Received: 16 July 2022 Revised: 12 March 2023 Accepted: 2 April 2023

DOI: 10.1002/aic.18115

RESEARCH ARTICLE
Process Systems Engineering

A new hybrid quantitative structure property

relationships-support vector regression (QSPR-SVR)
approach for predicting the solubility of drug
compounds in supercritical carbon dioxide

Imane Euldji 1 | Aicha Belghait 1 | Cherif Si-Moussa 1 | Othmane Benkortbi 1 |

Abdeltif Amrane 2

1
Department of Process and Environmental
Engineering, Biomaterials and Transport Abstract
Phenomena Laboratory (LBMPT), University of
The purpose of this work was to compare the performance of 7 meta-heuristics
Yahia Fares, Faculty of Technology, Medea,
Algeria algorithms namely: Dragonfly (DA), Ant Lion (ALO), Grey Wolf (GWO), Artificial Bee
2
Univ Rennes, Ecole Nationale Supérieure de Colony (ABC), Particle Swarm (PSO), Whale (WAO), and a hybrid Particle Swarm with
Chimie de Rennes, CNRS, Rennes, France
Grey Wolf (HPSOGWO) optimizers in terms of fine-tuning hyper-parameters of a
Correspondence hybrid quantitative structure property relationships (QSPR)-support vector regression
Imane Euldji, Department of Process and
Environmental Engineering Biomaterials and
(SVR) for the prediction of molar fraction solubilities of drug compounds in supercritical
Transport Phenomena Laboratory (LBMPT), carbon dioxide (SC-CO2). A dataset of 168 drug compounds, 13 inputs, and 4490 exper-
University of Yahia Fares, Faculty of
Technology, Medea 26000, Algeria.
imental data points was used to achieve the goal. All 7 models were statistically and
Email: euldji.imane@univ-medea.dz; imene. graphically approved while the HPSOGWO-SVR was found to over-perform with an
eull@gmail.com
average absolute relative deviation (AARD) of 0.706% and an AIC of
14,434,249. The
Funding information model was subjected to an external test (validation) using 160 experimental data points
Algerian Ministry of Higher Education and
Scientific Research, Grant/Award Number:
that were not used in the training and the test set. The overall results proved that the
PRFU Project A16N01UN260120220003; the obtained model has good predictivity ability and robustness.
University Yahia Fares of Medea

KEYWORDS
drugs, metaheuristic algorithms, solubility, supercritical carbon dioxide, support vector
regression

1 | I N T RO DU CT I O N
“Finish early, but with fewer errors.” Through decades, this concept
was adapted and sacred by the pharmaceutical industry. When it
comes to human life, any mistake or delay is indeed forbidden. From
discovering new drug candidates to valid them, those candidates pass
through a long and complicated process full of obstructs and issues
usually related to ineffectiveness caused by unsatisfactory pharmaco-
kinetics and pharmacodynamics, hence bioavailability. This ineffec-
tiveness occurs due to five main keys of critical compound properties
in early compound screening, such as solubility, dissociation constant,
permeability, stability, and lipophilicity.1,2
For more than decades, it has been clearly demonstrated that sol-
ubility is the major factor affecting the in vivo systemic exposure of
drug candidates without doubt.3–5 Solubility could be considered as a
big threshold in both preclinical and clinical phases. Where statistic
results had reported that more than 70% of the drug candidates were
eliminated in these stages due to poor water solubility. In other words,
solubility plays a key role in the formulation development to achieve
the bioavailability and therapeutic action of the drug at the target
site.6 As explained by Kakran et al.7 To overcome the challenge of
poor water solubility, numerical techniques were used, which can be
divided into three main categories: physical modification, chemical
modification, and miscellaneous methods.2 Supercritical fluid

AIChE J. 2023;e18115. wileyonlinelibrary.com/journal/aic © 2023 American Institute of Chemical Engineers. 1 of 17

https://doi.org/10.1002/aic.18115
2 of 17
technology (SCF), particle size reduction, complexation, co-solvency,
and electrospinning are the well-known methods adopted; while
8–31 32
SCF is the most promising approach in pharmaceutical research
thanks to the safety of the environment and the economy. The most
widely SCF used is carbon dioxide (SC-CO2), almost 98% of the appli-
cation of the pharmaceutical industry33 due to its many advantages:

low critical temperature (Tc = 31.10 C), critical Pressure
(Pc = 73.8 bar), nontoxic, nonflammable, and inexpensive. 32
Ideally,
the knowledge of solubility of pharmaceutical molecules, whatever it
is in or not in SC-CO2, for all compounds at different temperature and
pressure ranges, and mixing compositions for which data are required.
This can be only achieved through the use of computational methods
for solubility prediction; in view of the fact that the experimental
studies are very expensive and time-consuming. Consequently, efforts
in developing reliable models for predicting water solubility led to a
significant among of publications, in which different approaches were
proposed. Reviewing the literature timelines indicates that the solubil-
ity of solid compounds in SCF is usually predicted using a thermody-
namic approach based on equations of state (EoS) which is mainly
divided into three main classes: cubic EoS, complex noncubic EoS, and
conductor-like screening model (COSMO) based on quantum mechan-
ical calculation, empirical, or semi-empirical correlations or intelligent
34
computer techniques. More details are available in a previous paper.
Reddy and Garlapati35 proposed a new empirical model to correlate
the solubilities of 27 industrially important pharmaceutical compounds in
SC-CO2, which is developed based on the degree-of-freedom analysis,
the proposed model was found to correlate better in terms of average
absolute relative deviation (AARD) than exiting models mentioned in the
article. Amooey36 contributed by an empirical correlation base on tem-
perature and density models for 31 solubility data series of different
drugs in SC-CO2, the model has generally resulted in minimum values of
AARE% compare to commonly used semi-empirical models. Nejad
et al.,37 built an empirical equation using 16 publications to correlate the
solute solubility in SC-CO2 with temperature, pressure, and density of
pure CO2, the model produces reasonably accurate correlation of the
mole fraction solubility of solutes in SC-CO2 with respect to pressure,
temperature, and density of pure SC-CO2. Belghait et al.38 performed a
comparison study of the correlation performance of 21 semi-empirical
models using a dataset of 210 solid solutes in SC-CO2, counting 5550
data points, and proposed a density-based semi-empirical model.
Si-Moussa et al.39 investigated in a density-based model by simple modi-
fication of the six parameters of Jouyban's model to correlate the solubil-
ity of 100 drugs accounting 2891 experimental data points. Su and
Chen40 applied the regular solution model with the Flory–Huggins equa-
tion to correlate the solubility of 60 pharmaceutical molecules in
SC-CO2. Yazdizadeh et al.41 studied the effect of applying the cubic
equation of state and mixing rules to calculate the solubilities of 52 solid
compounds in SC-CO2 account 1776 experimental data points. Wang
42
and Lin used the Peng–Robinson with COSMOSAC EoS to predict the
solubility of 46 drugs in SC-CO2 account 1160 data points. Eric et al.43
applied a reliable model for the prediction of aqueous solubility based on
the implementation of an algorithm for the automatic adjustment of
descriptor's relative importance in counter-propagation acritical neural
networks, with a dataset of 374 diverse drug-like molecules.
EULDJI ET AL.
Baghban et al.44 utilized a least square support vector machine (LSSVM)
with RBF kernel function not coupling and coupling with PSO to esti-
mate the solubility of 33 different drug compounds in SC-CO2 base on
their physical property. El Hadj et al.45 established a hybrid model based
on a feed-forward artificial neural network and particle swarm optimiza-
tion algorithm (PSO-ANN) for predicting the solubility of solid drugs in
SC-CO2. Lasharboloki et al.,46 Mehdizadeh and Movagharnejad47 per-
formed a comparison study between ANN and thermodynamic modeling
approached for predicting the solubility of compounds in SC-CO2. Sodei-
fian et al.48 performed a comprehensive comparison among four
approaches, namely EoS, empirical, and semi-empirical, solution models,
and ANN method, for correlating solubilities of different pharmaceutical
compounds in SC-CO2. Mehdizadeh and Movagharnejad49 performed a
comparison study between the GA-LSSVM algorithm and seven semi-
empirical equations for modeling the solubility of 25 solutes in SC-CO2.
Vatani et al.50 tested the ability of methods based on empirical equations
and fuzzy-genetic models to estimate the solubility of solutes in SC-CO2.
The proposed models were compared to other empirical models. Huus-
konen et al.51 performed a QSAR study on a set of 191 drug-like com-
pounds extracted from the AQUASOL database based on their structural
and physicochemical properties to predict water solubility. Gurikov
et al.52 performed a hybrid thermodynamic/QSPR approach to develop a
robust model that would allow for the solubility prediction entirely based
on molecular structure and the parameters of two models (Chrastil equa-
tion and the modified, expanded liquid model), involving more than
300 original publications of solubility data for high-boiling point com-
pounds in SC-CO2 and its mixtures with modifiers. Valenzuela Roediger
et al.53 developed a hybrid QSAR-semiempirical model to predict the
parameters of the solubility equation of chrastil using a group of com-
pounds in SC-CO2 under different pressure and temperate conditions.
We have contributed to a previous study by an ANN-QSPR model for
predicting the solubility of drug compounds in SC-CO2 with a dataset of
148 molecule accounting 3971 EDP.34 None of the approaches men-
tioned earlier proved to be superior to others. However, it should be
noted that machine learning approaches, such as support vector machine
which has been recently improved by combining with meta-heuristics
techniques for a better convergence to desired solutions are right now
one of the hottest topics in various research fields.54–69 Classical tech-
niques for optimizing are usually time consuming and do not provide an
exact or feasible solution. Therefore, there is a necessity to implement
meta-heuristic algorithms. The term meta-heuristics refers to a global
search technique or all modern nature-inspired optimization algorithms,
used in various problems where the solution methods are inexact and
near-optimal. The algorithms are highly effective and have general appli-
cations with high performance and a great driving force for optimality.
Different systems inspired by nature can be introduced, such as genetic
algorithm (GA), and particle swarm optimizer (PSO). the optimal method
for a specific problem can be only select using comparison trials.70
The aim of this study was to select the best optimization algo-
rithm for fine tuning the support vector regression algorithm, in form
of a comparison study between seven (7) selected meta-heuristic
algorithms: Dragonfly (DA), Ant Lion (ALO), Grey Wolf (GWO), Artifi-
cial Bee Colony (ABC), Particle Swarm (PSO), Whale (WAO), and a
hybrid Particle Swarm with Grey Wolf (HPSOGWO) optimizers.
EULDJI ET AL. 3 of 17

(
On the other hand, this article aims to validate a hybrid QSPR-SVR 1X n      Xn  
Maximize
αi , αi αj , αj φðxi Þ  φ xj
ϵ αi ,αi
model able to predict and correlate the solubility of drug compounds 2 i, j¼1 i¼1
ð3Þ
in SC-CO2 with acceptable accuracy using various statistical and X
n  
þ yi αi , αi g
graphical appraisals, including an external test. i¼1

8 Xn 
> 
>
> αi
αi ¼ 0
2 | EXPERIMENTAL DATABASE <
i¼1
Subject to
>
> 0 ≤ αi ≤ C i ¼ 1, 2,3, …, n
>
:
A total of 168 drug compounds accounting for 4490 experimental data 0 ≤ αi ≤ C i ¼ 1,2, 3,…, n
points (EDP), solubility (mole fraction 0.000000001–0.131) measured in
supercritical carbon dioxide in the temperature range of 298–373.15 K Here αi , αi are nonlinear Lagrangian multipliers. Solving the dual
and a pressure range of 80–500 bars were collected (The detailed drug maximization problem in equation (3) gives the SVR function:
solubility data are tabulated in the Supporting Information). These data
were updated from previous work.34 QSPR\QSAR modeling was applied   Xn    
F x, αi , αi ¼ αi
αi φðxi Þ  φ xj þ b ð4Þ
to 148 drug compounds (3971 EDP) to determine the best-suitable com- i¼1

binations of features able to predict and correlate this property. The result
 
of that study ends up meeting all the OECD principles for QSAR valida- The vector inner-product (φðxi Þ  φ xj ) represents the mapping
 
tion and showed that a combination of 13 descriptors is sufficient for function. That is, it can be replaced by a kernel function k xi , xj as
modeling the solubility. Therefore, the selected PaDEL-descriptors were shown in Equation (4):
as follows: AATS3v, MATS2e, GATS4c, GATS3v, GATS4e, GATS3s,
nBondsM, AVP-0, SHBd, MLogP, and MLFER_S, with the addition of T(K)   Xn    
F x, αi ,αi ¼ αi
αi k xi , xj þ b ð5Þ
and P(MPa). The output property was converted to the corresponding i¼1

log-transformed property “-Ln(y2)” to guarantee the linear distribution as

shown in34 The final dataset was divided into two main sets. The first set In this study, the Gaussian kernel function was chosen
of 4330 EDP was retained for modeling; while the second set of Equation (6):
160 EDP was kept hidden from the models, that is, an external test.
  1
k xi ,xj ¼ pffiffiffiffiffiffi e
2ð σ Þ
1 x
μ 2
ð6Þ
σ 2π

