Applied Mathematical Modelling 37 (2013) 695–706

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Applied Mathematical Modelling

journal homepage: www.elsevier.com/locate/apm

Modelling and optimal control for a fed-batch fermentation process

Chongyang Liu a,⇑, Zhaohua Gong a, Bangyu Shen b, Enmin Feng c
a
School of Mathematics and Information Science, Shandong Institute of Business and Technology, Yantai 264005, China
b
School of Mathematical Science, Huaiyin Normal University, Huai’an 223300, China
c
School of Mathematical Sciences, Dalian University of Technology, Dalian 116024, China

a r t i c l e i n f o a b s t r a c t

Article history: The main control goal in fed-batch fermentation is to get a high concentration of produc-
Received 2 May 2011 tion. In this paper, a new nonlinear dynamical system, in which the feed rate of glycerol is
Received in revised form 15 February 2012 the control function and the switching instants between the batch and feed processes are
Accepted 29 February 2012
the variables, is proposed to formulate the fed-batch fermentation process of glycerol bio-
Available online 13 March 2012
conversion to 1,3-propanediol (1,3-PD). To maximize the concentration of 1,3-PD at the
terminal time, an optimal control model involving the nonlinear system and subject to
Keywords:
the continuous state constraints and the control constraint is presented. To seek the opti-
Nonlinear dynamical system
Optimal control
mal solution of the constrained optimal control problem, the control parametrization
Control parametrization enhancing enhancing transform together with the constraint transcription technique is first used to
transform convert the constrained optimal control problem into a sequence of mathematical pro-
Constraint transcription gramming problems. An improved Particle Swarm Optimization is subsequently con-
Fed-batch fermentation structed to solve the resultant mathematical programming problem. Numerical results
show that, by employing the obtained optimal strategy, 1,3-PD concentration at the termi-
nal time can be increased considerably.
Ó 2012 Elsevier Inc. All rights reserved.

1. Introduction

Fed-batch cultivation technique is a mode of bioreactors operation that provides distinct advantages over the other oper-
ation modes and has a widespread industrial application [1]. Concentration of substrate in cultivation medium of fed-batch
process can be externally manipulated by using the appropriate feed-rate profiles. Optimal control of fed-batch fermentation
process is one of the relevant problems in biotechnology. Consequently, optimal control of fed-batch fermentation processes
has been a topic of research for many years [2,3].
1,3-Propanediol (1,3-PD) is a valuable chemical intermediate that is suitable as a monomer for polycondensations to pro-
duce polyesters, polyethers and polyurethanes [4]. The microbial conversion of glycerol to 1,3-PD is particularly attractive in
that the process is relatively easy and does not generate toxic byproducts. Dissimilation of glycerol to 1,3-PD by Klebsiella
pneumoniae (K. pneumoniae) has been widely investigated since the 1980s due to its high productivity [5]. The critical con-
centrations of glycerol, 1,3-PD and other byproducts in the fermentation are determined [6]. The accumulation of 3-hydroxy-
propionaldehyde is investigated [7]. High key enzymes activities are obtained on the basis of optimal fermentation
conditions [8]. During the bioconversion of glycerol to 1,3-PD, the most efficient cultivation method is a fed-batch operation
which corrects pH by alkali addition for glycerol supply [9]. The fed-batch of bioconversion glycerol to 1,3-PD begins with
the cells being grown under the batch culture for some time, usually until close to the end of the exponential growth phase
(i.e., a period in which the number of new bacteria appearing per unit time is proportional to the present population). At this

⇑ Corresponding author.
E-mail addresses: chongyangliu@yahoo.cn (C. Liu), yt_gzh@yahoo.com.cn (Z. Gong).

0307-904X/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.apm.2012.02.044
696 C. Liu et al. / Applied Mathematical Modelling 37 (2013) 695–706

