Chemical Engineering Science 59 (2004) 5061 – 5068

www.elsevier.com/locate/ces

Enzymatic membrane reactor for the kinetic resolution of racemic

ibuprofen ester: modeling and experimental studies
Subhash Bhatia∗ , Wei Sing Long, Azlina Harun Kamaruddin
Department of Chemical Engineering, Universiti Sains Malaysia, Engineering Campus, Seri Ampangan, 14300 Nibong Tebal, Penang, Malaysia

Received 19 February 2004; received in revised form 24 May 2004; accepted 27 July 2004
Available online 5 October 2004

Abstract
The production of (S)-ibuprofen acid was studied in a hollow fiber membrane reactor, with the aim to develop a clean and ecofriendly
technology. The modeling and simulation of enzymatic membrane reactor was studied for lipase-catalyzed hydrolysis of racemic ibuprofen
ester in hollow fiber membrane reactor. Mathematical model was developed to simulate the behavior of enzymatic reaction in the membrane
matrix region. The model equation was derived considering reaction over immobilized enzyme in the membrane porous support with
the substrate flowing along the shell side. The model was simulated on the basis of experimental operating conditions, physical and
hollow fiber geometrical parameters. The model equation was a nonlinear second-order differential equation and solved numerically using
Matlab. The parameters studied were Thiele Modulus (
2 ), Bodenstein number (B0 ), transmembrane pressure (TMP) and intrinsic enzyme
kinetic constants (Vmax and Km ). Simulation results showed that a satisfactory product separation was achieved with 60% conversion
of (S)-ester, enantiomeric excess of substrate, ees in the range 35–43%, enantiomeric excess of product, eep in the range 80–85%, and
enantiomeric ratio (E value) of 11.2–15.3 at 4.34 < B0 < 13.89 and
2 < 1. The simulated results agreed with the experimental data
within an error of ±7.5%. The reaction–separation functionality of EMR system has shown the potential of membrane reactor application
for kinetic resolution of racemic compounds especially in overcoming the difficulties associated with conventional technology particularly
in downstream separation and enzyme recovery.
䉷 2004 Elsevier Ltd. All rights reserved.

Keywords: Chiral drugs; Enzyme; Membrane; Multiphase reactor; Diffusion; Separation