2.1 | Support vector regression

The support vector machines are classification (SVC) and regression

(SVR) tools that use the machine learning concepts to increase the pre-
dictive accuracy. It was first introduced in 1995 by Vladimir Vapnik for
the purpose of surpassing the traditional neural network algorithms that
had suffered from severe difficulties with generalization and producing
models.71,72 For regression modeling, the SVR hypothetical decreases
the error of predictability in a learning process and reduces overfit-
ting.73,74 The linear regression function is defined as follows74–77:
f ðxÞ ¼ ω  φðxÞ þ b
where φ (x) is the kernel function, w and b denote the weight vector
and the bias term, respectively. That can be obtained by minimizing
the cost function77,78:
1 Xk  
cost function ¼ ω2 þ C ζ
þ
i þ ζi
2 i¼1
8 þ
< yi
ðw  φðxi Þ þ bÞ ≤ ϵ þ ξi
> divided into two different phases: the nymph phase and the adult
Subject to ðw  φðxi Þ þ bÞ
yi ≤ ϵ þ ξ

>
: þ

i
ξi , ξi ≥ 0,i ¼ 1,2, 3,…, n
A standard dualization method using Lagrangian multipliers was
applied for easily solving the optimization problem in Equation (2).
The dual formulation of this problem is represented as follows79:
2.2 | Meta-heuristic approaches
2.2.1 | Dragonfly algorithm
The dragonfly algorithm (DA) is an optimization algorithm that
was first proposed by Seyedali Mirjalili in 2015.80 This algorithm
is inspired by the static and dynamic behavior of dragonflies in
ð1Þ nature. In the static swarm process, the dragonflies hunt prey;
the dragonflies behave similarly to the exploitation phase in
meta-heuristic algorithms in which they fly in small groups fre-
quently over a well-determined small area and much closer to the
land. While the dynamic behavior is similar to the exploration
phase, migratory swarms form as large groups (hundreds of thou-
ð2Þ sands of dragonflies) and fly in a single direction for long dis-
tances to find food resources. 79–81 The life cycle of agents is
phase. 82 The natural behavior of each dragonfly in the swarm
obliges the move toward nurturing sources and distract outward
enemies. 79,81
According to Reynolds,83 the behavior of swarm follows five dif-
ferent principles that are necessary in finding the weights solu-
tion79–81,83:
4 of 17 EULDJI ET AL.

Separation Xtþ1 ¼ X t þ ΔXtþ1 ð13Þ

The purpose of this step is to avoid the collision of individuals with
!
their neighbors that is close to its position, the static swarm. It is 0:1
e ¼ 0:1
1  I
ð14Þ
defined as follows: 2

X
n  
0:9
0:4
Si ¼ X
Xj ð7Þ w ¼ 0:9
i  ð15Þ
j¼1 I

where X and X j are the positions of the current individual and the jth
neighboring individual, respectively and n is the number of neighbor-
ing individuals.
Alignment
This step represents the velocity matching between dragonflies of the
same group. It is given by:
where s, a, c, f, e, and w are the weights of their corresponding ele-
ment. w is calculated using Equation (15), i is the current iteration and
I is the number of iterations, and e is calculated in Equation (14), s, a,
and c are three different random numbers between 0 and 2e; f is a
random number between 0 and 2. More details can be found in Refer-
ence [80].

P
n
2.2.2 | Ant Lion optimizer
Vj
j¼1
Ai ¼
X ð8Þ
n
This technique is inspired by the hunting mechanism of antlions in
nature and is proposed by Mirjalili84 in 2015. The antlions (doodle-
where vj is the velocity of neighboring individual j. bugs) belong to the Myrmeleontidae family of insects and Neuroptera
order. They have an average lifespan of about 3 years that it is spent
Cohesion as larvae except for 3–5 weeks of that period is spent in adulthood.85
The cohesion refers to the tendency of members toward the center of At the larvae phase, Ant Lions are known for their unique process of
the swarm's group, the neighborhood mass. It can be defined as: hunting and preferably of hunting ants. Using their massive jaw,
antlions dig conical pits in the sand. Then, the larvae hide and wait at
P
n
the bottom of that pit, sharp enough for the prey to be trapped in
Xj
j¼1 (most cases, ants). Once the antlion noticed the prey are inside the
Ci ¼
X ð9Þ
n
trap, they started to throw sands out of the hole across the prey. Con-
sequently, the ants will fail to escape from the pit and slide to the bot-
Attraction to food tom of that pit. After that, antlions would consume the prey and
Since individuals aim is to survive. The objective of attraction to food thrown away the leftovers. With this strategy, individuals prepare the
is that all dragonflies must move toward the food. As shown following pit for the next hunt. As well as the chance of survival increases.85,86
this mathematical formula: The mathematical representation of this algorithm is given as
follows84–86:
þ
Fi ¼ X
X ð10Þ

where Xþ shows the position of the food source. Random walks of Ants

Distraction from enemy
This final step refers to when individuals move far away from the
enemy's sources to survive; it is calculated as follows:
Ei ¼ X

X
XðtÞ ¼ ½0, cumsumð2r ðt1
1Þ, cumsumð2rðt2 Þ
1, …, cumsumð2rðtn Þ
1Þ
ð16Þ
where n is the maximum number of iterations, cumsum calculates the
ð11Þ cumulative sum, and t is the step of the random walk. Hence,

where X
shows the position of the enemy. r ðtÞ ¼

The position update of each dragonfly for the purpose of testing
another weight solution and getting another fitness value is obtained
by calculating ΔX and X using Equations (12) and (13)80,81:
ΔXi ¼ ðsSi þ aAi þ cCi þ fF i þ eEi Þ þ wΔXt ð12Þ
1 if rand > 0:5
ð17Þ
0 if rand < 0:5
Here, (t) is a stochastic function and rand is a random number
generated with uniform distribution at interval of [0, 1]. The positions
of ants are saved and considered during optimization in the matrix:
EULDJI ET AL. 5 of 17

