Natural Deep Eutectic Solvents (NADES): Phytochemical Extraction Performance Enhancer for Pharmaceutical and Nutraceutical Product Development
Abstract
:1. Introduction
2. NADES as an Alternative Solvent
Parameters | ILs | DES | NADES |
---|---|---|---|
Components | Ionic bonding: organic cation and organic or inorganic anion | Hydrogen bonding: HBA mixed with HBD | Hydrogen bonding: HBA mixed with HBD (primer metabolites that are found in nature) |
Melting point | Below 100 °C | Below 100 °C | Below 100 °C |
Polarity range | Wide | Wide | Wide |
Solubility | High | High | High |
Stability | Stable (liquid) | Some can turn back into solids | Some can turn back into solids |
Viscosity | High | High | High |
Thermolability | Heat resistant | Thermolabile | Thermolabile |
Separation | Easy | Hard | Hard |
Cost | Relatively high | Relatively low | Relatively low |
Preparation of solvent | Hard | Easy | Easy |
Toxicity | High | Lower than ILs | Low |
Biodegradability | Medium | High | High |
Environmentally friendly | Medium | High | High |
Recyclability | Yes | Yes | Yes |
3. Solubility of Compounds in NADES
4. Stability of Compounds in NADES
Plants | Bioactive Compounds | Selected DES/NADES (Molar Ratio in mol/mol) and Optimal Condition | Conventional Solvents for Comparison | Results | Refs. |
---|---|---|---|---|---|
Safflower (Carthamus tinctorius L.) | Carthamin | NADES that contain sugar, such as glucose-choline chloride, sucrose-choline chloride, xylitol-choline chloride; heating and stirring at 40 °C for 30 min. | Water and 40% ethanol | Natural safflower pigment was more stable in NADES that contained sugar than in water or 40% ethanol solution under various conditions (high temperature, light, storage time). | [40] |
Flower petals of Catharanthus roseus (L.) G.Don | Cyanidin (anthocyanins) | Lactic acid-glucose (5:1) using UAE for 30 min. | 3% formic acid in methanol | The extraction capacity of the selected NADES for anthocyanins was equal to that of the conventional solvent, but it had at least three times the stabilizing capacity for cyanidins. | [39] |
Roselle (Hibiscus sabdariffa L.) | Anthocyanins | Sodium acetate-formic acid (molarity ratio of 1:2); UAE at room temperature for 20 min. | Distilled water, 70% ethanol, and 80% methanol | Anthocyanins were more stable in the selected NADES with 0% additional water. | [45] |
Curcuma longa L. | Curcuminoids | Citric acid-glucose (1:1) and 15% water content; matrix/solvent ratio was 0.1/10 g/mL; 50 °C and 30-min extraction time with constant stirring. | Ethanol and methanol | At 80 °C, curcuminoids were more stable in NADES than in ethanol and methanol. The stability of curcuminoids test suggest that 4 °C, rather than 25 °C, is the best temperature for storing curcuminoids in NADES. | [28] |
Choline chloride-glycerol (1:1), mechanical stirrer for 24 h. | Methanol | Curcumin is more stable in NADES solution than in methanol. | [29] | ||
Rosemary (Rosmarinus officinalis L.) | Phenolics | Choline chloride-lactic acid (3:1) and 10% water; at 40 °C, 50–60 Hz, for 120 min using UAE. | Pure ethanol | Ethanolic extracts had a lower kinetic constant (kα) and half-life (t1/2) than NADES extracts, indicating that the NADES has a higher stabilizing capability than ethanol. | [43] |
Mulberry | Anthocyanins (Cyanidin-3-glucoside) | Choline chloride-lactic acid (1:2) with 20% water; using UAE for 10 min at 40 °C in the absence of light. | 80% ethanol and 0.4% HCl, lactic acid | Anthocyanin stability enhancement occurred in NADES solution compared to the tested acidified ethanol at 80 °C. If stored at −20 °C, only about 7% anthocyanins were lost in NADES, while in acidified ethanol, up to 20% were lost. After 3 months of storage at 4 °C and 25 °C, the anthocyanin concentration in NADES was 1.2- and 1.7-fold greater than that in acidified ethanol. | [46] |
