8354

Ind. Eng. Chem. Res. 2004, 43, 8354-8362

Solubility Modeling with a Nonrandom Two-Liquid Segment

Activity Coefficient Model
Chau-Chyun Chen* and Yuhua Song
Aspen Technology, Inc., Ten Canal Park, Cambridge, Massachusetts 02141

A segment contribution activity coefficient model, derived from the polymer nonrandom twoliquid model, is proposed for fast, qualitative estimation of the solubilities of organic nonelectrolytes in common solvents. Conceptually, the approach suggests that one account for the liquid
nonideality of mixtures of complex pharmaceutical molecules and small solvent molecules in
terms of interactions between three pairwise interacting conceptual segments: hydrophobic
segment, hydrophilic segment, and polar segment. In practice, these conceptual segments become
the molecular descriptors used to represent the molecular surface characteristics of each solute
and solvent molecule. The treatment results in component-specific molecular parameters:
hydrophobicity X, polarity Y, and hydrophilicity Z. Once the molecular parameters are identified
from experimental data for common solvents and solute molecules, the model offers a simple
and practical thermodynamic framework to estimate solubilities and to perform other phase
equilibrium calculations in support of pharmaceutical process design.
Introduction
Solvent selection is a critical task in the chemical
synthesis and recipe development phase of the pharmaceutical and agricultural chemical industries.1-3 The
choice of solvents directly impacts the reaction rates,
extraction efficiency, crystallization yield, etc. Proper
solvent selection results in faster product separation and
purification, reduced solvent emission and lesser waste,
higher yield, lower overall cost, and better production
processes.
Solubility is a key property of concern in solvent
selection because pharmaceutical product isolation is
often done through crystallization at reduced temperature and/or with the addition of antisolvent. Solubility
data involving new drug molecules and their precursors
in the solvents rarely exist, if any. Although limited
solubility experiments are taken for a few solvents as
part of the process development practice, the experimental task can multiply rapidly when one considers
the choices of solvents and solvent-antisolvent mixtures, the effect of temperature, the impacts of impurities, the possibilities of multiple polymorphs, etc. As a
result, solvent selection is largely dictated by researchers preferences or prior experiences.
Existing solubility estimation techniques are best
represented by the Hansen model,4 the UNIFAC group
contribution model,5 and perhaps the Abraham solvation model.6 From the three, Hansen and UNIFAC are
activity coefficient models that can be used for the
estimation of solubilities in pure solvents and in solvent
mixtures. Other popular activity coefficient models, such
as van Laar, Wilson, nonrandom two liquid (NRTL), or
UNIQUAC, are not practical because use of these
models requires the determination of binary interaction
parameters from phase equilibrium data for each of the
solute-solvent and solvent-solvent binary mixtures.
Solute-solvent phase equilibrium data are rarely avail* To whom correspondence should be addressed. Tel.: (617)
949-1202. Fax: (617) 949-1030. E-mail: chauchyun.chen@
aspentech.com.

able to support the use of these activity coefficient

models in pharmaceutical process design.
The Hansen model is a correlative model. It requires
experimental solubility data from which componentspecific solubility parameters can be determined for the
solutes. The UNIFAC model is a predictive model that
requires only chemical structure information for the
solutes and solvents. Unfortunately, although these
models have shown limited utilities for solubility estimation of chemicals with molecular weights in the low
100s g/mol, prior investigators2 have found that, because
of inherent assumptions with Hansen and UNIFAC,
they are inadequate in estimating solubilities for large,
complex organic molecules with molecular weights in
the range of 200-600 g/mol. UNIFAC fails for systems
with large complex molecules for which either the
UNIFAC functional groups are undefined or the functional group additivity rule becomes invalid. Additionally, neither Hansen nor UNIFAC is applicable to
electrolyte solutes, a major concern for the pharmaceutical industry because organic electrolytes account for
the majority of drug compounds.
Recent developments in computational chemistry
yielded COSMO-RS7 and COSMO-SAC,8 predictive
models that represent promising alternatives to UNIFAC. Like UNIFAC, the current COMOS-RS-type models are not applicable to electrolyte solutes.
In this paper, we present the NRTL segment activity
coefficient (NRTL-SAC) model as the thermodynamic
framework for solubility modeling. The NRTL-SAC
model is based on the polymer NRTL model,9 a derivative of the original NRTL model of Renon and Prausnitz.10 NRTL is one of the most successful molecular
thermodynamic models in the chemical industry. The
model and its derivatives have been widely used to
correlate and extrapolate phase behaviors of highly
nonideal systems with chemicals, electrolytes, oligomers, polymers, surfactants, etc.9,11 We show that the
NRTL-SAC model provides a simple and practical
thermodynamic framework for chemists and engineers
to perform solubility modeling in support of their

