These are not the final page numbers!

((
Research Article 1

Tippana Ashok Reddy

Dimensionless Empirical Model to Correlate
Chandrasekhar Garlapati*
Pharmaceutical Compound Solubility in
Supercritical Carbon Dioxide
The accurate experimental determination of pharmaceutical compound solubil-
ities at various temperature and pressure ranges in supercritical carbon dioxide
(ScCO2) is a challenging and time-consuming task. Therefore, prediction or corre-
lations of solute solubilities are essential for implementation of ScCO2 technolo-
gies to pharmaceutical industries. Solubilities of 41 pharmaceutical compounds in
ScCO2 are correlated by an empirical model, which is developed based on the
degree of freedom analysis. Its correlating ability is compared with existing solu-
bility models elaborated by other authors and evaluated in terms of global mean
absolute relative deviation, sum of squares due to error, root mean square devia-
tion, R2, and Adj. R2. The proposed model is found to correlate better than
existing models.

Keywords: Degrees of freedom, Empirical models, Solubility, Supercritical carbon dioxide

Received: May 21, 2019; revised: June 29, 2019; accepted: September 06, 2019
Supporting Information
available online DOI: 10.1002/ceat.201900283

1 Introduction models. The EOS approach requires an acentric factor, molar

The application of supercritical fluids in the field of pharma-
ceutical industry is growing rapidly. Unit operations such as
extraction, crystallization, and reaction depend on the solute
solubility in the solvent. Supercritical technology combines two
or more unit operations into a single unit operation [1, 2]. CO2
in its supercritical state effectively replaces the conventional
organic solvents. CO2 is attractive because of its nontoxic, non-
flammable chemical nature and tunable density along with an
easily attainable critical temperature (Tc1) = 304.12 K) and
moderate critical pressure (pc = 7.39 MPa) [1, 2].
Supercritical CO2 (ScCO2) is widely applied in the extraction
of heat-sensitive chemicals from natural products [1]. Proper
implementation of this ScCO2 technology in industries requires
reliable solubility data and there is great need to develop mod-
els for prediction of solubility data at desired temperatures and
pressures. The present study aims to develop a simple empiri-
cal model that gives more accurate information about the solu-
bility data.
2 Existing Solubility Models
In the last three decades, several methodologies have been
developed to correlate the solubility data. These methodologies
can be broadly categorized into equation-of-state (EOS) mod-
els, empirical and semi-empirical models, and computational
– Pondicherry University, Pondicherry Engineering College, Depart-
1) List of symbols at the end of the paper.
volumes, and vapor pressure data of the solids [3]. Experimen-
tal critical and physicochemical properties are rarely available
for complex solutes; in such case, group contribution methods
are required for their estimation. Hence, the application of
EOS models to predict solubility data is a tedious task and can
only be applied to solids with known properties.
New approaches in computational methodology like artificial
neural networks [4–7] and support vector [8, 9] are able to pre-
dict the solubility data with highest accuracy. But to train these
models, huge amounts of accurate experimental information is
required, which are scarcely available for all temperature and
pressure ranges. Similarly, pure-component properties for
complex multifunctional solid solutes, such as pharmaceuticals,
are not always available and need to be estimated by group
contribution methods [10]. However, using minimal known
properties of solutes, empirical and semi-empirical models are
successful in estimating solubility data with high efficacy [11].
Empirical models are very simple in application and the solu-
bility of a single solute depends on density, pressure, and tem-
perature of the supercritical solvent only. Hence, these models
are suitable to calculate solubility data for a broad range of
pharmaceutical compounds. In this work, 24 commonly used
empirical solubility models are considered and the respective
mathematical formulas are given in Tab. 1.
–
Tippana Ashok Reddy, Prof. Chandrasekhar Garlapati
chandrasekar@pec.edu, venimahesh@rediffmail.com
ment of Chemical Engineering, Puducherry, 605014, India.

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Research Article 2

Table 1. Name, mathematical formula, and literature source of solubility models. Ai–Ji are model constants.

