Sep Puriff Tech 41 (2005) 237-266 NR 3 Sep Acizi Org-Stanoiu A

Separation and Purication Technology 41 (2005) 237266
Review
Recovery and separation of organic acids by membrane-based solvent
extraction and pertraction
An overview with a case study on recovery of MPCA
S. Schlosser
, R. Kert esz, J. Mart ak

Department of Chemical and Biochemical Engineering, Slovak University of Technology, Radlinsk eho 9, 81237 Bratislava, Slovakia
Received 20 October 2003; received in revised form 14 July 2004; accepted 16 July 2004
Abstract
Various possibilities of the application of membrane-based solvent extraction (MBSE) and pertraction in recovery and separation of organic
acids, and in biotransformations are discussed. A short overview of the subject literature is presented. Factors, which have to be considered
in the development of MBSE application, will be discussed. Hybrid processes employing MBSE will be covered as well. Mass-transfer
characteristics of hollow ber contactors for MBSE of organic acids are presented. The kinetics of formation and decomposition of the
permeantextractant complex may inuence greatly the mass-transfer rate and should be taken into account in modelling. A case study on
recovery of 5-methyl-2-pyrazinecarboxylic acid (MPCA) by simultaneous MBSE and membrane-based solvent stripping shows potential of
this process. Optimised process parameters for MPCA are suggested on bases of simulations. Outlook for future applications of HF contactors
in extraction separations is discussed and potential for progress is envisaged, especially for higher value acids and integrated or hybrid
reaction-separation systems.
2004 Elsevier B.V. All rights reserved.
Keywords: Recovery; Separation; Organic acids; 5-Methyl-2-pyrazinecarboxylic acid; Solvents; Liquid membranes; Membrane-based solvent extraction;
Membrane-based solvent stripping; Pertraction; Hollow ber contactors; Simulation
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239
2. Recovery and separation of organic acids, integrated and hybrid processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
2.1. Recovery of organic acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
2.2. Separation of organic acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
2.3. Separation of isomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
2.4. Bioproduction of organic acids integrated with separation or downstream processing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247
2.5. Extractive biotransformations of organic acids in integrated and hybrid systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
3. Formulation of solvent and liquid membrane. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
3.1. Extractants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
3.2. Diluents and modiers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Presented in part at the membrane science and technology conference PERMEA 2003, Tatransk e Matliare, Slovakia, September
711, 2003 (http://sschi.chtf.stuba.sk/permea/).
Corresponding author. Tel.: +421 2 524 96743; fax: +421 2 524 96920.
E-mail address: schlosser@cvt.stuba.sk (
S. Schlosser).
1383-5866/$ see front matter 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.seppur.2004.07.019
238

S. Schlosser et al. / Separation and Purication Technology 41 (2005) 237266
3.3. Ionic liquids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
3.4. Toxicity and compatibility of solvent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
3.5. Co-transport and competitive transport (selectivity) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
4. Membrane contactors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
4.1. Factors affecting the performance of contactors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
4.2. Modelling and mass-transfer characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
5. Case studyrecovery of MPCA. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Nomenclature
A surface area (m
2
)
A
w
arithmetic mean value of the inner and outer
geometric surface areas of bers (m
2
)
c molar concentration of the solute (undissoci-
ated acid or acid in the complex) (mol m
3
)
D distribution coefcient ()
k individual mass-transfer coefcient (ms
1
)
K
e
overall mass-transfer coefcient in the extrac-
tor (ms
1
)
K
s
overall mass-transfer coefcient in the stripper
(ms
1
)
n molar ux (mol s
1
)
N
cs
number of contactors in series ()
N
ct
total number of contactors (both in parallel and
series) ()
r
e
rate constant of the extraction reaction, Eq. (3)
(ms
1
)
r
s
rate constant of the stripping reaction, Eq. (4)
(ms
1
)
R overall mass-transfer resistance (s m
1
)
Re Reynolds number ()
u linear velocity of the ow (ms
1
)
V volumetric owrate (m
3
s
1
)
Y
MA/OA
ratio of mineral acid to organic acid ux ()
Z concentration factor of the solute in the con-
centrate (output from the stripper) dened by
relation Z = c
R,n+1
/c
F1
()
n+1
concentration ratio
n+1
= c
S,n+1
/c
S,n+1
(ap-
proach to an equilibrium on the rafnate end
of the contactor in MBSE, c
S,n+1
= D
F
c
F,n+1
)
()
porosity of the wall ()
e
yield of the solute in extraction ()
conv
conversion of the reagent in the stripping solu-
tion ()
Subscripts
0 initial value
1 feed or stripping solution inlet end of a HF con-
tactor or a series of contactors
2 rafnate or stripping solution outlet end of a
HF contactor or a series of contactors
b boundary layer in the bulk phase
e extractor (MBSE)
F feed phase, feed boundary layer
i inner surface of the ber wall
n number of the contactor segments
o outside surface of the ber wall
R stripping solution; stripping interface
s stripper (MBSS)
S solvent phase, boundary layer in the solvent
w ber wall
Abbreviations
6-APA 6-aminopenicillanic acid
AOT sodium di(2-ethylhexyl)sulfosuccinate (an-
ionic surfactant)
BLM bulk liquid membrane
CF HF cross-ow hollow ber contactor
D2EHPA di(2-ethylhexyl)phosphoric acid
DLC double Lewis cell with layered BLM
DNNSA dinonylnaphtalenesulfonic acid
EC equilibrium cell for contacting two liquids
ELM emulsion liquid membrane
EXT solvent extraction
FSC at sheet contactor
HF hollow ber
MBSE membrane-based solvent extraction
MBSS membrane-based solvent stripping
MHS multimembrane hybrid system (LM between
two ion-exchange membranes)
MIBK methylisobutylketone
S. Schlosser et al. / Separation and Purication Technology 41 (2005) 237266 239

Abbreviations
MPCA 5-methyl-2-pyrazinecarboxylic acid
PAA phenylacetic acid
PF HF parallel ow hollow ber contactor
PT pertraction
RFC rotating lm contactor with BLM
SLM supported liquid membrane
TOA trioctylamine
TOMAC trioctylmethylammonium chloride
TOPO trioctylphosphine oxide
1. Introduction
Recovery and concentration of organic acids, as well as
separation of acid mixtures, have attracted a great interest
of researchers, especially in connection with their recovery
from fermentation broths, reaction mixtures and waste solu-
tions. Several older reviews including membrane-based sol-
vent extraction (MBSE), pertraction, solvent extraction and
extractive fermentations or bioconversions have been pub-
lished [18]. These papers partly covered also recovery of
organic acids, but a need for an updated review in this area
was actual.
Several processes employing partitioning of components
on one or two L/L interfaces have been developed to achieve
separation of mixtures. Membrane-based solvent extraction
is a relatively new alternative of classical solvent extraction
where mass-transfer between immiscible liquids occurs from
the immobilised L/L interface at the mouth of pores of a mi-
croporous wall, as shown in Fig. 1a and in detail in Fig. 2.
Basic information on MBSE is given in papers [5,912]. The
solvent can be regenerated by MBSS where the solute is re-
extracted into the stripping solution. Another method of re-
generation could be distillation of the volatile solvent, etc.,
depending on properties of the system. A schematic ow
sheet of the simultaneous MBSE and MBSS processes with
closed loop of the solvent is shown in Fig. 3. In this way,
recovery of the solvent and concentration of the solute can
be achieved. Preferable contactors for MBSE and MBSS are
Fig. 1. Processes with immobilised L/L interface(s). (a) Membrane-based solvent extraction (MBSE), (b) pertraction through supported liquid membrane
(SLM), (c) pertraction through bulk liquid membrane (BLM) with two immobilised L/L interfaces in a hollow ber (HF) contactor. F: feed (donor) phase, HF:
hollow ber (microporous, hydrophobic), M: membrane phase, R: stripping (acceptor) solution, S: solvent.
Fig. 2. Detail view of the two-phase system in membrane-based solvent
extraction (MBSE).
hollow ber contactors, which will be discussed in Section
4.
Extraction into capsules with a solvent, e.g. recovery of
phenylethanol (a product of phenylalanine bioconversion by
yeast) [13] or lactic acid from fermentation broth [14], at-
tracted an interest, recently. The polymeric core of the cap-
sule prevents direct contact of the solvent with biomass. This
process could be regarded as a batch MBSE.
An interesting variant of MBSE with dual mechanism of
separation is extraction from an ion exchange membrane,
which has been suggested by Kedem and Bromberg [15]
and Isono et al. [16,17]. The separation is performed by L/L
partitioning and is enhanced by an electrostatic rejection in
the ion exchange membrane, as will be described in Section
2.1.
A different approach used by Pronk [18] was revis-
ited by Isono et al. [19]. The fresh solvent with dissolved
reagents, N-(benzyloxycarbonyl)-l-aspartic acid (ZA) and
l-phenylalanine methyl ester (PM), was supplied to the sys-
tem and dispersed (emulsied) in an aqueous solution with
enzyme (Thermoase C-160). The reagents were deliberated
to the aqueous phase where they reacted via enzymatic
reaction. The product, N-(benzyloxycarbonyl)-l-aspartyl-l-
phenylalanine methyl ester (ZAPM, which is an aspartame
precursor) was extracted to the solvent and removed from a
reactor through a hydrophobic microporous membrane. C
4
to
C
7
alcohols, preferably 1-hexanol and 1-heptanol, were used
as the solvent. This biphasic hybrid process with an enzyme
240