2 3 possibility of catching new prey. The mathematical formula is the

A1,1 A1,2     A1,d
6 A2,1 A2,2     A2,d 7 following:
6 7
6 . .. .. .. .. 7
6 7
Mant ¼ 6 .. . . . . 7 ð18Þ    
6 7 Antliontj ¼ Antti if f Antti > f Antliontj ð22Þ
6 .. .. .. .. .. 7
4 . . . . . 5
An,1 An,2     An,d

where t represents the current iteration, Antliontj is the position of the

where MAnt is the matrix for saving the position of each ant, Ai, shows selected jth antlion at tth iteration, and Antti represents the position of
the value of the jth variable of ith ant, n is the number of ants, and d ith ant at tth iteration.
is the number of variables. According to the random walk, Ants update
their position with each step of optimization. The min–max normaliza- Elitism
tion equation is used to normalize the random walks: In the ALO algorithm, an elite refers to the best-obtained antlion
through the whole iteration. This elite affects the movement of the
 t   
X
ai  di
cti rest of the ants during iteration. Therefore, it is assumed that every
Xti ¼ i  t  þ ci ð19Þ
di
ai prey walks randomly around a selected antlion by the roulette wheel
and the elite altogether as follows:
where ai is the minimum of random walk of ith variable, di is the maxi-
mum of random walk of ith variable, cti is the minimum of ith variable RtA þ RtE
Antti ¼ ð23Þ
at tth iteration, and dti is the maximum of ith variable at tth iteration. 2

Trapping in Antlion's pit where RtA is the random walk around the antlion selected by the rou-
Antlion's trap affects the random walks of ants. It is given by: lette wheel at tth iteration, RtE is the random walk, and Antti represents
the position of ith ant at tth iteration.
cti ¼ Antliontj þ ct
ð20Þ
dti ¼ Antliontj þ dt
2.2.3 | Grey wolf optimizer
t t
where c represents the minimum of all variables at tth iteration, d
indicates the vector including the maximum of all variables at tth itera- The GWO is another meta-heuristic technique proposed by Mirjalili
tion, cti is the minimum of all variables for ith ant, dti is the maximum et al.,87 for solving optimized problems. This algorithm is mainly
of all variables for ith ant, and Antliontj shows the position of the inspired by the social leadership and hunting behavior of grey wolves
selected jth antlion at tth iteration. in nature.88 Grey wolves are social animals that live in a pack of 5–12
members. In each path, there are four types of wolves divided accord-
Building trap ing to their responsibilities and decisions making roles, during the pro-
In this step, the ALO involved a roulette wheel operator to select cess of prey hunting, to alpha (α) wolf as the group leader, beta (β)
antlions based on their fitness during optimization. This technique wolves as the second ones in command, then delta (δ) wolves the sub-
provides high chances of catching ants by the fitter antlions. ordinate ones, those three are considered as the best solution to lead
the rest wolves known as omega (ω) wolves, the fourth type, toward
Sliding Ants toward Antlion promising areas for the aim of retching the global solution.77,88,89
Here, the radius of the random walks hypersphere of ants is Those individuals have a special mechanism of hunting, considering
decreased adaptively in the mathematical modeling by applying the three main phases. In the beginning, grey wolves approach the prey
following Equation (21): using a process of tracking and chasing. Then, they encircle the prey
and harass it until the prey stops moving. The final step is to attack
ct them, as mentioned in Reference [90]. The GWO algorithm follows
ct ¼
I ð21Þ the following mathematical technique of hunting77,87–90:
t dt
d ¼
I
Encircling
t
where I is a ratio, c is the minimum of all variables at tth iteration, and The encircling behavior of prey by grey wolves is mathematically mod-
dt indicates the vector, including the maximum of all variables at tth eled as shown:
iteration.
! ! ! !
D ¼ jC  X p ðtÞ
X ðtÞj ð24Þ
Catching pray and rebuilding the pit
The following is the final hunting stage. Based on the position of the ! ! ! !
X ðt þ 1Þ ¼ X P ðtÞ
A  D ð25Þ
latest hunted ant, the antlions update their position to improve the
6 of 17 EULDJI ET AL.

!
Here, t is the current iteration, X P is the vector of the prey posi-
! ! !
tion, and X indicates the vector of the grey wolf position, A , C are
coefficient vectors which can be calculated as follows:
! ! ! !
A ¼ 2a  r 1
a
inspiration is from the behaviors of honeybees in finding food sources,
as well as sharing that information with the rest in the nest. In the
algorithm, individual bees are classified into three types (employed,
onlooker, and scout) where each agent plays different roles in the pro-
ð26Þ cess, as explained by Reference [81].

!
C ¼2!
r2 ð27Þ
2.2.5 | Particle swarm optimizer
!
where components of a are linearly decreased from 2 to 0, over the
course of iterations and r &!
!
r are random vectors in [0, 1].
1 2 The PSO is one of the most well-known population-based meta-
heuristic optimization algorithms. This technique was first introduced
Hunting by Kennedy and Eberhart93–95 in 1995. Its strategy was inspired by
The mathematical modeling assumes that α (the best candidate solution), the social behavior of bird flocking, fish schooling, a swarm of bees,
β, and δ have better knowledge about the location of the prey. For that sometimes from the social behavior of humans when it searches for
reason, it is mandatory to save the first three best solutions obtained so food.95,96
far and to update the positions of the other wolves (ω) according to those
solutions. The formulas of hunting mechanism are given by:
2.2.6 | Whale optimizer algorithm
! ! ! ! ! ! ! ! ! ! ! !
Dα ¼ j C1  X α
X j, Dβ ¼ j C2  Xβ
X j, Dδ ¼ j C3  Xδ
X j ð28Þ
The WOA is one of the meta-heuristic methods which was intro-
! ! !  ! ! ! !  ! ! duced by Mirjalili and Lewis.97 The inspiration comes from the
X1 ¼ Xα
A1  Dα , X2 ¼ Xβ
A2  Dβ , X3
! !  ! hunting behavior of humpback whales. Those humpbacks whales
¼ Xδ
A3  Dδ ð29Þ
have a special hunting behavior which is known as the bubble-net
feeding technique, used for hunting schools of fish. Therefore,
! ! !
! X1 þ X2 þ X3 whales create a 9-shaped net with bubbles that encircles the prey
X ð t þ 1Þ ¼ ð30Þ
3 and makes it easy for the whales to eat them during hunting. 98–100
This technique is described in more details in References [97,99].
where C1, C2, and C3 are calculated by Equation (27), Xα, Xβ, and Xδ The mathematical model for performing the optimization follows
are the first three best solutions at iteration t. A1, A2, and A3 are calcu- three phases:
lated as in Equation (26), and Dα, Dβ, and Dδ are defined as in
Equation (28). Encircling prey
Using the objective function each time the wolves are repositioned, In this phase, humpback whales encircle the prey that they have
an iteration occurred, and the solutions are re-evaluated. Then, the alpha, found. Then, modify their position toward the best search agent
beta, and delta wolves become the three best solutions, respectively. On through a course of iterations. This algorithm considers that the posi-
the other hand, the omega wolves update their positions in the next itera- tion of the target prey is the best or near to the optimum solution.
tion. These moves are repeated until the stopping criterion is met. The mathematical representation is given97,99,100:

! ! ! !
Attacking D ¼ jC  X  ðnÞ
X ðnÞj ð32Þ
The moment that wolves start the attack, the hunting mode is con-
cluded. This can be mathematically represented by the value of !
a ! ! ! !
X ðn þ 1Þ ¼ X ðnÞ
A  D ð33Þ
which is linearly decreased over the course of iterations controlling
the exploration and exploitation:
where n indicates the current iteration, X is the position vector of the
! !
a ðtÞ ¼ 2
ð2  tÞ=MaxIter ð31Þ best solution obtained so far iteration n, X is the position vector of
! !
each agent, A , C are calculated as follows:
Between the prey position and their current position, wolves change
their positions randomly. More details can be found elsewhere.87
! ! ! !
A ¼ 2a  r 1
a ð34Þ

!
C ¼ 2!
r2 ð35Þ
2.2.4 | Artificial bee colony

!
The artificial bee colony approach is proposed in 2005 by Karaboga where components of a are linearly decreasing from 2 to 0, over the
91 92 ! !
and Basturk, then its performance was analyzed in 2007. The course of iterations and r 1 & r 2 are random vectors in [0, 1].
EULDJI ET AL. 7 of 17

Bubble-net attacking method and exploitation of an individual wolf in the search space. For combin-
This attack combines two strategies that can be mathematically ing PSO and GWO variants, Equation (42a) is proposed for the veloc-
defined as follows: ity, while Equation (42b) for updating101:
1. Shrinking encircling mechanism: This technique is simulated by
! ! ! !
decreasing the value of a in (34) which is explained in Refer- dα ¼ j c 1  xα
ω  xj
ences [97,99]. ! ! ! !
dβ ¼ j c 1  xβ
ω  x j ð41Þ
2. Spiral updating position: the helix-shaped movement of hump- ! ! ! !
dδ ¼ j c 1  xδ
ω  x j
back whales is simulated using Equations (36) and (37):
      
! !0 ! vkþ1
i ¼ ω  vki þ c1 r 1 x1
xk1 þ c2 r 2 x2
xki þ c3 r 3 x3
xki ðaÞ
X ðn þ 1Þ ¼ D  e  cosð2πv Þ þ X ðnÞ
bv
ð36Þ ð42Þ
xikþ1 ¼ xki þ vkþ1
i ðbÞ

!0 ! !
D ¼ jX ðnÞ
XðnÞj ð37Þ

2.3 | Hybrid support vector regression models

Here, v is a random number in [
1,1], b is constant for defining
!
the shape of the logarithmic spiral, X is the position vector of the SVR is a robust supervised learning technique to solve nonlinear prob-
!
prey position, and X is the position vector of the humpback whale. lems, type regression. The main concern for researchers, with this
Note that there is a probability of 50% that the humpback whales approach, is the difficulty of defining their best hyper-parameters
swim either around the prey within a shrinking circle or along a helical values for a given database that can ensure sufficient accuracy with
path. Below is the mathematical formula: minimal error. Noted that unsuitable SVR parameter values may cause
over-fitting or under-fitting issues. Traditionally, the grid search algo-
8 ! ! !
! < X ðnÞ
A  D if p < 0:5 rithm and gradient descent algorithm were the most used algorithms
X ðn þ 1Þ ¼ ð38Þ
: !0 ! to determine SVM parameters. Those techniques reported many diffi-
D  ebv  cosð2πvÞ þ X ðnÞ if p > 0:5
culties such as convergence to local minima point, computational
complexity, and height computational time requirement led to the
where p is a random number in [0,1]. development of meta-heuristic optimization algorithms. Some of them
were adopted to determine the SVR parameters as a replacement to
Search for prey the traditional algorithms. GA and PSO can be distinguished. So far,
In the bubble net method, humpback whales search randomly for prey there is no consensus between researchers on which optimization
in order to find the position of the optimal agent. The mathematical technique is much suitable in every aspect, not even for a specific
formula is given by: optimizing problem. This leads to develop new algorithms as well as
comparing their performances when it is needed to.
! ! ! !
D ¼ jC  X rand
X j ð39Þ The present work aims to apply seven meta-heuristics algorithms:
DA, ALO, GWO, ABC, PSO, WOA, and HPSOGWO to seek out the
! ! ! ! optimal values of the three SVR parameters; the constant C (box-Con-
X ðn þ 1Þ ¼ X rand
A  D ð40Þ
straint), ε the epsilon, and σ the parameter of the kernel function
(Kernel-Scale) of the model, while Gaussian was chosen to be the kernel
where Xrand is a random position vector. More detail can be found function. The developed model was carried out by the fitrsvm function
elsewhere. 97–99
of MATLAB® R2021b. The cross-validation “holdout” method was set
to 0.3; 70% of the data were used for the training set, and 30% for the
test set. The meta-heuristic algorithm fed the SVR initially with a ran-
2.2.7 | Hybrid particle swarm optimization grey dom combination of hyper-parameters within their ranges. During sev-
wolf optimizer eral iterations depends on the algorithm used, the steps began with the
division of data and up until the development of the SVR model; it was
The hybridized version of particle swarm optimization with the GWO repeated and the minimum value of AARD obtained was saved as best.
algorithm was developed by applying a low-level co-evolutionary Then, each meta-heuristic algorithm generated a new population of
mixed hybrid, as explained by Reference [96]. The inspiration came to hyper-parameters for the SVR algorithm. The same set of steps were
improve the ability of exploitation in PSO with the ability of explora- repeated to achieve a new best AARD. That was for 100 trials; among
tion in GWO to benefit from both variant's strengths to reduce the which the minimum AARD corresponded to the resultant optimal
possibility of trapping into a local minimum.96,101 hybrid SVR model. Noted that to guarantee the robustness calculus was
The HPSOGWO algorithm uses the following modified equations. performed at various times. The association of the SVR model with the
Equation (41) is used to update the search space of the first three meta-heuristic algorithms selected (DA, ALO, GWO, ABC, PSO, WOA,
agent locations. The inertia constant is used to control the exploration and HPSOGWO) can build the following hybrid models (DA-SVR, ALO-
8 of 17 EULDJI ET AL.