Model Mathematical formula

Chrastil [12] B1
lnS2 ¼ A1 þ þ C1 lnrSCF (1)
T
Adachi, Lu [13]   E
lnS2 ¼ A2 þ B2 þ C2 lnrSCF þ D2 lnr2SCF lnrSCF þ 2 (2)
T
del Valle, Aguilera [14] B3 D3
lnS2 ¼ A3 þ þ C3 lnrSCF þ 2 (3)
T T
Kumar, Johnston [15] C4
lny2 ¼ A4 þ B4 rSCF þ (4)
T
 
Bartle et al. [16] y p C
ln 2 ¼ A5 þ B5 ðrSCF  rref Þ þ 5 (5)
pref T
Mitra, Wilson [17] p
lnS2 ¼ A6 lnp þ B6 T þ C6 pT þ D6 þ E6 (6)
T
Yu et al. [18] y2 ¼ A7 þ B7 p þ C7 p2 þ D7 pT ð1  y2 Þ þ E7 T þ F7 T 2 (7)
Gordillo et al. [19] lny2 ¼ A8 þ B8 p þ C8 p2 þ D8 pT þ E8 T þ F8 T 2 (8)
Méndez-Santiago, Teja [20] T lnðy2 pÞ ¼ A9 þ B9 rSCF þ C9 T (9)
 
Sung, Shim [21] B C
lny2 ¼ A10 þ 10 lnrSCF þ 10 þ D10 (10)
T T
Jouyban et al. [22] T
lny2 ¼ A11 þ B11 p þ C11 p2 þ D11 pT þ E11 þ F11 lnrSCF (11)
p
 
Sparks et al. [23]a),b) ðA12 þB12 rr;SCF þC12 r2r;SCF Þ E F
S2 * ¼ rr;SCF exp D12 þ 12 þ 122 (12)
Tr Tr
Garlapati, Madras [24] D13
lny2 ¼ A13 þ ðB13 þ C13 rSCF Þ lnrSCF þ þ E13 lnrSCF T (13)
T
 
Bian et al. [25] ðA þB r þC =lnTÞ D þ E14 rSCF
S2 ¼ rSCF14 14 SCF 14 exp 14 þ F14 (14)
T
Jafari et al. [26] lny2 ¼ A15 þ B15 p2 þ C15 T 2 þ D15 lnrSCF (15)
 
Haghbakhsh et al. [7] A16 þ B16 p þ C16 rSCF þ D16 p2 þ E16 r2SCF þ F16 prSCF
y2 ¼ 105 · 3 3 2 2 (16)
þG16 p þ H16 rSCF þ I16 prSCF þ J16 p rSCF
 
Keshmiri et al. [27] B E
lny2 ¼ A17 þ 17 þ C17 p2 þ D17 þ 17 lnrSCF (17)
T T
Hozhabr et al. [28] B18 r
lny2 ¼ A18 þ þ C18 SCF  D18 lnp (18)
T T
Khansary et al. [29] A19 p2
lny2 ¼ þ B19 p þ C19 þ ðD19 þ E19 pÞ lnrSCF (19)
T T
Bian et al. [30] B20 C20 rSCF
lny2 ¼ A20 þ þ þ ðD20 þ E20 rSCF Þ lnrSCF (20)
T T
Andonova, Garlapati [31] y2 ¼ A21 rBr;SCF
21
TrC21 (21)

Si-Moussa et al. [32] T

lny2 ¼ A22 þ B22 rSCF þ C22 r2SCF þ D22 rSCF T þ E22 þ F22 lnrSCF (22)
rSCF
Reddy et al. [33] y2 ¼ ðA23 þ B23 pr ÞTr2 þ ðC23 þ D23 pr ÞTr þ E23 (23)
Belghait et al. [34] H
lny2 ¼ A24 þ B24 rSCF þ C24 r2SCF þ D24 rSCF T þ E24 T þ F24 T 2 þ G24 lnrSCF þ 24 (24)
T
S2 b) r
a)
S2 * ¼ ; rr;SCF ¼ SCF .
rC;SCF rC;SCF