point glycerol and alkali are continuously fed into the reactor at some rates, without the removal of culture fluid. This helps
to maintain a suitable environment for the cells’ growth. At the end of the feed process, another batch phase starts again. The
above processes are repeated until the end of the final batch phase. Hence, it is decisive for improving the productivity of 1,3-
PD to optimize the feed rates and the switching instants between the batch and feed processes in fed-batch fermentation.
Determining the mathematical model can often be a very vital task since using non-accurate model in the calculations of
the optimal feed rate may lead to undesirable results. Initially, the batch model is extrapolated to fed-batch cultivation by
incorporating the dilution factors. Unstructured and nonsegregational models with specific rates of cell growth, metabolite
production, and substrate consumption have been used to model fed-batch fermentation [10–12]. The models have been
used for optimal control studies by a number of researchers [13,14]. Recently, nonlinear dynamical systems have been exten-
sively investigated to formulate the fermentation process. Based on an assumption that the feed of glycerol only occurs at
impulsive instants, nonlinear impulsive systems have been extensively investigated to formulate the fermentation process
[15–18]. Nonetheless, since the feed rate of glycerol is finite, it is not reasonable to describe the actual fed-batch fermenta-
tion by the impulsive dynamical systems. Moreover, these studies concentrate on deducing the optimality conditions of the
impulsive optimal control problem. In contrast, taking the feed of glycerol as a time-continuous process, we have proposed a
nonlinear multistage dynamical system to formulate the fed-batch process [19]. For this system, the parameter identification
problem was then investigated. Numerical simulations indicated this multistage dynamical system could describe the micro-
bial fed-batch fermentation better compared with the impulsive dynamical system [20]. Furthermore, taking the feed rate of
glycerol as the control function, a multistage optimal control model was also presented. Some computational approaches
were also developed to seek the optimal solution of the multistage optimal control problem [19,21]. Numerical results
showed that, by employing obtained optimal strategies, the concentration of 1,3-PD at the terminal time can be increased
considerably. However, in all of the above models, the switching instants between the batch and feed processes are decided
a priori.
In this paper, considering the feed process as a time-continuous process, we propose a new nonlinear dynamical system,
in which the feed rate of glycerol is taken as the control function and the switching instants between the batch and feed
processes as the variables, to formulate the fed-batch fermentation process. Especially, optimal control of such switched sys-
tem have been an active research area over the past decade, see, for example [22–25]. Nevertheless, to our knowledge, the
switched systems with continuous state constraints have rarely been considered.
Optimal control in fed-batch fermentation process is to maximize the final 1,3-PD productivity. For comparison, the
whole fermentation period is fixed. Therefore, the 1,3-PD concentration at the terminal time is taken as the performance in-
dex in this work. By the way, many studies have considered the same performance index in optimal control of the fed-batch
fermentation process [21,26,27]. Then, an optimal control problem subject to the continuous state constraints and the con-
trol constraint is presented. Incidentally, constrained optimal control problems have been extensively studied in the litera-
ture. Many interesting theoretical results can be found in [28]. For numerical computation, several successful families of
algorithms have been developed, see, for example [29–32]. In particular, the control parametrization enhancing transform
[31] has been used extensively in [33–35].
In this paper, to seek the optimal feed rate as well as the optimal switching instants in the constrained optimal control
problem, the control parametrization enhancing transform is first used to approximate the constrained optimal control prob-
lem. The constraint transcription and smoothing techniques [36] are then applied to dealing with the continuous state con-
straints. In the end, an improved Particle Swarm Optimization (PSO) algorithm is developed to solve the resultant
mathematical programming problems. Numerical results show that, by employing the obtained optimal strategy, the con-
centration of 1,3-PD at the terminal time can be increased considerably compared with previous results.
This paper is organized as follows. In the next section, Section 2, the mathematical model of the fed-batch fermentation
process is presented. Section 3 gives the constrained optimal control problem. Section 4 develops a computational approach
to solve the constrained optimal control problem, while Section 5 illustrates the numerical results. Finally, conclusions are
provided in Section 6.

2. Mathematical models in fed-batch fermentation

The fed-batch fermentation begins with a batch culture, then batch-fed glycerol and alkali are poured into the reactor in
order to provide nutrition and maintain a suitable environment for the cells’ growth. According to the actual fermentation
process, we assume that

(H1) The concentrations of reactants are uniform in the reactor, while time delay and nonuniform space distribution are
ignored.
(H2) The feeding media includes only fixed concentrations of glycerol and alkali. Moreover, the velocity ratio r of adding
alkali to glycerol is a constant.

Under the above assumptions (H1) and (H2), mass balances of biomass, substrate and products in the batch process are
written as follows:
 C. Liu et al. / Applied Mathematical Modelling 37 (2013) 695–706 697

8
> x_ 1 ðtÞ ¼ q1 ðxðtÞÞx1 ðtÞ;
>
>
>
> x_ 2 ðtÞ ¼ q2 ðxðtÞÞx1 ðtÞ;
>
>
>
< x_ ðtÞ ¼ q ðxðtÞÞx ðtÞ;
3 3 1
ð1Þ
> x_ 4 ðtÞ ¼ q4 ðxðtÞÞx1 ðtÞ;
>
>
>
>
> x_ 5 ðtÞ ¼ q5 ðxðtÞÞx1 ðtÞ;
>
>
:
x_ 6 ðtÞ ¼ 0;

where x1 ðtÞ; x2 ðtÞ; x3 ðtÞ; x4 ðtÞ; x5 ðtÞ and x6 ðtÞ are the concentrations of biomass, glycerol, 1,3-PD, acetate, ethanol and the vol-
ume of culture fluid at t in fermentor, respectively. xðtÞ :¼ ðx1 ðtÞ; x2 ðtÞ; x3 ðtÞ; x4 ðtÞ; x5 ðtÞ; x6 ðtÞÞT is the state vector. On the basis
of the previous work [37], the specific growth rate of cells q1 ðxðtÞÞ is expressed by

x2 ðtÞ
q1 ðxðtÞÞ ¼ D1 ; ð2Þ
x2 ðtÞ þ k1

where D1 is the maximum specific growth rate; k1 is the Monod saturation constant. The specific consumption rate of sub-
strate q2 ðxðtÞÞ is

q1 ðxðtÞÞ x2 ðtÞ
q2 ðxðtÞÞ ¼ m2 þ þ D2 : ð3Þ
Y2 x2 ðtÞ þ k2

In (3), m2 is the maintenance term of substrate consumption under substrate-limited conditions. Y 2 is the maximum growth
yield. D2 is the maximum increment of substrate consumption rate under substrate-sufficient conditions. k2 is the saturation
constant for substrate. The specific formation rates q‘ ðxðtÞÞ; ‘ ¼ 3; 4, of 1,3-PD and acetate are defined as
x2 ðtÞ
q‘ ðxðtÞÞ ¼ m‘ þ q1 ðxðtÞÞY ‘ þ D‘ ; ð4Þ
x2 ðtÞ þ k‘
where m‘ are the maintenance terms of product formations under substrate-limited conditions; Y ‘ are the maximum prod-
uct yields; D‘ are the maximum increments of product formation rates under substrate-sufficient conditions; and k‘ are sat-
uration constants for products. Moreover, the specific formation rate q5 ðxðtÞÞ of ethanol can be described by
 
