Ind. Eng. Chem. Res.

2004, 43, 5969-5982

5969

REVIEWS
Fermentation of Glucose to Lactic Acid Coupled with Reactive
Extraction: A Review
Kailas L. Wasewar, Archis A. Yawalkar, Jacob A. Moulijn, and
Vishwas G. Pangarkar*,
Mumbai University Institute of Chemical Technology, Matunga, Mumbai 400019, India, and
Reactor and Catalysis Engineering, Delft Chem Tech, Delft University of Technology,
Julianalaan 136, 2628 BL Delft, The Netherlands

Growing demand for biodegradable polymer substitutes for both conventional plastic materials
and new materials of specific uses such as controlled drug delivery or artificial prostheses draws
attention to the need for improvement of conventional processes for lactic acid production.
Reactive extraction with a specified extractant giving a higher distribution coefficient has been
proposed as a promising technique for the recovery of lactic acid. A critical analysis of the
available literature data has been made, and some general conclusions have been drawn. A
suitable extractant-diluent system for lactic acid extraction on the basis of distribution
coefficient, toxicity, and feasibility for backextraction is suggested. Also, methods for backextraction and recovery are suggested.
1. Introduction
For the last 2-3 decades, because of the sharp
increase in petroleum costs, there has been a resurgence
of interest in large-volume production of fermentation
chemicals, and the potential role of a new energyefficient fermentation technology is receiving growing
attention.
The current economic impact of fermentation chemicals, however, is still limited, in large part because of
difficulties of product recovery. Thus, for fermentation
products to penetrate the organic chemicals industry,
substantial improvements in the existing recovery
technology are needed.
Lactic acid is a commodity chemical produced by
fermentation and utilized in the food, chemical, and
pharmaceutical fields. Lactic acid is an important
chemical that can be converted to propylene glycol,
acrylic polymers, and polyesters. Lactate esters derived
from biolactic acid are being considered as alternative
benign solvents.1 In particular, an interesting application is the use of lactic acid as a monomer for the
synthesis of biodegradable homopolymers and copolymers.2,3 Lactic acid is a raw material for the production
of biodegradable poly(lactic acid). A growing demand for
biodegradable polymers, substitutes for both conventional plastic materials and new materials of specific
uses such as controlled drug delivery or artificial
prostheses, draws attention the need for improvement
of conventional processes for lactic acid production.4
* To whom correspondence should be addressed. Tel.:
+91-22-24145616. Fax: +91-22-24145614. E-mail: vgp@
udct.org, v_pangarkar@hotmail.com.
Mumbai University Institute of Chemical Technology.
Delft University of Technology.

The world market of lactic acid is growing every year.

The level of production is around 350 millions kg
year-1,5 and the worldwide growth is believed by some
observers to be 12-15% year-1.6
In December 1994, market prices in the U.S. for both
fermentation and synthetic food-grade 50 and 88% lactic
acid were $0.71 and $1.15 lb-1 ($1.56-2.53 kg-1),
respectively. Technical-grade 88% lactic acid was quoted
at $1.12 lb-1 ($2.47 kg-1).7
In April 2003, market prices in the U.S. for 88% foodgrade and technical-grade lactic acid were $0.77 and
$0.7 lb-1, respectively. The 50% solution for grade lactic
acid was $0.59 lb-1.8 These prices were 50% lower than
the prices of year 1994, illustrating the economics of
scale based on the increasing use of lactic acid.
Recovery of lactic acid from aqueous solutions is a
growing requirement in fermentation-based industries
and so is recovery from waste streams. Lactic acid can
be produced by the fermentation of biomass. For the
production of lactic acid, the pH is very important and
must be maintained between 5.5 and 6.5. However,
during fermentation, the accumulation of lactic acid
decreases the pH of the fermentation broth and the
activity of the lactic acid producing bacteria decreases.
Hence, the lactic acid accumulation inhibits the product
formation. Also, if levels of free lactic acid reach 1-2
wt % of total combined lactic acid, then the bacteria are
likely to die.9,10 The traditional recovery process of lactic
acid from fermentation broth is quite complicated.
Isolation of this acid from dilute solution or fermentation
broths is an economic problem because the vaporization
of water consumes much energy and a direct upgrading
of the dilute solution by evaporation is inefficient. Lactic
acid is nonvolatile, and hence distillation is not useful.
In conventional processes, lactic acid has been recovered
from the fermentation broth by precipitation of calcium

10.1021/ie049963n CCC: $27.50 2004 American Chemical Society

Published on Web 07/31/2004

5970 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004

lactate with calcium hydroxide. In this recovery scheme,

calcium lactate is precipitated, recovered by filtration,
and converted to lactic acid by the addition of sulfuric
acid. The dilute lactic acid product is then sequentially
purified using activated carbon, evaporation, and crystallization. These separation and final purification
stages account for up to 50% of the production costs.11,12
Thus, this method of recovery is expensive and unfriendly to the environment because it consumes lime
and sulfuric acid and also produces a large quantity of
calcium sulfate sludge as solid waste.13 Because of the
detrimental effect of low pH, reactor productivities are
low and the products are obtained in a dilute form. The
effects of end-product inhibition can be reduced by in
situ removal of lactic acid from fermentation broth by
several methods.
A number of processes for lactic acid recovery from
fermentation broth without precipitation have been
studied and reported in the literature: solvent extraction,14-30 membrane bioreactor,31-33 liquid surfactant
membrane extraction,34 adsorption,35-39 direct distillation,40 electrodialysis,41-46 reverse osmosis,47 anion
exchange,48-50 etc.
Electrodialysis and dialysis have the problem of
membrane fouling, which requires frequent cleaning of
the dialyzer. Moreover, large-volume dialysis units, even
greater than the volume of the fermentor vessel, would
be required in a commercial-scale unit.9 Electrodialysis
gives a higher extent of lactic acid separation but with
increased power and energy consumption.9 Also, large
amounts of byproduct salts from the ion-exchange
regeneration are formed. Adsorption or the ion-exchange
process requires regeneration of an ion-exchange resin
and adjustment of the feed pH to increase the sorption
efficiency, requiring large amounts of chemicals.46 During direct distillation, high-boiling internal esters as
dimers and polymers can be formed.40 In the extraction
of lactic acid from fermentation broth with microporous
hollow fiber membranes, there is a tendency to form an
emulsion.33 Liquid surfactant membrane extraction
exhibits a high complexity of operation due to swelling
of the membranes in liquid surfactants.50 Supported
liquid membranes often suffer from membrane instability.50
Reactive extraction with a specified extractant giving
a higher distribution coefficient has been proposed as a
promising technique for the recovery of carboxylic and
hydroxycarboxylic acids.14,51,52 Reactive liquid-liquid
extraction has the advantage that lactic acid can be
removed easily from the fermentation broth, preventing
lowering of the pH. Further, lactic acid can be reextracted and the extractant recycled to the fermentation process.53,54
A large number of literature studies are available on
the reactive extraction of lactic acid. Reactive extraction
strongly depends on various parameters such as the
distribution coefficient, degree of extraction, loading
ratio, complexation equilibrium constant, types of complexes (1:1, 2:1, etc.), rate constant of lactic acid-amine
reaction, properties of the solvent (extractant and
diluent), type of solvent, temperature, pH, acid concentration, salt present in the acid, water coextraction,
toxicity, feasibility of backextraction, and solvent for
backextraction. The results of these studies of the above
parameters are available in a scattered form. In the
present work, an attempt is made to combine the

available data on the reactive extraction of lactic acid

and to discuss the same in a concise manner.
A critical analysis of the available literature data has
been made, and some general conclusions concerning
the above-mentioned parameters have been drawn.
2. Types of Extractants
A good starting point for developing a new extractive
recovery process for lactic acid should be the identification of novel, more powerful extractants. In the reactive
extraction of lactic acid, the extraction system must
fulfill two basic requirements: a high distribution
coefficient (KD)

KD ) [HL]org/[HL]aq

(1)

and a high selectivity for lactic acid.

Further requirements of an extractant or a system
of extractants are55 (i) low viscosity, (ii) higher density
difference between the extractant and raffinate, (iii) a
medium interfacial tension, (iv) thermal stability, (v) low
enthalpy of vaporization, (vi) low melting points, (vii)
no reaction between the extractant and raffinate, (viii)
low solubility of the extractant in the raffinate, (ix) low
toxicity and good biological degradability, and (x) low
price and good availability.
Kertes and King17 categorized the extractant into
three major types: (I) conventional oxygen-bearing
hydrocarbon extractants [methyl isobutyl ketone (MIBK),
octanol, decanol, etc.], (II) phosphorus-bonded oxygenbearing extractants (tributyl phosphate, etc.), and (III)
high molecular weight aliphatic amines (Aliquat,
Alamine, etc.).
The first two categories are nonreactive extractants
and involve the solvation of the acid by donor bonds,
which are to be distinguished from strong covalent
bonds and from ionic interactions. In category III, a
chemical reaction is involved. The distinction between
the first two categories is based on the strength of the
solvation bonds and the specificity of solvation.17
The conventional extractants, such as ketones, ethers,
and alcohols, are not able to fulfill the basic requirements often because of their low distribution coefficients. The values of KD of lactic acid in various
extractants are given in Table 1. It can be seen that
the distribution coefficient of lactic acid is low (<1) in
conventional extractants, such as alcohols, ketones,
ethers, and aliphatic hydrocarbons.
Phosphorus-bonded oxygen donor extractants exhibit
significantly higher distribution coefficients than carbonbonded oxygen donor extractants under comparable
experimental conditions.17 It can be seen from Table 1
that KD for tributyl phosphate is higher than the
category I extractants.
For carboxylic acid extractions, both organophosphates, such as trioctylphosphine oxide (TOPO) and trin-butyl phosphate (TBP), and aliphatic amines have
large distribution coefficients.
Aliphatic amines and organophosphates, such as
TOPO and TBP, have been used successfully to extract
carboxylic acids.14,17,18,52,53,56,58,63-65 Aliphatic amines are
slightly more effective and less expensive than phosphorus-bonded oxygen-bearing extractants.14
The strong amine interactions with the acid allow for
formation of acid-amine complexes and thus provide
for high distribution coefficients. In addition, the high

Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004 5971
Table 1. Distribution Coefficients for Lactic Acid in
Various Solvent-Water Systems
solvent