10.1021/ie049463u CCC: $27.50 2004 American Chemical Society

Published on Web 12/15/2004

Ind. Eng. Chem. Res., Vol. 43, No. 26, 2004 8355

pharmaceutical process design. While this paper focuses

on modeling solubilities of organic nonelectrolytes,
future work will extend the model to organic electrolytes.

ln

lc
m

j xjGjmjm

k xkGkm

Solubility Modeling

xmGmm

mm
m
k xkGkm
k xkGkm

The solubility of a solid organic nonelectrolyte can be

described by the expression1,2

ln xSAT
)
I

fusS
Tm
1- ln SAT
I
R
T

(1)
ln lc,I
m )

for T e Tm

fusS ) fusH/Tm

j xj,IGjmjm

(2)

+ ln SAT
ln Ksp ) ln xSAT
I
I

(3)

Ksp corresponds to the ideal solubility of the solute.

NRTL Segment Activity Coefficient Model
The proposed NRTL segment activity coefficient
model builds on the segment contribution concept that
was first incorporated into the polymer NRTL model9
for systems with oligomers and polymers. In NRTLSAC, the activity coefficient expression is written in two
parts such that

ln I ) ln CI + ln RI

(4)

where CI and RI are the combinatorial and residual

contributions to the activity coefficient of component I.
The residual part, RI , is set equal to the local composition (lc) interaction contribution, lc
I , of the polymer
NRTL as follows:

ln RI ) ln lc
I )

lc,I
rm,I[ln lc

m - ln m ]
m

k xk,IGkm

xj )

J xJrj,J
I i

xj,I )

j xj,IGjmjm

mm
m
k xk,IGkm
k xk,IGkm

(7)

(8)

xIri,I

rj,I

i ri,I

(9)

where i, j, k, m, and m are the segment-based species

indices, I and J are the component indices, xj is the
segment-based mole fraction of segment species j, xJ is
the mole fraction of component J, rm,I is the number of
segment species m contained in component I, lc
m is the
activity coefficient of segment species m, and lc,I
m is the
activity coefficient of segment species m contained only
in component I. G and in eqs 6 and 7 are local binary
quantities related to each other by the NRTL nonrandomness factor parameter R:

G ) exp(-R)

(10)

Equation 5 is a general form for the local composition

interaction contribution to activity coefficients of components in the NRTL-SAC model. For monosegment
solvent components (S), eq 5 can be simplified and
reduced to the classical NRTL model as follows:
lc
)
ln I)S

lc,S
rm,S[ln lc

m - ln m ]
m

(11)

with

(5)

We then compute the segment activity coefficient, m,

from the NRTL equation.

(6)

xm,IGmm

xSAT
I

where
is the mole fraction of the solute I dissolved
in the solvent phase at saturation, fusS is the entropy
is the activity coefficient of
of fusion of the solute, SAT
I
the solute in the solution at saturation, R is the gas
constant, T is the temperature, and Tm is the melting
point of the solute. Given a polymorph, fusS and Tm
are fixed. At a fixed temperature, the solubility is only
a function of the activity coefficient of the solute in the
solution. Clearly, the activity coefficient of the solute
in the solution plays a key role in determining the
solubility.
Equation 1 is a simplified expression for solubility.
It ignores the contributions due to the difference between solid and liquid heat capacities at the melting
point and due to the pressure correction. When the
values of fusS and Tm are not available, the solubility
product constant, Ksp, can be introduced into eq 1 as an
adjustable parameter for data regression:

j xjGjmjm

Therefore

rm,S ) 1

(12)

ln lc,S
m ) 0

(13)

8356

Ind. Eng. Chem. Res., Vol. 43, No. 26, 2004

lc
ln I)S
)

j xjGjSjS
k xkGkS

xmGSm

j xjGjmjm

Sm
m
k xkGkm
k xkGkm

(14)

GjS ) exp(-RjSjS)

(15)

GSj ) exp(-RjSSj)

(16)

Equation 14 is the same as the classical NRTL model.10

The combinatorial part, CI , is calculated from the
Flory-Huggins term:

ln CI ) ln

I
xI

rI )

I )

+ 1 - rI

J r

(17)

i ri,I
rIxI

J rJxJ

(18)

(19)

