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Bioprocess Enigneering

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  • CG4017

    Bioprocess Engineering 2

    Course Notes, Autumn 2014, Part 2 of 2

    Dr Denise Croker, BM-028

    [email protected] 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. The temperature difference between the hot and cold bodies

    2. 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.

    (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.

    Heat transfer

    configurations for

    bioreactors: (a) jacketed

    vessel; (b) external coil;

    (c) internal coil; (d)

    baffle-type coil; (e)

    external heat exchanger

    From Bioprocess Engineering Principles by Pauline M. Doran

  • The variation of cooling water temperature with distance through the coil in internal coil-

    type 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.

    From Bioprocess Engineering Principles by Pauline M. Doran

  • The simplest form of HT

    equipment for small-scale

    external (to the reactor)

    operation is the double-

    pipe heat exchanger:

    Used for HT area

  • Shell and tube heat exchangers are used for HT area applications >15m2:

    Single pass shell and tube heat exchanger

    From Bioprocess Engineering Principles by Pauline M. Doran

  • Shell and tube heat exchangers are used for HT area applications >15m2:

    Single pass shell and tube heat exchanger

    From Bioprocess Engineering Principles by Pauline M. Doran

  • Shell and tube heat exchangers are used for HT area applications >15m2:

    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.

    Single pass shell and tube heat exchanger

    From Bioprocess Engineering Principles by Pauline M. Doran

  • Arrangement (a) is best since it

    avoids temperature cross-over of

    the heating and cooling fluids, as

    seen in (b)

    Double pass shell and

    tube heat exchanger

    Temperature profiles for

    different shell side entry

    positions

    From Bioprocess Engineering Principles by Pauline M. Doran

  • 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:

    (93)

    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.

    Heat transfer across a solid

    heat transfer surface

    TAhQb

    From Bioprocess Engineering Principles by Pauline M. Doran

  • Thermal boundary layer heat transfer coefficients for

    industrial heat exchange fluids

    From Bioprocess Engineering Principles by Pauline M. Doran

  • The rate of heat transfer by conduction through the pipe wall, Qw, can be obtained from

    Fouriers law: (94)

    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:

    (95)

    Eq. (95) can be rewritten as: (96)

    where Rw is the wall thermal resistance: (97)

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

    (98) and (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.

    dy

    dTkAQw

    wcwhww TB

    kATT

    B

    kAQ

    w

    ww

    R

    TQ

    kA

    BRw

    AhR

    h

    h

    1

    AhR

    c

    c

    1

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

    (100)

    In eq. (100):

    and from eqs. (97)-(99): or (101)

    where U = overall heat transfer coefficient. Thus: (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.

    cwhT RRRT

    R

    TQ

    ch TTT

    AhkA

    B

    AhR

    ch

    T

    11

    UAhk

    B

    hAR

    ch

    T

    1111

    TUAQ

  • 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:

    (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 time-

    and temperature-dependant nature. Heat transfer across a solid heat transfer

    surface with fouling of both surfaces

    From Bioprocess Engineering Principles by Pauline M. Doran

    fcchfh hhk

    B

    hhU

    11111

  • Fouling factors for typical scale deposits from

    industrial heat exchange fluids

    From Bioprocess Engineering Principles by Pauline M. Doran

  • 6.4 Heat transfer equipment design equations (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:

    (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:

    and (105)

    where h denotes the hot fluid, and c the cold fluid.

    TUAQ

    0 QEtMEtM ooii

    hhohih QEtEtM ccocic QEtEtM

  • 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:

    (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:

    (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:

    (108)

    Q in eq. (108) can be determined from the energy balance equation for cell bioreactors:

    Q = -Hr - Mv.hv - Q + Ws (92)

    QEtEtMEtEtM cicochohih

    QTTCpMTTCpM cicocchohihh

    QTTCpM cicocc

  • 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 counter-

    current 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

    the cold fluids at the ends of the exchanger. (109)

    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

    T1 and T2 are the inlet and exit temperatures of (110)

    the heat exchange fluid.

    )/ln( 12

    12

    TT

    TTTL

    2

    )(2 21 TTTT FA

  • 6.4.2 Evaluation of U, the overall heat transfer coefficient

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

    (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

    convective to conductive heat transfer rates. (111)

    where D = pipe or tank diameter and kfb =bulk fluid thermal conductivity.

    fcchfh hhk

    B

    hhU

    11111

    fbk

    DhNu

  • 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:

    (112)

    (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

    b

    DuRenumber,ReynoldsPipe

    b

    iii

    DNRenumber,ReynoldsImpeller

    2

    fb

    bp

    k

    CPrnumber,Prandl

  • Some examples of these correlations are given below.

