J.

of Supercritical Fluids 55 (2010) 462471

Contents lists available at ScienceDirect

The Journal of Supercritical Fluids

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

A comparison between models based on equations of state and density-based

models for describing the solubility of solutes in CO2
Michael Trk a, , Marlene Crone a , Thomas Kraska b
a
b

Karlsruhe Institute of Technology (KIT), Institut fr Technische Thermodynamik und Kltetechnik, Germany
Institut fr Physikalische Chemie, Department fr Chemie, Universitt zu Kln, Germany

a r t i c l e

i n f o

Article history:
Received 7 June 2010
Received in revised form 12 August 2010
Accepted 24 August 2010

a b s t r a c t
The poor dissolution behaviour of solid drugs in biological environment leads to a low bioavailability.
However, the dissolution rate of such drugs can be enhanced dramatically by reduction of the particle size. At present, supercritical uid based particle size reduction processes are gaining in importance
in pharmaceutical technology. For the design of such particle formation processes and the determination of their best operating conditions the knowledge of phase equilibrium and solute solubility in a
supercritical uid is essential. Today, models based on equations of state, together with different mixing
rules, are most widely used to correlate and predict the solubility in supercritical uids. Therefore the
accurate knowledge of the required solute data, such as critical parameters, acentric factor, solid molar
volume, and sublimation pressure of the solutes is essential. However, the common, non-equation of
state based group-contribution methods are mostly empirical and often lead to inconsistent and unreliable results. Thus, due to the lack of information on these data, density-based models are often used
for the correlation of experimental solubility data. In this investigation, the solubility of Salicylic acid, of
S-Naproxen, of RS-Ibuprofen and of Phytosterol in CO2 is correlated by different methods: two methods
for the pressuresolubility correlation and two methods for the densitysolubility correlation. In addition, the inuence of solute data predicted by different group-contribution methods is investigated. With
the exception of S-Naproxen all systems investigated can be modelled sufcient well with a non-cubic
equation of state while a cubic equation of state gives less accurate results. In addition, it is shown that
for the solutes investigated, the equation of state based method is very sensitive to the values of the
sublimation pressure.
2010 Elsevier B.V. All rights reserved.

1. Introduction
The knowledge of phase equilibrium and solute solubility in a
SCF is essential for the design of particle formation processes and
the determination of their best operating conditions. With regard to
the PGSS process (Particle Generation from Gas Saturated Solution),
the ability of the supercritical solvent to melt the solid and to form
saturated liquid phase is of major interest. In the GAS process (Gas
Anti-Solvent) the SCF acts as an anti-solvent while in case of the
RESS process (Rapid Expansion of Supercritical Solutions) enables
the solvent free formation of submicron particles. In addition, the
properties of the produced powders such as particle size and morphology are often strongly inuenced by the underlying phase
behaviour. Until today, much work has been done on producing
submicron poor water soluble substances by RESS and dissolu-

Corresponding author. Tel.: +49 721 608 2330.

E-mail address: tuerk@kit.edu (M. Trk).
0896-8446/$ see front matter 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.supu.2010.08.011

tion studies demonstrate that pharmaceuticals show a signicantly

improved dissolution rate [1].
Usually, in the processes named above, mixtures composed of
a supercritical solvent (1) and a solid (2) of low volatility differ
appreciably in mass, size, interaction strength, polarity, and shape.
The phase behaviour of such asymmetric mixtures shows some
interesting particularities, which are depicted in Fig. 1. Usually, the
triple point temperature of the solid (TTP,2 ) is markedly higher than
the critical temperature of the pure solvent (Tc,1 ). Beyond this, the
solubility of the supercritical solvent in the liquid phase of the
second component is limited. These facts lead to a melting point
depression of the second component and in addition, the critical
mixture curve is interrupted at two distinguished points. Close to
Tc,1 , the lower branch of the critical locus ends at the lower critical endpoint (LCEP). At higher temperatures, the solidliquidgas
three-phase-line (S2 LG line) interrupts the critical mixture curve
at the upper critical endpoint (UCEP). In the temperature range
between the TLCEP and TUCEP only a soliduid two-phase equilibrium (s2 = scf) exists for each pressure. In the region close to the

