The Journal of Supercritical Fluids 130 (2017) 327–336

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The Journal of Supercritical Fluids

journa l homepa ge: www.elsevier.com/locate/supflu

Extraction kinetics and ANN simulation of supercritical fluid extraction of MARK

sage herbal dust
Branimir Pavlić, Oskar Bera, Senka Vidović, Lazar Ilić, Zoran Zekovi ć
⁎

University of Novi Sad, Faculty of Technology, Bulevar Cara Lazara 1, 21000 Novi Sad, Serbia

A R T I C L E I N F O A B S T R A C T

Keywords: The aim of this research was optimization of supercritical fluid extraction (SFE) of sage herbal dust obtained as
Sage herbal dust by-product from filter tea factory. Extraction kinetics modelling and artificial neural network (ANN) simulation
Supercritical fluid extraction (SFE) were used for that purpose. Experiments were performed within expanded Box-Behnken experimental design on
Kinetics modelling three levels and three variables. Influence of pressure (100–300 bar), temperature (40–60 °C) and CO 2 flow rate
Artificial neural network (ANN)
(0.2–0.4 kg/h) on total extraction yield was determined. In order to determine initial slope, extraction curves
Optimization
were fitted with five modified empirical models. Since Sovová model provided the best accordance with ex-
perimental data, initial slope obtained by this model was used as response variable for optimization with ANN
and multivariable models (linear, exponential, logarithmic I and logarithmic II). Optimized SFE parameters for
maximized initial slope were pressure of 283 bar, temperature of 60 °C and CO 2 flow rate of 0.4 kg/h.

1. Introduction selectivity by changing of the pressure and/or temperature and possi-

Sage (Salvia officinalis L.) represents an interesting medicinal plant
which is commonly used in the form of the filter tea. Besides that, sage
leaves (Salviae folium), essential oil (Salviae aetheroleum ) and its tincture
are official drugs according to European Pharmacopoeia [1]. Sage has
great commercial value due to its various biological effects such as:
antidiabetic, antioxidant, gastroprotective, anti-inflammatory, spas-
molytic, antimicrobial and anticarcinogenic activities [2]. Its biological
potential could be attributed to particularly high content of valuable
bioactive compounds, polyphenols [3] and essential oil [4]. Recently,
there have been reports about the possible utilization of herbal dust
generated in filter tea factory for the recovery of various bioactive
compounds such as polyphenols [5,6], chlorophylls and carotenoids
[7]. Furthermore, sage herbal dust was successfully used as raw mate-
rial for extraction of polyphenols using novel extraction techniques
such as ultrasound-assisted extraction, microwave-assisted extraction
[8] and subcritical water extraction [9]. To the best of our knowledge,
sage herbal dust has not been utilized for recovery of lipophilic com-
pounds, i.e. essential oil.
Sage contains 0.7–5.2% (v/m) essential oil [10], which yield highly
depends on applied extraction technique, as well as on plant geo-
graphical origin. Even though sage essential oil has been commonly
obtained by hydrodistillation, in last decade supercritical fluid extrac-
tion (SFE) has been commonly used for that purpose. The reasons for
that are well-known advantages of SFE such as modulation of solvent’s
bility to obtain high-quality solvent-free extracts [11]. Extraction of
bioactives from medicinal plants is defined by the mass transfer phe-
nomena, physico-chemical interactions of solvent and solutes and
properties of the plant material. SFE could be characterized as the
diffusion-controlled process influenced by the solute’s molecular mass,
surface area and film thickness. Mathematical analysis of the SFE pro-
cess could be performed by application of approximated kinetic models.
This could be particularly important for the scaling of the SFE processes
from laboratory to pilot scale. Therefore, kinetic models used for SFE
could be based on heat and mass transfer analogy, or differential mass
balance equations [12].
S. officinalis was extracted by pressurized CO 2 at following condi-
tions: pressure of 9–128 bar and temperature of 25–50 °C and it could
be concluded that a part of essential oil was extracted immediately,
while the other fraction was gradually extracted with cuticular waxes
[13]. Glisic et al. [10] investigated isothermal (50 °C) SFE of sage at
100–300 bar pressure range and observed constant increase of total
extraction yield with the increase of pressure. However, essential oil
compounds (monoterpenes and oxygenated monoterpenes) were se-
lectively extracted at lower pressure (100 bar). Furthermore, Glisic
et al. [10] reported that content of diterpenes could be increased in
lipid extracts when ultrasonic pretreatment of sage was followed by SFE
fractionation. On the other hand, Akalin et al. [14] applied response
surface methodology (RSM) for optimization of pressurized batch
ethanol extraction at following experimental domain: temperature of

⁎
Corresponding author.
E-mail address: zzekovic@tf.uns.ac.rs (Z. Zeković).

http://dx.doi.org/10.1016/j.sup flu.2017.06.015
Received 9 May 2017; Received in revised form 22 June 2017; Accepted 23 June 2017
Available online 24 June 2017
0896-8446/ © 2017 Elsevier B.V. All rights reserved.
B. Pavlić et al. The Journal of Supercritical Fluids 130 (2017) 327–336