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Research Article 3

   
Experimental data ranges and literature sources of the phar- y2 ¼ A þ Bpr þ Cp2r Tr þ D þ Epr þ Fp2r (25)
maceuticals are presented in Tab. 2. Based on the functional
dependency, the solubility models in Tab. 1 may be classified as where y2 is the mole fraction of the solute, pr is the reduced
four categories, i.e., category I (models from Chrastil [12], pressure, Tr is the reduced temperature of ScCO2, and A–F are
Kumar and Johnston [15], Adachi and Lu [13], del Valle and the proposed model constants.
Aguilera [14], Sung and Shim [21], Sparks et al. [23], Garlapati
and Madras [24], Bian et al. (2011) [25], Bian et al. (2016) [30],
Andonova and Garlapati [31], Si-Moussa et al. [32], Belghait et 4 Methodology
al. [34]) is a function of density and temperature; category II
(models from Bartle et al. [16], Méndez-Santiago and Teja [20], For models with solubility in terms of S2 (kg m–3), the pharma-
Hozhabr et al. [28], Jafari et al. [26], Jouyban et al. [22], Kesh- ceutical solubility data is calculated from its mole fraction by:
miri et al. [27], Khansary et al. [29]) is a function of density,
temperature, and pressure; category III (Haghbakhsh et al. rSCF MW2 y2
S2 ¼ (26)
model [7]) is a function of density and pressure, and finally MWSCF ð1  y2 Þ
Category IV (models from Gordillo et al. [19], Mitra and Wil-
son [17], Reddy et al. [33], Yu et al. [18]) is a function of pres- where rSCF (kg m–3) is the density, MWSCF (kg mol–1) is the
sure and temperature. More details about these models are molecular weight of ScCO2, and MW2 (kg mol–1) and y2 are the
described in the corresponding literature. molecular weight and the mole fraction of the pharmaceuticals,
respectively. The value of critical density of ScCO2 (rC,SCF) is
467.6 kg m–3 [23]. The density data of the ScCO2 at various
3 New Model temperatures and pressures was determined by Wang et al.
[67].
The basis for the new model is the analysis of the degree of A nonlinear optimization procedure is applied to estimate
freedom. According to Gibbs’ analysis, the solubility of a single the model parameters. The optimization procedure reduces the
solute in a solvent is independently affected by the system tem- global mean absolute relative deviation percentage (AARD %).
perature and pressure. The simplest way to establish a relation For statistical analysis, the square of correlation coefficient
among the solubility and other parameters is through an (R2), adjusted R2 (Adj. R2), root mean square deviation
empirical model. The only difficulty lies in the empirical model (RMSE), and sum of squares due to error (SSE) are employed
to identify the correct functional relationship among the [10–30]. Higher values of R2 (~1) indicate the model ability in
parameters. To develop the functional relationship among the estimating data points closer to experimental values and R2 can
variables, a simple reasoning solubility as function of density be biased for models with different numbers of parameters.
was used which further can be fixed with temperature and Adj. R2 is a modification of R2, compares models with different
pressure of the solvent, considering the negligible effect on the adjustable parameters, and can have negative, less than or equal
solubility by viscosity, diffusivity, and polarity change with tem- to R2 values. RMSE and SSE closer to zero indicate the lesser
perature and pressure of the system. Using a similar reasoning, deviation of estimated data with experimental values. The rele-
Wang et al. [67] developed an expression for the density of vant mathematical formulas are:
ScCO2 in terms of a polynomial function of pressure and tem-

Ni  cal exp 
perature. In our previous work [33], solubility as function of 100 X y2  y2 
reduced temperature and pressure of the system was estab- AARD % ¼ exp (27)
Ni i¼1 y2
lished. This model was found to correlate weaker than other
literature models for compounds considered in this study. Ni 
P 2
exp
Solid solubility decreases with higher temperature at lower y2  y2cal
i¼1
pressure but increases with higher temperature at high pressure R2 ¼ 1  Ni  2 (28)
[16, 17]. This curvilinear behavior makes it difficult to define a P exp
y2  y2cal
single model applicable for both higher and lower pressure i¼1
ranges [16]. Furthermore, Sparks et al. [23] and Andonova and
Garlapati [31] proved the use of reduced parameters in solubil- Qð 1  R 2 Þ
Adj: R2 ¼ R2  (29)
ity modeling. Therefore, in this work, a new solubility model Ni  Q  1
for pharmaceutical compounds in terms of pressure and tem- " #
perature is proposed, for dimensional consistency the mole X
Ni
 exp 
cal 2
SSE ¼ y2  y2 (30)
fraction of the solid solute is used for solid solubility, reduced i¼1
temperature and reduced pressure are employed for tempera-
ture and pressure of the ScCO2. " #1=2
1 X
Ni
 exp 2
Reviewing the above discussion, considering Wang et al. RMSE ¼ y2  y2cal (31)
[67], Reddy et al. [33], and solubility curvilinear behavior after Ni i¼1
several trials, a polynomial model according to Eq. (25) is pro-
posed. The model was found to correlate better for pharmaceu- where y2 and y2 represent the mole fraction and global mean
tical compounds in ScCO2. value mole fraction of the solute. The superscripts cal and
exp denote calculated and experimental values, respectively.