KD

ref

diethyl ether
diisopropyl ether
MIBK
MIBK
MIBK
octanol
octanol
decanol
m-cresol
chloroform
hexane
chlorobenzene
1-chlorobutane
chloroform
methylene chloride
MIBK
1-decanol
1-octanol
tributyl phosphate
tri-n-pentylamine
tri-n-hexylamine
tri-n-octylamine
tri-n-decylamine
Alamine 336
Aliquat 336
Alamine 336

0.1
0.04
0.14
0.13
0.1
0.32
0.31
0.29
0.31
0.11
0.0003
no extraction
no extraction
no extraction
0.05
0.01
0.01
0.15
0.71
0.35
1.27
0.63
0.35
0.76
2.17
0.55

17
17
17
56
57
17
53
58
18
18
59
60
60
60
60
60
60
60
60
61
61
61
61
61
62
62

affinity of the organic base for the acid gives selectivity

for the acid over nonacidic components in the mixture.62
Primary amines yield a high mutual solubility with
water. Secondary amines can give quite high values of
KD but are subject to amide formation during regeneration by distillation. Primary alkylammonium lactates
either are excessively water-soluble at room temperature or exhibit surface-active properties or both. Lactates of secondary aliphatic amines are more stable and
organic solvent soluble, although gel formation interferes with phase separation. This trend of the extraction
power is, of course, dictated by the basicity of the
amine.17 KD for secondary amines is much more dependent upon the amine structure than is the case for
tertiary amines.63
Table 1 shows that the values of KD for tertiary
amines alone are slightly higher than those of other
extractants. However, as discussed later, a proper
combination of conventional tertiary amine and conventional extractant (diluent) gives significantly higher
values of the distribution coefficient.
For tertiary amine extractants, KD for lactic acid
typically exhibits a maximum value at an intermediate
solvent composition. This behavior apparently reflects
the combined effects of mass action for the chemical
reaction, on the one hand, and the activity coefficient
of the reaction complex in the solvent mixture, on the
other hand.63
The proton association constant is highest for tertiary
amines and increases with the number of carbon atoms,
although the nature of the diluent also has a marked
effect on the magnitude of the proton association
constant.17 Also, tertiary amine extractants are effective
with KD strongly dependent upon the nature of the
diluent used and the concentration of amine in that
diluent.63 The extractive capacity of tertiary amines
exceeds that of the primary and secondary ones significantly.
The diluent affects the basicity of the amine and thus
the stability of the ion pair formed and its solvation.
The stability of the complex governs the equilibrium

conditions of acid extraction, especially at low loading

ratios, where the equilibrium aqueous acid concentration is very low. Under such conditions, polar diluents
are more favorable than the zero-polarity, low dielectric
constant, aliphatic and aromatic hydrocarbons.17,66 Jung
et al.55 found that the distribution coefficient was
inversely proportional to the molar weight of the alcohols. More electronegative groups serve to decrease KD
because a decrease in the electron-donating ability of
the carbonyl oxygen diminishes its Lewis basicity.14 The
solvation of the whole amine acid complex is based on
dipole-dipole interaction and was found to play an
important role in the neutralization reaction between
acid and amine, which is promoted by increasing the
polarity of the diluent.
Yang et al.62 and Choudhury et al.67 studied the
interaction of carboxylic acids with tertiary and quaternary amines. The quaternary amine Aliquat 336 was
effective in the extraction of both dissociated and
undissociated forms of acids, whereas the tertiary amine
[Alamine 336 and trioctylamine (TOA)] could extract
only the undissociated acid. The polar diluent, octanol,
increased the extracting power of the tertiary amine by
providing more solvating capacity for the nonpolar
amine. In contrast, neither the polar nor the nonpolar
diluent was active when used with Aliquat 336.62
Tertiary amines are capable only of extracting undissociated acid and cannot be used under basic conditions.
In contrast, quaternary amines can extract acid under
both acidic and basic conditions. However, this may
become disadvantageous because it makes Aliquat 336
much more difficult to strip.62
From the above discussion, it can be concluded that
tertiary amines in diluents are the best suitable extractants for the extraction of lactic acid. One of the basic
criteria for the selection of the most effective system of
extractant is the distribution coefficient. Values of
distribution coefficients of lactic acid in various aminediluent compositions are given in Table 2. It is found
that 30% Alamine 336 in octanol has the highest value
of KD. The data in Table 2 suggest that higher concentrations of Alamine in diluent may give higher KD.
Indeed, San-Martin et al.69 found that the degree of
extraction increased up to a concentration of 40%
Alamine 336 in toluene and then remained constant as
a maximum equilibrium concentration was reached.
However, higher concentrations of Alamine 336 increase
the viscosity of the organic phase, which is not favorable
for extraction. Moreover, for extractions with high
concentrations (>25%) of amine in diluent, a third
emulsion phase was observed at the interface between
the aqueous and organic phases.62 Hence, these authors
suggested the use of 10-20% Alamine 336 in diluent.
3. Lactic Acid-Amine (Tertiary) Complex
In the previous section, it was found that tertiary
amine, Alamine 336, is the best suitable extractant for
reactive extraction of lactic acid, and hence in this
section only the lactic acid-amine complex is discussed.
The fundamental difference between oxygen- and nitrogen-bearing basic extractants in the extraction of
acids originates from the basic behavior of the acid
proton during the transfer from an aqueous to an
organic solution. In the systems with oxygen-bearing
solvents, whether carbon, phosphorus, or sulfur is
bound, the acid strength in the aqueous solution and
the hydrogen bond in the organic solution determine the

5972 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004
Table 2. Distribution Coefficients for Lactic Acid in Various Solvent Mixtures-Water Systems
extractant

diluent

KD

ref

15% Alamine 336

30% Alamine 336
50% Alamine 336
20% Alamine 336
30% Alamine 336
40% Alamine 336
20% Alamine 336
30% Alamine 336
40% Alamine 336
10% Alamine 336
20% Alamine 336
30% Alamine 336
50% Aliquat 336
25% Aliquat 336
50% Aliquat 336
50% Alamine
tri-n-hexylamine (12.2 alcohol-amine molar ratio)
tri-n-hexylamine (12.2 alcohol-amine molar ratio)
tri-n-hexylamine (12.2 alcohol-amine molar ratio)
diethylbutylamine (0.97 mol L-1)
tributylamine (0.97 mol L-1)
triamylamine (0.97 mol L-1)
TOA (0.97 mol L-1)
Alamine (0.4 mol L-1)
Alamine (0.8 mol L-1)
50% di-n-hexylamine
50% di-n-octylamine
50% di-n-decylamine
50% tri-n-pentylamine
50% tri-n-hexylamine
50% tri-n-octylamine
50% tri-n-decylamine
50% Alamine 336
50% TOA
30% TOA
90% TOA
90% TOA
TBP (3 mol dm-3)
TBP (3 mol dm-3) + n-octylamine (0.3 mol dm-3)
TBP (3 mol dm-3) + di-n-hexylamine (0.3 mol dm-3)
TBP (3 mol dm-3) + TOA (0.3 mol dm-3)
TBP (3 mol dm-3) + triisooctylamine (0.3 mol dm-3)
TBP (3 mol dm-3) + triethylhexylamine (0.3 mol dm-3)
TBP (3 mol dm-3) + TOA (0.2 mol dm-3)
TBP (3 mol/dm3) + TOA (0.3 mol dm-3)
TBP (3 mol dm-3) + TOA (0.3 mol dm-3)
TBP (3 mol dm-3) + TOA (0.3 mol dm-3)
TBP (3 mol dm-3) + TOA (0.3 mol dm-3)

oleyl alcohol
oleyl alcohol
oleyl alcohol
MIBK
MIBK
MIBK
decanol
decanol
decanol
octanol
octanol
octanol
kerosene
kerosene
2-octanol
2-octanol
1-butanol
2-butanol
isobutyl alcohol
chloroform
chloroform
chloroform
chloroform
toluene
toluene
oleyl alcohol
oleyl alcohol
oleyl alcohol
oleyl alcohol
oleyl alcohol
oleyl alcohol
oleyl alcohol
oleyl alcohol
MIBK
octanol
octanol
paraffin liquid
hexane
hexane
hexane
hexane
hexane
hexane
hexane
butyl acetate
toluene
chlorobenzene
1-decanol

3
4.5
6.5
0.72
2.68
4.24
12.57
16.44
23.37
15.35
19.69
25.95
0.90
0.20
0.78
2.50
22.1
12.5
23.6
1.8
1.4
2.7
4.5
0.83
2.06
0.757
11.1
7.76
0.72
2.94
1.90
1.66
2.62
3.75
0.90
1.2
0.4
0.75
0.17
0.51
3.4
1.5
0.78
2.4
2.8
2.8
3.0
2.9

68
68
68
56
56
56
58
58
58
53
53
53
62
62
62
62
55
55
55
66
66
66
66
69
69
61
61
61
61
61
61
61
61
67
67
67
67
70
70
70
70
70
70
70
70
70
70
70

extractability. On the other hand, the acid extracted into

an amine-containing organic phase is no longer to be
regarded as an acid but as an ammonium salt. It is thus
the extent of ion-pair association between the alkylammonium cation and the acid radical that determines
the extractability or, more precisely, the stability of the
organic-phase species.17
Thus, the extraction process is based on an acid-basetype reaction between the amine B and the lactic acid
HL
KE1

HLaq + Borg 798 BHLorg

KE )

[BHL]org
[B]org[HL]aq

of a 1:1 complex.17,56,58,69,71 Though the exact nature of

the chemistry involved in the uptake of extra acid is
not known and despite the obvious nonideality of the
organic phase under these conditions, distribution data
can be interpreted in terms of simple mass action
equations of the type17
KEn

nHLaq + BHLorg 798 BHL(HL)n,org

KEn )

(2)
(3)

where KE is the equilibrium complexation constant.