b1 b2
q5 ðxðtÞÞ ¼ q2 ðxðtÞÞ þ ; ð5Þ
c1 þ q1 ðxðtÞÞx2 ðtÞ c2 þ q1 ðxðtÞÞx2 ðtÞ
in which b1 ; b2 ; c1 and c2 are parameters for determination of yield of ethanol on glycerol.
Due to the feed of glycerol and alkali in the fermentation process, there exist dilute effects on the concentrations of
involving substances. Consequently, the batch model can be extrapolated to the feed process by incorporating the dilution
factors. Namely, mass balances of biomass, substrate and products in the feed process are given below:
8
> x_ 1 ðtÞ ¼ ðq1 ðxðtÞÞ  DðxðtÞ; uðtÞÞÞx1 ðtÞ;
>
>
>
> cs0
x_ 2 ðtÞ ¼ DðxðtÞ; uðtÞÞð1þr  x2 ðtÞÞ  q2 ðxðtÞÞx1 ðtÞ;
>
>
>
< x_ ðtÞ ¼ q ðxðtÞÞx ðtÞ  DðxðtÞ; uðtÞÞx ðtÞ;
3 3 1 3
ð6Þ
>
> x_ 4 ðtÞ ¼ q4 ðxðtÞÞx1 ðtÞ  DðxðtÞ; uðtÞÞx4 ðtÞ;
>
>
>
> x_ 5 ðtÞ ¼ q5 ðxðtÞÞx1 ðtÞ  DðxðtÞ; uðtÞÞx5 ðtÞ;
>
>
:
x_ 6 ðtÞ ¼ ð1 þ rÞuðtÞ;

where uðtÞ 2 R1 is the feed rate of glycerol in the feed process. cs0 > 0 denotes the concentration of initial feed of glycerol in
the medium. r > 0 is the velocity ratio of adding alkali to glycerol. Since uðtÞ P 0, the volume x6 ðtÞ of solution is nondecreas-
ing and x6 ðtÞ > 0 due to the positivity of the initial volume of culture fluid. Therefore, DðxðtÞ; uðtÞÞ is the dilution rate defined
by

ð1 þ rÞuðtÞ
DðxðtÞ; uðtÞÞ ¼ : ð7Þ
x6 ðtÞ

Now, let uðtÞ be the control function and suppose the switching instant si ; i 2 f1; 2; . . . ; 2Ng, between the batch and feed
processes satisfies that 0 ¼ s0 < s1 < s2 <    < s2N < s2Nþ1 ¼ T. In particular, s2jþ1 ; j 2 K1 :¼ f0; 1; 2; . . . ; Ng is the moment
of feed glycerol and alkali, s2j ; j 2 K2 :¼ f1; 2; . . . ; Ng is the moment of ending the feed, and N is a given constant in this pa-
per. Furthermore, denote the right-hand item of the ith equation in the system (6) by fi ðxðtÞ; uðtÞÞ for each
i 2 K3 :¼ f1; 2; . . . ; 6g and let

f ðxðtÞ; uðtÞÞ : ðf1 ðxðtÞ; uðtÞÞ; . . . ; f6 ðxðtÞ; uðtÞÞÞT : ð8Þ

Then, the nonlinear dynamical system describing the whole process of fed-batch fermentation can be formulated as:
698 C. Liu et al. / Applied Mathematical Modelling 37 (2013) 695–706

8
> _
xðtÞ ¼ f ðxðtÞ; uðtÞÞ;
>
>
< uðtÞ 2 U ; t 2 ðs ; s ;
i i1 i
ð9Þ
>
> xðs i1 þÞ ¼ xð si1 Þ; i ¼ 1; 2; . . . ; 2N þ 1;
>
:
xð0Þ ¼ x0 ;

where x0 is a given initial state, the notation + indicates the limit from the right, and

½ai ; bi ; if i even;
Ui ¼ ð10Þ
f0g; if i odd:

Here, a2j1 and b2j1 ; j 2 K2 , are positive constants which denote the minimal and the maximal rates of adding glycerol,
respectively. Thus, we define the class of admissible control functions as

U :¼ fu 2 L2 ð½0; T; R1 ÞjuðtÞ 2 U i ; i ¼ 1; 2; . . . ; 2N þ 1g; ð11Þ

where L2 ð½0; T; R1 Þ is the space of square-integrable Lebesgue measurable functions from ½0; T into R1 .
Since biological considerations limit the rate of switching, there are maximal and minimal time durations that are spent
on each of the batch and feed processes. On this basis, define the set of admissible switching instants as

C :¼ fðs1 ; s2 ; . . . ; s2N ÞT 2 R2N jqi 6 si  si1 6 .i ; i 2 K :¼ f1; 2; . . . ; 2N þ 1gg; ð12Þ

where qi and .i are the minimal and the maximal time durations, respectively. Accordingly, any s 2 C is regarded as an
admissible vector of switching instants.
There exist critical concentrations, outside which cells cease to grow, of biomass, glycerol, 1,3-PD, acetate and ethanol.
Hence, it is biologically meaningful to restrict the concentrations of biomass, glycerol and products in a set W defined as

Q
6
xT ðtÞ 2 W :¼ ½x‘ ; x‘ ; 8t 2 ½0; T: ð13Þ
‘¼1

For the system (9), some important properties are discussed as follows.

