001.docx
CHEMICAL ENGINEERING TRANSACTIONS
VOL. 83, 2021
A publication of
The Italian Association
of Chemical Engineering
Online at www.cetjournal.it
Guest Editors: Jeng Shiun Lim, Nor Alafiza Yunus, Jiří Jaromír Klemeš
Copyright © 2021, AIDIC Servizi S.r.l.
ISBN 978-88-95608-81-5; ISSN 2283-9216
Natural Deep Eutectic Solvent (NADES) Design Framework
for Extraction of Polyphenols from Jackfruit
Song Ying Thong, Azizul Azri Mustaffa*
School of Chemical and Energy Engineering, Faculty of Engineering, Universiti Teknologi Malaysia, 81310 UTM Johor
Bahru, Johor Darul Takzim, Malaysia.
azizulazri@utm.my
Jackfruit considered to be an underutilized fruit where around 60 % of it was dumped and this creates a critical
waste disposal which highly affects the environment. NADES have been widely used in many applications and
it has emerged as a new sort of green solvents used to replace the organic solvents with numerous advantages
like simple preparation, sustainability and environmentally friendly. The main aim of this research is to develop
a framework of NADES design for extraction of polyphenols from jackfruit by using computational approach
combined with mathematical models. The research methodology is divided into 3 stages. Stage 1 is mainly
about problem definition which required determining the needs for NADES and setting its target property values.
Stage 2 is mainly focus on the development of databases which involving the prediction of target property values
for both the NADES and polyphenols by either calculating using suitable property model which corresponding
to the target properties or using computational approach such as COSMOtherm and TmoleX to obtain the
missing information. In Stage 3, first screening process is based on the target properties of NADES and followed
by second screening process which is based on their solvation performance in extraction of polyphenols and
top 4 NADES were selected. This proposed method has been applied in a case study to select the top 4 NADES
for the extraction of quercetin, artocarpin and gallic acid from jackfruit. From the case study, the relative solubility
value of NADES 33 in quercetin, artocarpin and gallic acid from jackfruit is the highest which are 0.28547,
78.3101 and 0.0095 g/g. It showed that NADES 33 was the best extraction solvent for the polyphenols extraction
in current database out from 51 NADES candidates.
1. Introduction
Artocarpus heterophyllus which also known as jackfruit, is one of the species belongs to the mulberry family
(Moraceae). It consists of edible part which are pulp and seed and non-edible part which are rind and rachis
(Wade, 2019). In Malaysia, the planted area as well as the yield for jackfruit has increased from year 2013 to
2018. In year 2018, Malaysia has produced 31,023 t of jackfruit (Ministry of Agriculture and Agro-based Industry,
2018). Jackfruit has many advantages such as it can be used for medicinal purposes, provide nutrients for
human being and it can be process into diverse products like jams, beverages and preserves food
The non-edible part takes up as much as 60 % of the whole fruit which are consider as the unutilized waste. In
Kerala state in India, there are approximated 35 M of jackfruit waste are dumped annually. This dumping action
has created a critical waste disposal and environmental problems (Sundarraj and Vasudevan, 2018). Besides,
the flesh of jackfruit is highly perishable and often undergoes tissue softening and flavour loss which promotes
more jackfruit waste to be disposed. This research can help to minimize the jackfruit waste by carry out the
extraction of polyphenols from jackfruit.
NADES can be defined as a mixture which consist of two or three components that are typically plant-based
primary metabolites to form a new chemical compound without reaction and it will hinder the crystallization
process of each other with specific molar ratio (Gala et al., 2013). The interaction between the compounds occur
through intermolecular hydrogen bonds which one acting as the hydrogen bond acceptor (HBA) and the other
as the hydrogen bond donor (HBD) (Jeliński and Cysewski, 2018). Although ionic liquids (IL) and deep eutectic
solvents were discovered as options to replace the organic solvents to be versatile solvents that used for diverse
purposes but both the solvents still have some limitations to be applied in real chemical industry due to poor
DOI: 10.3303/CET2183091
Paper Received: 05/08/2020; Revised: 30/09/2020; Accepted: 06/10/2020
Please cite this article as: Song Y.T., Mustaffa A.A., 2021, Natural Deep Eutectic Solvent (NADES) Design Framework for Extraction of
Polyphenols from Jackfruit, Chemical Engineering Transactions, 83, 541-546 DOI:10.3303/CET2183091
541
biodegradability, biocompatibility and sustainability. NADES have emerged as a new type of truly green solvents
with many excellent advantages such as sustainability, biocompatibility, environment friendly, remarkable
solubilizing power and outstanding designability. NADES are potentially to act as solvent in many fields such as
extraction, biomass pre-treatment, pharmaceutical products, electrochemistry and biocatalyst (Dai et. al., 2013).
