Application of Deep Eutectic Solvents - American Chemical Society

Review pubs.acs.org/JAFC

Application of Deep Eutectic Solvents (DES) for Phenolic Compounds Extraction: Overview, Challenges, and Opportunities Mariana Ruesgas-Ramón,† Maria Cruz Figueroa-Espinoza,*,† and Erwann Durand*,‡ †

Montpellier SupAgro, UMR 1208 IATE, Montpellier F-34060, France CIRAD, UMR 1208 IATE, Montpellier F-34060, France

‡

ABSTRACT: The green chemistry era has pushed the scientific community to investigate and implement new solvents in phenolic compounds (PC) extraction as alternatives to organic solvents, which are toxic and may be dangerous. Recently, deep eutectic solvents (DES) have been applied as extraction solvents for PC. They have the advantages of biodegradability and ease of handling with very low toxicity. Nevertheless, the extraction process is affected by several factors: affinity between DES and the target compounds, the water content, the mole ratio between DES’ starting molecules, the liquid/solid ratio between the DES and sample, and the conditions and extraction method. On the other hand, PC recovery from DES is a challenge because they can establish a strong hydrogen bond network. Alternatively, another possibility is to use DES as solvent extraction as well as formulation medium. In this way, DES can be suitable for cosmetics, pharmaceutical, or food applications. KEYWORDS: phenolic compounds, deep eutectic solvents, natural deep eutectic solvents, green chemistry

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INTRODUCTION Phenolic compounds (PC) are the largest group of phytochemicals.1 They are present in almost all plants as secondary metabolites, playing an important role in their processes of growth and reproduction or providing them protection against pathogens and predators. PC are characterized by one or more aromatic rings bearing one or more hydroxyl groups in their chemical structure,2 and they have been extensively studied because they may help in the prevention of various diseases as they possess important biological properties such as anti-inflammatory, antiviral, analgesic, anticarcinogenic, antimicrobial (antifungal and antiviral), and antioxidant activities.3,4 In addition, the polyphenols including flavonoids (e.g., anthocyanins, flavonols, flavanols, condensed tannins, or proanthocyanidins) and nonflavonoids (e.g., phenolic acids, stilbenes, gallotannins, ellagitannins, and lignins) are the most abundant antioxidants from natural sources.5 PC are useful in food and cosmetic preservation due to their antimicrobial and antioxidant properties,6 especially compounds such as flavan-3-ols, flavonols, and tannins.7 These properties can be useful for food preservation as an alternative to consuming natural food products and in light of consumers’ growing concern about microbial resistance toward synthetic preservatives.8 As already mentioned, PC mainly concentrate in the plant kingdom, and one of the preliminary and critical steps before any application lies in their extraction.9 The most common techniques are liquid−liquid extractions (LLE) or solid-phase extractions (SPE).10 They employ solvents, mostly organic, such as acetone and ethyl acetate, or alkyl alcohols such as methanol (MeOH), ethanol (EtOH), and propanol or their mixtures.11 Even if organic solvents have excellent ability in PC dissolution and extraction, they show many intrinsic drawbacks, such as accumulation in the atmosphere (low boiling points), flammability, high toxicity, non-biodegradability,12 and cost. Additionally, from an environmental standpoint, these solvents © 2017 American Chemical Society

can no longer meet the trend of green chemistry. For all of those reasons, new alternative green methodologies and solvents are investigated to extract PC from plants. Supercritical fluids (SCF), mainly CO213 or water,14 could be an option, but their restricted range of molecule solubility, their high intrinsic reactivity, their high cost in equipment to obtain supercritical conditions, and the prized pure water (especially while contamination could happen, making water purification very difficult and expensive) do not offer real prospects for the future. Biomass-derived solvents, such as EtOH, limonene, ethyl lactate, glycerol, or 2-methyltetrahydrofuran, could also be used as another alternative. They are biorenewable, innocuous, and not very expensive, but their versatility and solvation properties are rather restricted. Ionic liquids (IL) are the first new multimolecular generation of solvents exhibiting unusual solvent properties. They consist in an association between an organic cation (such as an imidazolium or pyridinium) and a coordinating anion. They possess a very low vapor pressure, they are not flammable, and they are stable at high temperatures (around 200 °C). In addition, several possibilities exist to fine-tune their properties. Despite these features, the shortcomings are so significant that they cannot be hindered: high price, water stability, high toxicity, very low atom economy for their synthesis, difficulty in purifying, and poor biodegradability. Considering the aforementioned statements, finding and developing new green and efficient solvents for extraction processes is a great challenge, with high stakes. Received: Revised: Accepted: Published: 3591

March 9, 2017 April 11, 2017 April 17, 2017 April 17, 2017 DOI: 10.1021/acs.jafc.7b01054 J. Agric. Food Chem. 2017, 65, 3591−3601

