Fluid Phase Equilibria 375 (2014) 332–339

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Fluid Phase Equilibria

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

A simple correlation to predict drug solubility in supercritical

carbon dioxide
Ali Akbar Amooey ∗
Department of Chemical Engineering, University of Mazandaran, Babolsar, Iran

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

Article history: The availability of easy correlation of drug solubility in supercritical fluids without time-consuming calcu-
Received 13 March 2014 lations and difficult is crucially important for improvement of supercritical technology in pharmaceutical
Received in revised form 8 May 2014 industries. This work proposes a new correlation to predict drugs solubility in CO2 . The main advantages
Accepted 21 May 2014
are its simplicity and minimal input data, namely temperature and density. The proposed drug solubility
Available online 29 May 2014
correlation in CO2 has better performance (lower AARE%) respect to eight other empirical equations. Due
to data sets, the mean AARE for the proposed model was 6.88%.
Keywords:
© 2014 Elsevier B.V. All rights reserved.
Carbon dioxide
Drug solubility
Correlation

1. Introduction In the present work, the accuracy of a simple explicit correla-

Nowadays, supercritical fluids (SCFs) technology has wide
usages in different industrial fields such as chemical process and
processing of pharmaceuticals due to non-toxic, non-flammable
and high mass and heat transfer [1]. The solubility of drug in
SCF is significant information for designing the operating condi-
tions such as RESS (Rapid Expansion of Supercritical Solutions) [2],
SAS (Supercritical Anti-Solvent) [3], SEDS (Solution Enhanced Dis-
persion by Supercritical fluids) [4], and PGSS (Solution Enhanced
Dispersion by Supercritical fluids) [5]. However, it is necessary to
obtain reliable experimental solubility in supercritical region to
prevent disturbance to the equilibrium [6]. A correlation for esti-
mating the solubility of drugs in scCO2 would be very beneficial for
the preparatory design of related processes.
Many methods were employed to provide correlations the
experimental solid solubility in scCO2 . They are able to correlate
and predict these types of experimental data can be classified as
being either equation-of-state based correlations or density based
correlations like semi-empirical models; however, semi-empirical
models compared to equation-of-state correlations due to their rel-
ative ease of usage are often utilized and it is not needed to employ
physicochemical properties such as critical properties and subli-
mation pressure that cannot be directly obtained experimentally
and should be calculated by various methods [7].
tion using 31 previously published solubility data series of different
drugs in scCO2 were investigated. The correlation was proposed
based on temperature, density and evaluated and compared with
Chrastil [8], Sung and Shim [10], Adachi and Lu [11], Spark [12],
Gordillo [13], Mèndez-Santiago and Teja [14] and Keshmiri [15]
models by correlation of the solubility for the drugs. The results
show that the proposed drug solubility correlation works much
better than the others (lower AARE%).
2. Theoretical section
2.1. Empirical correlations
There are several correlations to predict the solid solubility in
scCO2 , such as empirical correlations. These models are density
based methods that the effects of temperature and pressure are
both considered and also indicate that there is a linear relationship
between solvent density and experimental data. The first model
that commonly used to correlate the solid solubility in scCO2 was
developed by Chrastil [8]. This equation is given as follows:
A2
ln S = A1 + + A3 ln  (1)
T

where S is the solubility (kg m−3 ) of the species in scCO2 ,  is the

solvent density (kg m−3 ), T is the temperature (K), A1 , A2 and A3 are
∗ Tel.: +98 1125342903. characteristic constants for the binary system that depend to molar
E-mail addresses: aamooey@umz.ac.ir, aliakbar amooey@yahoo.com mass of the solute.

http://dx.doi.org/10.1016/j.fluid.2014.05.025
0378-3812/© 2014 Elsevier B.V. All rights reserved.
 A.A. Amooey / Fluid Phase Equilibria 375 (2014) 332–339 333

Table 1
The reported details of solutes in supercritical CO2 .

