=V/F=1/D), together with throughput.
Need to know details of the biochemical/chemical kinetics (and i if an immobilised

species or heterogeneous catalyst is involved).
Can handle variations in reaction conditions, but no good for poorly mixed/viscous
reaction media or aerobic/low solubility gas-liquid reactions.
Once tR or is known, similar reactor sizing method used as in example in sect. 7.2.2.
Scale-up based on empirical mass transfer correlations

Three methodologies here, according to the type of reaction involved:
1) Mixing time-Reynolds number correlations
Scale-up is on the basis of achieving a desired mixing time, tm. Suitable for
homogeneous (liquid phase) reactions in viscous media. No good for multiphase or
heterogeneous reaction systems.
Mixing time, tm
Concentration response after tracer is injected into a stirred tank
Ni.tm, Dimensionless
Mixing Time,
Typical scenario:
Given a mixing time Rei
correlation: estimate one
of V, Di, Ni, or tm, from the
equation, given values for
the other three.
( Ni tm )min
1.54V
at high Rei
Di3
Method needs: Lab/pilot

reactor physical
dimensions and stirrer
speed. Viscosity/rheology
data, medium density. tm.
Rei, Impeller Reynolds No.,

( = NiDi2/ )
(144)
2) Scale-up based on principles of geometric & dynamic similarity

Geometric similarity seeks to retain the same relative physical proportions (both internal
and external) of the small-scale (lab) reactor in the production reactor.
Dynamic similarity seeks to retain the hydrodynamic (fluid flow) characteristics on

scale-up, via correlations with appropriate dimensionless numbers and the stirrer power
input.
Suitable for heterogeneous liquid-solid catalyst reactions in viscous media. No good for
aerobic/gas-liquid reactions.
The single most important operating parameter which can maintain geometric and
dynamic similarity is impeller power input, P. Comparison of power input magnitudes in
different sized vessels is facilitated by use of the power number, Np:
ND 2 N 2 D DT W H
Np
f
,
,
,
,
,
.....
etc

N 3D5
g
D
D
D
(145)
where the first and second terms inside the brackets are the Reynolds and Froude
numbers respectively, and the latter three terms are associated with vessel geometry:
D = impeller diameter, DT = tank diameter, W = baffle width, and H = tank height.
For geometric similarity, eq. (145) reduces to:

Np = f*(Rei , Fr)
(146)
A simple power law function is often used to quantify this function, f*:
Np = K' . Reia . Frb
(147)
where the values of K', a, and b must be determined by experiment and curve fitting.
Method needs: lab/pilot reactor physical dimensions, stirrer speed and power
consumption, viscosity/rheology data, medium density.
(from Chemical Engineering, Vol. 1 by Coulson & Richardson)
(from Chemical Engineering, Vol. 1 by Coulson & Richardson)
3) Scale-up on basis of maintaining desired kLa.

When gas-liquid mass transfer is the limiting factor in the overall reaction, this approach
is often used. Based on achieving the same kLa on the production scale as that which
gives best results on the lab scale, by using kLa - impeller power - operating variable
correlations.
Suitable for multiphase gas-liquid or gas-liquid-solid catalyst reactions (including
aerobic fermentations) in viscous media.
Method needs: kLa and stirrer power correlations. Viscosity/rheology data, medium
density.
7.2.5 Non-ideal reactor models

Based on solving the Navier-Stokes equations for fluid motion in tandem with
biochemical or chemical kinetic equations. Still essentially a research tool, but rapidly
coming into mainstream use in process engineering.
Can be applied to almost any system. Complex to use, heavily reliant on computational
power.
Method needs: Throughput, medium rheology, and reaction kinetic data.
Two mutually interdependent sets of parameters to evaluate:
Physical properties of the reactor contents: e.g. localised mass flow velocities,
viscosities, and temperatures.
Chemical/biochemical-originating properties of the reactor contents: e.g. changes in
composition, localised component flow rates, density and temperatures changes as a
result of chemical/biochemical reaction, and, reaction kinetics.
Assessing the physical property parameters involves solution of the Navier-Stokes

equations:
2u 2u 2u (148)
u
u
u
u
P
u v w g x
2 2 2
x
y
z
x
y
z
t
x
2v 2v 2v
v
v
v
v
P
u v w g y
2 2 2 (149)
x
y
z
y
y
z
t
x
2w 2w 2w
w
w
w
w
P

