C. R.

Chimie 20 (2017) 559e572

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Novel density-based model for the correlation of solid drugs

solubility in supercritical carbon dioxide
Cherif Si-Moussa*, Aicha Belghait, Latifa Khaouane, Salah Hanini,
Asmaa Halilali
Laboratory of Biomaterials and Transport Phenomena (LBMPT), Faculty of Science and Technology, University Yahia Fares of Medea,
Algeria

a r t i c l e i n f o a b s t r a c t

Article history: A novel density-based model derived by a simple modification of the Jouyban et al. model
Received 15 June 2016 has been proposed to correlate the solubility of solid drugs in supercritical carbon dioxide.
Accepted 27 September 2016 The six-parameter model expresses the solubility only as a function of the solvent density
Available online 29 October 2016
and the equilibrium temperature. This model is in contrast to the Jouyban et al.
(J. Superiority. Fluids 24 (2002) 19) model, which gives the solubility as a function of the
Keywords:
solvent density and the equilibrium temperature and pressure. The performance of the
Solubility
model has been tested on a database of 100 drugs that account for 2891 experimental data
Modeling
points collected from the literature. The comparison in terms of the mean absolute relative
Density-based models
deviation for each solid drug and for the entire database between the proposed model and
Solid drugs
models that have been suggested to be mostly more accurate demonstrates that the
Supercritical carbon dioxide
proposed model has the best global correlation performance, exhibiting an overall average
absolute relative deviation of 8.13%.
© 2016 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.

1. Introduction processing offers many advantages over conventional

The level of interest in the technology of supercritical
fluids (SCFs) has increased in recent decades because of its
economic and environmental impact. Currently, SCF tech-
nology has widespread utility ranging from food processing
to pharmaceutical applications [1]. Commonly, conven-
tional production processes of many pharmaceuticals
comprise a series of separation and purification operations
involving a series of organic solvent extraction and pre-
cipitation steps and end up very often with the recovery of
a large amount of organic solvents. Aside from of being
environmentally benign, less energy intensive, and more
effective in controlling product specification, SCF
* Corresponding author.
E-mail addresses: simoussa_cherif@yahoo.fr, simoussa.cherif@univ-
medea.dz (C. Si-Moussa).
methods of extraction, drug particle formation, and drug
delivery system design. Reduction of potentially harmful
organic solvents and steps required for product fabrication
are among the many advantages associated with SCF
technology. Being inexpensive, nontoxic, abundant, and
environmentally safe, supercritical carbon dioxide (scCO2)
can replace toxic and undesirable organic solvents that
either require extensive solvent recovery units or remain in
very small but still dangerous proportions [1e4].
The importance given to SCF technology is well illus-
trated by the growing published experimental data on the
solubility of solid solutes (e.g., polymers, foods, drugs,
nutraceuticals, pesticides, dyes, and metal complexes) in
scCO2 with and without cosolvents. Solubility is typically
defined as mole fraction (y2) or weight fraction (c2) of solute
in the SCF, which is in equilibrium with the bulk solute.
Various methods to measure solubility in SCFs have been
reviewed [4e9]. These methods can be divided into two

http://dx.doi.org/10.1016/j.crci.2016.09.009
1631-0748/© 2016 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
560 C. Si-Moussa et al. / C. R. Chimie 20 (2017) 559e572
major categories: static and dynamic. A compilation of most
of the published experimental data before 2004 is provided
by Gupta and Shim [4]. A series of review articles [5e9] on
high-pressure phase equilibria also present a compilation of
experimental investigations on the solubility of solid sol-
utes in SCF. This huge enthusiasm for these experimental
measurements is because the most important and decisive
factor affecting the efficacy and the correspondent technical
and economic success of most SCF processes is the accurate
knowledge of the equilibrium solubility of the materials to
be processed in the selected SCF solvent and/or the solu-
bility of that SCF in those materials.
Attempts at modeling the solubility of solid solutes in
the SCF phase for the purpose of correlation and/or pre-
diction have followed suit experimental investigations.
However, these modeling efforts have not yet been satis-
factory to the desired level of accuracy, which is one reason
why it is still a research subject of interest and more
experimental data are continuously being published, and
new compounds are being investigated. The solubility of a
solid solute in an SCF is a problem of phase equilibrium, and
as such, the straightforward and obvious modeling method
is the use of an equation of state (EoS) or an activity coef-
ficient method. Simple cubic EoS with various mixing rules
has been extensively used for calculation of solid solute
solubility in scCO2 [10e14]. The use of cubic EoS requires
critical properties, the acentric factor, sublimation pressure,
and the molar volume of the solute. In the absence of
experimental values of these parameters, which is more
often the case for complex pharmaceutical compounds,
they are estimated using group contribution (GC) methods.
Sublimation pressure may also be considered as an
adjusted parameter to be fitted to solubility data. The ac-
curacy of the correlation or prediction using the cubic EoS
depends considerably on the method used to estimate
these solid solute properties [10,11].
More complex and theoretical-sound state of the art EoS,
such as nonrandom hydrogen-bonding (NRHB) theory [15]
and the statistical associating fluid theory (SAFT) [16e18],
have also been used to predict or to correlate the solubility
of solids in SCFs. NRHB theory was applied for the modeling
of the solubility of six drugs in scCO2 by Tsivintzelis et al.
[15]. The solubility of the six drugs in scCO2 was correlated
by this EoS with the one temperature-independent binary
parameter fitted to the experimental data. For the applica-
tion of the NRHB model, physical and hydrogen-bonding
fluid-specific parameters are optimized using pure fluid
properties. For common fluids, such as alkanols, amines,
and others, vapor pressures and liquid densities are often
used. Furthermore, the hydrogen-bonding parameters can
be determined using calorimetric or spectroscopic data.
However, for most pharmaceuticals, extended experi-
mental data on physical properties do not exist [15].
Most SAFT-type models require five parameters for each
pure associating compound (three for nonassociation
ones). The three parameters for nonassociating fluids are
the segment number, the interaction energy, and the hard-
core segment diameter, which are either calculated using
GC methods, such as proposed by Tihic et al. [19] and used
by Abdallah El Hadj et al. [18] to correlate the solubility
solid drugs in scCO2, or estimated from vapor pressure and
liquid-density data over extended temperature ranges. In
the absence of such data for specific compounds, such as
polymers and pharmaceuticals, GC methods, such as GC-
SAFT [20], GC-SAFT variable range (SAFT-VR) [21e23], and
GC-SAFT-g [24], are used for the calculation of required
properties.
Activity coefficient models, such as UNIversal Functional
Activity Coefficient (UNIFAC), the regular solution theory
based models, and more sophisticated models, such as
conductor-like screening model (COSMO), cannot be used
for high-pressure phase equilibrium calculations without
being coupled with another model, namely, an EoS [15].
Activity coefficient models based on the COSMO method
[25] such as COSMOereal solvents [26] and COSMOesur-
face activity coefficient (COSMO-SAC) [27] have been used
to predict the thermodynamics in mixtures without data
fitting. Shimoyama and Iwai [28] developed a COSMO-
vacancy model to extend the range of applicability of pre-
dictive COSMO-SAC liquid model to supercritical condi-
tions. The model was successful in predicting the solubility
of 16 solid drugs in scCO2, where the melting points and
enthalpies of fusion were the only solute properties used,
and the molar volume of scCO2 was calculated using an EoS.
Recently, Wang and Lin [29] coupled the well-known Peng-
Robinson EoS with the COSMO-SAC model (PR þ COSMO-
SAC) to predict the solubility of 46 drugs in subcritical and
supercritical CO2. In the EoS, the interaction parameter, a,
and molecule covolume, b, are determined from the result
of first principle solvation calculation instead of using the
critical properties and acentric factor of pure substances.
Hence, the only experimental data required for drugs are
the melting temperature and the melting enthalpy. More
recently Wang et al. [30] analyzed the vapor pressure data
of 1125 compounds and proposed a modification of the
PR þ COSMO-SAC model [29] to improve the prediction of
saturated pressure that allows the application of the
method for the prediction of phase equilibrium containing
solid phase, such as solid drugs in supercritical solvents.
From this review of the EoS approach in modeling the
solubility of solid solutes in supercritical solvents, it is clear
that EoS whether predictive or correlative, with the
exception of the COSMO model, still rely on experimental
data that are required for fitting at least one binary inter-
action parameter used by mixing rules or the fitting of
other required compound properties or for the validation of
models. This finding is particularly true for complex
multifunctional chemicals, such as pharmaceuticals.
A simpler alternative to EoS models, even if it is also
limited to the range of experimental data from which the
models are derived, is the use of empirical models based on
the density of the SCF, pressure, and/or temperature. The
use of empirical and semiempirical models has been
extensively reported [31e58]. These models are based on
simple error minimization using the least square method to
determine the adjustable parameters of the model, and for
most of them there is no need to use physical properties of
the solute. Since the work of Stahl et al. [31], who proposed
a direct linear relationship between the logarithm of the
solubility of the solute in a compressed gas and the loga-
rithm of the density of the gas, several models have been
proposed by different authors with the aim of improving
 C. Si-Moussa et al. / C. R. Chimie 20 (2017) 559e572 561

the quality of correlation of new experimental data for The fugacity of solid solute in the supercritical phase is
which previous models may present poor correlation. The given by
main differences between the proposed models may be
summarized as follows: f2SCF ¼ y2 fSCF
2 P (3)

Here fSCF
2is the fugacity coefficient of the solid solute in
1. The number of adjusted parameters of the models,
the supercritical phase.
which vary from 3 to 10.
Combining Eqs. (1)e(3) gives the expression for the
2. Although most proposed models include a linear rela-
mole fraction solubility:
tionship between the logarithm of the solubility of the
solid solute and the logarithm of the SCF density, we  s 
P2sub fsat V
may find, in some models, more complex nonlinear re- y2 ¼ $ SCF
2
exp 2 P  P2sub (4)
P f2 RT
lationships between the logarithm of the solubility of
the solid solutes and the density of the SCF and equi- Eq. (4) shows that the solubility is the product of the
librium temperature and pressure. ideal solubility ðP2sub =PÞ and a correction term known as the
3. If one analyzes correlation results from previous works enhancement factor that reflects the nonideality of the
[42,44,47,50,53e56], particularly the work of Tabernero supercritical phase through the ratio ðfsat 2 =f2 Þ and the
SCF