280–320 °C, extraction time of 60–120 min and plant concentration in Table 1
ethanol of 8–12%. According to literature data, chemical profile of sage Experimental design with SFE parameters and obtained values of total extraction yield.
extracts obtained by SFE varies with applied extraction conditions.
Run Pressure Temperature [°C] CO2 flow rate Density [g/ Y [%]
However, the most abundant compounds in monoterpene fraction are [bar] [kg/h] cm3]
1,8-cineole, α-thujone and camphor, while sesquiterpene fraction is
usually consisted of viridiflorol [10,13]. Furthermore, diterpene poly- Box Behnken experimental design
1 100 60 0.3 0.290 1.81
phenols could be also present in these extracts [10,15]. Application of
2 300 50 0.2 0.871 5.66
batch ethanol-pressurized CO2 extraction at accelerated temperatures 3 200 40 0.4 0.840 6.58
(280–320 °C) could cause significant chemical alterations in sage oil, 4 200 60 0.2 0.724 5.07
which could result in large number of newly formed compounds with 5 200 40 0.2 0.840 5.14
relatively low content [14]. 6 300 60 0.3 0.830 7.82
7 100 50 0.4 0.384 3.57
The main goal of this research was to obtain different empirical
8 100 50 0.2 0.384 2.55
kinetic models which would be able to adequately describe SFE process 9 300 40 0.3 0.910 6.42
of sage herbal dust. Furthermore, another goal was to determine effects 10 200 60 0.4 0.724 7.48
of investigated SFE parameters (pressure, temperature and CO2 flow 11 200 50 0.3 0.784 5.56
12 100 40 0.3 0.629 2.75
rate) on initial slope of extraction curve and on model parameters. To
13 200 50 0.3 0.784 5.68
the best of our knowledge, artificial neural network (ANN) simulation 14 200 50 0.3 0.784 5.71
was not previously applied for mathematical modelling of SFE-sage 15 300 50 0.4 0.871 8.83
system. Therefore, fitting of extraction curves was followed by ANN and Additional experiments
multivariable modelling in order to determine optimal SFE conditions. 16 300 50 0.3 0.871 5.80
17 100 50 0.3 0.384 2.99
Initial slope of extraction curve was used as response variable in ANN
and multivariable optimization, since it represents solubility-controlled
extraction phase parameter. Table 1. Total extraction yield (Y) was measured after the each ex-
perimental run and result was expressed as grams of total extractable
2. Materials and methods compounds per 100 g of plant material (g/100 g), i.e. percentage (%).
The separator conditions were 15 bar and 25 °C.
2.1. Plant material
2.4. Modelling of the extraction curves
Sage (Salvia officinalis L.) originating from Montenegro was kindly
donated by local filter tea factory, Fructus DOO (Bačka Palanka, Experimentally obtained kinetic curves for each experimental run
Serbia). Aerial parts of sage herbal dust, obtained as by-product in filter (17 runs) were fitted to empirical models obtained from commonly
tea processing, was used as raw material in this research. Sample had used empirical equations used for modelling of SFE process. The first
mean particle size < 0.315 mm. model equation was obtained from the Brunner’s equation [17], which
represents a specific solution of Fick’s law:
2.2. Chemicals
Y = x0 (1 − e−kt ) (1)
Commercial carbon dioxide (Messer, Novi Sad, Serbia), purity > where Y represents the extraction yield (%), k is the rate constant
99.98%, was used for laboratory supercritical fluid extraction. All other (min−1), t is the extraction time (min) and x 0 is the initial content of the
chemicals were of analytical reagent grade. solute in the solid phase (g/g), which is usually obtained by the Soxhlet
extraction with suitable organic solvent. Adjustable parameter in this
2.3. Supercritical fluid extraction equation was k, while x 0 is constant. For mathematical modelling,
previous equation was modified with addition of one adjustable para-
The supercritical fluid extraction (SFE) experiments were performed meter (Y∞):
on laboratory scale high pressure extraction plant (HPEP, NOVA, Swiss,
Efferikon, Switzerland) described in detail by Pekić et al. [16]. The Model I : Y = Y∞ (1 − e− kt) (2)
main plant parts and properties, by manufacturer speci fication were: where Y∞ is the total extraction yield obtained for infinite extraction
gas cylinder with CO2, the diaphragm type compressor with pressure time and is specific for each experimental run, i.e. each set of process
range up to 1000 bar, extractor with heating jacket for heating medium parameters.
with internal volume 200 mL, maximum operating pressure of 700 bar, Similar model was proposed by Reverchon and Sesti Osseo [18] for
separator with heating jacket for heating medium (with internal volume SFE of basil oil:
200 mL, maximum operating pressure of 250 bar), pressure control
valve, temperature regulation system and regulation valves.
Sample (35.0 g) was placed in an extractor vessel and extraction
(
YN = 100 1 − e− ti
t
) (3)
process was carried out and extraction yield was measured after 15, 30, where YN is normalized extraction yield ((Y/Ymax)100) and ti is internal
45, 60, 90, 120, 180 and 240 min of extraction, in order to study the diffusion time. Approximating that t i for certain extraction system could
dynamics and kinetics of the process. First set of experiments consisted be considered as constant, addition of adjustable parameter (a) could
of Box-Behnken experimental design with three variables at three levels avoid use of ti [19]:
with three replicates at the central point (15 runs). Pressure (100, 200
−1
and 300 bar), temperature (40, 50 and 60 °C) and CO2 flow rate (0.2, a=
ti (4)
0.3 and 0.4 kg/h) were independent variables in the process, while all
other SFE parameters were held constant. Furthermore, experimental Adding Eq. (4) in Eq. (3) and a correction term (b), Reverchon and
design was expanded for two more runs, where different combinations Sesti Osseo model could be obtained:
of independent variables (pressure, temperature and CO2 flow rate)
YN = 100(1 − e(at +b) ) (5)
were applied in order to provide more detailed information about ex-
traction kinetics and in fluence of SFE parameters on total extraction Similarly to Eq. (2), modified Reverchon and Sesti Osseo model
yield. Expanded Box-Behnken experimental design is presented in could be obtained with addition of Y ∞ as adjustable parameter:

328
B. Pavlić et al.
Model II : Y = Y∞(1 − e (at+ b)) (6)
Third kinetic model could be derived by model proposed by
Esquivel et al. [20], given by the following equation:
t
me = x0 F ⎛ ⎞ small number of experimental data. ANN architecture was optimized by
⎝b + t ⎠ (7)
where m e is the mass of extract (g), F is the mass of solid material (g), t
is the extraction time (min), x0 is the initial content of the solute in the
solid phase (g/g) and b is adjustable parameter (min). Again, this
equation was modified with addition of one adjustable parameter
[21,22] and used in following form:
Model III : Y = Y∞ ⎛
t ⎞
⎝k + t⎠ (8)
where Y is the total extraction yield (%), while Y∞ and k are the ad-
justable parameters.
Fourth model was derived from kinetic model proposed by Kandiah
and Spiro [23]:
Y = x0 { 1 − [ ƒ1 e(−k1 t ) + ƒ2 e( −k2 t) ]} (9)
where f1 and f2 are the solute fractions extracted with the rate constant
k1 and k 2, respectively. This model was modified by the addition of Y ∞
as adjustable parameter in order to obtained final equation:
Model IV : Y = Y∞ {1 − [ƒ 1e ( −k1 t) + ƒ 2 e ( −k2 t) ]} (10)
Modelling of the SFE process from various plant material could be
successfully performed using simplified mathematical models reported
by Sovová [24]. These models were characterized by characteristic
times during the SFE process, i.e. characteristic time of mass transfer in
the fluid phase (t f), characteristic time of internal mass transfer (ti),
characteristic time of extraction equilibrium (teq) and mean residence
time of the solvent in the extractor (t r). For modelling of the extraction
process which includes a plug flow in the extractor, Sovová proposed
the following model:
Model V: Y = Y∞ G t for t ≤ t1 =
t G
1 Km q˙
t− t1
Y = Y∞ ⎛1 − (1 − G) e− ( ) ⎞ for t > t1
ti
⎝ ⎠ (11)
where G, Km and ti are adjustable parameters, while q̇ is the specific CO2
flow rate (kg CO2/kg plant h). K m is the mass-related partition coeffi-
cient which represents the equilibrium of the mass concentrations on
the particle surface and G is closely related to particle size and frag-
mentation.
2.5. Influence analysis and optimization
Two different approaches were used in order to determine the in-
fluence of pressure, temperature and CO2 flow rate on extraction ki-
netics parameters: artificial neural network (ANN) and fitting of mul-
tivariable models.
2.5.1. Artificial neural network (ANN)
All data analysis with ANN was performed using MATLAB software
(The Math Works Inc., License Number 1108951). The ANN models
with one hidden layer were designed using MATLAB Neural Network
Toolbox. The constructed ANN model had 3 inputs (pressure, tem-
perature and CO2 flow rate) and one output (initial slope (IS) obtained
from the V kinetic model – Sovová model) (Fig. 1).
Training of ANN was performed using the Bayesian regularization.
From all collected data, 85% has been used for training and 15% has
been considered for testing. Hyperbolic tangent sigmoid and linear
function were used as transfer functions for input-hidden and output
layer, respectively. Bayesian regularization updates the weight and bias
values according to Levenberg-Marquardt optimization which
329
The Journal of Supercritical Fluids 130 (2017) 327–336
minimizes a combination of squared errors and weights and then de-
termines the correct combination. Weights and biases values of ANN
model were presented in Table S1 (Supplementary material). Bayesian
regularization does not use data for validation and thus it is suitable for
varying the number of neurons in hidden layer and by changing initial
values of weights and biases.
In order to determine the relative importance and influence of input
variables on initial slope, assessment process based on the connection
weights partitioning (Yoon’s method) was applied. Also, the optimiza-
tion of the extraction procedure (maximizing the IS) was conducted in
MATLAB with built in functions fmincon and MultiStart with 15
random starting points in order to find global maximum.
2.5.2. Multivariable models
Besides ANN, multivariable models were also used to fit the de-
pendence of IS on pressure, temperature and CO 2 flow rate. Four dif-
ferent multivariable models were tested: linear, exponential and two
logarithmic functions (Eqs. (12)–(15)). Dependent variable chosen to
describe extraction kinetics was initial slope (IS) obtained from the V
kinetic model – Sovová model. IS was successfully used as kinetics
parameter in previous papers [25] and Sovová model exhibited the best
fit with experimental data.
Linear model: IS = b1 + b2 p + b3 T + b4 q (12)
Exponential model: IS = b1 + b 2 e b3 p + b4 e b5 T + b6 e b 7 q (13)
Logarithmic I model : IS = b1 + b2 ln(p) + b3 ln(T ) + b4 ln(q ) (14)
Logarithmic II model : IS = b1 + b 2 ln(pTq ) (15)
where b 1-b 4 (Eq. (12)), b1-b 7 (Eq. (13)), b1-b 4 (Eq. (14)) and b1-b2 (Eq.
(15)) are regression coeffi cients for linear, exponential, logarithmic I
and logarithmic II model, respectively. All fitting models were utilised
to determine the relative importance of variables on initial slope. Fit-
ting parameters in models were calculated using least square method
and experimental data points were normalized using feature scaling in
order bring all values into the range 0–1 for linear and exponential
models or into the range 1–2 for logarithmic functions.
Partial derivatives of multivariable models were used to calculate
and estimate the relative importance and influence of input variables on
initial slope:
∂IS
Infx i =
mean ( ) ⋅100[%]; i = 1…3
∂x i
∑n= 1
n= i ∂ IS
mean ( ) ∂ xn
(16)
where Inf xi is relative influence of independent variables (pressure,
temperature and CO2 flow rate, respectively) and xi is their respective
coded value.
2.6. Statistical analysis
The accordance between experimentally obtained extraction yields
and calculated values obtained from fitted model equations by five
mathematical models was established by the sum of squared errors
(SSer ) and coefficient of determination (R2).
3. Results and discussion
SFE was applied in order to recover lipophilic bioactive compounds
from sage herbal dust. Extractions were performed at different set of
SFE parameters and experimentally obtained values of total extraction
yield (Y) are presented in Table 1. It could be observed that Y was in
range from 1.81 to 8.83%, and the highest Y was obtained at pressure of
300 bar, temperature of 50 °C and CO2 flow rate of 0.4 kg/h. SFE of
terpenoid compounds from S. officinalis was comprehensively
B. Pavlić et al. The Journal of Supercritical Fluids 130 (2017) 327–336