System no. Solute Temperature (K) Pressure (bar) N Reference

1 Anastrozole 308–348 122–355 45 [16]

2 Atorvastatin 308–348 122–355 45 [1]
3 Atropine 308–348 122–355 45 [17]
4 Benzocaine 308–348 122–355 40 [18]
5 Bisacodyl 308–348 122–355 39 [19]
6 Budesonide 308–348 122–355 21 [20]
7 Clozapine 308–348 122–355 27 [21]
8 Codeine 308–348 122–355 44 [17]
9 Exemestane 308–348 122–355 45 [16]
10 Lovastatin 308–348 122–355 45 [1]
11 Medroxyprogesterone Acetate 308–348 122–355 40 [22]
12 Naproxen 308–348 122–355 58 [18]
13 Nimodipine 313–333 100–250 21 [23]
14 Nitrendipine 333–373 117–300 42 [24]
15 Flurbiprofen 308–323 89–245 27 [25]
16 Retinol 313–353 200–350 20 [26]
17 Squalane 303–328 79–275 34 [27]
18 Theophylline 313–353 199–349 24 [28]
19 Vitamin D2 (ergocalcifero) 313–353 200–300 19 [26]
20 Vitamin E (˛-Tocopherol) 313–353 199–349 24 [26]
21 Vitamin K1 313–353 200–350 24 [26]
22 Simvastatin 308–348 122–355 45 [1]
23 Fluvastatin 308–348 122–355 45 [1]
24 Rosuvastatin 308–348 122–355 45 [1]
25 Beclomethasone dipropionate 338–358 213–385 21 [20]
26 Ketoconazole 308–348 122–355 45 [29]
27 Clotrimazole 308–348 12.2–355 45 [29]
28 Cefixime trihydrate 308–328 183–335 18 [30]
29 Oxymetholone 308–328 183–335 18 [30]
30 Desoxycorticosterone acetate 308–348 122–355 45 [31]
31 Clobetasol propionate 308–348 122–355 45 [31]

Bartle et al. [9] semi-empirical model to correlate the solubility Mèndez-Santiago and Teja [14] based on dilute solutions theory,
of solute in SCF is: the following equation were introduced:
 
yP A2 T ln(yP) = A1 + A2 T + A3  (7)
ln = A1 + + A3 ( − ref ) (2)
Pref T
The last of the empirical equations to correlate solute solubility,
where Pref (1 bar) and ref (700 kg m−3 ) are reference pressure and was Keshmiri et al. model [15] with input of temperature, pres-
density, respectively. A1 , A2 and A3 are empirical constants. sure and density of pure supercritical CO2 . This equation is given as
Sung and Shim [10] proposed an equation to correlate the sol- follows:
ubility of solute in scCO2 by adding a term to Chrastil’s equation. A2 A5
ln y = A1 + + A3 P 2 + (A4 + ) ln  (8)
The resulting equation expresses in the form of following empirical T T
formula:
In all of the semi-empirical models, Ai coefficients are deter-
A2 A4 mined through data regression.
ln y = A1 + + (A3 + 2 ) ln  (3)
T T
where y is the solubility in mole fraction and  is the CO2 den- 2.2. Description of simple correlation
sity(kg m−3 ).
The next equation that is considered here was developed by Correlation of the experimental solubility data using previous
Adachi and Lu [11]. They modified Chrastil’s equation which led to equations was relatively resulted in poor outputs. So this research
the following expression: tried to present an approach to correlate solute solubility in CO2
with high accuracy compare with other empirical method using
A5 density and temperature.
ln S = A1 + (A2 + A3  + A4 2 ) ln  + (4)
T Eq. (8) presents the correlation for the estimation of solubility
The fifth equation that that is considered here was recently sug- of drug as a function of density of CO2 () and temperature (T)
gested by Spark et al. [12] based on Adachi–Lu model [11] that through multiple regression analyses. The unit of density () and
provided an improved correlation: temperature (T) are expressed in kg m−3 and Kelvin respectively.
This new correlation has nine independent variables (A1 –A9 ).
A5 A5
ln S = A1 + (A2 + A3  + A4 2 ) ln  + + 2 (5)
T T A1 + A2 / + A3 /2 + A4 ln T + A5 (ln T )2
ln y = (9)
Gordillo et al. [13] model unlike the mentioned equations (Eqs. 1 + A6 / + A7 ln T + A8 (ln T )2 + A9 (ln T )3
(1)–(5)) that do not comprise any term involving pressure, the pres- In order to evaluate the proposed correlation compare with
sure term was considered as given by following equation: other models in calculation of solubility, the available solubility
ln y = A1 + A2 P + A3 P 2 + A4 PT + A5 T + A6 T 2 (6) data of drugs in scCO2 had been collected from the literatures and
each model was used to them. Table 1 shows 31 binary solute scCO2
where P is the pressure (bar), y is the mole fraction of solute and T systems also the experimental temperature and pressure ranges
is the temperature (K). and data sources. The arithmetic average of the absolute values of
 334
Table 2a
Ai coefficients for 25 data by Chrastil et al., Sung and Shim and Adachi and Lu models.