et al. [54], who compared the correlation performance of effect of pressure on the fugacity of the solid, as it is known
nine semiempirical equations applied on a solubility for liquids, through the exponential term known as the
data set of 27 pharmaceutical compounds in scCO2- Poynting factor. In addition, for solids of very low volatility
containing 774 experimental data points, and the work as is the case with many solid drugs, sublimation pressure
of Bian et al. [56], who compared the correlation per- is very low and values of the saturated fugacity coefficient
formance of 15 semiempirical equations applied on a of the solid, fsat
2 , are very close to one. The expression for
solubility data set of 45 compounds in scCO2-containing the solid solubility of the solute is then reduced to
1130 experimental data points, one may clearly note that  s
there is no model that presents the best correlation for P2sub 1 V 
y2 ¼ $ SCF exp 2 P  P2sub (5)
all the experimental data of all solutes. However, models P f2 RT
with five or six adjustable parameters seem to correlate
with experimental data more accurately than models In fact, this equation gives the solubility in an implicit
with three adjustable parameters. form because fSCF 2 is a function of y2, T, P, and Z SCF (the
compressibility coefficient of the supercritical phase), itself
The aim of this work is to contribute to the improve- a function of y2, T, and P.
ment of the quality of density-based correlation of solid  
fSCF
2 ¼ f T; P; Z SCF ; y2 (6)
drug solubility in scCO2. This contribution will be based on
a simple modification of a Jouyban et al. [41] model. The
proposed model will then be evaluated on a large experi- Z SCF ¼ ZðT; P; y2 Þ (7)
mental data set collected from the literature, by compari-
son with the literature models that have been suggested in Eqs. (5)e(7) are the basis for calculating the solubility of a
several works [42,44,47,50,54e56], to assess the best cor- solid solute in an SCF by an EoS. The quality of predictions or
relation performance. correlations depends on the EoS, and even for the same EoS,
it depends also on the mixing rules. Moreover, this method
requires the solute properties, and the calculations are very
2. Modeling solid-SCF phase equilibrium sensitive to the accuracy of the solute properties [10,11,18].
If one takes the logarithm of Eq. (5),
The solubility of a nonvolatile pure solid (2) in an SCF
(1), y2, is determined from standard thermodynamic re- V2s P V2s P2sub 1
ln y2 ¼ ln P2sub  ln P  ln fSCF
2 þ $  $ (8)
lationships by equating fugacities in the solid phase and in R T R T
the supercritical phase for each component. This iso- For given T and P the volumetric properties of the sol-
fugacity criterion for this binary system is reduced to one vent are governed by Eq. (9):
equation, because the solvent is assumed insoluble in the
solid phase: P ¼ ZRT r1 (9)
Combining Eqs. (8) and (9), one can relate the solubility
f2S ¼ f2SCF (1) of the solute to the density of the solvent and the coefficient
The fugacity of the solid phase is given by of compressibility of the pure solvent at the given tem-
perature and pressure:
" #
VS  
f2S ¼ P2sub fsat exp 2 P  P2sub (2) V2s P2sub 1
2
RT ln y2 ¼ ln P2sub  lnðZRT r1 Þ  ln fSCF
2 þ V2 Z r1 
s
$
R T
HereP2sub , fsat S (10)
2 , and V2 are the sublimation pressure,
molar volume, and the fugacity coefficient of the saturated
solid.
562 C. Si-Moussa et al. / C. R. Chimie 20 (2017) 559e572
Although Eq. (10) gives the solubility in a complex im-
plicit form as mentioned previously, it shows how the
solubility of the solute could be related to the density of the
supercritical solvent. A density-based model can be
considered a simple empirical approximation to the right-
hand side of Eq. (10) that does not require any solute
parameter in contrast to EoS models. The next section
presents a brief review of density-based modeling.
2.1. Review of density-based modeling
Density-based models for the correlation of the solubi-
lity of a solid solute in a dense phase have evolved
considerably since the work of Stahl et al. [31]. Table 1
summarizes the density-based models that have been
proposed since this work. In this table, y2 is the solubility of
the solid solute in mole fraction, r1 is the density of the SCF
(in kg/m3), T is the temperature (in K), P is the pressure (in
bar), ai represents the characteristic parameters deter-
mined by fitting experimental data of the solute/solvent
considered. For the Sparks et al. model [42], the solubility is
expressed in a dimensionless form, whereas in the Bain
et al. model [47] the solute solubility, c2, is in kilograms per
cubic meter. In both models c2 is related to y2 by Eq. (27a),
in which Mw1 and Mw2 are the molecular weights of the
solvent and the solute, respectively. It is worth mentioning
that some of the models do not relate the solubility
explicitly to the density of the SCF solvent. The very few
models that require solute parameters whose numerical
values are not available for compounds of interest, such as
solid drugs, were not included in this work. Literature re-
views describing the basis and assumptions upon which
these models have been proposed, as well as comparisons
of the performance of the correlation of the solubility of a
variety of solid solutes between the various models, can be
found in Refs. [42,44,47,50,53e56]. Therefore, a brief re-
view is given here only for models that have been sug-
gested to have the best correlating performance.
The first model that established a linear relationship
under isothermal conditions between the logarithm of
solubility lny2 of a solute in an SCF and the logarithm of
fluid density lnr1 was proposed by Stahl et al. [31]. On the
basis of the theory that at equilibrium a solvato complex is
formed between associating solute and solvent molecules,
Chrastil [32] added a new term that takes account of the
effect of temperature. This led to the model given by Eq.
(12) in which a1 is the average association number, a2 is a
function of the enthalpy of solvation and enthalpy of
vaporization, a0 is a function of the average association
number and molecular weight of the solute and solvent.
With the availability of more and newer experimental
data, subsequent studies have demonstrated two major
drawbacks of Chrastil's equation: it is valid for solubilities
less than 100e200 kg/m3 and for a restricted temperature
range [33,34]. To account for the effect of solvent density on
solubility, Adachi and Lu [33] correlated the average asso-
ciation number to a second-order polynomial of the solvent
density, which led to the model given by Eq. (13), achieving
a significant decrease in the error between experimental
and calculated solubility data for some systems. The effect
of temperature on solubility was taken into consideration
in the del Valle and Aguilera [34] modification (Eq. (14)) by
adding a reciprocal of squared temperature term to
Chrastil's equation.
On the basis of a review of published experimental
solubility data in scCO2 and previously presented models,
Jouyban et al. [41] suggested the existence of
(1) a nonlinear relationship between lny2 and pressure in
isothermal conditions,
(2) a nonlinear relationship between lny2 and temperature
in isobaric conditions, and
(3) a linear relationship between lny2 and lnr1 in a certain
range of pressure and temperature.
They proposed Eq. (21) as a modification of Chrastil's
model in which they introduced the effect of pressure on
solubility as a second-order polynomial and a nonlinear
relationship that takes account of the combined effect of
temperature and pressure. The scarce use of the Jouyban
et al. model is the reason why Tabernero et al. [54] excluded
it from their comparative study, but Bian et al. [47] recog-
nized the good correlation performance of this model.
Another modification of Chrastil's model was proposed
by Sparks et al. [42] (Eq. (22)), in which both the effect of
the density in the average association number and the
change in the enthalpy of vaporization with the tempera-
ture have been considered. In other words, they combined
the Adachi and Lu [33] and the del Valle and Aguilera [34]
modifications in one model, which improved significantly
the results.
On the basis of a review of published experimental
solubility data in scCO2 and previously presented models,
Garlapati and Madras [44] noted the existence of
(1) a nonlinear relationship between ln(y2) and density
(r1) in isothermal conditions,
(2) a nonlinear relationship between ln(y2) and tempera-
ture in isopycnic conditions, and
(3) a linear relationship between ln(y2) and ln(r1T) in a
certain range of density and temperature.
They proposed Eq. (24) in which the average association
number is approximated by a linear relation of the solvent
density, and they added a term that takes account of
remark (3).
In addition to remarks (1) and (2) made by Garlapati and
Madras [44], Bian et al. [47] added the following remark.
When the system temperature increases under isobaric
conditions, the average association number will certainly
decrease because of the increase in the thermal motion of
its molecules; on the other hand, when the system pressure
increases under isothermal conditions, it will increase as a
result of shortening distances and increasing collisions
between molecules. Once the average association number
changes, the enthalpy of solvation and enthalpy of vapor-
ization will change. Taking account of the latter remark,
they proposed Eq. (26) where the average association
number is inversely proportional to the logarithm of tem-
perature and linearly proportional to the density of the
solvent. They carried a comparison of the correlation
 C. Si-Moussa et al. / C. R. Chimie 20 (2017) 559e572 563

Table 1
Density-based models for the correlation of solid solutes in supercritical fluids.

Model Equation Reference

Stahl et al. ln y2 ¼ a0 þ a1 ln r1 (11) [31]

Chrastil a2 [32]
ln y2 ¼ a0 þ a1 ln r1 þ (12)
T
Adachi and Lu   a4 [33]
ln y2 ¼ a0 þ a1 þ a2 r1 þ a3 r21 ln r1 þ (13)
T
del Valle and Aguilira a2 a3 [34]
ln y2 ¼ a0 þ a1 ln r1 þ þ 2 (14)
T T
Kumar and Johnston a2 [35]
ln y2 ¼ a0 þ a1 r1 þ (15)
T
Bartle et al. y2 P   a [36]
¼ a0 þ a1 r1  rref
2
ln ref 1 þ (16)
P T
Yu et al. [37]
y2 ¼ a0 þ a1 P þ a2 P 2 þ a3 PTð1  y2 Þ þ a4 T þ a5 T 2 (17)

Gordillo et al. [38]

ln y2 ¼ a0 þ a1 P þ a2 P 2 þ a3 PT þ a4 T þ a5 T 2 (18)

ndez-Santiago and Teja
Me T ln y2 P ¼ a0 þ a1 r1 þ a2 T (19) [39]

Sung and Shim

 a1  a2 [40]
ln y2 ¼ a0 þ ln r1 þ þ a3 (20)
T T
Jouyban et al. T [41]
ln y2 ¼ a0 þ a1 P þ a2 P 2 þ a3 PT þ a4 þ a5 ln r1 (21)
P
Sparks et al.
  ! [42]
a0 þa1 rr;1 þa2 r2r;1 a4 a5
c*2 ¼ rr;1 exp a3 þ þ 2
Tr Tr
(22)
c2 r T
c*2 ¼ ; r ¼ 1; T ¼
rc;1 r;1 rc;1 r Tc;1
Garlapati and Madras (2009) a1 [43]
ln y2 ¼ a0 lnðr1 TÞ þ þ a2 (23)
T
Garlapati and Madras (2010) a3 [44]
ln y2 ¼ a0 þ ða1 þ a2 r1 Þln r1 þ þ a4 lnðr1 TÞ (24)
T
Jafari Nedjad et al.
ln y2 ¼ a0 þ a1 P 2 þ a2 T 2 þ a3 ln r1 (25) [45]

Ch and Madras  ða0 1Þ a  [46]

P
þ a2 r1 þ a3
1
y2 ¼ exp (26)
P ref T

Bian et al. (2011) [47]


ða0 þa1 r1 þa2 =ln TÞ a3 þ a4 r1
c2 ¼ r 1 exp þ a5 (27)
T

r1 Mw2 y2
c2 ¼ (27a)
Mw1 ð1  y2 Þ

Haghbakhsh et al.
y2 ¼ 105 a0 þ a1 P þ a2 r þ a3 P 2 þ a4 r2 þ a5 P r [48]
 (28)
þ a6 P 3 þ a7 r3 þ a8 P r2 þ a9 P 2 r
  
Hezave and Lashkarbolooki Pðy2  a3  TÞ a1 [49]
ln ¼ a0 þ þ a2 r  rref (29)
P ref T

(continued on next page)

564 C. Si-Moussa et al. / C. R. Chimie 20 (2017) 559e572

Table 1 (continued )

Model Equation Reference

Keshmiri et al. a1  a4  [50]

ln y2 ¼ a0 þ þ a2 P 2 þ a3 þ ln r1 (30)
T T
Amooey
! [51]
a0 þ a1 =r þ a2 r2 þ a3 ln T þ a4 ðln TÞ
2
ln y2 ¼ (31)
1 þ a5 =r þ a6 ln T þ a7 ðln TÞ þ a8 ðln TÞ
2

Hozhabr et al. a1 a2 r [52]

ln y2 ¼ a0 þ þ  a3 ln P (32)
T T
Khansary et al. a0 a2 P 2 [53]
ln y2 ¼ þ a1 P þ þ ða3 þ a4 PÞln r1 (33)
T T
Bian et al. (2016) a1 a2 r1 [56]
ln y2 ¼ a0 þ þ þ ða3 þ a4 r1 Þln r1 (34)
T T

