Optimization of natural deep eutectic solvents extraction of flavonoids from Xanthoceras sorbifolia Bunge by response surface methodology

A green and efficient extraction of flavonoids from Xanthoceras sorbifolia Bunge by using ultrasound-assisted natural deep eutectic solvents combined with response surface methodology. Response surface methodology was used to optimize the extraction process. We aimed to test the scavenging ability of sixteen different NADESs and methanol extracts on DPPH and ABTS free radicals. The optimal extraction solvent was as follows: 1, 4-butanediol-acetic acid. With the best solvent the optimal extraction conditions were as follows: molar ratio 1:3, water content 33%, solid-liquid ratio 1:18 g mL^?1 and extraction time 33 min. Under these conditions, the yields of (?)-epigallocatechin, catechin, epicatechin, dihydromyricetin, taxifolin and myricetin were 9.99, 1.38, 11.08, 6.53, 0.84 and 0.54 mg g^?1, respectively. A total extraction yield of 30.37 mg g^?1 was obtained. The IC₅₀ values of DPPH and ABTS radical scavenging were 3.18 μg mL^?1 and 0.51 mg mL^?1, respectively. This study suggests that the extraction efficiency and antioxidant activity of 1, 4-butanediol-acetic acid were higher than traditional organic solvent methanol and have the advantages of environmental protection. The experiment provided a new method for the extraction of flavonoids from Xanthoceras sorbifolia Bunge.     

Choline chloride-based deep eutectic solvents do not improve the ethanolic extraction of carotenoids from buriti fruit (Mauritia flexuosa L.)

The aim of the present study was to evaluate the effect of choline chloride-based deep eutectic solvents (DESs) as co-solvents for the ethanolic extraction of total carotenoids from buriti fruit (Mauritia flexuosa L.). Choline chloride-based DESs were synthesized by the heating method. The systems were prepared using ethanol and DESs as a co-solvent in concentrations of 0.5–70.0% (w/v). In addition, a control condition was performed using ethanol as the sole solvent. The total carotenoid concentration in the systems was determined by spectrophotometry at 450 nm. The results showed that the ethanol used without co-solvent obtained total carotenoid yields of 10.06 ± 0.03 mg/g for the buriti pulp and 10.43 ± 1.27 mg/g for the buriti peel. In turn, the use of choline chloride-based DESs as co-solvents did not increase the ethanolic extraction yield of carotenoids. However, it was observed that the buriti peel can be a rich source of carotenoids with yields comparable to the fruit. Thus, it is suggested that new green solvents be evaluated to increase the recovery of total carotenoids from buriti fruit using ecofriendly processes.     

Therapeutic deep eutectic solvents assisted the encapsulation of curcumin in alginate-chitosan hydrogel beads

Alginate (ALG)-Chitosan (CHI) hydrogel beads have been broadly studied as vehicles for controlled drug delivery applications. However, encapsulation of poorly-water soluble compounds is somehow limited by the need to use emulsifying agents and/or organic solvents. This study aimed to encapsulate curcumin in ALG-CHI beads using as drug solubilizing vehicles deep eutectic solvents (DES). Using this approach hydrogel beads were successfully produced using extrusion-dripping method. The beads were vacuum-dried and freeze-dried which impairs their morphology, shape and dimensions features, as well as physicochemical properties. Vacuum-dried beads showed superior performance and were further evaluated as curcumin carriers for drug release control. The results indicated that swelling, degradation and in vitro release studies were influenced by the pH, highlighting the suitability of these systems for intestinal drug delivery. These outcomes indicate that the encapsulation of curcumin in pH-responsive ALG-CHI hydrogel beads using DES can be successfully accomplished, holding a great promise as encapsulation strategy of poorly water-soluble compounds for intestinal-targeted delivery of curcumin.     