F I G U R E 1 Flowchart of the hybrid

Start metaheuristic-QSPR-support vector
regression (SVR) model.

Data Collection
(168 Drug-like compounds)

Selection of 13 features from

Inputs Selection the previous QSPR modelling
study

Kernel function selection

(Gaussien)

Applied metaheuristics
Algorithms (DA, ALO, Dataset Division Test Set
GWO, ABC, PSO,
WOA & HPSOGWO)

Training Set

Optimizing The SVR

Hyperparameters Training SVR Model

Optimization Process
No Max
Evaluation of SVR
(iteration) ?
Model base on AARD%

Yes

Obtine Optimal SVR

hyperparamiters

Test and evaluate the SVR

model

End

SVR, GWO-SVR, ABC-SVR, PSO-SVR, WOA-SVR, and HPSOGWO-
SVR) respectively. The flowchart of the proposed SVR hybrid models is
summarized in Figure 1.
2.4 | Statistical criteria for evaluation of models'
performances
The evaluation of the performance of a regression model, also known as
validation, is now known as the most important concept for the
development and validation of any model. This process confirms the reli-
ability of the developed model for its possible application on a new set of
data, and confidence of prediction can thus be judged along with the pos-
sibility of receiving a statistical comparison judgment between several
models and various inputs of a model. Hence, a model can lead to the
false prediction of response if the developed model is not validated cor-
rectly. The prediction accuracy of the seven models was examined by
using various statistical criteria and through graphical appraisal, that is,
scatter plot, bar diagrams, and so on. More details are addressed in the
R&D section. The statistical performance indicators are given by:
EULDJI ET AL. 9 of 17

vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
uN  2 where r is the correlation coefficient between the observed and
u P obs
u pred
ti¼1 yi
yi predicted value of compounds with an interception, R2 is the coeffi-
RMSE ¼ ð43Þ
N cient of determination, RMSE is the root-mean-squared error,
AARD is the average absolute relative deviation, MSE is the
P N  obs   
i¼1 yi
yobs  ypred i
ypred mean squared error, RE is the relative error, AICs is the Akaike's
R ¼ r ¼ sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffisffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ð44Þ
P N  2 P N  2 information criterion, MAE is the mean absolute error Af is the preci-
yobs
i
yobs  ypred
i
ypred sion factor and Bf is the bias factor . The error parameters namely
i¼1 i¼1
AARD, RMSE, MSE, and MAE are usually used for comparison
N 
P 2 between different models and not to validate their performance while
yobs
i
ypred
i the statistics R, R2, Q2F1 , Q2F2 , Q2F3 , Af , Bf , and AICs are the statistical cri-
R2 ¼ r2 ¼ 1
i¼1
N  2 ð45Þ
P teria used for evaluation of models performance and validation. More-
yobs
i
yobs
i¼1 over, the statistics AICs and Q2F3 were found to the best suitable
statistics for the evaluation of similar studies as explained in
1X N
yobs
ypred References [102] and [103], respectively. More detail can be found
AARD% ¼ 100  j i obs i j ð46Þ
N i¼1 yi elsewhere.104–108

N  2
1X pred
MSE ¼ i
yi
yobs ð47Þ
N i¼1 2.5 | Applicability domain

According to the third OECD principle of the QSAR modeling valida-

yobs
ypred
RE% ¼ 100  j i predi j ð48Þ tion, any model should have an applicability domain (AD). It is a theo-
yi
retical region defined by the descriptors of the model used to define
the area each time a model can be used for screening new chemicals.
P
Nout 2
yobs
i
ypred
i In other words, chemicals whose structures are “similar” to the ones
i¼1
Q2F1 ¼ 1
ð49Þ
NPout  2 in the training set are the only molecules that can be predicted reli-
yobs
i
yTR
i¼1 ably. Therefore, it is quite impossible to predict all chemicals using a
single model. This study addressed the use of the Williams plot and
P
Nout 2 the Insubria's plot.107,109–112
yobs
i
ypred
i
i¼1
Q2F2 ¼ 1
ð50Þ
NPout  2
yobs
i
yOUT
i¼1 2.5.1 | William's plot

P
Nout  2
yobs
ypred =NOUT William's plot is a plot of standardized residuals vs. the leverage
i i
Q2F3 ¼ 1
i¼1N ð51Þ values refer to Hat (hi) diagonal values; it was used to visualize the
P TR  2
yobs
i
yTR =NTR respective AD and to discover the outlier's response. Those out-
i¼1
liers are usually compounds with standardized residuals greater
  than two ±3 SD units for y-axes and structurally influential chemi-
SSE 2np ðnp þ 1Þ
AICs ¼ Nln þ 2np þ ð52Þ cals (hi > h*) for x-axes in the model, where h* is a threshold lever-
N N
ðnp þ 1Þ
age value. The leverage (h) value of a compound is defined as
N 
X 2 follows:
pred
SSE ¼ i
yi
yobs ð53Þ
i¼0  
1
hi ¼ xi X T X xi ð57Þ

1 X
N
pred
MAE ¼ X i
yi
jyobs j ð54Þ where xi is the descriptor-row vector of the query compound, and X is
N i¼1
a k  n matrix containing the k descriptor values for each one of the
0 1 n training compounds.
P
N yobs
log i
B y
pred
C The warning leverage h* is given by:
@ i¼1
N
i
A
Bf ¼ 10 ð55Þ 3ðp þ 1Þ
h ¼ ð58Þ
n
0 1
PN yobs
jlog i j
B i¼1 ypred C
@ N
i
A
where n is the total number of samples in the training set, and p is the
Af ¼ 10 ð56Þ
number of descriptors involved in the correlation.
10 of 17 EULDJI ET AL.