M. Trk et al. / J. of Supercritical Fluids 55 (2010) 462471

Nomenclature
a
A

b
B
c
C
d
D
E
kij
lij

p
pc
R

S
T
Tm
TTP,2
Tc,1

vi
xi
y2

attraction parameter of the PengRobinson EoS; t

parameter of Eq. (6)
t parameter of the sublimation pressure curve of
Eq. (5) and Eq. (9)
temperature of the attraction term of the
PengRobinson EoS
co-volume parameter of the PengRobinson EoS; t
parameter of Eq. (6)
t parameter of the sublimation pressure curve of
Eq. (5) and Eq. (9)
t parameter of Eq. (7)
t parameter of the sublimation pressure curve of
Eq. (9)
t parameter of Eq. (7)
t parameter of the sublimation pressure curve of
Eq. (9)
t parameter of the sublimation pressure curve of
Eq. (9); enhancement factor
t parameter for the binary attraction
t parameter for the binary co-volume
acentric factor
pressure
critical pressure
gas constant
uctuation parameter of the LK-EoS
entropy of fusion
temperature
melting temperature
triple temperature of the solute
critical temperature of the solvent
molar volume of component i
mole fraction of component i
mole fraction of the solute in the supercritical solvent

463

Table 1
Physical properties of the substances investigated.
Solid

CAS number

M (g/mol)

Tm (K)a

hfus
(kJ/mol)a
i

Salicylic acid
RS-Ibuprofen
S-Naproxen
Phytosterol

69-72-7
15687-27-1
22204-53-1
83-46-5

138.12
206.28
230.26
414.72

431.5
348.6
427.7
411.5

27.8
25.5
31.4
18.9

Measured with DSC.

Therefore reliable solubility data are essential for an accurate

experimental design and for calculation of the concentration of
supercritical solutions at different operating conditions. Today,
models based on equations of state, together with different mixing
rules, are most widely used to correlate and predict the solubility in
SCFs. Therefore the accurate knowledge of the required solute data,
such as critical parameters, acentric factor, solid molar volume, and
sublimation pressure of the solutes is essential. However, the common estimation methods are mostly empirical and often lead to
inconsistent and unreliable results. Thus, due to the lack of information on these data, density-based models are often used for the
correlation of experimental solubility data.
The four substances, Salicylic acid, RS-Ibuprofen, S-Naproxen
and Phytosterol, studied in this work were selected due to their
importance and as examples for poor water soluble pharmaceutical
substances. In Table 1 some important physical properties of the
organic solids investigated here are summarized.
In this paper, solubility data of the above mentioned solids
in CO2 are correlated by four different methods: two methods
for the pressuresolubility correlation and two methods for the
densitysolubility correlation. In addition, the inuence of solute
data predicted by different estimation methods is investigated.
Thereby, it turned out that for the solutes investigated, the equation of state based method is very sensitive to the values of the
sublimation pressure.
2. Model description
2.1. Equations of state

two critical endpoints, small changes in pressure and temperature

result in a considerable increase of the solubility of the solid in the
supercritical solvent. Due to the higher solid solubility in the region
around the UCEP in comparison to the LCEP, the former region is
of major economic interest. For many processes, such as the RESS
process, it is desired to take advantage of the increased sensitivity of the solubility with respect to pressure near the UCEP, but to
avoid the formation of a liquid phase.

Cubic equations of state are often used to describe the experimental results of the solubility y2 of an organic solid in a
supercritical uid. These equations of state are empirical further
developments of the van der Waals equation of state [2]. In the
present investigation we used the original PengRobinson Equation
of State (PR-EoS) [3] to describe the solubility y2 .
p=

a(T )
RT
2
(v b)
v + 2bv b2

(1)

In Eq. (1) p is the pressure, T the temperature, v the molar volume, and R the gas constant. The PR-EoS was applied to binary
systems using the van der Waals 1-uid mixing rules:
a=

k
k 


xi xj aij

aij =

ai aj (1 kij )

(2a)

i=1 j=1

b=

k
k 


xi xj bij

bij =

bii + bjj
2

(1 lij )

(2b)

i=1 j=1

The parameters a and b can be calculated from the critical properties of the pure components. The binary interaction parameters
can be obtained by regression of the experimental data with the
EoS and the mixing rules (see Eqs. (2a), (2b)):
Fig. 1. Typical pT projection for an asymmetric mixture consisting of a supercritical
uid (1) and a low volatile solid (2).

a = 0.45724

R2 Tc2
(T, )
pc

(2c)

