Reactor Design For Cell Groth

CP504 Lecture 7
Cellular kinetics and associated reactor design:
Reactor Design for Cell Growth
07 Oct 2011
Prof. R. Shanthini
Cell Growth Kinetics

Using the population growth model, we could write the cell
growth rate (rX) as
r X = CX
(41)
where
: specific growth rate (per time)
CX : cell concentration (dry cell weight per unit volume)
07 Oct 2011
Prof. R. Shanthini
Batch Fermenter
Mass balance for the cell:
0 + (rX) V = 0 + d(VCX) / dt
which for a batch reactor with constant volume
reacting mixture gives
dCX / dt = rX
(42)
V for volume of the reacting mixture at time t

CX for concentration of the cells in V at time t
(rX) for cell growth rate in V at time t
07 Oct 2011
Prof. R. Shanthini
Batch Fermenter
Combining (41) and (42), we get
dCX
dt
= CX
(43)
If is a constant then integrating (43) gives,

CX = CX0 exp[(t-t0)]
(44)
where CX = CX0 when t = t0.
07 Oct 2011
Prof. R. Shanthini
Cell Growth Kinetics

Mostly, however, is not a constant with time. It depends on
CS, the substrate concentration.
The most commonly used model for is given by the Monod
model:
m CS
(45)
=
KS + C S
where max and KS are known as the Monod kinetic parameters.
Monod Model is an over simplification of the complicated
mechanism of cell growth.
However, it adequately describes the kinetics when the
concentrations of inhibitors to cell growth are low.
07 Oct 2011
Prof. R. Shanthini
Batch Fermenter
Substituting in (43) by the Monod Model given by (45), we get
dCX
dt
m CS
KS + CS
CX
(46)
Equation (46) could be integrated only if we know how CS

changes with either CX or t.
How to do that?
07 Oct 2011
Prof. R. Shanthini
Batch Fermenter
It is done as follows:
Stoichiometry could have helped. But we dont have such

a relationship in the case of cellular kinetics.
Therefore, we introduce a yield factor (YX/S) as the ratio
between cell growth rate (rX) and substrate consumption
rate (-rS) as follows:
YX/S = rX / (-rS)
(47)
We know (rX) from (41) and/or (42). But we dont know (-r S).
Therefore obtain an expression for (-rS) as shown in the next
slide.
07 Oct 2011
Prof. R. Shanthini
Batch Fermenter
Mass balance for substrate:
0 = 0 + (-rS) V + d(VCS) / dt
which for a batch reactor with constant volume
reacting mixture gives
dCS / dt = -(-rS)
(48)
V for volume of the reacting mixture at time t

CS for concentration of the Cells in V at time t
(rS) for substrate utilization rate in V at time t
07 Oct 2011
Prof. R. Shanthini
Batch Fermenter
YX/S =
rX
(47)
- rS
dCX / dt = rX
(42)
dCS / dt = -(-rS)
(48)
Combining the above equations, we get

dCX / dCS = -YX/S
which upon integration gives
(CX CX0) = YX/S (CS0 CS)
07 Oct 2011
Prof. R. Shanthini
(49)
9
Batch Fermenter
Substituting CS from (49) in (47) and integrating, we get
(
(
m (t - t0) =
KS YX/S
)( )
)( )
+1
CX0 + CS0YX/S
KS YX/S
CX0 + CS0YX/S
ln
CS0
CS
ln
CX
CX0
(50)
where
(CX CX0) = YX/S (CS0 CS)
07 Oct 2011
Prof. R. Shanthini
(49)
10
Batch Fermenter
Exercise 1:
The growth rate of E. coli be expressed by Monod kinetics
with m = 0.935 hr-1 and KS = 0.71 g/L.
Assume that YX/S is 0.6 g dry cells per g substrate.
CX0 is 1 g/L and CS0 = 10 g/L when the cells start to grow
exponentially (i.e., at t = 0).
show how CX, CS, and dCX/dt change with respect to time.
07 Oct 2011
Prof. R. Shanthini
11
Exercise 1 worked out using the calculator/spread sheet:

CS is varied from 10 g/L to 0.
CX is calculated using (49) as CX = 1 + 0.6 (10 CS)
t is calculated using (50) as follows:
0.935 t =
0.71 x 0.6
1 + 10 x 0.6
)( )
)( )
+1
0.71 x 0.6
1 + 10 x 0.6
ln
CX
1
ln
10
CS
CX is calculated using (46).