u
v
w g z
2 2 2 (150)
x
y
z
z
y
z
t
x
where:
= density
t = time
x, y, and z are distance
u, v, and w are linear flow rates in the x, y, and z directions respectively
g = gravitational constant
P = pressure
= viscosity.
Determination of the reactor chemical property parameters requires the use of the ideal
reactor design algorithm (mole balance, energy balance, kinetics, stoichiometry, etc.,)
on a localised basis for different regions within the reactor, each of which is assumed
to be ideally mixed, but with different space time values.
Sequential solution of the Navier-Stokes equations and the reactor design algorithms
gives, on convergence, a detailed quantitative picture of mixing within the reactor and
allows prediction of non-ideal reactor conversion and product distribution.
Example of application of a CFD method (from PhD project of Dan Lane, UL)
A computational fluid dynamics (CFD) package such as FLUENT is used to
build a physical simulation model of the reactor.
An advanced reaction engineering package such as gPROMS Multizonal is
used to construct a chemical simulation model of the different mixing zones
within the reactor.
Both packages are then used sequentially and if necessary, iteratively, to
solve the Navier-Stokes equations (FLUENT) and the reactor design
algorithms (gPROMS) for a given set of operating conditions.
Reaction
kinetics
Rheology
data
Ideal mixing model:

Polymath + Excel
Reactor design algorithms
gPROMS
Multizonal
CFD (FLUENT):
Navier-Stokes eqns
Non-ideal reactor model
Reactor mixing pattern, predicted conversion and product distributions
Application of a CFD calculation method for non-ideal reactor simulation
Reactor physical model

Feed
Internal recycle stream
Outflow
External recycle
Tank
volume
1362
m3
Direction of
rotation
CFD Velocity profile
Velocity decreases
Results: concentration profiles

250
45
ideal
non-ideal
240
Caustic (g/L)
Unreacted kaolin (g/L)
50
40
35
30
230
220
25
20
210
0
200
400
600
800
1000
200
Time (mins)
600
800
1000
Time (mins)
4.0
30
3.5
25
3.0
Sodalite (g/L)
Dissolved silica (g/L)
400
2.5
2.0
1.5
1.0
20
950m3 of 1362m3
tank used
15
10
~31% of tank
not used!
0.5
0.0
0
0
200
400
600
Time (mins)
800
1000
200
400
600
Time (mins)
800
1000
One small impeller vs. three

Velocity contours
Intermig impeller: velocity vectors
One small impeller vs. large intermig impeller

Velocity contours
9. RECAP & REVISION

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CG4017

The temperature difference between the hot and cold bodies

These in turn are influenced by a number of variables, including:

HT system physical size

As seen in section 5, energy balance calculations allow us to evaluate the energy

The HT requirements of bioreactors can be quite different depending on their scale of

From Bioprocess Engineering Principles by Pauline M. Doran

The simplest form of HT

Used for HT area <15m2

From Bioprocess Engineering Principles by Pauline M. Doran

Single pass shell and tube heat exchanger

From Bioprocess Engineering Principles by Pauline M. Doran

Single pass shell and tube heat exchanger

From Bioprocess Engineering Principles by Pauline M. Doran

Single pass shell and tube heat exchanger

Large HT surface area in a small volume.

Double pass shell and

Temperature profiles for

Arrangement (a) is best since it

From Bioprocess Engineering Principles by Pauline M. Doran

6.2 Heat transfer between fluids

In general thermal boundary layers are thinner

Heat transfer across a solid

Where h is the boundary layer heat transfer

Thermal boundary layer heat transfer coefficients for

From Bioprocess Engineering Principles by Pauline M. Doran

Eq. (95) can be rewritten as:

where Rw is the wall thermal resistance:

In a similar way, we can define the thermal boundary layer resistances:

Thus for the overall heat transfer rate, Q, we have:

and from eqs. (97)-(99):

where U = overall heat transfer coefficient. Thus:

6.3 Heat exchanger fouling factors

where hfh and hfc are the respective

Heat transfer across a solid heat transfer

Fouling factors for typical scale deposits from

From Bioprocess Engineering Principles by Pauline M. Doran

6.4 Heat transfer equipment design equations

where M = mass flow rate, Et = specific enthalpy, i = in, o = out.

M hCph Thi Tho M cCpc Tco Tci Q

M cCpc Tco Tci Q

6.4.2 Evaluation of U, the overall heat transfer coefficient

Impeller Reynolds number, Rei

(Pr represents the ratio of momentum to heat transfer)

w = wall fluid viscosity = fluid average density

Some examples of these correlations are given below.

Nu 0.023Re 0.8 Pr 0.4

(low viscosity fluids)

(high viscosity fluids)

Turbulent flow outside tubes without phase change:

when Remax 6 x 103

From Bioprocess Engineering Principles by Pauline M. Doran

From Bioprocess Engineering Principles by Pauline M. Doran

From Bioprocess Engineering Principles by Pauline M. Doran

From Bioprocess Engineering Principles by Pauline M. Doran

What is downstream processing?

Recovering the product

Downstream Separation Processes 1 (CG4003)

Isolation of solids and cellular agglomerates

Separation of intracellular products

Isolation of cells and macromolecular species

Isolation of macromolecular species and

Isolation of soluble products