1. Introduction enhances the effect of analgesia in animals (including hu-

Ibuprofen was first introduced in the market as a racemic
mixture in 1974 (Stahly and Starrett, 1997). There are many
industrial processes for (S)-ibuprofen acid, Boots and Al-
bermarle Corporation being the two major suppliers of bulk
active racemate, others include Nippon Petrochemicals,
followed by Boots–Hoechst–Celanese joint venture which
was founded in 1993 (Sheldon, 1993; Stahly and Starrett,
1997). The Boots process used isobutyl benzene as the
starting material. The pharmaceutical industries interest was
subsequently shifted to the production of (S)-(+)-ibuprofen
in 1989, when it was reported that (S)-(+)-ibuprofen rapidly
∗ Corresponding author. Tel.: +6-04-593-7788; fax: +6-04-594-1013.
E-mail address: chbhatia@eng.usm.my (S. Bhatia).
0009-2509/$ - see front matter 䉷 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.ces.2004.07.113
mans) than that of its racemate (Stahly and Starrett, 1997).
The production of optically pure (S)-ibuprofen acid is impor-
tant to avoid the consumption of unwanted (R)-enantiomer,
which is toxic to human health. Albemarle, Monsanto, Union
Carbide Corporation and Merck were later actively involved
in the production of single enantiomer (S)-ibuprofen, most
of which utilizing asymmetric routes (Liu, 1999; Laneman,
1999). The kinetic resolution route with the use of enzyme
was later developed by a number of companies including
Wisconsin Alumni Research Foundation (WARF), Sepracor,
Gist-Brocades and Rhône-Poulenc using selective hydrol-
ysis of racemic mixtures of ibuprofen esters (Stahly and
Starrett, 1997). The enzyme–substrate molecular recognition
is a critical step in enzyme-catalyzed reactions. Therefore
in this work, 2-ethoxyethyl-ibuprofen ester was chosen in
the kinetic resolution as it is an activated ester which could
5062 S. Bhatia et al. / Chemical Engineering Science 59 (2004) 5061 – 5068
enhance the lipase stereoselectivity and consequently its
affinity towards the chiral substrate.
Membrane as a carrier for enzyme immobilization was
first reported by Rony (1972), followed by Lewis and
Middleman (1974), Waterland et al. (1974) and Webster
and Shuler (1978). The reactor performance can be modeled
by formulating differential equations on the diffusion, reac-
tant consumption or product formation at each location. The
equations can be solved analytically or numerically with
appropriate boundary conditions specified to match the im-
posed operating conditions. Extensive work in this area has
been reviewed widely (Kim and Cooney, 1976; Prenosil and
Hediger, 1988; Wu et al., 1990, 1993; Salzman et al., 1999;
Calabrò et al., 2002). However, there are rarely reports on
the performance of enzymatic or multiphase membrane
reactors in chiral resolution. Matson and López (1990)
first described theoretically the phenomenon of enzymatic
kinetic resolution for a membrane reactor based on the
quantitative analyses of Chen et al. (1982). Wu et al.
(1990, 1993) worked on dimensionless analyses to examine
the effects of Thiele modulus, Biot number and enantiomer-
icratio on the performance of the separation system.
Fig. 1 shows the schematic diagram of a hollow fiber en-
zymatic membrane reactor (EMR) for the kinetic resolution
of racemic ibuprofen ester. The hydrophobic substrate is in-
troduced into the system in the organic stream in the shell
side and aqueous stream in the fiber lumen. The substrate
diffuses from the organic phase into the membrane where
hydrolysis reaction is taking place at the organic–aqueous
interface located in the membrane spongy region. Candida
rugosa lipase was used as the biocatalyst for the enzymatic
hydrolysis of racemic 2-ethoxyethyl-ibuprofen ester. This
lipase has shown great enantioselectivity in the catalysis of
(S)-ibuprofen ester. The reaction mechanism is presented
Fig. 1. Enzymatic membrane reactor setup for kinetic resolution of ibuprofen ester.
in Fig. 2. The (R)-ester is less active in the hydrolysis re-
action (Battistel et al., 1991; Giorno et al., 1997; Drioli and
Giorno, 1999; Madhav and Ching, 2001), making kS  kR
since the (S)-ester is converted to the (S)-acid at a faster rate
than the (R)-ester.
The purpose of carrying out a kinetic resolution in the
EMR is to recover the unreacted (less reactive) substrate
in the organic stream or/while enhancing the purity of one
of the product (single enantiomer) in the aqueous stream
within an acceptable range of optical purity. The efficiency
of the kinetic resolution was evaluated based on the optical
purity of the desired product, which is expressed in terms of
enantiomeric excess of the product (eep ) and also the opti-