464

M. Trk et al. / J. of Supercritical Fluids 55 (2010) 462471

with
(T, )=(1+0.37464+1.542260.269922 (1

T/Tc ))

(2d)

and
b = 0.0778

RTc
.
pc

(2e)

In Eqs. (2c)(2e) is the acentric factor, and Tc and pc the critical data. This procedure requires the accurate knowledge of the
various thermophysical data, such as critical data, acentric factor,
solid molar volume, and sublimation pressure of the solutes [46].
The correlation which was used to calculate the solubility of the
solute in the supercritical solvent is shown in Eq. (3). This equation
is a result of the equifugacity condition between the solid and the
uid phase, under the assumption that the solubility of the solvent
is negligible in the solid phase.
y2 (p, T ) =

p2,sub (T ) 2,sub (p2,sub , T )

exp
p 2 (p, T, y2 )

v2 (p p2,sub )

RT

(3)

Subscript 2 in Eq. (3) refers to the solid and therefore p2 ,sub is

the sublimation pressure of the solid at temperature T, 2 ,sub is the
fugacity coefcient at the sublimation pressure, 2 is the fugacity
coefcient for the solid in the SCF phase, and v2 is the molar volume
of the pure solid. Thereby, it is assumed that v2 is independent on
the pressure p. In this work 2 is calculated with the PR-EoS using
mixing rules given in Eqs. (2a) and (2b), while 2 ,sub can be considered as unit. Thus, the calculation of the solubility y2 requires the
knowledge of the solid sublimation pressure (p2 ,sub ), solid molar
volume (v2 ) and a reliable equation of state.
Besides the PR-EoS we also applied the accurate non-cubic
LeonhardKraska Equation of State (LK-EoS) to describe the solubility of a solid y2 :
p = pref (a, b) + ppert (a, b, )

with  = (, T )

(4)

The reference part of this EoS is based on the fundamental result

of van der Waals to describe the different contributions of the interaction (repulsion and attraction) by two additive terms. For the
repulsion the much later developed hard-sphere term of Carnahan and Starling is used while for the attraction the original van
der Waals term is used. A van der Waals type EoS is not able to
describe the near-critical region properly because they are analytical equations of state. At the critical point, due to innite density
uctuations, the uid exhibits non-analytical behaviour such as
divergences expressed, for example, by non-integer critical exponents. In order to correct the deviations in the near-critical region
the LK-EoS contains a perturbation term derived on the basis of
the reference EoS by introducing uctuations. These uctuations
do not diverge at the critical point but their contribution improves
the EoS in the near-critical region substantially. More details on
the LK-EoS and the application of the fugacity approach are given
in literature [7]. The critical parameters of the pure solute do not
need to be estimated by a group-contribution method because we
t the attraction and co-volume equation of state parameter for
the solute during the solubility correlation. For the same reason
also no kij parameter is required. The total number of parameters,
tted in this work by a MarquardtLevenberg algorithm, are four

namely two equation of state parameters of the pure solute and

two parameters for the solid saturation pressure. The experimental determination of the saturation pressure of low volatile organic
substances is difcult [5,6]. Often the solid saturation pressure is
unknown and has to be estimated by empirical methods as shown
in Section 3.1. Since the solid saturation pressure is required in
the correlation of the solubility, one can treat it as an adjustable
parameter during the t of the model parameters to solubility data.
If solubility data are available for different temperatures one can
build in a ClausiusClapeyron-like temperature dependence of the
solid saturation pressure:
ln

p

2,sub

p0

=A

B

(5)

In Eq. (5) A and B are adjustable parameters and p0 = 1 MPa

is the unit pressure. In several investigations it has been shown,
that this approach using the LK-EoS gives good correlation for
various solutes in CO2 and N2 O [810]. The sublimation pressure
obtained from the solubility correlation agrees well with available
experimental data and behaves systematically as function of the
molecular structure [8]. S-Naproxen turns out to be very difcult to
model with all approaches. Therefore we here compare three different correlation procedures: 1) the correlation Eq. (5) to the available
experimental data of the sublimation pressure [11], 2) tting Eq. (5)
to the literature data which are estimated with a group contribution of Coutsikos [12] and 3) treating the sublimation pressure as
adjustable property tting the parameters of Eq. (5) during the solubility correlation. Phytosterol, RS-Ibuprofen and Salicylic acid are
correlated by implementing Eq. (5) and tting its parameters to
the solubility isotherms. The value of the molar volume solute is
xed in all correlations to the value given in Table 2 and the compressibility of the solute is set to zero. The remaining parameters,
which are tted to the data, are the attraction parameter a and the
co-volume parameter b of the solute.
2.2. Density-based models
One of the most commonly used model, which correlates the solubility y2 of a solute in a SCF to the uids density has been proposed
by Stahl et al. [13] and by Kumar and Johnston [14]:
ln(y2 ) = a + b ln(Red )

with

Red =

1
1,c

(6)