Fig. 3. Flowsheet of MBSE with simultaneous regeneration of the solvent
by MBSS in HF contactors and recirculation of the solvent to extraction. In
both contactors the solvent ows in the contactor shell.
reaction and extractive separation allowed a continuous and
stable ZAPM production.
Aprocess similar to extraction, which is based on the same
mechanisms, is pertraction (PT) through a liquid membrane
where both extraction and stripping of the solute are realized
in one equipmenta three-phase contactor with two L/L in-
terfaces [6,12,2023]. Three types of liquid membranes (LM)
can be used, supported, bulk and emulsion LM. The sup-
ported liquid membrane (SLM) is formed by soaking the sol-
vent into pores of a microporous wall (with a pore diameter
preferably under 1 m), as schematically shown in Fig. 1b.
As examples can be given pertraction of propionic acid [24],
lactic acid [25] and phenylalanine [26] through SLM. A se-
rious problem, which has not been solved up to now, is the
short lifetime of SLM. This shortcoming could be overcome
by using bulk liquid membranes (BLM), with advantage in
the hollow ber (HF) contactor, shown in Fig. 1c [6,2729].
No problem with lifetime of BLM occurs. This is paid by a
doubled wall and a thicker liquid membrane layer between
walls (bulk membrane), comparing with SLM, what results
in higher mass-transfer resistance [12].
A rotary disc pertractor with BLM was suggested in pa-
pers [20,30] and widely studied in Boyadzhiev group also
for recovery of organic acids [3134]. In this contactor hy-
drophilic discs are xed on a rotating horizontal shaft. The
lower parts of the discs are immersed in compartments, which
are alternately lled with the stripping solution and the feed.
The remaining parts of the discs, on which lms of aque-
ous phases are formed due to rotation, are immersed in the
membrane phase. Mass transfer from the feed lms into the
stripping solution lms through the bulk liquid membrane
occurs.
Pertraction of acids from the feed into an emulsion of
the stripping solution is another conguration of the pertrac-
tion process. The continuous phase of emulsion acts as an
emulsion liquid membrane (ELM). In systems where aque-
ous solutions are separated, the membrane is formed from
the immiscible organic phase separating the aqueous feed
and the stripping solutions. Numerous papers on pertraction
of organic acids into emulsion have been published, e.g. for
lactic acid [35], phenylalanine [36,37], cephalosporin [38],
etc. Demirci et al. [39] suggested process where lactic acid is
pertracted into emulsion of the stripping solution owing in
the shell of the HF contactor. Thus, contact of three phases
is realized in this system.
Several mechanisms to achieve transport of solute(s)
through the L/L interface or through a liquid membrane can
be utilised. The separation mechanism could be based on
differences in physical solubility of the solutes or their solu-
bilisation into the solvent or reverse micelles or on the chem-
istry and rate of chemical or biochemical reactions occur-
ring on L/L interface(s). The complexing or solubilisation
agentextractant (carrier in the liquid membrane) forms by
reversible reaction complex(es) or aggregate(s) with the so-
lute, whichare soluble inthe solvent or membrane. The chem-
istry of reactive extraction and stripping in MBSEand MBSS,
as well as in PT, is identical with the classical solvent ex-
traction or stripping and is presented in several books, e.g.
[4,40,41].
Recently, enzymatic reactions on L/L interfaces were em-
ployed to achieve separations [4247]. An example of the
mechanismof transport through LMfacilitated by enzymatic
reactions is schematically shown in Fig. 4 [45]. The aque-
ous feed, e.g. a mixture of phenylacetic acid (PAA) and 6-
aminopenicillanic acid (6-APA) and the stripping phases ow
in the lumen of hydrophobic hollow bers with microporous
walls. Fibers are immersed in the immiscible organic phase
forming a liquid membrane. Carboxylic acid R
A
COOH (in
this example PAA), reacts at the L/L interface with alcohol
(ethanol was added to the feed) under the catalytic action
of enzyme E1 (lipase Candida rugosa, CLR) and the ester
formed dissolves in the membrane (in this example 20 vol.%
octanol in heptane) and is transported through it. On the
downstream L/L interface deesterication reaction proceeds
catalysed by ester E2 (lipase from porcine pancreas, PPL)
and PAAis deliberated to the stripping solution with a higher
pH than in the feed. The second acid R
B
COOH (6-APA) is
not transported via this mechanism. Thus, separation of acids
occurs, in the mentioned example the separation factor was
as high as 10. Physical solubility of acid in the membrane
can be an additional mechanism of its transport through the
membrane.
To avoid direct contact of biomass with the liquid mem-
brane, whose components are not seldom toxic, a multimem-
brane hybrid system (MHS) with both extraction and strip-
ping L/L interfaces immobilised in ion-exchange polymer
membranes was suggested by Kedem et al. [48,49]. MHS
was studied for the separation of carboxylic acids by Wodzki
and coworkers [5052].
The aim of this paper is an overview of recent publica-
tions on membrane-based solvent extraction (MBSE) and se-
lected papers on pertraction and classical solvent extraction
(including L/L equilibrium measurements) of organic acids,
both with stress on works, where hollow ber contactors are
applied or some less common acids are involved. Factors
inuencing formulation or selection of the solvent or mem-

Fig. 4. Scheme of the enzyme-facilitated transport of carboxylic acid through a bulk liquid membrane in a three-phase HF contactor, according Dai et al. [45].
brane phase for specic application will be discussed. Mass-
transfer characteristics of HF contactors will be presented, as
well. Based on experimental data a case study on recovery of
5-methyl-2-pyrazinecarboxylic acid (MPCA), an intermedi-
ate of industrial interest, by simultaneous MBSE and MBSS
will be discussed.
2. Recovery and separation of organic acids,
integrated and hybrid processes
There are several modes of operation of the separation
process to achieve the recovery or separation of organic acids:
(a) Simple process for the separation of reaction mixtures,
e.g. downstream processing in biotechnologies, or waste
solutions.
(b) Integrated processes where separation is accomplished in
parallel equipment connected to a reactor by circulation
loop. An example of an integrated fermentation process
is shown in Fig. 5 and will be discussed in Section 2.3.
(c) Hybrid systems where reaction(s) and separation are car-
ried out simultaneously in one equipment, as will be dis-
cussed in Sections 2.2 and 2.4 with an example shown in
Fig. 6.
It is worth to mention one of the rst widely studied in-
tegrated processesextractive fermentation for ethanol pro-
duction, which has been intensively studied up to a small
pilot plant stage [5355]. Compared to the continuous con-
ventional fermentation of a 195 g/Lglucose medium, the vol-
umetric productivity was more than doubled in an extractive
mode, with no deleterious effects on cell viability, specic
glucose consumption rate or ethanol yield. Despite a longer
effort, the economy of this process was not favourable to be
applied in a large scale [8]. A similar situation could occur in
application of extractive processes connected with recovery
of organic acids from fermentation broth or other technolog-
ical streams. The present costs for HF contactors limit the
application of MBSE mostly to higher added value products
or to cases where both rafnate and concentrate could be
economically utilised.
Analytical applications of pertraction through supported
liquid membranes are wide, as reviewed in papers [5662].
The analysis of various organic acids has been studied in
papers [6366], amino acids in papers [6774], acidic drugs
Fig. 5. Schematic owsheet of the fermentation unit with integrated MBSE and MBSS circuit for recovery of acids (product) from the fermentation broth.
242

Fig. 6. Scheme of the three-phase system in a hybrid extractive membrane
reactor for enzymatic transformation of reactant.
[62,7577], herbicides [78] and phenols and their derivatives
in papers [7982]. Equipment with planar SLM [5659] and
SLM in a hollow ber form [60,62,7578,8284] is used in
analytical applications.
2.1. Recovery of organic acids
Papers on MBSEand MBSS of various types of individual
organic acids and selected papers on their pertraction (mostly
in HF contactors) and extraction are listed in Tables 14.
Chemistry (mechanism) of L/L extraction, MBSE, MBSS
and pertraction are practically the same. Thus, information
on one process could be useful for another of the mentioned
processes. Papers on pertraction of organic acids through liq-
uid membranes facilitated by enzymatic reactions are given
in Table 5.
The recovery of phenol from the hydrocarbon fraction
with a phenol concentration of 24 wt.%by MBSS into an al-
kali solution has been recently applied industrially in Poland
[85,86]. The capacity of the plant with two rigs in series,
each with eight parallel HF contactors Liqui Cel 4 in. 28 in.
(Celgard) is about 650 kg h
1
. Both the hydrocarbon raf-
nate with less than 0.02 wt.% of phenol and the phenolate
concentrate (2530 wt.%) are recycled back to the technol-
ogy producing the waste stream. This probably resulted in a
favourable economy of the process.
Processes for recovery of valuable organic acids of indus-
trial interest fromaqueous waste solutions froman enzymatic
resolution process have been developed for dimethylcyclo-
propanecarboxylic acid (DMCCA) [87,88] and 5-methyl-2-
pyrazinecarboxylic acid (MPCA) [89,90] and will be dis-
cussed for the latter acid in Section 5. Recovery of DMCCA
froma highly acidic waste solution with pHbelow2 contain-
ing about 19 kg m
3
of DMCCA by MBSE and MBSS or
pertraction was suggested [88]. A solvent with 0.4 kmol m
3
of TOA in n-alkanes (dodecane fraction) was used [29,87].
A recovery of more than 90% of DMCCA and a concentrate
with about 200 kg m
3
of DMCCA was achieved.
Removal of p-nitrophenol from an aqueous solution, sim-
ulating wastewater, by MBSEin HFcontactors has been stud-
ied by Tompkins and coworkers [91,92]. Study on treatment
of wastewater containing nitrophenol by pertraction through
an emulsion liquid membrane is published in paper [93].
Recovery of sulfanilic acid from wastewater by MBSE in
HF modules with the ber length of 33.5 cm and the inner
ber diameter of 0.4 mm with the solvent containing 20%
trioctylamine, 30%octanol and 50%kerosene is described in
paper [158]. The distribution coefcient of sulfanilic acid is
concentration dependent and its value is 1.42 and 26.03 at the
equilibrium aqueous concentrations 70.2 and 701.2 g m
3
,
respectively. MBSE was found to be an efcient process with
recovery of acid up to 90% in the given contactor. Removal
of aconitic and oxalic acids from cane molasses and from
mixtures of organic acids by pertraction through supported
liquid membranes studied McMurray and Grifn [114].
Enzymatic reactions on L/Linterfaces open a newinterest-
ing way how to achieve separations. Papers on pertraction of
organic acids through liquid membranes facilitated by enzy-
matic reactions, described in Section 1, are listed in Table 5.
Some papers will be presented in Section 2.2 in more detail.
2.2. Separation of organic acids
Separation of mixtures of organic acids by MBSE and
pertraction is discussed in papers presented in Table 6. Some
papers on separation of organic acids by pertraction through
a liquid membrane facilitated by enzymatic reactions are
shown also in Table 5.
Separation of long-chain unsaturated fatty acids, e.g. oleic
andlinoleic acids, byMBSEbetweentwosolvents, acetonitril
and n-heptane, has been studied by Matsuba [175]. Solvents
owed countercurrently, acetonitril along the shell and n-
heptane in the lumen of a PTFE microporous tube (i.d. 2 mm,
pore size 1 m, tube length 5 m). Introduction of the acid
mixture feed in the middle of the shell was advantageous.
At low throughputs the equivalent length of one theoretical
stage was about 0.8 m and the purity of oleic acid of about
76%.
Isono et al. [16,17] studied a new process where
solvent extraction from a charged polymeric membrane
was performed in order to obtain a higher selectivity
by liquidliquid partitioning and electrostatic rejection ef-
fects. Aternary mixture of N-(benzyloxycarbonyl)-l-aspartic
acid (ZA), l-phenylalanine methyl ester (PM), and N-
(benzyloxycarbonyl)-l-aspartyl-l-phenylalanine methyl es-
ter (ZAPM) was used as the model system. Using a positively
charged membrane, only ZAPM was extracted into the or-
ganic phase and separations between ZA or PM and ZAPM
were achieved. The utility of this hybrid separation system
was demonstrated. Tert-amyl alcohol was used as solvent and
Selemion AMV or ASV membranes. The membrane with a
smaller pore size showed higher selectivity.
Wodzki and Nowaczyk [52] studied separation of propi-
onic and acetic acid in pertraction through a multimembrane
hybrid system. Addition of an extractant, TOPO or TBP, to
n-hexane increased the ux through the multimembrane, but
the value of the separation coefcient decreased. The ux in
binary transport of acetic and propionic acids is larger than
the sumof uxes of individual acids. It should be stressed that