cal purity of the remaining substrate, expressed in terms of
enantiomeric excess of the remaining unreactive substrate
(ees ). Optical purity was calculated from the molar frac-
tion of each enantiomer using the following equations (Chen
et al., 1982):
cR − c S
ees = , (1)
cS + c R
cpS − cpR
eep = (2)
cpS + cpR
cR and cS are the concentration of (R)- and (S)-ibuprofen es-
ter, respectively. cpS and cpR are the (S)- and (R)-ibuprofen
acid, respectively. The enantiomeric ratio (E) character-
izes the enantioselectivity of a particular enzyme and was
calculated from the overall hydrolysis conversion (X) and
the enantiomeric excess of the remaining substrate (Chen
et al., 1982):
ln[(1 − X)(1 − ees )]
E= . (3)
ln [(1 − X)(1 + ees )]
 S. Bhatia et al. / Chemical Engineering Science 59 (2004) 5061 – 5068
O CH3
kS
O + HO
O CRL, H2O
(S)-2-ethoxyethyl-ibuprofen ester
O kR
O CRL, H2O
O
(R)-2-ethoxyethyl-ibuprofen ester
Fig. 2. Lipase-catalyzed hydrolysis of racemic ibuprofen esters (CRL: Candida rugosa lipase).
X is calculated from initial concentration of racemic ibupro-
fen ester (c0 ) using Eq. (4); XS is the conversion of (S)-
ibuprofen ester based on initial (S)-ester concentration (cS0 )
given in Eq. (5).
c0 − cS
X= , (4)
c0
cS0 − cS
XS = . (5)
cS0
The Michaelis–Menten constants, Vmax and Km can also be
used to calculate the E value as
(Vmax /Km )(S)-ester
E= . (6)
(Vmax /Km )(R)-ester
In the present work, a model equation of kinetic resolu-
tion taking place in a hollow fiber membrane reactor has
been proposed by incorporating enzymatic reaction and mass
transfer for kinetic resolution of (R,S)-ibuprofen ester. A
good kinetic resolution of racemic ibuprofen ester in terms
of high chemical and optical yields of (S)-ibuprofen acid is
to be achieved in the enzymatic membrane reactor. The en-
zymatic kinetic resolution was measured in terms of enan-
tioselectivity and optical purity. The target values of ees
and eep were 50%, 90% respectively and E > 10 (Sheldon,
1993; Bornscheuer, 2000). The reliability of the model equa-
tion was verified by comparison with experimental data and
extension of the previous work reported (Long et al., 2003).
The model developed serves two purposes: (i) parameters
estimation for the design and operation of the EMR for
production of optically pure compound; (ii) optimization
of operational parameters of EMR to improve the kinetic
resolution process.
2. Materials and method
2.1. Enzymes and chemicals
Lipase from Candida rugosa EC 3.1.1.3 (Type VII, 724
units per mg solids) was obtained from Sigma-Aldrich
(MI). (R,S)-ibuprofen acid 99% and (S)-ibuprofen acid 99%
were purchased from Acros (Belgium). Other chemicals
5063
COOH
H O
(1)
(S)-ibuprofen acid 2-ethoxyethanol
COOH
CH3
H O
+ HO (2)
(R)-ibuprofen acid 2-ethoxyethanol
and reagents used were of analytical grade. The racemic
ethoxyethyl-ibuprofen ester was chemically synthesized
in the laboratory based on a method reported by Battistel
et al. (1991).
2.2. Enzyme immobilization on membrane reactor
The hollow fiber membrane module used was Koch ul-
trafiltration membrane HF1.0-45-XM50 (Koch Membrane
Inc, USA) made of hydrophilic polyacrylonitrile material.
2 g/L of Candida rugosa lipase solution was prepared using
phosphate buffer at pH 8. Enzyme immobilization on the
membrane spongy layer was carried out by ultrafiltration of
1 L lipase solution from shell side to fiber lumen with TMP
of 35 kPa and flow rate 300 mL/min at room temperature.
The volume of the buffer collected from the permeate and
retentate were recorded for protein measurement based on
BCA standard test tube protocol (Pierce, Rockford, IL). The
amount of protein (lipase) adsorbed onto the fibers of the
hollow fiber membrane reactor was measured as the differ-
ence between the protein content of the lipase buffer solu-
tions before and after the immobilization procedure.
2.3. HPLC analysis
The concentration of the optically pure (R)- and (S)-
enantiomer of ibuprofen ester and ibuprofen acid from
the hydrolysis reaction was determined by HPLC (Shid-
mazu Model 10VP, Japan) analysis using a reversed phase
(R,R)-Whelk-O1 Chiral Column (Regis Pirkle, USA)
with a UV detector. The mobile phase used was hex-
ane/isopropanol/acetic acid (98:2:0.5).
2.4. Modeling of enzymatic hydrolysis reaction in the
membrane matrix
The reaction rate of the enzymatic hydrolysis reaction was
obtained from the kinetic study based on rapid equilibrium
assumption by incorporating uncompetitive substrate inhi-
bition (i.e., (S)-ibuprofen ester) and noncompetitive product
inhibition (i.e., by-product 2-ethoxyethanol) (Long, 2004).
5064 S. Bhatia et al. / Chemical Engineering Science 59 (2004) 5061 – 5068