    Turbulent flow inside tubes without phase change:

    (low viscosity fluids) (115)

    when 104 Re 1.2 x 105 and 0.7 Pr 120 and L/D 60.

    (high viscosity fluids) (116)

    Turbulent flow outside tubes without phase change:

    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:

    (118) (119)

    Helical coil hx Jacket hx

    4.08.0023.0 PrReNu

    14.0

    33.08.0027.0

    w

    bPrReNu

    33.0PrReCNu 0.6max

    14.0

    33.062.087.0

    w

    bi PrReNu

    14.0

    33.062.036.0

    w

    bi PrReNu

  • 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

  • 7. DOWNSTREAM

    SEPARATION PROCESS - 2

  • 31

    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

  • 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

    Isolation of soluble products Adsorption

    Isolation of soluble products 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.

    33

  • http://www.halwachs.de/solvent-extraction.htm

    34

  • http://www.cheresources.com/liquid_extractor_design5.gif

    35

  • Aqueous-organic solvent extractions are used to isolate many pharmaceutical and

    biopharmaceutical products:

    Product Extractive solvent

    Antibiotics

    Penicillin Butyl acetate, amyl acetate, or methyl isobutyl ketone

    Erythromycin Pentyl acetate or amyl acetate

    Steroids N-hexane, pentane, or heptane

    Vitamins

    Vitamin B12 Isopropanol

    Alkaloids

    Morphine Butanol or benzene

    Codeine 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

  • From Bioprocess Engineering Principles by Pauline M. Doran

    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:

    (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.

    H

    L

    i

    iK

    ][

    ][

    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:

    (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:

    (19) for the light phase

    and: (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 the

    preferred (extracting) phase.

    T

    MA

    eK.

    K

    VV

    VY

    HL

    LL

    HL

    HH

    VKV

    VY

    41

  • From Bioprocess Engineering by M. L. Shuler & F. Kargi

    42

    Partition coefficient

    increases with

    potassium phosphate conc. ,

    resulting in

    more efficient separation of

    enzyme A

  • 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:

    (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.

    o

    Lc

    i

    i

    ][

    ][

    o

    Hc

    i

    i

    ][

    ][

    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.

    44

  • http://www.halwachs.de/mixersettler.gif

    45

  • http://www.rousselet-robatel.com/images/products/Mixer-Settler-pic-3lg.jpg 46

  • Rousselet Robatel 8 stage mixer-settler

    http://www.rousselet-robatel.com/products/laboratory-mixer-settlers.php 47

  • http://images.vertmarkets.com/crlive/files/Images/92F9B851-C50C-11D3-9A82-00A0C9C83AFB/pod2.jpg

    Tower extractors: general design

    48

  • (a) Oldshue-Rushton extractor; (b) Scheibel-York extractor ; (c) Rotating-disk extractor ; (d) Pulsed extractor

    http://accessscience.proxy.mpcc.edu/content.aspx?id=636100

    Types of tower extractors with mechanical agitation

    (a) (b) (c) (d)

    49

  • 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).

    50

  • http://images.vertmarkets.com/crlive/files/Images/92F9B851-C50C-11D3-9A82-00A0C9C83AFB/pod2.jpg

    Podbielniak (Pod) centrifugal L-L extractor

    51

  • 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

  • Liquid mixturecontaining

    adsorbate, A

    A-free liquid

    Packed bed adsorber

    A

    Step 1A

    Adsorbent pelletcross-section

    Adsorbent surfacestagnant liquid film(external boundary layer)

    A

    Catalyst pore

    Step 2Adsorption

    site

    Adsorption site surface

    A (liq)

    A (ads)

    Step 3

    Mass transfer and adsorption steps during adsorption of a liquid phase adsorbate, A

    External mass transfer

    Internal mass transfer

    (pore diffusion)

    Adsorption (and desorption)

    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.

    57

  • http://www.cee-environmental.com/public/data/companyProduct1231011370.jpg

    Moving bed adsorber

    58

  • 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:

    (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 KA

    is a constant.

    *

    **

    1 AA

    AAASmAS

    CK

    CKCC

    59

  • ***

    1 AA

    AAASmAS

    CK

    CKCC

    nAFAS CKC

    1**

    Langmuir isotherm:

    Freundlich isotherm:

    From Bioprocess Engineering Principles by Pauline M. Doran

    60

  • For liquid-solid systems, the Freundlich isotherm has been found to be more

    applicable:

    (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.

    nAFAS CKC

    1**

    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. The mixture containing the solute is continuously passed through the bed and

    amount adsorbed increases with time.

