Journal of Chromatography A 1651 (2021) 462295

Contents lists available at ScienceDirect

Journal of Chromatography A
journal homepage: www.elsevier.com/locate/chroma

Green non-conventional techniques for the extraction of polyphenols

from agricultural food by-products: A review
Imma Pagano a, Luca Campone b,∗, Rita Celano a, Anna Lisa Piccinelli a, Luca Rastrelli a
a
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, Fisciano, (SA) 84084, Italy
b
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza Della Scienza 2, Milano 20126, Italy

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

Article history: Food processing industry is accompanied with the generation of a great production of wastes and by-
Received 16 December 2020 products exceptionally rich in bioactive compounds (especially phenolics), with antioxidant activity. The
Revised 22 May 2021
recovery of these health molecules constitutes a key point for the valorization of by-products, with the
Accepted 25 May 2021
possibility of creating new ingredients to be used for the formulation of food and cosmetic products. One
Available online 28 May 2021
of the main limitations to reuse by-products is linked to the high cost to obtain bioactive compounds,
Keywords: consequently in order to exploit these resources commercially valuable it is necessary to develop inno-
Agricultural food by-products vative, economic and environmentally friendly extraction strategies. These extraction methods should be
Polyphenols able to reduce petroleum solvents, energy consumption and chemical wastes, protecting both environ-
Green extraction ment and consumers and ensuring safe and high-quality final products. The purpose of this review is
SFE to summarize current knowledge and applications of the new extraction techniques such as supercritical
PLE
fluid extraction, pressurized liquid extraction, ultrasound assisted extraction applied to polyphenols ex-
UAE
traction from agricultural food by-products. Particular attention has been paid to theoretical background,
highlighting mechanisms and safety precautions. Authors concluded that relevant results of these tech-
niques represent an opportunity to industrial scale-up, improving the extraction yields, minimizing time,
costs and environmental impact.
© 2021 Elsevier B.V. All rights reserved.

1. Introduction In the United Kindgom it is estimated that around 3.62Mt of

The agricultural and food industries produce a large amount
of by-products in the form of non-edible parts derived from the
cultivation and processing of crops. It is estimated that 140 bil-
lions of tons of biomass are generated each year from agricultural
by-products in liquid, solid and gaseous form [1,2]. Unfortunately
there is a lack of comprehensive information about the produc-
tion of agriculture residue in the world and there is no statical
source [3]. In this context, by-product amount is established start-
ing from product yield and residue to crop ratios: i.e. for wheat
as straw 475.14, soybeans as straw and pods 392.7, tomatoes as
leaves and stems 72.87 millions metric tons per year (MMT/year)
[1]. Food waste is the decrease in the quantity or quality of food
resulting from decisions and actions by retailers, food services and
consumers, and FAO (2019) estimated amount of food loss to about
14% of food production at global level [4]. Value of waste are
higher for fruits and vegetables than for cereals and pulses, espe-
cially in sub-Saharan Africa [4].
∗
Corresponding author.
E-mail address: luca.campone@unimib.it (L. Campone).
food is wasted in the primary production stage of food supply
chain: vegetables and starchy roots contribute 37% (the majority
potatoes and cereals) mainly for quality and aesthetic standards
[5].
Agricultural residues can be defined as primary or secondary
depending on their origin. Primary residues are solid vegetal
residues left in the field after harvesting or pruning. Secondary
residues are the portion derived from food processing industries
and discarded during the processing phase (hulls, husks, peels po-
mace, olive pits, nut shells, etc.) [1].
The production of agricultural waste varies from country to
country, in Europe over than 40% of initial weight is disposed while
in North Africa, East Central Asia and Latin America this percentage
is higher. For example the percentage amount of some agricultural
by-products is for artichoke about 50–60% of initial weight and for
orange about 60% [6].
Although by-products consist in a promising feedstock for sev-
eral uses, they are currently underutilised, and before starting a
valorisation process certain consideration must be address. First of
all, the raw materials are not homogenous and may come from dif-
ferent fields with differing cultivation procedures, conditions and