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Research Article 4

Table 2. Range and source of solubility data of various pharmaceuticals in ScCO2.

No. Compound MW [kg mol–1] y2 ·105 [–] T [K] p [MPa] Ni [–] Ref.
1 4-Aminosalicylic acid 153.14 0.35–3.59 308–328 11–21 15 [35]
2 2-Methylbenzoic acid 136.20 24.0–570 313.2–333.2 11–24.6 17 [35]
3 3-Methylbenzoic acid 135.14 18.40–534.00 313.2–333.2 11–24.6 18 [35]
4 4-Methylbenzoic acid 254.29 4.30–70.20 313.2–333.2 11–24.6 18 [36]
5 5-Hydroxy-methylfurfural 126.11 50.60–238.40 314.1–343.2 9.74–19.58 22 [37]
6 9,10-Antroquinone 208.22 0.09–7.40 308.15–318.15 8.41–30.63 17 [38]
7 Artemisinin 282.33 9.80–265.90 310.1–338.1 10–27 36 [39]
8 Azadirachtin 720.71 0.12–1.49 308.15–333.15 10–26 54 [40]
9 b-Carotene 536.87 0.00–0.17 310–340 9.7–26 27 [41]
10 Carbamazepine 236.27 0.30–9.40 308–348 12.2–35.5 39 [42]
11 Clozapine 326.82 0.12–4.19 318–348 12.16–35.46 27 [43]
12 Cyproterone acetate 416.94 1.30–26.10 308–348 12.2–35.5 40 [44]
13 Diazepam 284.74 16.00–111.00 308–348 12.2–35.5 45 [42]
14 Eflucimibe 469.73 0.00–0.16 308.15–318.15 9.33–30.19 20 [45]
15 Exemestane 296.40 1.26–187.58 308–348 12.2–35.5 45 [46]
16 Flurbiprofen 244.26 1.67–19.68 303–323 8.9–24.5 27 [47]
17 Ketoprofen 254.28 0.33–18.80 312.5–331.5 9–25 31 [48, 49]
18 Lamotrigine 256.09 0.03–0.59 318–348 12.16–35.46 36 [43]
19 Lovastatin 404.55 1.10–11.40 308–348 12.16–35.6 45 [50]
20 Medroxyprogesterone acetate 386.25 1.60–41.30 308–348 12.2–35.5 40 [42]
21 Methimazole 114.17 1.22–18.99 308–348 12.2–35.5 39 [51]
22 Methylparaben 152.15 10.80–121.30 308–348 12.2–35.5 40 [52]
23 Metronidazole benzoate 275.76 7.00–455.00 308–348 12.2–35.5 40 [53]
24 Naproxen 230.26 1.00–20.00 308–348 12.2–35.5 40 [54, 55]
25 Nifedipine 346.34 0.14–7.09 333.15–373.15 12.6–29.6 29 [56]
26 Nitrendipine 360.36 0.13–10.59 333.15–373.15 10–30 42 [57]
27 Penicillin G 334.39 0.42–6.33 313.15–333.15 10–35 18 [19]
28 Penicillin V 350.38 5.45–62.30 314.85–334.85 7.99–28.05 24 [56]
29 Phenazopyridine 213.24 0.44–20.21 308–348 12.2–35.5 45 [51]
30 Procaine 236.31 5.82–16.50 298–318 6.9–25.2 28 [57]
31 Propranolol 259.34 0.37–239.61 308–348 12.2–35.5 45 [51]
32 Protocatechuic acid 154.12 0.01–4.58 313–333 10–50 24 [58]
33 Tetraethylene glycol 582.26 135.00–263.00 318.15–333.15 13.33–21.13 20 [59]
bis(2-butoxyethyl) dimethyl
diphosphate
34 Tetraethylene glycol 606.33 141.00–271.00 318.15–333.15 12.25–19.43 20 [59]
bis(2-ethylhexyl) dimethyl
diphosphate
35 Theobromine 180.17 0.03–0.47 313–368.15 10–42 65 [60–62]
36 Xanthohumol 354.39 0.12–1.77 328–358 35–95 15 [63]
37 Piroxicam 331.35 1.17–51.20 308.15–338.15 16–40 28 [64]
38 Vitamin D2 396.65 2.90–104.00 313–353 20–32 19 [65]
39 Vitamin K 450.70 2.90–356.00 313–353 20–35 24 [65]
40 Vanillic acid 168.14 0.03–6.07 313–333 9–50 36 [48]
41 Zopiclone 388.81 0.15–2.19 313–333 10–25 21 [66]