Theorem 1. The function f ð; Þ in the system (9) satisfies the following conditions:
S
2Nþ1 S
2Nþ1
(a) f ð; Þ : R6þ  U i ! R6 , together with its partial derivatives with respect to x and u, are continuous on R6þ  Ui .
i¼1 i¼1
(b) f ð; Þ is affine in control u,

(c) There exists a constant K > 0 such that

S
2Nþ1
kf ðxðtÞ; uðtÞÞk 6 KðkxðtÞk þ 1Þ; 8ðxðtÞ; uðtÞÞ 2 R6þ  Ui ; ð14Þ
i¼1

where k  k is the Euclidean norm.

Proof

(a) This conclusion can be obtained by the expressions of f in (1) and (6).
(b) It is easy to verify that f is affine in control u by its definition.
(c) We can complete the proof using a method similar to the proof of Property 1 in [38]. h

Theorem 2. For each u 2 U and s 2 C, the nonlinear dynamical system (9) has a unique continuous solution denoted by xðju; sÞ.
Furthermore, xðju; sÞ satisfies the following integral equation
Z t
xðtju; sÞ ¼ x0 þ f ðxðsju; sÞ; uðsÞÞds; 8t 2 ½0; T ð15Þ
0

and is continuous in u and s.

Proof. This conclusion can be obtained from Theorem 1 and the theory of ordinary differential equations [39]. h
 C. Liu et al. / Applied Mathematical Modelling 37 (2013) 695–706 699

Theorem 3. If xðju; sÞ is a solution of the system (9) with given initial condition x0 , then it is uniformly bounded.

Proof. In view of Theorems 1 and 2, we obtain that, for each u 2 U and s 2 C,

Z t Z t
kxðtju; sÞk 6 kx0 k þ kf ðxðsju; sÞ; uðsÞÞkds; 6 kx0 k þ K kxðsju; sÞ þ 1kds; 8t 2 ½0; T:
0 0

By Gronwall inequality, it follows that

kxðtju; sÞk 6 M 01 ; 8t 2 ½0; T;
where M 01 :¼ ðkx0 k þ KTÞ expðKTÞ. h

3. Constrained optimal control problems

Basically, the control task of fed-batch fermentation lies in determination of the proper feed rate of glycerol and the
switching instants between the batch and feed processes to obtain as much 1,3-PD as possible at the terminal time of the
fermentation. Especially, physical limitations (11)–(13) are set during the fermentation process.
Then, the constrained optimal control problem may now be stated formally as:
Problem (P). Given the nonlinear dynamical system
8
> _
xðtÞ ¼ f ðxðtÞ; uðtÞÞ;
>
>
< uðtÞ 2 U ; t 2 ðs ; s ;
i i1 i
>
> xð si1 þÞ ¼ xð s i1 Þ; i ¼ 1; 2; . . . ; 2N þ 1;
>
:
xð0Þ ¼ x0
find a control u 2 U and a switching vector s 2 C such that the constraint (13) is satisfied and the cost functional
Jðu; sÞ :¼ x3 ðTju; sÞ ð16Þ
is minimized.
By similar arguments as those given for Theorem 5 in [38], we confirm the existence of the optimal solution for Problem
(P).

Theorem 4. Problem (P) has at least one optimal solution.

4. Computational approaches

In this section, we shall develop a numerical solution method to Problem (P).

4.1. Approximate problem (P(p))

For each pi P 1; i 2 f1; 2; . . . ; 2N þ 1g, let the time subinterval ½si1 ; si  be partitioned into npi subintervals with npi þ 1
partition points denoted by
sp0i ; sp1i ; . . . ; spnipi ; sp0i ¼ si1 ; spnipi ¼ si ; and spk1
i p
6 sk i :

Let npi be chosen such that npi þ1 P npi . The control is now approximated in the form of a piecewise constant function as
follows:
npi
P P
2Nþ1
up ðtÞ ¼ rpi ;k vðspi p
;sk i 
ðtÞ: ð17Þ
i¼1 k¼1 k1

p p
Here, vðspi p
;ski 
is the indicator function on the interval ðsk1
i
; ski  defined by
k1
(
p p
1; t 2 ðsk1
i
; ski ;
vðspi ;s i 
p ðtÞ ¼
k1 k 0; otherwise:
P2Nþ1
Let i¼1 npi ¼ j. Then, rp ¼ ððrp1 ÞT ; . . . ; ðrp2Nþ1 ÞT ÞT 2 Rj , where rpi :¼ ðrpi ;1 ; . . . ; rpi ;npi ÞT defines the heights of the approxi-
mate control (17). From (11), it is clear that

rpi ;k 2 U i ; k ¼ 1; 2; . . . ; npi ; i ¼ 1; 2; . . . ; 2N þ 1: ð18Þ

Let Np be the set of all those rp which satisfy the constraints (18).
700 C. Liu et al. / Applied Mathematical Modelling 37 (2013) 695–706

p
Note that ski ; k ¼ 1; 2; . . . ; npi ; i ¼ 1; 2; . . . ; 2N þ 1, taken as the decision variables will encounter numerical difficulties as
mentioned in [31]. For this reason, a control parametrization enhance transform is introduced to map these variable time
points into preassigned fixed knots in a new time scale. It is achieved by introducing a transform from t 2 ½0; T to
s 2 ½0; 2N þ 1 as follows:
_ ¼ v p ðsÞ;
tðsÞ tð0Þ ¼ 0; ð19Þ
where v p
is given by
np i
P P
2Nþ1
dki v i ðsÞ:
p
v p ðsÞ ¼ ð20Þ
i¼1 k¼1 i1þk1 k
np ;i1þnp
i i