https://doi.org/10.1016/j.chroma.2021.462295
0021-9673/© 2021 Elsevier B.V. All rights reserved.
I. Pagano, L. Campone, R. Celano et al.
processing; consequently, a standardization process is necessary.
Agricultural food by-products are characterized by their biological
instability due to their high microbial load that can affect prod-
uct safety and naturally accelerate microbial degradation and high-
water load which increases weight, leading to higher transporta-
tion costs. High values of Chemical Oxygen Demand (COD) and
Biochemical Oxygen Demand (BOD) mostly due to their organic
nature, also caused by the presence of compounds with antioxi-
dant and antimicrobial activity, prevent disposal via the classical
wastewater treatment, irrigation and fertilization of fields [7]. Agri-
cultural food by-products have been mainly utilized as animal feed,
in fuel and energy production, but recently researchers have be-
gun to explore the characteristics of these by-products as sources
of bioactive compounds (carotenoids, dietary fibers, minerals and
polyphenols) for pharmaceutical, cosmetic and nutraceutical sec-
tors due to the great chemical heterogeneity [8].
Amongst all the bioactive compounds that can be obtained from
agri-food by-products, in recent years, phenolic compounds have
attracted the attention of researchers due to their health bene-
fits [9]. Phenolic compounds are a large class of secondary plant
metabolites that are derivatives of pentose phosphate, shikimate
and phenylpropanoid pathway [10]. From the chemical point of
view phenolic compounds showing a broad range of structure
from rather simple phenolic molecules to high polymerised com-
pounds; the simpler compound consists of an aromatic ring with
one or more hydroxyl substituents e.g. phenolic acids. Despite this
wide range of chemical structures this class of compounds is of-
ten called polyphenols. However, in order to make their classifica-
tion easier, it is possible to divide the polyphenols into two ma-
jor types, flavonoids and non-flavonoids. The flavonoids are built
around a C6-C3-C6 carbon skeleton (flavones, flavanones, flavonols,
dihydroflavonols, flavan-3-ols, flavan-3,4-diols, chalcones, dihydro-
calchones and aurones). Non-flavonoids include phenolic acids, cin-
namic acids, stilbenes and lignans [11]. Chemically, polyphenols
possess an aromatic and a benzene ring with one or more hydroxyl
groups. Several studies have reported that a diet rich in these
bioactive compounds correlates with the prevention of degenera-
tive and cardiovascular diseases [12,13]. Phenolic compounds ex-
hibit a wide range of physiological properties such as antioxi-
dant, anticarcinogen, antimutagen, antiallergen and antiaging ac-
tivity, moreover, they can be used in functional foods as natural
antioxidants.
Chemical determination of polyphenols involve combining ad-
vanced separation tools with advanced sample preparation tech-
niques. Sample preparation is a vital step for the selective and effi-
cient extraction of target compounds. It converts the plant matrix
into a suitable sample for subsequent analytical techniques. Cur-
rently the development and application of modern techniques for
sample preparation provide several advantages.
The preparation and extraction of bioactive polyphenols de-
pends on the individual structure of the sample matrix and also
on chemical properties of desired compounds. For liquid samples,
liquid-liquid extraction (LLE) is performed, whereas for solid sam-
ples, solid-liquid extraction (SLE) is carried out. Amongst all pa-
rameters to consider, the chemical properties of target compounds
are important features in the selection of the most appropriate
extraction process. In particular, polarity, molecular structure, and
number of hydroxyl groups play a crucial role in polyphenols ex-
traction, and so must be considered with great attention. Moreover,
phenolic compounds in plant and foods are often associated by
hydrophobic and/or hydrogen bonds with carbohydrates, proteins,
and lipids, resulting in the alteration of polarity of not bounded.
After the extraction drying steps such as air-drying, oven-drying
or freeze-drying, are often necessary in order to concentrate ex-
tracted compounds or to avoid their degradation, preserving the
antioxidant activity of samples. For these reasons also drying steps
2
Journal of Chromatography A 1651 (2021) 462295
must be take into consideration to select the best extraction
techniques.
Conventional extraction techniques usually include Soxhlet and
maceration. The main drawbacks of these techniques are: a large
volume of solvents is required, the organic solvents used are of-
ten hazardous, long extraction times, low selectivity and low yields
of extraction. Alternative techniques are currently in demand to
overcome all these disadvantages. These non conventional tech-
niques must provide short extraction times, and reduced volumes
of hazardous organic solvents; they are straightforward in execu-
tion, with a decreased use of energy and water [14]. In line with
aim of Green Chemistry, the green extraction can be defined as
being “based on the discovery and design of extraction processes
which will reduce energy consumption, allows use of alternative
solvents and renewable natural product, and ensure a safe and
high quality extract/product” [15]. Based on the above, the use
of alternative solvents, renewable raw materials for botanical ex-
tracts, and decreased energy consumption by energy recovery are
demanded.
Solvent selection depends on the format of the raw botanical
material and its bioactive compounds, cost and availability. Almost
all solvents originate in crude oil, with only ethanol derived from
fermentation. Water represents the obvious solution, but only for
the extraction of polar compounds.
Valorisation of by-products involves increasing the added value
of these agricultural by-products, initially only used as fertilizers
or animal feed and recently under consideration for energy pro-
duction [16] or as potential sources of bioactive ingredients [17].
Most of these products do not see further use due to the lack of
suitable extraction techniques [18]. Extracting bioactive compounds
from by-products must follow standard and simple principles:
• maximization of extraction yield;
• adaptation to industry demands; clarification and removal of
toxic impurities;
• maintaining functionality and preventing deterioration as a
consequence of extraction; maintaining the food grade of the
final product [19].
In solid-liquid extractions, the compounds of interest should be
dissolved in the solvent while interfering compounds should re-
main in the matrix [20]. These ideal conditions are rarely reached,
so it is necessary to continue researching better extraction con-
ditions for the improvement of recovery of these compounds, fo-
cusing on solvent, particle size, temperature, pressure, time and
amount of matrix.
Qualitative and quantitative studies of bioactive compounds in
plants are principally based on the selection of a correct method
of extraction [18]. Green Chemistry is the conception of chemistry
acting with the aim to protect the environment by developing pro-
cedures which restrict the use and generation of hazardous sub-
stances [21]. Green and non-conventional extraction techniques are
based on respecting the ideals of Green Chemistry: the most used
are supercritical fluid extraction (SFE), pressurized liquid extraction
(PLE) and ultrasound assisted extraction (UAE) [22].
2. SFE supercritical fluid extraction
Supercritical fluid extraction (SFE) is used at the laboratory and
commercial scale to extract target compounds or to recover large
scale of bioactive compounds, for example the well-known decaf-
feination of coffee beans. Supercritical fluid exceeds its specific
critical pressure and temperature, and so possesses properties of
both liquids (low surface tension, high solvent power) and gases
(decreased viscosity, high diffusivity), and these may be modulated
by small variations in the pressure and temperature. Furthermore,
supercritical fluids spread easily due to low viscosity and show
I. Pagano, L. Campone, R. Celano et al.
rapid penetration due to low surface tension within the solid ma-
trix, increasing extraction efficiency [23]. The critical temperature
is defined as the hottest temperature allowing gases to transition
into liquids under high pressures, with the critical pressure be-
ing the greatest pressure under which liquids transition to gases
at high temperatures [23]. The most frequently used supercritical
fluid is carbon dioxide, CO2 , (Tc=31.1 °C and Pc=7.38 MPa) and rep-
resents the ideal solvent for SFE. It has generally recognized as safe
(GRAS) status by the European Food Safety Authority and United
States Food and Drug Administration [24–27]. CO2 is non-toxic, in-
ert, inexpensive, non-carcinogenic, not flammable, harmless, and
food-grade. The supercritical region lies above the critical pressure
and temperature, and under these conditions CO2 exists in a phase
with gas and liquid properties.
Carbon dioxide allows for minimal alteration of bioactive com-
pounds, preserving their functional and biological properties, and
is easily dispersed from samples as a gas at room temperature[28].
Sc-CO2 provides a gentle treatment for heat-sensitive materials
[25].
The main parameters that affect the extraction are: tempera-
ture, pressure, time, solvent-to-feed ratio, and co-solvent concen-
tration [29]. A unique characteristic of a supercritical fluid (SCF)
solvent is the sharp variability of density, with the variation of
pressure and temperature, on which also depends the solvent ca-
pacity at the supercritical fluid state. The increase of temperature
leads to a decrease of density, facilitating analyte diffusion, favour-
ing mass-transfer kinetics, and decreasing surface tension [30]. In
order to optimize transport properties, it’s possible to vary sol-
vation power by adjusting pressure and temperature [28]. In ap-
proaching the critical point, the properties of the solvent begin to
change quickly in response to small pressure variations. Sc-CO2 has
a particular and easily tunable density range that allows selective
extractions of target compounds [31]. Supercritical carbon diox-
ide is intrinsically non-polar and it is an excellent solvent for ex-
traction of non-polar compounds and some low molecular weight,
volatile, and less effective in the extraction of polar compounds
such as polyphenols. Low polarity is the main drawback of this
technique. To overcome this the addition of small amounts of a
cosolvent can be used. A cosolvent is an organic substance i.e.
ethanol, acetonitrile, acetone, methanol or water, which is often
added in a small concentration (1 to 5 mol%) to the supercritical
fluid in order to change the solvent characteristics, such as polarity
and specific interactions, without changing the density and com-
pressibility of the original SCF solvent [31].ì. By selecting a cosol-
vent or just simply changing the molar ratio of a selected modifier,
the properties of the fluids can be drastically modified. Although
water could be the solvent that attracts the most interest as a co-
solvent in the SFE process the most common polar solvents used
as a modifier in SFE remain ethanol and methanol. The main draw-
back of water as cosolvent in SFE, compared to other polar solvents
such as methanol and ethanol, is the low solubility since only 0.3%
(v/v) of water can be completely miscible with CO2 . This low sol-
ubility could not sufficiently improve the polarity of CO2 as much
as methanol and other polar solvents [32]. Ethanol represents the
best choice due to its lower toxicity [24]. Addition of ethanol in-
creases the critical temperature, so the extraction temperature and
pressure must be increased to keep the solvent mixture in its crit-
ical region. A solvent modifier can be introduced and mixed with
CO2 by installing a second pump feeding into a mixing chamber,
or it can be injected directly into sample before extraction [25].
Compounds must be soluble in Sc-CO2 but it is possible to vary
solubility by varying the temperature and pressure during extrac-
tion. Moreover, modifiers can further increase solubility. Generally,
when the pressure increases, solvent density and solubility of de-
sirable compounds increase. In this case, a smaller volume of sol-
vent is thus required for each extraction [25].
3
Journal of Chromatography A 1651 (2021) 462295
SFE can be divided into two steps: the solubilisation of bioac-
tive compounds from the solid matrix, and their separation in Sc-
CO2 solvent. The reduction of pressure and the increase of tem-
perature at the end of extraction releases the extract from solvent
[23]. Once the compounds are extracted, solvent can be easily re-
moved by evaporation [33].
SFE aims to be highly selective, with quick extraction times,
prevention of pollution and use of non-toxic organic solvents [28].
SFE is more environmentally friendly than conventional solvent ex-
traction, is rapid, automatable, and selective; it avoids using large
volumes of toxic solvents and has tunable solvent density. Fur-
thermore the lack of light and air in the course of extraction de-
creases the degradation of compounds [34]. In addition, the re-
peat reflux of the supercritical fluid around samples allows for
complete extraction. SFE is an environment-friendly technique as
it uses minimal amount of organic solvents, the supercritical fluid
can be reused and recycled, thus minimizing waste and materials
[22]. Another advantage is the coupling of SFE and analytical chro-
matographic techniques including gas chromatography (GC) or su-
percritical fluid chromatography (SFC) [35]. The principal disadvan-
tages of SFE are the high cost of equipment and setup [35]. More-
over, optimising SFE involves awareness of thermodynamic data
(solubility, selectivity) as well as kinetic data (mass transfer coef-
ficients) [35]. Ultrasound assisted SFE is another technique which
provides decreased extraction time and increased extraction yields
over regular SFE [33].
SFE technology preserves the bioactivity of the recovered com-
pounds improving the functional characteristics of final extract. In
fact the low temperature allows to recover thermolabile and oxid-
able compounds [36].
A further application of SFE is Supercritical Antisolvent Frac-
tionation (SAF). In this case, carbon dioxide is used as an anti-
solvent. SAF involves a flow of Sc-CO2 and a flow of a polar mix-
ture of liquids, in continuous contact as they traverse a pressurized
chamber. Usually, the polar mixture consists of a sample extracted
from raw material with an ethanol/water mixture. Polar compo-
nents in the liquid mixture are insoluble in Sc-CO2 and thus pre-
cipitate, while less polar compounds and ethanol dissolve into the
Sc-CO2 flow and may be recovered later through reducing pressure
downstream [37]. Technical parameters are critical, such as pres-
sure, mass percentage of water in feed and mass ratio of feed: sc-
CO2 [38]. The lipophilic nature of CO2 is the main advantage of
SAF, as it allows polar compounds present in organic extracts to be
separated and concentrated.
2.1. Applications SFE
The focus of this review is the use of Sc-CO2 to extract polyphe-
nols from various by-products. Table 1 lists the main polyphenols
and the experimental conditions of extraction provided by recent
studies.
The by-products receiving most attention include grape
residues, guava seeds, onion skins, and cacao hulls. It is possi-
ble to use low concentrations of a solvent modifier (ethanol in
most cases) to extract polar compounds. Temperature, pressure,
and extraction time are the main independent variables that can
be changed. The efficiency of extraction is measured in terms of
extraction yield or percentage total phenols. A wide range of tem-
peratures (40–90 °C) is reported (Table 1). The recommended ex-
traction pressure varies between 20 and 30 MPa; at high pres-
sures there is an increase in solvent density. A recent study in-
vestigated response surface methodology, with the aim of opti-
mizing extraction of nutraceutical compounds from the by-product
of brown onion skin, using supercritical carbon dioxide/cosolvent.
Onion skins are rich in polyphenols but remain under-explored as
a by-product. The study optimized pressure, temperature and sol-
I. Pagano, L. Campone, R. Celano et al. Journal of Chromatography A 1651 (2021) 462295