performance of their proposed model with 11 previous
models, 10 of which correspond to Eqs.
(12)e(15),(18),(19),(21),(22),(24),(26), the 11th was a
model proposed by Sparks et al. [42] in which the average
association number was approximated by a linear relation
to solvent density instead of a second-order polynomial as
in Eq. (22). The models of Bian et al. [47], Sparks et al. [42],
Jouyban et al. [41], and Adachi and Lu [33] were the best at
correlating the experimental data of 54 different solid
solutes.
On the basis of the same arguments raised by Jouyban
et al., Keshmiri et al. [50] proposed, however, a five-
parameter model (Eq. (30)), in which the effects of pres-
sure and temperature are assessed differently. Khansary
et al. [53] considered that the different empirical linear and
nonlinear relationships put forward in previous works could
be regarded as rules of thumb for new model developments.
They proposed a five adjustable parameters model (Eq.
(33)), in which the effects of pressure, temperature, and
solvent density on solubility are explicitly expressed.
Recently, Bian et al. [55] proposed a new approach,
based on combinations of individual forecasting models in
economics, where the proposed model can be viewed as a
weighted contribution of models. The models they have
selected for combination are those judged from previous
works to be the mostly more accurate empirical models (Ch
and Madras [46], Garlapati and Madras [44], Adachi and Lu
[33], Jouyban et al. [41], Sparks et al. [42], and Bian et al.
[47]). They obtained the weights by using the solution of a
linear mixed nonnegative programming problem. Bian
et al. [55] tested different combinations of two, three, and
four models. They found that the three-model combination
(Sparks et al. [42], Jouyban et al. [41], and Bian et al. [47])
was the most accurate (average absolute relative deviation
[AARD] ¼ 4.37%). However, the difference in the capacity of
correlating the 1116 experimental data points between the
eight combinations of models tested in terms of AARD was
not very significant (4.37%  AARD  4.77%).
More recently, Bian et al. [56] proposed the five-
parameter model (Eq. (34)) shown in Table 1, based on
the following empirical observations depending on the
system considered:
(1) a linear relationship between ln(y2) and lnr1 in
isothermal conditions,
(2) a linear relationship between ln(y2) and r1 =T in
isothermal conditions, and
(3) a linear relationship between ln(y2) and r1lnr1 in
isothermal conditions.
Coelho et al. [58] presented a comparison between seven
density-based models (four three-parameter models, one
four-parameter model, and two five-parameter models) and
the Soave-Kwong-Redlich (SRK) cubic EoS. The comparison
concerned a very limited data set of four compounds of
interest to the food industry. Although general conclusion
cannot be drawn because of the limited data set, the results
of Coelho et al. [58] show that the five-parameter models of
Garlapati and Madras [44] and Khansary et al. [53] per-
formed better than the other models considered. This study
confirmed also the results of previous investigations
[10e13,18] that the solubility correlation using the EoS
approach is very sensitive to the accuracy of solute prop-
erties (critical properties and sublimation pressure) and
leads to significantly higher deviations than the density-
based models.
2.2. Improved density-based model
Reviewing the previously presented empirical models
and the comparative studies [41,47,51,53e56] indicates the
following:
1. In most studies, the AARD is used as a criterion of
comparison of model performance to correlate the
experimental data.
2. The three-parameter models such as [32,35,36,39,43]
are the least accurate in correlating experimental data.
3. The models in which the solubility of the solid solute is
expressed as a function of temperature, pressure, and
the density of the SCF do not take into account the phase
rule, because for an SCF only two of these three variables
need to be fixed; thus, there is a sort of redundancy in
these models.
 C. Si-Moussa et al. / C. R. Chimie 20 (2017) 559e572 565

Table 2
Sources and ranges of solubility data of solid drugs in supercritical carbon dioxide.

No. Solid drug Mw (g/mol) T (K) P (MPa) log10(y2) Ni Reference

1 4-Aminoantipyrine 203.2400 308.20e328.20 10.03e22.04 3.4353e4.9830 21 [60]

2 4-Aminosalicylic acid 153.1350 308.00e328.00 11.00e21.00 4.4449e5.4559 15 [61]
3 5-Fluorouracil 130.0770 308.15e328.15 12.50e25.00 4.8356e5.4202 18 [62]
4 Anastrozole 293.3700 308.00e348.00 12.20e35.50 3.4203e5.4437 45 [63]
5 Aspirin 180.1570 308.15e328.15 12.00e25.00 3.4597e4.2007 24 [64]
6 Atropine 289.3690 308.00e348.00 12.20e35.50 2.7773e4.2218 45 [65]
7 Atorvastatin 558.6400 308.00e348.00 12.16e35.46 2.8398e6.0000 45 [66]
8 Azadirachtin 720.7140 308.15e333.15 10.00e26.00 4.8268e5.9208 54 [67]
9 Azelaic acid 188.2210 313.15e333.15 10.00e30.00 4.9948e6.3768 14 [68]
10 Benzocaine 165.1891 308.00e348.00 12.20e35.50 1.9165e3.5686 40 [68]
11 Bisacodyl 361.4000 308.00e348.00 12.20e35.50 3.2343e5.0458 39 [70]
12 Budesonide 430.5340 338.00e358.00 21.30e38.50 4.5361e5.2269 21 [71]
13 Caffeine 194.1900 313.00e353.00 19.90e34.90 2.9469e3.5482 24 [72]
14 Capecitabine 359.3502 308.00e348.00 15.20e35.40 3.7991e5.5686 40 [73]
15 Carbamazepine 236.26860 308.00e348.00 12.20e35.50 4.0269e5.5229 39 [65]
16 Cefixime trihydrate 507.5000 308.00e328.00 18.30e33.50 6.5200e6.7959 18 [74]
17 Celecoxib 381.3700 323.20e343.20 15.00e30.00 3.8182e4.8182 18 [75]
18 Cetirizine 388.8880 308.15e338.15 16.00e40.00 2.3080e4.9788 28 [76]
19 Chlormezanone 273.7000 308.20e328.20 11.91e23.99 3.2636e5.3010 21 [77]
20 Chlorpheniramine maleate 390.8600 308.00e338.00 20.00e40.00 3.3706e4.8125 24 [78]
21 Cinnarizine 368.5000 308.15e328.15 13.97e24.00 3.6882e5.5376 21 [79]
22 Climbazole 292.7600 313.20e333.20 10.55e39.89 2.3116e3.2076 24 [80]
23 Clobetasol propionate 466.9700 308.00e348.00 12.20e35.50 5.4559e7.0000 44 [81]
24 Clofenamic acid 247.6800 313.00e333.00 12.00e36.00 4.4505e5.8125 24 [82]
25 Clotrimazole 344.8371 308.00e348.00 12.20e35.50 3.9722e6.6990 45 [83]
26 Clozapine 326.8231 318.00e348.00 12.16e35.46 4.3778e5.9208 27 [84]
27 Codeine 299.36420 308.00e348.00 12.20e35.50 2.9101e4.3979 45 [65]
28 Cortisone acetate 402.4800 308.15e373.15 8.24e22.65 5.3830e6.9586 30 [85]
29 Cyproheptadine 278.4000 308.00e338.00 16.00e40.00 2.5100e4.4750 28 [86]
30 Cyproterone acetate 416.9380 308.00e348.00 12.20e35.50 3.5834e4.8861 40 [87]
31 Dexamethasone 392.4610 308.15e328.15 10.00e35.07 5.5513e5.9245 30 [88,89]
32 Diazepam 284.7400 308.00e348.00 12.20e35.50 2.9547e3.7959 45 [65]
33 Diclofenac acid 331.3400 308.15e338.15 12.00e40.00 2.7033e4.6308 32 [90]
34 Diflunisal 250.1980 308.20e328.20 9.10e24.60 5.0930e6.2644 21 [91]
35 Docetaxel 807.8793 308.00e338.00 15.20e35.40 3.2984e4.4318 32 [73]
36 Dutasteride 528.5000 308.00e348.00 12.20e35.50 3.7940e7.0000 45 [92]
37 Exemestane 296.4000 308.00e348.00 12.20e35.50 2.7268e4.8996 45 [63]
38 Finasteride 372.5000 308.00e348.00 12.20e35.50 3.4782e4.4737 45 [92]
39 Fluoxetine hydrochloride 345.7900 308.15e338.15 16.00e40.00 3.0904e4.5768 28 [93]
40 Flurbiprofen 244.2609 303.15e323.15 8.90e24.50 3.7059e4.7768 27 [94]
41 Flutamide 276.1000 308.00e348.00 12.20e35.50 3.2930e5.3372 45 [92]
42 Fluvastatin 411.4700 308.00e348.00 12.16e35.46 3.2211e5.3010 45 [66]
43 Gabapentin 171.2400 308.00e338.00 16.00e40.00 2.1331e4.0472 28 [95]
44 Gemfibrozil 250.3400 308.20e328.20 10.01e22.02 2.3778e4.5317 21 [96]
45 Ibuprofen 206.2808 308.15e318.15 8.00e22.00 2.1675e4.5229 29 [97]
46 Imipramine HCl 316.8700 313.50e323.50 30.00e50.00 5.0044e5.2924 10 [98]
47 Isoniazid 137.1393 308.00e313.00 13.00e18.50 5.2182e6.2757 18 [99]
48 Ketoconazole 531.4310 308.00e348.00 12.20e35.50 3.7582e6.3010 45 [83]
49 Ketoprofen 254.2806 313.15e328.15 9.00e25.00 3.7258e5.4815 15 [100]
50 Lamotrigine 256.0910 318.00e338.00 12.16e35.46 5.3372e6.3979 27 [84]
51 Letrozole 285.3100 308.00e348.00 12.20e35.50 4.0809e6.0000 45 [63]
52 Levonorgestrel 384.5000 308.00e338.00 12.20e35.50 5.5376e6.3979 36 [101]
53 Lovastatin 404.5500 308.00e348.00 12.16e35.46 3.9431e4.9586 45 [66]
54 Mandelic acid 152.1500 308.15e328.15 10.10e23.06 2.5370e4.5686 21 [102]
55 Medroxyprogesterone acetate 386.2460 308.00e348.00 12.20e35.50 2.0458e4.7959 40 [87]
56 Mefenamic acid 241.2900 308.15e338.15 16.00e40.00 2.2262e4.0804 28 [103]
57 Megestrol acetate 312.5000 308.00e338.00 12.20e35.50 4.0600e5.5376 36 [101]
58 Meloxicam sodium salt 373.3800 303.00e323.00 14.90e25.50 4.8941e5.3556 15 [104]
59 Metaxalone 221.3000 308.20e328.20 11.95e24.00 3.8297e6.2366 21 [77]
60 Methimazole 114.1700 308.00e348.00 12.20e35.50 2.7215e4.2676 40 [105]
61 Methocarbamol 241.2000 308.20e328.20 11.99e22.05 3.3125e4.5528 21 [77]
62 Methylparaben 152.1473 308.00e348.00 12.20e35.50 2.9161e3.9666 40 [70]
63 Metronidazole benzoate 275.7600 308.00e348.00 12.20e35.50 2.3420e4.1549 40 [69]
64 Nabumetone 228.3000 308.20e328.20 10.00e22.00 2.5719e4.4056 21 [106]
65 Naproxen 230.2592 313.10e333.10 8.96e19.31 4.4976e5.7212 18 [107]
66 Nicotinic acid 123.1100 313.15e373.15 4.50e30.20 4.9825e6.5086 22 [108]
67 Nifedipine 346.3350 333.15e373.15 12.60e29.60 4.1495e5.8697 29 [109]
68 Niflumic acid 282.2200 313.20e353.20 19.00e31.00 4.6799e5.1487 21 [75]
(continued on next page)
566 C. Si-Moussa et al. / C. R. Chimie 20 (2017) 559e572

Table 2 (continued )

No. Solid drug Mw (g/mol) T (K) P (MPa) log10(y2) Ni Reference

69 Nimodipine 418.4403 313.00e333.00 10.00e25.00 4.3737e6.2218 21 [110]

70 Nitrendipine 360.3600 308.00e328.00 8.00e20.00 4.1993e6.0000 15 [111]
71 Norfloxacin 319.3309 313.15e323.15 9.94e30.33 4.6126e5.9136 15 [112]
72 Ofloxacin 361.3675 318.15e323.15 10.11e30.08 5.8729e6.4089 10 [112]
73 O-Nitrobenzoic acid 167.1200 308.00e328.00 10.00e21.00 4.4484e5.8182 15 [113]
74 Oxymetholone 332.4770 308.00e328.00 12.10e30.50 3.8268e4.7959 20 [74]
75 Paclitaxel 853.9061 308.15e328.15 10.00e27.50 5.2076e5.9208 21 [62]
76 Penicillin G 334.3901 313.15e333.15 10.00e35.00 4.1986e5.3768 18 [44]
77 Penicillin V 350.3800 314.85e334.85 7.99e28.05 3.2396e4.2636 24 [114]
78 Pentoxifylline 278.3000 308.15e328.15 11.98e24.00 2.8633e4.5229 21 [79]
79 Phenazopyridine 213.2385 308.00e348.00 12.20e35.50 2.6944e4.3565 45 [106]
80 Phenylephrine hydrochloride 203.6660 308.15e338.15 16.00e40.00 2.5391e3.9957 28 [115]
81 Pindolol 248.3210 298.00e318.00 8.00e27.50 3.6498e4.5686 30 [116]
82 Piracetam 142.2000 308.15e328.15 12.00e24.00 4.4283e5.1249 21 [79]
83 Piroxicam 331.3460 308.15e338.15 16.00e40.00 3.2907e4.9318 28 [117]
84 Prednisolone 360.4400 308.15e373.15 8.24e22.65 6.1379e9.0000 28 [85]
85 Prednisone 358.4300 308.15e373.15 8.24e22.65 6.0491e9.0000 28 [85]
86 Propranolol 259.3435 308.00e348.00 12.20e35.50 1.6205e3.4461 45 [105]
87 Pyrocatechol 110.1107 333.15e348.15 10.00e35.00 2.4149e3.9136 22 [118]
88 Rosuvastatin 481.5381 308.00e348.00 12.16e35.46 3.6126e5.5229 45 [66]
89 Salicylamide 137.1361 308.20e328.20 10.00e22.00 3.6778e5.0731 21 [106]
90 Salicylic acid 138.1200 308.15e318.15 9.26e15.79 3.4001e4.0132 20 [119]
91 Simvastatin 418.5662 308.00e348.00 12.16e35.46 3.2716e5.6990 45 [66]
92 Spironolactone 416.5731 308.00e338.00 16.00e40.00 2.3002e4.2041 28 [120]
93 Sulindac 356.4100 308.15e338.15 16.00e40.00 2.0610e4.4377 28 [121]
94 Tetramethylpyrazine 136.2000 318.00e338.00 10.00e30.00 0.8827e2.0000 15 [122]
95 Theobromine 180.1700 313.00e353.00 19.30e34.50 4.3270e5.0555 23 [72]
96 Theophylline 180.1700 313.00e353.00 19.90e34.90 4.4789e4.9872 24 [72]
97 Thymidine 242.2286 308.15e328.15 10.00e30.00 5.0969e5.9208 25 [62]
98 Tolfenamic acid 461.7100 313.00e333.00 12.00e36.00 4.7418e5.7932 24 [82]
99 Triclocarban 315.5800 313.20e333.20 10.93e38.96 3.0605e4.0458 24 [80]
100 Zopiclone 388.8080 313.00e333.00 10.00e25.00 4.6596e5.8239 21 [110]