Table 1
Papers on MBSE or MBSS of carboxylic acids and selected papers on their pertraction (PT) and solvent extraction (EXT)
Acid Process Solvent (extractant/diluent) Contactor type Literature
Acetic acid MBSE TOA/(MIBK; octanol; n-alkanes) HF [94]
PT Amines/n-alkanes FSC [24]
PT in MHS (TOA; TOPO; TBP)/hexane FSC [50,52]
EXT (Aliquat 336; TBP; TOPO; Alamine
336)/xylene
EC [95]
EXT Tertiary amines/diluents EC [96]
Propionic acid MBSE; PT (SLM) Amines/n-alkanes PF HF FSC [24]
MBSE TOA/xylene PF HF [97]
PT in MHS (TOA; TOPO; TBP)/hexane FSC [50,52]
Butyric acid MBSE, MBSS TOA/n-alkanes CF HF [98100]
MBSE, MBSS Amines/(corn oil, oleyl alcohol) CF HF [101]
PT (BLM) TOA/n-alkanes PF HF [98,102,103]
PT (layered BLM) TOA/n-alkanes DLC [104]
Valeric acid MBSE, MBSS Amberlite LA-2/toluene PF HF [105108]
EXT (Amines; Aliquat 336; TBP)/(kerosene; n-
heptane; toluene)
EC [109]
Dimethylcyclopropan-carboxylic acid (DMCCA) MBSE TOA/n-alkanes CF HF [87]
PT TOA/n-alkanes PF HF [29,87,110]
5-Methyl-2-pyrazinecarboxylic acid (MPCA) MBSE, MBSS TOA/xylene CF HF [89,90,111]
PT (layered BLM) TOA/xylene DLC [112]
Succinic acid MBSE n-Butanol FSC [113]
Aconitic, oxalic, malic acids PT (SLM) TBP/Shellsol 2046 FSC [114]
Abbreviations used are explained in Nomenclature.
Table 2
Papers on MBSE or MBSS of hydroxycarboxylic acids and selected papers on their pertraction (PT) and solvent extraction (EXT)
Lactic acid MBSE, MBSS PT Tertiary amines/(n-alkanes, isodecanol, isotridecanol) CF HF PF HF (PT) [115]
MBSE, MBSS Aliquat 336/Shellsol A PF HF [108,116]
MBSE TOPO/kerosene PF HF [117]
MBSE (TOA; TOPO)/(oleyl alcohol, n-hexane) PF HF [118]
MBSE Alamine 336/(kerosene, oleyl alcohol) PF HF [119]
MBSE, MBSS Alamine 336/2-octanol HF [120]
MBSE, MBSS (Amines; Aliquat 336)/(n-alkanes; oleyl alcohol) PF HF [121]
MBSE TOA/xylene CF HF [97]
MBSE TOMAC/oleyl alcohol PF HF [122]
MBSS TOMAC/oleyl alcohol PF HF [123]
MBSE, MBSS TOMAC/1-decanol CF HF [124]
MBSE into capsules with solvent TOPO, TOA, TBP Packed column [14]
PT Tertiary amines/(n-alkanes, isodecanol, isotridecanol) PF HF [115,125]
PT (EML) TBP/(isooctane, SPAN80) HF [39]
PT (ELM) Amines/n-alkanes Agitated vessel [35]
PT (SLM) TOA/xylene FSC [25]
EXT (Amines; TOA; TOPO; TOMAC; TBP)/(kerosene; hex-
ane; toluene; oleyl alcohol)
EC [126]
EXT (Amines; trialkylphosphinoxides)/(kerosene; oleyl alco-
hol)
EC [127]
EXT in situ Alamine 336/oleyl alcohol Agitated vessel [128]
Citric acid MBSE TOA/xylene CF HF [97,129]
PT (BLM) TOA/MIBK PF HF [130]
PT (SLM) Amines/(hydrocarbons, alcohols) FSC [25,131]
PT (ELM) Alamine 336/(n-alkanes and chloroform) Agitated vessel [132]
244

Table 3
Papers on MBSE or MBSS of amino acids and antibiotics and selected papers on their pertraction (PT) and solvent extraction (EXT)
Phenylalanine MBSE Aliquat 336/(kerosene, isodecanol) PF HF [133,134]
MBSE, MBSS TOMAC/(n-heptane, hexanol) PF HF [135]
MBSE, MBSS Aliquat 336/xylene HF [136]
MBSE, MBSS D2EHPA/n-alkanes CF HF [137]
MBSE AOT/oleyl alcohol PF HF [138]
PT (SLM) D2EHPA/n-alkanes FSC [26]
PT (SLM) D2EHPA/n-heptane HF [139]
PT (ELM) D2EHPA/dodecane Agitated vessel [36]
PT (ELM) D2EHPA/n-alkanes Agitated column [140]
PT (BLM) D2EHPA/kerosene DLC [141]
PT (ELM) Agitated vessel [37]
PT (BLM) D2EHPA/n-alkanes RFC [32]
l-Isoleucine PT (BLM) D2EHPA/kerosene DLC [142]
Phenylalanine, l-isoleucine EXT Reversed micelles with polyoyalkylene
copolymers/(octanol, xylene)
EC [143]
l-Lysine PT (BLM) D2EHPA/n-alkanes RFC [31]
Tryptophan, dipeptide MBSE PT (SLM) AOT/oleyl alcohol PF HF [138]
Tryptophan MBSE Aliquat 336/Shellsol A PF HF [108]
N-(Benzyloxycarbonyl)-l-
aspartyl-l-phenylalanine methyl
ester
MBSE tert-Amylalcohol FSC [16,17]
Antibiotics: Penicillin G MBSE, MBSS Amberlite LA2/(kerosene, isodecanol) CF HF [144,145]
MBSE, MBSS Amberlite LA2/kerosene PF HF [146]
MBSE, MBSS Amberlite LA2/(butylacetate; decanol) HF [147]
PT PF HF [148]
PT (ELM) Amberlite LA2/kerosene Agitated column [149]
Cephalosporine MBSE Aliquat 336/n-heptane PF HF [150]
PT (ELM) Aliquat 336/(n-heptane, kerosene) Agitated vessel [38]
Cephalexin [151]
Erythromycin PT (SLM) Decanol FSC [152]
Tylosin PT (BLM) Isodecanol; octanol RFC [33,34]
Bacteriocins (nisin, variacin,
carnocin)
EXT Alkanes, toluene, decanol, butylacetate EC [153]
Table 4
Papers on MBSE or MBSS of other organic acids, phenol and its derivatives and selected papers on their pertraction (PT) and solvent extraction (EXT)
Mevinolinic acid (MV-819) MBSS, MBSE Isopropyl acetate PF HF [154]
4-Methyltiazole, 4-cyanothiazole MBSE Toluene; benzene PF HF [155]
Diltiazem PT (BLM) Decylalcohol PF HF [156]
7-Aminocephalosporanic acid PT (BLM) Aliquat 336/butylacetate DLC [157]
p-Aminobenzenesulfonic acid MBSE TOA/(kerosene, octanol) PF HF [158]
2-Aminoethanesulfonic acid EXT Ionic liquids EC [159]
Nucleotides (adenosine derivatives) PT Quaternary ammonium salt/isooctane DLC [160]
Oxygenates (aromas) from citrus oil MBSE, MBSS Cyclodextrine derivatives PF HF [161]
Phenol MBSE Cyanex 923/kerosene PF HF [162]
MBSE, MBSS Cyanex 923/n-alkanes CF HF [163,164]
MBSE, MBSS 1-Decanol and other solvents CF HF [107,124,165]
MBSE N,N-di(1-methyl-heptyl) acetamide/kerosene PF HF [166]
MBSE Aliphatic alcohols PF HF [167]
MBSS Aromatic hydrocarbons CF HF [85,86]
MBSS MIBK PF HF FSC [168]
PT Cyanex 471X/n-alkanes PF HF [169,170]
PT (BLM) Alkylcyclohexane PF HF [171,172]
PT (ELM) Shellsol T (parafnic solvent) Agitated vessel [173]
Nitrophenol MBSE 1-Octanol PF HF [91]
MBSS 1-Octanol PF HF [92]
PT (ELM) Kerosene Agitated vessel [93]

Table 5
Papers on pertraction of organic acids through liquid membranes facilitated by enzymatic reactions on L/L interfaces
Acid(s) Enzyme(s) Liquid membrane Contactor type Literature
2-Phenoxypropionic, phenylacetic and man-
delic acids
Two lipases Isooctane (layered BLM) DLC [42,43]
Phenylacetic and mandelic acids; pheny-
lacetic acid and 6-amino-penicillanic acid
(separation of acids)
Two lipases 20 vol.% octanol in n-heptane (BLM) Three phase PF HF [45]
Aromatic carboxylic acids Two lipases Isooctane and other HC (SLM) FSC [47]
Ionic liquids (SLM) FSC [174]
S,R-ibuprofen (separation of enantiomers) Two lipases Ionic liquids (SLM) FSC [46]
the transport rate in the MHS system is lower than through
a simple liquid membrane due to additional diffusion resis-
tance in ion-exchange membranes.
The separation of penicillin G from phenylacetic acid
(PAA) by pertraction through SLMwith Amberlite LA-2 dis-
solved in 1-decanol, supported on a microporous polypropy-
lene membrane was studied by Lee [176]. The individual per-
meability of each component in the mixture was lower than
that in a single component system. This suggests a strong
transport competition effect between components. The max-
imum separation factor was found to be 1.8 under a liquid
membrane resistance controlled mechanism.
Based on distribution coefcients of individual amino
acids Kelly [177] estimated separation factors as a ra-
tio of individual distribution coefcients for extractants
D2EHPAand dinonylnaphtalenesulfonic acid (DNNSA) dis-
solved in toluene were estimated. Separation factors calcu-
lated for pairs of amino acids were within the range of 2.0
(glycineaspartic acid) to 20.1 (alanineglycine) and should
be validated.
Alipase-facilitated selective and continuous separation of
difcult-to-separate mixtures of organic acids has been de-
veloped in a HF contactor with BLM [45]. The contactor
consists of two bundles of well-mixed hydrophobic microp-
orous polypropylene hollow bers. The solvent and separa-
tion mechanism used in this system are described in Section
1 and Fig. 4. Separation of two binary acid mixtures was
studied: (1) phenylacetic acid (PAA) and mandelic acids; (2)
PAAand6-aminopenicillanic acid(6-APA). The strippingso-
lution enriched in PAA. The separation factors of PAA over
mandelic acid and PAA over 6-APA were as high as 20 and
10, respectively. Much higher enzyme activities and enzyme
stability were achieved in the HF contactor due to immobil-
isation of enzyme by adsorption and continuous removal of
the ester produced. The transport rate of PAA in the HF con-
tactor was 224 times higher than the maximumrate measured
in batch experiments.
2.3. Separation of isomers
Separation of isomers, especially enantiomers, attracted
a great interest of researchers. Related papers are listed in
Table 7. Hybrid processes for enzymatic resolution of enan-
tiomers or their derivatives are of great importance and are
given in Table 8. Selective pertraction of enantiomers through
liquid membranes facilitated by enzymatic reactions on L/L
interfaces, presented in Table 5, can be also used for their sep-
aration. Lipase-facilitated transport of (S)-ibuprofen through
Table 6
Separation of mixtures of organic acids and their derivatives
Acids Separation process Solvent (extractant/diluent) Contactor type Literature
Oleic, linoleic acids MBSE Acetonitril andn-heptane (distributionbe-
tween two organic solvents)
HF (single tube) [175]
N-(benzyloxycarbonyl)-l-aspartic
acid, l-phenylalanine methyl ester,
N-(benzyloxycarbonyl)-l-aspartyl-l-
phenylalanine methyl ester
MBSE from charged membrane tert-Amyl alcohol FSC [16,17]
Acetic and propionic acids PT (MHS with BLM) No carrier/(C
6
C
10
alkanes, toluene, cy-
clohexane, octanol, MIBK)
FSC [51]
(TBP, TOPO, TOA)/n-hexane FSC [50,52]
Penicillin G, phenylacetic acid PT (SLM) Amberlite LA-2/1-decanol FSC [176]
Lactic and citric acids PT (SLM) TOA FSC [25]
Amino acids EXT (D2EHPA; DNNSA)/toluene EC [177]
Succinic and acetic acids EXT Tertiary amine/(octanol; n-heptane) EC [178]
Binary mixtures of lactic, propionic,
dichloroacetic, trichloroacetic, and hy-
drochloric acids
EXT (Primene JMT, tris(2-ethylhexyl)amine,
TOA)/various diluents
EC [179]
Binary mixtures of lactic, glutaric, malic, and
maleic acids
EXT Primene JMT/various diluents EC [180]
246