The reaction rate is presented as Eq. (7): Table 1

Membrane module characteristics and physical parameters
Vmax cS
=
 , (7) Present study
cb c2
(Km + cS ) 1 + + S a (mm) 0.56 (0.022 in)
KIp KI s
c (mm) 1.12 (0.044 in)
b/a 1
where cb is the byproduct concentration of alcohol; KIp
c/a 2
is the product inhibition constant for 2-ethoxyethanol and MWCO, Daltons 50000
KI s is the substrate (ibuprofen ester) inhibition constant. Nominal membrane area, (m2 ) 0.093 (1.0 ft 2 )
The enzymatic hydrolysis of racemic ibuprofen ester took No. of fibers, N 65
place with the immobilized lipase in the membrane porous Internal fiber radius, a (mm) 0.56
Skin thickness, b-a (mm) 0.0001
matrix, at which the substrate flows in from the shell side.
Porous support, c-b (mm) 0.56
The reaction layer represented the boundary between water Active fiber length, L (cm) 43.2
and organic phase at which lipase was active. The following Porosity, p 0.8
assumptions were made in the development of the model:

(1) Steady state operation; equation becomes:

(2) Homogeneous enzyme distribution in the porous sup-
port; d 2 CS 1 dCS
+ (B0 + 1)
(3) Validity of Fick’s law; dR 2 R dR
(4) The diffusion coefficients for ibuprofen acid and ester
2 CS
= (12)
were assumed to be the same. (1 + p )(CS / + 1) + (CS2 s /)
Eq. (8) represents the model equation accounting the hydrol-  is molar fraction of byproduct and substrate ( =cb /cS0 ).
ysis kinetics of racemic ibuprofen ester and mass transfer in Similarly, the mass balance equation for the less reactive
a hollow fiber membrane reactor: (R)-ibuprofen ester was related to E value by the following

2  expression:
dcS d cS 1 dcS
u(r) + Deff + = p . (8) d 2 CR 1 dCR
dr dr 2 r dr + (B0 + 1) ·
dR 2 R dR
The model equation includes the expression for the convec- (
2 /E)CR
tive flux and enzymatic rate equation. u(r) is the radial flow = , (13)
(1 + p )(CR / + 1) + (CR2 s /)
velocity expressed as (Prenosil and Hediger, 1988):
where CR denotes the dimensionless concentration of the
F
u(r) = , (9) (R)-ester. Other dimensionless groups are defined as:
2LrN
F Km a 2 p Vmax
where F is the volumetric flow rate of substrate stream; L B0 = ; = ;
2 = ;
is the effective length of fiber; r is the fiber radius and N is 2LN D eff cS0 Km Deff
cS0 cb
the number of fibers. The driving force was predominantly s = ; p = (14)
KI s KIp
induced by pressure difference across the membrane where
radial convection was the only mass transport in the porous cs0 is the initial substrate concentration of (S)-ibuprofen
support. ester at fiber external radius (i.e., surface concentration
Initially, there is no substrate in the spongy matrix and it at r = c). B0 is the Bodenstein number which is the ra-
was assumed that the enzyme concentration in the spongy tio of convective mass transfer to effective diffusivity
matrix is constant. It was also assumed that the bulk substrate (Prenosil and Hediger, 1988).  represents the dimension-
concentration was equal to the substrate concentration at the less Michaelis–Menten constant;
2 is the Thiele modulus
external surface of the membrane. The boundary (r = c) for enzymatic hydrolysis of ibuprofen ester which refers
and centerline symmetry (r =b) conditions in dimensionless to intrinsic reaction–diffusion process as a measure of
form are given as mass-transfer limitation for a particular enzymatic reac-

 tion (Bailey and Ollis, 1986); a is the length of internal
R dCS fiber radius; Deff is the effective diffusion coefficient for
CS + = 1, R = c/a, (10)
B0 dR ester; s is the dimensionless substrate inhibition constant
and p is the dimensionless product inhibition constant for
dCS
= 0, R = b/a. (11) 2-ethoxyethanol.
dR Table 1 shows the physical parameters of the membrane
Eq. (8) was transformed into dimensionless form after in- module used in the present research. The collocation tech-
corporating reaction rate equation (Eq. (7)) and the resultant nique was employed in the solution of one-dimensional
 S. Bhatia et al. / Chemical Engineering Science 59 (2004) 5061 – 5068 5065