This work focused on the screening and selecting of the top 4 NADES as extraction solvent for polyphenols
from jackfruit for solvent design purpose. Nowadays, the application of NADES for extraction of phenolic
compounds from plant increase rapidly. Extraction of flavonoids from Scutellaria baicalensis by using NADES
has been conducted in recent study (Oomen et al., 2020). In another recent work, extraction of alkaloids and
polyphenols from Pneumus boldus leaves using different NADES (Torres-Vega et al., 2020). Currently, the
existing practice by most of the solvent extraction is trial-and-error experimental method which need to consume
lots of time and cost. It is not practical to conduct the experiments in determining the most optimal NADES as
repeated procedures are required as there are plenty of possible choices of NADES could be synthesized from
different components (Rahman et al., 2020). In this study, NADES design utilized a computational approach to
reduce the usage of laboratory test, prevent waste of materials and shorten operation time which can provide
an easier and faster way for researchers to apply the best NADES in extraction of polyphenols.
2. Methodology
Methodology for NADES design framework for extraction of polyphenols from jackfruit has been developed as
shown in Figure 1. This methodology consists of three major stages.
Figure 1: Step by step flowchart for methodology
2.1 Stage 1: Problem definition
In this stage, the needs of the NADES design have to identify by referring to the published literatures. Generally,
the needs of the extraction solvent to be designed can be classified into three groups which are performance,
safety and environmentally friendly. This is followed by translating the needs into its compatible target properties.
For the target property constraints, it can be set in term of lower and upper boundary or as fixed values. The
range of the target property values can be obtained from the literature search and by comparison with the
existing solvents utilized for extraction process.
2.2 Stage 2: Method of development of databases
Two group of components were required to prepare for the combinations of NADES. MATLAB is used to
determine the possible combinations that can generated from the list of components that have been prepared
(MATLAB, 2018). An extensive search was done and data collection was performed for the NADES, polyphenols
from jackfruit and suitable property models from published studies and reliable online database such as
ChemSpider and PubChem. All the data obtained were stored in Excel database. After that, the possible
combinations of NADES that generated from MATLAB were screened with those found in published literatures
to eliminate the NADES without enough information. For the case that there are missing data for target
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properties of NADES and polyphenols from jackfruit, TmoleX software was utilized to generate the molecular
structures of compounds. COSMOtherm software is then used for the prediction of the selected target property
values. Next, the property models that selected were insert into MATLAB for calculation of target property
values. The data that obtained were transferred into Excel database. The Excel databases were act as an input
for this NADES design framework for extraction of polyphenols from jackfruit.
2.3 Stage 3: Method of screening
NADES candidates were reduce significantly based on the selected target properties in this stage. The first step
was imported the database that have been developed in stage 2 into MATLAB. There are two screening part
will be conducted in this stage. NADES candidates were first screened based on the constraints of target
properties for NADES and followed by second screened based on the solubility of polyphenols in NADES.
Elimination of NADES candidates were performed once their values are not within the range of constraints that
have been set. The following step was arranged and sorted the NADES candidates according to their values of
relative solubility from the greatest to lowest. Top 4 NADES were selected.
3. Results and discussion
3.1 Framework for user who wish to design NADES
Figure 2 presents the general NADES design framework for extraction of polyphenols from jackfruit for user. As
not every user has the computational approach such as COSMOtherm and TmoleX software, they are
encouraged to find the suitable property models to estimate the values of their desired target properties.