    2. Eventually the bed becomes fully loaded/saturated.

    3. Desorption of concentrated solute is carried out.

    4. 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.

    62

  • From Bioprocess Engineering Principles by Pauline M. Doran

    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. The mixture containing the solute is continuously passed through the bed and

    amount adsorbed increases with time.

    2. Eventually the bed becomes fully loaded/saturated.

    3. Desorption of concentrated solute is carried out.

    4. 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

  • From Bioprocess Engineering Principles by Pauline M. Doran

    65

  • 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

  • From Bioprocess Engineering Principles by Pauline M. Doran

    67

  • 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:

    (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

    where Z = ionic charge

    IKS

    SS

    o

    .log

    2].[5.0 iZiI71

  • From Bioprocess Engineering by M. L. Shuler & F. Kargi

    72

  • 2. Solubility reduction at reduced temperatures (
  • Lysine isoelectric point

    http://upload.wikimedia.org/wikipedia/commons/7/7e/Lysine_pI.png

    74

  • 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

    Undersaturated

    Supersaturated

    The amount of solute dissolved

    in the solution is greater than

    the solubility

  • 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

  • cb

    ci

    cs

    Crystal face Bulk solution

    cb - ci

    ci - cs

    Concentration

    85

  • 7.8.2.2

    86

  • (27)

    (28)

    Combining to eliminate ci:

    87

  • (29)

    88

  • Solu

    bilit

    y

    Temperature

    MX.yH2O (hydrated salt)MX (anhydrous salt)

    NaCl

    KNO3

    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

    From: Chemical Engineering, vol. 2 Coulson & Richardson, p673-681

    Continuous crystallisation equipment

    End view

    Votator crystalliser

    92

  • http://www.labx.com/v2/adsearch/morepics.cfm?chpics=1&chback=

    1&adzone=431000&pic=431030&cn=0&adnumber=431030

    Votator crystalliser

    93

  • From: Chemical Engineering, vol. 2 Coulson & Richardson, p673-681

    Oslo cooler crystalliser

    Supersaturation

    Nucleation &

    growth

    94

  • From: Chemical Engineering, vol. 2 Coulson & Richardson, p673-681

    Oslo evaporative crystalliser

    Supersaturation

    Nucleation &

    growth

    Vacuum

    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

    From Bioprocess Engineering Principles by Pauline M. Doran

  • 8.1 Bioreactor design

    Fed batch (no external mass transfer limitations)

    For single cell fermentation reactions, time dependence of

    Reaction mixture volume, V: (120)

    Cell concentration: (121)

    Substrate concentration: (122)

    Product concentration: (123)

    where F = volumetric feed rate, D = dilution rate(=F/V), other parameters as in section 2.

    Fed batch

    bioreactor

    Fdt

    dV

    )( Dxdt

    dx

    xmY

    q

    YssD

    dt

    dsS

    PS

    P

    XS

    i

    pDxqdt

    dpp

  • FB bioreactor, quasi-steady state* operation:

    Total cell mass in reactor, Mx: (124)

    where Mx,o = cell mass at start of substrate feeding and tfb = time from start of feeding

    Reactor substrate concentration: s 0 (125)

    Product concentration: 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.

    fbiXSoxx tFsYMM )(,

  • 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,

    Substrate concentration: (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,

    Substrate concentration: (128)

    Cell concentration: (129)

    Product concentration: (130)

    sK

    sssD

    m

    i

    max

    D

    DKs S

    max

    D

    xqpp

    p

    i

    s

    PS

    p

    XS

    i

    mY

    q

    Y

    D

    ssDx

  • Steady state cell and substrate concentrations

    as a function of dilution rate in a chemostat

    Cell washout: D > MAX

    From Bioprocess Engineering Principles by Pauline M. Doran

  • From eq. (129), assuming no product formation or maintenance requirement:

    (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:

    (132)

    Usually Ks

  • Cell washout: Dcrit Dopt

    Chemostat biomass productivity

    From Bioprocess Engineering Principles by Pauline M. Doran

    The value of D for maximum Qx, Dopt, can be obtained by differentiating eq. (134) with

    respect to D and equating to zero:

    (135)

    iS

    Sopt

    sK

    KD 1max

  • 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.