where rI and I are the total segment number and

segment mole fraction of component I, respectively.
Conceptual Segment Contribution Concept. The
essence of NRTL-SAC resides in its use of the conceptual
segment contribution concept. While UNIFAC decomposes molecules into a large set of predefined functional
groups based on the chemical structure, NRTL-SAC
maps molecules into a few predefined conceptual segments, or molecular descriptors, based on expressed
characteristics of molecular interactions in solutions.
Specifically, for each solute and solvent molecule, NRTLSAC describes their effective surface interactions in
terms of three types of conceptual segments: hydrophobic segment, polar segment, and hydrophilic segment. Equivalent numbers of the conceptual segments
for each molecule are measures of the effective surface
areas of the molecule that exhibit surface interaction
characteristics of hydrophobicity (X), polarity (Y), and
hydrophilicity (Z). These molecular measures, i.e., X, Y,
and Z, are to be determined not from the molecular
structure but from the interaction characteristics of the
molecules in solution as expressed in their experimental
phase equilibrium data.
The pairwise segment-segment interaction characteristics of these conceptual segments are represented
by their corresponding binary NRTL parameters. The
determination of these binary NRTL parameters is
discussed in the next section. Given the NRTL parameters for the pairwise segment-segment interactions
and the molecular measures (X, Y, and Z) for the
molecules, we apply eqs 4-9 to compute activity coefficients for the segments and the molecules in solution.
In other words, the phase behavior of the mixtures will
be accounted for based on the segment compositions of
the molecules and their pairwise segment-segment
interactions.
The conceptual segment contribution approach represents a practical alternative to the UNIFAC functional
group contribution approach. This approach is suitable
for use in the industrial practice of carrying out mea-

surements for a few selected solvents and then using a

model to quickly predict other solvents or solvent
mixtures and to generate a list of suitable solvent
systems. The NRTL-SAC model aims to provide such a
thermodynamic framework. With NRTL-SAC, available
experimental data are used to identify molecular parameters for the solutes, and the model is used to
extrapolate to other solvent systems that are also
described in terms of the same set of molecular descriptors.
Conceptual Segments and NRTL Binary Parameters. Three conceptual segments are initially identified
for nonelectrolyte molecules: hydrophobic segment,
polar segment, and hydrophilic segment. Additional
conceptual segments may be introduced when we expand the scope to cover organic electrolytes, charged
molecules, zwitterions, etc. To enhance the usability of
NRTL-SAC, the choice of conceptual segments is meant
to be a minimal set rather than a comprehensive set.
These conceptual segments are chosen to simulate the
interaction characteristics of representative molecular
surfaces that significantly contribute to the liquid-phase
nonideality of real molecules. Here the hydrophilic
segment simulates polar molecular surfaces that are
hydrogen bond donor or acceptor. As such, it represents molecular surfaces with the tendency to form a
hydrogen bond. The hydrophobic segment simulates
molecular surfaces with the adversity to form a hydrogen bond. The polar segment simulates polar molecular
surfaces that are electron pair donor or acceptor. While
the hydrophobic and hydrophilic segments have their
strong and clear physical meanings and unique contributions to the liquid-phase nonideality, in our drive to
minimize the number of conceptual segments and for
practical purposes, we lumped all other surface interactions with the polar segment.
With the conceptual segments identified, real molecules are then selected as reference molecules for the
conceptual segments and available phase equilibrium
data of these reference molecules are used to identify
NRTL binary parameters for the conceptual segments.
In choosing the reference molecules, we prefer those
molecules with distinct molecular characteristics (i.e.,
hydrophobic, hydrophilic, or polar) and with abundant,
publicly available phase equilibrium data.
We focus our study on the 59 solvents reviewed for
use in pharmaceutical process design by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH).12 We also consider water, triethylamine, and n-octanol in this study because they are used
extensively in pharmaceutical processes. Additional
solvents can be considered in the future. Table 1 shows
these 62 solvents and their molecular characteristics.
Hydrocarbon solvents (aliphatic or aromatic), halogenated hydrocarbons, and ethers are mainly hydrophobic.
Ketones, esters, and amides are both hydrophobic and
polar. Alcohols, glycols, and amines may have both
substantial hydrophilicity and hydrophobicity. Acids are
complex molecules, exhibiting hydrophilicity, polarity,
and hydrophobicity. Also shown in Table 1 are the
available NRTL binary parameters for various solventwater and solvent-hexane binary systems. We obtained
these binary parameters by fitting the available data
compiled by DECHEMA for phase equilibrium at or
around room temperature. We deliberately ignore the
temperature dependency of these parameters because

Ind. Eng. Chem. Res., Vol. 43, No. 26, 2004 8357
Table 1. NRTL Binary Parameters for Common Solvents in Pharmaceutical Process Design
solvent (component 1)
acetic acid
acetone
acetonitrile
anisole
benzene
1-butanol
2-butanol
n-butyl acetate
methyl tert-butyl ether
carbon tetrachloride
chlorobenzene
chloroform
cumene
cyclohexane
1,2-dichloroethane
1,1-dichloroethylene
1,2-dichloroethylene
dichloromethane
1,2-dimethoxyethane
N,N-dimethylacetamide
N,N-dimethylformamide
dimethyl sulfoxide
1,4-dioxane
ethanol
2-ethoxyethanol
ethyl acetate
ethylene glycol
diethyl ether
ethyl formate
formamide
formic acid
n-heptane
n-hexane
isobutyl acetate
isopropyl acetate
methanol
2-methoxyethanol
methyl acetate
3-methyl-1-butanol
methyl butyl ketone
methylcyclohexane
methyl ethyl ketone
methyl isobutyl ketone
isobutyl alcohol
N-methyl-2-pyrrolidone
nitromethane
n-pentane
1-pentanol
1-propanol
isopropyl alcohol
n-propyl acetate
pyridine
sulfolane
tetrahydrofuran
1,2,3,4-tetrahydronaphthalene
toluene
1,1,1-trichloroethane
trichloroethylene
m-xylene
water
triethylamine
1-octanol