boundary value problem of ordinary differential equation by
means of Matlab boundary value problems solver.
3. Results and discussion
The reaction model equation (Eq. (12)) was simulated on
the basis of experimental operating conditions, physical and
geometric variables, e.g., fiber geometry, number of fibers,
the axial and radial Peclet numbers. Only radial coordinates
were considered since axial gradient was too small in com-
parison to radial gradient. The hydrophobic racemic ibupro-
fen ester diffuses from the organic phase into the membrane
surface, partitions and diffuses within the hydrophilic mem-
brane where it is converted to a polar (S)-ibuprofen acid
by lipase. The input parameters used in the simulation were
obtained from the experimental results and are presented
in Table 2. The effective diffusivity (Deff ) of substrate and
product in the hollow fiber membrane was calculated based
on a method given by Treybal (1981) and Wu et al. (1993).
with the reactor geometry, kinetic parameters, feed substrate
concentration and process variables (Eq. (14)). The E value
of the immobilized lipase obtained from the experiment was
in the range 11.2–15.3 and was higher than the target value of
E > 10. A good fit was observed between simulated results
and experimental values within an error of ±7.5%.
3.2. Effect of Bodenstein number (B0 )
The EMR performance was studied by simulation of
model incorporating the effect of B0 (which relates propor-
tionally to volumetric organic flow rate) on the efficiency
of kinetic resolution. The efficiency of kinetic resolution
was measured by parameter ees (enantiomeric excess of
the residual substrate) and the results are shown in Fig. 4.
Fig. 4 shows the dimensionless concentration profile across
the porous membrane support, at which a constant profile
across the membrane matrix (1 < R < 2) was observed. The
concentration profiles of the (S)-ibuprofen ester are only

3.1. Comparison between simulated results and 100

experimental data
90

The model reliability was verified by comparing the simu- 80

lated results obtained from the model with the experimental 70
data obtained from the kinetic resolution carried out in the
ees, eeP (%)

60 Exp. ees
enzymatic membrane reactor. Enzyme loading is an impor-
50 Exp. eep
tant factor controlling the optical purity of (S)-acid and (R)-
ester. A parameter that incorporates the enzyme loading is Sim.ees
40
the Thiele Modulus (
2 ), a function of membrane porosity Sim.eep
30
(p ), Km , Vmax , effective diffusivity of substrate (Deff ) and
fiber internal radius (r). Fig. 3 compares both the experimen- 20
tal and simulated results for the influence of hydrolysis con- 10
version on ees and eep at fixed parameters of
2 =0.01, B0 =
0
13.89 and =1.46. The E value was determined experimen- 0 5 10 15 20 25 30
tally prior to solving Eqs. (12) and (13). The resultant con-
centration profiles ofCS and CR were used for the computa- Overall conversion, X (%)
tion of ees and eep using Eqs. (1) and (2), respectively. The Fig. 3. Comparison between experimental and simulated results on the
actual operating conditions were manipulated based on these influence of hydrolysis conversion on ees and eep at
2 =0.01, B0 =13.89
dimensionless numbers since the parameters were associated and  = 1.46.

Table 2
Input parameters obtained from experimental results for simulation of reaction in the membrane matrix

Parameter Description Simulated range Experimental value

Vmax (mmol L−1 h−1 ) Maximum reaction rate for racemic ester 2.8–10 3.27
Km (mmol L−1 ) Michaelis–Menten constant for racemic ester 25–50 36.74
KI s (mmol L−1 ) Substrate inhibition constant for ester 40–80 49.52
KIp (mmol L−1 ) Product inhibition constant for alcohol 250–1000 354.20
Cs0 (mmol L−1 ) Initial concentration of (S)-ibuprofen ester 5–200 25
Deff (cm2 min−1 ) Effective diffusivity of ibuprofen ester and acid 4 × 10−5 − 4 × 10−4 3.23 × 10−4
p Dimensionless product inhibition constant 0.01–0.25 0.03
s Dimensionless substrate inhibition constant 0.25–8 2
 Dimensionless Michaelis–Menten constant 0.73–7.3 1.5