In Eq. (6) 1 is the density of CO2 at the equilibrium temperature

T and pressure p, 1,c is the critical density of CO2 , and a and b
are two empirical constants. Mendez-Santiago and Teja [15] have
shown that the following equation:
T ln(E) = c + d 1

(7)

can be used to calculate the solubility of numerous solids in CO2 . In

Eq. (7) the enhancement factor E can be regarded as a normalized
solubility because it removes the effect of the sublimation pressure.
E is dened as the ratio of the mole fraction of the solid over the
solubility in an ideal gas:
E=

y2 p
p2,sub (T )

(8)

Table 2
Values of the pure component parameters for the solids investigated using different group-contribution methods (numerary in brackets correspond to number of GCM).

Salicylic acid (14)

RS-Ibuprofen (13)
S-Naproxen (14)
Phytosterol (12)
a

Estimated value [16].

Tb (K)

Tc (K)

571646
542673
584743
584993

738913
717891
768990
7071219

pc (MPa)
4.55.7
2.12.5
1.92.7
0.961.2

()
0.760.89
0.740.87
0.780.94
0.791.2

vi (m3 /mol)a
9.59 105
1.88 104
1.78 104
4.11 104

M. Trk et al. / J. of Supercritical Fluids 55 (2010) 462471

Since the constants c and d in Eq. (7) are independent of

temperature, the solubility data for binary systems at different temperatures should collapse to a single straight line when plotted in
terms of Tln E vs. the solvents density. The lower limit of this linear
behaviour is about half while the upper limit is around the twofold
of the critical density of the solvent [15]. The fact that all isotherms
collapse to a single line allows determining the self-consistency of
the experimental data and allows identifying data sets that are not
consistent with other data.

465

vc
Group contribution
methods
FormanThodos

3. Results and discussion

Tb / Tc
Edminstermethod

Tc

3.1. Estimation of critical constants (Tc and pc ) and acentric

factor ()

Tb

Coutsikos

For the calculation of the solubility in a supercritical uid using

an EoS it is necessary to have critical properties and acentric factors of all components. In addition molar volumes and sublimation
pressures of the solid components are required. If some of these
data are not available, estimation techniques might be employed.
As shown in Fig. 2, there are a few methods, which use group or
atomic contributions to estimate critical properties [16].

pc

Millercorrelation

Fig. 2. Schematic representation of the various ways to use different estimation

techniques [16] for calculating Tc , pc and .

103

10 1

(a) Salicylic acid

(b) RS-Ibuprofen

102
10 0

100

p2,sub (Pa)

p2,sub (Pa)

101

-1

10

10-2
10-3

10 -2
[19]
Eq. (5)
[12]

[18]
[12]

-4

10

10

2,4

10 -1

2,6

2,8

3,0

3,2

-3

2,8

2,9

-1

1000/T (K )

3,0

3,1

3,2

3,3

3,4

-1

1000/T (K )
1

10

(c) S-Naproxen

p2,sub (Pa)

10

-1

10

-2

10

10-3
2,4

[11]
[12]
Eq. (5)

2,6

2,8

3,0

-1

1000/T (K )
Fig. 3. Comparison between experimental and calculated sublimation pressure data for a) Salicylic acid, b) RS-Ibuprofen, and c) S-Naproxen.