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Research Article 5

Ni means the number of data points and Q is the number of in-
dependent variables in each model.
5 Results and Discussion
The solubilities of 41 pharmaceutical compounds with a large
number of experimental data points are considered for the
development of the new model. The correlating ability is
assessed in terms of AARD, Adj. R2, R2, RMSE, and SSE. The
statistical paired t test is conducted for
global mean AARD and Adj. R2 of the pro-
posed model with all literature models to a) 2.8
determine the significance of difference
between the mean values.
The solubility model developed in this
study may be viewed as a category-IV mod- 2.4
el. The global mean AARD differences be-
Mole fraction, y2 x10 [-]
3
Concerning category-I models, the Belghait et al. model
[34] is able to predict much better with the least global
mean AARD (12.979 %) and the Chrastil model [12] exhibits
a poor correlating ability with the corresponding global
mean AARD being 19.032 %. From the category-II models,
the Méndez-Santiago and Teja model [20] has an inferior
correlating ability with highest global mean AARD
(22.312 %) and the model from Keshmiri et al. [27] corre-
lated much better with minimum global mean AARD
(12.978 %). However, there is an insignificant change in
Experimental data at 318.15 K
Experimental data at 323.15 K
Experimental data at 328.15 K
Experimental data at 333.15 K
Proposed model data

tween category-IV models with the new

model are found to be statistically significant
at 99.96 % confidence level (paired t test, 2.0
p < 0.0004) and similarly Adj. R2 is found to
be statistically significant (paired t test,
p < 0.05). An efficient model should yield a
lower value of AARD, RMSE, SSE, and high-
er values of Adj. R2 and R2. These facts are 1.6
readily seen in Tab. 3 for the proposed mod-
el, therefore, it can be stated that the new
model (Eq. (25)) is able to correlate much
better than the other category-IV models. 1.2
To ascertain the efficacy of the proposed 12 14 16 18 20 22
model, the drug compounds tetraethylene Pressure [MPa]
glycol bis(2-butoxyethyl) dimethyl diphos-
phate, tetraethylene glycol bis(2-ethylhexyl)
dimethyl diphosphate (compounds 33 and b) 2.8
Experimental data at 318.15 K
34 from Tab. 2), and methimazole (com- Experimental data at 323.15 K
pound 21 from Tab. 2) are depicted in Experimental data at 328.15 K
Figs. 1a, 1b, and 2, respectively. Experimental data at 333.15 K
2.4 Proposed model data
The drug compound from Tab. 2 having
an optimal pressure is chosen to validate
Mole fraction, y2 x10 [-]
3

the estimating capacity of the proposed

model at high pressures, as displayed in
Fig. 3. In Fig. 4, the solid solubility calcu- 2.0
lated using category-IV models are com-
pared with the experimental data for flurbi-
profen at 313 K.
The parity plot in Fig. 5 indicates the rela-
1.6
tion between all the experimental data con-
sidered in this study (1281 data points) with
the model (Eq. (25)) predictions. Clustering
of points around the diagonal (y = x) line de-
picts the agreement between estimated and 1.2
experimental solubility data. Tab. 3 summa- 10 12 14 16 18 20