Sys. no. Chrastil et al. Sung and Shim Adachi and Lu

A1 A2 A3 A1 A2 A3 A4 A1 A2 A3 A4 A5

1 −18.5 −8878.8 5.4 58.7 −35,071.9 −6.1 3897.5 24.2 −2.7 3.2E−03 −1.2E−06 −9162.7
2 −35.9 −10,312.9 8.8 23.03 −30,340.9 4.6 486,432.5 26.1 −2.8 4E−03 −1.5E−06 −10,840.7
3 −8.2 −7328.6 3.4 −55.9 8899.1 6.8 −394,132.1 1.1 1.9 2.5E−04 7.1E−08 −7610.9
4 −13.2 −5860.5 3.8 −18.1 −5242.8 4.3 −107.3 −5.4 2.1 8.8E−04 4.4E−07 5772.3

A.A. Amooey / Fluid Phase Equilibria 375 (2014) 332–339

5 −28.3 −5777.2 5.6 −17.3 −9474.5 4.7 90,212.1 54.2 −9.8 5.5E−03 1.9E−06 6275.3
6 −31.6 −5467.5 5.4 34.3 −28,577.2 0.5 604,651.7 320.8 −60.07 2.2E−02 7.4E−06 −5643.7
7 −18.5 −5077.3 3.4 −117.2 28,676.9 10.5 −837,656.2 13.6 −2.2 1.6E−03 −2.4E−07 −5776.7
8 −16.7 −4854.9 3.5 20.6 −17,562.4 0.86 308,636.2 −13 3.6 −1.2E−03 1.03E−06 −5640.4
9 −13.7 −11,550.8 6.1 58.9 −36,191.5 −4.7 3666.5 27.3 −1.4 2.6E−03 −7.7E−07 −12,066.7
10 −15.5 −3800.4 2.6 −14.3 −3762.9 2.4 −5119.04 5.9 −1.85 2.3E0−3 −1.1E−06 −3593.9
11 −23.2 −4018.2 4 57.3 −31,383.4 −1.8 665,678 −3.2 1.3 −5.2E−04 9.5E−07 −5176.7
12 −14 −5179.1 2.9 23.5 −17,958.7 0.3 310,872.5 −6.3 2.2 7.6E−04 7.7E−07 −5898.3
13 −16.9 −6586.5 3.7 −87.1 16,476.4 9.2 −563,283 −37.9 8.3 2.3E−03 1.1E−06 −6726.7
14 −15.4 −4970.5 3.3 13.3 −15,155.7 1.1 281,136.2 −12.6 3 −8.7E−05 2.1E−07 −5190
15 −22.1 −7948.3 5.7 86.7 −42,304.5 −2.3 800,595.8 171.7 −30.3 1.2E−02 4.2E−06 −8333.4
16 −35.4 −3109.6 5.1 −6.1 −13,072 3 246,161.3 313.9 −59.7 2.2E−02 −7.6E−06 −3877.1
17 −28.5 −4416.7 5.4 −10.5 −10,091 4.1 134,312.2 42.6 −8.3 5.9E−03 −2.4E−06 −4535.8
18 −13.7 −3338.9 1.9 −18.7 −1583.9 2.2 −42,925.2 −18.8 2.8 −1.7E−04 8.6E−09 −3292.7
19 −27.1 −4982.9 5.2 34 −26,665.6 1 528,270.3 −192.5 36.9 −1.2E−02 5E−06 −5127.1
20 −46 −4845.3 8.1 −70.7 3818.8 9.8 −211800.1 105.6 −19.5 8.5E−03 −2.6E−06 −5375.1
21 −50.7 −3893.2 8.4 −30.3 −11,057.7 6.9 175,214.1 −254 47.1 −1.5E−02 5.7E−06 −4010.2
22 −35.5 −6204 6.8 5.8 −20,237.1 3.8 340,829 46.4 −8.9 6.6E−03 −2.6E−06 −6513.9
23 −24.8 −7519.1 5.7 10 −19,367.3 3.3 287,764.1 47.1 −7.8 5.3E−03 −2E−06 −8015.1
24 −27.7 −5823.9 5.4 7.7 −17,888.5 2.8 293,019.2 39.2 −7.5 5.6E−03 −2.3E−06 5990.1
25 −29 −5162.2 4.9 46.5 −31,648.5 −0.7 692,999.9 349.1 65.7 2.4E−02 8.6E−06 −5284.1
26 −58.69 8.636 −11,971 −104.27 1.0811E+004 14.0519 −5.33E+5 354 67 2.3E−9 6.7E−5 −3425
27 −62.90 8.046 −7967.2 −42.1643 −7.2337E+003 8.0311 −2.0079E+003 45.4548 −1.5004 −2.3985E+003 3.2894E+005 −7.5436E+003
28 −13.16 0.762 −3047 −9.1921 −3.1818E+003 0.5112 7.4486E+003 42.106 −3.718 −1.4450E+003 2.4936E+005 −2.9663E+003
29 −30.56 3.229 −3270 −85.9406 1.4969E+004 7.7447 −4.3826E+005 15.6302 0.0105 −588.9164 1.6706E+004 −3.6348E+003
30 −55.74 6.46318 −4991.1 −35.8744 −5.4362E+003 6.1588 2.2318E+004 −0.2147 3.1105 −1.1157E+003 1.7557E+005 −4.6476E+003
31 −62.68 6.88648 −5264.3 −69.2055 4.2501E+003 8.3508 −2.1176E+005 −15.4851 4.5081 −657.1181 5.8776E+004 −4.7076E+003
Table 2b
Ai coefficients for 25 data sets by Spark et al. and Gordillo et al.