Table 1
Extraction conditions used to extract polyphenols from agricultural food by-products using supercritical fluid extraction.

By-product Target compounds Extraction conditions References

Elder berry and Anthocyanins, Modifier ethanol with CO2, Tc 40 °C at 15, 35 MPa [39]
grape marc phenols
Wheat germ Phenolic 10, 60 min extraction time, Tc (40, 60 °C) at 14.8, 60.2 MPa [40]
compounds
Canola Phenolic Modifier ethanol (95%) with CO2, 60 min extraction time, flow rate of CO2 70 g/min, Tc 50 °C [41]
compound and Pc 40 MPa
Strobilanthes Flavonoids Modifier ethanol with CO2 , 40, 60, 80 min extraction time, Tc (40, 50, 60 °C) at 10, 15, 20 MPa [42]
crispus
Psidium guajava L. Phenolic Modifier ethylacetate and ethanol with CO2, 120 min extraction time, Tc (40, 50, 60 °C) at 10, [43]
seed compounds 20, 30 MPa
Grape residues Polyphenols, Supercritical antisolvent extraction: methanol, Tc 40 °C, 11 MPa [44]
anthocyanins
Arbutus unedo Phenolic Modifier ethanol (0% to 20%) with CO2 , 60 min extraction time, flow rate of CO2 at 15 g/min, Tc [45]
fruits compounds 30 °C, 5 MPa
Spearmint leaves Flavonoids, Modifier ethanol with CO2 , 30, 60, 90 min extraction time, Tc (40, 50, 60 °C) at 10, 20, 30 MPa [46]
catechins
Wine grapes Flavonoids, 99.9% pure CO2 as solvent at Tc/Pc of 40 °C/35 MPa, S/F ratio of 6.6 [47]
phenolic acids
Coffee Phenolic Pc of 20 (husk) and 10 MPa (spent coffee), 4% and 8% ethanol (w/w) as solvents, Tc 50 (coffee [48]
compounds husks) and 60 °C(coffee grounds)
Bitter melon Flavonoids Modifier ethanol with CO2 40, 50, 60 min extraction time, Tc (30, 40, 50 °C) at 25, 30, 35 MPa [49]
Grape seeds Phenolic Temperature 44–46 °C, pressure 1.53–16 MPa [50]
compounds
Grape bagasse Anthocyanins, 20 g of bagasse as feed material, CO2 + 96% ethanol 10% (w/w) as modifier, Tc40 °C, 2 extraction [51]
catechins, flavonols cycles at Pc 2 and 35 MPa, S/F ratio 80 and 115, respectively
Blackberry bagasse Anthocyanins Modifier ethanol (10%) with CO2 , 55 min extraction time, flow rate of CO2 at 10 mL/min, Tc [52]
(Rubus sp.) 60 °C, 15 MPa
Punica granatum L. Flavonoids Modifier ethanol (80%) with CO2 , 120 min extraction time, flow rate of CO2 at 2 g/min, Tc 55 °C, [53]
peel 30 MPa
Cacao pod husk Phenolic Modifier ethanol with CO2 , 2.5 h extraction time, Tc 50 °C, 20 MPa [54]
compounds
Onion skin Flavonoids Modifier ethanol (85%) with CO2 , 120 min extraction time, flow rate of CO2 at 10 mL/min, Tc [55]
40 °C, 10 MPa
Wine-making Polyphenols Modifier ethanol (20%) with CO2 , 60 °C, 25 MPa, flow rate of CO2 at 2 mL/min, flow rate of [56]
by-products ethanol at 0.4 mL/min
Grape marc Polyphenols Modifier ethanol (10%) with CO2 , 40 °C, 8 MPa, flow rate of CO2 at 6 Kg/h, ethanol 449.73 g/L [57]
Apple pomace Phenolic Modifier ethanol (5%) with CO2 , 45 °C, 30 MPa, flow rate of CO2 at 2 L/h, 120 min [58]
compounds