For the case which user would like to add extra components of NADES that are not including in this database,
user may insert that selected component into the Excel database manually. By adding the extra components,
more possible combination of NADES may occur. Users have to find the missing data of the new NADES formed
themselves either using computational approach or mathematical model. This is important for user to ensure
that they have enough information for the new NADES that just add into the database so that the data can
transfer and proceed for screening process. If the user does not have any computational approach like TmoleX
and COSMOtherm software, they can find the data of NADES from published study or using the property model
suggested. For the user who have the TmoleX and COSMOtherm software, it will be much more easy and
efficient way to find out the prediction target property values of NADES generated.
Figure 2: NADES design framework for user
3.1.1 Stage 1: Problem definition
Users are required to select their own needs for the NADES and translate the needs into compatible target
properties. The target property constraints can be obtained from the related published study.
3.1.2 Stage 2: Method of development of databases
Users are requested to prepare the list of components for the combination of NADES. Data collection of NADES,
polyphenols from jackfruit and property models were then performed from published literatures as this
information are needed for screening process in stage 3. Property models were encouraged to be used for
estimation of target property values.
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3.1.3 Stage 3: Method of screening
Excel database which act as the input for framework should import into MATLAB by users. Then, users need to
screen the NADES candidates based on each target properties for NADES. This is followed by second screening
process which based on the solubility of polyphenols in NADES. The top 4 NADES which polyphenols can
solubilize better in it were selected.
3.2 Case Study: NADES design for extraction of quercetin, artocarpin and gallic acid from jackfruit
The main objective of this case study was to show the detailed guideline by using the proposed framework.
Quercetin presents in large amounts in both the jackfruit leaf and seed which can help to improve blood sugar
control. Besides, artocarpin can be found in jackfruit wood which helps to slow the growth of bacteria and
enhance the antimicrobial activities. According to the research conducted by Singh, it is showed that the flesh
of jackfruit contains high amount of gallic acid (Singh et al., 2015). Due to these factors, quercetin and artocarpin
were choose as the targeted flavonoids while gallic acid was choose as the targeted phenolic acid to be
extracted out from jackfruit in this case study by following the research methodology in Figure 1.
3.2.1 Stage 1: Problem definition
According to the published studies, the requirements of NADES include thermally stable in liquid phase, not
harmful to human being and environment, can flow smoothly without outside effort and has good solvation
performance in extraction out the desired polyphenols. These criteria were translated into corresponding target
properties and the constraints for target properties are obtained from literature search and by comparison with
the commonly used solvents for extraction of polyphenols. The target properties identified were boiling point,
toxicity, viscosity and solubility. The values for target properties can be predicted by using computational
approach like COSMOtherm software or using mathematical model available in published literatures. Table 1
display the NADES design requirements and its constraints for each target properties.
Table 1: NADES design requirements and constraints
NADES design requirements Target properties Target values Unit Reference
Thermally stable to maintain in liquid
phase
Boiling point, Tb 400 - 800 ˚C Mirza et al., 2015.
Not harmful to human being and
environment
Toxicity, EC50 < 2.0 - Rahman et al.,
2017.
Not too sticky and can flow smoothly
without outside effort
Viscosity, µ < 6.0 cP Troter et al., 2016.
Good solvation performance of
polyphenols from jackfruit
Solubility, δ Depend on
targeted
polyphenols
g (𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠)
g (solution)
Sut et al., 2017.
3.2.2 Stage 2: Method of development of databases
As organic acid based NADES that obtained from published studies were utilized in this case study, components
1 of NADES that selected to be used were lactic acid, malic acid and citric acid while components 2 of NADES
were consist of 17 different hydrogen bond acceptor group. This has successfully formed 51 possible
combinations of NADES using MATLAB by inserting the HBA group and HBD group into the database. An
extensive search on published literatures which related with the NADES experimental results were performed
to obtain the molar ratio for NADES (Dai et al., 2013). Only 34 out of 51 NADES candidates can undergo the
screening process while others were excluded due to missing data of molar ratio. TmoleX and COSMOtherm
were used to estimate the selected target properties like boiling point and relative solubility while property
models were used to predict the target property values of toxicity and viscosity. The databases must contain the
physicochemical properties of NADES and polyphenols together with the corresponding parameters that used
in each property model. Excel database was act as a “brain” in this research which provides input for the
MATLAB software to execute the commands.