Sys. no. Spark et al. Gordillo et al.

A1 A2 A3 A4 A5 A6 A1 A2 A3 A4 A5 A6

1 62.3 −3.1 3.5E−03 −1.3E−06 −32,846.2 3,876,356 −11.5 −6.8E−02 −6.4E−05 3.3E−04 1.7E0−2 −9.5E−05
2 13.7 −0.5 3.7E−03 −1.3E−06 −10,841.4 65,463.8 −30.4 −0.1 1E−04 5.2E−04 0.17 −4.3E−04
3 −84 2.9 −4.3E−4 4.5E−07 44,992.9 −8,610,210 −109 −0.04 −3.3E−05 2.1E−04 0.6 −9.4E−04
4 14.7 1.91E−03 −5.2E−07 −18,362.2 2,060,590.6 −16.1 −0.08 −3.8E−5 3.3E−04 0.09 −2.3E−04 24.2

A.A. Amooey / Fluid Phase Equilibria 375 (2014) 332–339

5 74.3 −11 6E−03 −2.1E−06 −16,159.7 1,617,599.9 2.25 −0.07 −4.5E−05 3.3E−04 −0.03 −6E−05
6 331 −60 2.2E−02 −7.4E−06 −13,146.5 1,304,413.1 15.7 −0.04 1.3E−05 1.3E−04 −0.13 1.6E−04
7 −110 −2.5 1.7E−03 −2.7E−07 77,610.5 −1.4E+07 −107 −0.08 −2.1E−05 3E−04 0.61 −1E−03
8 −18.4 3.7 −1.3E−3 1E−06 −2239.6 −556,645.8 −16.6 −0.03 −3.3E−05 1.8E−04 0.06 −1.3E−04
9 −81.7 −0.2 1.7E−03 −3E−07 55,697.5 −1.1E+07 −155 −0.04 −7.5E−05 2.8E−04 0.86 −1.3E−03
10 1.66 −1.8 2.3E−03 −1.1E−06 −949.9 −432,744.4 −34.8 −0.04 −3.3E−05 1.8E−04 0.16 −3E−04
11 1.7 1.25 −5E−04 9.3E−07 8590.6 1,405,643.3 11.2 −0.04 −2.5E−05 2E−04 −0.1 9.2E−05
12 2.6 2.15 −7E−04 7.4E−07 −11,489.9 915,185.8 −4.7 −0.05 −1.3E−05 1.9E−04 −0.02 4.3E−06
13 −29.9 8.3 −2.3E−3 1.1E−06 −11,981.8 847,883.7 22.9 −0.2 −1.6E−04 8.9E−04 −0.1 −7E−05
14 58.3 2.16 4.4E−04 −1.1E−07 −52,535 8,334,735.8 76.9 −0.02 −8.6E−05 2E−04 −0.4 6.4E−04
15 122.4 −32 0.012 −4.3E−06 27,285.1 −5,568,631 −53.7 −0.09 −7.9E−05 4E−04 0.3 −5.5E−04
16 352.5 −75 0.03 −9.1E−06 26,174.5 −5,055,526 −39.2 −1.9E−03 −2.8E−05 7.4E−05 0.17 −3E−04
17 50.4 −8.3 6E−03 −2.4E−06 −9313.7 752,921.2 111.8 −0.17 −1.4E−04 7.7E−04 −0.63 7.5E−04
18 −14.6 2.2 6.2E−05 −8.4E−08 −4087 132,096.7 −27.7 −0.02 7.9E−06 7.4E−05 0.1 −1.5E−04
19 85.7 −3.1 4E−03 −1.8E−06 −51,991.6 7,769,482.8 35.6 −0.06 −3.9E−05 2.6E−04 −0.23 2.7E−04
20 −180 19.9 −7.5E−3 3.8E−06 48,118.2 −8,893,613 −88 4.4E−03 −4.3E−05 8.9E−05 −0.48 −7.7E−04
21 −248 46.3 −0.014 5.6E−06 −5095.8 180,552.6 −15 −0.03 −4.1E−05 2E−04 0.085 −2.3E−04
22 55.9 −9.0 6.7E−03 2.7E−06 −12,408.2 964,745.1 −13.9 −0.09 −7.6E−05 4.3E−04 0.087 −3E−04
23 45.7 −7.8 5.3E−03 −2E−06 −7121.7 −146,209.8 −26.4 −0.08 −5.3E−05 3.7E−04 0.14 −3.2E−04
24 55.8 −7.8 5.7E−03 −2.3E−06 −16,330.4 1,692,425.3 12.05 −0.07 −6.4E−05 3.5E−04 0.052 −2E−04
25 408.5 −66 0.024 −8.7E−06 −46,930.8 7,240,589.7 59.9 −0.04 9.4E−06 1.4E−04 −0.39 5.2E−04
26 39.5 −49.6 0.034 −8.9E−06 −7543 765,321 47.6722 −651.0995 −173.4861 1.93E+005 −2.33E+004 1.6709E+6
27 28.16 −34.9 0.024 −8.9E−06 −9876 7779 20.0318 −676.9790 −565.0825 2.1634E+005 −8.3629E+003 −3.7492E+005
28 23.6402 −1.4962 −806.67 1.36E+005 −1.94E+003 −1.46E+005 −2.5146 −4.9228 38.4412 −1.0849E+003 −5.4429E+003 4.63E+005
29 −12.2061 3.8234 163.8081 −7.16E+004 −5.58E+003 3.17E+005 −8.3084 −368.2482 3.1549 1.0850E+005 1.9681E+003 −1.31E+006
30 −29.8053 7.2619 −334.3181 9.31E+004 −5.4917E+003 1.0987E+005 75.4775 −604.6209 −223.5521 1.8664E+005 −4.7043E+004 6.42E+006
31 −32.4767 6.7452 −176.596 −3.7467E+003 −5.5762E+003 1.4201E+005 −33.9603 −542.3691 218.4880 1.53E+005 2.16E+004 −4.61E+006