A closer look in the antimicrobial properties of deep eutectic solvents based on fatty acids

Microbial infection is a serious and challenging clinical complication that has attracted widespread interest in last decades. In this context, we present a strategy based on deep eutectic solvents (DES) to explore these unmet medical needs. DES systems based on saturated fatty acids, namely, capric acid (CA), myristic acid (MA), lauric acid (LA) and stearic acid (SA) were produced and fully characterized at a physicochemical level. The thermal characterization results indicate a depression of the melting point in DES form when compared with the starting compounds to near-physiological levels, whereas via polarized optic microscopy insights on the homogeneity/separation of the counterparts were obtained. Regarding, physicochemical properties, temperature also has a great effect on the viscosity of the eutectic systems, the higher the temperature the lower the viscosity observed. The antimicrobial potential of DES systems was evaluated against a broad spectrum of microorganisms. The obtained results show that DES retain the antimicrobial of the counterparts possibly present synergistic effects between components, mainly in the CA:MA formulation. The systems revealed significant antimicrobial activity against the tested Gram-positive bacteria and C. albicans, with the CA:LA system showing the greatest overall inhibitory/bactericidal activity. This system was then used for a biofilm removal/detachment assay where relevant activity is evident against the prementioned organisms and E. coli without need of additional physical force. The obtained results illustrate the potential of saturated fatty acid-based DES when compared with isolated fatty acids as preventive/therapeutic options against microbial infections and/or components of novel thermoresponsive biomedical devices for antibacterial purposes.     

A novel strategy to improve the recovery of phenolic compounds from Pistacia lentiscus L. fruits using design-based statistical modeling for ultrasound-deep eutectic solvents extraction and the evaluation of their antioxidant potential

Recently, there has been increasing interest in using alternative green technologies for the isolation of bioactive metabolites from medicinal plants. This study was designed to select the optimal solvent for phenolic compounds (TPC) extraction from Pistacia lentiscus L. black fruits (PBF) and the development of an experimental model by response surface methodology using ultrasound-assisted deep eutectic solvents (UAE-DES). The characterization and the antioxidant capacity of PBF phytochemicals using a multi-test system in-vitro were investigated. The highest amount of phenolic compounds (TPC: 183.95 ± 0.01 mg GAE/Gdw) was obtained using choline chloride-acetic acid solvent DES, under the optimum extraction conditions: 28.3% of water percentage, 40 °C of extraction temperature, and 18 min of extraction time. Moreover, DES extract had a more important antioxidant capacity with no significant difference compared to the control (Ascorbic acid). Furthermore, HPLC-DAD and TLC analysis indicated the presence of rutin and Cyanidin-3-glycoside in fraction number 4 after fractionation using the HP-20 diaion resin column. This extraction media has proved to be an alternative approach for the extraction of bioactive compounds as a sustainable and safe extraction media for pharmaceutical and industrial applications.     

Green approach to extract bioactive compounds from orange peel employing hydrophilic and hydrophobic deep eutectic solvents

Consumer interest in natural products with advantageous biological impacts on their health has increased in recent years. Therefore, academic and industrial communities have concentrated their research on developing sustainable techniques for extracting bioactive compounds from natural resources. In the present study, extracts rich in bioactive compounds from orange peel were obtained using novel hydrophilic and hydrophobic deep eutectic solvents (DESs). Bioactive compounds such as carotenoids and polyphenols, their stability, antioxidant capacity, permeability, and biological activity were determined to consider their inclusion in food formulations. The results demonstrated that the highest total carotenoid values were obtained with hydrophobic DESs using DL-Menthol: camphor (163.5 ± 1.1 mg/100g_fw), DL-Menthol: Eucalyptol (168.7 ± 1.7mg/100g_fw), and lauric acid: octanoic acid (153.1 ± 7.1 mg/100g_fw). Total polyphenols were higher in hydrophilic DESs such as proline: malic acid (282.8 ± 7.3 mg/100g_fw). The antioxidant values showed that hydrophobic extracts have higher antioxidant activity than traditional solvents. Carotenoid stability was also improved using DL-Menthol: camphor, while lactic acid: glucose and proline: malic acid showed a better capacity to stabilize polyphenols. To simulate carotenoid and polyphenol permeation, the Parallel Artificial Membrane Permeability Assay (PAMPA) was used and demonstrated that DESs can enhance the permeability of these bioactive compounds. Biological tests were also performed, and the antiproliferative effect in HeLa cells showed only 26.70% cell viability in DL-Menthol: camphor extracts. Based on the presented results, DESs can be used to extract hydrophilic and hydrophobic compounds from orange peels, and the obtained extracts could be included in food formulations, avoiding the solvent elimination process.     