Considering this, and on the basis of the findings of drugs in scCO2 were collected from the literature and were
Jouyban et al. [41], a modification that simplifies their correlated with the eight models. Table 2 displays 100 bi-
model is proposed based on the following: nary solute scCO2 systems as well as the experimental
temperature and pressure ranges and data sources. It
1. Previous empirical findings upon which density-based should be noted that all the collected data were assumed
modeling is based. correct. The AARD was determined to provide a reliable
2. There is a linear relationship between the pressure and accuracy criterion to compare the accuracy of the models,
density at fixed temperature and a certain range of possessing different numbers of curve-fitting parameters.
pressure. The AARD can be written as
3. Because the volumetric properties (P, T, r1) of scCO2 are
governed by the phase rule, only two variables need to
100 X
N
yexp  ycal
be fixed. AARD ð%Þ ¼ 2 2
(36)
N i¼1 yexp
2

Just as the density expansion of the virial EoS is more

accurate than the pressure expansion at increased pres-
sures [59], replacing the pressure by density in the Jouyban 3. Results and discussion
et al. [41] model would lead, a priori, to better correlation of
the solubility. Data from experimental measurements of the solubility
The proposed model is therefore of solid solutes in SCFs are reported in the literature, more
often by the intensive state variables: temperature, pres-
T
ln y2 ¼ a0 þ a1 r1 þ a2 r21 þ a3 r1 T þ a4 þ a5 ln r1 (35) sure, and solubility. The solubility is expressed either in
r1 units of mass of soluble solid solute in a volume of solution
in equilibrium with the pure solid solute or in mole fraction
The parameters a0ea5 are obtained from regression of
of the solute in the supercritical phase. Note that the values
the experimental data.
of the solubility are very low when expressed in molar
To compare the correlative performance of the proposed
fractions. As mentioned previously, the last three decades
model with other models, a set of eight models that have
have been marked by a significant number of studies on the
been suggested recently [54e56] to have the best correla-
measurement of the solubility of solid solutes in scCO2,
tion performance, was selected. The solubility data of 100
including numerous solid drugs.
 C. Si-Moussa et al. / C. R. Chimie 20 (2017) 559e572 567

Table 3
Estimated model parameters (ai) of the model proposed in this work (Eq. (35)) for the 100 drugs considered.

No. a0 a1 a2 a3 a4 a5

1 333.91 0.07251 1.55  105 6.12  106 30.34111 54.33453

2 300.287 0.0931 2.22  105 4.77  105 26.78015 48.91598
3 2856.04 1.27481 0.00039 1.01  105 38.36335 538.8038
4 262.11 0.08145 1.61  105 7.07  105 23.3253 41.77072
5 43.83214 0.088543 4.05  105 4.19  105 20.38589 17.3615
6 131.4653 0.01148 2.05  107 0.000118 15.8007 23.1136
7 275.142 0.08384 1.60  105 8.94  105 24.1454 43.38118
8 222.326 0.09077 2.42  105 5.63  105 15.92733 36.9064
9 305.1877 0.013857 1.66  106 0.00013 37.0519 51.8162
10 10.05584 0.01959 6.60  107 7.72  105 3.80024 2.88614
11 77.77971 0.00529 9.19  107 9.28  105 9.39991 15.3031
12 1128.914 0.572145 0.0002 6.81  105 8.13235 222.418
13 120.552 0.0067 2.79  106 2.14  105 18.02041 15.99816
14 13.75667 0.071958 3.30  105 6.06  105 20.72101 12.7081
15 135.0307 0.147712 5.71  105 3.51  105 26.05973 36.9962
16 21.93157 0.01833 4.88  106 4.85  105 6.07003 5.32296
17 341.078 0.07899 1.66  105 1.99  105 31.63075 54.73179
18 317.281 0.02262 6.88  106 8.14  105 49.47085 43.37128
19 234.084 0.00654 1.22  105 5.57  105 35.55722 31.4782
20 106.8562 0.16026 5.22  105 0.000204 57.2256 7.74003
21 265.596 0.217796 9.68  105 4.10  106 115.3331 14.7502
22 154.13 0.029543 1.69  105 1.48  105 29.14851 19.06914
23 287.3706 0.068205 2.19  105 9.25  105 23.9234 53.2504
24 293.208 0.06297 1.13  105 2.61  105 29.90687 45.82619
25 217.757 0.05831 1.05  105 5.93  105 18.50421 33.48974
26 647.7329 0.110936 3.43  105 0.000181 62.8639 111.833
27 118.6692 0.01346 5.16  106 9.36  105 15.2758 20.5678
28 108.467 0.0684 2.98  105 2.76  105 3.429694 18.37946
29 211.8769 0.106825 3.94  105 0.000108 7.237829 46.6076
30 238.1777 0.034356 5.19  106 7.32  105 23.4978 42.0553
31 82.64781 0.01054 5.20  106 4.65  105 14.8406 14.5072
32 81.45396 0.002502 1.32  106 6.43  105 7.30592 15.5991
33 118.329 0.06704 1.33  105 0.000103 6.799404 18.81183
34 117.9632 0.030546 1.65  105 8.32  105 9.32795 24.2007
35 281.0399 0.116924 4.38  105 8.95  105 1.4997 56.5648
36 228.403 0.04322 4.26  106 5.48  105 21.95793 33.90646
37 192.596 0.08718 1.74  105 0.000118 15.73473 30.75498
38 302.8109 0.068543 2.52  105 0.000106 22.7291 55.2465
39 537.598 0.25983 7.68  105 8.41  105 9.812528 98.95053
40 205.394 0.04717 7.95  106 5.91  105 28.68469 30.29182
41 186.55 0.023145 1.09  105 0.000102 20.3335 33.7139
42 5.167317 0.00819 4.40  106 9.47  105 1.10902 4.5213
43 357.553 0.00124 1.54  105 2.92  105 58.05735 49.37206
44 704.118 0.23074 7.07  105 1.99  105 47.82098 123.2081
45 256.998 0.06097 4.92  106 6.99  105 26.26448 40.30101
46 12,355 6.579034 0.00187 0.00068 591.9505 2467.39
47 6515.35 1.28613 0.000329 0.00068 744.2133 1077.031
48 167.186 0.0399 2.64  107 0.000101 20.65338 22.94356
49 141.5879 0.083332 4.05  105 7.95  105 3.70116 31.4735
50 22.4241 0.0045 3.33  106 4.30  105 1.158043 0.538126
51 35.10967 0.02185 1.96  105 0.0001 2.786269 11.7478
52 230.88 0.06539 1.85  105 2.18  105 21.602 36.4095
53 102.45 0.02195 1.07  106 2.79  105 9.014762 14.73499
54 295.747 0.10019 2.36  105 9.01  105 28.37983 47.8683
55 95.8311 0.03673 1.30  105 3.32  105 8.151631 14.35616
56 214.513 0.06436 1.40  105 8.02  105 20.48066 32.96468
57 169.579 0.0092 3.88  106 0.000108 24.798 28.871
58 1624.16 0.90527 0.000281 0.000119 44.0891 320.7279
59 35.0598 0.113437 5.70  105 8.54  105 40.24724 10.0175
60 226.5972 0.017148 4.48  106 0.000104 24.9282 39.1657
61 400.299 0.06815 7.74  106 4.59  105 51.33682 61.25143
62 84.0022 0.0372 7.92  106 5.46  105 7.562351 12.46796
63 257.96 0.06176 1.43  105 2.36  105 25.55464 41.10095
64 105.454 0.06154 1.42  105 6.90  105 1.362211 18.14281
65 240.522 0.07268 1.91  105 3.42  105 21.20399 38.7047
66 33.1442 0.03461 1.01  105 5.73  105 0.655012 3.899973
67 29.08865 0.02598 6.47  106 8.73  105 5.54546 6.5935
68 13.75492 0.02952 8.16  106 5.63  105 10.3614 2.57467
(continued on next page)
568 C. Si-Moussa et al. / C. R. Chimie 20 (2017) 559e572

Table 3 (continued )

No. a0 a1 a2 a3 a4 a5

69 57.4741 0.05532 1.21  105 9.20  105 1.50031 8.993218

70 119.148 0.07376 2.00  105 8.41  105 5.661167 19.71953
71 1912.328 0.39439 0.00015 0.000556 183.351 330.995
72 1359.79 0.43159 0.000132 2.54  105 122.7584 233.9027
73 388.333 0.12816 3.04  105 6.89  105 34.44473 64.19007
74 41.8925 0.0033 3.70  106 6.54  105 8.25917 8.88317
75 1006.32 0.11918 3.93  105 0.00017 168.8394 155.5943
76 224.6789 0.025636 1.15  105 0.000127 21.0055 40.8712
77 101.416 0.06353 2.10  105 4.66  105 4.667168 17.49912
78 352.552 0.05179 3.30  106 3.26  105 41.94947 53.78755
79 33.1213 0.01884 1.94  106 6.68  105 3.847684 3.057963
80 355.568 0.17741 4.98  105 8.99  105 8.975403 64.4528
81 68.74698 0.004456 2.15  106 4.08  105 7.00159 13.5184
82 343.133 0.0182 4.59  106 2.39  105 50.39958 50.2686
83 567.2505 0.09314 2.65  105 0.000178 54.843 98.5152
84 193.026 0.12081 5.31  105 4.68  105 7.52461 33.68521
85 152.842 0.12285 4.76  105 0.000122 5.696566 25.7895
86 50.99776 0.03535 8.35  106 0.000119 7.18326 9.33889
87 91.473 0.02081 3.87  106 1.62  105 7.186239 13.81712
88 138.121 0.02273 9.61  107 4.67  105 14.9385 19.30491
89 146.614 0.06657 1.62  105 5.46  105 7.149813 24.518
90 276.323 0.05122 8.56  106 1.63  105 34.43189 42.82894
91 93.9377 0.00999 4.93  106 5.92  105 11.33474 11.3662
92 522.961 0.077963 3.12  105 0.000217 41.6145 91.6123
93 239.605 0.02929 9.98  106 0.000132 44.77625 31.26755
94 266.645 0.12543 3.07  105 9.66  105 20.74828 46.44233
95 54.2958 0.15951 5.90  105 9.94  105 27.1185 17.68296
96 4.17623 0.05683 1.86  105 5.79  105 13.2033 2.525788
97 1037.74 0.43452 0.000143 2.61  105 44.22912 189.9748
98 99.9916 0.03954 4.07  106 7.86  105 9.564865 13.88758
99 177.147 0.009528 9.73  106 2.50  106 31.66024 23.13632
100 314.429 0.12333 3.85  105 3.21  105 21.63374 53.90277