Fig. 1. Schematic structure of the ANN architecture

used for optimization (8 hidden neurons).

researched in the last decade [10,26,27]. Babovic et al. [28] performed

SFE of sage at increased temperature (100 °C) and moderate pressure
(250–300 bar) in order to increase solvent selectivity towards diterpene
polyphenols (carnosic acid, carnosol and epirosmanol), however, Y was
decreased (1.53%). On the other hand, Glisic et al. [10] compared SFE
with conventional extraction techniques used for essential oil recovery
(Soxhlet extraction and hydrodistillation). Y of essential oil obtained by
hydrodistillation was 0.5%, while the highest Y obtained by SFE was
4.28%, which was achieved at the same set pressure (300 bar) and
temperature (50 °C), i.e. CO 2 density (0.871 g/cm3), as it was the case
in this work (Table 1). Fornari et al. [26] proposed two-stage fractio-
nation sage extracts obtained by SFE at 300 bar and 40 °C. First extract
was separated at 100 bar and 40 °C yielding 1.39%, while conditions in
Fig. 2. Influence of pressure on SFE kinetics at 50 °C and 0.3 kg CO2/h.
second separator were 10 bar and 40 °C providing 3.23% yield of ex-
tract rich in essential oil compounds.

3.1. Influence of SFE parameters on total extraction yield

Box-Behnken experimental design was expanded with two addi-

tional experiments (runs 16 and 17) in order to provide more thorough
analysis of SFE parameters (pressure, temperature and CO2 flow rate)
influence on Y (Table 1). Influence of pressure was determined at 100,
200 and 300 bar, while temperature (50 °C) and CO2 flow rate (0.3 kg/
h) were held constant and obtained kinetic curves were presented on
Fig. 2. It could be observed that Y increased from 2.99 to 5.80% with
increase of pressure from 100 to 300 bar for total extraction time
(240 min). Furthermore, Y increase was more pronounced for pressure
increase from 100 to 200 bar, while further increase of pressure Fig. 3. Influence of CO2 density on Y at 50 °C and 0.3 kg CO 2/h.

(300 bar) did not provide significant Y increase. This is rather expected,
since CO 2 density at 50 °C and pressures of 100, 200 and 300 bar is