3.2.3 Stage 3: Method of screening
Screening process is required in order to reduce the NADES candidates according to the priority of the target
properties by using MATLAB. 34 NADES candidates were first screened based on the boiling point. Then,
toxicity was the second priority target property to screen the NADES candidates. This can ensure that green
solvent which will not threaten human and environment can be achieved. Then it is followed by viscosity
screening of NADES candidates. Lastly, NADES candidates are screened down by solubility value to ensure
that they have good solvation performance for extraction of polyphenols from jackfruit. Top 4 NADES were
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selected for each polyphenol based on relative solubility value from the highest to lowest. It was clearly show
that the numbers of NADES candidates were reduced based on the priority screening from 34 NADES
candidates to 6 feasible candidates. Figure 3 exhibits the hierarchy of NADES screening process from stage 2
to stage 3.
Figure 3: Hierarchy of NADES screening process
The results of NADES can exhibit in two aspects which are solvation performance and costing. The screened
result of NADES candidates based on solubility of each polyphenol in NADES is shown in Figure 4. It is clearly
showing that top 3 NADES for quercetin, artocarpin and gallic acid are exactly same which are NADES 33, 32
and 31. All their components consist of citric acid and L-proline but with different mole fraction. The only
difference that can be observed based on Figure 4 is the fourth NADES which is NADES 27 for quercetin,
NADES 19 for artocarpin and NADES 30 for gallic acid.
Figure 4: Top 4 NADES for each polyphenol with relative solubility value
From Figure 4, it is illustrated that NADES 33 can extract more quercetin than common organic solvent, ethanol
while the others did not manage to do it. This situation happens most probably because of some NADES did
not include in the screening process due to missing of data. There is possibility that the NADES that excluded
has better solvation performance. For artocarpin, all the top 4 NADES has greater solvation performance
compared to the ethanol. Moving on to gallic acid, Figure 4 exhibits that ethanol can extract more gallic acid
than the top 4 NADES. The top 4 NADES for gallic acid have ordinary low relative solubility which means that
they can only extract very limited amount of gallic acid from jackfruit. In this case, the components for NADES
should have more variety rather than just use 3 components as HBD to form the combinations of NADES. By
doing this, more possible combinations can be generated which can make the results more accurate. For this
case, it obviously shows that the NADES available in the database did not have good solvation performance in
extracting the gallic acid compared to the organic solvent based on Figure 4.
Table 2 shows the cost utilized for each NADES with their components and molar ratio.
Table 2: Cost utilized for each NADES
NADES Components 1 Components 2 x1 x2 Cost (MYR)
NADES 33 Citric acid L-Proline 0.25 0.75 468.00
NADES 32 Citric acid L-Proline 0.33 0.67 427.19
NADES 31 Citric acid L-Proline 0.50 0.50 340.46
NADES 27 Citric acid Adonitol 0.50 0.50 1,502.27
NADES 19 Citric acid D-Xylose 0.50 0.50 367.04
NADES 30 Citric acid Ribitol 0.50 0.50 1,606.50
COMMON Ethanol 1.00 241.55
Based on the comparison in term of costing, it shows that the cost that use NADES as extraction solvent are
much higher rather than using ethanol as extraction solvent. Although the costing for NADES are higher than
ethanol, but NADES still have its advantages as green solvents such as sustainability, biocompatibility and
Possible
combinations
(51 NADES
candidates)
Selected
NADESs
(34 feasible
NADES
candidates)
Boiling point
screening
(24 feasible
NADES
candidates)
Toxicity
screening
(13 feasible
NADES
candidates)
Viscosity
screening
(8 feasible
NADES
candidates)
Solubility
screening
(6 feasible
NADES
candidates)
545
environmentally friendly. It depends on the person for their desired factors that they would like to consider with.
For instance, if the company want to use the green solvent which will not harm the environment, they can have
NADES as their option but if the company only have limited budgets on their projects, they still can choose to
use organic solvent which are cheaper.