When h < h*, the observed and predicted values have a high
probability while molecules with hi > h* hardly influence the quality of
fit of the developed model. However, these compounds may not be
an outlier because of low residuals.
It can be observed that compounds with a high value of leverage
and good fitting in the developed model may stabilize the model. In
contrast, compounds with bad fitting in the developed model can be
outliers. Hence, the standardized residual and the leverage must be
utilized at once for the description of the applicability of the domain
of the expanded model.
2.5.2 | Insubria graph
The Insubria graph is a plot of diagonal values versus predicted values
that are used in the case of chemicals without experimental data to
provide a visualization of interpolated and extrapolated predictions. A
zone of higher reliability is always provided for both structures (<h*)
and (
ln(y2)) predictions (between the maximum and the minimum
value of the observed solubility of the training set).
3 | RESULTS AND DISCUSSION
PSO, ABC, ALO, GWO, then DA, with errors of 0.7280, 0.7345,
0.7419, 0.7481, 0.7508, respectively. This conforms to the over-
perform of the meta-heuristic HPSOGWO over the rest six algorithms
in terms of minimizing the cost function (AARD%) and the conver-
gence capacity. Table 1 shows the hyper-parameters of the best per-
formances so far from each meta-heuristic's algorithms used for
tuning the parameters of the hybrid QSPR-SVR algorithm.
Figure 3 represents the scatter plots, that is, predicted versus
observed values of the solubility fraction of drug compounds in SC-
CO2 for the global, train, and test sets for the top three hybrid SVR
models of the best iteration. In general, all the plots of all algorithms
could give a positive correlation between the calculated values and
the experimental values with a few outliers. This confirms the good
quality of all models and proves their ability in predicting.
Table 2 lists the statistics results about AARD, RMSE, MSE, MAE,
r, R2, Q2F1 ,Q2F2 , Q2F3, and AIC for the top three developed models. It can
be observed from Table 2 that the calculated parameters were all valid
with high correlation coefficient r as well as great robustness and the
coefficients of determination R2 were above 1 in addition to the
RMSE, MSE, and MAE of all models which were below 0.3. In sum-
mary, the results above were in total agreement with the acceptability
criteria of the statistical validation of regression models.

3.1 | Comparisons of performances TABLE 1 Hyperparameter of the SVR models.

Parameters models C σ ε
This study had adopted various analysis methods such as convergence
curve to compare the performance of the seven hybrid QSPR-SVR DA-SVR 102.2490 1.7118 0.0076

models and to determine the best-suitable meta-heuristic algorithm so far ALO-SVR 65.0157 1.7484 0.0066
for tuning the hyper-parameters of the SVR model for a dataset of GWO-SVR 60 2 0.0068
168 drug compounds, accounting for 4490 experimental data points ABC-SVR 60 1.6724 0.0067
regarding solubility in supercritical carbon dioxide, and 13 selected inputs. PSO-SVR 62.4902 1.7045 0.0068
Figure 2 represents the convergence curve of the seven selected WOA-SVR 52.0924 1.5791 0.0063
optimization approaches. It is clearly demonstrated, based on the HPSOGWO-SVR 62.9392 1.6780 0.0065
objective function (AARD%) for an amount of 100 iterations, that the
Abbreviations: ABC, Artificial Bee Colony; ALO, Ant Lion optimizers; DA,
hybrid HPSOGWO, colored in blue, led to the lowest error (0.7063),
Dragonfly; GWO, Grey Wolf; HPSOGWO, hybrid particle Swarm with
subsequently the WOA algorithm with an error of 0.7271. The perfor- Grey Wolf optimizers; PSO, Particle Swarm optimizers; SVR, support
mance of this approach was asymptotic to HPSOGWO. Thereafter, vector regression; WAO, Whale optimizers.

F I G U R E 2 Convergence
curve of the seven algorithms.
EULDJI ET AL. 11 of 17

F I G U R E 3 Scatter plots predicted versus observed values for the (1) global, (2) train and (3) test sets, for the top three models: (A) Particle
Swarm optimizers (PSO), (B) Whale optimizers (WOA), (C) hybrid particle Swarm with Grey Wolf optimizers (HPSOGWO).

TABLE 2 Statistics parameters of the seven SVR models.

Statistics models AARD% RMSE MSE MAE r R2 Q2F1 Q2F2 Q2F3 Af Bf AICs

PSO-SVR 0.7280 0.1968 0.0387 0.0709 0.9971 0.9941 0.9941 0.9941 0.9941 1.0073 0.9999
14051.7736

WOA-SVR 0.7271 0.1929 0.0372 0.0705 0.9972 0.9944 0.9944 0.9944 0.9945 1.0073 0.9997
14225.7070

HPSOGWO-SVR 0.7063 0.1883 0.0355 0.0693 0.9973 0.9946 0.9946 0.9946 0.9947 1.0070 0.9996
14434.2487

Abbreviations: AARD, average absolute relative deviation; Af, precision factor; AIC, Akaike's information criterion; Bf, bias factor HPSOGWO, hybrid particle Swarm
with Grey Wolf optimizers; MAE, mean absolute error; MSE, mean squared errorPSO, Particle Swarm optimizers; RMSE, root-mean-squared error, SVR, support
vector regression; WAO, Whale optimizers.
 12 of 17 EULDJI ET AL.

95 F I G U R E 4 Bar distribution diagrams of the

absolute relative error [%] versus number of data
85
points in percentage of the training set.
75
Number of Data Points in %

65
55
45 PSO
WOA
35
HPSOGWO
25
15
5
-5
1 2 3 4 5 6 7 8 9 10 11
Absolute Relative Error %

60 F I G U R E 5 Bar distribution diagrams of the

absolute relative error [%] versus number of data
50 points in percentage of the test set.
Number of Data Points in %

40

PSO
30
WOA

20 HPSOGWO

10

0
1 2 3 4 5 6 7 8 9 10 11
Absolute Relative Error %

F I G U R E 6 William's plot for

hybrid particle Swarm with Grey
Wolf optimizers-support vector
regression (HPSOGWO-SVR)
model.

Consequently, all the models performed well in model development,
assuming an excellent prediction ability of future data. The models
were therefore stable, robust, and predictive, even if the
HPSOGWO-SVR led to the best performances and the best AIC
value of
14434.2487.
In order to quantitatively visualize the distribution of relative
errors, and to compare the generalization capacity, the tendency of
over-fitting of the different models, Figure 4, and Figure 5, illustrated
a bar distribution of the relative error for both training and test set,
respectively.
EULDJI ET AL. 13 of 17

F I G U R E 7 Insubria graph for

the hybrid particle Swarm with
Grey Wolf optimizers-support
vector regression (HPSOGWO-
SVR) model.