Table 7
Separation of enantiomers, structural isomers and stereo-isomers
Isomers Selector (extractant)/diluent Separation process Contactor type Literature
Leucine N-n-dodecyl-l-hydroxyproline/octanol MBSE PF HF [184]
N-(3,5)-dinitrobenzoyl-leucine (S)-N(1-naphthyl)leucine ester or amide/ hex-
ane
MBSE, MBSS PF HF
a
[183]
Norephedrine, etc. R,R- and S,S-dihexyltartrate or R,R- and S,S-
tartaric acid/heptane
MBSE PF HF [185]
Propanolol (S,S)-di-n-dodecyltartrate/chloroform MBSE PF HF [108]
o-, p-Nitroaniline or cis-, trans-stilbene Cyclodextrin derivatives in aqueous BLM PT (BLM) PF HF [181]
Phenylalanine Cu(II) N-n-decyl-l-hydroxyproline/(Paranox
100, hexanol, decane)
PT (ELM) Batch mixer [186,187]
Amino acids Crown ethers/(2,2,4-trimethylpentane or
chloroform)
PT (layered BLM) DLC [188,189]
Series of amino acids hydrochlorides Nopol or (2S)-()-methyl-1-butanol PT (SLM) FSC [190]
Triptophan; -phenylethylamine Chiral phosphoric and phosphonic acid es-
ters/dihexylether
PT (SLM) FSC [72,74]
Mandelic acid Cinchonidine/(dodecane, decanol 1:1) PT (BLM) DLC [191]
a
Hydrophilic bers.
SLM based on ionic liquids is an example of this novel ap-
proach [46]. Separation of structural isomers of o- and p-
nitroaniline and stereoisomers of cis- and trans-stilbene by
pertraction in a HF contactor were presented by Mandal et al.
[181]. Kinetic resolution of chiral aromatic amines with -
transaminase using an enzyme-membrane reactor combined
with MBSE of ketone in HF contactor increased enantiosep-
aration, as shown in paper [182].
Chiral selectors developed for chromatography could be
promising for larger scale separation of enantiomers by
MBSE in HF contactors. Chiral selectors derived from N-
(1-naphthyl)leucine have been used in a HF contactor with
hydrophilic bers (Sepracor) to separate the enantiomers of
amino acid derivatives [183]. Enantiomeric purities exceed-
ing 95% have been obtained in a single pass through the
system.
A successful industrial application of hybrid system with
a HF contactor for production of the drug dilthiazem inter-
mediate was reported by L opez and Matson [44]. Aplant was
built for enzymatic resolution of dilthiazem chiral interme-
diate in an extractive enzymatic membrane reactor. This is
the rst published industrial application of HF contactors in
a hybrid bioreactor. A two (three) phase system involved in
this process is schematically shown in Fig. 6. The enzyme is
entrapped in the macroporous sponge part of the hydrophilic
hollow ber membrane made of a polyacrylonitrile copoly-
mer. The enzyme is loaded to the membrane during ultraltra-
tion of an aqueous enzyme solution owing at the beginning
in the shell of a HF contactor. A dense layer of the mem-
brane (skin), retaining enzyme, is on the inner side of the
hollow ber. After immobilisation of the enzyme in the wall,
a toluene solution of reactant, racemic ()-trans-methyl-
methoxyphenylglycidate, is owing in the shell. In the ber
lumen an aqueous buffer solution with bisulte anion ows
countercurrently. The enzymatic deestericationcatalysedby
lipase proceeds on the L/Linterface. The deliberated (2S,3R)-
Table 8
Hybrid processes with enzymatic resolution of enantiomers or their esters
Enantiomers or
their esters
Preferentially transported
or formed compound
Enzyme Solvent
(membrane)
Separation
process
Contactor
type
Literature
()-trans-Methyl-
methoxyphenyl-glycidate
in toluene
(2S,3R)-methoxyphenyl-
glycidic acid
Lipase Aqueous buffer MBSS PF HF
a
[44]
Phenylalanine methylesters d-Phenylalanine
methylester
-Chymotrypsin (D2EHPA, TOMAC,
AOT)/isooctane
MBSE PF HF [192]
1-Phenyl-1,2-ethanediol 2-Hydroxy-acetophenone Glycerol dehydroge-
nase
Hexane MBSE PF HF [193]
Phenylalanine methylesters l-Phenylalanine -Chymotrypsin solu-
tion in emulsion
n-Alkanes, cyclohexane,
kerosene
PT (ELM) Batch mixer [194]
Phenylalanine isopropylesters
hydrochloride
R-Phenylalanine Esterase Subtilisin
Carlsberg
N,N-Diethyldodecan-
amide/dodecane
PT (SLM) PF HF [195]
Ibuprofen (S)-Ibuprofen Two lipases Ionic liquids PT (SLM) FSC [46]
1-(2-Naphthyl)-ethanol ester (S)-1-(2-Naphthyl)-
ethanol
Lipase Peruoro-hexanes PT (layered BLM) U-tube [196]
a
Hydrophilic bers.

methoxyphenylglycidic acid is extracted to the buffer. The re-
quired product (2R,3S)-methyl-methoxyphenylglycidate re-
maining in toluene is an intermediate for dilthiazem synthe-
sis. In the commercial plant with a capacity of 75 tonnes per
year, which has been built in Japan, 24 contactors with a
surface area of 60 m
2
each are installed.
Two chiral alcohols, (1R)-(+)-6,6-dimethylcyclo-
[3.1.1]hept-2ene-2-ethanol (nopol) and (2S)-()-methyl-1-
butanol, immobilised in the pores of a polyethylene lm
were used for the enantioselective transport of amino acid
hydrochloride as described by Bryjak et al. [190]. The
stereoselectivity of the pertraction varied from 0.39 to
1.52 depending on both the type of the chiral membrane
phase and the properties of the amino acid. SLM with
nopol was more efcient. Enzymatic resolution of racemic
1-phenyl-1,2-ethanediol was carried out by enantioselective
oxidation combined with MBSE in HF contactor. The
product inhibition is overcome by continuous extraction
[193].
Enantioselective transport of ibuprofen through SLMwith
ionic liquid facilitated by enzyme (lipase) catalyzed reactions
on interfaces was studied by Miyako et al. [46,47]. Resolu-
tion of 1-(2-naphthyl)ethanol was achieved by a combina-
tion of an enzyme-catalysed kinetic resolution with a u-
orous triphasic separative reaction [196]. Peruorohexanes
were used as a liquid membrane. Highly enantioselective hy-
drolysis of (R,S)-phenylalanine isopropyl ester by Subtilisin
Carlsberg was achieved in a continuous production of (S)-
phenylalanine in a HF contactor with liquid membrane as a
reactor [195].
2.4. Bioproduction of organic acids integrated with
separation or downstream processing
A scheme of an integrated process for the fermentation
production of organic acids and MBSE with MBSS for re-
covery of acid from a broth is shown in Fig. 5. The installed
periodical bleed and feed operation of the fermenter may
lead to continual or semicontinual operation of fermentation
[197]. Removal of the product from a broth can avoid prod-
uct inhibition and increase the productivity of fermentation
[101,198,199]. The solvent can be regenerated by stripping,
as shown in Fig. 5, or in case of volatile acids (acetic and pro-
pionic acid) by vacuum distillation [200]. More lipophilic
acids with low water solubility in undissociated form, e.g.
DMCCAand MPCA, can be separated fromthe loaded strip-
ping solution by decreasing its pH well under acid pK
a
when
organic layer of acid is formed. Lean stripping solution can
be recirculated to the MBSE. Papers on formation of inte-
grated or hybrid systems with MBSE, some of them using
HF contactors, are shown in Table 9. Design and optimisa-
tion of reactive extraction for organic acids recovery is also
addressed in literature [201203].
A fully integrated process for the microbial production
and recovery of the aromatic amino acid l-phenylalanine
is presented in papers [199,218,219]. Using a recombinant
l-tyrosine (l-Tyr) auxotrophic Escherichia coli production
strain, a fed-batch fermentation process was scaled-up from
a 20-L scale to 300-L pilot scale. In technical scale fer-
mentation l-phenylalanine was continuously recovered via
a fully integrated reactive extraction system with simulta-
neous MBSE and MBSS in HF contactors. This prevented
product inhibition of microbial l-phenylalanine production.
Concentration factor higher than 4 was achieved in the strip-
ping phase. A doubling of l-Phe/glucose yield was observed
when kerosene/D2EHPA was added to the fermentation so-
lution in the bioreactor to simulate a fully integrated l-
phenylalanine separation process. The nal product purity
after l-phenylalanine precipitation was higher than 99%.
Production of propionic acid by fermentation is hindered
by low productivity and product inhibition [221]. An extrac-
tive fermentation process using a secondary amine extractant
and a HF contactor to selectively extract propionic acid from
the fermentation broth was developed to produce propionate
from lactose by Propionibacterium-Acidipropionici [209].
Compared to the conventional batch fermentation, the ex-
tractive fermentation had ve-fold higher productivity, more
than 20% higher propionate yield, higher nal product con-
centration (75 g L
1
or higher), and higher product purity.
Acetate and succinate production in the extractive fermen-
tation were signicantly reduced. The improved fermenta-
tion performance can be attributed to the reduced product
inhibition and a possible metabolic pathway shift to favour
more propionic but less acetic and succinic acid production.
The process was stable and gave consistent long-termperfor-
mance over the 1.5-month period studied.
Cell immobilization to increase productivity and extrac-
tive fermentation to reduce product inhibition were investi-
gated [198]. Propionic acid concentration in the extractive
fermentation was maintained at 13 g L
1
by concurrent ex-
traction with a liquid extractant consisting of 40 vol.% trilau-
rylamine in oleyl alcohol (a nal concentration of 71 g L
1
propionic acid was obtained in non-extractive mode). Yields
of propionic and acetic acids were doubled and higher overall
productivities were obtained in the extractive fermentation.
The extractant also exhibited selectivity for propionic acid
over acetic acid, thus partially purifying the former. In both
fermentation modes, productivity was enhanced by cell im-
mobilization in calcium alginate beads. An economic analy-
sis of a modied version of the fermentation based on several
favourable assumptions showed that the extractive fermen-
tation could, at best, approach economic feasibility. For the
assumed conditions, the production cost of the propionic acid
was 1.16 US$ kg
1
. This cost was reduced to 0.94 US$ kg
1
when the value of the acetic acid by-product was included.
An extractive fermentation process for production of bu-
tyric acid from glucose, using immobilised cells of Clostrid-
iumtyrobutyricumin a brous bed bioreactor, was developed
[101]. The solvent with 10 vol.% of Alamine 336 in oleyl al-
cohol was used. Simultaneous MBSE and MBSS were done
inHFcontactors for selective removal of butyric acidfromthe
fermentation broth. The fermentation pH was self-regulated
248