The details of the experimental data used in this work
and their references are listed in Table 2. Considering the
experimental data collected, it is worth mentioning that
there may be some differences between experimental data
for a given solute from different sources. With regard to the
density of CO2, we have used the data provided in the
experimental solubility data source. Otherwise, the den-
sities of CO2 for different sets of temperature and pressure
were calculated using the carbon dioxide property data
available through the National Institute of Standards and
Technology web database [123].
Adjustments of the parameters of the selected literature
models (Eqs. 13,21,22,24,27,30,33,34) together with the
proposed model (Eq. 35) were carried out using genetic
algorithms (ga MATLAB function) to obtain initial estimates
of the parameters. To avoid convergence to local minima,
optimization using genetic algorithm is run 20 times. The
set of model parameters with best fit is saved and then used
as an initial approximation in the least square fitting
(lsqcurvefit MATLAB function) with the use of the Lev-
enbergeMarquardt algorithm as a computation option. In
both cases, Eq. (36) was used as the objective function to be
minimized. The results of parameter estimations for the
proposed model are shown in Table 3. Parameters of the
other models can be accessed in the supplementary
material.
The AARDs (%) of each model equation with each drug
compound are shown in Table 4, in which the best AARD for
the correlation of the solubility data of each binary system
is shown in bold.
Table 4 shows that the AARD ranges between 0.61% and
55.77%, but when considering the best AARDs only (bold)
they range between 0.61% and 15.38% with an average of
4.83%. The minimum AARD (0.61%) and the maximum
AARD (15.38%) are both obtained by the Bian et al. [47]
model (Eq. (27)) for the systems 6 (scCO2eatropine) and
16 (scCO2ecefixime trihydrate), respectively. This demon-
strates that for the 100 systems considered, empirical
modeling as a whole correlates with the experimental data
quite satisfactorily. However, the global comparison be-
tween the performances of different models indicates that
the model proposed in this work gives the best correlating
performance, where the AARD ranges between 0.86% and
23.64% with an average of 8.13%. The second best corre-
lating performance is given by the Bian et al. [47] model,
where the AARD ranges between 0.61% and 25.57% with an
average of 8.40%. The third best correlating performance is
given by the Sparks et al. [42] model (Eq. (22)), where the
AARD ranges between 0.70% and 29.66% with an average of
8.96%. As shown in Fig. 1, these three models together with
the recent model of Bian et al. [56] represent the best
correlation of 82% of the 100 systems considered. Beside
this, the proposed model for calculating the solubility is
simpler as it requires only the temperature and CO2 density.
Furthermore, Table 4 confirms the results of previous
comparative studies [41,47,51,53e56], insofar as there is not
 C. Si-Moussa et al. / C. R. Chimie 20 (2017) 559e572 569

Table 4
Average absolute relative deviation (AARD, %) for 100 drugs calculated for each of the 09 studied correlations.

No. Equation

(13) (21) (22) (24) (27) (30) (33) (34) (35)

1 6.33 7.13 6.38 7.44 7.62 7.59 8.84 7.82 6.73

2 2.42 4.15 5.27 1.66 1.73 2.26 3.53 7.83 1.92
3 8.22 6.74 16.95 6.04 5.76 7.69 8.17 15.18 6.72
4 7.22 10.15 3.98 7.38 7.41 9.26 10.06 5.51 6.97
5 3.00 5.65 2.68 4.71 4.45 5.39 5.44 3.43 3.31
6 17.66 19.45 21.54 16.98 15.38 16.68 16.80 20.22 16.24
7 4.04 11.94 11.17 5.90 5.44 9.09 10.64 11.16 3.84
8 2.67 5.25 9.99 3.36 3.43 2.60 3.70 11.02 3.05
9 21.51 17.69 5.68 21.86 19.82 16.81 15.80 8.57 17.04
10 11.99 8.33 12.22 11.13 6.26 11.05 12.55 15.78 9.67
11 10.85 7.17 0.70 12.24 6.10 12.96 15.06 1.95 9.16
12 10.11 8.55 2.71 12.07 11.86 8.69 10.04 4.54 9.83
13 3.43 2.88 24.02 2.95 2.86 3.20 5.42 18.75 2.90
14 5.87 11.71 12.72 9.09 8.56 11.07 11.44 12.43 6.95
15 13.08 15.04 7.40 15.83 15.43 17.63 18.02 4.58 11.85
16 2.33 3.01 5.40 0.70 0.61 2.11 1.81 4.24 2.22
17 2.25 2.87 13.02 1.80 1.44 1.75 2.93 11.20 1.42
18 5.36 8.12 5.91 4.88 4.62 5.84 11.18 7.63 4.11
19 4.12 4.76 9.15 5.14 4.79 5.61 7.34 10.45 4.13
20 8.83 12.85 5.16 6.62 6.08 6.91 6.51 5.40 7.35
21 5.35 4.80 8.13 5.89 5.97 5.63 8.35 6.28 4.12
22 4.14 3.72 11.57 3.83 3.37 2.83 5.51 10.86 2.39
23 14.38 12.02 8.53 15.82 9.59 14.80 16.71 11.86 10.95
24 4.99 6.76 12.95 5.32 5.18 4.97 5.99 12.94 4.80
25 2.83 8.63 6.91 4.76 4.58 7.03 8.34 5.53 3.71
26 24.09 17.77 7.61 24.82 17.13 22.72 25.86 12.68 15.02
27 12.67 10.69 8.35 12.26 10.72 14.28 13.31 8.38 12.68
28 14.46 23.84 3.42 17.32 12.71 21.66 37.53 10.79 15.40
29 7.24 6.93 4.02 8.46 7.60 8.90 9.93 4.95 7.10
30 11.04 10.25 3.74 10.69 7.67 10.32 9.70 3.62 5.55
31 7.72 4.39 4.20 8.29 7.50 6.48 5.89 5.78 7.42
32 7.47 5.00 14.28 7.54 3.42 7.93 8.11 12.24 3.53
33 6.60 13.19 5.10 5.31 4.22 5.81 5.84 5.84 5.01
34 12.47 10.05 9.30 13.29 10.60 15.54 14.52 14.85 11.05
35 6.14 6.34 2.94 8.34 6.40 8.33 9.09 3.82 5.83
36 3.98 10.80 3.81 7.23 6.72 10.01 10.26 3.74 5.05
37 18.16 26.38 21.16 10.85 10.16 19.91 17.71 19.37 20.60
38 16.43 15.28 7.38 18.85 12.01 19.00 21.22 7.68 11.57
39 9.67 13.63 29.66 10.24 10.13 10.45 9.48 13.59 9.82
40 5.15 5.85 8.83 5.39 5.36 6.19 5.97 9.00 5.23
41 19.77 13.39 2.85 19.65 13.11 15.90 18.84 3.77 15.63
42 8.28 6.87 3.83 10.09 4.40 11.42 12.19 3.00 3.71
43 10.31 11.77 16.65 10.82 10.49 10.19 12.58 10.85 9.61
44 10.67 15.42 7.42 11.79 11.11 13.98 16.48 7.55 11.35
45 8.40 11.35 15.82 11.90 11.69 10.63 9.73 13.22 6.22
46 12.95 7.20 6.45 13.00 11.36 7.37 7.64 7.44 7.67
47 8.33 6.51 3.18 6.89 5.21 5.70 6.73 7.00 5.37
48 9.32 18.40 2.69 11.91 11.53 18.89 14.67 3.57 12.20
49 8.49 6.20 3.61 10.84 8.38 9.31 9.86 3.61 6.18
50 2.97 7.32 6.38 11.68 6.60 24.60 23.47 9.59 4.31
51 14.86 18.75 7.42 19.87 18.27 19.84 19.50 9.22 13.96
52 9.64 11.02 2.30 9.99 10.08 9.51 10.52 3.37 9.54
53 4.08 7.90 13.88 4.95 4.82 4.88 4.25 23.63 4.29
54 3.90 4.49 5.95 3.58 3.36 7.57 7.75 5.48 3.56
55 24.13 26.21 4.75 25.69 22.49 27.77 26.21 6.04 23.64
56 3.61 5.96 5.70 3.82 3.49 3.89 6.98 6.05 3.42
57 22.38 23.88 3.05 20.04 20.80 19.99 18.96 3.97 21.10
58 4.29 4.95 7.73 5.71 5.73 4.89 5.74 7.53 3.20
59 22.96 11.68 4.10 23.93 25.57 22.18 19.93 4.97 22.89
60 14.05 9.08 23.69 14.12 10.10 12.43 13.49 22.59 9.46
61 4.01 5.96 4.02 4.36 4.12 4.28 5.13 4.21 3.82
62 5.85 5.02 10.21 5.15 3.72 7.24 7.47 10.45 5.21
63 15.55 14.43 7.19 9.96 9.62 14.80 19.48 7.51 12.86
64 2.89 9.02 4.17 3.72 3.47 5.59 5.68 5.43 1.75
65 3.83 4.94 1.56 4.08 3.67 3.84 4.34 2.29 3.77
66 21.41 16.02 14.61 21.28 14.11 18.83 26.28 12.48 17.68
67 16.11 10.00 19.77 16.36 11.15 13.15 17.14 17.54 12.16
(continued on next page)
570 C. Si-Moussa et al. / C. R. Chimie 20 (2017) 559e572

Table 4 (continued )

No. Equation

(13) (21) (22) (24) (27) (30) (33) (34) (35)

68 1.91 3.21 4.08 1.17 1.04 0.93 1.87 6.94 0.86

69 7.38 8.45 16.35 8.08 6.48 6.65 10.14 13.14 4.80
70 7.79 9.11 7.67 9.38 8.44 7.55 9.68 8.70 8.25
71 29.32 13.42 1.18 31.33 12.87 19.66 27.33 1.05 14.93
72 8.85 10.50 1.80 9.17 8.43 7.80 8.42 1.74 6.64
73 3.66 6.06 19.62 3.07 3.52 4.10 5.23 21.31 3.12
74 3.83 3.87 10.03 3.74 2.54 2.92 3.79 9.65 2.83
75 16.86 16.77 6.71 16.52 7.92 12.49 16.95 6.54 8.92
76 23.00 11.04 3.41 22.63 16.49 24.05 19.19 4.11 15.57
77 3.76 5.42 2.63 9.07 9.13 7.10 8.30 4.65 4.97
78 5.69 6.54 8.39 5.99 6.04 5.75 6.61 8.41 5.61
79 7.43 7.20 14.30 8.31 6.59 11.08 10.89 13.60 6.67
80 10.81 13.14 22.30 11.35 11.20 11.25 11.57 16.32 10.41
81 8.64 14.08 10.75 8.21 9.19 16.36 13.76 11.67 7.67
82 4.27 3.37 2.92 3.23 3.24 3.66 5.28 3.24 2.75
83 16.03 15.17 5.32 14.04 13.60 14.42 14.40 5.26 13.86
84 19.60 38.04 3.75 29.75 25.26 29.66 55.77 4.61 19.03
85 27.04 36.81 6.25 33.86 24.71 22.91 48.31 7.65 21.04
86 15.83 7.47 15.23 15.74 10.73 14.05 15.17 18.33 11.29
87 6.58 10.34 10.75 8.34 7.14 9.94 8.52 17.05 6.57
88 3.71 7.69 8.38 7.20 6.92 8.84 9.83 8.85 3.82
89 2.75 7.69 9.80 3.55 3.43 5.01 4.31 12.29 1.78
90 3.61 3.70 25.74 3.64 3.41 3.83 3.87 24.97 3.63
91 6.57 9.38 10.24 9.73 8.98 11.29 12.95 8.62 5.92
92 12.01 20.04 16.36 9.84 7.61 11.41 13.75 14.49 9.69
93 8.44 12.69 3.69 8.84 6.74 9.46 10.97 9.11 6.70
94 2.90 10.54 17.97 2.74 2.83 2.99 2.90 30.38 3.63
95 4.48 4.41 12.14 4.43 4.43 3.83 3.28 21.31 3.17
96 5.34 4.19 26.64 5.33 4.24 4.82 5.09 35.29 4.61
97 23.02 22.89 3.31 14.59 14.50 22.41 22.11 3.37 22.88
98 4.53 7.91 5.82 4.71 3.70 4.31 4.81 5.34 3.60
99 5.83 3.56 5.01 5.88 4.71 5.17 6.05 5.04 5.15
100 5.96 5.32 4.48 6.56 5.28 5.45 7.26 3.70 5.77
Minimum AARD 1.91 2.87 0.70 0.70 0.61 0.93 1.81 1.05 0.86
Maximum AARD 29.32 38.04 29.66 33.86 25.57 29.66 55.77 35.29 23.64
Average 9.57 10.44 8.96 10.17 8.40 10.47 11.94 9.61 8.13

cal exp
a model that can best correlate all of the systems of the Linear Fit: log(y 2 )=(1)log(y2 )+(-0.017), R=0.998
experimental data set. 0
Validation and performance of the models selected in Data Points
this study are shown as scatter plots for the 2891 experi- Best Linear Fit
cal exp
mental points of the database. Fig. 2 shows the scatter plot log(y2 ) = log(y2 )
-2
of the proposed model. These plots are generated using the