    Steady state biomass balance:

    (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: (137)

    Steady state limiting substrate balance:

    (138)

    or

    (139)

    Chemostat with

    immobilised cell

    particles 0 VxVxFx imTss

    S

    imT

    x

    xD

    1

    0 VY

    xV

    Y

    xFsFs

    XS

    imT

    XS

    si

    imTSXS

    i xxY

    ssD

  • Combining eqs. (137) and (139) and substituting the Monod equation (3) for gives:

    (140)

    Eq. (140) graphically:

    imTXSi

    XSi

    S xYss

    YssD

    sK

    s

    max

    From Bioprocess Engineering Principles by Pauline M. Doran

    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:

    (141)

    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

    z

    F

    A

    sK

    s

    dz

    ds

    m

    T max

  • For aerobic reactions, aeration is done in a separate vessel to avoid liquid

    maldistribution in bed due to trapped air bubbles:

    Unsuitable for processes that evolve large amounts of gas, e.g. CO2, since gas

    bubbles can become trapped in bed.

    From Bioprocess Engineering Principles by Pauline M. Doran

    Plug flow bioreactor with external medium aeration

  • 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.

    From Bioprocess Engineering Principles by Pauline M. Doran

    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

    From Bioprocess Engineering Principles by Pauline M. Doran

  • Airlift reactors:

    (a) and (b) internal

    loop vessels,

    and (c) external loop

    From Bioprocess Engineering Principles by Pauline M. Doran

    Airlift reactors

  • 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 < 0.32uG

    0.7 (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.

    From Bioprocess Engineering Principles by Pauline M. Doran

    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 treatment.

    From Bioprocess Engineering Principles by Pauline M. Doran

    Trickle bed reactor for aerobic processes

  • 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.

  • From Bioprocess Engineering Principles by Pauline M. Doran

    Concentration response after tracer is injected into a stirred tank

    Mixing time, tm

  • Rei, Impeller Reynolds No.,

    ( = NiDi2/ )

    Ni.t

    m, D

    ime

    nsio

    nle

    ss

    Mix

    ing T

    ime

    , 3

    1.54( )i m min i

    i

    VN t at high Re

    D

    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.

    Method needs: Lab/pilot

    reactor physical

    dimensions and stirrer

    speed. Viscosity/rheology

    data, medium density. tm.

    (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:

    (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.

    etc

    D

    H

    D

    W

    D

    D

    g

    DNNDf

    DN

    PN Tp .....,,,,,

    22

    53

  • 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:

    (148)

    (149)

    (150)

    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.

    2

    2

    2

    2

    2

    2

    z

    u

    y

    u

    x

    u

    x

    Pg

    z

    uw

    y

    uv

    x

    uu

    t

    ux

    2

    2

    2

    2

    2

    2

    z

    v

    y

    v

    x

    v

    y

    Pg

    z

    vw

    y

    vv

    x

    vu

    t

    vy

    2

    2

    2

    2

    2

    2

    z

    w

    y

    w

    x

    w

    z

    Pg

    z

    ww

    y

    wv

    x

    wu

    t

    wz

  • 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.

  • Non-ideal reactor model

    Ideal mixing model:

    Polymath + Excel

    Reactor design algorithms

    Reaction

    kinetics Rheology

    data

    gPROMS

    Multizonal

    CFD (FLUENT):

    Navier-Stokes eqns

    Reactor mixing pattern, predicted conversion and product distributions

    Application of a CFD calculation method for non-ideal reactor simulation

  • Reactor physical model Feed

    External recycle

    Internal recycle stream

    Outflow

    Direction of

    rotation

    Tank

    volume

    1362 m3

  • CFD Velocity profile

    Velocity decreases

  • Results: concentration profiles

    950m3 of 1362m3

    tank used

    ~31% of tank

    not used!

    0 200 400 600 800 100020

    25

    30

    35

    40

    45

    50

    ideal

    non-ideal

    Un

    reac

    ted

    ka

    oli

    n (

    g/L

    )

    Time (mins)

    0 200 400 600 800 1000210

    220

    230

    240

    250

    Ca

    us

    tic (

    g/L

    )

    Time (mins)

    0 200 400 600 800 10000.0

    0.5

    1.0

    1.5

    2.0

    2.5

    3.0

    3.5

    4.0

    Time (mins)

    Dis

    so

    lve

    d s

    ilic

    a (

    g/L

    )

    Time (mins)

    0 200 400 600 800 10000

    5

    10

    15

    20

    25

    30

    So

    da

    lite

    (g

    /L)

  • One small impeller vs. three

    Velocity contours

  • Intermig impeller: velocity vectors

  • One small impeller vs. large intermig impeller

    Velocity contours

  • 9. RECAP & REVISION