335
 336
Table 2c
Ai coefficients for 25 data sets by Kishmiri models and Mèndez-Santiago and Teja models.

Sys. no. Kishmiri et al. Mèndez-Santiago-Teja Bartle et al.

A1 A2 A3 A4 A5 A1 A2 A3 A1 A2 A3

1 58.81 −35,088.1 −0.706 −6.13 3900.9 30.5 −14,480.9 3.9 28.9416 −1.12E+004 0.0115
2 22.47 −28,999.6 −96.89 −0.5164 2889.005 37.1 −17,841.3 5.8 35.54 0.0173 −13,250
3 −219.27 70,553.34 −319.67 33.92 −11,233.9 26.8 −11,796.1 2.8 28.096 −1.03E+004 0.0092
4 −76.07 15,764.57 −15.53 13.10 −3205.2 −10,424.9 2.9 3 23.7954 −8.22E+003 0.0094

A.A. Amooey / Fluid Phase Equilibria 375 (2014) 332–339

5 −107.58 23,176.97 0.0038 16.32 −4133.9 21.5 −11,250.4 3.8 21.37 −8.53E+003 0.013
6 −403.14 153,313.6 −1387.66 58.45 −22,645.9 15.5 −10,222.1 3.8 16.8912 −8.1E+003 0.0123
7 −608.07 211,970.5 −870.08 89.34 −31,549.4 16.2 −9550.4 2.9 19.1352 −8.81E+003 0.0126
8 −148.17 46,913.74 −366.44 22.06 −7296.17 19.6 −9576.6 3 17.8761 −7.76E+003 0.0103
9 −115.24 29,252.36 −323.93 20.28 −5711.41 40.3 −17,594.1 4.3 38.6950 −1.40E+004 0.0126
10 −3.82 −9869.33 66.66 0.691 828.8 13.5 −7712.7 2.3 13.48 0.0073 −6074
11 −47.96 10,646.56 −324.74 6.703 −1808.94 16.5 −9155.1 3.2 18.6773 −7.67E+003 0.0129
12 −89.33 25,154.13 −247.41 13.46 −4234.06 18.3 −9595.7 2.6 18.7051 −7.93E+003 0.0094
13 −181.76 42,293.36 −100.38 28.51 −8293.93 21.8 −11,171.1 3 52.7106 1.4444E+004 −0.0027
14 −139.20 41,392.72 −281.73 17.42 −4621.91 16.6 −8809.9 3.2 14.94 −6.79E+003 0.009
15 −188.59 58,979.66 −325.33 27.33 −8903.62 30.4 −13,800.8 3.7 33.49 −1.08E+004 0.0131
16 −112.85 36,806.36 −504.56 16.10 −5444.31 11.3 −8353.4 3.6 14.9033 −5.44E+003 0.0117
17 86.02 −44,251.61 241.73 −58.16 4371.62 21.3 169.8 3.6 20.93 −7.24E+003 0.0117
18 −78.53 19,682.36 −185.23 38.17 −5291.45 10.7 −7052.9 2.1 14.78 −5.38E+003 0.0062
19 202.55 −93,624.7 393.65 −27.89 12,756.79 20 −10,210.2 3.7 17.5608 −6.80E+003 0.0107
20 −129.01 40,674.7 −476.71 18.51 −6037.03 21.4 −11,384.3 5.0 15.2743 −5.68E+003 0.0122
21 −2.5 −20,042.3 −22.95 1.12 2412.50 18.3 −10,472 5.1 16.77 −6.35E+003 0.0153
22 −0.026 −16,719 −77.54 1.306 1651.34 23.6 −12,624.1 4.7 22.60 0.0143 −9013
23 −45.308 2590.208 −161.29 8.373 −1324.16 27.2 −13,434.2 4.1 −14,630 0.2023 27.478
24 34.36 −26,924.1 0.677 −3.85 3139.24 21.3 −11,424.2 3.9 −10,943 0.1640 17.89
25 −302.05 111,924.7 −1039.08 43.84 −16,685 14.7 −9710.4 3.5 15.6105 −7.60E+003 0.0114
26 −59.1559 −1.50E+3 −61.0167 12.1384 −1.36E+3 −17,406 0.2182 33.5 39.74 0.01542 −15,150
27 −49.9106 −3.2440E+003 −50.2886 9.1323 −577.7495 −13,484 0.2102 24.23 28.16 6.72 −34.9
28 −8.8950 −990.08 −44.7968 1.0034 −253.25 −6365 0.07 3.86 5.431 0.005 −4952
29 −31.2332 −5.8071E+003 103.1530 4.5821 128.2976 −7495 0.12 10.9 12.81 0.008 −5463
30 −19.5616 −1.2031E+004 36.8869 3.6802 1.0634E+003 −11,466 0.1424 17.256 20.13 0.01258 −7675.5
31 −25.2806 −1.1432E+004 31.9160 4.1068 933.6065 −11.580 −11,580 17.506 16.83 0.01288 −7799.9
Table 3
Different parameters for data sets produced by proposed model.