p
In (20), dki P 0; k ¼ 1; 2; . . . ; npi ; i ¼ 1; 2; . . . ; 2N þ 1, are decision variables. Let dp be the vector whose components are
p
dki ; k ¼ 1; 2; . . . ; npi ; i ¼ 1; 2; . . . ; 2N þ 1, and Xp be the set of all such dp . Clearly,
Z s np l p    
PP
i1 dj l P
k1
p p k1 k1 k
tðsÞ ¼ v p ðgÞdg ¼ þ dj i þ dki s  i þ 1  ; 8s 2 i  1 þ ;i  1 þ ð21Þ
0 l¼1j¼1 npi j¼1 npi npi npi

and
np i
P P
2Nþ1
p
tð2N þ 1Þ ¼ dki ¼ T: ð22Þ
i¼1 k¼1

Let
wp ðsÞ ¼ up ðtðsÞÞ:
Then
npi
P P
2Nþ1
wp ðsÞ ¼ rpi ;k v i ðsÞ:
i¼1 k¼1 i1þk1 k
np ;i1þnp
i i

Define

~xðsÞ :¼ ðxðsÞT ; tðsÞÞT

and
~f ð~xðsÞ; rp ; dp Þ :¼ ððv p ðsÞf ðxðtðsÞÞ; wðsjrp ÞÞT ; v p ðsjdp ÞÞT :

xðjrp ; dp Þ be the solution of the following system corresponding to the control parameter vector ðrp ; dp Þ 2 Np  Xp :
Let ~
8
_ ~ p
< ~xðsÞ ¼ f ð~xðsÞ; r ; d Þ;
p
> s 2 ði  1; i;
~xði  1þÞ ¼ ~xði  1Þ; i ¼ 1; 2; . . . ; 2N þ 1;
>
:
~xð0Þ ¼ ðxT0 ; 0ÞT :

Then, the constraint (13) can be rewritten as

ð~x1 ðsÞ; ~x2 ðsÞ; ~x3 ðsÞ; ~x4 ðsÞ; ~x5 ðsÞ; ~x6 ðsÞÞT 2 W; 8s 2 ½0; 2N þ 1: ð23Þ
Now, we may specify the approximate problem (P(p)) as follows.
Problem (P(p)). Subject to the system of differential equations
8
_ ~ p
< ~xðtÞ ¼ f ð~xðsÞ; r ; d Þ;
p
> s 2 ði  1; i;
~xði  1þÞ ¼ ~xði  1Þ; i ¼ 1; 2; . . . ; 2N þ 1;
>
:
~xð0Þ ¼ ðxT0 ; 0ÞT

find a combined vector ðrp ; dp Þ 2 Np  Xp such that the constraints (22) and (23) are satisfied and the cost functional
Jðrp ; dp Þ :¼ ~x3 ð2N þ 1jrp ; dp Þ ð24Þ

is minimized.

4.2. Continuous state constraints

Since constraint (23) in Problem (P(p)) is a continuous state constraint, Problem (P(p)) can be viewed as a semi-infinite
programming problem. An efficient algorithm for solving optimization problems of this type is discussed in [36]. We will
now brief discuss the application of this algorithm to Problem (P(p)).
 C. Liu et al. / Applied Mathematical Modelling 37 (2013) 695–706 701

Let
g ‘ ð~xðsjrp ; dp ÞÞ :¼ ~x‘ ðsjrp ; dp Þ  ~x‘ ;
g 6þ‘ ð~xðsjrp ; dp ÞÞ :¼ ~x‘  ~x‘ ðsjrp ; dp Þ; ‘ ¼ 1; 2; . . . ; 6:
The constraint (23) is equivalently transcribed into
Gðrp ; dp Þ ¼ 0; ð25Þ
p P12 R T p
where Gðr ; d Þ :¼ l¼1 0 maxf0; g l ð~
p
xðsjr ; d ÞÞgds. However, Gð; Þ is non-differentiable at the point g l ¼ 0; l 2
p

f1; 2; . . . ; 12g. We replace (25) with

Z 2Nþ1
e e;c ðrp ; dp Þ :¼ c þ P
12
G ue ðg l ð~xðsjrp ; dp ÞÞÞds P 0; ð26Þ
l¼1 0

where e > 0; c > 0 and

8
< g;
> if g < e;
ue ðgÞ ¼ ðgþeÞ2 ð27Þ
> 4e ; if  e 6 g 6 e;
:
0; if g > e:
Thus, Problem (P(p)) is approximated by a sequence of Problems {ðP e;c ðpÞÞ} defined by replacing constraint (25) with (26).
e e;c ð; Þ can be computed by the following theorem.
Then, the gradient of the constraint G

e e;c ðrp ; dp Þ given in (26), it holds that its gradients with respect to parameterized control rp and dp
Theorem 5. For the constraint G
are, respectively,

e e;c ðrp ; dp Þ Z i1þnkp e ~xðsjrp ; dp Þ; rp ; dp ; ~kðsÞÞ

@G i @ Hð
¼ ds;
@ rpi ;k i1þk1
np
@ rpi ;k
i

and
e e;c ðrp ; dp Þ Z i1þnkp e ~xðsjrp ; dp Þ; rp ; dp ; ~kðsÞÞ
@G i @ Hð
pi ;k
¼ ds;
@d i1þk1
np
@dpi ;k
i

where

e ~xðsjrp ; dp Þ; rp ; dp ; ~kðsÞÞ ¼ P
12
Hð ue ðg l ð~xðsjrp ; dp ÞÞÞ þ ~kT ðsÞ~f ð~xðsjrp ; dp Þ; rp ; dp Þ;
l¼1

and
~kðsÞ ¼ ð~k1 ðsÞ; ~k2 ðsÞ; ~k3 ðsÞ; ~k4 ðsÞ; ~k5 ðsÞ; ~k6 ðsÞ; ~k7 ðsÞÞT
is the solution of the costate system
!T
_ e ~xðsjrp ; dp Þ; rp ; dp ; ~kðsÞÞ
@ Hð
~kðsÞ ¼ ;
@ ~x
with the boundary conditions
~kð2N þ 1Þ ¼ ð0; 0; 0; 0; 0; 0; 0ÞT ;
~kðiÞ ¼ ~kðiþÞ; i ¼ 1; 2; . . . ; 2N:

Proof. We can complete the proof using a method similar to the proof of Theorem 5.3. in [19]. h

4.3. Optimization algorithms

Each of Problems {(P e;c ðpÞÞ} is a mathematical programming problem which can be solved by various optimization meth-
ods such as gradient-based techniques [29,30]. However, all those techniques are only designed to find local optimal solu-
tions. In contrast, stochastic evolution methods generally lead to better results than deterministic ones. Among these
stochastic evolution methods, PSO algorithm introducing by Kennedy and Eberhart in [40] exhibits distinct advantages. Pres-
ently, PSO has been applied to optimizing the fermentation processes [19,41–43]. In a typical PSO, each particle ‘flies’ over
the search space to look for promising regions according to the experiences of both its own and those of the groups. Thus, the
social sharing of information takes place and individuals profit from the discoveries and previous experiences of all other
particles in a wide landscape during their search process around the better solutions. Traditionally, the original PSO method
702 C. Liu et al. / Applied Mathematical Modelling 37 (2013) 695–706

deals with unconstrained optimization problems. However, what we need to solve is an optimization problem with both
control bounds and state constraints, to which the original PSO can not be applied directly. By the way, although there exist
many constraint handling techniques in the evolutionary computation, see, for example [44], the treatment of continuous
state constraints is rarely considered. We present a handling technique for this type of constraints in the sequel. As a result,
the following strategies are added to the original PSO proposed in [40].

(I) (Handling the control constraint). If there is bound violation for a control parameter in the ith individual at the mth
step, then that parameter is generated randomly between given lower and upper bounds using the following
equation:

rpi i ;k ðmÞ ¼ rplow

i ;k
þ r pi i ;k ðrpupp
p ;k
i ;k  r i Þ;
low k 2 f1; 2; . . . ; npi g; i 2 f1; 2; . . . ; 2N þ 1g;
p ;k p ;k
where rlow i
and rupp i
are, respectively, the lower and the upper bounds of the control parameter which can be obtained by
pi ;k
(18). ri is a random parameter which is taken uniformly from ½0; 1,
(II) (Dealing with the continuous state constraints). For the parameter of the ith individual at the mth step, test the value
of G e e;c ðrpi ðmÞ; dp ðmÞÞ. If G
e e;c ðrpi ðmÞ; dp ðmÞÞ ¼ 0, then the parameterized control is feasible. Otherwise, that is,
i i
e e;c ðrpi ðmÞ; dp ðmÞÞ > 0, move the parameter towards the feasible region in the direction of  e
p p
G e;c ðri ðmÞ;di ðmÞÞ
G i p
@ r ðmÞ
and
i
e p p
G e;c ðri ðmÞ;di ðmÞÞ
 p
@di ðmÞ
with Armijo line search.
(III) (Stopping criteria). The algorithm stops when the maximal iteration M is reached.
Based on the above improved PSO algorithm, we can obtain an approximately optimal control and optimal switching in-
stants for Problem (P) as shown in the following algorithm.

Algorithm: 1
Step 1. Choose initial values of e and c.
Step 2. Solve Problem ðP e;c ðpÞÞ using the improved PSO algorithm to give ðrp; p;
e;c ; de;c Þ.
xðsjrp;
Step 3. Check feasibility of g l ð~ p;
e;c ; de;c ÞÞ P 0 for s 2 ½0; 2N þ 1; l ¼ 1; 2; . . . ; 12.

Step 4. If ðrp; p;

e;c ; de;c Þ is feasible, go to Step 5. Otherwise, set c ¼ ac. If c < c
, where c
 is a prespecified positive constant, go
to Step 6. Otherwise go to Step 2.
Step 5. Set e ¼ be. If e > e, where e is a prespecified positive constant, go to Step 3. Otherwise go to Step 6.
Step 6. If min npi P P, where P is a predefined positive constant, go to Step 7. Otherwise, go to Step 1 with npi
i2f1;2;...;2Nþ1g
increased to npi þ1 for each i.
Step 7. Stop and construct up; and sp; from ðrp; p;
e;c ; de;c Þ according to (17) and (21).
p; p;
Then, ðu ;s Þ obtained is an approximately optimal solution of Problem (P).

Remark 1. In the algorithm, e is a parameter controlling the accuracy of the smoothing approximation. c is a parameter
controlling the feasibility of the constraint (23).

Table 1
The critical concentrations and the parameters in (2)–(5).

‘ m‘ Y‘ D‘ k‘ c‘ x‘ x‘

1 – – 0.67 0.28 0.025 0.01 6

2 2.20 113.6 28.58 11.43 0.06 15 2039
3 2.69 67.69 26.59 15.50 5.18 0 1036
4 0.97 33.07 5.74 85.71 50.45 0 1026
5 – – – – – 0 60.9
6 – – – – – 4 7

Table 2
The bounds of feed rates in Phs. I–IX [19].