12a

21a

12b

1.365
0.880
1.834

0.797
0.935
1.643

2.445
0.806
0.707

-1.108
1.244
1.787

1.490
-0.113
-0.165

-0.614
2.639
2.149

-0.148
1.309
0.884
1.121

0.368
-0.850
-0.194
-0.424

0.269
-0.168
1.430
1.534

2.870
3.021
2.131
4.263

-0.824
1.576

1.054
-0.138

0.589

0.325

1.245

1.636

1.246
0.533
-0.319
0.771

0.097
2.192
2.560
0.190

-0.940

1.400

-0.414

0.398

1.478

1.155

0.062

2.374

1.412
-0.036

-1.054
1.273

0.021
-0.583

2.027
3.270

0.496
-0.320
0.049
0.657

-0.523
2.567
2.558
1.099

-0.665

1.664

0.631
1.134
-0.869
0.535
1.026

1.981
-0.631
1.292
-0.197
-0.560

10.949
-0.908
-0.888

6.547
1.285
3.153

21b

3.207

4.284

1.983
0.450
-0.564
-1.167
-2.139
1.003
-0.024
-1.593

3.828
1.952
1.109
2.044
0.955
1.010
1.597
1.853

1.380

-1.660

12c

21c

3.692
-2.157
-1.539

5.977
5.843
5.083

5.314
4.013
3.587

7.369
7.026
4.954

6.012
2.833

9.519
4.783

0.508

3.828

1.612

3.103

-0.340

-1.202

6.547

10.949

6.547

10.949

0.103
1.389
0.715
-0.042

0.396
-0.566
2.751
3.029

-0.598

5.680

0.823
0.977
0.592
-0.235
1.968

2.128
4.868
2.702
0.437
2.556

-0.769

3.883

-1.479

5.269

-0.029
0.197
0.079
1.409
-0.990
1.045
1.773

3.583
2.541
2.032
2.571
3.146
0.396
0.563
4.241

7.224

-0.169
0.301

4.997
8.939

1.200

1.763

solvent characteristics
complex
polar
polar
hydrophobic
hydrophobic
hydrophobic/hydrophilic
hydrophobic/hydrophilic
hydrophobic/polar
hydrophobic
hydrophobic
hydrophobic
hydrophobic
hydrophobic
hydrophobic
hydrophobic
hydrophobic
hydrophobic
polar
polar
polar
polar
polar
polar
hydrophobic/hydrophilic
hydrophobic/hydrophilic
hydrophobic/polar
hydrophilic
hydrophobic
polar
complex
complex
hydrophobic
hydrophobic
polar
polar
hydrophobic/hydrophilic
hydrophobic/hydrophilic
polar
hydrophobic/hydrophilic
hydrophobic/polar
polar
hydrophobic/polar
hydrophobic/polar
hydrophobic/hydrophilic
hydrophobic
polar
hydrophobic
hydrophobic/hydrophilic
hydrophobic/hydrophilic
hydrophobic/hydrophilic
hydrophobic/polar
polar
polar
polar
hydrophobic
hydrophobic
hydrophobic
hydrophobic
hydrophobic
hydrophilic
hydrophobic/polar
hydrophobic/hydrophilic

a NRTL binary parameters for various solvent-hexane systems. The NRTL nonrandom factor parameter, R, is fixed as a constant
of 0.2. In these binary systems, the solvent is component 1 and hexane is component 2. s were determined from available VLE and LLE
data. b NRTL binary parameters for various solvent-water systems. The NRTL nonrandom factor parameter, R, is fixed as a constant
of 0.3. In these binary systems, the solvent is component 1 and water is component 2. s were determined from available VLE data.
c NRTL binary parameters for various solvent-water systems. The NRTL nonrandom factor parameter, R, is fixed as a constant of 0.2.
In these binary systems, the solvent is component 1 and water is component 2. s were determined from available LLE data.

these parameters are reported here only to illustrate

ranges of values for these binary parameters.
Table 1 shows that all hydrophobic solvents (1) exhibit
similar repulsive interactions with water (2) and both
12 and 21 are large positive values for the solventwater binaries. When the hydrophobic solvents also

carry significant hydrophilic or polar characteristics, we

see that 12 becomes negative while 21 retains a large
positive value.
Interestingly, we see similar repulsive, but weaker,
interactions between the polar solvent (1) and hexane
(2), a representative hydrophobic solvent. Both 12 and