rizes the global mean statistical parameters Pressure [MPa]

of all the models considered for this study. Figure 1. Variation of mole fraction with pressure for (a) tetraethylene glycol bis(2-bu-
Correlation coefficients and all statistical pa- toxyethyl) dimethyl diphosphate + ScCO2 and (b) tetraethylene glycol bis(2-ethylhexyl)
rameters for category I–IV literature models dimethyl diphosphate + ScCO2. Experimental data from Ren at al. [59]. The solid lines
and the proposed model are presented in the are model predictions based on the proposed model at 318.15, 323.15, 328.15, and
Supporting Information (Tabs. S1–Tab. S20). 333.15 K, respectively.

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Research Article 6

Table 3. Global mean statistical parameters of solubility models.

Solubility model No. of constants R2 Adj. R2 SSE RMSE AARD %

Category I

Chrastil [12] 3 0.827463 0.820333a) 5.20 ·10–2 2.74 ·10–2 19.032b)

Sparks et al. [23] 6 0.867770 0.862193c) 9.50 ·10–5 6.89 ·10–4 18.708d)

Si-Moussa et al. [32] 6 0.865604 0.860239c) 4.81 ·10–7 6.71 ·10–5 18.407b)

Andonova, Garlapati [31] 3 0.887053 0.882767c) 3.63 ·10–7 5.84 ·10–5 17.360b)

Kumar and Johnston [15] 3 0.891142 0.887123e) 4.50 ·10–7 6.14 ·10–5 17.259b)

Sung and Shim [21] 4 0.893239 0.889193c) 3.66 ·10–7 5.86 ·10–5 17.237b)

Garlapati, Madras [24] 5 0.899681 0.895757c) 3.49 ·10–7 5.67 ·10–5 16.851b)

del Valle, Aguilera [14] 4 0.854040 0.848555a) 1.06 ·10–7 3.52 ·10–5 16.559b)

Bian et al. (2016) [30] 5 0.903844 0.900337e) 4.46 ·10–7 6.04 ·10–5 15.651d)

Adachi, Lu [13] 5 0.862263 0.856946a) 4.13 ·10–2 2.42 ·10–2 14.968d)

Bian et al. (2011) [25] 6 0.864703 0.859540a) 8.99 ·10–7 9.38 ·10–5 13.932f)

Belghait et al. [34] 8 0.912020 0.908761e) 3.87 ·10–7 5.53 ·10–5 12.979f)

Category II

Méndez-Santiago, Teja [20] 3 0.829820 0.826431a) 2.95 ·10–5 8.82 ·10–5 22.312b)

Bartle et al. [16] 3 0.806834 0.799367g) 1.03 ·10–6 8.92 ·10–5 22.068b)

Jafari et al. [26] 4 0.871504 0.865687c) 3.56 ·10–7 6.05 ·10–5 20.162b)

Jouyban et al. [22] 6 0.919336 0.915693e) 4.04 ·10–7 6.06 ·10–5 14.781d)

Hozhabr et al. [28] 4 0.914393 0.911298a) 2.56 ·10–7 5.03 ·10–5 14.971d)

Khansary et al. [29] 5 0.919620 0.916509e) 3.35 ·10–7 5.42 ·10–5 14.523d)

Keshmiri et al. [27] 5 0.936877 0.934410e) 2.51 ·10–7 4.62 ·10–5 12.978f)

Category III

Haghbakhsh et al. [7] 10 0.774835 0.765931g) 3.73 ·10–7 5.73 ·10–5 18.276b)

Category IV

Gordillo et al. [19] 6 0.853380 0.847148g) 8.47 ·10–7 9.10 ·10–5 25.614b)

Yu et al. [18] 6 0.744399 0.734277g) 4.60 ·10–7 2.57 ·10–2 22.232b)

Reddy et al. [33] 5 0.766830 0.757501g) 5.49 ·10–7 7.25 ·10–5 20.397b)

Mitra, Wilson [17] 5 0.899795 0.895695c) 3.50 ·10–2 2.18 ·10–2 14.626b)