Review

Journal of Agricultural and Food Chemistry

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USE OF DEEP EUTECTIC SOLVENTS (DES) AS LIQUID PHASE FOR EXTRACTION PROCESS Over the past few years, new kinds of solvent, DES, have been developed as analogues of IL. They differ from IL in two main aspects: the source of the starting materials and, to a lesser extent, the synthesis. DES is a mix between a halide salt or another hydrogen bond acceptor (HBA) and a hydrogen bond donor (HBD). Compared to related IL, they offer many advantages such as low price, chemical inertness with water, and ease of preparation, and most of them are biodegradable with very low toxicity.15 The most common DES are formed by choline chloride (ChCl) with cheap and safe HBD, the most popular ones being urea, ethylene glycol, and glycerol,16 but other alcohols, amino acids, carboxylic acids, and sugars have also been commonly used.17 Those solvents are characterized by a well-defined composition, which displays a unique and minimum melting point in the solid−liquid phase diagram, significantly lower than the melting points of the individual components, highlighting noncovalent affinities at the molecular level. In most cases, DES may be used liquid at room temperature or at a temperature below 70 °C.18 Very recently a new term, “natural deep eutectic solvents” (NaDES),19 was introduced to describe such a liquid obtained by combining molecules abundantly present in nature. They are called “natural” because they might play an important role as a liquid phase for solubilizing, storing, or transporting non-watersoluble metabolites in living cells and organisms.20 There are some evident connections between DES and NaDES, and some of those mixtures are even labeled with different names in the literature, although they are precisely the same.18 DES and NaDES may, however, retain special features; this is the case with NaDES, which are exclusively formed by nonionic species, which involve different driving forces to create the liquid because the “hole theory”21 (for explanation, see below) put forward to explain the molecular motion in DES is difficult to consider. In general, DES and NaDES share very similar physicochemical properties (strong ability to dissolve protic molecules, low vapor pressure, and miscibility with water among others). Those liquids may be prepared by three different ways that could be adjusted with some modifications (heating time, temperature, etc.) according to the nature of the compounds. (i) Heating and stirring method: The components are placed in a closed bottle and heated at 60 °C under magnetic agitation until a clear liquid is formed. Importantly, when carboxylic acids are used as HBD in combination with ChCl, heating is not recommended to avoid the formation of impurities as esters between ChCl and the acid; instead, grinding DES components in a mortar with a pestle at room temperature is preferred to form the liquid phase.22 (ii) Evaporating method: Components are dissolved in water and evaporated at 50 °C with a rotatory evaporator. The obtained liquid is put in a desiccator with silica gel until it reaches a constant weight. (iii) Freeze-drying method: Based on the freeze-drying of a mix of the aqueous solutions of the individual counterparts, this method is not frequently used.23 Viscosity is an important parameter in the consideration of a solvent for extraction (favors mass transfer, processing, handling, etc.). Although the fluidity of the mixture can be adjusted, because of the nature of starting molecules, the size of the species, the mole ratio, the water content, and the

temperature, most of the DES exhibit higher viscosity than many conventional solvents, but similar to that of IL (>100 cP at room temperature). The very low mobility of free species within the DES comes from the presence of an extensive hydrogen bond network between each component and, to a lesser extent, van der Waals and electrostatic interactions.16 Fluidity may also be explained by the “hole theory”, which assumes that, on melting, the ionic material contains empty spaces that arise from thermally generated fluctuations in local density. Thus, the viscosity is related to the free volume and the probability of finding holes of suitable dimensions for the solvent molecules/ions to move into vacant sites.21 The free volume can be increased by lowering the surface tension with smaller ions. In addition, it has been already shown that the viscosity decreases significantly when the temperature increases.20,24,25 For example, the viscosity of glucose/ChCl/ water is decreased by two-thirds when the temperature increases from 20 to 40 °C. As depicted in Table 1, the polarity of DES is very close to that of water and to those of the most polar organic solvents Table 1. Solvent Polarity of Some DES solvent composition water MeOH EtOH ChCl/glycerol ChCl/glycerol ChCl/glycerol ChCl/1,2-ethanediol ChCl/xylose ChCl/glucose 1,2-propanediol/ChCl/water sorbitol/ChCl/water fructose/ChCl/water xylitol/ChCl/water ChCl/citric acid proline/malic acid/water citric acid/glucose glucose/tartaric acid malic acid/ChCl/water

mole ratio

ET (kcal/mol)

ref

1:1 1:2 1:3 1:2 2:1 1:1 1:1:1 1:2.5:0.3 1:2.5:2.5 1:2:3 2:1 1:1:3 1:1 1:1 1:1:2

63.10 55.00 51.90 58.49 58.07 57.96 57.10 50.69 50.43 50.07 49.98 49.81 49.72 48.30 48.05 47.81 47.73 44.81

57 57 57 26 26 26 58 59 59 20 60 60 20 59 20 59 59 20

(MeOH, EtOH, etc.). The organic acid-based DES are the most polar, followed by the amino acid- and sugar-based DES, whereas polyalcohol-based DES are less polar.20 With regard to the polarity of ChCl-based DES, it increases as a function of the quaternary ammonium salt’s concentration.26 This characteristic is also affected by the addition of water into the composition of DES. This feature is due to the rupture of a hydrogen bond between the initial constituents, provoking a dramatic change in the structure of DES. In recent years, the search for DES has intensified due to their huge chemical diversity, wide field of applications, biodegradable properties, sustainability, and acceptable toxicity profile.27 DES have been mostly used as solvents for synthesis reactions (either enzymatic or chemical),28,29 metal processing,30 purification and processing in biodiesel production,30 removal of environmental contaminants and separation of azeotropes,31 or isolation and fractionation of compounds.32 The interest in DES (or NaDES) for PC extraction from plant materials is increasing, because they are very good solvents with rare solvation properties. The main striking 3592

DOI: 10.1021/acs.jafc.7b01054 J. Agric. Food Chem. 2017, 65, 3591−3601

Review

Journal of Agricultural and Food Chemistry Table 2. DES as Solvent for PC Extraction from Different Vegetable Sources DES composition

mole ratio

% water (v/v)

Lonicera japonica

1:6

10

5-CQA, CA, 3,5-DCQA, 3,4-DCQA and 4,5-DCQA

Cajaus cajan

1:2

20

ChCl/betaine hydrochloride/ ethylene glycol

Equisetum palustre L.