2 Thiele modulus 0.1–10 0.002–0.65
5066 S. Bhatia et al. / Chemical Engineering Science 59 (2004) 5061 – 5068
Fig. 4. Effect of
2 on concentration profiles at  = 1.46 and B0 = 13.89.
shown. The concentration of the less reactive substrate is not
shown as its concentration was relatively low.
The B0 was studied in the range of 4.34 to 34.73 (equiva-
lent to 25 < F < 200 mL/ min) at fixed  =3.65 and
2 =1.
The B0 was varied from the lower limit of B0 = 4.34 since it
was impractical to operate the system below the flow rate of
25 mL/ min due to unstable conditions. These F values were
the flow rates of bulk ester at the shell side. An ees value
of 7.96% was obtained at single passage of fiber with B0
approaching 4.34. This indicates that lower volumetric flow
rates resulted in better resolution. This was probably due to
the diffusive transport limitation of the substrate in the radial
direction (lateral migration) at increased flow rate (higher
B0 ). The increase in B0 value shows a reduced ees value
attainable across the fiber centerline. A drastic reduction of
initial substrate concentration at the beginning of aqueous-
organic boundary layer (at the boundary R=2) was observed
(Fig. 4). Therewas an intense reaction layer (i.e., the spongy
matrix) at which the substrate simultaneously reacted with
the active immobilized enzyme as a result of rapid diffusion
of the substrate molecules into the membrane pore.
3.3. Effect of Thiele modulus (
)
Thiele Modulus has the physical interpretation of a first-
order reaction rate (since ester hydrolysis was presumed to
be independent of water concentration and the reaction is
pseudo first-order type) divided by a diffusion rate.
2 is the
ratio of the reaction rate occurring on the membrane surface
to the molecular diffusion rate in the radial direction. A large
value of
2 (
2 > 1) indicated the reaction was diffusion
limited and small value of
2 (
2 < 1) means the reaction
was limited by reaction kinetics rather than diffusion.
Fig. 5 shows the predicted substrate concentration profiles
at
2 = 0.1, 0.5, 1, 10 and 20 at fixed value of B0 = 13.89
and  = 1.46. The Michaelis–Menten parameters are given
Fig. 5. Effect of B0 on concentration profiles at
2 = 1 and  = 3.65.
in Table 2. It was found that increased enzyme loading (in-
crease in
2 ) resulted in decreased substrate concentration
across the spongy region. This is because higher enzyme
loading (higher
2 ) indicated higher enzyme activity in the
membrane.
2 value of 0.1 implies that the reaction on the
surface is so slow and no diffusional limitations exist. Thus
no significant concentration gradient could build up within
membrane matrix in the direction normal to the membrane.
An increase of
2 resulted in a steep gradient of the simu-
lated conversion of (S)-ibuprofen ester, due to fast reaction
rate in the membrane matrix. Over the values of
2 = 10
and 20, diffusional limitations had a profound effect on de-
creasing the yield of pure (S)-enantiomer and intraparticle
diffusion limitation probablyoccurred.
3.4. Effect of dimensionless Michaelis constant ()
The dimensionless Michaelis Constant () is a mea-
sure of the coupling effect of Km and cs0 . The effect of
dimensionless Michaelis Constant is shown in Fig. 6. The
(S)-ibuprofen ester concentration was varied from 5 to
50 mM at fixed
2 = 1, B0 = 13.89 (F = 80 mL/ min) and
Km = 36.74 mmol L−1 (obtained from experiment). The
figure shows almost zero substrate concentration gradient
in the radial concentration at R = 1, due to the fact that
the substrate could not leave the layer because it does not
dissolve in the aqueous phase.
3.5. Relationship between enzyme loading, effective
diffusion coefficient and Thiele modulus
The effective diffusion coefficient (Deff ) is a function of
enzyme loading and serves as one of the variables deter-
mining the value of Thiele Modulus (
2 ). Table 3 shows
the value of effective diffusion coefficient (Deff ) at various
enzyme loading on the spongy layer. The resultant value of
 S. Bhatia et al. / Chemical Engineering Science 59 (2004) 5061 – 5068 5067

100
Cs0 = 50 mmol L ; Θ = 0.73
-1
Dimensionless Concentration, C

1 ees = 0.18 % 90
ees = 2.76 % Cs0 = 30 mmol L-1; Θ = 0.12
0.995 80
Cs0 = 25 mmol L-1; Θ = 1.46
ees= 3.17 % 70
0.99
Cs0 = 10 mmol L ; Θ = 3.65
-1

eeP (%)
60
0.985
ees = 4.90 % 50
0.98 40 Sim.at Thiele Modulus=0.002
Cs0 = 5 mmol L-1; Θ = 7.3 Sim.at Thiele Modulus=0.011
0.975 30
Sim.at Thiele Modulus=0.65
0.97 20 Exp. at [E]=0.92 g /m2
ees = 5.67 % Exp. at [E]=1.78 g/m2
10
0.965 Exp. at [E]=2.85 g/m2
1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2
0
Radial Coordinate, R
0 10 20 30 40 50 60 70 80 90 100
Fig. 6. Effect of  on concentration profiles at
2 = 1 and B0 = 13.89. Conversion of (S)-Ibuprofen Ester (%)