-4
log(y2 )
cal

-6

-8

-10
-10 -8 -6 -4 -2 0
exp
log(y2 )

Fig. 2. Scatter plot of the entire data set of the drug solubility calculated
using the model proposed in this work (Eq. (35)) versus experimental
Fig. 1. The number of systems best correlated by each model equation. solubility.
 C. Si-Moussa et al. / C. R. Chimie 20 (2017) 559e572
Table 5
Validation agreement vector (a [slope], b [y intercept], and R [correlation coefficient]) calculated for the nine studied models.
Validation agreement vector Equation
(13) (21) (22) (24)
a 0.9949 0.9947 0.9953 0.9946
b 0.0219 0.0226 0.0199 0.0232
R 0.9974 0.9974 0.9977 0.9973
postreg function of MATLAB, in which the calculated solu-
bility in logarithmic scale is plotted against experimental
solubility. The scatter plot shows the dispersion of the
cloud of points of the whole data set around the first
bisector (log(ycal) ¼ log(yexp)), the degree of dispersion can
be evaluated from the equation for the best linear fit
(log(ycal) ¼ a. Log(yexp) þ b), where a is the slope and b is
the intercept, which together with the correlation coeffi-
cient R are used as a validation agreement vector. The ideal
performance is achieved when [a ¼ 1, b ¼ 0, and R ¼ 1]. The
values of a, b, and R for the seven selected models and the
proposed model are summarized in Table 5. According to
the a value close to 1, the b value close to 0, and R close to 1,
clearly the proposed model has the best validation agree-
ment vector and as such the best overall correlation
performance.
4. Conclusions
The novel density-based model proposed in this work
has been derived by simple modification of the six-
parameter Jouyban's model to correlate the solubility of
solid drugs in scCO2. The modification considers the phase
rule insofar as the solubility of the solid solute in the su-
percritical phase is expressed only as a function of the
solvent density and the equilibrium temperature, in
contrast to Jouyban's model that gives the solubility as a
function of the solvent density and the equilibrium tem-
perature and pressure. The performance of the model has
been tested on a database of 100 drugs that account for
2891 experimental data points collected from the litera-
ture. The correlative performance of the proposed model
has been compared with that of seven previous models that
have been selected on the basis of being suggested in
previous works to possess the best correlating perfor-
mance. This study demonstrates that for the data set
considered, empirical modeling as a whole correlates with
the experimental data quite satisfactorily with an AARD
range of 0.61%e15.38% and an overall average of 4.83%. The
global comparison between the performances of different
models indicates that the model proposed in this work
gives the best correlating performance, where the AARD
ranges between 0.86% and 23.64% with an average of 8.13%.
Acknowledgments
The authors gratefully acknowledge the Algerian Min-
istry of Higher Education and Scientific Research (CNEPRU
Projects: No. J0102620110007 and No. J0102620140015)
and the University Yahia Fares of Medea.
571
(27) (30) (33) (34) (35)
0.9960 0.9947 0.9936 0.9951 0.9960
0.0172 0.0228 0.0274 0.0209 0.0171
0.9980 0.9973 0.9966 0.9976 0.9980
Appendix A. Supplementary data
Supplementary data related to this article can be found
at http://dx.doi.org/10.1016/j.crci.2016.09.009.
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 Supporting Information
Novel density-based model for the correlation of solid drugs solubility in
supercritical carbon dioxide
Nouveau modèle basé sur la densité pour la corrélation de la solubilité des
médicaments solides dans le dioxyde de carbone supercritique
Cherif Si-Moussa*, Aicha Belghait, Latifa Khaouane, Salah Hanini, Asmaa Halilali

Laboratory of Biomaterials and Transport Phenomena (LBMPT), Faculty of Science and Technology,
University Yahia Fares of Medea, Algeria.
*
Corresponding author E-mail: simoussa_cherif@yahoo.fr
simoussa.cherif@univ-medea.dz
Phone Number: +213 553 73 53 63.

Table A1. Estimated model parameters (ai) of the Adachi and Lu [33] model (Eq. (13)) for the
100 drugs considered.

N° a0 a1 a2 a3 a4
1 -9.11984 1.020306 0.002054 -1.17E-06 -3796.38
2 -17.1125 4.635946 -0.0007 4.41E-07 -7251.62
3 -2175.09 404.946 -0.1381 4.83E-05 -3794.71
4 24.19225 -2.69092 0.003211 -1.18E-06 -9162.68
5 206.9313 -38.8145 0.01719 -6.82E-06 -5977.08
6 0.732202 1.968459 0.000212 9.03E-08 -7615.39
7 25.84269 -2.74967 0.004402 -1.53E-06 -10843.8
8 -17.8041 4.475928 -0.00123 6.82E-07 -6512.8
9 -34.2679 6.753621 -0.00271 1.56E-06 -4999.21
10 -5.42749 2.149439 0.000885 -4.35E-07 -5772.32
11 54.21231 -9.81476 0.005595 -1.92E-06 -6275.28
12 851.0694 -161.942 0.063252 -2.41E-05 -5085.06
13 11.47671 -2.03017 0.001763 -3.89E-07 -4403.26
14 208.7887 -39.1273 0.0177 -6.48E-06 -8036.87
15 324.6742 -60.7787 0.024089 -8.75E-06 -6733.77
16 24.52551 -5.83458 0.002251 -7.84E-07 -3015.31
17 -22.3217 4.713688 0.000197 -7.85E-08 -6389.21
18 134.418 -22.8396 0.0128 -4.16E-06 -13307.1
19 87.15567 -15.7521 0.010393 -4.07E-06 -9038.6
20 54.72113 -7.23107 0.004603 -1.24E-06 -11579
21 376.4609 -68.2993 0.030189 -1.08E-05 -14358.8
22 63.10158 -13.1258 0.007608 -3.05E-06 -2876.16
23 123.96 -25.086 0.01144 -4.20E-06 -4291.74
24 4.734759 -0.76 0.002213 -8.80E-07 -6104.26
25 8.904327 -1.45589 0.003494 -1.28E-06 -7550.79
69 -49.3522 10.48836 -0.00325 1.46E-06 -6583.37
70 -22.4879 5.577738 -0.00175 1.05E-06 -6318.84
71 -117.182 33.88552 -0.01514 6.91E-06 -22409.3
72 -0.20497 6.170453 -0.00384 2.20E-06 -14095.6
73 12.06593 0.444165 0.001328 -4.62E-07 -9924.01
74 -12.3195 1.521687 0.001436 -8.08E-07 -3572.2
75 -283.417 53.49711 -0.01891 6.97E-06 -4958.78
76 -24.9317 7.204638 -0.00403 2.54E-06 -7589.92
77 -22.7947 5.274491 -0.00275 1.64E-06 -4084.97
78 14.37416 -1.69853 0.004137 -1.67E-06 -8056
79 31.56776 -5.09025 0.003367 -1.03E-06 -6078.59
80 -157.187 31.94277 -0.0098 3.75E-06 -9025.93
81 -1.83476 -0.08477 -0.00076 1.11E-06 -2332.54
82 45.02465 -8.73659 0.004653 -1.71E-06 -4710.62
83 279.3302 -51.2947 0.020923 -7.14E-06 -8921.79
84 -64.456 12.15188 -0.00733 5.06E-06 -4712.61
85 -32.6441 7.373924 -0.00362 3.21E-06 -8288.3
86 18.43544 -0.38031 0.000788 2.34E-07 -8877.25
87 8.967544 -2.35518 0.002603 -1.13E-06 -2752.01
88 39.30817 -7.60703 0.005621 -2.27E-06 -5988.81
89 -46.6286 9.33177 -0.00244 9.15E-07 -4922.03
90 32.71414 -4.9996 0.002986 -1.06E-06 -5854.94
91 46.18877 -8.89654 0.006619 -2.60E-06 -6516.58
92 375.5604 -65.0413 0.025028 -9.08E-06 -14032.9
93 221.1327 -35.7378 0.016335 -5.80E-06 -17131.9
94 12.01741 3.108689 -0.00108 5.70E-07 -10663.6
95 -92.1512 18.16802 -0.00736 3.31E-06 -4935.43
96 -18.7843 2.781096 -0.00017 8.66E-09 -3292.72
97 -587.781 111.0336 -0.04267 1.66E-05 -3228.79
98 22.06997 -2.89607 0.002517 -9.50E-07 -7785.25
99 84.14898 -16.0319 0.007737 -2.74E-06 -4622.69
100 -38.4118 8.155411 -0.00313 1.62E-06 -5630.24
40 -26.3607 -0.41197 -0.00712 0.002487 0.029449 1.825606
41 -48.8247 -0.01291 -4.75E-05 0.000158 2.175674 4.505684
42 -32.9271 -0.04447 -2.00E-05 0.000189 0.184869 3.050293
43 -17.7996 -0.09514 3.39E-05 0.000204 -3.94762 3.159583
44 -24.5646 -0.22601 0.000206 0.00037 -3.23419 5.568559
45 -38.1207 -0.20328 2.63E-05 0.000608 -0.51745 5.244878
46 -133.095 0.09481 -0.0001 2.79E-05 13.27559 12.5363
47 197.9982 -0.67591 0.000659 0.001125 -13.6964 -22.2468
48 -17.3714 -0.86583 0.000279 0.002512 -0.22286 1.585238
49 -43.6402 -0.08624 -1.73E-05 0.000283 -0.31358 5.19865
50 -3.79887 -0.05984 4.14E-05 8.39E-05 -2.71456 0.014546
51 -26.7965 -0.06573 -2.07E-05 0.00024 -0.43444 2.13242
52 -21.3351 -0.00928 -1.79E-05 7.22E-05 0.035942 0.813575
53 -20.92 -0.03188 -8.18E-06 0.000111 -0.15673 1.596712
54 -34.4225 -0.03333 -9.80E-05 0.000265 0.172298 3.18396
55 -5.79447 -0.0381 3.54E-05 4.02E-05 -2.34653 0.612144
56 -30.7204 -0.5849 0.000594 0.001745 -0.1499 3.809688
57 -38.6073 -0.00388 -3.87E-05 0.00011 1.279419 3.154908
58 -55.8673 0.015138 -7.94E-05 0.000128 2.653203 4.764705
59 -29.1598 -0.12094 2.25E-05 0.00032 -3.24191 4.094047
60 -37.9033 0.019073 -6.50E-05 9.46E-05 2.256356 2.858281
61 -44.4188 -0.05088 -0.00013 0.000356 0.754337 4.158305
62 -12.1901 -0.03027 -1.27E-05 0.000123 -0.21246 0.427134
63 -23.95 -0.02547 -1.38E-05 0.000116 0.105575 2.200506
64 -39.963 -0.08806 -4.28E-05 0.000331 0.359451 4.703819
65 -20.075 -0.88253 0.002229 0.002169 -0.14213 2.19874
66 -15.9421 -0.01913 -1.15E-05 9.04E-05 0.067023 0.13357
67 -16.8844 -0.063 4.65E-05 0.000115 -1.36397 1.679868
68 -84.4145 0.103453 -0.00016 6.15E-05 8.16934 6.236351
69 -28.992 -0.10537 1.06E-05 0.000304 -0.56064 3.014652
70 -21.998 -0.09727 -2.57E-06 0.000296 -0.6903 2.083694
71 -35.4082 -2.42048 -0.00682 0.009176 0.186891 1.887909
72 11.10791 -1.39331 0.002382 0.003842 -0.18437 -2.97566
73 -19.6265 -0.16832 2.86E-05 0.000473 -1.19301 1.934468
74 -29.0043 -0.04834 3.04E-06 0.000147 -0.17309 3.030287
75 -298.356 -0.00707 -5.22E-07 4.01E-05 7.25756 40.38961
76 -32.1013 0.020873 -9.93E-05 0.000151 2.169479 1.134067
77 0.932694 -0.06159 5.03E-05 9.84E-05 -1.68885 -0.32771
78 -77.2949 0.033115 -0.00023 0.00028 3.304631 7.439919
79 -30.3645 -0.00558 -4.33E-05 0.000118 0.996001 2.407657
80 -15.5619 -0.0401 -1.95E-05 0.000178 0.075 0.681228
81 -16.17 0.036951 -3.02E-05 -5.71E-05 0.131926 0.662251
82 -29.6934 -0.01706 -6.71E-05 0.000154 0.401692 2.204034
Table A3. Estimated model parameters (ai) of the Sparks et al. [42] model (Eq. (22)) for the 100
drugs considered..