Table 9
Production of organic acids by extractive fermentations with integrated or in situ extractive separation of acid or with downstream recovery of acid from broth
Product Process for separation of acid Solvent (extractant/diluent) Contactor type Literature
Acetic and butyric acids PT (SLM) TOPO/kerosene FSC [204206]
EXT (Oleyl alcohol, isodecanol)/ kerosene EC [207]
Acetic acid MBSE Amines/(MIBK, chloroform) HF [94]
Propionic acid MBSE TOPO/kerosene PF HF [24,208]
EXT Trilaurylamine/(octanol, dodecanol,
oleyl alcohol)
EC [200]
MBSE HF [198]
MBSE, MBSS Di-tridecylamine/oleyl alcohol PF HF [209]
Butyric acid MBSE, MBSS Amines/(corn oil, oleylalkohol) CF HF [101]
EXT in situ Hostarex A327/oleyl alcohol Agitated vessel [210,211]
Lactic acid MBSE in situ Alamine 336/oleyl alcohol HF in fermenter [119]
MBSE TOMAC/oleyl alcohol PF HF [122]
MBSE TOA, Amberlite LA2 PF HF [121]
PT (EML) TBP/isooctane, various other solvents
tested
PF HF [39]
EXT Alamine 336/oleyl alcohol EC, agitated vessel [212215]
EXT in situ Alamine 336/oleyl alcohol Agitated vessel [128]
EXT and electrodialysis (Amines, Cyanex 923)/(kerosene,
butylacetate, oleyl alcohol)
EC [127]
MBSE TOPO; TOA+TBP Packed column with capsules [14]
Gibberellic acid EXT Polyalkoxylates Mixer/settler [216,217]
l-Phenylalanine MBSE, MBSS 1030 vol.% D2EHPA/kerosene CF HF [199,218,219]
Penicillin G MBSE, MBSS or electrodialysis Amberlite LA2/(kerosene, isode-
canol)
PF HF [144]
Cephalosporin MBSE, MBSS Aliquat 336/n-heptane PF HF [38]
Lincomycin EXT Octanol, decanol EC [220]
at pH 5.5 by an acid removal by extraction. Compared with
conventional fermentation, extractive fermentation resulted
in a much higher product concentration in stripping solution
of >300 g L
1
and product purity of 91% was achieved. It
also resulted in higher reactor productivity 7.4 g L
1
h
1
and
butyric acid yield of 0.45, g/g. Without on-line extraction to
remove the acid products, at the optimal pH of 6.0, the nal
butyric acid concentration was only similar to 43.4 g L
1
,
butyric acid yield was 0.423, g/g, and reactor productivity
was 6.8 g L
1
h
1
. These values were much lower at pH 5.5:
20.4 g L
1
, 0.38, g/g, and 5.11 g L
1
h
1
, respectively. The
improved performance for extractive fermentation can be at-
tributed to the reduced product inhibition by selective re-
moval of butyric acid from the fermentation broth. The sol-
vent was found to be toxic to free cells in suspension, but not
harmful to cells immobilised in the brous bed. The process
was stable and provided consistent performance for the entire
2-week period of study.
Lactic acid production from cellulosic biomass by cellu-
lase and Lactobacillus delbrueckii in a fermenter-extractor
employing a bundle of microporous hollow bers placed in
situ in the fermenter was studied [119]. This bioreactor sys-
tem was operated under a fed-batch mode with continuous
removal of lactic acid by extraction. A solvent mixture of
20% Alamine 336, 40% oleyl alcohol, and 40% kerosene
was found effective in the extraction of lactic acid. A change
of pH from an initial value of 5.0 down to 4.3 improved the
overall performance of the simultaneous saccharication and
extractive fermentation over that of constant pH operation.
Recovery of diltiazem from an alkaline aqueous feed so-
lution as diltiazem malate in a l-malic acid containing aque-
ous strip stream using pertraction in a three phase hollow
ber contactor has been studied [156]. The resistance to mass
transfer is primarily controlled by the feed side mass-transfer
coefcient due to the high partition coefcient of diltiazem
for a decyl alcohol liquid membrane and the instantaneous
reaction in the strip side of the membrane. However, due
to larger thickness of the liquid membrane, the membrane
resistance is quite important, as well. In spite of the low dilti-
azem concentration in the feed solution, high concentrations
of diltiazemmalate in the stripping solution were achieved. A
suggested diffusion model describes effectively the observed
behaviour of the HF contactor. A preliminary cost analysis
and comparison with packed bed column solvent extraction
shows that pertraction can be competitive.
2.5. Extractive biotransformations of organic acids in
integrated and hybrid systems
The chemical and pharmaceutical industry has primarily
relied upon established chemical methods for the synthesis
of target products and their intermediates, but is now turn-
ing more and more to enzymatic and biotechnological fer-
mentation processes. For the industrial implementation of
many biotransformations alternative methods are develop-
ing. Among them extractive separations employing solvents
intwoandthree phase systems integratedwithtransformation
or even forming hybrid system with biotransformation and

separation occurring in one space. Good insight to this subject
can give books [2,4,222] and overview papers [3,7,223,224]
and a general book on biotransformations [225]. Papers on
biotransformations of organic acids integrated with extrac-
tive separation of the product or realized in hybrid systems
are presented in Table 10. References to papers on hybrid
processes with enzymatic resolution of esters of enantiomers
are given in Table 8.
An enzyme reactor integrated with MBSE in a HF contac-
tor was used for the synthesis of N-(benzyloxycarbonyl)-l-
aspartyl-l-phenylalanine methyl ester (ZAPM), the precursor
of the articial sweetener, aspartame [230,231]. The synthe-
sis of ZAPM in the reactor proceeded by an enzymatic re-
action between N-(benzyloxycarbonyl)-l-aspartic acid and
l-phenylalanine methyl ester in the aqueous phase. The syn-
thesized ZAPM in the aqueous phase was mainly extracted
into the organic phase and the aqueous phase concentration
could be kept low. This results in high conversion of ZAPM
in this system. The reaction model, which was based on the
material mass balance equations, was discussed to estimate
the performance of the extractive enzyme reactor system. It
was shown that, 1-hexanol and 1-heptanol were proper sol-
vents for this system [19]. An alternative approach with in
situ extraction and solvent removal through a microltration
membrane [19] is discussed in the introduction. Murakami
and Hirata [232] studied the same system and used in situ
extraction with butylacetate in an integrated mixer-settler. A
model of the enzymatic synthesis of taste dipeptides with si-
multaneous extraction in a HF contactor is presented in paper
[235].
Conversion of fumaric acid (FA) to l-malic acid (LMA)
was carried out in a bioreactor divided by two supported
liquid membranes into three compartments feed, reaction
and product [227]. SLM between the feed and reaction
compartments was made of TOPO (10 vol.%) in ethyl ac-
etate and was selective toward the substrate, fumaric acid.
The reaction/product compartments SLM, made of D2EHPA
(10 vol.%) in dichloromethane, was selective toward the
product, l-malic acid. Yeast engineered to overproduce the
enzyme fumarase was immobilisedinsmall glasslike beads of
the alginatesilicate solgel matrix and placed in the reaction
compartment and served as the catalyst. The conversion of
almost 100%, while in the industrial process only 70%, was
achieved. In contrast to the existing industrial biocatalytic
process resulting in l-malic acid salts, direct production of
the free acid is described.
3. Formulation of solvent and liquid membrane
Solvents used in the extraction of organic acids are mostly
not single components. The physical solubility of more hy-
drophilic acids in organic solvents is usually low. The dis-
tribution coefcients of such acids, like acetic acid, lactic
acid, and phenylalanine, in common hydrocarbon solvents or
ethers and higher alcohols, are well below 1. The addition of
solvation or complexing agents extractant (in case of liq-
uid membranes called carrier) to the base solvent diluent
can increase the partitioning of acid into the organic phase.
Several acidextractant complexes have a limited solubility
in the solvent resulting in the formation of a precipitate or a
second organic phase similarly as in the extraction of lactic
acid with TOA in n-alkanes. Selection of a proper diluent or
an additional co-solvent, a modier, can solve this problem.
An example is the use of a higher alcohol modier, like isode-
canol in case of extraction of lactic acid with TOAextractants
[115].
The selection of solvents for the extraction of organic acids
or for their pertraction (the solvent forms a liquid membrane)
and some related general aspects are discussed in papers
[4,12,200,228,240243]. Computer-aided solvent design for
extractive fermentation directed mostly to ethanol fermenta-
tion is presented by Wang and Achenie [244]. In the selection
and formulation of the solvent several aspects should be con-
sidered for the given separation. Some of them will be dis-
cussed below together with solvents used in various systems
listed in overview tables.
3.1. Extractants
As follows from Tables 1 to 10 a great variety of solvents
and extractants were studied in extraction of organic acids.
The most important extractants (carriers) used in formulation
of solvents for MBSE, pertraction or extraction of organic
acids, with references to selected papers on L/L equilibrium
in these systems, are presented in Table 11.
Less common carriers of amino acids as microemul-
sions [138] and reverse micelles [135,245] were also studied.
Oligomeric extractants (PPO, PEO) and their block polymers
forming reverse micelles have been examined for the trans-
port of phenol [246] and amino acids (Phe, isoleucin) [143].
Ionic liquids as solvents or extractants of organic acids are
discussed in Section 3.3.
Matsumoto et al. observed synergistic extraction of lactic
acid [247] and other organic acids [248] when a mixture of
alkylamines and TBP was used. The value of the distribu-
tion coefcient of lactic acid in the solvent with 3 kmol m
3
of TBP and 0.3 kmol m
3
of TOA in n-hexane was 3.4
while for single extractants in n-hexane this value was well
below 1.
Higher concentration of the extractant (carrier) does not
necessarily leads to an increase of the mass-transfer rate de-
spite the fact that the value of the distribution coefcient
increases proportionally. With increasing concentration of
the carrier (TOA) from 0.2 to 0.6 kmol m
3
the ux of bu-
tyric acid through a layered bulk liquid membrane increased
only by 16%, while the product of the diffusion coefcient
and the distribution coefcient (theoretical permeability) in-
creased 2.7 times [104]. Such behaviour can be related to
the kinetics of reactions of formation and/or decomposition
of the complexes [26,104,112,269] and will be discussed
below.
2
5
0
S
.
S
c
h
l
o
s
s
e
r
e
t
a
l
.
/
S
e
p
a
r
a
t
i
o
n
a
n
d
P
u
r
i
c
a
t
i
o
n
T
e
c
h
n
o
l
o
g
y
4
1
(
2
0
0
5
)
2
3
7
2
6
6
Table 10
Biotransformations of organic acids integrated with extractive separation of the product or realized in hybrid systems
Product Carbon source or reactant(s) (micro-
organism or biocatalyst)
Process for separation of the product Solvent Contactor type
a
Literature
Itaconic acid Citric acid (Aspergillus terreus) Hybrid bioreactor with two SLM (D2EHPA, TOA)/(octanol;
dichloromethane)
FSC [226]
Fumaric acid l-Malic acid (Sacharomyces cerevisiae) D2EHPA/dichloromethane FSC [227]
-Hydroxyisobutyric acid 2-Methyl-1,3-propanediol (Acetobacter
alei)
EXT TOPO/isooctane screening of
solvents
EC [228]
MBSE TOPO/isooctane PF HF [229]
N-(Benzyloxycarbonyl)-l-aspartyl-
l-phenylalanine methyl ester
N-(Benzyloxycarbonyl)-l-aspartic
acid and l-phenylalanine methyl ester
(thermolysin)
MBSE tert-Amylacohol PF HF [230,231]
EXT into dispersion +MF Hexanol, heptanol FSC [19]
EXT in situ Butylacetate agitated vessel [232]
N-Formyl-l-aspartyl-l-
phenylalanine methyl ester
N-Formyl-l-aspartic acid and l-phenyl-
alanine methyl ester (thermolysin)
EXT in situ 1-Butanol agitated vessel [233]
Dipeptide aspartam (ZalaPheOMe) ZAlaOH and PheOMe (thermolysin) EXT in situ Ethyl acetate agitated vessel [234]
MBSE PF HF [235]
Isovaleraldehyde Isoamyl alcohol (Gluconobacter oxy-
dans)
MBSE Isooctane PF HF [236]
S-Phenylethanol Acetophenone (dehydrogenase fromCan-
dida boidinii)
MBSE Isooctane HF [237]
2-Phenylethanol Phenylalanine (Sacharomyces cerevisiae) EXT Dibutyl sebacate uidised bed with capsules [13]
EXT in situ Oleic acid agitated vessel [238]
3-Cyanobenzoic acid 1,3-Dicyanobenzene (hydratase from
Rhodococcus)
EXT Ionic liquid agitated vessel [239]