8358

Ind. Eng. Chem. Res., Vol. 43, No. 26, 2004

Table 2. NRTL Binary Parameters for Conceptual

Segments in NRTL-SAC
segment 1
segment 2
12
21
R12 ) R21

X
Y1.643
1.834
0.2

X
Z
6.547
10.949
0.2

YZ
-2.000
1.787
0.3

Y+
Z
2.000
1.787
0.3

X
Y+
1.643
1.834
0.2

21 are small but positive values for the solvent-hexane

binaries. On the other hand, the interactions between
hydrophobic solvents and hexane are weak, and the
corresponding NRTL binary parameters are around or
less than unity, characteristic of nearly ideal solutions.
The interactions between polar solvents (1) and water
(2) are more subtle. While all 21 are positive, 12 can be
positive or negative. Apparently, different polar molecules exhibit different interactions, some repulsive and
others attractive, with hydrophilic molecules. For example, acetonitrile and acetone are hydrogen bond
acceptors, and they form hydrogen bonds with water.
Both 12 and 21 are positive for the acetone-water and
acetonitrile-water binaries. For example, dimethyl
sulfoxide is a compound with excellent solvation capacity and high dielectric constant (48.75 at 25 C). 12 is
negative and 21 is positive for the dimethyl sulfoxidewater binary.
Hexane and water are the obvious choices as the
reference molecules for the hydrophobic and hydrophilic
segments, respectively. The selection of the reference
molecule for the polar segment requires attention to the
wide variations of interactions between polar molecules
and water. Ultimately, we choose acetonitrile as a
representative of polar molecules, and we introduce a
mechanism to tune the way we characterize the polar
segment.
The chosen values for the NRTL binary interaction
parameters, R and , for the three conceptual segments
are summarized in Table 2. As mentioned earlier, we
ignore the temperature dependency of the binary parameters. The binary parameters for the hydrophobic
segment X (1)-hydrophilic segment Z (2) are determined from available liquid-liquid equilibrium (LLE)
data of the hexane-water binary mixture (see Table 1).
We fix R at 0.2 because it is the customary value for R
for systems that exhibit liquid-liquid separation. Here
both 12 and 21 are large positive values (6.547 and
10.950). They highlight the strong repulsive nature of
the interactions between the hydrophobic and hydrophilic segments. The binary parameters for the hydrophobic segment X (1)-polar segment Y (2) are determined from available LLE data of the hexane-acetonitrile binary mixture (see Table 1). Again, we fix R at
0.2. Both 12 and 21 are small positive values (1.643 and
1.834). They highlight the weak repulsive nature of the
interactions between the hydrophobic and polar segments.
The binary parameters for the polar segment Y (1)hydrophilic segment Z (2) are determined from available
vapor-liquid equilibrium (VLE) data of the acetonitrile-water binary mixture (see Table 1). We fix R at
0.3 for the hydrophilic segment-polar segment pair
because this binary does not exhibit liquid-liquid
separation. We fix 21 at a positive value (1.787), and
we allow 12 to vary between -2 and +2 to reflect the
fact that the interaction between the polar molecule and
water can be negative or positive as shown in Table 1.
In practice, this is achieved by allowing for two types
of polar segments, Y- and Y+. For the Y- polar

segment, the values of 12 and 21 are -2 and +1.787,

respectively. For the Y+ polar segment, they are 2 and
1.787, respectively. Note that both the Y- and Y+ polar
segments exhibit the same repulsive interactions with
hydrophobic segments as those discussed in the previous
paragraph. Also, an ideal solution is assumed for the
Y- polar segment and Y+ polar segment binary, i.e.,
12 ) 21 ) 0.
We understand that the treatment above is somehow
arbitrary and it only reflects our own limited molecular
insights at this time. However, the treatment is designed to capture the general trends of the NRTL binary
parameters that we have observed for systems with
hydrophobic, polar, and hydrophilic molecules. Further
investigation may bring improved treatments.
Molecular Parameters for Solvents. The application of NRTL-SAC requires an extensive databank of
molecular parameters for common solvents used in the
industry. As mentioned earlier, we focus on the common
solvents used in the pharmaceutical industry.12 For each
solvent, there can be up to four molecular parameters,
i.e., X, Y-, Y+, and Z. Because of the fact that these
molecular parameters represent certain pairwise surface interaction characteristics, often only one or two
molecular parameters are needed for most solvents. For
example, alkanes are hydrophobic and are well represented with hydrophobicity, X, alone. Alcohols are
hybrids of hydrophobic and hydrophilic segments and
are primarily represented with X and Z. Ketones, esters,
and ethers are polar molecules with varying degrees of
hydrophobic contents. They are well represented by X
and Ys.
Determination of solvent molecular parameters involves regression of available experimental VLE or LLE
data for binary systems of solvent and the abovementioned reference molecules (i.e., hexane, acetonitrile,
and water) or their substitutes. Solvent molecular
parameters X, Y-, Y+, and Z are the adjustable
parameters in the regression. If binary data are lacking
for the solvent with the reference molecules, data for
other binaries may be used as long as the molecular
parameters for the substitute reference molecules are
already identified.
Table 3 lists the molecular parameters identified for
the 62 solvents. We used the VLE or LLE data taken
at or around room temperature and available in the
DECHEMA database. Among the ICH solvents, because
of the lack of sufficient experimental binary phase
equilibrium data, we are less comfortable with the
molecular parameters identified for anisole, cumene,
1,2-dichloroethylene, 1,2-dimethoxyethane, N,N-dimethylacetamide, dimethyl sulfoxide, ethyl formate,
isobutyl acetate, isopropyl acetate, methyl butyl ketone,
tetralin, and trichloroethylene. In fact, we are not able
to locate any public data for methyl butyl ketone (2hexanone) and, therefore, its molecular parameters were
set to be the same as those for methyl isobutyl ketone.
The NRTL-SAC model with the molecular parameters
does qualitatively capture the interaction characteristics
of the solvent mixtures and the resulting phase equilibrium behavior. As an example, Figures 1-3 show the
binary phase diagrams for the water-1,4-dioxaneoctanol system. We compare the predictions from the
NRTL model with the binary parameters in Table 1 to
the predictions from the NRTL-SAC model with the
molecular parameters in Table 3. The predictions with
the NRTL-SAC model are broadly consistent with the