Fig. 8. Comparison between experimental and simulated results on the

effect of
2 on (S)-ester conversion and optical purity of (S)-acid product.
Table 3
Parameters used in the simulation
the remaining less reactive substrate (ees ) increased with
[E] (g/m2 ) Deff (cm2 / min)a Vmax (mmol l−1 h−1 )b
2 conversion whereas the optical purity of the (S)-acid product
0 4.890 × 10−3 — — decreased with conversion at all enzyme loading. However,
0.14 2.843 × 10−3 — — the overall ees values were seen to decline with increase in
0.92 1.291 × 10−3 1.89 0.002 the value of
2 . The same qualitative trend was also ob-
1.78 3.228 × 10−4 3.27 0.011 served inthe eep -
2 relations. An increase in enzyme load-
2.85 1.004 × 10−5 5.69 0.65
ing resulted in a higher Thiele Modulus due to elevated rate
a Determined experimentally. constant as well as a concomitant decrease of the effective
bValues obtained enzyme kinetic study from hydrolysis reaction in the
diffusivity (Prazeres et al., 1993; Wu et al., 1993). The ees
EMR. and eep values achieved were 35–40% and 80–85%, respec-
tively within this loading range. These results were close to
100
the target values of 50% ees and 90% eep .
Exp.at [E]=0.92g/m2 Figs. 7 and 8 also show that the predicted ees and eep
90
Exp.at [E]=1.78g/m2 values (curves shown by
2 ) were of the same order of mag-
80 Exp.at [E]=2.85g/m2 nitude as that obtained from the experiments. This revealed
Sim.at Thiele Modulus=0.002 that a good agreement was achieved between experimen-
70
Sim.at Thiele Modulus=0.011 tal data and simulated results at a maximum difference of
60 Sim.at Thiele Modulus=0.65 ±4.8%. The conversion played an important role in deter-
eeS (%)

50 mining the optical purity of less reactive (R)-ibuprofen ester.

40
Although substrate conversion increased with increasing en-
zyme loading (or Thiele Modulus,
2 ), it is associated with
30 reduced ees and eep values.
20 The key parameters responsible for the highest optical pu-
10
rity in the kinetic resolution of racemic ibuprofen ester in an
EMR were low organic flow rate, sufficient amount of en-
0 zyme loading, high Deff , high Vmax and low Km . Depending
0 10 20 30 40 50 60 70 80 90 100
on whether optically pure product or substrate are of inter-
Conversion of (S)-Ibuprofen Ester (%)
est, a kinetic resolution should be performed to reach either
Fig. 7. Comparison between experimental and simulated results on the conversion of less than 50% in order to achieve high eep
effect of
2 on (S)-ester conversion and optical purity of the remaining or conversion of more than 50% for high ees (Bornscheuer
less reactive (R)-ester. et al., 2000).

4. Conclusions

2 calculated from Eq. (14) is given in the last column.
Figs. 7 and 8 show the effect of (S)-ester conversion on ees The mathematical model representing the diffusion
and eep at different enzyme loading. The optical purity of of (S)-ibuprofen acid and the hydrolysis reaction in the
5068 S. Bhatia et al. / Chemical Engineering Science 59 (2004) 5061 – 5068
membrane matrix was developed. The optimum para-
meters obtained from the simulation results were:
4.34 < B0 < 13.89 at
2
1. The concomitant optimum
experimental operating conditions could be devoted: or-
ganic flow rate of 80 mL/min in the lumen (B0 = 13.89)
and TMP of 40 kPa. An increase in enzyme loading re-
sulted in a higher Thiele Modulus and a reduction in eep ,
ees and conversion respectively. The ees and eep values
were 43% and 85%, respectively at (S)-ester conversion of
60% (XS = 60%) at enzyme loading of 1.92–1.78 g/m2 .
The E value obtained was in the range of 11.2–15.3. The
simulated results were in agreement with the experimen-
tal data. The results were close to the desired values of
ees = 50%, eep = 90% and E > 10. The present study
has shown that EMR system is a promising route for the
production of single-enantiomer compounds by kinetic
resolution as this technology leads to the achievement of
optical purities of the remaining substrate and the desired
product.
Acknowledgements
The authors would like to acknowledge the IRPA long-
term grant supported by Malaysian Ministry of Science,
Technology and Environment which resulted in this article.
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