From both Figures 4 and 5, all models showed good distribution,

since the majority of the data points fall to the range of 0 to less than
1, more than 90% for the training set, and more than 51% for the test
set. In other words, all models had similar generalization capacity and
showed no over-fitting. In conclusion, these results demonstrate that
the HPSOGWO algorithm is superior to the other six models in terms
of optimizing the SVR hyper-parameters. Overall, the results also illus-
trate that the HPSOGWO-SVR model has a high quality of fast learn-
ing and great generalization capacity to solve nonlinear regression
issues. The SVR is an effective and powerful technique for forecasting
the solubility of the drug compounds in SC-CO2.
Figure 6 shows a plot of standardized residual (Y-axis) versus
leverage values (X-axis) referred to as the Williams plot, for the
HPSOGWO-SVR model while the reliable prediction zone of the
model based on structural similarity to the training compounds (lever-
age value) and the predicted value of solubility was defined with the
Insubria graph in Figure 7.
Analyzing Figure 6, there was no structural influential compound in
the whole dataset that had leverage higher than the warning h*
(0.0139). 98.24% of the whole dataset was located within the horizontal
lines (range of ±3), and only 1.76% showed a distribution without the
suspected limit. Due to its high predictive ability, the proposed model
F I G U R E 8 Scatter plot predicted versus observed for hybrid
could be used to screen existing databases or virtual chemical structures
particle Swarm with Grey Wolf optimizers-support vector regression
to identify solubility. In this case, the applicability domain can serve as a (HPSOGWO-SVR) model, validation set.
valuable tool for filtering out “dissimilar” chemical structures.
In Figure 7, a plot of leverages values (X-axis) versus predicted
values (Y-axis) for both training and test set referred to as the Insubria As mentioned earlier in this article, the whole dataset was ran-
graph of the HPSOGWO was considered. The terms “-lny (Max)” and domly divided into two main sets. The first set (4330 EDP) for model
“-lny (Min)” refer to the maximum (20.7233) and the minimum development and the second set (160 EDP) was kept hidden from the
(2.0956) value of observed solubility in the training set, respectively. build model HPSOGWO-SVR to check the model's capacity in predict-
The predicted results are reliable if both conditions: hi < h* and -lny ing untested data (Figure 8).
(Min) <
lny (Pred) <
lny(Max). Good-of-fit, robustness, and predictive power were confirmed by
We found that all compounds from the test set were located the values of R (0. 9951), R2 (0.9900), Q2F1 (0.9900), Q2F2 (0.9900), Q2F3
within the model's applicability domain. This demonstrates that the (0.9900), relatively low values of errors, AARD% (1.6034), RMSE
model obtained in this work has high applicability to new drugs, and it (0.3102), MSE (0.0962). Moreover, the scatterplot of Figure 8 shows a
can be applied it in order to screen and prioritize them for future visual correlation between observed and predicted solubility fraction
experiments or for filling the data gap. values for the validation set.
14 of 17
Those results confirmed the high quality of the model
HPSOGWO-SVR. Since the error values were close to the training
and test sets and there were no significantly large residual values for
the validation set displayed in Figure 8, it can be concluded in the
absence of over-fitting of the model. In summary, the HPSOGWO-
SVR model has by far the best robustness (>0.9) and high predictive
power and can be recommended for predicting future data falling into
the defined applicability domain.
4 | C O N CL U S I O N
In this article, for the first time, a comparative study was adopted
between seven meta-heuristic algorithms in terms of fine-tuning hyper-
parameters of a hybrid QSPR-SVR model defined for predicting drug
solubility in supercritical carbon dioxide. Solubility of 168 drug com-
pounds was first collected and then correlated with their molecular
structure by QSPR technique and two independent intensive state vari-
ables (temperature and pressure) of a previous study. The seven meta-
heuristic algorithms DA, ALO, GWO, ABC, PSO, WOA, and HPSOGWO
responsible for the seven models DA-SVR, ALO-SVR, GWO-SVR, ABC-
SVR, PSO-SVR, WOA-SVR, and HPSOGWO-SVR were all statistically
and graphically approved, while the hybrid HPSOGWO-SVR model
over-performed the six other models. The HPSOGWO-SVR model
proved to have good predictivity ability and robustness, and thus it can
be used to estimate the solubility for drug compounds without experi-
mental data available in the literature. The validity of the model predic-
tions was further guaranteed by the external test on 160 EDP
compared to experimental values, considering new compounds which
should belong to the applicability domain (William's plot & Insubria
graph). The SVR model presented in this work showed better statistical
parameter values and better predictability results. However, due to the
stochastic nature of all swarm intelligence algorithms, it is never guaran-
teed to find an optimal solution for any problem, which always opens
the door for new possibilities.
AUTHOR CONTRIBUTIONS
Imane Euldji: Methodology (equal); validation (equal); visualization
(equal); writing – original draft (equal); writing – review and editing
(equal). Aicha Belghait: Resources (equal); writing – review and editing
(equal). Cherif Si-Moussa: Methodology (equal); supervision (equal);
writing – original draft (equal); writing – review and editing (equal).
Othmane Benkortbi: Methodology (equal); supervision (equal);
writing – original draft (equal); writing – review and editing (equal).
Abdeltif Amrane: Writing – review and editing (equal).
ACKNOWLEDGMENTS
The authors gratefully acknowledge the Algerian Ministry of Higher
Education and Scientific Research (PRFU Project A16N01UN26
0120220003) and the University Yahia Fares of Medea.
CONF LICT OF IN TE RE ST ST AT E MENT
The authors no conflict of interest.
EULDJI ET AL.
DATA AVAILABILITY STAT EMEN T
The additional data of this article can be found online on (Database-
SvM.PDF). Software, web servers and calculation tools belong to their
respective developers and copyright holders. All statistical and graphic
analyzes have been obtained with codes that we have developed
using the Matlab® R2021B environment.
OR CID
Imane Euldji https://orcid.org/0000-0002-8025-4996
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How to cite this article: Euldji I, Belghait A, Si-Moussa C,
Benkortbi O, Amrane A. A new hybrid quantitative structure
property relationships-support vector regression (QSPR-SVR)
approach for predicting the solubility of drug compounds in
supercritical carbon dioxide. AIChE J. 2023;e18115. doi:10.
1002/aic.18115