Table 11
The most important extractants (carriers) used in the formulation of solvents for MBSE, pertraction or extraction of organic acids and some related papers on
L/L equilibria in these systems
Abbreviation Trade name Extractant (carrier) Acid type Literature on L/L equilibria
Simple organic solvents (non-reactive) Carboxylic acids [240]
Phenol [165]
Amines and their salts Carboxylic and hydroxycarboxylic acids [109,241243,249252]
TOA Trioctylamine Carboxylic and hydroxycarboxylic acids [253258]
Alamine 336 Trialkylamines with C
8
and C
10
n-
alkyls
Carboxylic and hydroxycarboxylic acids [96,212,259,260]
Hostarex A327 Trialkylamines with C
8
to C
12
n-
alkyls
Carboxylic acids [87]
Amberlite LA2 Di-alkylamines with branched
C
12
C
15
alkyls
Carboxylic acids [261,262]
Antibiotics [4,263]
TOMAC Trioctylmethylammonium chloride Carboxylic acids amino acids [264,265]
Aliquat 336 Tri-alkylmethylammonium chlo-
ride
Carboxylic and hydroxycarboxylic acids [95]
Amino acids [133]
Antibiotics [157]
D2EHPA Di-2-ethylhexylphosphoric acid Amino acids [26,36,266,267]
TBP Tri-n-butyl phosphate Carboxylic and hydroxycarboxylic acids [126,240,247]
TOPO Tri-n-octylphosphine oxide Carboxylic acids [268]
Cyanex 923 Tri-n-alkylphosphine oxides with
C
6
and C
8
n-alkyls
Phenol [163]
Another phenomenon arising from an increase of the car-
rier concentration in the LM phase is aggregation or forma-
tion of a microemulsion, which can block the interface re-
sulting in lower diffusion coefcients. With increasing con-
centration of D2EHPA in LM the value of the distribution
coefcient of phenylalanine increases proportionally. How-
ever, the dependences of the ux through both the extrac-
tion and stripping interface of the layered BLM go through a
maximum[12]. This can be probably related to the formation
of a microemulsion observed at higher D2EHPA concentra-
tions as it was also observed in pertraction of phenylalanine
through SLM [26].
The solubility of extractant (carrier) in aqueous solutions
is an important parameter inuencing its losses. It is con-
nected also with the solvent toxicity and compatibility and
will be discussed in Section 3.4. Alowsolubility of D2EHPA
in metal extraction applications, where solutions with high
salt concentrations and acidities are involved, may be not
the case in biotechnology applications where a low salinity
and nearly neutral pH is typical. The solubility of D2EHPA
in aqueous solutions strongly depends on the salt concen-
tration. In pure water the solubility of D2EHPA is as high
as 956 ppm, in 0.1 kmol m
3
sodium sulphate solution it is
304 ppm whereas it is only 12 ppm in a 1 kmol m
3
sodium
sulphate solution[40]. Luet al. [270] publishedlower value of
D2EHPAsolubilityinwater at 25
C, whichis 87.0 g m
3
and
at pH 1.98 is 52.7 g m
3
. Solubility of D2EHPA decreases
with increasing concentration of chlorides and HCl. Rela-
tively high solubility of D2EHPA results in a low lifetime of
SLM [26].
3.2. Diluents and modiers
To nd a suitable extractant (carrier) forming a com-
plex with the target solute is only half of the success. The
soluteextractant complex has to be soluble in the diluent
forming with the extractant a solvent. The achievement of
this goal requires in many cases selection of an appropriate
diluent or addition of a modier to the solvent, e.g. isodecanol
to n-alkanes and trioctylamine (TOA) in the solvent for lactic
acid [115]. The diluent type may have a great inuence on the
solvent performance. In extraction of MPCA from solutions
with higher content of mineral salts with solvents contain-
ing TOA, the value of the distribution coefcient is much
higher for xylene as a diluent than for n-alkanes [271]. When
considering separation integrated with bioprocess toxicity as-
pects should be taken into account, as discussed in Section
3.4. Lower alcohols, which are popular modiers, should be
avoided. Isotridecanol, available as a technical product (Uni-
par, NL), is a good compromise [272].
The diluent effect in extraction of organic acids is ad-
dressed in papers [94,96,126,178,247,268]. The diluent ef-
fect in systems with enzymatic reactions studied Miyako et
al. [46,47]. In extraction of lactic acid with tertiary amines,
the value of the distribution coefcient of a 50% mixture of
Alamine 336 with oleyl alcohol was found to be higher than
that of pure amine [212].
Addition of 30 wt.% of isodecanol to the solvent with
0.4 mol dm
3
of Hostarex A327 changed completely course
of concentration dependence of the distribution coefcient,
which value was increasing with decreasing concentration
252

of DMCCA in aqueous phase [29,87]. For the solvent with
0.4 mol dm
3
of TOA in n-alkanes the value of the distribu-
tion coefcient of DMCCA was decreasing with decreasing
concentration of acid.
3.3. Ionic liquids
Ionic liquids (IL) are composed of organic cations and ei-
ther organic or inorganic anions that remain liquid over a wide
temperature range, including room temperature [273,274].
ILs are a newgroup of solvents or extractants of great interest
recently studied as potential green solvents [273,275277].
Practically zero vapour pressure of IL and temperature sta-
bility makes them attractive solvents in many applications
as reaction medium. A higher viscosity at room tempera-
tures could be their less favourable property. Solvent extrac-
tion of organic acids by ionic liquids was studied in papers
[278281], erythromycin by Cull et al. [239] and chlorophe-
nols by Bekou et al. [282]. Transport of amines and neutral
organic substances through liquid membranes from IL is of
concern in papers of Fortunato et al. [283] and Branco et
al. [284]. Pertraction of organic acids through liquid mem-
branes facilitated by enzymatic reactions on L/L interfaces
using IL as a liquid membrane was studied by Miyako et al.
[46,174]. Tailoring of ionic liquids to achieve good partition-
ing of target solutes and acceptable viscosity of IL may lead
to interesting results.
Experiments with developmental IL show promising
results in extraction of organic acids, especially of lactic
acid [279281]. In extraction of butyric acid, lactic acid
and phenol fairly higher distribution coefcients were found
for solvents with tested developmental ionic liquid IL-A
compared to the solvents containing tertiary amines. The
value of the distribution coefcient of lactic acid is up to
30 at lower acid concentrations, what is promising. IL-A
acts as an extractant forming undissociated lactic acid/IL-A
complexes 1:1 and 2:1 (lactate anions are not extracted)
[281]. In the pertraction of LA through SLM the value of the
overall mass-transfer coefcient increases with decreasing
concentration of lactic acid in the aqueous phase what cor-
relates with increasing value of its distribution coefcient.
Increased concentration of the carrier IL-A did not change
the value of the mass-transfer coefcient in pertraction
of LA contrary to the increased value of the distribution
coefcient. This may indicates that the slower kinetics of the
interfacial reaction in decomposition of the complex plays a
role or higher viscosity of membrane is responsible of this.
Separation of taurine (2-aminoethanesulfonic acid) and
sodium sulfate by leaching a solid mixture by ionic liquids
is another example of their application [159]. Dialkylimida-
zolium chloride ionic liquid as leaching agent and organic
solvent as precipitating agent (lower alcohols, like ethanol,
are effective) were developed. Selective separation of taurine
from a solid mixture containing a large amount of sodium
sulfate could be realized with 6798.5% yield in a single
separation step.
3.4. Toxicity and compatibility of solvent
Toxicity of the solvent for microorganisms or its inhibitory
effect on the catalytic activity of enzymes or the biologic ac-
tivity of the product are important properties of the solvent,
which have to be considered in their evaluation. Papers con-
cerning these items for the solvents or their components are
listed in Table 12.
The parafn (probably parafnic oil, not specied)
severely reduces the biological activity of the extracted bac-
teriocin nisin, while toluene, kerosene and isooctane were
found suitable [153]. Strategies for reducing solvent toxicity
in extractive fermentations are discussed in paper [213]. Co-
immobilization of soybean oil with cells in carrageenan gel
beads decreased greatly toxic effect of Alamine 336 in lactic
acid fermentation. Toxicity of tertiary amine Alamine 336 to
Lactobacillus delbreucki was suppressed by the second stage
extraction of amines with oleyl alcohol before returning the
broth to the fermentation [212].
Logarithm of the distribution coefcient of a given com-
pound in the n-octanol/water system, log P, is traditionally
used as a simple criterion to guide the choice of solvents for
biphasic enzymatic reactions from point of view of their bio-
compatibility with enzyme [200,285]. However recently, it
was found that log P is not a very reliable parameter for the
solvent choice for enzymatic transformations [286].
Wider screening of 17 solvents and their components for
their toxicity to Rhizopus arrhizus showed that solvents with
tertiaryamines (HostarexA327, TOA), secondaryamine with
isotridecanol as modier and pure trihexylphosphate (THP)
are suitable from point of view of biomass compatibility
[272]. Toxicity of alcohols decreased with increasing molec-
ular mass. Octanol and isodecanol and solvents containing
them are toxic. Isotridecanol is medium toxic. Earlier study
[287] showed that TBP is practically lethal for fungi. Siebold
et al. [127] have found that except kerosene and oleyl alcohol,
the biocompatibility of other chemicals tested was unsatisfac-
tory for various Lactobacilli studied. Demirci et al. [39] tested
toxicity of various solvents in lactic acid biolm fermenta-
tions with Lactobacillus casei performed in solvent-saturated
media and found solvent with 5 vol.% of TBP in isooctane
acceptable. This result compared with TBP toxicity to fungi,
where TBP was found lethal, shows that toxicity tests should
be done for every microorganism of interest and cannot be
extrapolated.
Tong et al. [264] suggest to use a solvent with relatively
toxic extractant TOMAC in oleyl alcohol and remove dis-
solved TOMAC in adsorption column with ion-exchange
resin Amberlite IR-120B before returning the broth to fer-
menter. This resulted in satisfactory extractive fermentation
of lactic acid. A similar approach, but with L/L extraction of
secondary amine dissolved in the broth by oleyl alcohol in
the second stage before its returning to fermenter, was used
by Jin and Yang [209] in propionic acid production. Immo-
bilization of cells into calcium alginate gell reduces toxicity
of the solvent to microorganisms [198].

Table 12
Papers concerning toxicity of solvents or their components to micro-organisms or their compatibility with enzymes
Target product Micro-organism or enzyme Solvent or its components Literature
Propionic and acetic acids Propionibacterium acidipropionici Amine extractants, TOPO, solvents in kerosene [24]
Trilaurylamine/(octanol, dodecanol, oleyl alco-
hol)
[200]
Propionic acid Propionibacterium-acidipropionici Di-tridecylamine/oleyl alcohol [209]
Butyric acid Clostridium butyricum Hostarex A327 in oleyl alcohol; oleyl alcohol;
trihexylphosphate; isotridecanol
[210]
Alamine 336/oleyl alcohol [101]
Lactic and itaconic acids, biomass grows Bacteria, yeasts, and fungi two of them each 11 organic solvents with 5 extractants and single
diluents and modiers
[287]
Lactic acid Various Lactobacilli (Amines, Cyanex 923)/(kerosene, butylacetate,
oleyl alcohol)
[127]
Lactobacillus delbreucki Tertiary amines [3]
Alamine 336/oleyl alcohol [128,212,213]
Rhizopus arrhizus 17 organic solvents with 5 extractants and single
diluents and modiers
[272]
Lactobacillus casei subsp. rhamnosus Amine extractants, TOPO, TBP, various dilu-
ents, Span 80
[39,288]
TOMAC/oleyl alcohol [264]
Lactobacillus rhamnosus Aliquat 336/kerosene [289]
TOPO, TOA+TBP in encapsulated solvents [14]
3 ionic liquids, toluene, hexane [290]
-Hydroxy-isobutyric acid Acetobacter alei (TOPO, TOA, Aliquat 336)/(hexane, dodecane,
isooctane, oleyl alcohol)
[228]
2-Phenylethanol Sacharomyces cerevisiae Oleic acid [238]
Alcohol (reduction of ketone) Three enzymes 10 single component organic solvents [286]
Higher alcohols as isotridecanol and oleyl alcohol are
preferable modiers or diluents for extractants when consid-
ering toxicity. Their higher viscosity is less favourable and
possibly compromise to use them in combination with the
diluent of lower viscosity as dodecane fraction could work.
3.5. Co-transport and competitive transport (selectivity)
Co-extraction of mineral acids and other components of
the feed can inuence transport rate of target acid and its
purity. Co-extraction of H
2
SO
4
and competitive extraction of
HCL during pertraction of lactic acid and MPCAwas studied
by Kubi sov a et al. [291] and in papers [90,292], respectively.
In pertraction of MPCA from feeds with mixed salts and
constant ionic strength the ux of MPCA through BLM with
carrier TOA dropped by one order of magnitude when the
concentration of chlorides increased from 0 to 1 kmol m
3
.
The ratio of the uxes of mineral acids to the ux of MPCA
increased from 1 to 4 [112]. Thus, in MBSE of MPCA with
amines it is important to avoid the presence of chlorides in
the treated solution.
Competitive uptakes of lactic acid and glucose have been
measured for the extractant Alamine 336 in various diluents
[293]. The extent of water coextraction depends strongly on
the diluent used, and larger amounts of water coextracted
correspond to larger uptakes of glucose. Co-extraction during
reactive extraction of phenylalanine using Aliquat 336 was
studied in paper [294].
Water transport or formation (in neutralisation reactions)
should be taken into account in material balances of the sys-
tem [26,89,90,137]. It decreases the concentration factor of
the target solute achieved in extractive separation.
4. Membrane contactors
There are two main types of hollow ber (HF) contactors,
those with parallel owor cross-owof phases. Acylindrical
HF contactor with cross-ow of phases is shown in Fig. 7.
More details on their construction and sizes available are
presented in the producer web site [295]. Reviews on two-
phase HF contactors are presented in works [5,10,11,296].
Three phase HF contactors for pertraction are described in
papers [6,2729,297].
HF contactors have a large interfacial area per unit vol-
ume of the contactor without requirement of dispergation of
one phase, what can be advantageous in systems sensitive to
emulgation [123,163]. The volume ratio of phases could be
varied practically without limitations. Disadvantage of HF
contactors is connected with additional mass-transfer resis-
tance introduced by porous wall(s) immobilising L/L inter-
face(s). Some problems with swelling of HF and especially
of potting material of HF in solvents may occur.
The function of contactors in the simultaneous MBSE and
MBSS with an arrangement as shown in Fig. 3, is coupled.
They react similarly as a pertractor with a supported liquid
membrane. The differences are only in the overall resistance
in the pertractor, which is smaller. In addition, it is not nec-
essary in PT to pump the solvent in its circulation loop, as it
is used in the simultaneous MBSE and MBSS process.
254