Phases I–II III IV–V VI VII VIII–IX

Upper bounds [mL s1] 0.2524 0.2390 0.2524 0.2657 0.2924 0.3058
Lower bounds [mL s1] 0.1682 0.1594 0.1682 0.1771 0.1949 0.2038
 C. Liu et al. / Applied Mathematical Modelling 37 (2013) 695–706 703

Remark 2. It is important for the validity of the above algorithm to choose the parameters a; b; e and c . Especially, the
parameters a and b must be chosen less than 1. e and c
 are two sufficient small values such that the algorithm is effective.

5. Numerical results

On the basis of the reactant composition, cultivation conditions, determination of biomass, substrate and metabolites
were reported in [45]. Under anaerobic conditions at 37  C and pH 7.0, the critical concentrations x and x for the cells’
growth and the parameters in (2)–(5) are listed in Table 1. Moreover, to solve numerically the nonlinear dynamical system
(9), the initial state, velocity ratio of adding alkali to glycerol, concentration of initial feed glycerol, fermentation time and the
number of switchings are x0 ¼ ð0:1115 g L1 ; 495 mmol L1 ; 0; 0; 0; 5 LÞT ; r ¼ 0:75; cs0 ¼ 10762 mmol L1 ; T ¼ 24:16 hr, and
2N ¼ 1354, respectively.
In order to save computational time, the fermentation process is partitioned into the first batch phase (Bat. Ph.) and
phases I–IX (Phs. I–IX) according to the number of switchings. The same feed strategies are adopted in each one of Ph. I
to Ph. IX. Furthermore, the time durations for two adjacent processes, i.e., a feed process and its succeeding batch process,
s1 Þ
in Ph. I to Ph. IX are equal and assumed to be 3600ðT n
s. It should be mentioned that this approach had been adopted to
obtain the experimental data in the actual fermentation process. Moreover, the bounds of feed rates in Phs. I–IX are listed
in Table 2 [19]. The bounds of the time duration in each of Phs. I–IX are listed in Table 3 [27].
In the improved PSO algorithm, the number of initial particles swarm Np, the maximal iteration Mp, the inertia weight xp ,
and the acceleration constants c1 ; c2 are, respectively, 200, 100, 0.5, 2, 2. These parameters are derived empirically after
numerous experiments. In Algorithm 1, the initial values of u and s are chosen as those in [19], the smoothing and feasible
parameters were initially selected as e ¼ 0:1 and c ¼ 0:01, and then subsequently adjusted according to the guidelines in
Algorithm 1. In particularly, the parameters a and b were chose as 0:1 and 0:01 until the solution obtained is feasible for
the original problem. The process was terminated when e ¼ 1:0  108 and c  ¼ 1:0  107 . It is worth mentioned that in

Table 3
The bounds of time durations in the Bat. Ph. and Phs. I–IX [27].

Phases Bounds Values [s] Bounds Values [s]

Bat. q1 19080 .1 19440

I q2j 2 .2j 8
ðj ¼ 1; . . . ; 28Þ q2jþ1 92 .2jþ1 98
II–V q2j 4 .2j 10
ðj ¼ 29; . . . ; 378Þ q2jþ1 90 .2jþ1 96
VI–VIII q2j 1 .2j 7
ðj ¼ 379; . . . ; 666Þ q2jþ1 93 .2jþ1 99
IX q2j 1 .2j 3
ðj ¼ 667; . . . ; 677Þ q2jþ1 97 .2jþ1 99

Table 4
The optimal switching instants in fed-batch fermentation process.

Phases Switching instants Optimal values [s]

Bat. s1 19084.9
I s2j 19084.9 + 100.282 (j  1)
(j ¼ 1; . . . ; 28) s2jþ1 19092:543 þ 100:282j
II s2j 21901.369 + 100.282 (j  29)
(j ¼ 29; . . . ; 65) s2jþ1 21892.8 + 100.282 (j  28)
III s2j 25613.049 + 100.282 (j  66)
(j ¼ 66; . . . ; 126) s2jþ1 25603.2 + 100.282 (j  65)
IV s2j 31730.356 + 100.282 (j  127)
(j ¼ 127; . . . ; 245) s2jþ1 31720.4 + 100.282 (j  126)
V s2j 43660.404 + 100.282 (j  246)
(j ¼ 246; . . . ; 378) s2jþ1 43654 + 100.282 (j  245)
VI s2j 56992.716 + 100.282 (j  379)
(j ¼ 379; . . . ; 459) s2jþ1 56991.6 + 100.282 (j  378)
VII s2j 65115.519 + 100.282j  460)
(j ¼ 460; . . . ; 522) s2jþ1 65114.5 + 100.282 (j  459)
VIII s2j 71433.213 + 100.282 (j  523)
(j ¼ 523; . . . ; 666) s2jþ1 71432.2 + 100.282 (j  522)
IX s2j 85873.987 + 100.282 (j  667)
(j ¼ 667; . . . ; 677) s2jþ1 ðj – 677Þ 85872.9 + 100.282 (j  666)
704 C. Liu et al. / Applied Mathematical Modelling 37 (2013) 695–706

0.3 0.3
Ph.I

Optimal Feeding Strategy (mL/s)

Optimal Feeding Strategy (L/h)
0.25 Bat. Ph. 0.25
0.3

0.2 0.2 0.2

0.1
0.15 0.15
0
0 2 4 6 8 10
0.1 0.1

0.05 0.05

0 0
0 1 2 3 4 5 0 20 40 60 80 100
Time (h) Time (s)