1:1:2

20

ChCl/1,4butanediol

Pyrola incarnata Fisch

1:4

30

46 pinostrobin chalcone, pinostrobin, longistyline C, cajaninstilbene acid, cajanuslactone, cajanol, apigenin-6,8-di-C-α-L-arabinoside, and apigenin-8-C-α-L-arabinoside kaempferol-3-O-β-D-glucopyranoside-7-O-β-D-glucopyranoside, kaempferol-3-O-β-D40 rutinoside-7-O-β-D- glucopyranoside, luteolin-7-O-β-D-glucopyranoside, quercetin-3-O-βD-glucopyranoside, apigenin-5-O-β-D-glucopyranoside, genkwanin-5-O-β-Dglucopyranoside, luteolin, genkwanin, and apigenin hyperin, 2′-O-galloylhyperin, quercitrin, quercetin-O-rhamnoside, chimaphilin, 43, amentoflavone, and myricetin 44

Chamaecyparis obtusa Camellia sinensis, Radix scutellariae green tea Prunella vulgaris L. Salviae miltiorrhizae Platycladi cacumen grape skin

1:5 1:2

20

catechin, ECG, EGCG, EGC, EC, wogonoside, baicalein, baicalin, and wogonin

30

catechin, EGCG, ECG, rosmarinic acid, and salviaflaside rosmarinic acid, salvianolic acid, lithospermic acid, myricitrin, quercitrin, amentoflavone, and hinokiflavone

36, 45

1:1

25 10 0.25:1a

39

pigeon pea roots

1:7

30

(+)-catechin, delphinidin-3-O-glucoside, cyanidin-3-O- glucoside, petunidin-3-O-glucoside, peonidin-3-O-glucoside, malvidin-3-O-glucoside, and quercetin-3-O-glucoside genistin, genistein, and apigenin

grape skin

4:1

3:7a

total anthocyanins content

49

Flos sophorae

1:2.5

3:7a

quercetin, kaempferol, and isorhamnetin glycosides

41

ChCl/1,3butanediol ChCl/maltose

ChCl/lactic acid ChCl/ethylene glycol ChCl/laevulinic acid ChCl/oxalic acid ChCl/1,6hexanediol citric acid/D(+)-maltose L-proline/ glycerol a

source

1:5 1:4 1:2

target compounds

ref 33

38, 47 37, 35

48

Water/DES (w/w).

polyphenol structures (esters, glycosides, amides, etc.).11 Thus, inherent properties of plant material in terms of structure and composition combined with the diversity of PC result in a high difficulty to both predict the right material−solvent system and find the best methodology to extract those molecules. The extraction of PC by DES has been recently explored and includes compounds such as phenolic acids, flavonoids, and stilbenes from different vegetable sources (Table 2). DES for the Extraction of Phenolic Acids. In 2016, Peng et al.33 evaluated the potential of 12 different ChCl, oxalic acid, and lactic acid based DES in the chlorogenic acid (5-CQA), caffeic acid (CA), 3,5-dicaffeoylquinic acid (3,5-DCQA), 3,4dicaffeoylquinic acid (3,4-DCQA), and 4,5-dicaffeoylquinic acid (4,5-DCQA) extractions from Lonicerae japonicae Flos assisted by microwaves. The best extraction yield of each compound depends on the couple ChCl/HBD. For example, for a mole ratio of 2:1, the most effective DES were ChCl/1,3-butanediol for 5-CQA and 3,5-DCQA, ChCl/propanedioic acid for CA, ChCl/urea for 3,4-DCQA, and ChCl/ethylene glycol for 4,5DCQA. Extraction rates were improved 1.5-fold (5-CQA), 1.6fold (3,5-DCQA), 9.5-fold (CA), 119.2-fold (3,4-DCQA), and 2.7-fold (4,5-DCQA) when compared to water extraction. Global extraction yields of these chlorogenic acids were improved when using ChCl/ethylene glycol, ChCl/1,3butanediol, and ChCl/1,4-butanediol at mole ratios of 1:4, 1:6, and 1:4, respectively. Finally, these yields were enhanced by a factor of 1.6−3.6 when 10% of water was added to the composition. The optimal conditions for extracting those PC ware liquid/solid concentration of 9 mL/g at 60 °C during 20 min at 700 W. In a very similar study, Park and co-workers,34 investigated the phenolic acids (5-CQA and CA) extraction from Herba artemisiae scopariae using DES and MeOH/H2O (60:40, v/v) as a binary mixture. Twelve DES were tested, and the best result was obtained with tetramethylammonium chloride/urea