Green tea (Camellia sinensis (L.) Kuntze) | Catechins (epigallocatechin-3-gallate (EGCG)) | Betaine-glycerol-glucose (4:20:1) and 30% water; using UAE for 45 min at ambient temperature. | Water, methanol, 70% methanol, and 70% ethanol | NADES is more efficient in EGCG extraction than 70% ethanol. The decrease in EGCG levels in NADES was smaller than in the comparison conventional solvent. | [44] |
5. Bioactivity of Compounds from NADES Extract
Plants | Bioactive Compounds | Extraction Methods Using DES/NADES | Conventional Solvents for Comparison | Results | Refs. |
---|---|---|---|---|---|
Rosemary (Rosmarinus officinalis L.) | Phenolics | Choline chloride-lactic acid (3:1) and 10% water at 40 °C, 50–60 Hz, for 120 min using UAE. | Pure ethanol | DES-based extracts presented higher antioxidant capacity than the alcohol extract (DPPH and FRAP assays). | [43] |
Curcuma longa L. | Curcuminoids | Citric acid-glucose (1:1) and 15% water; matrix-solvent ratio was 0.1/10 g/mL, at 50 °C for 30 min with constant stirring. | Ethanol and methanol | Radical scavenging activity (RSA) of curcuminoids was greater in NADES (87.0%) than in methanol (86.3%) but lower than ethanol (90.0%). | [28] |
Fruit Wastes (peel and kernel) of Mangifera pajang Kosterm. | - | Choline chloride-ascorbic acid and 10% water. | Water | Antioxidant capacity against DPPH free radicals of the extract in NADES increased (1.3–14.64%) compared to the antioxidant extract in water. | [47] |
Ixora javanica (Blume) DC. flower | Flavonoids and anthocyanins | Choline chloride-propylene glycol (1:1) for 5 min at 57 °C; matrix-solvent ratio was 0.02 g/mL, using UAE. | Ethanol | The selected NADES extract had higher inhibition of DPPH free radical and tyrosinase activity than ethanolic extract. | [52] |
Elderberry (Sambucus nigra L.) Flowers | Polyphenols | l-lactic acid-glycine and 15% water; solvent-matrix ratio was 60 mL/g, and stirring at 200 rounds per min. | Deionized water, 60% ethanol, and 60% methanol | The NADES extract showed the highest reducing power and antiradical activity toward DPPH than conventional solvent extracts. | [56] |
Onion (Allium cepa L.) peel | Phenolics | Choline chloride-urea-water (1:2:4); MAE at 100 Watt, solvent-matrix ratio was 54.97 mL/g, for 15.03 min. | 70% aqueous methanol with Soxhlet extraction | Under the optimized MAE conditions, the NADES extract had the higher antioxidant activity in FRAP assay (636.18 μmol AAE/g dry weight) than extract from conventional solvent. | [48] |
Lavandula pedunculata subsp. lulsitanica (Chaytor) Franco | Phenolic | Choline chloride-urea (1:2); UAE for 60 min. | Water, 80% ethanol and methanol | The extract in selected NADES showed higher antioxidant activity (DPPH and ABTS assay) than extract in the conventional solvent. In addition, this extract also provides good activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes, but it was less potent against tyrosinase (Tyr). | [49] |
Cinnamon bark (Cinnamomum burmannii (Nees & T.Ness) Blume)) | trans-cinnamaldehyde, coumarin, and trans-cinnamic acid | Choline chloride-glycerol (2:1) with 20% water content; matrix-solvent ratio was 1:4 w/w; UAE, 35 W, 42,000 Hz for 30 min. | 96% ethanol | NADES extraction from cinnamon had DPP IV inhibitory activity of 205.0 μg/mL. | [53] |
Sappan wood (Caesalpinia sappan L.) | Brazilin | Choline chloride-glycerol (1:2) 47.6 % water content; matrix-solvent ratio was 2:1 w/w; UAE, 35 W, 42,000 Hz for 50 min. | 96% ethanol | NADES extract from sappan wood had DPP IV inhibitory activity 1254.0 μg/mL. | [53] |