466

M. Trk et al. / J. of Supercritical Fluids 55 (2010) 462471

Table 3
Constants of Eq. (5) for the sublimation pressure data (p0 = 1 Pa) and temperature
range over which the data were determined.
Solute

B (K)

T range (K)

Salicylic acid
RS-Ibuprofen
S-Naproxen
Phytosterol

34.6
42.1
39.7
45.9

11484
14554
15431
18919

368408
296337
341397
298343

3.2. Sublimation pressure data

Experimental sublimation pressure data were available for RSIbuprofen [18], Salicylic acid [19] and S-Naproxen [11] in literature.
However, since no data has been reported for Phytosterol, pi,sub
was calculated for all four substances using the Coutsikos correlation [12] for solids. This group-contribution model is based on the
concept of the hypothetical liquid.
ln(pi,sub ) = A + B/T + C ln(T ) + D T + E T 2 +

Several group-contribution methods (GCM) for the normal

boiling temperature, which is necessary to estimate the critical
temperature by some methods, the critical temperature, and the
critical pressure are used to analyze the reliability of this correlation method and to study the inuence of each parameter. It should
be noted that this refers to the estimation methods which are not
based on equations of state. The acentric factor has been calculated by the Edminster-GCM [16]. The estimated properties of the
four solids investigated using various GCM are shown in Table 2.
In the case of CO2 the physical properties are taken from NIST
(Tc = 304.21 K, pc = 7.38 MPa and = 0.225) [17].

 S   1 T 
m
i
T

T
(9)

The constants A to E can be estimated via the

AbramsMassaldiPrausnitz equation, while for the entropy of
fusion (Si ) at the melting point (Tm ) a simple group-contribution
scheme is proposed [12].
In this study, Eq. (5) was used to correlate the experimental
data for the sublimation pressure. For Phytosterol, the sublimation
pressure data obtained from Coutsikos correlation have also been
successfully correlated using Eq. (5). The values for the parameter
A and B are summarized in Table 3 together with the temperature
range over which the data were determined.

10 -3

-2

10

(b) CO2 /RS-Ibuprofen [24]

(a) CO2 /Salicylic acid

y2 (-)

y2 (-)

10 -4
-3

10

10 -5
308 K [20]
313 K [20]
318 K [20]
328 K [20]
323 K [23]

10 -6
-0,8

308 K
313 K
323 K
-4

-0,4

0,0

ln( 1/

0,4

10

0,8

-0,4

) (-)

0,4

ln( 1/

1,C

(c) CO2 /Naproxen [6]

0,8

) (-)

1,C

323 K
333 K
343 K

313 K
323 K
333 K
343 K
353 K

-4

y2 (-)

10

y2 (-)

10 -4

0,0

(d) CO2 /Phytosterol [28]

10 -5
-0,2

-5

0,0

0,2

0,4

ln( 1/

) (-)
1,C

0,6

0,8

10

0,2

0,4

ln( 1/

0,6

) (-)
1,C

Fig. 4. Solubility versus reduced solvent density for a) CO2 /Salicylic acid [20,23], b) CO2 /RS-Ibuprofen [24], c) CO2 /S-Naproxen [6], and d) CO2 /Phytosterol [28]. The solid
lines are calculated with Eq. (6).

M. Trk et al. / J. of Supercritical Fluids 55 (2010) 462471

467

Table 4
Constants of Eq. (6) for the solubility of solids in sc-CO2 .
T (K)

Number of data
points

ARD (%)

308.15
313.15
318.15
328.15
313.15
333.15
308.15
318.15
323

11
15
12
11
12
11
8
12
7

10.520
9.982
9.799
9.186
10.099
8.678
10.351
9.491
10.002

3.980
3.462
3.553
3.619
3.949
2.630
3.914
3.206
4.531

5.9
7.0
8.1
6.0
13.0
14.8
0.9
6.9
3.3

RS-Ibuprofen [24]

308.15
313.15
318.15

15
6
8

9.125
8.806
8.112

5.944
6.330
5.523

5.2
4.5
21.9

S-Naproxen [25]

313.1
323.1
333.1
308
318
328
338
348
313.15
313
323
333
343
353

6
6
6
8
8
8
8
8
9
3
4
5
5
6

13.266
12.513
11.940
13.614
12.170
11.953
11.004
10.706
13.979
13.230
12.613
12.120
11.570
10.830

4.431
3.952
3.653
4.657
3.123
3.419
2.634
3.084
6.018
4.165
4.079
3.942
3.912
3.924

6.4
7.6
6.9
6.9
7.2
14.0
20.8
31.6
6.5
1.9
2.1
5.4
1.4
4.1

323.2
333.2
343.2

8
7
8

12.437
11.632
11.185

5.741
5.143
5.790

9.0
3.7
3.5

Salicylic acid [20]

Salicylic acid [21]

Salicylic acid [22]
Salicylic acid [23]

S-Naproxen [26]

S-Naproxen [27]
S-Naproxen [6]

Phytosterol [28]

ARD =

1
N

N

y

2,calc y2,exp

y2,exp

100.