example is rutin solvation. Rutin, which is a heteroside with sugar residues, is paradoxically almost insoluble in water. This phenomenon may be explained by the presence of flat aromatic hydrophobic groups that are able to establish “π-stacking” interactions stronger than solvation forces. The stability of the building block created by the π-stacking of a large number of aromatic rings is strengthened by the surrounding hydrogen bonds of their polar hydroxyl groups (phenols). This leads to the formation of aggregates that can reach high sizes, which at room temperature become insoluble and precipitate in the aqueous phase. Interestingly, it is by masking the polar groups (phenolics −OH), by transformation into glycol ethers, that the water insolubility is over-ridden (e.g., troxerutin is totally water soluble). The transformation of free −OH groups into ethers destabilizes the stacks in favor of a solvation and solubilization by water molecules. In other words, the van der Waals interactions become weaker than the steric hindrance of the ether groups, leading to a dispersion of the aromatic rings in the aqueous phase. In the pioneering work of the potential application of this category of solvent for PC solubilization,19 it was found that hydrated DES (or NaDES) had a strong ability to dissolve the rutin, as well as other cellular metabolic compounds, 50−100-fold higher than that in water. In these media, the hydrogen interactions between DES (or NaDES) and a solute are so strong (stronger than water solute) that they prevail over the rest of the solute−solute electrostatic forces.

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DES FOR THE EXTRACTION OF PC In the plant kingdom, PC may distribute in the tissue at cellular (e.g., cell wall) and subcellular levels (e.g., vacuoles).3 Concomitantly, PC comprise a huge family in which the chemical structures may be significantly diverse. Indeed, more than 8000 phenolic structures have been reported so far, going from simple, low molecular weight, single aromatic ring compounds to the large complex tannins and derivative 3593

DOI: 10.1021/acs.jafc.7b01054 J. Agric. Food Chem. 2017, 65, 3591−3601

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Journal of Agricultural and Food Chemistry

was obtained after 8 min at 66 °C, using a liquid/solid ratio of 35 mL/g. (+)-Catechin was also extracted from grape skin by testing five different ChCl-based DES with HBDs such as glycerol, oxalic acid, malic acid, and sorbose.39 The extraction was carried out with a liquid/solid ratio of 10 mL/g for 50 min at 65 °C. The best extraction yield was reached with ChCl/oxalic acid (1:1 mole ratio) in binary mixture with 25% (w/w) of water. In the same study, the extraction of quercetin-3-Oglucoside from the grape skin was also evaluated, and the best result was achieved with ChCl/glycerol (1:2 mole ratio). In addition, the extraction yield increased 4-fold compared with conventional organic solvents when 25% (w/w) of water was added, highlighting once again the positive effect of water addition in DES to promote PC extraction. In 2015, Qi et al.40 evaluated the extraction of nine flavonoids from Equisetum palustre L. using nine different ChCl- or betaine-based DES. The best extraction yield of the target compounds was reached when ethylene glycol was used as HBD. In addition, ethylene glycol in combination with ChCl showed the best extraction yield for higher polar flavone compounds, whereas associated with betaine it showed better extraction for the relatively weak polar ones. This result pointed out the importance of the correct selection of the DES for extracting the desired compound(s). Finally, the most efficient extraction using DES was reached with a mixture of ChCl/ betaine hydrochloride/ethylene glycol (1:1:2 mole ratio), with a maximal yield obtained with the addition of 20% (v/v) of water at 60 °C with a liquid/solid ratio of 25 mL/g. Quercetin, kaempferol, and isorhamnetin were extracted from Flos sophorae by different mixtures between ChCl, Lproline, citric acid, or betaine as HBA and glycerol, xylitol, glucose, adonitol, or malic acid as HBD.41 The results showed that ChCl/glucose (1:1 mole ratio), ChCl/xylose (5:2), and Lproline/glucose (5:3) were the most effective for quercetin extraction, whereas ChCl/xylose (5:2) and L-proline/glucose (5:3) were the best for isorhamnetin and kaempferol. To improve the extraction yields, the authors explored new DES by combining L-proline as HBA, with glycerol or xylitol as HBD, and the results showed that L-proline/glycerol (1:2.5) was significantly more efficient than other DES, as well as MeOH. Myricetin and amentoflavone were extracted from Chamaecyparis obtusa by different ChCl/alcohol DES.42 The extraction was carried out at 70 °C with a liquid/solid ratio of 10 mL/g. The results indicated that ChCl/1,4-butanediol was the best DES, and the amount of amentoflavone extracted was higher than the one of the myricetin. Moreover, the extraction yields were also affected by the mole ratio between DES’ counterparts. For example, the amount of extracted flavonoids was improved while the ChCl/1,4-butanediol mole ratio was decreased from 1:1 to 1:5, mostly due to a decrease in viscosity and surface tension. Finally, 30% (v/v) of water content in DES was beneficial for PC extraction. Interestingly, the amounts of myricetin and amentoflavone extracted were 8- and 83.5-fold higher than with water and 1.06- and 1.02-fold higher than with MeOH. In 2015, Yao and associates43 used the same ChCl/1,4butanediol for the extraction of hyperin, 2′-O-galloylhyperin, quercitrin, quercetin-O-rhamnoside, and chimaphilin from Pyrola incarnata Fisch. A mole ratio of 1:4 between starting molecules was tuned to provide the best conditions, allowing a correct balance between diffusion, viscosity, surface tension, and physicochemical properties. Also, the addition of water