Ind. Eng. Chem. Res., Vol. 43, No. 26, 2004 8359
Table 3. NRTL-SAC Molecular Parameters for Common
Solvents
solvent name

Y-

Y+

acetic acid
acetone
acetonitrile
anisole
benzene
1-butanol
2-butanol
n-butyl acetate
methyl tert-butyl ether
carbon tetrachloride
chlorobenzene
chloroform
cumene
cyclohexane
1,2-dichloroethane
1,1-dichloroethylene
1,2-dichloroethylene
dichloromethane
1,2-dimethoxyethane
N,N-dimethylacetamide
N,N-dimethylformamide
dimethyl sulfoxide
1,4-dioxane
ethanol
2-ethoxyethanol
ethyl acetate
ethylene glycol
diethyl ether
ethyl formate
formamide
formic acid
n-heptane
n-hexane
isobutyl acetate
isopropyl acetate
methanol
2-methoxyethanol
methyl acetate
3-methyl-1-butanol
methyl butyl ketone
methylcyclohexane
methyl ethyl ketone
methyl isobutyl ketone
isobutyl alcohol
N-methyl-2-pyrrolidone
nitromethane
n-pentane
1-pentanol
1-propanol
isopropyl alcohol
n-propyl acetate
pyridine
sulfolane
tetrahydrofuran
1,2,3,4-tetrahydronaphthalene
toluene
1,1,1-trichloroethane
trichloroethylene
m-xylene
water
triethylamine
1-octanol

0.045
0.131
0.018
0.722
0.607
0.414
0.335
0.317
1.040
0.718
0.710
0.278
1.208
0.892
0.394
0.529
0.188
0.321
0.081
0.067
0.073
0.532
0.154
0.256
0.071
0.322

0.164
0.109
0.131

0.157
0.513
0.883

0.217

0.448
0.257
0.707
1.340
1.000
1.660
0.552
0.088
0.052
0.236
0.419
0.673
1.162
0.247
0.673
0.566
0.197
0.025
0.898
0.474
0.375
0.351
0.514
0.205
0.210
0.235
0.443
0.604
0.548
0.426
0.758

0.190
0.007
0.082
0.030
0.219

0.194
0.030
0.564
2.890
0.086
0.081
0.318
0.049
0.141
0.041
0.089
2.470

0.154
0.149
0.043
0.224
0.036
0.224

0.485
0.355
0.330
0.172
0.141
0.424
0.039
0.541
0.691
0.208
0.832
1.262
0.858
0.157
0.372

Figure 1. Txy phase diagram for a water-1,4-dioxane mixture

at atmospheric pressure.

0.401
0.507
0.237
0.421
0.338
0.165
0.280
0.341

0.108
0.498
0.027
0.251
0.337
0.538
0.469
0.251
0.480
0.469
0.067

0.322

0.252

0.562
0.560

Figure 2. Txxy phase diagram for a water-octanol mixture at

atmospheric pressure.

0.314

0.485
0.305

1.216
0.223
0.030
0.070
0.134
0.135

0.426

0.040
0.555

0.320

0.003
0.587
0.174

0.248
0.511
0.353
0.457

0.304
0.287
0.285
0.021

Figure 3. Txy phase diagram for an octanol-1,4-dioxane mixture

at atmospheric pressure.