330
B. Pavlić et al.
Fig. 4. Influence of temperature on SFE kinetics at 300 bar and 0.3 kg CO2 /h.
0.384, 0.784 and 0.871 g/cm3 , respectively. Therefore, significant in-
crease of CO 2 density is proportional with the increase of Y (Fig. 3).
Similar influence of pressure at isothermal conditions (50 °C) was re-
ported by Glisic et al. [10]. Furthermore, pressure has been the most
important SFE parameter infl uencing Y [26]. Increase of pressure leads
to increase of CO2 density increasing solvating power of CO2 and re-
ducing its selectivity towards volatile compounds. It is not always
suggested to perform SFE at the highest pressure, since it is possible to
dilute target compounds content in extract. However, it must be con-
sidered that concomitant compounds would not necessarily decrease
extracts quality and bioactivity.
Temperature effect on Y was investigated at 40, 50 and 60 °C, while
pressure and CO 2 flow rate were held constant (300 bar and 0.3 kg/h).
Kinetic curves are presented at Fig. 4. The highest Y (7.48%) after
240 min of extraction time was at 60 °C, while the lowest Y (5.68%)
was observed at 50 °C under isobaric conditions, suggesting the com-
plexity of the temperature influence on supercritical CO2 and plant
material. Increased temperature causes decrease of CO2 density and
further decrease of its solvating power. On the other hand, temperature
affects vapour pressure of the solute causing increase of solubility,
particularly for volatile compounds. According to results, relatively
high Y was obtained at 40 °C, which decreased when extraction was
performed at 50 °C (Fig. 4), due to decrease of CO2 density from 0.840
to 0.784 g/cm3. Further increase of temperature provided the highest Y,
suggesting prevailing influence on vapour pressure of sage terpenoids
over decrease of CO2 density at 60 °C (0.724 g/cm3 ). According to lit-
erature data, there is no information about temperature influence on Y
in similar experimental domain (40 –60 °C). Other SFE of sage were
either focused on influence of pressure [10], particle size [29], or on
batch ethanol-pressurized CO 2 extraction at temperature range
280–320 °C [14], which is not suitable for comparison with present
data. However, similar influence of temperature in the same experi-
mental domain (40–60 °C and 300 bar) on SFE of lavender essential oil
was reported by Nađalin et al. [30].
CO2 flow rate influence on Y was investigated at isothermal-isobaric
conditions (50 °C and 300 bar) and kinetic curves are presented on
Fig. 5. Influence of CO2 flow rate on SFE kinetics at 300 bar and 50 °C.
331
The Journal of Supercritical Fluids 130 (2017) 327–336
Fig. 5. It could be observed that the highest Y (8.83%) was achieved
when the highest CO2 flow rate (0.4 kg/h) was applied. On the other
hand, there was no significant difference in kinetic curves obtained at
0.2 and 0.3 kg/h (Fig. 5). CO2 flow rate influence mass transfer prop-
erties such as axial dispersion, convective mass transfer coefficient and
accumulation in the fluid phase, contrary to pressure and temperature
which affect both mass transfer and thermodynamic properties [11].
Extraction efficiency could be increased with reduction of mass transfer
resistance which could be achieved with high interstitial velocity,
which was achieved with 0.4 kg/h CO 2 flow rate. However, influence of
CO2 flow rate must be also evaluated from the economic point of view
since increased solvent consumption consequently increases opera-
tional costs. Furthermore, SFE kinetic curves could be divided in few
extraction periods controlled by different mass transfer mechanisms
controlled by convection, solubility and internal diffusion [31].
Therefore, influence of CO2 flow rate must be evaluated together with
extraction time and extraction kinetics modelling would be essential for
that purpose.
3.2. Extraction kinetics modelling
The extraction kinetics of lipophilic compounds from sage herbal
dust at different set of pressure, temperature and CO2 flow rate
(Table 1) was observed after 15, 30, 45, 60, 90, 120, 180 and 240 min.
Obtained experimental data were fitted to the empirical models de-
scribed with Eqs. (2), (6), (8) , (10) and (11) and calculated parameters
for five applied models are presented in Table 2. Accordance between
experimental data and applied models was described by sum of squared
errors (SS er) and coefficient of determination (R 2) which were pre-
sented in Table S2 (Supplementary material). According to statistical
parameters, i.e. relatively low SSer and particularly high R 2, it could be
observed that all applied models represented adequate approximation
of experimental data (Table S2). Furthermore, model V provided the
best fit with experimental data according to mean value of SS er and R2
(0.0675 and 0.9973) (Fig. 6f). Model I was described with Y ∞ and k as
adjustable parameters. Furthermore, Y∞ was calculated parameter in
all investigated models. According to results from Table 2, it could be
observed that investigated SFE parameters exhibited similar influence
on Y ∞ as it was the case with experimentally observed Y. This is rather
expected since Y∞ represents asymptotic value of total extraction yield
specific for each set of pressure, temperature and CO2 flow rate. On the
other hand, k from the model I was the highest at 200 bar
(0.0165 min−1) and the lowest at 300 bar (0.0109 min−1) at fixed set
of temperature (50 °C) and CO2 flow rate (0.3 kg/h). Furthermore, k
was the lowest at 50 °C (0.0109 min−1) and the highest at 60 °C
(0.0182 min−1) at constant pressure and CO2 flow rate, as it was the
case with Y (Fig. 4). Experimental and fitted curve of model I for the
sample 14 (central point; 200 bar, 50 °C and 0.3 kg CO2 /h) with char-
acteristic model parameters is presented on Fig. 6a. According to data
from Table 2, it could be observed that Y∞ was very similar for models I
and II, however, influence of SFE parameters on a was rather complex
due to addition of correction term b. Addition of one adjustable para-
meter slightly increased agreement of experimental data and model II
(Table S2). However, it could be observed that fitting curves of models I
and II were very similar for sample 14 (Fig. 2a and b). In model III (Eq.
(8)), calculated Y∞ was generally the highest for experimental runs
(Table 2), however, trend of SFE parameters influence on Y ∞ was the
same as it was observed in other models. Influence of SFE parameters
on k from model III was completely opposite from the model I (Table 2),
which is expected since Y decreases with the increase of k (Eq. (8)).
According to statistical data (SSer and R2 ), model III (modified Esquivel
et al. model) exhibited the lowest fit with experimental results (Table
S2), contrary to SFE of winter savory [32] and coriander seeds [25] at
same equipment and similar set of SFE parameters, where Esquivel
et al. model exhibited better fit than one-stage diffusion model. Model
IV (modified Kandiah and Spiro model) could be separated on two
B. Pavlić et al. The Journal of Supercritical Fluids 130 (2017) 327–336