In Fig. 3 the comparison between calculated and experimental

data for RS-Ibuprofen, S-Naproxen and Salicylic acid are shown.
In case of RS-Ibuprofen, the Coutsikos correlation represents the
experimental data quite well. The relative deviation between
experimental and calculated values increases from 2.3% at 313 K
to 17.5% at 343 K. Larger deviations between experimental and
modelled values are found for S-Naproxen. For this substance, the
relative deviation decreases from 87% at 313 K to 62% at 343 K.
Applying the Coutsikos correlation for Salicylic acid leads to calculated values which are up to two orders of magnitude lower than
the experimental data. Thus, it is obviously, that the deviations are
larger (100%) than for S-Naproxen.

31) MPa, no other solubility data has been reported for Phytosterol
[28].
For all investigated substances, the experimental results show
trends which are similar to those observed for other solids in the
supercritical region. In agreement with Eq. (6) and as it is illustrated in Fig. 4, relationship between the logarithmic solubility
and the reduced density shows the expected linear behaviour for
all isotherms. At constant temperature, the solubility of a solute
increases almost linear with the solvents density and therewith
solvent power. Fig. 4 also shows the pronounced temperature
effect on the solubility in the region outside the retrograde
region. In this region, the effect of the temperature on the solute
sublimation pressure overlays the effect of the solvent density,

3.3. Correlation of experimental solubility data

3.3.1. Density-based models
The inuence of the system temperature and the solvents density is depicted in Fig. 4 which shows the solubility of Salicylic acid
[2023], RS-Ibuprofen [24], S-Naproxen [6,2527], and of Phytosterol [28] as a function of the reduced CO2 density. Experimental
data of the solubility of Salicylic acid in CO2 are available in literature for temperatures ranging from (308333) K and pressures
ranging from (835) MPa, while solubility data of RS-Ibuprofen
were measured at pressures in the range of (822) MPa, temperatures of (308 and 313) K, and up to 17 MPa for 318 K. For
S-Naproxen, experimental solubility data for temperatures ranging from (308353) K within the pressure range of (1235) MPa
are published in literature. Although each individual set of data
follows mostly a common trend, in some cases the published
data exhibit different trends with respect to temperature or pressure [6]. To our knowledge, with the exception of our own data
in the range from (323343) K and pressures between (14 and

Table 5
Constants of Eq. (7) for the solubility of solids in sc-CO2 .
Number of
isotherms

c (K)

d (K dm3 /mol)

ARD (%)

Salicylic acid [20]

Salicylic acid [21]
Salicylic acid [22]
Salicylic acid [23]

4
2
2
1

1180.3
1206.5
1457.9
792.4

116.9
116.3
102.3
138.3

0.9
2.1
0.7
0.3

RS-Ibuprofen [24]

1783.0

166.7

0.7

S-Naproxen [25]
S-Naproxen [26]
S-Naproxen [27]
S-Naproxen [6]

3
5
1
5

2304.5
2126.6
1787.5
1871.4

133.2
143.2
167.9
150.4

1.6
2.7
0.4
1.9

Phytosterol [28]

1610.9

206.8

1.7

 y
N

ARD =

1
N

2,calc y2,exp

y2,exp
1

100.

468

M. Trk et al. / J. of Supercritical Fluids 55 (2010) 462471

3

6x103

4x10

(a) CO2 /Salicylic acid

(b) CO2 /RS-Ibuprofen [24]

[20]
[21]
[22]
[23]

T ln(E) (K)

T ln(E) (K)

3x10

308 K
313 K
323 K

5x103

4x103

2x10

3x103

1x10

2x103
4

12

16

20

24

12

16

20

24

(mol/dm )

(mol/dm )

6x103

6x10

(c) CO2 /S-Naproxen

(d) CO2 /Phytosterol [28]

[6]
[25]
[26]
[27]

5x103

T ln(E) (K)

T ln(E) (K)

5x10

4x103

4x10

323 K
333 K
343 K
3

3x10

3x103
4

12

16

20

24

12

16

20

24

(mol/dm )

(mol/dm )

6x10

(e) CO2 /Naproxen

p2,subcalculated according:

[11]
[12]
[16]

T ln(E) (K)

5x10

4x10

3x10

2x10

12

16

20

24

(mol/dm )
1
Fig. 5. T ln E versus solvent density for a) CO2 /Salicylic acid [2023], b) CO2 /RS-Ibuprofen [24], c) CO2 /S-Naproxen [6,2527], d) CO2 /Phytosterol [28], and e) CO2 /S-Naproxen
[11,12,16].