vent modifier and in order to improve the efficiency of extraction a
response surface Box–Behnken design was applied. Optimized con-
ditions calculated from chemometric analysis (40 °C, 10 MPa and
with 85% ethanol as solvent) yielded desirability levels of 87% with
a 16% extraction yield [55]. This work represents the first time that
SFE was applied to extract bioactive compounds from dried onion
skins, recovering 18 compounds, and furthermore this process can
be scaled up to industrial levels.
Another recent example of valorisation was demonstrated with
cacao pod husk, extracting phenolic compounds by means of su-
percritical fluid. This by-product is derived from the chocolate in-
dustry. A Box-Behnken design is used here as well, to find the best
extraction conditions to obtain a phenolic compound enriched ex-
tract. As in the previous example, temperature, pressure, and use
of ethanol as a co-solvent were the main variables under investi-
gation. dependant variables consisted of yield, total phenolics and
total antioxidant capacity (ABTS assay). Under the optimized condi-
tions (60 °C, 29.9 MPa and 13.7% ethanol) the extraction yield was
0.52%, with the resulting extract possessing 12.97 mg GAE/g and
0.213 mmol TE/g. SFE is highly selective towards antioxidant com-
pounds, and moreover it can be considered as a potential method
for the valorisation of low cost, easily available and underexploited
cacao pod husk by-product [54].
The economic feasibility of large-scale SFE operation was eval-
uated by Farías-Campomanes et al., this study reports extraction
of phenolics form grape bagasse. Kinetic parameters for extrac-
tion and costs of extract preparation were estimated. Chosen ex-
perimental conditions: CO2 with 10% ethanol (w/w) at 40 °C and
20–35 MPa. These results indicate that an industrial SFE plant is
feasible with a capacity of 0.5m3 , yielding an extract with a phe-
nolic concentration expected to be close to 23 g/kg of extract,
with the estimated cost of manufacture of US$ 133.16/kg. SFE pro-
cess was more efficient than Soxhlet to extract target compounds
(23 vs 1.8 g/Kg extract), even if the extraction yield was lower
[51]. Another interesting application was performed by Aresta and
collaborators. SFE was successfully employed for the extraction of
polyphenols from wine-making by-products (pomace, skins, and
seeds). Final extract was characterized in terms of the total an-
tioxidant capacity and polyphenol content. A comparison with con-
ventional technique was performed (solid-liquid extraction with
ethanol 70%). The SFE approach may represent a friendly strategy
due to the very limited used volume of ethanol for the extraction
of polyphenols [56].
Da Porto et al., developed a combined process based on ultra-
sounds coupled to SFE for the recovery phenolic compounds from
grape marc. This study revealed an increase of the recovery of
polyphenols of 28% than traditional SFE [57]. Ferrentino et al., re-
ported the recovery of polyphenols from apple pomace. SFE extract
presents an antioxidant activity 2.74 times greater than Soxhlet ex-
traction besides was obtained in shorter time (2 vs 6 h) [58].
3. Pressurized liquid extraction (PLE)
At elevated pressures and temperatures solvents possess differ-
ent characteristics which can improve extraction speed. Ideally, de-
sired compounds would show higher solubility in the chosen sol-
vent and interfering compounds should remain insoluble in the