extraction curves presented on Fig. 6d. Fitted extraction curve for

ti [min]

139.66

115.78
143.71
117.82

137.51
118.47
157.49

57.20

66.27
77.20
80.50

76.55
93.26
65.97
72.24
88.26

78.49
model IV was very similar to I and II model curves (Fig. 6a, b and d).
Part 1 of the extraction curve represents the fraction extracted in so-
lubility-controlled extraction period, while part 2 represents the frac-
t1 [min]

tion extraction in diffusion controlled period. It could be observed that

45.00

46.41
36.92

31.32
47.39
32.82

35.21
21.77
51.86
45.00
14.99

52.26

54.57
48.39
19.77

45.00

17.77
Y∞ in this model was generally similar to Y∞ obtained in models I and
II, however, SFE parameters significantly influence the fractions ob-
tained in first and second phase of extraction, as well as kinetic coef-
0.14322

0.09012

0.07800

0.04740

0.06030
0.10836

0.10128
0.08454
0.08958

0.07134
0.06924
0.12042
0.05568
0.12300

0.08442

0.09846
0.06810
ficients for these periods (k 1 and k2 ) (Table 2). At fixed set of pressure
Km

and CO 2 flow rate, f1 was the highest at 50 °C (0.692%). Similarly, f 1

was also the highest at middle level of CO 2 flow rate at constant pres-
sure and temperature (Table 2). On the other hand, f 1 was 0.844, 0.500
0.5713

0.4531
0.5724
0.5602

0.3588
0.4044

0.3860

0.2640

0.3047

0.3998
0.2871
0.5943
0.4772
0.1755

0.6303

0.5113
0.4708

and 0.692% at pressure of 100, 200 and 300 bar, respectively, at fixed
G

temperature and CO2 flow rate. Model IV represented better approx-

imation of experimental data than models I and II (Table S2), as it was
Model V

Y∞ [%]

the case with SFE of basil at similar experimental domain [33]. The
5.66

5.78
5.89
7.82

3.52
2.12

5.55

3.72

3.23

6.54
9.25
5.94
6.86
5.26

8.37

2.88
7.20

lowest mean SSer (0.0675) and the highest R 2 (0.9973) were obtained
for the model V (Sovová model), therefore, this model exhibited the
best fit with the experimental data. The most important parameters in
]
−1

Sovová model are characteristic times of the extraction steps [24]. It

k2 [min

0.0037

0.0140

0.0175
0.0106
0.0160
0.0137
0.0134

0.0234

0.0177
0.0206

0.0206

0.0137
0.0166
0.0086

0.0470
0.0104

0.0852

could be observed that t 1 was < 60 min for all SFE runs, suggesting that
constant extraction rate in the first phase of extraction is solubility-
controlled process due to good transport properties of supercritical CO2.
f2 [%]

Due to direct effect on concentration gradient, CO 2 flow rate exhibited

0.502

0.680
0.500
0.468

0.156
0.663

0.500

0.093

0.244

0.310
0.697
0.500
0.500
0.500

0.387

0.379
0.320

greater influence on t1 comparing to pressure and temperature

(Table 2). Another characteristic time is t i , which represents the internal
diffusion-controlled extraction phase. Even though it is expected that ti
]
−1

should be flow-independent parameter [24], CO2 flow rate significantly

k 1 [min

0.0711

0.0045

0.0078
0.0244
0.0160
0.0137
0.0134

0.0148

0.0108
0.0097

0.0208

0.0292
0.0166
0.0396

0.0087
0.0104

0.0124

affected ti in the range from 0.2 to 0.4 kg/h, while temperature effect on
ti was negligible (Table 2). Fitted extraction curve of the model V and
run 14 with characteristic times could is presented on Fig. 6e. Mass-
f 1 [%]

0.303
0.500
0.500
0.500

0.613

0.621
0.681

0.498

0.320
0.500
0.532

0.844
0.337

0.500

0.907

0.758

0.692

related partition coefficient (Km) was between 0.0603 and 0.1432 and
was strongly influence by SFE parameters. Furthermore, all SFE para-
meters also exhibited high influence G, which is rather expected since
Model IV

Y ∞ [%]

this parameter is associated with particle fragmentation degree and

9.39
5.71
7.01
5.29

7.82

2.62
6.86

5.61

5.78
5.76
8.04

3.29
2.50

5.69

3.74

3.71

6.50

rupture of the cells occurs during SFE [30].