Sys. no. A1 A2 A3 A4 A5 A6 A7 A8 A9

1 −1.706E+14 −2.5866E+16 2.7418E+18 −1.8248E+13 8.2858E+12 5.9740E+14 3.7143E+12 −1.0671E+12 8.3746E+10

2 −3.3102E+14 −6.4417E+16 7.1764E+18 3.1613E+12 1.0206E+13 1.0430E+15 −1.8631E+11 −2.7544E+11 7.0132E+10
3 −1.1143E+9 −2.4884E+11 1.7141E+13 4.6775E+7 2.7172E+7 1.3318E+10 −1.2458E+7 −1.5199E+6 6.9032E+5
4 −2.8997E+3 −1.4862E+5 −7.2411E+6 184.763 56.7371 1.7868E+4 31.2729 2.713 −1.4129
−1.4368E+15 −2.6849E+17 −2.5075E+14 −1.1746E+12

A.A. Amooey / Fluid Phase Equilibria 375 (2014) 332–339

5 4.2175E+19 8.8753E+13 5.0107E+15 6.4956E+12 6.1041E+12
6 1.9919E+015 1.3923E+018 −1.8257E+020 1.2871E+015 −3.1231E+014 −6.6176E+016 9.0054E+013 −5.4403E+013 6.9521E+012
7 −1.5078E+10 −1.0497E+12 6.1956E+13 1.2035E+09 2.4938E+08 4.7541E+10 8.3282E+08 −2.4675E+08 1.7899E+07
8 −1.2937E+12 −5.1442E+14 5.4802E+16 1.4079E+11 1.5917E+10 1.6091E+13 −1.9760E+10 −4.0816E+9 1.5143E+9
9 −3.9577E+12 −4.9565E+15 4.3889E+17 8.0566E+11 3.6744E+10 1.4914E+14 −7.8200E+11 −9.7102E+9 2.6289E+10
10 3.9375E+15 −4.3049E+18 1.0816E+18 −6.2359E+15 8.3984E+14 2.4685E+17 −2.2720E+14 7.3907E+12 8.8221E+12
11 −5.6632E+20 −3.5727E+23 1.1211E+25 1.0577E+20 7.3030E+18 2.6370E+22 2.1944E+18 −3.3251E+18 4.1759E+17
12 −5.6661E+07 −3.2522E+10 1.4417E+12 −8.6030E+06 3.6518E+06 2.0012E+09 1.7262E+05 −2.1737E+05 3.0998E+04
13 1.4974E+19 −6.8671E+24 −3.0339E+26 −7.3057E+20 8.0609E+19 4.3197E+23 −6.0817E+19 −2.4967E+20 4.7340E+19
14 −2.0145E+1 −1.0506E+21 1.3144E+23 −7.2756E+16 5.5493E+17 −4.3132E+18 1.7511E+17 3.4411E+15 −4.2825E+15
15 −3.58E+27 −1.63E+30 4.020E+32 7.3152E+26 −7.4853E+24 2.6729E+27 −9.4160E+25 2.8415E+23 3.3692E+24
16 6.3804E+13 −1.1008E+16 −6.4145E+15 −6.3997E+12 −6.0390E+11 8.1825E+14 −2.7457E+12 1.7977E+11 5.1743E+10
17 9.5334E+12 −4.2697E+15 2.2416E+15 −1.4292E+12 1.4297E+10 2.4416E+14 5.6879E+11 −4.4517E+11 6.1671E+10