(1:4 mole ratio). The extraction yields were similar when 50, 65, and 80% of DES were added in a mixture with MeOH/H2O (60:40, v/v). Finally, the extractions carried out for 30 min at 89 W with a liquid/solid ratio of 10 mL/g drastically increased 5-CQA and CA extractions by 177 and 138% respectively, compared with MeOH/H2O (60:40, v/v). Rosmarinic acid and salviaflaside from Prunella vulgaris L. have been extracted using six different alcohol-based DES, with different mole ratios ranging from 1:2 to 1:6.35 The highest yield was reached with ChCl/ethylene glycol at a 1:4 mole ratio, whereas increasing HBD concentration caused a significant decrease in PC extraction yields. We previously highlighted the difficulty in dealing with DES’ viscosities for extraction processes. Water addition is a good way to decrease viscosity while maintaining (or even increasing) PC extraction efficiency. In the same study, authors carried out experiments at different water contents (from 0 to 100%, v/v). The best yield was obtained when water was added at 40% (v/v). Finally, the extraction was optimized with the following conditions for rosmarinic acid and salviaflaside, respectively: water ratio of 36 and 30% (v/v), liquid/solid ratio of 14 and 12 mL/g, and extraction for 46 and 32 min at 86 and 89 °C. The extraction of phenolic acids was also tested with betaine-, L-proline-, or ChCl-based DES.36 In total, 43 DES with different combinations were tested for the extraction of bioactive naturally occurring compounds, including PC, from five Chinese herbal medicines. In all cases, the conditions were 25% (v/v) water, liquid/solid ratio of 40 mL/g, and temperature of 50 °C. The best yields of extraction for salvianolic acid, rosmarinic acid, and lithospermic acid were obtained with ChCl-based DES, especially ChCl/laevulinic acid (1:2) and ChCl/acetamide (1:1). In addition, the extraction yields with betaine- and L-proline-based DES were higher than the ones performed with MeOH. DES for the Extraction of Flavonoids. In 2016, Duan et al.36 evaluated the potential of DES for the extraction of icariine from five Chinese herbal medicines. The authors showed that this flavonol glycoside was highly extractable with L-prolinebased DES, and the results emphasized that 14 DES exhibited higher yields for icariine extraction than MeOH, with the best results obtained when lactic acid was used in association with Lproline (1:1 mole ratio). Similarly, catechin, EGCG, and ECG have been extracted with a series of ChCl/alcohol DES from green tea.37 Although the extraction efficiency could be limited by the physicochemical properties (viscosity, surface tension, and polarity of DES), the amounts of both EGCG and ECG extracted with ChCl/ ethylene glycol (1:5 mole ratio) were higher than with MeOH or water. The extraction was optimized by heating for 30 min at a temperature of 75 °C, with a liquid/solid ratio of 16 mL/g and with DES containing 30% (v/v) water. One year later, Li et al.38 investigated the extraction of EGCG, EC, and EGC from Camellia sinensis leaves by different ChCl-based DES made of HBDs that belong to the family of alcohols, organic acids, and saccharides. They showed that lactic acid as HBD allowed extracting three catechins at higher yields. Additionally, viscosity had an important effect on the extraction efficiency. For example, when the mole ratio of ChCl paired with lactic acid was changed from 1:1 to 1:2, a significant increase was observed (by approximately 20%). On the other hand, the extraction yield of the compound was increased by 20% after the addition of water at 20% (v/v), and the optimal extraction 3594