0.316
1.000

0.557
0.766

0.105
0.032

0.624

0.335

calculations from the NRTL model that are generally

understood to represent experimental data within engineering accuracy.
Model Applications
To test the usability of NRTL-SAC with solubility
modeling of pharmaceuticals, we apply the model to
aspirin with the room-temperature solubility data compiled by Frank et al.2 Of the 23 solvents in Frank et

al.s compilation, we focus on the 14 solvents for which

we have molecular parameters available in Table 3. We
first fit the aspirin solubility data for all 14 solvents.
The regression results are shown in Table 4 and Figure
4. The regressed molecular parameters for aspirin are
given in Table 5. With NRTL-SAC, the root-meanexp
2
1/2
- ln xcal
square (rms) error in ln x, [N
i (ln xi
i ) /N] ,
for the fit is 0.506 (here x is the solubility of the solute,
i.e., mole fraction, and N is the number of data used in
the correlations). Acetic acid, a strong proton donor, is
the outlier in this case. With acetic acid removed, the
rms error in ln x for the fit drops significantly to 0.362.
While there is room for further optimization of NRTL-

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Ind. Eng. Chem. Res., Vol. 43, No. 26, 2004

Table 4. Solubility of Aspirin at Room Temperaturea

literature data
solvent

wt %

mole
fraction

methanol
acetone
ethanol
1,4-dioxane
acetic acid
methyl ethyl ketone
2-propanol
isoamyl alcohol
chloroform
diethyl ether
n-octanol
1,2-dichloroethane
1,1,1-trichloroethane
cyclohexane

33
29
20
19
12
12
10
10
6
5
3
3
0.5
0.005

8.053 10-2
1.163 10-1
6.007 10-2
1.029 10-1
4.347 10-2
5.174 10-2
5.924 10-2
5.155 10-2
4.057 10-2
2.119 10-2
2.186 10-2
1.670 10-2
3.706 10-3
2.335 10-5

NRTL-SAC
(mole fraction)

NRTL-SAC
(four solvents)b
(mole fraction)

UNIFAC
(mole fraction)

Hansen
(mole fraction)

7.950 10-2
1.084 10-1
3.907 10-2
1.130 10-1
1.709 10-1
4.838 10-2
3.257 10-2
4.552 10-2
4.547 10-2
1.127 10-2
2.491 10-2
1.352 10-2
2.743 10-3
4.962 10-5

8.053 10-2
1.163 10-1
3.208 10-2
1.204 10-1
1.670 10-1
5.016 10-2
2.903 10-2
4.195 10-2
4.057 10-2
9.081 10-3
2.015 10-2
1.232 10-2
2.001 10-3
2.335 10-5

7.722 10-2
8.782 10-2
1.606 10-2
5.699 10-2
9.522 10-2
6.596 10-2
2.897 10-2
1.490 10-2
9.735 10-2
1.685 10-2
1.453 10-2
3.969 10-2
3.750 10-2
9.351 10-4

4.256 10-2
7.892 10-2
4.643 10-2
1.997 10-2
9.053 10-2
5.642 10-2
7.174 10-2
5.155 10-2
3.369 10-2
2.558 10-2
3.664 10-2
2.809 10-2
2.238 10-2
4.695 10-3

aLiterature data, UNIFAC prediction results, and Hansen correlation results are taken from Frank et al.2
solvents are acetone, cyclohexane, methanol, and chloroform.

The four representative

Table 5. NRTL-SAC Molecular Parameters for Solutes

solute

MW

no. of solvents

T (K)

aspirin
aspirin
p-aminobenzoic acid
benzoic acid
camphor
ephedrine
lidocaine
methylparaben
testosterone
theophylline
estriol
estrone
morphine
piroxicam
hydrocortisone
haloperidol

180.16
180.16
137.14
122.12
152.23
165.23
234.33
152.14
288.41
180.18
288.38
270.37
285.34
331.35
362.46
375.86

14
4
7
7
7
7
7
7
7
7
9a
12
6
14b
11c
13d

298.15
298.15
298.15
298.15
298.15
298.15
298.15
298.15
298.15
298.15
298.15
298.15
308.15
298.15
298.15
298.15

0.103
0.039
0.218
0.524
0.604
0.458
0.698
0.479
1.051

Y-

0.853
0.499
0.773
0.665
0.401
0.827

0.681
0.089
0.124
0.068
0.596
0.484
0.771
0.757

Y+

ln Ksp

rms error in ln x

1.160
1.372
1.935
0.450
0.478

0.777
0.799
0.760
0.405

-2.630
-2.582
-2.861
-1.540
-0.593
-0.296
-0.978
-2.103
-3.797
-6.110
-7.652
-6.531
-4.658
-7.656
-6.697
-4.398

0.506
0.533e
0.284
0.160
0.092
0.067
0.027
0.120
0.334
0.661
0.608
0.519
1.007
0.665
0.334
0.311

0.679

0.293
1.218
0.233
1.208
0.291
1.521

0.970

1.803
1.248

0.193
0.172
0.683
0.669
0.341
1.928
0.196
1.811
0.169
0.611
0.131

a With THF excluded. b With 1,2-dichloroethane, chloroform, diethyl ether, and DMF excluded.
chloroform and DMF excluded. e 14 solvents.