Fig. 7. Hollow ber contactor with cross-ow of phases (Liqui Cel Extra-Flow, Celgard).
4.1. Factors affecting the performance of contactors
Both composition of the feed and its pH can greatly in-
uence the transport rate in extraction. Components, which
compete the transport of target solute(s) should be avoided
or kept at minimum concentration, see Section 3.5. The ef-
fect of components of the fermentation broth, especially of
biosurfactants, on mass transfer in liquidliquid extraction
studied Pursell et al. [298]. Adsorption lm of surfactants on
interface decreases the extraction rate. The inuence of com-
position of the solvent on the performance of contactors was
already discussed.
Hydrodynamic conditions in HF contactors play an im-
portant role in selection of optimal process parameters for
MBSE. In MBSE of organic acids, it is useless to increase
the linear feed velocity in bers of HF contactors much above
4 cms
1
[12,89,111,137]. The optimum shell side Reynolds
number in MBSE of butyric acid is about 0.9 [100]. For
MPCA this value is only about 0.2, as shown in Fig. 8b,
and for MBSE of phenylalanine by a solvent with D2EHPA
the optimum value of Re
shell
is around 2 [299]. Typically, the
dependence of the overall length of bers (number of con-
tactors) in MBSE plus MBSS goes through a minimum, as
shown in Fig. 8b. From these data it is clear that the role of
hydrodynamic conditions in HF contactors may not be so de-
cisive in MBSE and MBSS of organic acids comparing with
solutes with a very high distribution coefcient, like some
metals.
The composition of the stripping solution, e.g. stripping
reagent type [123,126] and its concentration in the stripping
solution [90,95,123] may considerably inuence the perfor-
mance of the stripper. The most important is to have an excess
of reagent and to avoid the formation of a boundary layer de-
pleted in the reagent.
4.2. Modelling and mass-transfer characteristics
In modelling and simulation of MBSE and MBSS of or-
ganic acids with reactive extractants (carriers) it is important
to take into account the kinetics of extraction and stripping re-
actions, as will be discussed below. The concentration depen-
dence of the distribution coefcient of organic acids, which
cannot be small, shouldbe takenintoaccount, as well. This in-
uences the value of the concentration driving force and may
result in the concentration dependent overall mass-transfer
coefcient, see Eq. (1).
Models considering constant mass-transfer
coefcient in MBSE are presented in papers
[9,10,105,106,108,116,117,124,133,162,165,300]. Models
considering variable distribution coefcients are presented
in papers [124,133]. Models of MBSE and/or MBSS
taking into account reaction kinetics of formation and
decomposition of the extractantacid complex(es) in
extraction and stripping L/L interfaces are presented in
papers [12,90,97,100,145,301]. Reaction kinetics resis-
tances were included in model of pertraction in papers
[26,29,302].
Using diffusion and kinetic resistances in a series ap-
proach; the following equations have been derived for the
overall mass-transfer resistance in MBSE [90,111]. For the
steady state or quasi-steady state conditions, when uxes in
the individual boundary layers are equal (accumulation in
boundary layers can be neglected), the following relation can
be derived for the overall mass-transfer resistance in MBSE,
taking into account the resistance connected with the kinet-
ics of the reaction of formation of the permeantextractant
complex
R
e
=
1
K
e
=

e
k
F
+
A
i,e
A
w,e
k
Sw
D
+
A
i,e
e
A
o,e
k
Sb
D
+
1
r
e
(1)
where the overall mass-transfer resistance is composed of
four individual resistances. The overall mass-transfer coef-
cient is dened for concentrations in the aqueous phase and
the effective surface area of L/L interface
n
e
= K
e
A
ei
c
F
c
S
D
S
(2)
The kinetics of formation and decomposition of the
permeantextractant complex(es) via interfacial reactions
can be in the rst approximation described by the rst-order
rate equations [12,29,90,100]
n
e
= r
e
A
i,e
e
c
FS
(3)
n
s
= r
s
A
i,s
s
c
SR
(4)

where c
FS
is the concentration of MPCA in the feed phase
close to the extraction interface and c
SR
is the acid concen-
tration in the solvent close to the stripping interface. The rate
constants r
e
and r
s
are, de facto, lumped parameters reecting
the kinetics of interfacial reactions of the complex formation
or decomposition, equilibrium and the kinetics of competi-
tive adsorption or desorption of molecules of the complexes
and the free extractant molecules on/from the interface. Dif-
ferent approaches were used in papers where in modelling of
extraction or MBSE and MBSS reaction kinetics have been
taken into account. Reactions on the L/L interface are con-
sidered in papers on MBSE of lactic and citric acids [97],
butyric acid [99,100], MPCA [89,90], penicillin G [303] and
phenylalanine [137]. Homogeneous reactions of acid with
an extractant were supposed in papers devoted to MBSE of
penicillin G [145] and phenylalanine [219] and extraction of
lactic acid [259,304].
In the case when the kinetics of the stripping reaction
inuences the overall resistance in MBSS and for situations
with a zero resistance in the stripping solution boundary layer
(excess of reagent), the following equation was derived
R
s
=
1
K
s
=
A
i,s
s
A
o,s
k
Sb
+
A
i,s
A
w,s
k
Sw
+
1
r
s
(5)
Eqs. (1) and (5) represent the diffusion-reaction models of
MBSE and MBSS, and without the last terms for resistance
based on the reaction kinetics, they represent the diffusion
models for the estimation of the overall mass-transfer resis-
tance or the overall mass-transfer coefcients in these pro-
cesses. The estimation of the individual mass-transfer coef-
cients is discussed in papers [5,10,11,100].
Mass-transfer characteristics of two-phase HF contactors
in several systems are presented in Table 13. Data for contac-
tors Liqui Cel (Celgard) with cross-ow of phases of labora-
tory size 2.5 in. 8 in. and pilot plant contactors 4 in. 13 in.
and 4 in. 28 in. (which can be used also for smaller produc-
tion plants) are available for some systems. The values of
the lumped rate constants of extraction and stripping reac-
tions, dened by Eqs. (3) and (4), for some organic acids and
solvents are listed in Table 14.
It is evident from Table 13 that in most systems the
value of the overall mass-transfer coefcient in stripping is
lower, not seldom one order of magnitude, comparing with
MBSE. This is connected with a slower decomposition of the
extractantacid complex on stripping interface. The values of
the lumped rate constants on extraction interface are higher
than the rate constants for stripping reactions, as documented
in Table 14. The only exception among systems shown in
Table 13 is lactic acid with the low value of the distribution
coefcient reecting weaker interaction between lactic acid
and the extractant.
The analysis of mass-transfer resistances showed, that the
kinetics of the acidcarrier complexes formation and/or de-
composition should be taken into account in most systems.
The contribution of the mass-transfer resistances based on
reaction kinetics to the overall resistances in MBSE and
MBSS of MPCAwith the solvent with TOAis up to about 50
and 60%, respectively [90]. The proposed reaction-diffusion
model gives a much better t to the experimental values than
a pure diffusion model. The mean values of the lumped rate
constant of the extraction and stripping reactions for MPCA
are shown in Table 14. The contribution of the diffusion resis-
tance in the feed and the solvent boundary layer is small and is
less than 10% (under reasonable hydrodynamic conditions).
Juang et al. [302] estimated that the mass-transfer resis-
tances based on reaction kinetics participate in the overall
resistance in pertraction of lactic acid through SLM by 30 to
80% depending on acid and carrier concentrations. Lazarova
et al. [145] did analysis of the mass-transfer resistances in
MBSE and MBSS of penicillin G with the solvent contain-
ing the secondary amine Amberlite LA2 and concluded that
the mass-transfer resistance based on reaction kinetics can
participate in the overall resistance in MBSE up to 32% and
in MBSS up to 79% depending on the process parameters.
A short-cut method for the design and simulation of two-
phase HFcontactors with variable mass-transfer and distribu-
tion coefcients taking into account reaction kinetics in the
stripping interface is presented in paper [100] in this issue
and method considering reaction kinetics in both interfaces
in paper [299].
5. Case studyrecovery of MPCA
5-Methyl-2-pyrazinecarboxylic acid (MPCA) is a valu-
able acid of industrial importance. The waste solution of
MPCA resulting from downstream processing of the enzy-
matic resolution technology contains much mineral salts and
their pHis below2. MPCAhas to be concentrated fromabout
16 kg m
3
by a factor of 10, at least. From this concentrate
pure MPCA is recovered as an organic phase formed after
decreasing its pH<2 (low water solubility of undissociated
MPCA, the same refers also to DMCCA).
Mass-transfer characteristics of HF contactors in MBSE
and MBSSof MPCAare presented in paper [90]. The concen-
tration dependence of the distribution coefcient of MPCA
in the solvent used has a favourable course with increasing
value of D with decreasing acid concentration [89,271]. This
is an opposite situation comparing with butyric acid, where
the value of the distribution coefcient decreases with de-
creasing concentration [253]. This has a positive effect on
the length of bers in HF modules needed to achieve required
yield.
Compositions of streams in laboratory tests and supposed
also in a pilot unit for recovery of MPCA from process solu-
tion were following:
Feed: aqueous solution containing of about 0.12 kmol m
3
MPCA, 1 kmol m
3
Na
2
SO
4
; with pH
F
kept constant at 2.5
by the addition of H
2
SO
4
.
Solvent: 0.4 kmol m
3
TOA in xylene.
2
5
6
S
.
S
c
h
l
o
s
s
e
r
e
t
a
l
.
/
S
e
p
a
r
a
t
i
o
n
a
n
d
P
u
r
i
c
a
t
i
o
n
T
e
c
h
n
o
l
o
g
y
4
1
(
2
0
0
5
)
2
3
7
2
6
6
Table 13
Mass-transfer characteristics of HF contactors in MBSE and MBSS of different organic acids based on experimental data
Solute Solvent Contactor type c
F0
(mol m
3
) D at c
F0
u
F
(cms
1
) K
e
10
6
(ms
1
) c
S1
(mol m
3
) u
S
(cms
1
) K
s
10
6
(ms
1
) Literature
Butyric acid 0.4 kmol m
3
TOA in n-alkanes CF HF
a
100 3.0 1.78 6.0 150 0.084 2.4
a,e
[87,98100]
300 3.5 1.78 9.1
a,d
DMCCA S1 CF HF
a
127 31.7 0.37 10.5 678.9 0.074 0.81
a
[87,305]
MPCA 0.4 kmol m
3
TOA/xylene CF HF
a
100 3.9 1.34 8.56
c
0.084 1.7
a,d
[89,90,111]
Lactic acid S2 CF HF
a
543 0.79 0.14 0.30 102 0.27 1.0
a
[115]
S3 CF HF
a
545 0.52 0.14 0.32 70 0.11 1.3
a
S4 PF HF 280 0.50 1.33 0.53 0.66 [116]
10% TOPO in kerosene PF HF
+
0.330.5
+
[117]
S5 PF HF 100 0.24 0.5 1.02 [122]
TOMAC in decanol CF HF
a
154 0.032
f
1 10
4f
[124]
Valeric acid S6 49 1.9 1.81 15.7 0.47 [106]
4-Methyl-thiazole Benzene 354 21.8 1.2 15.0 0.32 [155]
Cyano-thiazole Benzene 118 6.0 1.2 4.3 0.32 [155]
Phenyl-alanine 0.75 kmol m
3
D2EHPA in n-alkanes CF HF
a
50 2.5 3 2.5
a,d
10 0.08 0.60
a
[137]
30 0.89
a
S7 CF HF
c
0.288
c
0.077
c
[199]
40 mol m
3
Aliquat 336 in xylene 40 1.3 0.100.23 [136]
Penicillin G S8 CF HF
b
13.3 1.11
b
0.13
b
[145]
S9 PF HF 10 15 1.14 [147]
Phenol MIBK PF HF 0.18 [168]
Isopropyl-benzene CF HF
c
320 1.25
c+
3.5
c+
Based on data [86]
80 1.25
c+
9.8
c+
S10 PF HF 2.77 [162]
30% TBP in kerosene 7 6.3
x
[306]
7 14.5
xx
1-Decanol CF HF
a
31.9 25.4 4.8
f
2.2 10
3f
[124]
p-Nitro-phenol 1-Octanol PF HF 0.72 89.2
e
6.5 [91]
0.2 [92]
Sulfanilic acid S11 PF HF 6.14 >26 0.33 1.6 0.073 [158]
0.20 1.1 0.073
Phenyl-glycine TOMAC in decanol CF HF
a
16.4 0.33 0.5
f
0.053
f
[124]
Abbreviations used are explained in Nomenclature and under this table. Contactors: Liqui Cel Extra Flow (Celgard) with cross-ow of phases, size: a: 2.5 in. 8 in.; b: 4 in. 13 in.; c: 4 in. 28 in.; d: circulation
method; e: concentration independent value; f: specic formulation of the model equations; +: the organic phase ows in bers, x: straight bers; xx: coiled bers. Solvents: S1: 0.4 kmol m
3
Hostarex A327,
30 wt.% isodecanol in n-alkanes; S2: 0.4 kmol m
3
Hostarex A327, 0.8 kmol m
3
isotridecanol in n-alkanes; S3: 0.4 kmol m
3
Hostarex A327, 0.8 kmol m
3
isodecanol in n-alkanes; S4: 30% Aliquat 336 in
Shellsol; S5: 0.5 kmol m
3
TOMAC in oleyl alcohol; S6: 10% Amberlite LA2 in toluene; S7: 10 vol.% D2EHPA in kerosene; S8: 0.115 kmol m
3
Amberlite LA-2, 10% isodecanol in kerosene; S9: 60 mol m
3
Amberlite LA-2 in butylacetate; S10: Cyanex 923 in kerosene; S11: 20% TOA, 30% octanol in kerosene.