Generally, the simple stoichiometric reaction (eq 2)
is not suitable for describing the formation of a complex
of acid and amine molecules because the organic phase
extracts more acid than would be expected on the basis

[BHL(HL)n]org
[BHL]org[HL]aqn

(4)
(5)

The extent to which the organic phase (amine +

diluent) can be loaded with the acid is expressed as the
loading ratio, z.

z)

[HL]org
[B]T,org

[HL]org
[B]org + [BHL(HL)n]org

(6)

The loading ratio, z, can be related with the equilibrium

Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004 5973
Table 3. Equilibrium Complexation Constants of Lactic
Acid-Amine in Various Solvent Mixture-Water Systems

Figure 1. n:1 lactic acid-amine complex structure: (a) 1:1; (b)

2:1; (c) 3:1.

complexation constant for a n:1 lactic acid-amine

complex by the following equation:

z
) KEn[HL]aqn
n-z

(7)

For very dilute, slightly loaded organic solutions,

when z e 1, a 1:1 lactic acid-amine complex is formed.
Formation of a 1:1 lactic acid-amine complex is common, and its structure is shown in Figure 1a. The
formation of 2:1 and 3:1 lactic acid-amine complexes
depends on the lactic acid concentration in the aqueous
phase, and the ratio of 1:1 to 2:1 complex formation is
diluent dependent.18 At higher concentrations of lactic
acid, the 2:2 and 3:1 complexes can be formed.22,56,58 This
overloading phenomenon results from a second lactic
acid molecule hydrogen bonding to the lactic acid that
is already involved in the 1:1 complex (Figure 1b). A
third lactic acid molecule can then hydrogen bond to the
second one in the same way, enabling loadings above
two, and the 3:1 complex is shown in Figure 1c.
Different diluents solvate the various complexes and
the amine to different extents, thereby changing the
activity coefficients. Generally, the greater the ionizing
acidity of the acid, as measured by pKa, the more it is
extracted. The strength of solvation of the complex by
the diluent decreases in the following order:18 alcohol
(e.g., 2-ethyl-1-hexanol) > nitrobenzene > proton-donating halogenated hydrocarbon (e.g., methylene chloride,
chloroform, and 1,2-dichloroethane) > ketone (e.g.,
MIBK, diisobutyl ketone, and 2-heptanone) > halogenated aromatic (e.g., dichlorobenzene and chlorobenzene) > benzene > alkyl aromatic (e.g., toluene and
xylene) > aliphatic hydrocarbon (e.g., hexane, heptane,
and octane).
Juang and Huang27 also observed the formation of
three complexes of lactic acid with TOA. The values of

extractant

diluent

log KE1

log KE2

Alamine 336
Alamine 336
Alamine 336
Alamine 336
Alamine 336
Alamine 336
Alamine 336
TOA

chloroform
xylene
toluene
toluene
MIBK
decanol
octanol

2.57
-0.11
0.26
0.22
1.01
1.66
1.87
0.12

-0.45
-0.02
0.35
0.19
1.00
1.26
1.04
-1.09

log KE3
-1.29
-0.9
-1.01

-0.02

ref
18
72
71
69
56
58
53,73
27

the equilibrium complexation constants of a lactic acidamine complex in various diluents are shown in Table
3. In many studies, the complex 3:1 is not favored
because the concentration of lactic acid in the organic
phase is not high enough. This situation (because there
is low concentration, <10% in the fermentation broth,
only 1:1 and 2:1 lactic acid-amine complexes can be
formed) is frequently encountered in fermentation
processes for the production of lactic acid.69,71 It can be
seen that Alamine 336 in chloroform has a higher
equilibrium complexation constant than other diluents.
However, chloroform is not a safe solvent, banned in
most laboratories and certainly not acceptable for use
in the process industry. Similarly, the ethers, because
of their high volatility/possible toxicity, and MIBK,
because of its nonbiodegradable nature, are not suitable.
Hence, octanol (a higher complexation constant than
those of other diluents except chloroform) is the most
suitable solvent in terms of the equilibrium complexation constant.
Wardell and King14 found that there is no apparent
reaction product in the aqueous phase for a low amine
concentration in the solvent but that a significant
amount of the acid-amine complex develops in the
aqueous phase at higher amine concentrations. Apparently, the diluent is a much better solvent for the acidamine complex than the amine itself. A more polar
diluent may be a more effective solvent for the acidamine complex at high amine concentration.
4. Effect of the Temperature on Extraction
Kertes and King17 found that there is only a very
slight effect, if any, of temperature in the 20-90 C
range on the distribution coefficient of lactic acid into
physical solvents like alcohols, ketones, diethyl carbinol,
and ether solvents without amine.
The effect of the temperature on the extraction of
lactic acid has also been studied by Tamada and King74
using Alamine 336. Equilibrium complexation constants
for the lactic acid-Alamine 336 complex in MIBK and
chloroform at various temperatures are given in Table
4. It can be seen that the equilibrium complexation
constant decreases with increasing temperature; i.e.,
extraction decreases with increasing temperature. The
complexation reactions in the organic phase involve a
proton-transfer reaction or hydrogen-bond formation
and are expected to be exothermic.75 The complex
formation increases the order of the system, and hence
the entropy should decrease. Therefore, as the temperature increases, the amount of acid extracted decreases.74 Table 5 gives the effect of the temperature
on the distribution coefficient of lactic acid in the
Alamine 336-MIBK system. Matsumoto et al.70 and
Tamada and King74 found that the distribution coefficients of lactic acid decrease with increasing temperature for the amine extractant, while the temperature

5974 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004
Table 4. Effect of the Temperature on the Equilibrium
Complexation Constant of the Lactic Acid-Alamine 336
Complex in MIBK and Chloroforma
T, C

log KE1

log KE2

log KE3

0
25
50
75
0
25
55

1.68
1.31
1.12
0.67
3.37
2.57
1.74

0.07
0.21
-0.04
0.08
-0.62
-0.46
-0.36

-0.07
-0.35
-0.26
-0.15

MIBK

chloroform

a Adapted from Tamada and King.74 Copyright 1990 American

Chemical Society.

Table 5. Effect of the Temperature on the Distribution

Coefficient of Lactic Acid in Various Extractants
KD
T, C

TBP70

TOA in
TBP70

0
25
30
40
50
55

0.68
0.64
0.61
0.56

2.6
2.4
1.9
1.5

Alamine in
MIBK74

Alamine in
chloroform74

13.3
4

22.3
16.7

1.8

6.7

0.83

2.5

Table 6. Enthalpies and Entropies of the Lactic

Acid-Alamine 336 Complexa

thermic in chloroform than in MIBK. The entropy

decrease is greater in chloroform than in MIBK.
Tamada and King74 found that the 1:1 lactic acidAlamine 336 complexation is much more exothermic and
involves a much greater loss of entropy than the
formation of 2:1 or 3:1 lactic acid-Alamine 336 complexes. They concluded that the 1:1 lactic acid-Alamine
336 complexation involves the formation of an ion pair,
but higher complexes involve hydrogen-bond formation.
A comparison of the thermodynamic parameters for
2:1 complex formation of lactic acid with the amine in
chloroform and MIBK reveals a contrast to the 1:1
behavior. In chloroform, H21 is a small, positive
quantity, indicating an increase in the system entropy
upon the addition of the second acid molecule to the 1,1
complex. This is consistent with the hypothesis that
chloroform orders itself around the 1:1 complex. The
addition of the second molecule disrupts the chloroformcomplex interaction, which requires energy and increases the overall randomness of the system.74 Tamada
and King74 compared the values of the heat of mixing
in an aqueous phase, heat transfer from the organic to
aqueous phase, and enthalpy and entropy of complexes
of lactic acid with those of succinic acid and found that
it is possible to relate the heat of mixing of the acid in
diluent with the heat of mixing of the complex in the
solvent.

complex
H, kcal mol-1
S, kcal

mol-1

K-1

diluent

1:1

2:1

3:1

transfer

MIBK
chloroform
MIBK
chloroform

-5.6
-12.1
-12.6
-29.0

-0.4
1.9
-0.9
4.2

-0.4

1.1

-2.1
---

0.7
---

a Adapted from Tamada and King.74 Copyright 1990 American

Chemical Society.

effect is relatively small in the extraction with tributyl

phosphate only.
It is found that the effect of the temperature on the
extraction of lactic acid depends on the diluent and
extractant. Generally, the effect of the temperature on
the extraction of lactic acid with diluents only is very
low. However, extraction decreases with an increase in
temperature when an amine-diluent system is used.
5. Thermodynamics of the Lactic Acid-Amine
Complex
As discussed in section 4, because of the exothermic
nature of the complexation reaction and the decrease
in entropy in the same, the amount of lactic acid
extracted decreases with an increase in the extraction
temperature.
If the enthalpy and entropy of reaction are assumed
to be constant over the short temperature range of
relevance to industrial practice, the expression

K)

-H S
+
RT
R

(8)

predicts that a plot of ln K vs 1/T gives a straight line.

The slope is proportional to the enthalpy change of the
reaction, and the intercept is proportional to the entropy
change.
The values of H and S for the formation of 1:1, 2:1,
and 3:1 lactic acid-Alamine 336 complex in MIBK and
chloroform are shown in Table 6.74 The enthalpies of
the lactic acid-Alamine 336 complex are more exo-

6. Effect of the pH on Extraction

There has been increasing interest in using anaerobic
bacteria for organic acid production from biomass.
However, the use of these bacteria for acid production
is usually limited by the low acid concentration (<5%)
attained in the fermentation broth. This is due to the
strong inhibition caused by the acid product.76 Many
fermentations operate best or only work at all under
conditions where the pH exceeds the pKa of the lactic
acid being produced. Under basic conditions in which
the pH exceeds the pKa, the solution largely contains a
lactate salt rather than the free lactic acid. Because it
is the free acid that is transferred and taken up in most
separation processes that recover the free lactic acid,
these processes tend to exhibit low capacities and/or
rates under these conditions.22 Extractive fermentation
has been used successfully to remove the inhibiting
product in situ and thus to increase the bioreactor
productivity.77,78 However, most extractants work efficiently only at acidic pHs, and acidogenic anaerobes
generally have poor growth rates at low pH. It is thus
important to find an extractant that will work well at a
relatively high pH. Furthermore, it is essential to
understand the effects of pH on extraction as well as
on fermentation before an extractive fermentation
process can be designed.79
Yang et al.62 studied two aliphatic amine extractants,
tertiary amine (Alamine 336) and quaternary amine
(Aliquat 336), for their abilities to extract organic acid
at various pHs. They developed a model equation to
predict the values of KD at any pH as

KD )

K1 + K2Ka/[H+]
1 + Ka/[H+]

(9)

where K1, K2, and Ka are constants.62

Figure 2 shows the effect of the pH on the distribution
coefficient for lactic acid extraction with 50% Aliquat

Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004 5975
Table 7. Sensitive Indexes of Lactic Acid in Various
Diluentsa

type of diluent
diluent containing
chlorine atoms

Figure 2. Effect of the pH on the distribution coefficient for lactic

acid extraction with 50% Aliquat 336 in kerosene. Reproduced with
permission from Yang et al.62 Copyright 1990 American Chemical
Society.