The aerial part of Sideritis scardica Griseb. and Plantago major L. | Phenolics and flavonoids | Choline chloride-glycerol (1:2) with 30% water; citric acid-1,2-propanediol (1:4); extraction using UAE without heating for 1 h. | 70% ethanol | NADES extracts were effective against Streptococcus pyogenes, Escherichia coli, Staphylococcus aureus, and Candida albicans. They also have minimal genotoxicity and cytotoxicity. | [55] |
Grape pomace from Vitis vinifera L. and Olive pomace | Phenolics | Choline chloride-citric acid (2:1) with 30% water; extraction using UAE and MAE. | 70% ethanol | In HeLa and MCF-7 cells, the NADES extracts of both pomaces were more cytotoxic than the ethanolic extract. | [57] |
Astragali Radix (Mikvetch Root) | Flavonoids and saponins (acetylastragaloside I) | Glucose-fructose-sucrose (32:32:5 by weight) and water. | - | The NADES-imitated honey enhanced the quantities of active components as well as their immunological effectiveness. | [58] |
Grape skin (Vitis vinifera L.) | Phenolics | Choline chloride-malic acid (1:1) with 30% water; UAE, at 65 °C, for 50 min. | 70% methanol | The NADES extract had the highest antioxidant (ORAC values were 371 μmol TE/g dry weight) and antiproliferative activities (about 20% of the cells were viable.). | [59] |
Mentha piperita L. | Phenolics | Choline chloride-malic acid (1:1) Choline chloride-sorbitol (1:1) Choline chloride-fructose (1:1) | 70% ethanol | The NADES containing organic acids showed bacterial growth inhibition at a lower concentration than conventional solvent. In FRAP test, most NADES extracts were able to neutralize DPPH radicals better than 70% ethanol and had a similar capacity to decrease Fe3+ to Fe2+ ions. | [36] |
6. Bioavailability of Compounds in NADES
7. Applications of NADES in Pharmaceuticals and Nutraceuticals
8. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Plants | Bioactive Compounds | Selected DES/NADES (Molar Ratio in mol/mol); Optimal Conditions | Conventional Solvents for Comparison | Results | Refs. |
---|---|---|---|---|---|
Spent Coffee ground | Chlorogenic acid | Betaine-triethyleneglycol (1:2) and 30% water and matrix-solvent ratio was 1:15 (g/mL) using ultrasonication at 65 °C for 20 min. | 70% methanol | Compared to choline chloride-based NADES and 70% methanol, betaine-triethylene glycol (1:2) was demonstrated to be the most powerful in extracting total chlorogenic acids from spent coffee grounds. | [24] |
Herba artemisiae scopariae (Artemisia argyi H.Lév. & Vaniot) | Chlorogenic acid | Proline-malic acid (1:1) using pre-treatment with ultrasonic for 30 min followed by continuous stirring for 2 h. | Water and ethanol | In comparison to other NADES and conventional solvents, the chosen NADES with the highest solvation free energy had the best impact for chlorogenic acid extraction. | [25] |
Blueberry leaves | Chlorogenic acid | Choline chloride-1,3-butanediol (1:2) using negative pressure of −0.07 Pa; solvent-matrix ratio was 17.01 mL/g, at 59.03 °C, for 24.12 min. | - | NPCE was used for extraction The method is efficient for extraction of Chlorogenic acid (NPCE > MAE > HRE > UAE). | [26] |
Lonicera Japonica Thunb. | Chlorogenic acid, caffeic acid, 3,4-dicaffeoylquinic acid (3,4-DCQA), 3,5-dicaffeoylquinic acid (3,5-DCQA), and 4,5-dicaffeoylquinic acid (4,5-DCQA) | Choline chloride-1,3-butanediol (1:6) with 10% water; solvent-matrix ratio was 9 mL/g, at 60 °C for 20 min using MAE. | - | MAE was an efficient method of extracting five phenolic compounds from L. japonica flos (MAE>UAE and HRE). | [27] |
Curcuma longa L. | Curcuminoids | Citric acid-glucose (1:1) and 15% water; at 50 °C, solvent-matrix ratio was 0.1/10 g/mL, for 30 min with constant stirring. | Ethanol and methanol | Citric-acid-glucose yielded the most curcuminoids, followed by malic acid-glucose (1:1) > ethanol > methanol. Curcumin at 21.18 mg/g, bisdemethoxy curcumin at 16.54 mg/g, and demethoxy curcumin at 15.12 mg/g. | [28] |