N° a0 a1 a2 a3 a4 a5
1 4.266605 2.29615 -1.06105 41.79919 -93.5425 42.34818
2 4.74742 -0.36235 0.249248 57.7718 -121.126 50.80566
3 210.1014 -176.703 42.1542 146.0342 -349.142 175.7669
4 1.805545 5.26698 -1.40794 53.75856 -108.929 42.39458
5 -15.6479 21.96067 -6.07537 -16.1905 35.07081 -28.5969
6 3.411048 0.037912 0.303232 -64.4303 147.1707 -92.5976
7 3.293641 6.881175 -1.66457 31.31936 -55.5112 10.69074
8 4.227556 -1.53099 0.657316 4.251561 -9.52259 -6.25432
9 5.051836 -3.24483 1.472155 -2.35084 -5.00291 -6.0721
10 3.998217 1.407746 -0.52304 30.61069 -61.0476 22.60798
11 -2.58937 9.031424 -2.18424 24.81038 -53.6335 17.75318
12 -75.5655 79.9942 -21.2084 49.42153 -114.134 55.67169
13 -2.61591 7.294594 -1.7021 24.22715 -56.3857 22.90195
14 -15.5422 24.06998 -6.03634 6.292086 -12.9889 -7.22445
15 -34.7672 40.07025 -10.3808 68.07968 -148.144 68.52066
16 -1.4425 2.177923 -0.39609 -59.7052 107.687 -61.3793
17 6.165681 0.147617 -0.06607 54.37853 -119.749 54.01126
18 -4.75263 18.37492 -4.10902 70.13234 -134.704 48.20629
19 -2.08292 14.35366 -3.95435 41.23064 -81.3405 26.98137
20 8.171704 -1.35728 0.944932 -52.3963 123.6918 -85.7158
21 -32.9048 46.87992 -11.715 114.5501 -221.856 91.24552
22 -2.17137 9.677509 -2.74491 49.55211 -110.304 53.47533
23 -9.98314 16.03392 -4.03042 -5.14109 -4.39042 -5.22375
24 2.85774 3.075947 -0.8539 0.111358 -5.49971 -7.7122
25 3.489753 5.395911 -1.38644 21.00896 -47.7959 12.36466
26 -0.13059 4.155092 -0.7326 -119.113 254.4097 -148.924
27 3.161072 -0.44598 0.722099 4.660563 -8.70708 -5.25915
28 4.224353 -3.74926 2.130937 23.49872 -71.0581 35.06892
29 -25.6884 32.70599 -7.45737 20.43664 -31.4907 -1.57621
30 0.664882 1.240889 0.664149 -43.4593 82.95554 -49.2736
31 4.113878 -4.44257 1.620851 9.111226 -36.5669 15.75804
32 -0.70558 3.260139 -0.43939 -5.0953 9.42531 -12.6757
33 5.849424 -0.26942 0.319725 -22.3829 59.96678 -48.5519
34 -0.06473 4.812428 -1.33795 65.4525 -147.148 68.63582
35 -26.4202 29.24745 -7.34247 25.11394 -42.9033 9.652382
36 2.178814 9.058664 -2.42185 11.19073 -26.6302 0.790219
37 2.987772 3.226347 -0.44067 -75.9947 182.5378 -119.493
38 -5.73863 9.670535 -2.46197 -12.2231 26.48802 -24.142
39 35.58979 -25.8227 6.716083 -3.52356 9.228878 -19.9067
83 -20.4086 26.15218 -5.88596 -54.5359 121.5289 -79.9513
84 6.752759 -8.10668 4.799623 6.922876 -35.3616 11.13591
85 5.59349 -2.84803 2.876711 17.33109 -46.7017 10.9282
86 1.510138 2.472573 -0.06323 19.39916 -26.8796 -1.24923
87 1.175128 4.190867 -1.32606 -1.95794 -1.61975 -4.14632
88 -0.32155 8.237975 -2.35773 24.26038 -54.6247 18.79736
89 7.651528 -3.77975 0.993492 19.26114 -43.7002 14.37794
90 -0.25482 4.236041 -1.02481 3.45136 -5.15856 -7.24524
91 -0.41177 9.712416 -2.67704 18.6135 -41.5061 10.80811
92 -28.3979 29.82582 -7.20944 -85.6358 215.6752 -138.702
93 -13.8336 23.22546 -5.73749 105.5712 -190.027 70.85605
94 3.37665 -1.87891 0.725168 108.7242 -202.888 89.38264
95 17.07497 -16.9543 5.274977 -28.0997 54.7141 -38.9474
96 3.812314 -0.54592 0.071535 0.272186 -13.1019 1.25093
97 80.69997 -77.9047 20.74732 -512.856 1050.669 -554.079
98 1.057498 3.6152 -0.9395 -14.7727 32.44778 -30.7525
99 -4.7813 10.35503 -2.47708 -55.4719 115.58 -69.3753
100 6.014493 -4.18235 1.626347 16.46386 -38.3539 10.51671
40 21.61535 -3.28065 0.001443 -7970.61 0.687288
41 -3.58782 6.388402 0.000172 -6377.66 -2.36971
42 89.83902 13.89948 0.001045 -12399.7 -12.7965
43 -295.215 -21.972 -9.63E-05 1358.976 34.58816
44 -1168.98 -150.488 -0.00131 46939.06 162.9711
45 -204.032 -23.1857 0.000158 -5.3065 28.3728
46 -751.259 124.4193 -0.01706 -22.026 -0.18871
47 -23927.7 -3588.54 0.003972 1073686 3575.951
48 599.7194 86.16614 0.001576 -39843.7 -86.0137
49 -153.807 -10.9213 -0.00016 -2.66431 17.53702
50 838.3729 120.1708 0.001092 -44104.8 -122.287
51 472.0099 72.57652 0.000563 -32061.2 -70.0053
52 -438.792 -68.4865 0.001137 16749.16 66.19992
53 68.02711 15.99505 -0.00013 -7902.04 -12.8196
54 -691.006 -104.863 0.00152 22729.39 104.9045
55 -1275.94 -192.328 0.001496 58276.58 189.689
56 -155.413 -18.6185 0.001428 -2575.71 21.86757
57 1510.52 222.0583 0.001093 -77495.9 -222.36
58 -41.8382 6.282655 -9.33E-05 -4561.94 0.236916
59 -1834.67 -261.586 0.001204 73188.65 268.0679
60 335.3158 48.9689 0.000837 -20910.3 -48.9451
61 49.53262 9.141799 0.000972 -12560.2 -6.80333
62 -237.085 -36.9029 0.000737 6281.7 36.28229
63 -1154.73 -170.894 0.000983 50296.09 170.8312
64 37.21054 19.49887 -0.00082 -8615.28 -11.4365
65 -1.19539 2.009714 0.000596 -6043.05 -0.5656
66 -159.999 -22.5211 0.000307 4314.799 22.65651
67 357.7914 55.34569 0.000533 -23930.7 -53.5824
68 122.9856 27.95161 -0.00026 -11032.6 -22.9291
69 300.8203 52.99762 -0.00031 -21813.3 -47.8744
70 190.4845 32.63677 8.89E-05 -15424.5 -29.7722
71 10234.27 1504.962 0.000707 -499770 -1505.53
72 -227.504 -45.9361 0.001161 -14.0048 41.29972
73 -819.44 -119.161 0.000344 28660.82 121.553
74 -39.0452 4.564433 -0.00039 -3299.13 0.950989
75 -665.126 -102.348 0.000638 26912.68 100.3068
76 1584.524 226.9832 0.001385 -81397.5 -230.135
77 272.4584 41.86974 0.000143 -16726.9 -40.8576
78 -497.67 -59.4574 -1.01E-05 13511.62 67.91547
79 16.24948 0.795067 0.001086 -6567.04 -1.18323
80 -393.198 -52.7156 0.000435 9319.534 56.68642
81 -748.556 -117.737 0.001475 32874.58 113.7072
82 -1125.36 -162.534 0.000309 47632.23 164.6774
Table A5. Estimated model parameters (ai) of the Bian et al. (2011) [47] model (Eq. (27)) for the
100 drugs considered.