4
I. Pagano, L. Campone, R. Celano et al.
solid matrix [20]. In order to realize this effect, some parameters
must be optimized, including solvent to feed ratio, size of particles,
concentration of solvent modifiers, time, and temperature. Conven-
tional techniques, for example Soxhlet and maceration, are expen-
sive in terms of consumption of time and solvents. Furthermore,
parameters such as diffusivity, viscosity and density may be mod-
ulated by adjusting temperature and pressure.
During PLE, pressure is applied, and temperatures may thus ex-
ceed the boiling point of solvent. This technique allows solutes to
be transferred from a solid matrix, obtaining a fast extraction rate
due to: interactions between the liquid solvent and molecules in
the matrix; high temperatures and pressures increasing extraction
efficiency.
At high temperatures (50–200 °C) an increased mass transfer
and extraction rate occur: the dissolution process is favoured, dif-
fusion rate is increased, destruction of the solute-matrix linkage is
easier, solvent viscosity and surface tension are decreased, lead-
ing to an enhanced wetting of plant matter. A decrease in sur-
face tension leads to the generation of solvent cavities, with con-
sequent dissolution of compounds [24,28]. Increasing temperature
decreases the dielectric constant, lowering the polarity of the sol-
vent [28]. Application of pressure (range 10–15 MPa) keeps the
solvent in its liquid state [28]. The pressure allows the solvent
to penetrate the pores of the matrix. This pressure is most often
10 MPa for PLE. Pressurized solvent is very versatile, but an ap-
propriate combination of solvent and solutes is necessary [24]. Ob-
viously, food grade solvents must be employed, such as water or
ethanol or mixture of both. Ethanol is cheap and possesses GRAS
status. If ethanol is completely eliminated, regulations on organic
solvents can be avoided and costs involved in evaporating solvent
can be removed. Furthermore, there are some advantages in us-
ing an ethanol-water mixture: ethanol improves the solubility of
solutes while water helps desorption of solutes from matrix. The
addition of ethanol lowers the boiling point and can improve effi-
ciency yield too.
Elevated temperatures can also affect extraction yield due to in-
creased mass transfer and extraction rate. The temperature range
usually falls in the range of 100–180 °C, as temperature higher
than 140–150 °C, may cause degradation of thermo-labile com-
pounds or formation of undesirable products due to Maillard re-
action [29]. Matrix characteristics can influence PLE, as the nature
of target compounds, particle size and moisture are unique to each
vegetal sample [24].
PLE may run in static mode, dynamic mode or in combination.
Extraction enhancers can be used to increase extraction efficiency,
and these include drying agents, dispersing agents and other addi-
tives [59].
This advanced green technique allows for quicker extraction
and higher yield compared to other solid extraction techniques,
leading to commercial viability as an alternative technique to ob-
tain valuable bioactive molecules from by-products [29]. In the
case where the chosen solvent is water at 100%, PLE is known
as pressurized hot water extraction (PHWE) or subcritical water
extraction (SWE). Under these conditions, water possesses polar-
ity comparable to alcohols, and represents a good solvent for a
broad base of analytes, due to its dielectric constant decreasing
as temperature is increased. PHWE allows the reduction of or-
ganic solvent consumption, quick extraction time, low costs, it is
environmentally-friendly due to the nature of water (non-toxic, re-
cyclable, readily available) and thus, it constitutes a suitable tech-
nique for industrial applications [60]. At room temperature, wa-
ter has a dielectric constant approaching 80, but this drops to
the region of 30 at 250 °C, becoming comparable to methanol
(Fig. 1) promoting the solubilisation of less polar compounds. In
this way, PHWE can be used to extract low polar and non-polar
compounds, i.e. carotenoids, curcuminoids, lipids, and essential oils
5
Journal of Chromatography A 1651 (2021) 462295
Fig. 1. Change in dielectric constant of water as a function of temperature.
[28,61–64]. In avoiding toxic solvents, the resulting extracts can be
certifiably safe. This technique presents some drawbacks: high in-
vestment cost, risks of unwanted reactions at elevated tempera-
tures (caramelization, Maillard reaction) and subsequent tub clog-
ging due to caramelization [22].
3.1. Applications PLE
As mentioned previously, polyphenols are very interesting com-
pounds due to their antioxidant activities. This is reflected in the
literature, where there are several studies on the development of
new extraction methods with some examples reported in Table 2.
Recently Pagano and co-workers studied the by-products of
agro-industrial artichokes with the aim of extracting flavone gly-
cosides (FLs) and caffeoylquinic acids (CQAs). The primary vari-
ables influencing the efficiency of PHWE and isomerization of CQA
(number of cycles, solvent modifier, temperature, and extraction
period) were optimized using response surface design. The opti-
mized extraction method thoroughly extracts 93–105% of CQAs and
90–105% of FLs from the external bracts and leaves of artichokes.
The high temperatures did not significantly generate artefacts in
this case. The PHWE extracts had antioxidative effects (EC50 11–
83 μg/mL) on human hepatocarcinoma HepG2 cells, as measured
by a cellular antioxidant activity assay [85].
PLE was employed in extracting the polyphenols and antioxi-
dants present in industrial apple pomace: temperatures were ap-
plied in two ranges, between 160 and 193 °C, or 75 and 125 °C.
A DPPH assay was used to measure antioxidant activity, and total
phenol content was measured. Response values were maximised
through response surface methodology. The highest antioxidant ac-
tivity was provided by a 200 °C temperature, but unavoidable for-
mation of unwanted compounds including hydroxymethylfurfural
was observed. To overcome this limitation, lower temperatures
were recommended between 75 and 125 °C. Under these condi-
tions, the highest level of antioxidant activity was provided by 60%
ethanol at 102 °C. PLE extracts showed 2.4 times greater activity
than in traditional solid-liquid extraction. Therefore, this technique
could represent an improvement over conventional techniques for
the extraction of antioxidants [67].
Temperature can affect extraction yield. Monrad and co-authors
demonstrated that a high temperature is necessary to extract pro-
cyanidins from red grape pomace efficiently. Experimental condi-
tions were 80 °C and 6.8 MPa. The study aimed to optimize the
recovery of procyanidins from dried Sunbelt red grape pomace us-
ing GRAS solvents, optimising the temperature and solvent used.
Results revealed the potential value of this technique for the grape
juice industry as a innovative method for extracting procyanidins
from grape by-products with subsequent uses as nutraceuticals or
food supplements [66].
New insight into the efficacy of PLE was evaluated by García
and collaborators on the recovery of bioactive compounds from
pomegranate peel as material recycling. Pomegranate peel repre-
I. Pagano, L. Campone, R. Celano et al. Journal of Chromatography A 1651 (2021) 462295

Table 2
Extraction conditions used to extract polyphenols from agricultural food by-products using pressurized liquid extraction.

By-product Target compounds Extraction conditions References

Bitter melon Phenolic acids and 1 g, water, 10 MPa, 200 °C, 2 mL/min flow rate, 60 min, 120 mL solvent volume [65]
(Momordica catechins
charantia)
Red grape pomace Procyanidins 50% ethanol, pressure 6.8 MPa, temperature 80–140 °C, 0.5 g [66]
Apple pomace Phenolic acids, 60% ethanol, pressure 10.3 MPa, temperature 102 °C, 5 min, 1 g [67]
flavonols and
dihydrochalcones
Citrus pomaces Flavones Temperature 200 °C, pressure 1.4 MPa, 60 min [68]
Pomegranate peel Hydrolyzable 10 g, 100% water, pressure 10.2 MPa, temperature 40 °C, 5 min [69]
tannins
Red grape pomace Anthocyanins 0.5 g, 50 and 70% ethanol, pressure 6.8 MPa, temperature 40–140 °C [70]
Oregano, tarragon Phenolic acids, 1.5 g, ethanol and water and mixture 25/75- 50/50- 75/25, 10.34 MPa, 20 min, 50–200 °C [71]
and wild thyme flavones,
flavanones and
flavonols
Onion skin Flavonols 100% water, pressure 9–13.1 MPa, temperature 165 °C, 15 min, 1.5:2.5 sample: DE [72]
Potato peel Phenolic acids 100% water, pressure 6 MPa, temperature 180 °C, 30 min, 2 mL/min [73]
Abuticaba (Plinia Anthocyanins Pressure 5 MPa, temperature280 °C, 9 min (static mode), 4.5 g, ethanol [74]
cauliflora) skin
Citrus (Citrus Flavanones 1 cycle of PHWE at 170 °C temperature and pressure 10.13 MPa, 10 min [75]
unshiu)
Pomegranate seeds Phenolic acids Temperature 220 °C, 30 min, pressure 6 MPa, solid to water ratio 1:40 [76]
Potato peels Anthocyanins 10 g/min, time 3 h, pressure 20 MPa, temperature 80 °C, ethanol 80% pH 2.6 [77]
Mango peels Phenolic Temperature 180 °C, 90 min, solid to water ratio 1:40 and pH 4 [78]
compounds
Mango peel Polyphenols Ethanol, 330 min [79]
Spent coffee Phenolic acids Temperature 177 °C, 55 min, pressure 5 MPa, 14.08 g/L [80]
grounds
Raspberry pomace Polyphenols Temperature 80 °C, pressure 10,3 MPa; ethanol/water (50:50), 15 min [81]
White grape Phenolic Temperature 210 °C, pressure 10 MPa, 30 min, 5–10 mL/min [82]
pomace compounds
Grape pomace Proanthocyanidins Temperature 90 °C, pressure 10.3 MPa, water/ethanol (85:15) [83]
Cocoa bean hulls Phenolic Temperature 70 °C, pressure 10 MPa, ethanol, 20 min [84]
compound,
anthocyanins
Artichoke bracts Phenolic acids and Temperature 93 °C, number of cycles 2, ethanol 10% v/v, static time 5 min, 1 g, 10.34MPa [85]
and leaves flavones
Grape marc Anthocyanins Temperature 40 °C, pressure 10 MPa, acidified ethanol/water (50:50), 40 min [86]
Wine-making Catechins, tannins, Temperature 100 °C, number of cycles 2, ChClUl 30% (Choline chloride combined with urea), [87]
by-products flavonols, static time 10 min, 2 g, 10.34MPa
hydroxycinnamic
acids
Pomegranate peel Phenolic acids, Temperature 200 °C, ethanol 77% v/v, 10.34MPa [88]
flavonoids,
hydrolysable
tannins