07 Oct 2011
Prof. R. Shanthini
12
specify
CS
Calculate
CX using
(49)
Calculate t
using (50)
Calculate
dCX/dt
using (46)
10
9.95
1.03
0.0317
0.9335
9.8
1.06
0.0624
0.9332
9.85
1.09
0.0923
0.9329
Continue
until CS
becomes 0
07 Oct 2011
Prof. R. Shanthini
13
CS
07 Oct 2011
Prof. R. Shanthini
CX
14
CS
07 Oct 2011
Prof. R. Shanthini
CX
15
Exercise 1 worked out using an ODE solver:

Programme written in MATLAB
[t,y] = ode45(@CP504Lecture_07,[0:0.01:3],[1; 10]);
function dydt =CP504Lecture_07(t,y)
%data given
mumax = 0.935;
% per hr
Ks
= 0.71;
% g/L
YXS
= 0.6;
%Monod model
mu = mumax*y(2)/(Ks+y(2));
%rate equations
rX = mu*y(1);
rS = -rX/YXS;
dydt=[rX; rS]
07 Oct 2011
Prof. R. Shanthini
16

plot(t,y(:,1),'b',t,y(:,2),'r')
legend('Cell','Substrate')
ylabel('Concentration (g/L)')
xlabel('Time (h)')
07 Oct 2011
Prof. R. Shanthini
17

mumax = 0.935;
plot(t,y(:,1),'b',t,y(:,2),'r')
Ks
= 0.71;
legend('Cell','Substrate')
mu= mumax*y(:,2)./(Ks+y(:,2));
ylabel('Concentration (g/L)')
rX = mu.*y(:,1);
xlabel('Time (h)')
plot(t,rX,'g')
07 Oct 2011
Prof. R. Shanthini
18
Plug-flow Fermenter at steady-state

F
CXi, CSi
F
CX, CS
= V/F
(
)()
( )( )
m =
KS YX/S
CXi + CSiYX/S
KS YX/S
CXi + CSiYX/S
ln
+1
CSi
CS
ln
CX
CXi
(51)
where
(CX CXi) = YX/S (CSi CS)

07 Oct 2011
Prof. R. Shanthini
(52)
19
Continuous Stirred Tank Fermenter (CSTF) at steady-state
F
CXi, CSi
V
CX, CS
F
CX, CS
Mass balance for cells over V:

FCXi + rX V = FCX
07 Oct 2011
Prof. R. Shanthini
(53)
20

Equation (53) gives
V
F
CX - CXi
rX
(54)
Introducing Dilution Rate D as

F
D =
(55)
in (54), we get
1
D
07 Oct 2011
CX - CXi
rX
Prof. R. Shanthini
(56)
21

Since rX = CX, (56) becomes
1
D
CX - CXi
CX
(57)
If the feed is sterile (i.e., CXi = 0), (57) gives

(58)
CX (D ) = 0
which means either CX = 0
07 Oct 2011
or
Prof. R. Shanthini
D=
22

If D = , then
D
m CS
KS + C S
(59)
(59) can be rearranged to give CS as

CS =
KS D
m - D
(60)
To determine CX, we need to write the mass balance for

substrate over the CSTF
07 Oct 2011
Prof. R. Shanthini
23
F
CXi, CSi
V
CX, CS
F
CX, CS
Mass balance for substrate over V:

FCSi = FCS + (-rS) V
07 Oct 2011
Prof. R. Shanthini
24

which is rearranged to give
(-rS) = D (CSi - CS)
(61)
(56) gives
rX = D (CX - CXi )
Using the above equations in the definition of yield factor, we get
(CX CXi) = YX/S (CSi CS)
07 Oct 2011
Prof. R. Shanthini
(62)
25

Since the feed is sterile, (62) gives
CX = YX/S (CSi CS)
(63)
(60) is
KS D
CS =
(60)
m - D
Therefore, we have
CX
= YX/S
07 Oct 2011
CSi -
KS D
m - D
Prof. R. Shanthini
(64)
26

CS =
KS D
(60)
m - D
which is valid only when D < m

CX = YX/S
CSi -
KS D
m - D
(64)
which is valid only when

CSi > KS D / (m - D)
D < CSi m / (KS + CSi)
07 Oct 2011
Prof. R. Shanthini
27
Since
D < CSi m / (KS + CSi) < m
critical value of the Dilution Rate is as follows:

DC = CSi m / (KS + CSi)
07 Oct 2011
Prof. R. Shanthini
(65)
28

If m equals or less than DC, then CX is negative.
That is impossible.
So, when m equals or less than DC,
We need to take the solution
CX = 0 of (58), not D =
Substituting CX = 0 in CX = YX/S (CSi CS) gives
CS = CSi
07 Oct 2011
Prof. R. Shanthini
29

CX = 0 means no cell in the reactor.
CS = CSi means substrate is not utilised.
Since the CSTF has a sterile feed (CXi = 0),
no reaction takes place unless we inoculate with the
cells once again.
So, CSTF gets into a WASHED OUT situation.
To avoid CSTF getting into WASHED OUT situation,
we need to maintain D = F / V < DC
07 Oct 2011
Prof. R. Shanthini
30

Exercise 2
The growth rate of E. coli be expressed by Monod kinetics
with m = 0.935 hr-1 and KS = 0.71 g/L.
Assume that YX/S is 0.6 g dry cells per g substrate.
The feed is sterile (CXi = 0) and CSi = 10 g/L.
show CX and CS changes with dilution rate.
07 Oct 2011
Prof. R. Shanthini
31

Plot the following using excel / MATLAB
From (60): CS =
0.71 D
0.935 - D
From (64): CX = 0.6 10 -
g/L
0.71 D
0.935 - D
g/L
From (65): DC = CSi m / (KS + CSi)

= 10 x 0.935 / (0.71+10) = 0.873 per h
07 Oct 2011
Prof. R. Shanthini
32
07 Oct 2011
Prof. R. Shanthini
DC = 0.873
33

Reactor Design For Cell Groth

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Reactor Design For Cell Groth

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CP504 Lecture 7

Cellular kinetics and associated reactor design:

Reactor Design for Cell Growth

Cell Growth Kinetics

: specific growth rate (per time)

CX : cell concentration (dry cell weight per unit volume)

V for volume of the reacting mixture at time t

If is a constant then integrating (43) gives,

where CX = CX0 when t = t0.

Cell Growth Kinetics

Equation (46) could be integrated only if we know how CS

Stoichiometry could have helped. But we dont have such

V for volume of the reacting mixture at time t

Combining the above equations, we get

Exercise 1 worked out using the calculator/spread sheet:

CX is calculated using (46).

Exercise 1 worked out using the calculator/spread sheet:

Exercise 1 worked out using the calculator/spread sheet:

Exercise 1 worked out using the calculator/spread sheet:

Exercise 1 worked out using an ODE solver:

Exercise 1 worked out using an ODE solver:

Exercise 1 worked out using an ODE solver:

Plug-flow Fermenter at steady-state

(CX CXi) = YX/S (CSi CS)

Continuous Stirred Tank Fermenter (CSTF) at steady-state

Mass balance for cells over V:

Continuous Stirred Tank Fermenter (CSTF) at steady-state

Introducing Dilution Rate D as

Continuous Stirred Tank Fermenter (CSTF) at steady-state

If the feed is sterile (i.e., CXi = 0), (57) gives

Continuous Stirred Tank Fermenter (CSTF) at steady-state

(59) can be rearranged to give CS as

To determine CX, we need to write the mass balance for

Continuous Stirred Tank Fermenter (CSTF) at steady-state

Mass balance for substrate over V:

Continuous Stirred Tank Fermenter (CSTF) at steady-state

Continuous Stirred Tank Fermenter (CSTF) at steady-state

Continuous Stirred Tank Fermenter (CSTF) at steady-state

which is valid only when D < m

which is valid only when

Continuous Stirred Tank Fermenter (CSTF) at steady-state

D < CSi m / (KS + CSi) < m

critical value of the Dilution Rate is as follows:

Continuous Stirred Tank Fermenter (CSTF) at steady-state

Continuous Stirred Tank Fermenter (CSTF) at steady-state

Continuous Stirred Tank Fermenter (CSTF) at steady-state

Exercise 2 worked out using the calculator/spread sheet:

From (64): CX = 0.6 10 -

From (65): DC = CSi m / (KS + CSi)

Exercise 2 worked out using the calculator/spread sheet:

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