3.3. ANN simulation and multivariable modelling

k [min]

122.79

188.89

112.59
75.65
68.67
85.37
86.12

57.16

86.83
88.38

47.72

56.27
65.11
38.99

87.38
38.82

71.24

Recent optimization studies of SFE focus on application of novel

statistical techniques (RSM and ANN) in order to determine the best set
Model III

of process parameters (pressure, temperature, CO 2 flow rate, extraction

11.88
7.42
9.40
7.08
8.03
9.78

3.46
8.89

6.97
4.89
7.13
7.44

8.59
8.83

4.00
1.99

4.68
Y∞

time, particle size, cosolvent concentration, etc.), which would provide

the highest Y, or the highest yield of target compound(s). RSM has been
Calculated parameters of five empirical models applied for SFE kinetics modelling.

commonly applied procedure in most of the optimization studies [34],

− 0.0178

− 0.0072

− 0.0226
−0.0735

−0.0174
0.0337
0.0312
0.0048
0.0146
0.0244

0.0249
0.0139

0.0271
0.0184
0.0045
0.0251

0.0032

however, application of ANN for this purpose is gaining more and more
attention recently [35–40]. From economical point of view, the main
b

drawback of this approach is limitation for optimization of industrial

scale processes, since Y is usually the main response. Y is measured at
−0.0225
−0.0215
−0.0080
−0.0183
−0.0173
−0.0143
−0.0110
−0.0122
−0.0193
−0.0170
−0.0145
−0.0135
−0.0108
−0.0190
−0.0145
−0.0142
−0.0136

the end of the SFE process which lasts until the complete exhaustion of
the plant material, i.e. internal diffusion-controlled period. This is
a

hardly scalable on the industrial processes since it is not economically

feasible to perform extractions until diffusion-controlled period due to
Model II

Y∞ [%]

high time consumption. Therefore, it was proposed in our previous

7.34
5.59
3.16
5.65
5.73
9.11
6.18
3.05
1.70
5.65
6.93
5.28
5.63
7.66
3.64
2.55
6.58

study that initial slope calculated from the kinetic curves could be
suitably used as response for optimization study [25], to make opti-
]

mization more applicable to large scale processes. Initial slope would

−1

0.0225
0.0160
0.0137
0.0134
0.0104
0.0182
0.0151
0.0134
0.0131
0.0232
0.0206
0.0074
0.0181
0.0165
0.0145
0.0109
0.0129
k [min

adequately represent solubility-controlled extraction phase, where ex-

traction rate is constant (Fig. 6). Therefore, initial slope obtained from
the Sovová model was used as response variable, since this model
showed the best fit with experimental data (Table S2, Supplementary
Model I

Y∞ [%]

material).
1.66
5.70
7.01
5.29
5.69
7.70
3.62
2.58
6.63
7.32
5.62
3.26
5.65
5.77
9.08
6.19
3.01

Results obtained by ANN could significantly vary with initial value

of parameters used for construction of ANN and fitting, as well as with
Table 2

Run

number of hidden neurons used for ANN construction. Therefore, the

10
11
12
13
14
15
16
17
1
2
3
4
5
6
7
8
9

number of neurons in hidden layer was varied from 1 to 20 and the

332
B. Pavlić et al.
Fig. 6. Experimental data and fitting curves of sample 14 (200 bar, 50 °C and 0.3 kg CO 2/h) for five kinetic models.
training process of each network was repeated 10 times with random
initial values of weights and biases in order to avoid mentioned influ-
ences on ANN results. The result of this procedure was creation of 200
ANNs in total. Neural networks with coefficient of determination (R2)
higher than 0.5 were used for further analysis (198 of 200 ANNs). R2
value showed rising trend with increase of the number of neurons in the
hidden layer. Mean value of R2 was 0.768 for all created ANN, while the
best fitting was achieved with neural network with 8 hidden neurons
(R 2 = 0.917, SSer = 0.0013). Therefore, this ANN was used for further
optimization calculations in order to avoid “overfitting” with high
number of hidden neurons. In order to avoid large number of regression
coefficients in ANN which were obtained by relatively small number of
experiments, experimental data were fi tted by alternative multivariable
models (linear, exponential, logarithmic I and logarithmic II).
Regression plots for ANN and multivariable models with fitting quality
parameters (SSer and R 2) are presented on Fig. 7. According to SS er and
333
The Journal of Supercritical Fluids 130 (2017) 327–336
R2, ANN model exhibited the best fit with the experimental data, while
the logarithmic model II with the highest SSer (0.0038) and the lowest
R2 (0.747) exhibited the poorest fit. R2 value was in correlation with
number of regression used in each model, which is rather expected
since addition of regression coefficients in the model equation would
increase the accordance with the experimentally obtained results.
Therefore, accordance between experimental results and model equa-
tions in increasing order was: ANN, exponential, logarithmic I, liner and
logarithmic II, while SS er for these models was 0.0013, 0.0019, 0.0035,
0.0036 and 0.0038, respectively.
Weight matrices obtained by ANN were used for calculation of re-
lative importance and its infl uence (Inf) on response variable. For ANN
optimization, influence of each variable was calculated by equation
proposed by Yoon et al. [41], while the same influence in multivariable
models was calculated by partial derivatives of model presented in Eq.
(16). Therefore, ANN simulation provided quantification of SFE
B. Pavlić et al. The Journal of Supercritical Fluids 130 (2017) 327–336

Fig. 7. Regression plot for ANN with best performance (8 hidden neurons) and multivariable models.