4. Conclusions
A NADES design framework for extraction of polyphenols from jackfruit has been developed. Computational
approach was used to help for the prediction of the target property values, automatic calculation and screening
of the results. Based on the framework, list of potential candidates of NADES were generated and selected for
performance evaluation. According to the case study, NADES 33 was the best extraction solvent from current
database which has the greatest performance as it has the greatest relative solubility in quercetin, artocarpin
and gallic acid from jackfruit. As this research only covered the screening part, validation of the methods may
be proceeding for future works. By doing this, the accuracy of the NADES selected can be known.
Acknowledgements
The authors would like to express their appreciation towards Dr. Norazah Basar from Faculty of Science and
Mrs. Nur Rahilah Haji Abd Rahman for their support and also financial support from Universiti Teknologi
Malaysia through its COE Research University Grant with a vote number of Q.J130000.2446.04G20.
References
Dai Y., van Spronsen J., Witkamp G.J., Verpoorte R., Choi Y.H., 2013, Natural deep eutectic solvents as new
potential media for green technology, Analytica chimica acta, 766, 61-68.
Gala U., Pham H., Chauhan H., 2013, Pharmaceutical applications of eutectic mixtures, Journal of Developing
Drugs, 2(3), 1-2.
Jeliński T., Cysewski P., 2018, Application of a computational model of natural deep eutectic solvents utilizing
the COSMO-RS approach for screening of solvents with high solubility of rutin, Journal of Molecular
Modeling, 24(7), 180.
MATLAB, 2018, 9.4.0.813654 (R2018a), The MathWorks Inc, Natick, Massachusetts, United States.
Ministry of Agriculture and Agro-based Industry, 2018, Agrofood statistic 2018, Putrajaya: Information and
Statistical Management Dept, Policy and Strategic Planning Division (In Malay).
Mirza N.R., Nicholas N.J., Wu Y., Kentish S., Stevens G.W., 2015, Estimation of normal boiling temperatures,
critical properties, and acentric factors of deep eutectic solvents, Journal of Chemical & Engineering
Data, 60(6), 1844-1854.
Oomen W.W., Begines P., Mustafa N.R., Wilson E.G., Verpoorte R., Choi Y.H., 2020, Natural deep eutectic
solvent extraction of flavonoids of scutellaria baicalensis as a replacement for conventional organic solvents,
Molecules, 25(3), 617.
Rahman N.R.H.A., Yunus N.A., Mustaffa A.A., 2017, Ionic liquid screening for solvent design of herbal
phytochemical extraction, Chemical Engineering Transactions, 56, 1075-1080.
Rahman N.R.H.A., Yunus N.A., Mustaffa A.A., 2020, Ionic liquid solvent design framework for extraction of
phytochemicals using microwave-assisted method, Chemical Engineering Transactions, 78, 577-582.
Singh A., Maurya S., Singh M., Singh U.P., 2015, Studies on the phenolic acid contents in different parts of raw
and ripe jackfruit and their importance in human health, International Journal of Applied Science-Research
and Review, 2(2), 069-073.
Sundarraj A.A., Vasudevan T., 2018, Jackfruit taxonomy and waste utilization, Vegetos: An International Journal
of Plant Research and Biotechnology, 31(1), 67-73.
Sut S., Faggian M., Baldan V., Poloniato G., Castagliuolo I., Grabnar I., Perissutti B., Brun P., Maggi F.,
Voinovich D., Peron G., 2017, Natural deep eutectic solvents (NADES) to enhance berberine absorption: An
in vivo pharmacokinetic study, Molecules, 22(11), 1921.
Torres-Vega J., Gómez-Alonso S., Pérez-Navarro J., Pastene-Navarrete E., 2020, Green extraction of alkaloids
and polyphenols from peumus boldus leaves with natural deep eutectic solvents and profiling by HPLC-
PDA-IT-MS/MS and HPLC-QTOF-MS/MS, Plants, 9(2), 242.
Troter D.Z., Zlatković M.Z., Đokić-Stojanović D.R., Konstantinović S.S., Todorović Z. B., 2016, Citric acid-based
deep eutectic solvents: Physical properties and their use as cosolvents in sulphuric acid-catalysed
ethanolysis of oleic acid, Advanced Technologies, 5(1), 53-65.
Wade L., 2019, Review: Florida’s best fruiting plants: Native and exotic trees, shrubs, and vines by Charles R.
Boing, Selbyana, 30(1), 127.
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