M. Trk et al. / J. of Supercritical Fluids 55 (2010) 462471

469

Fig. 6. Solubility versus pressure for a) CO2 /Salicylic acid [2123], b) CO2 /RS-Ibuprofen [24], c) CO2 /Phytosterol [28], and d)f) CO2 /S-Naproxen [6]. The three different
correlations used for S-Naproxen are described in the text. Note that the scaling of the axes is different in the four systems because of large differences in solubility.

resulting in an increase of the solute solubility with increasing

temperature.
To conrm the reliability of the experimental data, we examined the consistency of solubility data using Eq. (6) and the values
obtained for a and b are summarized in Table 4 along with the
average relative deviation (ARD). The lines depicted in Fig. 4 are
calculated with Eq. (5) and demonstrate that there is a good correlation between calculated values and the experimental data. As
can be seen from the ARD listed in Table 4, most of the experimental data are satisfactorily correlated with this empirical correlation
with an overall ARD ranging from (0.915)% for Salicylic acid, from
(4.522)% for RS-Ibuprofen, from (1.432)% for S-Naproxen and
(3.59.0)% for Phytosterol. Thereby it should be considered that the
solubility of RS-Ibuprofen is up to three-hundred times higher than
for the other three solids.

The results of tting Eq. (7) to the experimental solubility data

are depicted in Fig. 5 and summarized in Table 5 for all substances
investigated. As can be seen from Fig. 5, most of the Salicylic acid
solubility data published from different authors collapse to a single line. Thereby, the experimental sublimation pressure data from
Davies and Jones [19] were used to calculate E. For the majority
of the data correlated, an agreement between experimental and
calculated data better than 1.0% was reached. For the CO2 + RSIbuprofen system, we were able to correlate all data with an
ARD-value of 0.7% using the experimental sublimation pressure
data from Ertel et al. [18]. For these data, the pronounced linear
trend was observed for a density range starting around 6 mol/dm3
(about 0.6c ) to about 20 mol/dm3 (about two-fold of c of CO2 ),
which represent the upper limit of the available experimental
data.

470

M. Trk et al. / J. of Supercritical Fluids 55 (2010) 462471

Table 6
Resulting values obtained from tting the four parameters of Eqs. (4) and (5) to the experimental solubility data.
Solute

a (K)

b (cm3 mol1 )

B (K)

Salicylic acid
RS-Ibuprofen
S-Naproxen (1)
S-Naproxen (2)
S-Naproxen (3)
Phytosterol

987.828
1071.39
883.735
892.276
805.23
660.357

34.029
52.4292
81.2094
86.9116
53.4022
106.492

17.7586
31.2614
25.9397
35.8954
17.2568
15.9749

9740.14
14565.9
15442.4
19194.7
11048.6
11847.3

Table 7
Summary of calculation results for the solute solubility in sc-CO2 using various models. It should be noted that the rst two are deviations in the density, the second two in
pressure.
Solute

Number of: isotherms/data sources

Salicylic acid
RS-Ibuprofen
S-Naproxen
Phytosterol

9/4
3/1
13/3
3/1

ARD =

1
N

N

y

2,calc y2,exp

y2,exp

Kumar & Johnston ARD (%)

0.915
4.522
1.432
3.59

Mendez-Santiago & Teja ARD (%)

PR-EoS ARD (%)

0.32.1
0.7
0.42.7
1.7

1044
1633
1433
3777

LK-EoS ARD (%)

5
9
10
7

100.