DOI: 10.1021/acs.jafc.7b01054 J. Agric. Food Chem. 2017, 65, 3591−3601

Review

Journal of Agricultural and Food Chemistry

In addition, 20% (v/v) of water was added to improve the extraction yield, and the condition for extraction was set at 60 °C after 12 min, with a liquid/solid ratio of 15 mL/g. Under this condition, the extraction of baicalin, wogonoside, baicalein, and wogonin was increased by 4.03-, 3.8-, 4.6-, and 4.3-fold, respectively, in comparison with EtOH/H2O (60% v/v). Finally, other flavonoids such as genistin, genistein, and apigenin were also extracted with nine ChCl-based DES and two glucose-based DES from pigeon pea roots.48 The parameters to promote extraction were examined and optimized as follows: 80 °C for 11 min using ChCl/1,6hexanediol (1:7 mole ratio) with 30% (v/v) of water and a liquid/solid ratio of 14 mL/g. Using these optimized conditions, the extraction yields in genistin, genistein, and apigenin were improved by 1.50-, 1.27-, and 1.64-fold, respectively, compared with the amounts reported in the literature using EtOH 70% (v/v) under the same conditions. DES for the Extraction of Anthocyanins. In 2015, Jeong et al.49 investigated anthocyanin extraction from grape pomace carried out with 10 different ChCl-based DES in association with different classes of HBDs including carboxylic acids (Dand L-malic acids and citric acid), sugar alcohols (glycerol and maltitol), monosaccharides (D-(−)-glucose, D-(−)-fructose, D(−)-galactose, and D-(−)-ribose), and disaccharides (sucrose and D-(+)-maltose). The combinations with citric acid, maltitol, fructose, and D-(+)-maltose showed significantly higher levels of total anthocyanins, in comparison with MeOH/H2O (80:20, v/v). To improve the extraction yields, the authors evaluated the association of citric acid with fructose, maltose, or maltitol. Citric acid/maltose (4:1 mole ratio) in binary mixture with water (DES/water 3:7 (w/w)) showed the best extraction yield. After optimization of the parameters, 42.55 mg of cyanidin-3,5diglucoside (equiv/g grape skin) could be extracted from grape pomace at room temperature (45 min) with a liquid/solid ratio of 8.3 mL/g, a total 1.85-fold more than with MeOH 80% (v/ v). Likewise, delphinidin-3-O-monoglucoside, cyanidin-3-Omonoglucoside, petunidin-3-O-monoglucoside, peonidin-3-Omonoglucoside, malvidin-3-O-monoglucoside, malvidin-3-Oacetylmonoglucoside, peonidin-3-(6-O-p-coumaroyl)monoglucoside, and malvidin-3-(6-O-p-coumaroyl)monoglucoside were extracted from the grape skin using five ChCl-based DES.39 According to the results, the best extraction yields were obtained with ChCl/oxalic acid (1:1 mole ratio) followed by ChCl/malic acid (1.5:1 mole ratio). The acidity of the solvents could be the key in the efficient extraction of anthocyanins because the pH is very important in the anthocyanin equilibrium forms and stability. That is why acid DES (ChCl/oxalic acid and ChCl/malic acid) allowed for the highest concentration of total free anthocyanins, whereas lowering DES’ acidity results in a decrease of the extraction capacity. In addition, the extraction yields were enhanced with a water addition of 25% (w/w), leading to 5- and 2-fold higher total anthocyanin extraction capacity in comparison with water or aqueous MeOH, respectively. Finally, the best parameters for extraction were obtained at 65 °C after 50 min, using a liquid/ solid ratio of 10 mL/g. Total PC and anthocyanins extractions were also evaluated (at 65 °C after 50 min) from the skin grape by six diverse ChCl-based DES in binary mixture with 30% (w/w) of water.15 The best PC extraction efficiency was reached with ChCl/ fructose (1.9:1 mole ratio) followed by ChCl/malic acid (1:1 mole ratio), ChCl/xylose (2:1 mole ratio), ChCl/glucose (2:1

improved the extraction yields, and the optimal extraction was found with 30% (v/v) of water content in DES at 70 °C with a liquid/solid ratio 10 mL/g. Quercetin, myricetin, and amentoflavone from Chamaecyparis obtusa leaves were also extracted using a binary mixture of 16 different DES combined with 5 different solvents (water, MeOH, EtOH, chloroform, and acetone).44 The best yields of the three target compounds were obtained when Me(Ph)3PBr/ ethylene glycol (1:5 mole ratio) was combined with MeOH, and the DES/MeOH ratios of 50, 65, and 80% (v/v) extracted a similar amount of compounds. However, at 65 and 80%, precipitation occurred in the mixture and, therefore, the optimal ratio for extraction was set at 50%. The extraction method was optimized by heating at 60 °C for 120 min with a liquid/solid ratio of 10 mL/g. In these conditions, the quantities of quercetin, myricetin, and amentoflavone extracted were 0.325, 0.086, and 0.050 mg/g, respectively. When these compounds were extracted from the same source, but with a different DES (ChCl/1,4-butanediol 1:2 mole ratio),42 the quantities of extracted myricetin and amentoflavone were significantly different, respectively 0.029 and 0.507, stressing once again the importance of finding the proper DES, under optimal conditions, to favor the extraction of the desired PC. In another study, myricitrin, quercitrin, amentoflavone, and hinokiflavon were extracted from Platycladi cacumen by 12 types of ChCl-, betaine-, and L-proline-based DES.45 Pure MeOH or a mixture between MeOH and water (50:50, v/v) was used as reference. Overall, the extraction efficiencies were better with DES than with MeOH, water, or their mixture. Moreover, the extraction yields with acid-, amide-, or alcoholbased DES were superior to those of sugar-based DES. According to the results, ChCl/laevulinic acid with a mole ratio of 1:2 showed the best extraction capacity, being efficient for the extraction of both polar compounds (myricitrin and quercitrin) and less polar ones (amentoflavone and hinokiflavone). The best conditions were found after 30 min of extraction by ultrasound bath (UAE), with a liquid/solid ratio of 40 mL/g and 10% (v/v) of water. Different compounds were extracted from Cajanus cajan’s leaves by 14 DES, using ChCl, citric acid, or lactic acid as one of the components in different DES mixtures.46 In this study, aqueous EtOH (60 or 80% v/v) was used as reference. The results showed a similar extraction yield for apigenin-6,8-di-Cα-L-arabinoside and apigenin-8-C-α-L-arabinoside (polar compounds), between ChCl/ethylene glycol (1:2 mole ratio), ChCl/1,4-butanediol (1:2 mole ratio), and aqueous EtOH (60% v/v). On the other hand, pinostrobin chalcone, pinostrobin, and cajanuslactone (weak polar compounds) showed a similar yield of extraction with ChCl/lactic acid (1:2 mole ratio) and EtOH aqueous (80% v/v). However, the authors have chosen ChCl/maltose (1:2) as extraction solvent because it was better for both groups of compounds, and the best extraction conditions were found after 12 min at 60 °C, with a liquid/solid ratio of 30 mL/g and 20% (v/v) of water, reaching a total compound extraction of 10.907 mg/g. Four main flavonoids (baicalin, wogonoside, baicalein, and wogonin) from Radix scutellariae were extracted by 13 different combinations of DES and compared with EtOH/H2O (60% v/ v).47 The ChCl/lactic acid (1:2 mole ratio) showed the higher extraction efficiency for wogonoside, baicalein, and wogonin, whereas ChCl/glycerol (1:2 mole ratio) was better for baicalin. However, the authors have selected ChCl/lactic acid (1:2 mole ratio) for the simultaneous extraction of the target compounds. 3595