sents 10.5% of the pomegranate fruit fresh weight. PLE method
was developed using a mixture of ethanol:water and under opti-
mal conditions (after experimental design) total phenolic content
(TPC) content was 164.3 ± 10.7 mg gallic acid equivalent (GAE)/g
DW, in terms of phenolic acids, flavonoids, and hydrolysable tan-
nins [88].
Sequential PLE process with change of solvent and increase of
temperature in the second step was performed to extract antho-
cyanins from grape marc [86].
In recent years, the use of alternative solvents, DESs (deep eu-
tectic solvents) has been emerging for the green extraction of phe-
nolic compounds from agricultural by-products. DES is a mixture
of a halide salt or another hydrogen bond acceptor (HBA) and one
or two hydrogen bond donors (HBDs). DESs are usually formed
by choline chloride (quaternary ammonium salt) as HBA and un-
charged compounds, such as sugars, amines, carboxylic acids, alco-
hols as HBDs [89]. This new generation of solvents possesses excel-
lent biocompatibility and low toxicity. Unfortunately, the high vis-
cosity of these solvents results in time-consuming solvent transfer
operations and slow mass transfer. Adding water to DES helps to
overcome these problems. If natural components (choline chloride,
sucrose, trehalose) are used for the formulation of eutectic mix-
tures, DESs are known as NADESs (natural deep eutectic solvents).
A modern methodology was applied to extract valuable phenolic
compounds from wine-making by-products by NADESs as cosol-
vent. Choline chloride combined with urea 30% at temperature of
100 °C led to an efficient and superior extraction compared to only
subcritical water in terms of significant increase of phenolic con-
tent (i.e. for catechin an increase of 45.05% and for epicatechin of
47.98%). The temperature rise allowed an increase in the phenolic
content (40–120 °C). The implementation of subcritical water with
NADESs to recover phenolic compounds from winery by-products
had never be done before [87].
4. Ultrasound assisted extraction (UAE)
Ultrasounds are a form of sound wave beyond the frequencies
humans are able to perceive; as sound waves, they travel through
media as a compression and expansion. At high enough frequen-
cies this leads to cavitation, in which bubbles are formed, grow
and then collapse due to high pressure and temperature (4726 °C
and 101 MPa). In a plant matrix, cavitation facilitates leaching from
the matrix by increasing mass transfer and solvent diffusivity; af-
ter breaking cell wall, solutes diffuse and are captured. A study of