Fig. 8. Total number of the HF contactors Liqui Cel 4 28 in. (effective ber length 63.5 cm) in MBSE and MBSS of MPCA, as well as the overall number of
contactors vs. the MPCAyield in MBSE at Re
shell
=0.2 (a), vs. the shell side Reynolds number for
e
=0.90 (b) and vs. the approach to equilibriumon outlet side
of the contactor for
e
=0.90, Re
shell
=0.2 (c). Estimated for 40 contactor segments and
n+1
=0.70. Values of the other process parameters:

V
F1
= 100 Lh
1
,
c
F1
=116 mol m
3
, pH
F
2.43, Y
MA/OA
=1, Z=10,
conv
=0.7.
Stripping solution: aqueous solution of NaOH
(0.5 kmol m
3
) with the addition of ammonia
(10.1 kmol m
3
) to keep the basicity of the stripping
solution above 0.3 kmol m
3
.
For the design and simulation of HF contactors for pi-
lot plant recovery of MPCA by simultaneous MBSE and
MBSS the short-cut method as published in paper [100] was
used. The contactor has been divided mostly into 40 seg-
ments with the same inlet to outlet concentration difference
in the feed phase. The mean values of the distribution coef-
cient and overall mass-transfer coefcient in the segment,
Table 14
Lumped rate constant of the extraction and stripping reactions, dened by Eqs. (3) and (4), in MBSE and MBSS or in pertraction (PT) of organic acids
Solute Solvent Process r
e
10
6
(ms
1
) r
s
10
6
(ms
1
) Reference
Butyric acid 0.4 kmol m
3
TOA in n-alkanes MBSE and MBSS in HF contactor
+
4.8 [99,307]
PT in HF contactor 5.6 [102,103]
PT through layered BLM 8.4 Based on data in [104]
Pure n-alkanes PT in HF contactor 29.2 [102,103]
MPCA 0.4 kmol m
3
TOA in xylene MBSE and MBSS in HF contactor
+
14.2 6.0 [90]
Phenylalanine 0.75 kmol m
3
D2EHPA in n-alkanes MBSE and MBSS in HF contactor
+
4.3 1.1 [137]
Lactic acid S3 (see under Table 13) MBSE and MBSS in HF contactor
+
0.38 5.2 Based on data in [115]
S2 (see under Table 13) MBSE and MBSS in HF contactor
+
0.44 2.7
DMCCA Pure n-alkanes PT in HF contactor 5.8 Based on data in [29,87,305]
0.4 kmol m
3
TOA in n-alkanes 1.9
Abbreviations used are explained in Nomenclature. +: Liqui Cel Extra-ow 2.5 in.8 in. (Celgard).
dened for the logarithmic mean concentration in the seg-
ment, were used in simulation, as suggested in paper [100].
In this system the number of contactors sharply decreases
with the number of segments used in simulation. A conver-
gence of the simulation results was achieved for about 20
segments. The number of contactors in MBSE and MBSS
is sensitive to the increase in MPCA yield in MBSE above
90%, as shown in Fig. 8a. Dependences of the total num-
ber of contactors (length of bers) on the shell Reynolds
number and the concentration ratio at the rafnate end of
the contactor (approach to the equilibrium) exhibit a min-
imum at about 0.2 and 0.7, respectively (Fig. 8b and c).
258

Fig. 9. Scheme of a continuous pilot plant unit for recovery of MPCA from mother liquor (ML) by MBSE and MBSS in hollow ber contactors. 1: container of
ltered ML; 2: polishing (safety) lters of the feed; 3a, 3b: HF contactors for MBSE; 4: static mixer; 5: container of H
2
SO
4
; 6a, 6b: HF contactors for MBSS
of the solvent; 7: container of the regenerated solvent; 8: polishing (safety) lters of the solvent; 9: container of the stripping solution (concentrate of MPCA);
10: safety lters of the stripping solution; 11: container of NaOH; 12: container of NH
4
OH; C
1
to C
3
: main pumps; C
4
, C
5
: dosing pumps of solutions for pH
adjustment; CU: central unit for data acquisition and safety switching off pumps; pH1, pH2, pH3: pH sensors; R1, R2: owmeters (rotameters); V1 to V5:
valves; VP1, VP2: relief valves; VR1, VR2: metering valves for p adjustment.
These values are quite different comparing with MBSE of
butyric acid presented in paper [100] of 0.9 and 0.4, respec-
tively.
Based on simulations for contactors Liqui Cel
4 in. 28 in. (Celgard, with an effective length of bers
of 0.6 m) for the feed with owrate

V
F1
= 0.10 m
3
h
1
(u
F
=1.9 cms
1
) and composition c
F1
=0.116 kmol m
3
and pH
F0
1.5 the optimised process parameters suggested in
MBSE are: yield of MPCA 90%,
n+1
=0.70, Re
shell
=0.2.
In MBSS for concentration factor Z=10 and co-transport of
mineral acids Y
MA/OA
=1 should be

V
S1
= 0.121 m
3
h
1
(u
R
=1.2 cms
1
), c
R1,reag
=2.14 kmol m
3
, and for
conv
=0.70 follows

V
R2
= 9.0 Lh
1
, c
R2
=1.16 kmol m
3
.
The number of contactors Liqui Cel 4 in. 28 in. (Cel-
gard, with an effective length of bers of 0.6 m) [295]
in series, as resulted from simulations for the mentioned
process data, was found 2 for both MBSE and MBSS,
what are reasonable numbers. The technological owsheet
of a pilot plant unit for recovery of MPCA is shown in
Fig. 9. These results document potential of application of
HF contactors in recovery of MPCA from waste solu-
tions.
6. Conclusions
Several processes based on partitioning of components on
one or two L/Linterfaces have been designed to achieve sepa-
ration of mixtures, and numerous papers on recovery and sep-
aration of organic acids have been published. Not so much of
this is reected in industrial applications of MBSEor pertrac-
tion. It is hoped that potential for further progress exists. As
shown, some applications are matured enough to be applied
in future. This is especially probable for more hydropho-
bic acids like butyric and higher acids, DMCCA, MPCA,
phenylalanine, etc. Development in extractive fermentation
process for production of propionic acid shows its potential,
as well.

Further progress couldbe connectedalsowiththe develop-
ment of new extractants and new formulations of solvents or
membrane phases. Tailored ionic liquids may become of im-
portance in extractive separations. Development of effective
and less expensive contactors, preferably hollow ber ones,
would help in the application of these processes. Technolo-
gies with higher added value products have a greater potential
for application of MBSE, simultaneous MBSE and MBSS as
well as PT.
Reactionseparation hybrid or integrated systems with
one or two immobilised L/L interface are of special interest.
An increased productivity and yield of the synthesis or bio-
transformation due to in-line separation can justify increased
costs of the separation process. Situation when both separa-
tion process streams, concentrate and rafnate, can be utilised
is benecial for economy of the process as documented by
phenol recovery application. Biocompatibility of solvents is
an important issue. When aiming at some application from
the very beginning the system should be designed and evalu-
ated in full width of all aspects, which can inuence the feed
composition, acid separation, solvent biocompatibility and
economy of the process.
Mass-transfer and reaction kinetics constrains should not
be neglected. The kinetics of formation and decomposition
of the permeantextractant complex on L/L interface may
inuence greatly the mass-transfer rate in separation pro-
cess and should be taken into account in its modelling and
simulation.
A case study on recovery of MPCA by simultaneous
MBSE and MBSS shows potential of this process. The op-
timised process parameters for this system are suggested on
bases of simulations.
Acknowledgement
Support of the grant from the Slovak Grant Agency No.
VEGA 1/9136/02 is acknowledged.
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An overview with a case study on recovery of MPCA

, R. Kert esz, J. Mart ak

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