DOI: 10.1021/acs.jafc.7b01054 J. Agric. Food Chem. 2017, 65, 3591−3601

Review

Journal of Agricultural and Food Chemistry Table 3. Conditions To Improve PC Extraction Using DES/MAE, DES/UAE, or DES/HE conditions target compounds myricetin, amentoflavone catechin, EGCG, ECG quercetin, kaempferol, isorhamnetin glycosides 5-CQA, CA, 3,5-DCQA, 3,4-DCQA, 4,5-DCQA rosmarinic acid, salviaflaside hyperin, 2′-O-galloylhyperin, quercitrin, quercetin-O-rhamnoside, chimaphilin EC, EGCG, ECG, EGC pinostrobin chalcone, pinostrobin, longistyline C, cajaninstilbene acid, cajanuslactone, cajanol, apigenin-6,8-di-C-α-L-arabinoside, apigenin-8-C-α-L-arabinoside genistin, genistein, apigenin anthocyanins, (+)-catechin, quercetin-3-O-glucoside a

extraction methoda

time (min)

temperature (°C)

HE HE UAE MAE HE MAE MAE MAE

40 30 45 20 46/32 20 8 12

70 75 20 60 86/89 70 66 60

MAE UAE

11 50

80 65

power (W)

330−450 700 700

600

ref 42 37 41 33 35 43 38 46 48 39

MAE, microwave-assisted extraction; UAE, ultrasound-assisted extraction; HE, heat extraction.

mg/g), and apigenin (0.266 mg/g) were obtained by MAE. This method showed increased extraction yields up to 1.9-fold over HE and UAE or 1.64-fold compared to EtOH 80% (v/v) in water. In 2014, Zhang et al.37 evaluated the potential of HE (at 20 or 60 °C for 30 min) and UAE (at 75 W for 30 min) with DES for the extraction of flavanols from green tea. The extraction was more effective by heating, reaching totals of 3.63, 35.25, and 114.2 mg/g of catechin, ECG, and EGCG, respectively. In a similar study,35 the phenolic acids extraction from Prunella vulgaris was also compared using UAE (at 79 W for 30 min) and HE (at 20 or 80 °C for 30 min). The amounts of rosmarinic acid and salviaflaside extracted by HE at 80 °C were remarkably higher than those obtained by HE at room temperature or with UAE. The optimal extraction method achieves yields up to 3.658 and 1.02 mg/g of rosmarinic acid and salviaflaside, respectively. The HE efficiency is mainly attributed to the temperature effect that reduces the DES viscosity, allowing a better solubility and/or better diffusion of the DES into the vegetable matrix. Nevertheless, the extraction capacity for a proper DES may change according to the nature of the target compounds. For example, quercetin, kaempferol, and isorhamnetin glycosides extracted from Flos sophorae by UAE or HE with the same conditions showed that the extraction of quercetin was method-dependent, whereas those of kaempferol and isorhamnetin were not.41 In this work, UAE was selected as the best method because of its simplicity and its higher efficiency for all flavonoids. In another study, UAE and MAE were used and compared for the extraction of anthocyanins and flavonols from the grape skin.39 The extraction was carried out in the same range of temperature (30−90 °C) and time (15−90 min). Regardless of the method used, the most effective extraction was reached at 65 °C for 50 min, but UAE allowed for higher yields, with, respectively, 30, 1.09, and 0.65 mg/g of total free anthocyanins, (+)-catechin, and quercetin-3-O-glucoside. In 2015, Peng et al. investigated the extraction capacity of five target phenolic acids (5-CQA, 3,5-DCQA, CA, 3,4-DCQA, and 4,5-DCQA) from Lonicerae japonicae Flos, assisted by microwave (MAE, at 60 °C and 700 W, for 20 min), heat (HSE, at 80 °C for 180 min), or ultrasound (UAE, at 60 °C for 45 min).33 MAE showed the best performance, with 0.148 mg/ g extracted CA, corresponding to an improvement factor of 2.34 compared to UAE. Likewise, MAE (at 70 °C and 1000 W for 20 min) was also found to be the best approach to improve

mole ratio), and ChCl/glycerol (1:2 mole ratio). The extraction values ranged from 18 to 100 mg/g. In addition, ChCl/malic acid was the most suitable solvent for the extraction of anthocyanins, confirming the importance of the acid pH. DES for the Extraction of Stilbenes. In 2015, Wei et al.46 studied the extraction of longistyline C and cajaninstilbene from Cajanus cajan’s leaves using 14 different DES made of ChCl, citric acid, and lactic acid. Although EtOH (80% v/v) and ChCl/maltose (1:2 mole ratio) showed similar amounts of extraction for the compounds (4.692 and 4.370 mg/g for longistyline C and 7.533 and 6.978 mg/g for cajaninstilbene), the combination between ChCl and maltose was the best DES in comparison with the other DES mixtures (2.21- and 2.74fold more for longistyline C and cajaninstilbene, respectively). The best parameters for extraction were obtained with a temperature of 60 °C after 12 min, using a liquid/solid ratio of 30 mL/g and 20% (v/v) of water.