Proposed model 6 0.946262 0.944368 9.18 ·10–8 3.17 ·10–5 9.406

a)
The mean Adj. R2 are significantly different from 0.944368 (paired t test, p < 0.005); b) the mean AARD values are significantly different
from 9.406 % (paired t test, p < 0.0005); c) the mean Adj. R2 are significantly different from 0.944368 (paired t test, p < 0.05); d) the mean
AARD values are significantly different from 9.406 % (paired t test, p < 0.005); e) the mean Adj. R2 are not significantly different from
0.944368 (paired t test, p < 0.05); f) the mean AARD values are significantly different from 9.406 % (paired t test, p < 0.05); g) the mean Adj.
R2 are significantly different from 0.944368 (paired t test, p < 0.0005).

global mean AARD of Hozhabr et al. [28], Khansary et al.
[29], and Jouyban et al. [22] models when compared with
the model from Keshmiri et al. [27], but large differences
are found among the other statistical parameters. Hence, it
can be ascertained that along with AARD other statistical
parameters may be considered while validating the correlat-
ing efficiency of the model.
Although the present work only deals with category-IV
models, the performance of the proposed model is also com-
pared with other category models. Among all the 25 models,
the new model has the least global mean value of AARD,
RMSE, SSE, and highest global mean value of R2 and Adj. R2.
The global mean Adj. R2 differences between the new model
and category I–III models other than Bian et al. (2016) [30],

Chem. Eng. Technol. 2019, 42, No. 00, 1–11 ª 2019 WILEY-VCH Verlag GmbH & Co. KGaA www.cet-journal.com
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Research Article 7

6
Experimental data at 308 K
2.0 Experimental data at 318 K Data Point
Experimental data at 328 K exp cal
Experimental data at 338 K 5 y 2 =y 2
Experimental data at 348 K

x 10 [-]
Proposed model data

3
1.5
4
Mole fraction, y2 x 10 [-]
4

exp
Mole fraction, y2
3
1.0

0.5
1

0
0.0
12 18 24 30 36

Pressure [MPa] 0 1 2 3 4 5 6

cal 3
Mole fraction, y 2 x 10 [-]
Figure 2. Variation of mole fraction with pressure for methima-
zole + ScCO2. Experimental data from Yamini et al. [51]. The sol- Figure 5. Parity plot of the solubility data estimated by the pro-
id lines are model predictions based on the proposed model at posed model (Eq. (25)) with corresponding experimental data
308, 318, 328, 338, and 348 K, respectively. (1281 data points).

Experimental data at 328 K Hozhabr et al. [28], Jouyban et al. [22], Keshmiri et al. [27],
1.6
Experimental data at 343 K Khansary et al. [29], Kumar and Johnston [15], and Belghait
Experimental data at 358 K
Proposed model data et al. [34], are found to be statistically significant (paired t test,
p < 0.05).
Mole fraction, y2 x 10 [-]

The proposed model global mean AARD is found to be

5

1.2
significantly different from the category I–III models global
mean AARD (paired t test, p < 0.05). Therefore, when compar-
0.8 ing all the statistical parameters, the newly proposed model is
able to correlate the solubility data with least AARD, RMSE,
SSE, and highest values of R2 and Adj. R2 for the literature
0.4 pharmaceutical compounds when compared with other empir-
ical and semi-empirical models considered in this study.
Among the six parameter models, the model from Bian et al.
0.0 (2011) [25] is the best one for estimating the solubility data
30 40 50 60 70 80 90 100
after the new model, and the model from Gordillo et al. [19]
Pressure [MPa]
was found to have poor accuracy in estimating solid solubility
Figure 3. Variation of mole fraction with pressure for xanthohu- in ScCO2. Furthermore, the models from Keshmiri et al. [27]
mol + ScCO2. Experimental data from Kostrzewa et al. [63]. The with five and from Belghait et al. [34] with eight parameters
solid lines are model predictions based on the proposed model are highly efficient in estimating the pharma solubility after the
at 328, 343, and 358 K, respectively. proposed model. Notably, the model from Hozhabr et al. [28]
is the only four-parameter model which is able to estimate drug
Experimental data at 313 K solubility very much closer to other models with five to eight
1.2
Mitra and Nancy at 313 K parameters.
Yu et al. at 313 K
Gordillo et al. at 313 K
In Fig. 6, the global mean AARD % values of all 25 models
Reddy et al. at 313 K are depicted. The overall order for the correlating ability of the
Mole fraction, y2 x 10 [-]