N° a0 a1 a2 a3 a4 a5
1 -110.177 0.000319 686.6397 -45305.3 -2.70156 87.43924
2 128.3576 -0.00305 -733.513 32386.31 9.126778 -118.398
3 394.3362 -0.00992 -2412.67 122376.6 34.94714 -261.006
4 103.1524 -0.00099 -589.268 25127.92 4.937997 -94.0379
5 -80.8891 0.00455 490.1476 -29084.9 -10.6337 65.48666
6 -55.7797 0.006652 339.1893 -17372.4 -15.6035 37.77048
7 23.4447 0.001567 -109.004 -3046.84 -1.09863 -26.7516
8 -36.8452 0.000547 232.9229 -20309 -1.22024 37.5548
9 -709.396 0.025856 4196.638 -221701 -68.7264 601.0382
10 226.1728 -9.43E-05 -1313.92 77393.86 2.586782 -235.377
11 222.3472 0.001848 -1312.32 78386.37 0.522586 -222.294
12 307.7058 -0.00332 -1852.43 107892.6 15.61683 -271.353
13 85.96546 0.001095 -509.153 28846.8 0.445814 -81.6398
14 -17.948 0.004207 108.1332 -10082.9 -6.44249 17.54353
15 38.48461 0.003301 -271.514 11729.72 -1.67961 4.225307
16 -165.847 0.003527 980.0564 -58001.9 -9.58921 153.1978
17 75.11455 -0.00357 -405.103 13025.24 9.39974 -78.9239
18 147.0099 7.54E-05 -812.097 35836.42 4.440996 -165.471
19 97.29795 0.000441 -519.489 23369.57 0.819002 -125.58
20 -143.609 0.008996 812.6351 -49853.6 -17.1478 167.2909
21 132.554 -0.00364 -705.977 21036.18 12.3576 -145.924
22 63.83044 -0.0046 -309.435 9466.104 9.773685 -94.9359
23 211.2917 0.004697 -1267.94 82089.23 -5.29468 -216.471
24 -61.0013 0.000354 390.2494 -30377.9 -1.21613 48.67058
25 17.80317 0.000642 -73.7961 -3028.49 0.18774 -30.4394
26 397.652 0.003891 -2359.17 150836.8 -3.30074 -411.355
27 185.2372 0.001243 -1101.57 64800.68 1.579424 -174.638
28 120.0024 -0.00505 -703.042 33207.75 15.14701 -106.209
29 90.97533 0.005547 -540.193 30793.39 -7.20383 -90.2857
30 77.54877 0.005564 -485.528 35191.85 -8.07865 -75.7373
31 188.9345 -0.00038 -1105.18 66792.52 2.964144 -200.907
32 80.52385 0.002964 -489.395 30282.78 -3.5833 -72.2287
33 -8.35983 0.003915 72.69395 -7366.78 -8.49935 -4.77916
34 274.8225 -0.00064 -1604.87 92339.59 5.340593 -279.715
35 159.3527 0.005394 -966.341 61976.63 -8.19259 -147.126
36 -38.2697 0.002166 261.5539 -22127.1 -3.50868 17.39778
37 -332.824 0.007465 1989.112 -125977 -19.5995 322.0476
38 194.7538 0.005654 -1175.72 77259.66 -8.52267 -190.675
39 -46.8594 0.000265 317.1835 -29100.9 -0.10626 34.79436
83 -7.45806 0.012426 7.065167 10694.4 -23.7381 -0.19143
84 94.7884 -0.00401 -565.96 22393.41 15.09433 -70.9223
85 181.9474 -0.00255 -1084.85 51094.06 14.21548 -146.856
86 174.7965 0.003493 -1044.44 61553.38 -3.22901 -159.277
87 -64.0675 0.001424 390.2459 -26280.9 -2.82028 58.86419
88 39.97556 0.000919 -215.583 8101.568 -0.38865 -47.5828
89 125.3265 -0.00288 -696.885 34193.45 6.673552 -139.247
90 2256.159 -0.06598 -13223.6 690774.5 177.9684 -2007.79
91 53.04805 0.002063 -293.097 14110.47 -2.33638 -64.7778
92 -218.86 0.012237 1276.155 -72583.2 -29.1136 219.2721
93 271.984 0.000867 -1578.34 83228.3 2.873326 -261.007
94 122.5667 -0.00344 -711.633 27978.22 9.810273 -84.2005
95 -93.0726 0.002079 526.2905 -37926.6 -2.27552 122.1091
96 121.3493 0.004802 -751.851 52437.13 -7.6694 -113.471
97 -1213.08 0.031452 6966.401 -390033 -73.7195 1266.593
98 11.23306 0.002708 -47.1602 0.243877 -5.96199 -23.2186
99 -256.705 0.003868 1542.689 -95307.6 -10.9508 233.6633
100 -69.4541 -0.00079 426.0721 -33603.3 1.693502 73.14789
40 108.2931 -46739.5 0.000628 -14.2224 5918.931
41 -170.168 46100.87 6.60E-06 26.0096 -7539.02
42 -32.1757 -2904.61 6.75E-06 6.366203 -545.789
43 29.65503 -40524.7 -2.09E-06 -0.53205 4451.258
44 -30.7269 -7733.82 -1.48E-05 7.025627 134.5854
45 27.49333 -22795.2 -2.52E-06 -0.85284 2135.052
46 704.4725 -291349 -1.72E-05 -99.3648 41019.85
47 2472.203 -807859 -2.81E-05 -351.66 114626.7
48 71.05744 -42233.4 0.000479 -7.63423 4795.812
49 -122.038 23330.79 -2.26E-06 19.91802 -4460.91
50 -322.746 101195.2 1.12E-05 46.93446 -15364.8
51 -48.3075 2042.786 2.26E-06 9.384471 -1566.68
52 94.71719 -41600 3.93E-06 -14.5306 5670.679
53 -26.4165 -433.42 -1.01E-06 4.283725 -522.06
54 128.1255 -55551.4 1.93E-05 -16.8157 7207.323
55 134.9009 -56038.8 5.29E-06 -20.5767 8058.516
56 0.708181 -25718.3 0.00029 2.803817 2530.453
57 -150.761 38838.2 8.96E-06 22.55124 -6336.47
58 -216.183 58070.34 9.92E-06 31.55997 -9015.07
59 -292.572 74264.51 4.52E-05 45.44641 -12204.7
60 -105.336 27536.68 9.00E-06 15.93466 -4568.16
61 102.9884 -51283.4 2.04E-06 -12.0819 6213.299
62 27.66025 -16697.1 3.97E-06 -3.27903 1813.606
63 105.7033 -46508.3 3.75E-06 -14.8154 6283.583
64 -152.359 36725.79 -6.59E-06 25.03734 -6490.98
65 45.6665 -26092.1 0.000858 -6.44836 3262.444
66 -18.9388 857.8394 1.15E-05 2.010372 -532.702
67 -70.7092 15462.81 1.41E-05 10.63314 -2912.97
68 -79.3377 15924.94 1.08E-06 11.61443 -2857.61
69 -138.991 33935.7 2.57E-06 22.36912 -6108.09
70 -25.447 -1433.2 7.94E-06 4.946395 -632.967
71 -684.242 212747.2 0.001641 109.722 -34796.2
72 301.3549 -101670 0.000688 -41.7889 13465.65
73 77.5364 -36646.5 1.81E-06 -8.87213 4085.072
74 -128.083 30843.44 9.99E-07 19.65627 -5209.54
75 427.9515 -141929 1.03E-08 -62.9929 20305.64
76 -55.3853 11414.44 1.20E-05 8.90361 -2466.13
77 -12.4048 -1330.94 5.82E-06 2.08194 -268.133
78 16.65913 -26417.8 -2.44E-06 0.373846 2695.519
79 0.732845 -10693.1 6.40E-06 0.808935 912.9853
80 -24.0088 -7164.44 1.83E-06 6.266406 -179.797
81 128.6553 -45810.6 1.53E-05 -20.808 6886.817
82 122.2365 -51721.7 -2.77E-06 -17.5212 6991.506
Table A7. Estimated model parameters (ai) of the Khansary et al. [53] model (Eq. (33)) for the
100 drugs considered.

N° a0 a1 a2 a3 a4
1 -7453.18 -0.1918 -0.00519 2.418639 0.028411
2 -7806.65 -0.11274 -0.00348 2.036597 0.017317
3 -3839.98 -1.34618 0.000927 1.549174 0.191537
4 -9661.08 -0.11921 -0.00609 2.858749 0.018975
5 -6575.41 -0.11455 -0.00891 1.703888 0.018488
6 -7210.16 -0.04389 -0.00224 2.031322 0.00718
7 -12471.5 -0.24045 -0.00826 4.312135 0.037269
8 -6721.11 -0.07025 -0.00418 1.304041 0.011203
9 -6926.38 -0.1351 0.013085 1.635816 0.017497
10 -7898.39 -0.10653 0.001507 2.902254 0.015066
11 -6936.29 -0.17376 -0.00534 1.75023 0.026961
12 -660.618 -0.00952 -0.00217 -1.9261 0.003385
13 -3873.92 -0.11205 -0.00823 0.353509 0.018733
14 -9273.53 -2.52436 -1.0367 2.513859 0.396032
15 -4864.76 -0.06208 -0.00549 0.288977 0.01117
16 -4628.77 -0.09529 -0.00134 -0.02615 0.014145
17 -8350.24 -0.16827 -0.00816 2.317851 0.026322
18 -19213.7 -0.55197 -0.01203 7.702708 0.083222
19 -12285.6 -0.39393 -0.01925 4.424412 0.061172
20 -17228 -0.3472 -0.00067 6.866846 0.050171
21 -16077.8 -0.55315 -0.04334 5.552751 0.0895
22 -7365.8 -0.29681 -0.00662 2.670138 0.044408
23 -4896.59 -0.20264 -0.00617 0.067627 0.03151
24 -8027.13 -0.17466 -0.00584 2.042319 0.026739
25 -10086.2 -2.64656 -0.90486 2.971013 0.407763
26 -5099.19 -0.10048 -0.00303 0.450852 0.016035
27 -4100.04 -0.08145 -0.0074 0.398158 0.014177
28 -3794.73 -0.17843 -0.03279 -0.56535 0.031979
29 -13841.3 -0.3902 -0.00963 5.149135 0.059311
30 -1529.09 -0.16135 -0.00336 -0.86504 0.025246
31 -2800.49 -0.09836 0.00279 -0.59629 0.013885
32 -3255.71 -0.06035 -0.00178 0.190646 0.009752
33 -10392.2 -0.10607 -0.00175 3.596658 0.015991
34 -6138.87 -0.12801 0.012109 1.181479 0.017148
35 -8221.78 -0.07386 -0.00062 2.483929 0.010965
36 -10931.8 -0.34124 -0.01169 3.406001 0.052592
37 -10965.7 -0.07083 -0.00719 3.524126 0.012416
38 -4345.47 -0.02254 0.000658 0.489499 0.003701
39 -11955.9 -0.27043 -0.00293 4.33922 0.039959
 83 -13950.2 -0.38724 -0.00331 5.267635 0.057001
84 -3741.39 -0.233 -0.04401 -1.41982 0.0434
85 -7369.74 -0.22036 1.03E-05 0.737624 0.035542
86 -7712.64 -0.04407 0.003635 2.596851 0.006254
87 -3817.85 -0.12099 -0.00868 0.661091 0.019756
88 -7964.61 -0.19562 -0.00642 2.190893 0.030077
89 -9283.64 -0.1339 0.013104 3.464367 0.01671
90 -5274.48 -0.09379 -0.00743 1.21543 0.015333
91 -8779.49 -0.24595 -0.0076 2.635138 0.03779
92 -14625.7 0.020204 0.00271 5.729948 -0.00376
93 -19242 -0.17677 -0.00276 7.754721 0.02637
94 -7799.98 0.163762 0.003462 2.983361 -0.02438
95 -3413.06 -0.02992 -0.00024 -0.18712 0.00495
96 -5684.7 -0.10964 0.003255 1.181685 0.015014
97 -3737.96 -0.10797 0.010626 -0.00394 0.014201
98 -8858.49 -0.08804 -0.0007 2.351833 0.013015
99 -5559.06 -0.21605 -0.01026 1.289497 0.034011
100 -5569.45 -0.09975 -0.01485 0.709641 0.017407
40 26.681737 -8431.329582 0.309567 -2.548572 0.001305
41 -41.540668 5009.122535 -13.488153 2.876752 0.005800
42 -11.923510 -1133.707285 -8.994457 0.390091 0.004788
43 -60.868645 -15147.105175 6.267602 15.100240 -0.002999
44 -33.480363 -17603.809412 17.323995 12.758922 -0.008588
45 -14.650769 -8342.472417 -0.804960 5.279131 0.000483
46 -721.533029 -24.762418 0.125780 119.060502 -0.016403
47 393.971378 -180481.043087 178.531476 17.794232 -0.075704
48 5.629806 -7904.701456 -4.794971 0.122372 0.003498
49 -53.120825 1.915699 -8.041914 7.089166 0.003100
50 -17.528449 3064.056420 -9.051807 -0.999218 0.004508
51 -22.996224 -476.033726 -11.008991 1.939566 0.005093
52 17.793663 -7653.361401 3.740973 -2.236509 -0.000382
53 -21.597484 -2616.415576 -1.382439 3.114097 0.000434
54 18.410770 -10370.056724 -0.366545 -0.090713 0.001703
55 23.574001 -6850.900313 3.869167 -3.196122 0.000066
56 -4.713503 -8114.080841 -1.782595 2.117132 0.002322
57 -23.456110 4626.948612 -12.758184 -0.484333 0.006278
58 -36.405574 -2887.963370 -2.085435 5.031425 0.001003
59 -41.507272 65.492134 -15.547304 4.110110 0.008027
60 -17.988995 4644.776271 -12.264731 -0.778326 0.005913
61 6.780389 -12489.753734 2.733130 2.771515 -0.000234
62 7.662586 -4321.182147 -1.647302 -0.927694 0.001461
63 16.122468 -8617.315111 3.819983 -0.536525 -0.000445
64 -46.941641 -2681.739203 -3.243727 8.150755 0.000523
65 1.556316 -7768.133749 2.990988 1.191657 -0.000606
66 -10.619075 -1550.797299 -3.869904 0.241727 0.001904
67 -24.436603 995.759961 -10.169591 1.646007 0.004516
68 -31.200249 -456.549384 -3.767191 3.356018 0.001501
69 -42.194124 -473.060614 -8.250455 5.575769 0.003016
70 -15.976235 -4429.663615 -2.479498 3.029461 0.001115
71 -199.184161 51390.252453 -92.283970 8.571518 0.037378
72 70.262594 -17945.455519 6.254925 -5.569643 -0.001250
73 10.043493 -12151.884006 2.966279 2.111061 -0.000835
74 -44.220254 2061.002144 -7.838834 4.815261 0.003019
75 212.949157 -15877.874534 11.523679 -31.238452 0.000759
76 -30.311452 10185.255905 -22.436755 -1.776658 0.010354
77 -8.126878 -2475.595788 -1.648597 1.153590 0.000803
78 -33.017507 -9977.529468 2.414575 8.421309 -0.000995
79 -0.893990 -1760.999116 -5.616772 -0.862830 0.003429
80 -4.767637 -8821.554317 -0.183208 3.168367 0.000639
81 7.447993 698.447094 -3.449584 -3.830978 0.002914
82 3.071186 -10253.523478 7.044097 2.191157 -0.002593