0.3 0.3
Ph.II Ph.III
Optimal Feeding Strategy (mL/s)

Optimal Feeding Strategy (mL/s)

0.25 0.25
0.3 0.3

0.2 0.2 0.2 0.2

0.1 0.1
0.15 0.15
0 0
0 2 4 6 8 10 0 2 4 6 8 10
0.1 0.1

0.05 0.05

0 0
0 20 40 60 80 100 0 20 40 60 80 100
Time (s) Time (s)

0.3 0.3
Ph.IV Ph.V
Optimal Feeding Strategy (mL/s)

Optimal Feeding Strategy (mL/s)

0.25 0.25
0.3 0.3

0.2 0.2 0.2 0.2

0.1 0.1
0.15 0.15
0 0
0 2 4 6 8 10 12 0 2 4 6 8 10
0.1 0.1

0.05 0.05

0 0
0 20 40 60 80 100 0 20 40 60 80 100
Time (s) Time (s)

0.3 0.3
Ph.VI Ph.VII
Optimal Feeding Strategy (mL/s)

Optimal Feeding Strategy (mL/s)

0.25 0.25
0.3 0.3

0.2 0.2 0.2 0.2

0.1 0.1
0.15 0.15
0 0
0 0.5 1 1.5 2 0 0.5 1 1.5 2
0.1 0.1

0.05 0.05

0 0
0 20 40 60 80 100 0 20 40 60 80 100
Time (s) Time (s)

0.3 0.3
Ph.VIII Ph.IX
Optimal Feeding Strategy (mL/s)

Optimal Feeding Strategy (mL/s)

0.25 0.25
0.3 0.3

0.2 0.2 0.2 0.2

0.1 0.1
0.15 0.15
0 0
0 0.5 1 1.5 2 0 0.5 1 1.5 2
0.1 0.1

0.05 0.05

0 0
0 20 40 60 80 100 0 20 40 60 80 100
Time (s) Time (s)

Fig. 1. The optimal feeding strategy of glycerol in fed-batch fermentation process.

the first step, a small value of c was required to ensure feasibility. After that the c hardly changed as e was decreased. The
specified constant P in Algorithm 1 is 2. Note also that only a small improvement (less than 0:01) was obtained by re-solving
the problem with 5.
 C. Liu et al. / Applied Mathematical Modelling 37 (2013) 695–706 705

1200
1,3−PD concentration in this paper.
Experimental data [18].
1,3−PD concentration in [19].
1000

Concentration of 1,3−PD (mmolL−1)

800

600

400

200

0
0 5 10 15 20 25
Fermentation Time (hr)

Fig. 2. The changes of 1,3-PD concentration with respect to time in fed-batch fermentation process.

Applying Algorithm 1 to the Problem (P), we obtain the optimal feed rates of glycerol in Phs. I–IX as shown in Fig. 1 and
the optimal switching instants listed in Table 4. Here, all the computations are performed in Visual C++ 6.0 and numerical
results are plotted by MATLAB 7.10.0. In particular, the ODEs in the computation process are numerically calculated by im-
proved Euler method [46] with the relative error tolerance 104 . In detail, the blue1 line in the first subfigure of Fig. 1 indi-
cates the feeding rate, which is identically equal to zero, of glycerol and the time duration in the Bat. Ph. Accordingly, the
blue lines in the next 9 subfigures illustrate the feed rates of glycerol in conjunction with time durations of a feed process
and its succeeding batch process in Ph. I to Ph. IX, respectively. To show the feed rates of glycerol in the feeding processes for
Ph. I to Ph. IX better, 9 small subfigures are also incorporated in the corresponding 9 subfigures, respectively.
Under the obtained optimal feed rates and the optimal switching instants, the computational concentration of 1,3-PD at
the terminal time is 1025:3 mmol L1 which is increased by 28.64% in comparison with experimental result 797 mmol L1
appearing in [18] for numerical simulation. Furthermore, compared with the obtained 1,3-PD concentration
925:127 mmol L1 in [19], which is computed in case that the same number of phases is considered and the switching in-
stants between the batch and feed processes are decided a priori, the concentration of 1,3-PD at the terminal time obtained
in this paper is increased by 10.83%. Hence, it is decisive for enhancing the productivity of 1,3-PD to optimize the feed rate of
glycerol and the switching instants between the batch and feed processes in fed-batch fermentation of glycerol to 1,3-PD.
The concentration change of 1,3-PD obtained by the optimal strategy is shown in Fig. 2. For the purpose of comparison,
the experimental data appearing in [18] and the 1,3-PD concentration obtained in [19] are also shown in Fig. 2. From
Fig. 2, we conclude that 1,3-PD concentration at the terminal time in this paper is actually higher than the ones previously
reported.

6. Conclusions

In this paper, a nonlinear dynamical system was proposed to describe the bioconversion of glycerol to 1,3-PD in fed-batch
fermentation. In order to obtain a high concentration of 1,3-PD at the terminal time, an optimal control mode subject to the
continuous state constraints and the control constraint was presented. A computational approach was developed to seek the
optimal solution of the constrained optimal control problem. Numerical results verified the validity of the mathematical
model and the effectiveness of the computational method.

Acknowledgements

The supports of the Natural Science Foundation for the Youth of China (No. 11001153), the TianYuan Special Funds of the
National Natural Science Foundation of China (No. 11126077), the Shandong Province Natural Science Foundation of China
(No. ZR2010AQ016) and the National Natural Science Foundation of China (No. 11171050) are gratefully acknowledged.

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