18 −8.7285E+10 −3.3641E+14 6.5639E+15 −2.5635E+11 4.4773E+10 2.4274E+13 −5.5615E+9 7.5650E+8 1.0162E+8
19 6.7549E+003 1.1177E+006 2.4012E+009 −2.3921E+003 −78.5042 −1.3038E+006 −324.2038 18.0988 17.9877
20 −9.0934E+27 −4.8461E+30 1.9232E+33 7.2744E+26 1.4659E+26 −4.1533E+29 −1.8011E+26 5.3024E+25 1.3408E+24
21 −2.8902E+12 −3.1957E+15 9.6657E+17 9.6723E+11 −5.3960E+10 −1.4949E+14 −1.9128E+11 2.8969E+10 2.9086E+9
22 −1.3033E+22 −3.6911E+24 4.9154E+26 1.7605E+19 4.0836E+20 3.7943E+22 −2.8712E+19 −7.4902E+18 3.6820E+18
23 −1.3062E+8 −5.5816E+10 3.3618E+12 −6.6519E+7 1.6256E+7 2.6116E+9 2.6554E+6 −4.1563E+5 −4.4919E+3
24 −2.7638E+9 −3.7967E+12 4.5035E+14 4.8973E+8 2.2284E+6 6.1832E+10 2.3616E+7 −1.1081E+8 2.0135E+7
25 9.6541E+7 −1.9659E+11 1.3628E+13 −6.3840E+7 1.3298E+7 1.2345E+10 −9.0143E+6 2.3408E+6 −1.9277E+5
26 7.8686E+007 1.5248E+010 −2.3439E+012 −9.1325E+006 −8.6058E+005 −9.7478E+007 1.0137E+006 −1.0753E+005 −1.7016E+004
27 −8.9525E+021 −1.7668E+024 2.1018E+026 −8.2019E+020 1.3051E+020 1.9138E+022 −8.4717E+018 −6.6347E+018 2.0984E+018
28 −1.1790E+006 −5.5810E+006 9.2470E+009 −1.1140E+006 2.2508E+005 −1.5034E+006 −3.3536E+005 1.3324E+005 −1.2973E+004
29 −6.9210E+010 −3.6201E+013 −2.8044E+015 −3.5000E+010 8.4460E+009 2.2538E+012 1.2023E+009 −1.3728E+008 −1.4053E+007
30 2.0441E+005 4.0957E+007 −4.0195E+009 −1.8768E+004 −2.9582E+003 −8.8728E+005 −571.3967 23.5570 −2.8110
31 −7.66E+018 −1.5307E+021 7.3856E+022 6.5878E+017 1.4602E+017 7.5001E+019 4.9661E+016 −1.11E+015 −1.48E+015

337
338 A.A. Amooey / Fluid Phase Equilibria 375 (2014) 332–339

Table 4
AARE (%) for 31 experimental data sets produced by various equations.

Sys. no. Proposed model K. Keshmiri et al. Chrastil et al. Sung and Shim Adachi and Lu Spark et al. Gordillo et al. Mèndez-Santiago and Teja Bartle et al.