■

IMPROVEMENT OF PC EXTRACTION WITH DES Besides the proper selection of solvent, the extraction is also affected by the conditions of extraction.9 Microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE), heating extraction (HE), and enzyme-assisted extraction (EAE) are different strategies that may promote the PC extraction. DES have already been combined with three procedures: UAE, MAE, and HE (Table 3). Besides their aptitude to improve PC extraction, such a combination may lower the volume of solvent, decrease the operation cost, and shorten the extraction time. In 2013, Bi and co-workers42 examined the extraction of flavonoids from Chamaecyparis obtuse made by HE (at 60 or 20 °C for 30 min) and UAE (at 75W for 30 min). The best results were obtained when HE was applied. The conditions were improved by fine-tuning the temperature and the time of processing, allowing extraction yields to reach 0.031 and 0.518 mg/g for myricetin and amentoflavone, respectively. Although the amounts of PC extracted were slightly different, the conditions (60 °C for 1 h) match those obtained when DES and MeOH in binary mixture were used in the extraction of the same flavonoids by HE.44 Genistin, genistein, and apigenin extractions were carried out by 11 combinations of DES, using HE, UAE, and MAE.48 After optimization, the highest yields were reached with ChCl/1,6hexanediol (1:7 mole ratio). In addition, the maximum extracted amounts of genistin (0.469 mg/g), genistein (0.641 3596

DOI: 10.1021/acs.jafc.7b01054 J. Agric. Food Chem. 2017, 65, 3591−3601

Review

Journal of Agricultural and Food Chemistry Table 4. PC Recovery from DES by SLE target compound hydroxysafflor cartomin carthamin hydroxysafflor cartomin carthamin baicalin wogonoside baicalein wogonin 5-CQA CA 3,5-DCQA 3,4-DCQA 4,5-DCQA kaempferol-3-O-β-D-glucopyranoside-7-O-β-Dglucopyranoside kaempferol-3-O-β-D-rutinoside-7-O-β-Dglucopyranoside luteolin-7-O-β-D-glucopyranoside quercetin-3-O-β-D-glucopyranoside apigenin-5-O-β-D-glucopyranoside genkwanin-5-O-β-D-glucopyranoside luteolin apigenin genkwanin EGCG ECG EGC EC myricitrin quercitrin amentoflavone hinokiflavone quercetin kaempferol isorhamnetin glycoside a

recovery yield (%) 92.00 92.00 84.00 71.00 86.00 90.00 84.10 79.50 85.00 81.80 79.25 80.03 85.96 86.01 85.52 53.73−67.73

solvent (DES) L-proline/malic

acid/water (1:1:3)a

SLE resin: HP-20

ChCl/sucrose/water (4:1:4)a

ref 27

27

ChCl/lactic acid (1:2)a + 20%b water

resin: ME-2

47

ChCl/1,3-butanediol (1:6)a + 10%b water

resin: NKA-9

33

ChCl/betaine hydrochloride/ethylene glycol (1:1:2)a

resins: NKA-9, AB-8, HPD-826

40

ChCl/lactic acid (1:2)a + 20%b water

resin: AB-8

38

ChCl/laevulinic acid (1:2)a + 10%b water

resins: AB-8, X-5, HP-20, HPD-750, LX-5, LX-38

45

cartridge: C-18

41

61.97−73.91 49.61−64.52 76.88−89.25 66.37−83.67 65.63−78.55 45.71−70.48 37.54−65.12 39.29−57.14 86.10 76.30 84.50 75.20 63.31−92.07 90.56−98.82 84.30−97.19 50.10−77.44 81.00 87.00 87.00

L-proline/glycerol

(1:2.5)a + waterc

Mole ratio. b% (v/v). cWater/DES (3:7 w/w).

the PC extraction from Pyrola incarnata Fisch, in comparison to UAE (at 70 °C for 40 min, 40 KHz) and HE (time = 60 min, temperature = 70 °C).43 The MAE efficiency is mainly due to the rapid heating, which significantly accelerates the extraction process, decreases extraction time, and increases extraction yield.50 For example, the extractions of catechins from Camellia sinensis by DES were more similar to those with HE after 60 min than those with MAE after only 8 min, with, respectively, 87.6, 40.7, 16.2, and 12.9 mg/g EGCC, EGC, ECG, and EC.38 According to the method, diverse factors are responsible for the PC extraction efficiency. For example, the UAE efficiency extraction is due to cavitation bubbles in the DES, and the ultrasonic wave passage produces damage in the plant cell wall, causing release of cell content into the medium. However, the waves can produce adverse effects, such as PC degradation or production of free radicals within gas bubbles.11 Alternatively, MAE induces molecular motion in materials or solvents with dipoles, resulting in sample heating, cell rupture, and release of active components.9 Besides, MAE allows reducing the volume of solvent used and the extraction time (generally