Fig. 8. Relative influence of SFE parameters obtained for all applied models.

334
B. Pavlić et al.
Table 3
Optimization of SFE conditions for maximal initial slope and comparison with experi-
mental results.
Pressure Temperature [°C] CO2 flow Initial slope [%
[bar] rate [kg/h] min−1 ]
Experimental 200 60 0.4 0.13347
ANN model 283 60 0.4 0.13858
parameters influence on initial slope, comparing to influence analysis of
SFE parameters on Y, which was discussed previously (Chapter 3.1).
Relative infl uence of SFE parameters on initial slope obtained by ANN
and multivariable models is presented on Fig. 8. It could be observed
that pressure was the most influential parameter with 35.18%, while
relative influence of temperature and CO2 flow rate was 23.84 and
32.98%, respectively. Quantitative influence of SFE parameters was in
accordance with literature data about ANN modelling of SFE of essen-
tial oil from Launaea acanthodes [40] and Coriandrum sativum [25].
However, temperature exhibited negative influence on initial slope in
SFE of C. sativum (Zeković et al., 2017), while in this work all SFE
parameters exhibited positive influence (Fig. 8). Positive influence of
pressure could be explained by increased solubility power of CO 2 at
elevated pressure, while increased CO2 flow rate directly affects the
concentration gradient and decreases mass transfer limitations. Since
temperature affects both solute vapour pressure and CO2 density, i.e.
solubility power, positive influence indicated that its in fluence on in-
crease of vapour pressure would be more expressed comparing to de-
crease of solvent density. Therefore, it could be concluded that positive
influence of temperature on extraction rate is directly connected with
increase of vapour pressure of volatile sage terpenoids. The same dis-
tribution of SFE parameters influence was obtained by linear, ex-
ponential and logarithmic I model (Fig. 8), suggesting that adequate
calculation of relative influence could be obtained with multivariable
models with less regression coefficients. However, logarithmic II model
showed limitation in determination of relative influence (Fig. 8), since
all SFE parameters were described with one regression coeffi cient (b2)
from Eq. (15).
Initial slope was the response variable used for the ANN optimiza-
tion within investigated experimental domain of SFE parameters
(pressure, temperature and CO2 flow rate). Determination of optimal
conditions was performed in MATLAB using ANN with 8 hidden neu-
rons which showed the best accordance with experimental data.
Predicted value of initial slope at calculated optimal conditions as well
as maximal experimentally observed value of initial slope, are pre-
sented in Table 3. Predicted SFE conditions which provided the highest
value of initial slope (0.13858% min −1) were pressure of 283 bar,
temperature of 60 °C and CO2 flow rate of 0.4 kg/h. Furthermore, it
could be noted that pressure was the only different variable in experi-
mentally observed and predicted optimized conditions. Finally, ANN
simulation provided increase of initial slope for 3.83% comparing to the
highest experimentally obtained initial slope observed in sample 10.
4. Conclusions
SFE was successfully utilized as novel extraction technique for the
recovery of lipophilic bioactive compounds from sage herbal dust ob-
tained as by-product from filter tea factory. Experiments were per-
formed using expanded Box-Behnken experimental design with pres-
sure (100, 200 and 300 bar), temperature (40, 50 and 60 °C) and CO2
flow rate (0.2, 0.3 and 0.4 kg/h) as independent variables. The highest
yield (8.83%) was achieved at following conditions: 300 bar, 50 ° C and
0.4 kg CO 2/h. Kinetic curves were fitted with five commonly used
empirical models. According to fitting quality parameters (SSer and R2),
all applied models fitted well with the experimental data, however,
Sovová model (V model) exhibited the best fi t due to the lowest SSer
335
The Journal of Supercritical Fluids 130 (2017) 327–336
(0.0675) and the highest R2 (0.9973). Initial slope obtained from this
model was used as a response variable for ANN simulation multi-
variable modelling, since it represents solubility-controlled extraction
phase which could be applicable for optimization of industrial scale
processes. Predicted SFE conditions which provided the highest value of
initial slope (0.13347% min−1) were pressure of 283 bar, temperature
of 60 °C and CO 2 flow rate of 0.4 kg/h, which was 3.83% higher com-
paring to the highest experimentally obtained initial slope observed in
sample 10. It could be observed that all SFE parameters exhibited po-
sitive influence on initial slope, which was con firmed by both ANN and
multivariable modelling. Furthermore, multivariable models exhibited
adequate fit with experimental data, which provided obtaining of
model equations with less regression coefficients comparing to ANN
model. Further perspectives of this work would be comparison of ex-
tracts sage extracts obtained by SFE with extracts obtained by con-
ventional techniques (hydrodistillation and Soxhlet extraction with
organic solvents) in terms of chemical profile and yield of terpenoid
compounds responsible for bioactive potential of this plant.
Acknowledgements
The authors would like to thank the Fructus (Bačka Palanka, Serbia)
for kind donation of sage herbal dust sample.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.sup flu.2017.06.015.
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