6
I. Pagano, L. Campone, R. Celano et al.
the matrix reported fragmentation under irradiation, with an en-
hanced hydration matrix [90]. Some authors observed erosion of
the raw plant material after ultrasound treatment, resulting in en-
hanced extraction [90].
This technique is not time consuming and does not consume
solvent [22].
UAE uses ultrasonic energy (>20 kHz), it makes cavitation bub-
bles, which collapse producing high shear. This mechanism ensures
a complete extraction. In particular, the suspended powdered sam-
ple induces asymmetric bubble collapse [91]. Bubbles absorb en-
ergy until this reaches an unsustainable limit before collapsing:
this collapse is called cavitation in sonochemistry [24] .
UAE combines the merits of acoustic excitation and solvents
to extract desirable compounds. Ultrasounds provide instantaneous
formation and collapse of cavitation bubbles, generating instanta-
neous high pressure and temperature. Thus, solvent penetration
into cellular parts, cell wall disruption, and the subsequent release
of analytes are very efficient [33]. Ultrasound is applied directly by
a probe system or indirectly by a water bath [23].
Temperature and pressure change after implosions, causing
shear disruption, cell membrane thinning and breakdown of cells.
The penetration of solvent into cells is thus enhanced and the
mass transfer of desired compounds into solvent is increased. The
implosions accelerate the diffusion by causing turbulence. Ultra-
sonic wave implosions provide easier hydration and subsequent
swelling of the matrix. Some parameters are fundamental: fre-
quency and intensity of ultrasound, viscosity and surface tension
of the medium, pressure and temperature.
UAE acts in two steps: solvent enters the matrix following dis-
ruption of the cellular matrix, particle size is reduced, with me-
chanical effects; extracts are washed out of the matrix with the
increase of surface area of contact between solid and liquid phases
[92]. A suitable solvent is mixed with the sample and sonicated at
a specific temperature for a precise amount of time. This technique
has been used in both static and dynamic mode [14]. To increase
the extraction efficiency ultrasounds are also used in conjunction
with another innovative extraction technique [93]. UAE can de-
grade active principles from plant matrices, as a result of oxidative
pyrolysis caused by hydroxyl radicals under cavitation.
UAE represents an inexpensive green extraction technique and
it is very simple; it allows rapid extraction of thermo-labile com-
ponents at low/mild temperature. In the last decade, some patents
have been registered regarding the use of ultrasounds for the ex-
traction of ingredients. In particular, Mitchell and collaborators in-
vented a process for the fractionation and extraction of new ac-
tive compounds from plant material [94,93] and several processes
for isolating lignin, cellulose and water-insoluble compounds from
biomass [95–97], without degrading them. These patents demon-
strate the potential industrial applicability of this extraction tech-
nique using high frequency pulses and shear forces, with the cor-
related advantages.
4.1. Application UAE
The potential of UAE has been explored by several studies in
recent years: Table 3 presents some examples of ultrasound being
used to extract polyphenols from by-products.
Some authors investigated extraction of polyphenols from or-
ange (Citrus sinensis L.) peel (an abundant food by-product), with
a focus on flavanones, by means of ethanol used as a food
grade solvent [100]. A response surface methodology (RSM) was
used to evaluate process settings, feeding into a central com-
posite design (CCD) approach. Statistical analysis showed opti-
mised conditions of a 40 °C process temperature, sonication power
of 150 W and an ethanol: water ratio of 4:1 (v/v). The re-
sulting phenolic content was high (275.8 mg gallic acid equiva-
7
Journal of Chromatography A 1651 (2021) 462295
lent/100 g FW), as was flavanone concentration (70.3 mg naringin
and 205.2 mg hesperidin/100 g FW) and extraction yield (10.9%),
proving the efficiency of UAE in comparison with conventional
techniques. Furthermore, studies on antioxidant activity ((2,2 -
diphenyl-1-picrylhydrazyl radical) DPPH• and (Oxygen Radical ab-
sorbance Capacity) ORAC assays) demonstrated that UAE is suitable
for preparing antioxidant-rich extracts from by-products.
There has been much recent demand for new extraction meth-
ods to be developed, to reduce extraction time and obtain extracts
with high yield and biological activity. Some researchers have
performed studies on dried peel from pomegranate marc, aim-
ing to improve antioxidant yields, activities and extraction kinet-
ics by continuous ultrasound-assisted extraction (CUAE) and pulsed
ultrasound-assisted extraction (PUAE). For CUAE, the major factors
studied were treatment time and intensity level, whereas for PUAE
intensity level, number of repeat pulses, pulse duration and inter-
val were the deciding elements. The results show that treatment
time is the only one of these variables with significant effects on
the activity of extracted antioxidants. All factors were found to sig-
nificantly affect the antioxidant yield; with a 59.2 W/cm2 intensity,
PUAE at a pulse duration of 5 s and interval of 5 s was found to
have similar antioxidant yields as CUAE (14.5% and 14.8%) and sim-
ilar DPPH scavenging activities (5.8 and 5.5 g/g) with a 60 min ex-
traction time, at 25 ± 2 °C with a water/peel ratio of 50/1, w/w.
CUAE and PUAE improved antioxidant yield by 24% and 22% and
decreased time of extraction by 90% and 87%, respectively, when
compared to conventional extraction [109].
As agricultural and industrial by-products, olive leaves repre-
sent an inexpensive, renewable and abundant source of polyphe-
nols. Şahin and Şamlı, optimised ultrasound-assisted extraction
of olive leaf extract, by means of a response surface methodol-
ogy [111]. The ideal combination of solvent concentration (0–100%
ethanol (EtOH), v/v), solid to solvent ratio (25–50 mg/mL) and ex-
traction time (20–60 min) were investigated by response surface
methodology (RSM). The final settings were found to be 500 mg
solid to 10 mL solvent ratio, extraction time of 60 min and a 50%
EtOH solvent. Solvent concentration was the most significant pa-
rameter in affecting extraction performance of UAE of those inves-
tigated. During the production of olive oil, olive pomace contains
also high-added value compounds. Ultrasound increases the aque-
ous extraction of phenolic compounds with high antioxidant activ-
ity, improving the extraction efficiency of water and yielding ex-
tracts at these conditions: 250 W power, extraction time 75 min,
2 g dried pomace/100 mL water as recently reported by Goldsmith
and co-authors [117]. Quercetin is the most abundant compound of
onion by-products and UAE was successfully employed to extract
this important bioactive compound [104,113].
Several studies demonstrated as main advantages of UAE reduc-
tion of time and energy. For example, this technique was success-
fully applied for the extraction of phenolic compounds from red
araçá peel, with an increase of 12% in the content of anthocyanins
and a 25% reduction time of extraction compared to maceration
[123].
In the last years, DES solvents have emerged as new sustainable
eco-friendly extractants.
To enhance the extraction efficiency, DES can be combined with
UAE. The heat generated by ultrasounds decreases the DES viscos-
ity, enhancing its penetration into vegetable matrix. For example,
an environmentally friendly method for the extraction of phenolic
compounds was developed by de los Ángeles Fernández and col-
laborators. The combination of lactic acid, glucose and 15% water
(LGH-15) were utilized in onion, tomato, olive and pear industrial
by-products. A high-efficiency and very versatile UAE method was
developed. To demonstrate the potential of LGH-15, comparison of
extraction efficiency was made with methanol and water, and re-
I. Pagano, L. Campone, R. Celano et al. Journal of Chromatography A 1651 (2021) 462295

Table 3
Extraction conditions used to extract polyphenols from agricultural food by-products using ultrasound assisted extraction.