In case of S-Naproxen, the enhancement factor was calculated

with the experimental sublimation pressure of Perlovich et al. [11].
Similar to Salicylic acid most of the solubility data published from
different authors collapse to a single line. In most cases, the ARD
value is less than 2%, which compares well with experimental
uncertainty.
As mentioned above, for Phytosterol no experimental sublimation pressure data has been reported in literature. Thus, pi,sub was
obtained with the Coutsikos correlation [12] for solids to calculate
the enhancement factor E. It is shown in Fig. 5 that, according to
Eq. (7), the three solubility isotherms collapse to a single straight
line when plotted in terms of Tln E vs. the CO2 density. This fact
and the very low ARD-value of 1.7% conrmed the consistency and
reliability of the experimental solubility data.
For comparison and in order to investigate the inuence of
different GCM, Eq. (7) was tted to the enhancement factor data calculated with the sublimation pressure which was estimated with
the Watson correlation [16]. As depicted in Fig. 5, this curve shows
a signicant deviation up to 35% which is the result of the noticeably higher values from the estimated sublimation pressure data.
Applying the Coutsikos correlation [12] leads to signicant higher
values for E from around 1012%.
3.3.2. Equation of state
In addition to these empirical correlation approaches, we have
employed two equations of state methods for the correlation of the
solubility. While one can only correlate the solubility as function
of the density with the empirical methods discussed above, one
also can correlate the solubility as function of the pressure with an
equation of state approach. This is important since the measured
and controlled property in technical processes is rather the pressure than the density. Of course it is possible to calculate pressure
from density and vice versa using an accurate equation of state
in a second task afterwards, however the direct EoS method gives
correlations in one pour and provides properties not available in
the above mentioned methods. The correlation results obtained
from the LK-EoS are shown in Fig. 6 and summarized in Table 6.
For Phytosterol, RS-RS-Ibuprofen and for Salicylic acid the correlation is very good over the complete temperature and pressure
range. The correlation of the S-Naproxen solubility data is more
difcult. The chosen temperature dependence of the saturation
pressure is apparently not suitable to correlate all isotherms with
the same accuracy. Even treating the parameters of the saturation
pressure curve adjustable (p2,sub,C ) (Eq. (5)) gives some deviation

for the isotherm at 313 K. Using the saturation pressure estimated

by the method of Coutsikos [12] (p2,sub,A ) we get even worse results.
It seems that S-Naproxen is an exception because for all other
substances correlated with this method the agreement is very
good.
The second equation of state approach is based on the PR-EoS
for the binary systems as described above. It is summarized in
Table 7 that this approach leads to signicant higher deviations
than the density-based models and the LK-EoS. Depending on the
GCM the ARD values range for Salicylic acid from (1044)%, for RSIbuprofen from (1633)%, for S-Naproxen from (1433)% and for
Phytosterol from (3777)%. These ndings are conrmed by other
results published in literature. For RS-Ibuprofen, the deviations are
similar to those reported by Charoenchaitrakool et al. [24] who correlated the solubility data using the PR-EoS with van der Waals
mixing rules. Depending on the GCM the deviations between modelling and experimental data range from (644)%. Coimbra et al. [5]
investigated the use of traditional cubic EoS in combination with 3
mixing rules in order to correlate the solubility of RS-Ibuprofen and
S-Naproxen in CO2 at 313 K. Depending on the EoS and the mixing
rules, the ARD-value range for S-Naproxen from (3.931)% and for
RS-Ibuprofen from (4.554)%.
4. Conclusions
The solubility of four pharmaceutical substances in supercritical
carbon dioxide is correlated with empirical correlation models and
Equation of State approaches. For the four systems considered in
this investigation, one can conclude that:
a) the cubic EoS approach lead to deviations between experimental and calculated solubility data which are up to one order
of magnitude higher than for the empirical Kumar & Johnston
approach and up to two orders of magnitude higher than for the
Mendez-Santiago and Teja approach;
b) the LK-EoS leads to similar deviations than the Kumar & Johnston
approach.
It should be considered that the empirical approaches can only
correlate the solubility as function of the density while the Equation
of State approaches allow the practically more important correlation as function of the pressure. In order to obtain most accurate
correlations a non-cubic Equation of State should be used which

M. Trk et al. / J. of Supercritical Fluids 55 (2010) 462471

accurately reproduces the pvT behaviour of the pure solvent in the

near-critical region.
Acknowledgments
This work was supported primarily by the Deutsche Forschungsgemeinschaft (DFG, Tu 93/7-1, 7-2, Kr 1598/26-1, 26-2) which the
authors gratefully acknowledge. The authors thank Boris Stehli for
his helpful contributions to this investigation.
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