336 in kerosene.62 The KD value increased with a

decrease in the pH except at extremely high or low pHs,
where KD does not change significantly with the pH.62
Because literature reports indicate that the optimum
pH values for the fermentation and extraction of lactic
acid are different, Choudhury et al.67 studied the effects
of the initial pH (pH ) 2, 4, and 6) on the extraction of
lactic acid by TOA and Aliquat 336 in MIBK, octanol,
and paraffin liquid. They concluded that a lower pH
favors the extraction of lactic acid for both of the
extractants. Because the formation of a quaternary
ammonium salt is the first step in the extraction of lactic
acid by TOA, the extraction will be greater at acidic pH.
However, in the case of Aliquat 336, because of its
quaternary amine nature, the extraction of lactic acid
was less influenced by the pH of the aqueous phase in
comparison with the tertiary amine, TOA.
pH is directly related with lactic acid concentration.
The distribution coefficients are higher at lower acid
concentrations when aqueous acid concentrations are
below 10 g L-1.52,63 Generally, the distribution coefficient
is constant for a low concentration of lactic acid and
decreases for higher concentration.56,58 Hence, it is
beneficial to carry out reactive extraction at a lower
lactic acid concentration for a high distribution coefficient, which requires a smaller amount of extractant
and also avoids the product inhibition of microorganisms
due to the acid. The situation may, however, change if
microbial strains that can tolerate higher lactic acid
concentrations are developed and made available for
industrial use.
7. Water Coextraction
The mutual solubility between an aqueous solution
and a given solvent at a fixed temperature is affected
by the nature of the acid and its concentration. With
weak organic acids, mutual solubilities cause substantial volume change.17 The extent of the volume change
is, of course, related to the coextraction of water along
with that of the acid. The organic-phase volume increased about 10% with corresponding decreases in the
aqueous phase when Aliquat 336 was used.62 On the
other hand, Yang et al.62 observed no significant volume
change when Alamine 336 was used. For extractions
with high concentrations (>25%) of amine in diluent, a
third emulsion phase was also observed at the surface
between the aqueous and organic phases.62 Volume
change depends on the type of diluent and the type and
concentration of extractant as well as temperature.
The volume change in the extraction is related with
the coextraction of water. Water coextraction, i.e., water
that enters the organic phase with the solute, may also

diluent

methyl chloride
1-chlorobutane
chlorobenzene
chloroform
carbon-bonded
MIBK
oxygen donor
1-octanol
diluent
1-decanol
phosphorus-bonded tributyl phosphate
oxygen donor
diluent

average
sensitivity sensitivity
index
index
1.87
2.04
2.28
4.27
0.61
0.68
0.74
0.48

2.62

0.68
0.48

a Adapted from Han and Hong.60 Copyright 1998 Marcel

Dekker.

affect process economics. For example, it may be necessary to recover pure acid from an aqueous solution
produced from the extract during regeneration.
Starr and King80 found that water removal from the
organic phase could decrease the solubility of carboxylic
acid. This phenomenon was applied for the stripping
method of carboxylic acid by the removal of water from
the organic phase. The amounts of coextracted water
and lactic acid extracted are increased with an increase
in the number of moles of TOA. However, the type of
active diluent is a more important factor than the
number of moles of TOA for extraction of lactic acid.60
Han and Hong60 introduced the sensitivity index,
which represents the amount of lactic acid extracted
with the variation of the water content in the organic
phase. This was defined as the inverse of the slope of
the amount of lactic acid extracted versus the water
content in the organic phase. The sensitivity indices in
various diluents for three types of active diluents
containing chlorine atoms, carbon-bonded oxygen donor
active diluents, and phosphorus-bonded oxygen donor
active diluents are given in Table 7. The sensitivity
index decreases in the order active diluents containing
chlorine atoms > carbon-bonded oxygen donor active
diluents > phosphorus-bonded oxygen donor active
diluents.
Tamada and King74 performed studies to compare the
coextraction of water, which accompanies the extraction
of various other acids by Alamine 336 in chloroform,
MIBK, and various alcohols. Monocarboxylic acids carry
less water with them than dicarboxylic acids, which may
reflect the tendency of coextracted water molecules to
associate with the carboxylate group.74 Tamada and
King74 found that, for the extraction of lactic acid by
Alamine 336 in chloroform and MIBK, water coextraction increases with increasing temperature.
In general, selectivity of the acid over water in the
extraction by amine extractants is high relative to the
results with conventional solvents. The water carried
into the extract would be minimal compared to the
amount of water used in an aqueous backextraction, and
therefore it has little effect upon process viability.18
8. Effect of Lactose and Salt on Extraction
To study the influence of salt (NaCl) and lactose on
the extraction of lactic acid, San-Martin et al.69 carried
out several experiments to determine the distribution
equilibrium of lactic acid. Their results indicated that
the extraction of lactic acid with Alamine 336 dissolved
in toluene is not affected by lactose. Variations of the

5976 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004
Table 8. Effect of NaCl on the Extraction of Lactic Acid
with Alamine 336 (20%, v/v) in Toluene at 25 Ca
lactic acid,
g L-1

NaCl,
g L-1

KD

40
40

0
3.5

0.71
0.61

lactic acid,
g L-1

NaCl,
g L-1

KD

diluent

rate
constant, s-1

40

5.0

0.53

MIBK56
decanol58

1.4
0.2

a Reproduced with permission from San-Martin et al.69 Copyright 1992 John Wiley & Sons Ltd. on behalf of Society of Chemical
Industry (SCI).

distribution coefficient of lactic acid for various sodium

chloride concentrations in the aqueous phase are given
in Table 8. It can be seen that if sodium chloride is
present, less lactic acid is extracted by the organic
phase. This was explained by San-Martin et al.69 by
assuming that chlorine from sodium chloride and H+
ion from lactic acid yield hydrochloric acid, which is
extracted by the amine. This may be due to a stronger
acid like HCl competing for the reaction with the amine.
They also found that the chloride extraction does not
take place in the absence of lactic acid.
9. Kinetics
Wasewar et al.53,56,58 studied the kinetics of reactive
extraction of lactic acid using Alamine 336 in various
diluents (MIBK, decanol, and octanol). They used the
theory of extraction accompanied by a chemical reaction.
Doraiswamy and Sharma81 have given an exhaustive
discussion on the theory of extraction accompanied by
a chemical reaction. Four regimes of extraction accompanied by reaction (very slow, slow, fast, and
instantaneous) have been identified depending upon the
physicochemical and hydrodynamic parameters. When
the reaction is reversible, the solute has a finite equilibrium concentration in the bulk and the driving force
needs to be modified by incorporating the equilibrium
concentration. The extraction involves partitioning of
the solute available in the aqueous phase to the organic
phase.

Aaq f Aorg
The solute A partitioned in the organic phase combines with the organic reactant (amine), B, according
to

A + zB S Complexorg
Using the guidelines given by Doraiswamy and Sharma,81 Wasewar et al.53,56,58 found that in a stirred cell
the system belongs to regime 3, extraction accompanied
by a fast general order chemical reaction occurring in
the diffusion film; the expression for regime 3 is

xm 2+ 1D k

RA ) [A*]

Table 9. Rate Constants of the Lactic Acid-Alamine 336

Reaction in Various Diluents

m-1
[B0]n
A mn[A*]

(10)

The reaction was found to be zero-order in Alamine

336 and first-order in lactic acid. The rate constants for
the lactic acid-Alamine reaction in various diluents are
given in Table 9. Table 9 indicates that octanol is a
better solvent than the other two solvents based on
kinetic considerations.
Wasewar et al.54 studied the kinetics for the backextraction of lactic acid from a loaded organic phase
(lactic acid + Alamine + octanol) using aqueous trimethylamine (TMA). The theory of extraction accom-

diluent

rate
constant, s-1

octanol53

24

panied by chemical reaction was used to obtain the

kinetics. The reaction between lactic acid and aqueous
TMA in a stirred cell falls in regime 3, extraction
accompanied by a fast chemical reaction occurring in
the diffusion film. The reaction was found to be zeroorder in TMA and first-order in lactic acid with a rate
constant of 16.67 s-1.
10. Toxicity
The presence of an organic solvent can give rise to a
series of physical microbial and biochemical effects on
the catalytic activity of the microorganisms. Toxicity of
the organic solvent and extractant to microbes is the
critical problem in extractive fermentation. The degree
of toxicity depends on the combination of microbe and
extractant solution used. Bar and Gainer78 attempted
to develop extractive fermentations for lactic, citric, and
acetic acids and encountered problems of solvent toxicity
and poor extraction. Brink and Tramper82 reported that
the least toxicity is expected from solvents of low
polarity in combination with high solvent molecular
weight. Avoidance of direct contact of the organism with
the organic, amine-bearing phase can substantially
reduce toxic effects.
To reduce the solvent toxicity, several investigators
have used membranes to prevent direct contact of the
solvent with the cell containing broth.83-85 Immobilization is another method to protect the cells by reducing
the contact of the immiscible solvent with the microbes.
Matsumura and Markl83 attempted to make a Porapack Q barrier to solvent molecules beneath the surface
of gel beads as a protection against octanol dissolved in
the medium. A calcium alginate immobilized gel system,
with entrapped vegetable oil, has been reported to
provide protection from octanol, benzene, phenol, and
toluene.86
With regard to solvent toxicity, Bar and Gainer78 have
differentiated the toxicity of the solvent due to the
soluble portion of the solvent (molecular level toxicity)
from that due to the presence of two phases (phase level
toxicity). They have observed that the diluents ndodecanol and methyl oleate were only toxic at the
phase level whereas paraffin oil was totally nontoxic to
Lactobacillus delbrueckii. They had also observed that
the extractant tri-n-dodecylamine exhibited both phase
level and molecular level toxicities.
The toxicity effect of extractants, TOA67 and Alamine
336,19 and diluents, MIBK, octanol, paraffin liquid,67
and oleyl alcohol,19 at molecular and phase levels are
given in Tables 10 and 11, respectively. It is observed
that TOA exhibited symptoms of molecular level toxicity
at 5% saturation level. In the case of phase level toxicity,
they observed that TOA is highly toxic even at a low
phase ratio of 100:1 (aqueous-organic).67 At the phase
level, paraffinic liquid was toxic and both octanol and
MIBK were highly toxic. While the phase level toxicity
of octanol was very high and its molecular level toxicity
was low. It can be revealed that paraffin liquid is the
most suitable diluent for the simultaneous extraction
of lactic acid during fermentation. However, paraffin

Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004 5977
Table 10. Molecular-Level Toxicity
% cell growth
compared to control ref

diluent-extractant
saturated TOA
75% saturated TOA
20% saturated TOA
10% saturated TOA
5% saturated TOA
2% saturated TOA
100% MIBK
50% MIBK
100% octanol
saturated with 15% Alamine 336
saturated with 50% Alamine 336
saturated with 100% Alamine 336
50% Alamine 336 (immobilized cells)
50% Alamine 336 (immobilized cells,
using soybean oil)
100% Alamine 336 (immobilized cells)
100% Alamine 336 (immobilized cells,
using soybean oil)

11.4
11.1
14.2
28.1
72.6
100
61.7
86.7
83.4
68.8
55.6
8.3
55.6
72.2

67
67
67
67
67
67
67
67
67
19
19
19
19
19

2.8
66.7

19
19

Table 11. Phase-Level Toxicity

diluent-extractant
25:1 (Aq.-TOA)
50:1 (Aq.-TOA)
100:1 (Aq.-TOA)
1:1 (Aq.-paraffin liquid)
1:1 (Aq.-MIBK)
1:1 (Aq.-octanol)
oleyl alcohol
15% Alamine 336 in oleyl alcohol
30% Alamine 336 in oleyl alcohol
15% Alamine 336 in oleyl alcohol
(immobilized cells)
30% Alamine 336 in oleyl alcohol
(immobilized cells)

% cell growth
compared to control

ref

6.7
6.5
5.6
96.45
3.74
12.46
96.7
41.7
0
73.3

67
67
67
67
67
67
19
19
19
19

41.2

19

liquid has a lower distribution coefficient than octanol;

hence, octanol can be used for the reactive extraction
of lactic acid from fermentation broth provided that the
phase level toxicity is avoided by an immobilized cell
system.67
It can be seen that adding soybean oil in immobilized
cells significantly reduces the toxicity.20 The solvent
affected the cells through both the water-soluble portion
and the immiscible portion of the solvent. While immobilization significantly protected the cells from the
immiscible solvent phase, the water-soluble part of the
solvent still caused toxicity to the microorganisms due
to diffusion of the solvent into the matrix. Adding
soybean oil to the -carrageenan matrix could trap the
diffusing solvent molecules and therefore reduce the
toxic effect from the water-soluble portion of the solvent.20
Tik et al.25 obtained a maximum total lactic acid
concentration (2.5 times that without extraction) when
15% Alamine 336 in oleyl alcohol together with immobilized cells with 15% sunflower oil was used. Coimmobilization with sunflower oil probably affected the
metabolism of the microorganism. Fats and oils are used
as carbon sources, and they are broken down to glycerol
and fatty acids. Fatty acids are used as the source of
adenosine triphosphate, while glycerol is converted to
pyruvate via glycolysis. Then, lactate is formed from
pyruvate under anaerobic conditions.87 Therefore, lactic
acid production increased with an increase in the
sunflower oil concentration. The sunflower oil can also
extract Alamine 336 that diffused into the gels and
prevent the toxic effect of the solvent. These are the

reasons why sunflower oil was used in the extractive

fermentation experiments.25
From the above discussion, it can be seen that, for
lactic acid extraction, Alamine 336 in oleyl alcohol,
which has the highest KD value, would serve as an ideal
extraction system unless the higher phase level toxicity
of octanol is reduced by using an immobilized enzyme
system.
11. Process
Yabannavar and Wang21 suggested an efficient extractive fermentation process for the production of lactic
acid. To extract the lactic acid during fermentation, the
medium from the fermentor was passed through a
mixer-settler and the aqueous phase was recycled. The
medium from the fermentor was mixed with the solvent
(15% Alamine 336 in oleyl alcohol) in the mixer, and
the mixture was later separated into two phases in the
settler. The extractive fermentation was controlled
through a pH controller. The controller monitored the
pH decrease in the fermentor due to lactic acid formation and, accordingly, activated (through on/off control)
the inlet solvent and exit fluid pumps to initiate the
extraction operation. Thus, by removal of the product
during fermentation, the pH and the product concentration were maintained constant.21 Yabannavar and
Wang21 have given two processes for the regeneration
of lactic acid from a loaded organic phase. Details of
these are given later under the Backextraction of Lactic
Acid section.
Wasewar et al.53 studied reactive extraction of lactic
acid in batch and semibatch modes using Alamine 336
in diluents (MIBK, decanol, and octanol) and suggested
an efficient extractive fermentation process for the
production of lactic acid. They extended the equilibrium
and kinetics data for the in situ reactive extraction from
the fermentation broth and developed a mathematical
model for the slurry phase reactor with glucose in the
continuous aqueous phase, the amine dissolved in a
diluent in the dispersed organic phase, and the immobilized cells as the solid phase. Comparison of semibatch, batch, and plain fermentation without recovery
operation clearly indicated the superiority of semibatch
operation. Comparison of the various modes showed
that the productivity of the semibatch mode yields an
order of magnitude higher productivity than the batch
mode, and therefore this scheme fits in perfectly with
the definition of process intensification.88 A similar
approach was used by Gaidhani et al.89,90 for the
hydrolysis of Penicillin G. Lactic acid extracted in the
organic phase can be backextracted with a stronger
volatile amine like TMA in the aqueous phase. The TMA
can be stripped and recovered by absorption in water
and recycled to obtain a closed-loop system as shown
by Wasewar et al.53 The process suggested is a sustainable process because it does not consume any extra
reagent and also does not produce a large waste stream
like in the conventional process.53 The various processes
available in the literature have the following common
components: (1) fermenter with reactive extraction, (2)
regeneration and recycle of the reactive extractant by
different techniques, and (3) recovery of lactic acid.
Inasmuch as the main difference is only in step 2 above,
all of the processes can be depicted by a single flowsheet
as shown in Figure 3. Step 2 is discussed individually
for the different techniques suggested in section 12.

5978 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004

Figure 3. Generalized flow sheet for fermentation of glucose to lactic acid coupled with semibatch reactive extraction and recovery of
lactic acid-extractant.

12. Backextraction of Lactic Acid

Tamada and King74 considered two approaches for
regeneration through backextraction into an aqueous
phase. These involve changes in the equilibrium relationship through a swing of temperature and a swing
of diluent composition. Yabannavar and Wang21 suggested two methods for recovery of lactic acid from a
loaded solvent phase: using NaOH and using HCl. The
available regeneration methods for lactic acid from a
loaded organic phase are described individually in the
following:
Using NaOH. In the first recovery method, Yabannavar and Wang21 suggested the backextraction of lactic
acid from a loaded organic phase (lactic acid + Alamine
336 + oleyl alcohol) (Figure 3) with small volume of a
sodium hydroxide solution [1:10 (v/v) NaOH-solvent].
NaOH in excess of stoichiometric amounts can be used
to ensure complete lactic acid recovery. Yabannavar and
Wang21 obtained 100% recovery of lactate. The resultant
high product concentration is certainly desirable from
the point of economic product recovery.
However, the acid is then present as sodium lactate.
One must add an appropriate acid (e.g., sulfuric acid)
to return it to the free acid form. This approach has the
same drawbacks as the classical calcium precipitation
process for direct recovery from the aqueous feed. Both
sulfuric acid and NaOH are consumed, and a waste salt
sludge is formed, which requires disposal.
Using HCl. In the second recovery method (Figure
3) suggested by Yabannavar and Wang,21 concentrated
HCl is used to essentially displace the lactic acid from
the loaded organic phase (lactic acid + Alamine 336 +
oleyl alcohol). In this method, undissociated lactic acid
is obtained instead of lactic acid. More than stoichiometric amounts of HCl were necessary to recover most
of the product from the solvent. The lactic acid recovered
through backextraction with HCl is in the undissociated
form. It is possible to regenerate the solvent by distilling
off the volatile HCl. Ricker et al.64 have detailed a
similar regeneration process where acetic acid was
removed from the solvent by distillation. This method
has the drawbacks that aqueous HCl is highly corrosive
and requires special material of construction (glass
lined-graphite).

Using Distillation and Ammonia. Jung et al.55

suggested the process (Figure 3) for extraction of lactic
acid using tri-n-hexylamine in various solvents.
The regeneration of the accumulated extract consisting
of butanol-water-tri-n-hexylamine-lactic acid was
achieved by distillation of the light components butanol
and water, followed by reextraction of the acid with a
concentrated solution of ammonia.55 As the end product,
a highly concentrated solution of ammonium lactate is
obtained. The lactic acid can be isolated from lactate,
for instance, as a hydroxycarboxylic acid or as an ester
by ion exchange91 or in situ esterification,57 respectively.
The salt solution is concentrated by evaporation and
heated so as to decompose ammonium lactate, forming
product lactic acid along with ammonia for recycle.
However, ammonia lactate forms amides when heated.
Using TMA. Poole and King92 suggested a reactive
extraction process (Figure 3) in which a high molecular
weight, organic-soluble amine in an appropriate organic
diluent is used as the forward extractant and an
aqueous solution of a low molecular weight amine is
used for backextraction.
To avoid consumption of chemicals and creation of a
salt byproduct, the aqueous base, which is volatile,
enables thermal decomposition of the acid-base complex in the aqueous backextract. The decomposition
forms carboxylic acid as a product and free base as a
vapor that can be reabsorbed in water and recycled for
reuse in backextraction.
The most obvious water-soluble, volatile base is
ammonia. However, ammonia and both primary and
secondary amines form amides when they are heated
in mixtures with carboxylic acids.93-95 The amides are
sufficiently stable so that it is difficult to reverse the
process and recover the amine. Hence, Poole and King92
and Wasewar et al.54 employed TMA for backextraction
of lactic acid from the loaded organic phase (lactic acid
+ MIBK-octanol + Alamine 336). They found that
essentially 100% of the acid is backextracted into the
aqueous phase at conditions in which there is at least
1 mol of TMA for every equivalent weight of acid.
The studies on the thermal regeneration of TMA
showed that practically 100% of the TMA can be
regenerated by employing a low pressure (200 mmHg)

Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004 5979

coupled with heating to 100-120 C.54,95 In an actual

industrial unit, the thermal regeneration of off-gases
containing water vapor and TMA can be first cooled in
a falling-film type of condenser where most of the TMA
will be absorbed by the condensing water vapor.54 It is
well-known that when the direction of heat and mass
transfer is the same (such as in this case), relatively
high mass-transfer coefficients are realized.96 Thus, a
falling-film condenser cum absorber can yield good
recovery of TMA-water vapors. Final polishing of the
exhaust can be done in an additional falling-film
absorber in order to maintain a low pressure drop. TMA
is highly soluble in water under proper operating
conditions and a well-designed absorber; hence, negligible quantities of TMA are expected to escape.54
The organic phase, which is recycled to the fermentor,
may contain residual dissolved TMA, which should be
removed in a stripper before the recycle because TMA
can affect the bioactivity of the enzyme.
Temperature-Swing Regeneration. In a temperature-swing extraction/regeneration scheme,74 the extraction is carried out at relatively low temperature,
producing an acid-loaded organic extract and an aqueous raffinate waste stream containing the unwanted
feed components. During regeneration, the extract is
contacted with a fresh aqueous stream at a higher
temperature to produce an acid-laden aqueous product
stream and an acid-free organic phase. The concentration of the acid achievable in this stream depends on
the amount of change in the extraction equilibrium
between temperatures and can be higher than that in
the original aqueous feed stream.18
Because of the lower enthalpy change, the extraction
of lactic acid by Alamine 336 in MIBK and chloroform
does not show as large a temperature effect.97 Hence,
temperature-swing regeneration would be less effective
for lactic acid.
Diluent-Swing Regeneration. Tamada and King97
suggested the diluent-swing regeneration process (Figure 3) for lactic acid. Baniel et al.15 also described
regeneration by backextraction following a change in
the diluent composition. In the diluent-swing process,
extraction is carried out in a solvent composed of the
amine and a diluent that promotes distribution of the
acid in the organic phase. The composition of the acidladen organic phase leaving the extractor is then
altered, by either removal of the diluent or addition of
another diluent, to produce a solvent system that
promotes distribution of the acid to the aqueous phase.
This altered organic phase is contacted with a fresh
aqueous stream in the regenerator to produce the acidladen aqueous product and the acid-free solvent for
recycle to the extractor.97 Adjustment of the diluent
composition can also occur before this solvent reenters
the extractor. This approach involving more than one
diluent appears to be more complicated than the TMA
approach, where an easily removable volatile amine
(TMA) is the only externally introduced component. This
process has the disadvantage of diluting the extract
stream and requiring distillation of large amounts of
solvent (after the regeneration) to obtain the same shift
in the active/inert diluent ratio.
Gas-Antisolvent-Induced Regeneration. A drawback to the diluent-swing regeneration15,74 is that
changes in the extractant-phase composition generally
involve a distillation step to separate the active and
inert diluents. To avoid this energy expense, a new

process is proposed by McMorris and Husson98 (Figure

3) that will replace the inert liquid diluent with a gas
antisolvent. Here, antisolvent is used to denote a
substance that has a low capacity to solubilize the
extracted acid. In this process, the diluent composition
change will be effected by pressurizing it with a gas
antisolvent (e.g., propane). A benefit of this process over
conventional recovery techniques is that the diluent
components can be easily separated (e.g., by a flash
distillation) without using a distillation step.98 Estimated energy requirements for a diluent-swing process
involving the gaseous diluent, propane, were lower by
at least a factor of 14 than those for a diluent-swing
process involving the inert liquid diluent, dodecane.98
From the above discussion, it can be seen that
regeneration of lactic acid from the loaded organic phase
by a gas-antisolvent-induced method is the best suitable
method because this process does not require any toxic
material like TMA and also the energy requirement is
low because of the lack of a distillation step compared
to other processes.
13. Process Economics
The cost of the fermentation product depends on the
fermentation process and recovery of the product. In
conventional processes, 50% of the cost of production is
contributed by the fermentation process and the other
50% by the recovery and purification stages. Production
costs of lactic acid can be reduced by increasing the
productivity and using the proper recovery method.
There are a number of in situ recovery methods for lactic
acid recovery (as mentioned earlier in the Introduction
section). The advantages/disadvantages of various recovery
methods for lactic acid are summarized in Table 12.
It can be seen from Table 12 that reactive extraction
is attractive for the recovery of lactic acid. Reactive
liquid-liquid extraction has the advantage that lactic
acid can be removed easily from the fermentation broth.
The extraction process if operated properly is selfadjusting, and therefore the expensive pH control
system used in the conventional process can be dispensed. Further, lactic acid can be reextracted and the
extractant recycled to the fermentation process. In
addition, as mentioned earlier, fermentation coupled
with reactive extraction has a relatively very high
productivity (approximately 25 times) compared to the
plain fermentation, which reduces the fixed plant cost
for a given production capacity. However, considering
enzyme stability and extractant toxicity, a biomembrane
reactor with enzyme immobilized in the pores of a
hydrophilic membrane appears to be more attractive.
This theme needs urgent attention.
14. Conclusion
It is important to have an efficient and sustainable
process for the separation of lactic acid from the
fermentation broth. Although commercial processes for
lactic acid recovery are based on the classical method
of separation, the result of work on reactive extraction
of lactic acid is promising. Extensive literature available
on the reactive extraction of lactic acid with respect to
equilibria, kinetics, solvent toxicity, recovery, etc., is
analyzed. The effects of various parameters on the
reactive extraction of lactic acid are given.
The main parameters for the selection of a diluentextractant system for extraction are the distribution

5980 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004
Table 12. Advantages/Disadvantages of Various Recovery Methods for Lactic Acid
recovery method
calcium hydroxide precipitation

dialysis

electrodialysis
ion exchange

distillation
hollow fiber membrane extraction
liquid surfactant membrane extraction (LEM)
supported liquid membranes
membrane bioreactor

reactive extraction

advantages/disadvantages
advantage: simple and reliable process
drawbacks: consumption of large quantities of reagents (H2SO4 and lime); huge amount
(ca. 2.5 tons) of waste per ton of lactic acid; disposal problem of waste;
very poor sustainability
advantage: good potential
drawbacks: membrane fouling; frequent cleaning is required; large dialysis unit as
compared to fermenter is required; technology is not mature enough for
application on a large scale for bulk chemicals
advantage: simultaneous separation and concentration of lactic acid
drawbacks: higher power consumption; small amount of byproduct salt;
need for substantially more information for commercial use
advantage: reliable technology
drawbacks: regeneration of ion-exchange resin and adjustment of feed pH to increase
the sorption efficiency requires a large amount of chemicals; waste stream
generated creates treatment/disposal problem
advantage: well-established/reliable technology
drawbacks: formation of high-boiling internal esters, dimers, and polymers of
lactic acid during distillation
advantage: large interfacial area for mass transfer can be obtained in a compact unit
drawback: tendency to form emulsion
advantage: large interfacial area for mass transfers in a compact unit
drawback: complexity of operation and swelling/instability of the LEM
advantage: large interfacial area for mass transfers in a compact unit
drawback: often suffers from membrane instability
advantage: continuous separation of products enhances the process
productivity; avoids toxicity due to extractant by
immobilization of biocatalyst in membrane
drawback: difficult cleaning and sterilization
advantage: closed-loop process; proper combination of extractant and diluent;
proper choice of backextractant yields high productivity;
practically all data needed for commercial design are available
drawbacks: most extractants work efficiently at low pH, while most microbial strains
give higher productivity at higher pH; toxicity of extractant toward the microbial
strain needs to be eliminated; development of new strains, which are robust
and work at low pH, is required

coefficient and complexation constant, toxicity, and

feasibility for backextraction.
From the available study, it can be seen that Alamine
336 in proper diluent (octanol and oleyl alcohol) is the
best extractant in terms of the distribution coefficient,
toxicity, and feasibility for backextraction. For the
diluent selection, oleyl alcohol is a better diluent than
octanol. The solvent toxicity versus the microorganism
can be prevented by immobilization of cells with 15%
sunflower oil.25
For the forward extraction process suggested by
Yabannavar and Wang,21 Wasewar et al.s work53 can
be used because, by removal of the product during
fermentation, the pH and the product concentration
were maintained constant. For backextraction, the gasantisolvent-induced method is the most suitable method
because this process does not require any toxic material
like TMA and also the energy requirement is low
because of the lack of a distillation step compared to
other processes. The process suggested is a sustainable
process because it does not consume any extra reagent
and also does not produce a large waste stream as in
the conventional process.
15. Scope and Directions for Future Work
As discussed earlier most extractants have a very
good extraction capacity at lower pH of the media. On
the other hand, most microbial strains available for
conversion of glucose to lactic acid afford high activity
at higher pH. This is the classical dilemma faced by the
process developers. In view of this, there is an urgent
need to either develop extractants, which work at higher
pH or strains and which yield good conversion to lactic
acid at lower pH. In view of the rapid advances being
made in developing tailor-made strains, the latter option

is likely to be more appropriate. Thus, future work

should focus on the development of new strains suitable
for operation at lower pH.
The growing demand of lactic acid draws attention
to the improvement of a conventional recovery process
for lactic acid production. Reactive extraction using
amine is an emerging prospective method for the
recovery of lactic acid from fermentation broth. Economical evaluation data of various processes of lactic
acid production and its recovery are not available.
Therefore, it is necessary to focus on the economical
evaluation of various processes of lactic acid production
and its recovery for the economical comparison.
Nomenclature
[A] ) lactic acid concentration (kmol m-3)
[B] ) amine concentration in the organic phase (kmol m-3)
[BHL] ) 1:1 lactic acid-Alamine complex concentration in
the organic phase (kmol m-3)
DA ) diffusivity of solute A (lactic acid) in solvent (m2 s-1)
[HL] ) lactic acid concentration (kmol m-3)
KE1 ) 1:1 lactic acid-Alamine equilibrium complexation
constant (m3 kmol-1)
KE2 ) 2:1 lactic acid-Alamine equilibrium complexation
constant [(m3 kmol-1)2]
KE3 ) 3:1 lactic acid-Alamine equilibrium complexation
constant [(m3 kmol-1)3]
KEn ) n:1 lactic acid-Alamine equilibrium complexation
constant [(m3 kmol-1)n]
k1 ) first-order rate constant (s-1)
KD ) distribution coefficient
kmn ) rate constant for a reaction that is mth order in
species A and nth order in species B [kmol m-3 s-1 (m3
kmol-1)m+n]
R ) gas constant in eq 12 (kJ mol-1 K-1)
RA ) specific rate of extraction of lactic acid (kmol m-2 s-1)

Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004 5981
RO ) initial rate of extraction of lactic acid (kmol m-2 s-1)
T ) temperature (K)
z ) loading ratio [kmol of lactic acid (kmol of amine)-1]
H ) enthalpy change of the reaction in eq 12 (kJ mol-1)
S ) entropy change of the reaction in eq 12 (kJ mol-1
K-1)
Subscripts
aq ) aqueous phase
org ) organic phase
T ) total
0 ) initial
Superscript
* ) equilibrium

Literature Cited
(1) Watkins, K. A solvent business: Ethyl lactate seeks to
replace workhorses like acetone and methylene chloride. Chem.
Eng. News 2002, 14, 15 and 16.
(2) Buchta, K. Lactic acid. Biotechnology 1983, 3, 409-412.
(3) Datta, R.; Tsai, S. P.; Bonsignore, P.; Moon, S. H.; Frank,
J. R. Technology and economic potential of poly (lactic acid) and
lactic acid derivatives. FEMS Microbiol. Rev. 1995, 16, 221-231.
(4) Lipinsky, E. S.; Sinclair, S. Is lactic acid a commodity
chemical? Chem. Eng. Prog. 1986, 82, 26-32.
(5) Anonymous. Chem. Mark. Rep. 1992, Aug 3, 14.
(6) Bahner B. Chem. Mark. Rep. 1994, Mar 21, 14.
(7) Anonymous. Chem. Mark. Rep. 1994, Dec 12, 30.
(8) Chemical Economics Handbook; SRI International: Menlo
Park, CA, 2003.
(9) Litchfield, J. H.; Microbiological production of lactic acid.
Adv. Appl. Microbiol. 1996, 42, 45-95.
(10) Chahal, S. P. Lactic acid. Ullmanns Encyclopedia of
Industrial Chemistry, 5th ed.; VCH Publishers: Weinheim, Germany, 1990; Vol. 15, pp 97-105.
(11) Chaudhuri, J. B.; Pyle, D. L. Emulsion liquid membrane
extraction of organic acids. 1. A theoretical model for lactic acid
extraction with emulsion swelling. Chem. Eng. Sci. 1992, 47 (1),
41-48.
(12) Eyal, A. M.; Bressler, E. Mini-review industrial separation
of carboxylic acid and amino acids by liquid membranes: applicability, process considerations and potential advantages. Biotechnol. Bioeng. 1993, 41, 287-295.
(13) Shreve, R. N.; Brink, J. A. Chemical Process Industries,
4th ed.; McGraw-Hill: New York, 1977; p 542.
(14) Wardell, J. M.; King, C. J. Solvent equilibria for extraction
of carboxylic acids from water. J. Chem. Eng. Data 1978, 23, 144148.
(15) Baniel, A. M.; Blumbrerg, R.; Hadju, K. Recovery of acids
from aqueous solutions. U.S. Patent 4,275,234, 1981.
(16) Baniel, A. M. Process for the extraction of organic acids
from aqueous solution. EP 0 049 429, 1982.
(17) Kertes, A. S.; King, C. J. Extraction chemistry of fermentation product carboxylic acids. Biotechnol. Bioeng. 1986, 28, 269282.
(18) Tamada, J. A.; Kertes, A. S.; King, C. J. Extraction of
corboxylic acids with amine extractants. 1. equilibria and law of
mass action modeling. Ind. Eng. Chem. Res. 1990, 29, 1319-1326.
(19) Yabannavar, V. M.; Wang, D. I. C. Analysis of mass
transfer for immobilized cells in an extractive lactic acid fermentation. Biotechnol. Bioeng. 1991, 37, 544-550.
(20) Yabannavar, V. M.; Wang, D. I. C. Strategies for Reducing
Solvent Toxicity in Extractive Fermentations. Biotechnol. Bioeng.
1991, 37, 716-722.
(21) Yabannavar, V. M.; Wang, D. I. C. Extractive Fermentation
for Lactic Acid Production. Biotechnol. Bioeng. 1991, 37, 10951100.
(22) King, C. J. Amine-Based Systems for Carboxylic Acid
Recovery. CHEMTECH 1992, May, 285-291.
(23) Lazarova Z.; Peeva, L. Solvent extraction of lactic acid from
aqueous solution. J. Biotechnol. 1994, 32 (1), 75-82.
(24) Frieling, P.; Schugerl, K. Recovery of lactic acid from
aquesous model solutions and fermentation broths. Process Biochem. 1999, 34, 685-696.

(25) Tik, N.; Bayraktar, E.; Mehmetoglue, U. In-situ reactive

extraction of lactic acid from fermentation media. J. Chem.
Technol. Biotechnol. 2001, 76, 764-768.
(26) Kyuchoukov, G.; Marinova, M.; Molinier, J.; Albet, J.;
Malmary, G. Extraction of lactic acid by means of a mixed
extractant. Ind. Eng. Chem. Res. 2001, 40, 5635-5639.
(27) Juang, R.; Huang, R. Equilibrium studies on reactive
extraction of lactic acid with an amine extractant. Chem. Eng. J.
1997, 65, 47-53.
(28) Hartl, J.; Marr, R. Extraction processes for bioproduct
separation. Sep. Sci. Technol. 1993, 28 (1-3), 805-819.
(29) Wang, C. J.; Bajpai, R. K.; Iannotti, E. L. Nondispersive
extraction for recovering lactic acid. Appl. Biochem. Biotechnol.
1991, 28/29, 589-602.
(30) Bailey, R. B.; Joshi, D. K.; Michaels, S. L.; Wisdom, R. A.
Production of lactic acid by continuous fermentation using an
inexpensive raw material and a simplified methods of lactic acid
purification. U.S. Patent 4,771,001, 1988.
(31) Moueddeb, H.; Sanchez, J.; Bardot, C.; Fick, M. Membrane
bioreactor for lactic acid production. J. Membr. Sci. 1996, 114, 5971.
(32) Juang, R.; Huang, R. Kinetic Studies on Lactic Acid
Extraction with Amine using a Microporous Membrane-based
Stirred Cell. J. Membr. Sci. 1997, 129, 185-196.
(33) Tong, Y.; Hirata, M.; Takanashi, H.; Hano, T.; Kubota, F.;
Goto, M.; Nakashio, F.; Matsumoto, M. Extraction of lactic acid
from fermented broth with microporous hollow fiber membranes.
J. Membr. Sci. 1998, 143, 81-91.
(34) Sirman, T.; Pyle, D. L.; Grandison, A. S.; Extraction of
organic acids using a supported liquid membrane. Biochem. Soc.
Trans. 1991, 19 (3), 274-279.
(35) Dai, Y.; King, J. Selectivity between lactic acid and glucose
during recovery of lactic acid with basic extractants and polymeric
sorbents. Ind. Eng. Chem. Res. 1996, 35, 1215-1224.
(36) Tsao, G. T.; Lee, S. J.; Tsai, G.-J.; Seo, J.-H.; McQuigg, D.
W.; Vorhies, S. L.; Iyer, G. Process for producing and recovering
lactic acid. U.S. Patent 5,786,185, 1998.
(37) Kaufman, E. N.; Cooper, S. P.; Davison, B. H. Screening
of resins for use in a biparticle fluidized-bed bioreactor for the
continuous fermentation and separation of lactic acid. Appl.
Biochem. Biotechnol. 1994, 45-46, 545-554.
(38) Kuo, Y.; Munson, C. L.; Rixey, W. G.; Garcia, A. A.;
Frierman, M. Use of adsorbents for recovery of acetic acid from
aqueous solutions IsFactors governing capacity. Sep. Purif.
Methods 1987, 16, 31-64.
(39) Evangeliesta, R. L.; Mangold, A. J.; Nikolov, Z. L. Recovery
of lactic acid by sorption-resin evaluation. Appl. Biochem. Biotechnol. 1994, 45-46, 131-144.
(40) Cockrem, M. C. M.; Johnson, P. D. Recovery of lactate and
lactic acid from fermentation broth. U.S. Patent 5,210,296, 1991.
(41) Hongo, M.; Nomura, Y.; Iwahara, M. Novel method lactic
acid production by electrodialysis fermentation. Appl. Environ.
Microbiol. 1986, 52 (2), 314-319.
(42) Heriban, V.; Skara, J.; Sturdik, E.; Ilavsky, J. Isolation of
the lactic acid using electrodialysis. Biotechnol. Tech. 1987, 7 (1),
63-68.
(43) Boyaval, P.; Corre, C.; Terre, S. Continuous lactic acid
fermentation with concentrated product recovery by ultra-filtration
and electrodialysis. Biotechnol. Lett. 1987, 9 (3), 207-212.
(44) Nomura, Y.; Iwahara, M.; Hongo, M. Lactic acid production
by electrodialysis fermentation using immobilized growing cells.
Biotechnol. Bioeng. 1987, 30, 788-793.
(45) Siebold, M.; Frieling, P.; Joppien, R.; Rindfleisch, D.;
Schugerl, K.; Roper, H. Comparison of the production of lactic acid
by three different lactobacilli and its recovery by extraction and
electrodialysis. Process Biochem. 1995, 20 (1), 81-95.
(46) Lee, E. G.; Moon, S.; Chang, Y. K.; Yoo, I.; Chang, H. N.
Lactic acid recovery using two-stage electrodialysis and its modelling. J. Membr. Sci. 1998, 145, 53-66.
(47) Timmer, J. K. M.; Kromkamp, J.; Robbertsen, T. Lactic
acid separation from fermentation broth by reverse osmosis and
nanofiltration. J. Membr. Sci. 1994, 92, 185-197.
(48) Monteagudo, J. M.; Aldavero, M. Prodcution of lactic acid
by lactobacillus delbrueckii in chemostat culture using an ionexchange resin system. J. Chem. Technol. Biotechnol. 1999, 74,
627-634.
(49) Cao, X.; Yun, H. S.; Koo, Y.-M. Recovery of lactic acid by
anion-exchange resin Amberlite IRA-400. Biochem. Eng. J. 2002,
11, 189-196.