Proposed model at 313 K

0.9 models in terms of global mean AARD is: proposed model >
4

Belghait et al. > Keshmiri et al. > Bian et al. (2011) > Khansary
et al. > Mitra and Wilson > Jouyban et al. > Adachi and Lu >
0.6
Hozhabr et al. > Bian et al. > del Valle and Aguilera > Garlapati
and Madras > Sung and Shim > Kumar and Johnston > Ando-
0.3 nova and Garlapati > Haghbakhsh et al. > Si-Moussa et al. >
Sparks et al. > Chrastil > Jafari et al. > Reddy et al. > Bartle
et al. > Yu et al. > Méndez Santiago and Teja > Gordillo et al.
0.0

8 12 16 20 24

Pressure [MPa]

Figure 4. Variation of mole fraction with pressure for flurbipro-

fen + ScCO2 at 313 K. Experimental data from Duarte et al. [47].

Chem. Eng. Technol. 2019, 42, No. 00, 1–11 ª 2019 WILEY-VCH Verlag GmbH & Co. KGaA www.cet-journal.com
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Research Article 8

25 Category-I
Category-II
Category-III
Category-IV
20
Global Mean AARD %

15

10

Figure 6. Global mean AARD %

5 of category I–IV literature mod-
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 els and the proposed model.
Model Equation No

6 Conclusions Q [–] number of independent variables in

each model
Determination of proper solubility values is imperative for R2 [–] square of correlation coefficient
the development of high-pressure technologies in the phar- RMSE [–] root mean square deviation
maceutical industries. In this work, a simple empirical model S [kg m–3] solubility of pharmaceutical
is developed for correlating the solubilities in terms of compound
reduced pressure and temperature and successfully evaluated SSE [–] sum of squares due to error
with 41 industrially important pharmaceutical compounds. T [K] temperature of supercritical CO2
Being the dimensionless solubility model in terms of temper- y [–] mole fraction
ature and pressure, it can be applied without ambiguity of y [–] average mole fraction
units. Accurate solid solubility can be calculated using the
proposed model for compounds without density data. The Greek letter
proposed model is found to correlate better than the existing r [kg m–3] density
models considered in this study.
Sub- and superscripts

Acknowledgment 2 solute (pharmaceutical drug)

c at critical point
The corresponding authors thank Prof. Giridhar Madras, IISc cal calculated mole fraction
Bangalore, India, for his inspiration and support. exp experimental mole fraction
r reduced
The authors have declared no conflict of interest. ref reference
SCF supercritical fluid

Symbols used Abbreviations

EOS equation-of-state
AARD [–] average absolute relative deviation ScCO2 supercritical CO2
Adj. R2 [–] adjusted R2
Ai–Ji [–] model coefficients
MW [kg mol–1] molecular weight
Ni [–] number of data points
p [MPa] pressure of supercritical CO2

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Research Article 9

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Research Article 11

Research Article: Determination of Dimensionless Empirical Model to 25 Category-I

Category-II
proper solubility values is imperative for Correlate Pharmaceutical Compound Category-III
Category-IV

the development of high-pressure Solubility in Supercritical Carbon 20

Global Mean AARD %

technologies in the pharmaceutical Dioxide
industries. A simple empirical 15

dimensionless model is proposed for T. A. Reddy, C. Garlapati*

correlating the solubilities in terms of 10

reduced pressure and temperature and Chem. Eng. Technol. 2019, 42 (XX),
successfully evaluated with 41 XXX K XXX 5
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
industrially important pharmaceutical Model Equation No

compounds, compared with 24 existing DOI: 10.1002/ceat.201900283

empirical models.

Supporting Information
available online

Chem. Eng. Technol. 2019, 42, No. 00, 1–11 ª 2019 WILEY-VCH Verlag GmbH & Co. KGaA www.cet-journal.com