By-product Target compounds Extraction conditions References

Grape seeds Phenolic compounds, US bath (40 kHz, 250 W, 10 L), temperature [98]
anthocyanins 33–67 °C, time 16–34 min, 2 g, 100 mL ethanol,
ethanol concentration: 33–67%
Orange peel Polyphenols 30 W, temperature 30 °C, time 40 min, and 30 W, [99]
temperature 40 °C, time 10 min, 2 g in 80%
methanol
Orange peel Flavonoids Ethanol:water ratio 4:1 (v/v), 40 °Cand 150 W UP, [100]
extraction time 30 min
Citrus peel Flavonoids 60 kHz, temperature40 °C, water as solvent, [101]
extraction time 30 min, citrus peel:water ratio
1:10 g/mL
Rice bran Polyphenols US bath (35 kHz, 140 W), temperature 51–54 °C, [102]
time 40–45 min, ethanol 65–67% (v/v)
Prunella vulgaris L. plant Flavonoids Ethanol 41% (v/v), temperature 79 °C, time [103]
30.5 min, liquid to solvent ratio 30:1 (mL/g)
Onion skin Quercetin 43.8% ethanol (v/v), 21.7 min, 606.4 W [104]
Grapes Flavonoids Water–ethanol (50:50), extraction temperature [105]
10 °C, 200 W and 24 kHz, extraction time 6 min,
1g
Marjoram Flavone, phenolic acid, US probe (20 kHz, 19 mm), 0.5 g, 25 mL, [106]
diterpene MeOH/H2 O 80/20% (v/v), time 5– 15 min,
temperature 15–35 °C
Apple pomace Flavans, flavonols, phenolic Solid liquid ratio 150 mg/mL, US bath (25 kHz, [107]
acids 150 W), temperature 40 °C, time 40 min, 50 mM
malate buffer pH 3.8
Black chokeberry Polyphenols US bath (30 kHz, 100 W), temperature 20–80 °C, [108]
time 0–255 min, ethanol:water ratio 50:50 (v/v)
Pomegranate peel Polyphenols US bath (20 kHz, 2.4–59.2 W), temperature 25 °C, [109]
time 60 min, water/peel ratio 50:1 w/w
Hawthorn seed Flavonoids Ethanol 72% (v/v), temperature 91 °C, time [110]
37 min, 40 W, solid to liquid ratio 1:18
Olive leaves Flavonoids 50% ethanol, sample/solvent ratio (500 mg dried [111]
leaf to 10 mL), 220 V and 50 Hz, extraction time
60 min
Grape seeds Flavonols, tannins, US bath (20 kHz, 150 W), temperature 30 °C, time [112]
anthocyanins 30 min, methanol
Onion Quercetin US bath (40 kHz, 469 W), temperature 49 °C, time [113]
15–35 min, ethanol 59% (v/v)
Wheat dried distiller’s grain Total polyphenols US bath (24 kHz, 400 W), temperature 20 °C, time [114]
0–20 min, water
Chilean papaya Isothiocyanates, phenolic 5 g papaya seeds + 250 mL of 80% aqueous [115]
acids, and flavanols methanol, 42 kHz and 130 W of ultrasound bath
extractor, extraction time 10 min, solid liquid
ratio of 1:2
Riceberry bran Phenolic acids, flavonoids, 5 g powder + 100 mL of 65% aqueous ethanol, [116]
anthocyanins 43 kHz of ultrasound bath extractor, extraction
time 40 min, temperature 51 °C
Olive pomace Phenolic compounds 250 W, 75 min, 2 g/100 mL water [117]
Potato (peel and outer layer) Caffeoylquinic acid 55% (v/v) ethanol/water ratio, 34 kHz, extraction [118]
time 35 min, temperature 35 °C, solid liquid ratio
of 1/10 (w/v)
Olive leaves Oleuropein, phenolic acids, 250 mg powder olive leaves + 20 mL of 50% [119] [115] [115] [115]
flavonoids acetone, 37 kHz ultrasound bath extractor,
extraction time 10 min, 60 °C, solid liquid ratio of
1:2
Onion, tomato, olive and pear by-products Phenolic compounds lactic acid, glucose and 15% water NADES [120]
(LGH-15), 200 W, 20 kHz, 30–60 min, 40 °C
Spent coffee grounds Phenolic compounds 1,6-hexanediol:ChCl molar ratio of 7:1 (HC-6) [121]
67.5% w/w, 10 min, 60 °C
Spent coffee grounds Chlorogenic acid, 244 W, 40 °C, 40 min, 1.17 g/mL SL, ethanol [122]
protocatechuic acid
Red araçá peel Anthocyanins 154 W, 90 min, 40 KHz, ethanol 90%+0.1% HCl [123]

sults confirm a good extractability both for polar and weak polar
compounds compared to traditional solvents [120].
DESs show promising uses due to their many advantages: their
synthesis is cheap and simple; are tailor-made solvents, they in-
volve low toxicity and biodegradability and therefore represent ex-
cellent alternative to commonly green solvents. Moreover, these
solvents present the possibilities over the conventional solvents to
design them for specific aims, low volatility and higher extraction
capacity. However, in large scale application, for the recovery of
valuable compounds from agricultural by-products, further studies
are mandatory.
5. Conclusions and future perspective
With the increase in environmental awareness, there is grow-
ing interest in circular economy and on the valorisation of food

8
I. Pagano, L. Campone, R. Celano et al.
by-products which are still underestimated. Agricultural and food
by-products are usually considered a great problem for industry
in terms of cost and environmental effects induced by their dis-
posal. Nowadays, these matrices are considered as a cheap source
of bioactive compounds usable as functional additives in different
products, leading at same time benefits for environment. However,
in order to make food by-products interesting and economically
sustainable source of bioactive compounds, the selection and op-
timization of a suitable environmentally friendly extraction tech-
nologies which allow the recovery and sustainability of target ana-
lytes is indispensable. Sustainability and circularity of processes are
key words for industrial sector, reducing postharvest losses, val-
orizing by-products, and extracting bioactive compounds.
The large amount of agricultural by-products determines the
need to develop scalable technology for industrial application able
to rapid, applicable, efficient, with high recovery, short process
time, low costs, and allow the use of small volume of organic sol-
vent.
Conventional extraction techniques to obtain these high added
values ingredients which are time, and energy consuming, labo-
rious, employ large amount of toxic solvents have been consid-
ered the limiting factor until now. At present, development and
the improvement of innovative extraction techniques such as UAE,
PLE and SFE which are characterized by low organic solvent con-
sumption, short time extraction, high selectivity, and good extrac-
tion yields open new perspectives in the recycling of agricultural
food by-products. These techniques may be easily scalable, pro-
viding interesting advantages for the industrial applications aimed
to produce new ingredients for both food supplements and func-
tional foods. Some of the applications reported in the previous
section highlighted that these non-conventional extraction tech-
nologies possess a great prospective for the efficient extraction of
bioactive compounds from agricultural food by-products. The cor-
rect use of these extraction techniques is closely related to under-
standing of the extraction mechanism and to the selection of ex-
traction conditions. Several instrumental parameters influence di-
rectly and indirectly the extraction process, so finding the right
extraction conditions is not easy and often require a multivariate
analysis. For these reasons in order to obtain the best extraction
parameters the use of multivariate experimental design strategies
(Design of Experiments, DOE) that simultaneously change variables
in different experiments are preferable if not even mandatory.
The extraction techniques are in continuous and constant de-
velopment: i.e. the use of alternative solvents, such as ionic liq-
uids and DESs, can reduce the environmental impact. Further the
combination of ultrasound with SFE processes, that can be a feasi-
ble mean to enhance the extraction kinetics, increases the global
extraction yield and reduces the extraction time and thus oper-
ational costs, without compromising the quality of the final ex-
tracts. There are many other possibilities from combination of ex-
traction processes or using of several technologies in parallel in or-
der to promote the production of bioactive ingredients from food
by-products. Another application that could increase extraction ef-
ficiency is the combination of an enzymatic hydrolysis (at high
pressure) with the supercritical fluid extraction or with pressurized
liquid extraction.
Finally, one of the last aspects to consider, concerns the pos-
sibility of scaling up the extraction method. Currently, only a few
SFE applications have been used on a industrial scale, while in the
case of PLE, although the scale-up process is easy, it is not very
widespread.
Agricultural by-products can be used as an extraction material
and phenolic compounds recovered by advanced techniques could
be introduced again into the production chain in order to con-
tribute to required circular and sustainable economy.
9
Journal of Chromatography A 1651 (2021) 462295
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper. The authors declare no
conflict of interest.
CRediT authorship contribution statement
Imma Pagano: Writing – review & editing. Luca Campone:
Conceptualization, Writing – review & editing, Supervision. Rita
Celano: Software, Writing – review & editing. Anna Lisa Piccinelli:
Writing – original draft, Writing – review & editing. Luca Rastrelli:
Project administration, Funding acquisition, Supervision.
Acknowledgement
Financial support from the Italian Ministry of University and
Research (MIUR) through grant “Dipartimenti di Eccellenza 2017
to University of Milano Bicocca, Department of Biotechnology and
Biosciences is also acknowledged.
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