1 6.92 9.72 11.06 10.54 17.68 17.31 34.34 6.98 7.019

2 4.13 10.14 12.09 11.23 19.80 6.01 28.53 8.54 3.6
3 12.97 16.08 18.90 17.35 17.75 17.31 28.50 19.90 17.06
4 6.29 11.41 11.81 12.20 11.75 11.24 20.53 13.09 12.15
5 6.07 11.03 15.97 15.57 14.53 16.32 11.60 13.93 9.21
6 6.61 12.82 13.12 12.79 9.97 10.47 88.54 12.78 10.83
7 10.27 19.60 28.27 30.19 24.36 77.07 61.91 25.54 19.79
8 10.08 12.96 17.93 16.26 12.68 12.91 32.83 16.43 12.77
9 8.30 16.01 22.64 22.23 18.32 10.73 36.01 21.70 19.89
10 4.58 4.89 5.34 5.27 7.55 3.92 20.20 5.52 5.4
11 10.67 15.35 25.58 22.45 10.33 9.36 5.34 22.19 16.42
12 13.01 16.69 20.62 19.20 14.23 14.43 12.05 19.78 18.66
13 3.92 6.3 9.03 8.6 9.64 9.66 40.01 12.51 16.8
14 12.02 10.81 15.18 14.09 14.04 12.00 16.35 16.91 10.97
15 6.09 8.95 11.41 9.33 12.97 20.30 13.62 14.12 12.08
16 6.30 6.06 8.94 8.55 14.62 10.37 14.34 8.63 8.58
17 5.47 7.60 6.84 6.86 5.02 3.36 31.88 5.71 6.48
18 4.92 5.89 5.33 5.34 5.21 5.35 70.41 5.69 5.46
19 3.92 7.28 9.60 6.21 25.21 16.14 4.82 7.81 8.44
20 1.82 4.93 14.43 14.06 14.14 7.41 22.37 14.95 4.23
21 4.08 4.31 5.03 4.48 3.74 4.63 31.92 4.91 4.85
22 6.24 11.42 11.75 20.24 9.31 17.98 43.18 9.10 7.0
23 3.26 14.34 27.85 15.32 13.92 15.83 23.77 11.52 12.8
24 5.73 9.87 8.62 9.23 12.23 18.41 39.32 5.16 7.4
25 8.31 11.46 11.95 11.57 14.41 17.72 8.21 11.81 10.6
26 7.76 10.37 15.8 6.26 8.84 6.3 17.42 11.5 6.2
27 4.16 6.4 9.8 4.27 5.38 4.5 9.49 4.9 4.5
28 1.29 2.17 2.56 2.24 2.13 2.13 2.12 3.56 3.73
29 2.71 2.92 5.94 3.06 3.53 3.47 5.23 6.28 5.86
30 7.76 9.61 9.3 9.97 8.95 8.48 9.85 13.4 8.9
31 10.57 12.98 13.6 14.08 13.59 13.46 11.47 10.4 11.9

Mean 6.65 10.01 13.10 11.90 12.12 13.05 25.62 11.78 9.98

the relative errors (AARE) was determined to provide an indication
of the accuracy of the correlation. The AARE can be written as:
 
100   yexp − ycal 
N
AARE% =  yexp 
N Sung and Shim 9%, Adachi and Lu 12%, Spark et al., 19.3%, Gordillo
i=1
In this equation, N is the number of data points, yexp is the
experimental solubility of the drug solute and ycal is the calculated
solubility.
3. Results and discussion
Modeling of drug solubility due to the experimental limitations
is necessary. The constants and AAREs of different mentioned mod-
els should be calculated by least squares approach. Then different
coefficients (Ai ) for Chrastil et al., Sung and Shim and Adachi and Lu
were shown in Table 2a, for Spark et al. and Gordillo et al. were rep-
resented in Table 2b and Keshmiri et al., Mèndez-Santiago and Teja
and Bartle et al. were represented in Table 2c. Parameters (A1 –A9 )
for 31 published data sets produced by the suggested model have
been illustrated in Table 3. Table 4 represents AAREs for all data
10% (Keshmiri et al. with 10.01% and Bartle et al., 9.98%). In the
new proposed model 35.3% of 31 compounds have AARE under 5%
whereas this value for the same amount of compounds in the other
models are as follows: K. Keshmiri et al., 16.1%, Chrastil et al., 6%,
(10)
et al., 3.2%, Mèndez-Santiago and Teja 9.6% and Bartle 16.2%.
For consistency of the proposed model, solubility data of Cloza-
pine in CO2 was selected and the corresponding experimental and
predicted solubility of carbon dioxide at constant temperatures and
different density are presented in Fig. 1. As this figure shows that
the proposed model has good agreements with the data and the
trend of the curves.
5.05
T=308 K
4.05 T=318 K
T=328 K
10 y

3.05 T=338 K
5

sets produced by proposed model and eight empirical correlations.

Results disclosed that the suggested model was more accurate com- T=348 K

pared with previous published empirical equations. 2.05

The mean AARE% values for Chrastil, Sung and Shim, Adachi and
Lu, Spark, Gordillo and Mèndez-Santiago, Teja, Keshmiri and Bartle
models were 13.97, 13.16, 13.33, 14.64, 29.62, 12.64, 10.64 and 9.98 1.05

respectively. Whereas the mean AARE% values for suggested model

is 6.88.
0.05
It is important to notice that in Table 4, for 18 compounds from 300 400 500 600 700 800 900 1000
the total 31, Gordillo’s model provides the worst fit. Sung and 3
ρ(kg/m )
Shim and Mèndez-Santiago and Teja equations provided similar
results in terms of AARE. Two models provided an AARE around Fig. 1. Solubility of clozapine in CO2 at different density and temperatures.
 A.A. Amooey / Fluid Phase Equilibria 375 (2014) 332–339
4. Conclusion
In the present work, a new correlation based on density and
temperature was suggested and its accuracy was compared with
other commonly used semi-empirical correlations using 31 pub-
lished solubility data sets. The proposed correlation has generally
resulted in minimum values of AARE% respect to other model with
respect to temperature, and density of CO2 . The main advantage of
using this correlation is that it does not need to complicated com-
putations. The predictions showed excellent agreement with those
reported in the literature.
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