Choline chloride-glycerol (1:1), mechanical stirrer for 24 h. | Methanol and water | The percentage of curcuminoids extracted from three commercial turmeric powders from different suppliers in NADES (0.94–1.26%) was higher than in water (0.06–0.08%). However, it is still lower than methanol (5.05–5.09%). | [29] | ||
Choline chloride-lactic acid (1:1) and 20% water content; 5% solid loading; at 30 ± 2 °C in 20 min using UAE. | - | The maximum curcuminoids yield was 77.13 mg/g; The solubility of curcuminoids was 13.7 mg/mL. | [30] | ||
Sucrose-lactic acid-water (1:5:7) 15–20 min, solvent-matrix ratio was 14.5–16.5 mL/0.2 g depending on the NADES using MAE. | 80% methanol | NADES showed a high yield of curcuminoids and antioxidants compared to 80% methanol. | [33] | ||
Scutellaria baicalensis Georgi | Baicalein, scutellarein, wogonin, and oroxylin A (flavonoid aglycones); baicalin, scutellarin, wogonoside, and oroxyloside (flavonoid glycosides) | Proline-citric acid (1:1) with 40% water or citric acid-β-alanine (1:1) with 50% water; for 30 min, extract with UAE at room temperature. | 80% methanol and 70% ethanol | The yield of aglycon flavonoids extracted with NADES was 2–6 times that of 80% methanol. However, as compared to aqueous methanol, the number of glycosides extracted with NADES was only 1.5–1.8 times greater. | [34] |
Peumus boldus Molina | Boldine and phenolics | l-proline-oxalic acid (1:1) with 20% water; 340 rpm, at 50 °C for 50 min. | Methanol and water | The selected NADES was eight times more efficient for extraction of boldine than methanol. No significant differences of TPC in extracts obtained with methanol and NADES. | [32] |
Bioactive Compounds | Selected DES/NADES | Route | Results | Refs. |
---|---|---|---|---|
Rutin | Proline-glutamic acid | Oral | Improved pharmacokinetics due to increased blood concentration | [62] |
Berberine | Proline-malic acid-lactic acid-water (1:0.2:0.3:0.5) | Oral | Improved pharmacokinetics due to increased blood concentration | [61] |
Curcumin | Choline chloride-glycerol (1:1) | - | Solubility in gastric and intestinal media was increased | [29] |
Caffeine | Choline-glutamine and choline-phenylalanine | Topical | Appropriate for in vitro skin application when formulated as oil-in-water emulsions and gels; increased drug loading while preserving formulation stability | [63] |
Calycosin-7-O-β-D-glucoside | Glucose-fructose-sucrose (32:32:5 by weight) and water | Oral | Increased blood concentration | [58] |
Hydroxysafflor yellow A (HSYA) and anhydrosafflor yellow B (ASYB) | l-proline-acetamide | Oral | Improved pharmacokinetics due to increased blood concentration | [64] |
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Hikmawanti, N.P.E.; Ramadon, D.; Jantan, I.; Mun’im, A. Natural Deep Eutectic Solvents (NADES): Phytochemical Extraction Performance Enhancer for Pharmaceutical and Nutraceutical Product Development. Plants 2021, 10, 2091. https://doi.org/10.3390/plants10102091
Hikmawanti NPE, Ramadon D, Jantan I, Mun’im A. Natural Deep Eutectic Solvents (NADES): Phytochemical Extraction Performance Enhancer for Pharmaceutical and Nutraceutical Product Development. Plants. 2021; 10(10):2091. https://doi.org/10.3390/plants10102091
Chicago/Turabian StyleHikmawanti, Ni Putu Ermi, Delly Ramadon, Ibrahim Jantan, and Abdul Mun’im. 2021. "Natural Deep Eutectic Solvents (NADES): Phytochemical Extraction Performance Enhancer for Pharmaceutical and Nutraceutical Product Development" Plants 10, no. 10: 2091. https://doi.org/10.3390/plants10102091