5982 Ind. Eng. Chem. Res., Vol. 43, No. 19, 2004
(50) Zihao, W.; Kenfeng, Z. Kinetic and mass transfer for lactic
acid recovered with anion exchange method in fermentation
solution. Biotechnol. Bioeng. 1995, 47, 1-7.
(51) King, C. J. In Handbook of Solvent Extraction; Lo, T. C.,
Baird, M. H. I., Hanson, C., Eds.; Wiley-Interscience: New York,
1983; p 567.
(52) Wennersten, R. Extraction of carboxylic acid from fermentation broth using solution of tertiary amine. J. Chem. Technol.
Biotechnol. 1983, 33B, 85-94.
(53) Wasewar, K. L.; Heesink, A. B. M.; Versteeg, G. F.;
Pangarkar, V. G. Intensification of enzymatic conversion of glucose
to lactic acid accompanied by reactive extraction. Chem. Eng. Sci.
2003, 58 (15), 3385-3394.
(54) Wasewar, K. L.; Heesink, A. B. M.; Versteeg, G. F.;
Pangarkar, V. G. Intensification of Conversion of Glucose to Lactic
Acid: Equilibria and Kinetics for Back Extraction of Lactic Acid
using Trimethylamine. Chem. Eng. Sci. 2004, 59, 2315-2320.
(55) Jung, M.; Schierbaum, B.; Vogel, H. Extraction of Corboxylic Acid from Aqueous Solutions with the Extractant System
Alcohol/Tri-n-Alkylamines. Chem. Eng. Technol. 2000, 23, 70-74.
(56) Wasewar, K. L.; Heesink, A. B. M.; Versteeg, G. F.;
Pangarkar, V. G. Reactive extraction of lactic acid using Alamine
336 in MIBK: equilibria and kinetics. J. Biotechnol. 2002a, 97
(1), 59-68.
(57) Holten, C. H. Lactic acid; Verlag Chemie: Weinheim,
Germany, 1979.
(58) Wasewar, K. L.; Heesink, A. B. M.; Versteeg, G. F.;
Pangarkar, V. G.; Equilibria and kinetics for reactive extraction
of lactic acid using Alamine 336 in decanol. J. Chem. Technol.
Biotechnol. 2002, 77, 1068-1075.
(59) Hano, T.; Matasumoto, M.; Ohtake, T.; Sasaka, L.; Kawano
Y. Extraction equilibria of oraganic acid wit tri-n-octylphosphineoxide. J. Chem. Eng. Jpn. 1990, 23, 734-738.
(60) Han, D. H.; Hong, W. H. Water-Enhanced Solubilities of
Lactic Acid in Reactive Extraction Using Trioctylamine/Various
Active Diluents Systems. Sep. Sci. Technol. 1998, 33 (2), 271281.
(61) Honda, H.; Toyama, Y.; Takahashi, H.; Nakareko, T.;
Kobayashi, T. Effective Lactic acid Production by Two-Stage
Extractive Fermentation. J. Ferment. Bioeng. 1995, 79 (6), 589593.
(62) Yang, S.; White, S. A.; Hsu, S. Extraction of Corboxylic
Acids with Tertiary and Quaternary Amines: Effect of pH. Ind.
Eng. Chem. Res. 1991, 30, 1335-1342.
(63) Ricker, N. L.; Michaels, J. N.; King, C. J. Solvent properties
of organic bases for extraction of acetic acid from water. J. Sep.
Process Technol. 1979, 1 (1), 36-41.
(64) Ricker, N. L.; Pittman, E. F.; King, C. J. Solvent extraction
with amines for recovery of acetic acid from dilute aqueous
industrial streams. J. Sep. Process Technol. 1980, 1 (2), 23-30.
(65) Yabannavar, V. M.; Wang, D. I. C. Integration of extraction
with fermentation for organic acid production. Annual meeting of
AIChE, Miami, FL, Nov 1986.
(66) Ratchford, W. P.; Harris, E. H.; Fisher, C. H.; Willits, C.
D. Extraction of lactic acid from water solution. Ind. Eng. Chem.
1951, 43, 778-781.
(67) Choudhury, B.; Basha, A.; Swaminathan, T. Study of Lactic
Acid Extraction with Higher Molecular Weight Aliphatic Amines.
J. Chem. Technol. Biotechnol. 1998, 72, 111-116.
(68) Yabannavar, V. M.; Wang, D. I. C. Reactive extraction of
lactic acid. Ann. NY Acad. Sci. 1987, 506, 523-535.
(69) San-Martin, M.; Pazos, C.; Coca, J. Reactive extraction of
lactic acid with Alamine 336 in the presence of salts and lactose.
J. Chem. Technol. Biotechnol. 1992, 54, 1-6.
(70) Matsumoto, M.; Takahashi, T.; Fukushima K. Synergistic
extraction of lactic acid with alkylamine and tri-n-bytylphosphate: effects of amines, diluents and temperature. Sep. Purif.
Technol. 2003, 33, 89-93.
(71) San-Martin, M.; Pazos, C.; Coca, J. Reactive extraction of
lactic acid with Alamine 336. J. Chem. Technol. Biotechnol. 1996,
65, 281-285.
(72) Sato, T.; Watanabe, H.; Nakamura, H. Extraction of lactic,
tartaric, succinic, and citric acids by means of trioctylamine.
Bunseki Kagaku 1985, 34, 559-563.
(73) Wasewar, K. L.; Heesink, A. B. M.; Versteeg, G. F.;
Pangarkar, V. G. (University Institute of Chemical Technolgy,
Mumbai, India). Reactive extraction of lactic acid using Alamine
336 in octanol: equilibria and kinetics. Unpublished work, 2003.

(74) Tamada, J. A.; King, C. J. Extraction of corboxylic acids

with amine extractants. 3. Effect of Temperature, Water Coextraction and Process Consideration. Ind. Eng. Chem. Res. 1990,
29, 1333-1338.
(75) Tamada, J. A.; King, C. J. Extraction of corboxylic acids
with amine extractants. 2. Chemical interactions and interpretation of data. Ind. Eng. Chem. Res. 1990, 29, 1327-1333.
(76) Herrero, A. A. End-product inhibition in anaerobic fermentation. Trends Biotechnol. 1983, 1, 49-53.
(77) Daugulis, A. J. Integrated reaction and product recovery
in bioreactor systems. Biotechnol. Prog. 1988, 4, 113-122.
(78) Bar, R.; Gainer, J. L. Acid fermentation in water-organic
solvent two-liquid-phase systems. Biotechnol. Prog. 1987, 3, 109114.
(79) Hsu, S. T. Effects of pH on extractive fermentation for
propionic acid production from whey lactose. M.S. Thesis, Department of Chemical Engineering. The Ohio State University,
Columbus, OH, 1989.
(80) Starr, J. N.; King, C. J. Water-enhanced solubility of
carboxylic acids in organic solvents and its application to extraction
processes. Ind. Eng. Chem. Res. 1992, 31, 2572.
(81) Doraiswamy, L. K.; Sharma, M. M. Heterogeneous Reaction: Analysis, Examples, and Reactor Design, Vol 2: Fluid-FluidSolid-Reactions, 1st ed.; John Wiley & Sons: New York, 1984; pp
17-41.
(82) Brink, L. E. S.; Tramper, J. Optimization of organic solvent
in multiphase biocatalysis. Biotechnol. Bioeng. 1985, 27, 12581269.
(83) Matsumura, M.; Markl, H. Elimination of ethanol inhibition. Biotechnol. Bioeng. 1986, 28, 534-541.
(84) Frank, G. T.; Sirkar, K. K. Alcohol prodcution by yeast
fermentation and membrane extraction. Biotechnol. Bioeng. Symp.
1985, 15, 621-632.
(85) Cho, T.; Shuler, M. L. Multimembrane bioreactor for
extractive fermentation. Biotechnol. Prog. 1986, 2 (1), 53-60.
(86) Tanaka, H.; Harada, S.; Kurosawa, H.; Yajima, M. A new
immobilized cell system with protection against toxic solvents.
Biotechnol. Bioeng. 1987, 30, 22-30.
(87) Lehninger, A. L. Biochemistry, 2nd ed.; Worth Publishers: New York, 1997; pp 284-558.
(88) Stankiewicz, A. I.; Moulijn, J. A. Process intensification:
transforming chemical engineering. Chem. Eng. Prog. 2000, 96,
22-34.
(89) Gaidhani, H. K.; Wasewar, K. L.; Pangarkar, V. G.
Intensification of Enzymatic Hydrolysis of Penicillin G: 1. Equilibria and Kinetics of Extraction of Phenyl Acetic acid by Alamine
336. Chem. Eng. Sci. 2002, 57, 1979-1984.
(90) Gaidhani, H. K.; Tolani, V. L.; Pangarkar, K. V.; Pangarkar, V. G. Intensification of Enzymatic Hydrolysis of Penicillin
G: 2. Model for Enzymatic Reaction with Reactive Extraction.
Chem. Eng. Sci. 2002, 57, 1985-1992.
(91) Schierbaum, B.; Vogel H. Isolation of carboxylic acids from
aqueous solutions by extraction with dialkylcarboxylic amides/
trialkyl amines. Chem. Eng. Technol. 1999, 22, 37-41.
(92) Poole, L. J.; King, C. J. Regeneration of carboxylic acidamine extracts by back-extraction with an aqueous solution of a
volatile amine. Ind. Eng. Chem. Res. 1991, 30, 923-929.
(93) Streitwieser, A. Jr.; Heathcock, C. H. Introduction to
organic chemistry; Macmillan: New York, 1976; Chapters 17 and
18.
(94) Mitchell, J. A.; Reid, E. E. The pervaporation of aliphatic
amides. J. Am. Chem. Soc. 1931, 53, 1879-1883.
(95) Poole, L. J.; King, C. J. Regeneration of amine-carboxylic
acid extracts; Report LBL-28614; Lawrence Berkeley Laboratory:
Berkeley, CA, 1990.
(96) Bennett, C. O.; Myers, J. F. Momentum, heat and mass
transfer; McGraw-Hill Book Co., Inc.: New York, 1962; p 538.
(97) Tamada, J. A.; King, C. J. Extraction of carboxylic acids
by amine extractants; Report LBL-25571; Lawrence Berkeley
Laboratory: Berkeley, CA, Jan 1989.
(98) McMorris, J.; Husson, S. M. Gas antisolvent-induced
regeneration of lactic acid-laden extractants. Sep. Sci. Technol.
2001, 36 (5 and 6), 1129-1148.

Received for review January 9, 2004

Revised manuscript received May 17, 2004
Accepted June 21, 2004
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