Figure 4. NRTL-SAC results for aspirin solubility at 298.15 K.

Solubility data2 for all 14 solvents are fit simultaneously with
NRTL-SAC.

SAC including both molecular descriptors and parameters, the results are considered to be very satisfactory.
To test the predictive capability of NRTL-SAC, we
also fit the aspirin solubility data using only four
representative solvents (i.e., acetone for the polar
solvent, cyclohexane and chloroform for the hydrophobic
solvents, and methanol for the hydrophilic solvent) and
then use the identified molecular parameters to estimate the aspirin solubilities in the other 10 solvents.
As shown in Table 5, the molecular parameters for

With hexane excluded.

With

Figure 5. NRTL-SAC results for aspirin solubility at 298.15 K.

Solubility data2 for 4 solvents are fit with NRTL-SAC, while the
other 10 are predicted.

aspirin only change slightly. Likewise, the rms error in

ln x for all 14 solvents only increases slightly from 0.506
to 0.533. The comparison of experimental data vs
computed solubilities is given in Figure 5, which shows
a quality of fit similar to that shown in Figure 4. In
other words, these molecular parameters are found to
be relatively independent of the number of solvents used
as long as proper representative solvents (hydrophobic,
hydrophilic, and polar) are included. This study with
aspirin and other similar studies suggest that the

Ind. Eng. Chem. Res., Vol. 43, No. 26, 2004 8361

extract and test the solubility data for the eight molecules reported by Lin and Nash.14 We also test the
model against six additional molecules with sizable
solubility data sets.
We apply the model with the solvents that are
included in Table 3. The molecular parameters determined for the solutes and the rms errors in ln x for the
fits are summarized in Table 5. A good representation
of the solubility data is obtained. The average rms error
in ln x for the 14 solutes (aspirin excluded) summarized
in Table 5 is 0.37. It corresponds to (45% accuracy in
solubility predictions. Certainly, the quality of the fit
reflects both the effectiveness of NRTL-SAC and the
quality of the molecular parameters identified from the
limited available experimental data for the solvents.
Figure 6. UNIFAC results for aspirin solubility at 298.15 K.
Solubility data2 for all 14 solvents are predicted with UNIFAC.

Conclusions
The NRTL-SAC model is a practical thermodynamic
framework for solubility modeling in pharmaceutical
process design. The model requires only componentspecific molecular parameters that represent the surface
interaction characteristics of the molecules. For solute
molecules, these parameters are identified from solubility measurements of the solute in a few representative
solvents, i.e., hydrophobic, hydrophilic, and polar solvents. The model is a useful tool for qualitative correlation and prediction of phase behavior, i.e., solubility, of
systems with large, complex pharmaceutical solutes in
common solvents.
Figure 7. Hansen correlation results for aspirin solubility at
298.15 K. Solubility data2 for all 14 solvents are fit simultaneously
with Hansen.

NRTL-SAC molecular descriptors are good representations of molecular surface interaction characteristics and
that the solvent molecules used to identify molecular
parameters for the solute can be thought of as molecular
sensors used to elucidate the surface interaction
characteristics of the solute molecule in solution. These
molecular sensors probe and express the solutesolvent interactions in terms of binary phase equilibrium data, i.e., solubility.
Note that, during the data regression, all experimental solubility data, regardless of their order of magnitude, were assigned with a standard deviation of 20%.
In addition to the experimental data and the NRTLSAC results for aspirin at room temperature, Table 4
also includes the UNIFAC prediction results and the
Hansen correlation results reported by Frank et al.2 To
be sure of the UNIFAC predictions and the Hansen
correlations, we duplicated Franks results. With UNIFAC and Hansen, the rms errors in ln x for the 14
solvents are 1.352 and 1.600, respectively. Figures 6 and
7 show the comparisons of experimental data and
computed solubilities with UNIFAC and Hansen. The
outliers could be attributed to either poor experimental
data or poor model representations. Given that the
NRTL-SAC results are clearly superior to those of
UNIFAC and Hansen, the results illustrate the relative
inability of UNIFAC and Hansen to capture solvent
effects on the solubility of aspirin.
The data compilation of Marrero and Abildskov13
provides a good source of public solubility data for large,
complex chemicals. To further test NRTL-SAC, we first

Acknowledgment
The authors are grateful to Hsien-Hsin Tung, Daniel
E. Bakken, Christopher Rentsch, and Jose E. Tabora
of Merck for their critical evaluation of NRTL-SAC,
UNIFAC, and Hansen models for solubility modeling
of Merck compounds in solvents and solvent mixtures.
We also thank Prof. John Prausnitz for his warm
encouragement and insightful critiques on the manuscript.
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Received for review June 18, 2004

Revised manuscript received September 29, 2004
Accepted October 18, 2004
IE049463U