Deep eutectic solvents as sustainable extraction media for plants and food samples: A review

With the introduction of the concept of green chemistry, eco-friendly extraction processes are moving from an option to a must. Therefore, the discovery and development of new solvents with less hazardous ecotoxicological profiles are required urgently to replace, reduce, or even eliminate petroleum ones. Recently, making up a novel class of solvents as an alternative to ionic liquids (ILs), natural deep eutectic solvents, NADES might be considered as one of the most promising discoveries in the field of green chemistry. Investigated as potential green tools and especially in the field of extraction of valuable compounds from medicinal plants and food. In this article, we attempt to provide an overview of knowledge regarding natural DESs as novel solvents technology. Their formation, structure, some physicochemical properties, and especially, with emphasis on their beneficial applications in the extraction and separation process of valuable compounds from different plants families and food samples. Biological activities and industrial application of eutectic bio extracts are summarized, and further perspectives are discussed.     

Study on extraction and antioxidant activity of polysaccharides from Radix Bupleuri by natural deep eutectic solvents combined with ultrasound-assisted enzymolysis

A green and efficient extraction method for Radix Bupleuri polysaccharide (RBP) by natural deep eutectic solvents (NADES) combined with the ultrasonic-assisted enzymolytic extraction (UAEE) was established. Using UAEE, the NADES with different ion combinations were selected to extract RBP. The best technical conditions of NADES combined with UAEE were determined by a single factor experiment and response surface optimization experiment. The results showed that the best extraction process of RBP with NADES was as follows: the molar ratio of urea to choline chloride was 1:3, the water content was 20%, the ratio of material to liquid was 1:30, the ultrasonic power was 400 W, the temperature was 57.34 °C, pH was 4.89, and the amount of enzyme was 2.63%. The extraction rate of RBP was 10.1042%, and the relative error compared with the predicted value was 2.03%. The reuse of NADES not only has little effect on the extraction rate of RBP but also has the highest extraction rate when it is reused for the third time, indicating that NADES has certain recyclability. The in vitro antioxidant activity of polysaccharides extracted from Radix Bupleuri by NADES showed that the extract had a specific ability to DPPH, ABTS, and hydroxyl radicals. Therefore, this study proposed a new, green, and recyclable extraction method for extracting RBP from Radix Bupleuri, which provided a theoretical basis for the in-depth understanding of the physical and chemical properties of RBP and the development and utilization of its biological activities.     

Natural deep eutectic solvents improve the solubility of acetylcholinesterase reactivator RS194B

Natural deep eutectic solvents (NADES) were studied as alternative solvents for the preparation of oxime RS194B, which is considered as a potent antidote for organophosphate (OP) poisoning. OPs are irreversible inhibitors of the essential enzyme acetylcholinesterase (AChE) and standard oximes used in therapy are insufficiently effective in the central nervous system. Nowadays, the focus is on the centrally active reactivators of phosphylated AChE such as oxime RS194B. The shortcoming of this oxime is its low solubility in water, and the aim of this study was the enhancement of the compound's solubility by preparing oxime formulations in NADES. The solubility of RS194B in various NADES was predicted by the COSMOtherm program and experimentally determined using high efficient liquid chromatography. The best oxime solubility was achieved with NADES citric acid:glucose (1:1) solvent with 30% (w/w) of water. Over a one-month period, there was no difference in the stability of oxime formulations in NADES and a reference solvent. Initial tests on the potential effects on enzyme activity showed that the selected NADES inhibits AChE, and its level should be kept below 0.2% in order for the enzyme to keep above 90% activity. Reactivation kinetic parameters of sarin- and VX-inhibited AChE were determined for both NADES and the reference solvent formulations of the oxime. Results showed an improvement in the AChE reactivation, as a consequence of the higher affinity of phosphylated AChE for the RS194B formulation in NADES. Although further optimizations are needed, this study is the first to show the NADES potential in formulating antidotes for nerve agent poisoning.     

The evaluation of five bioactive compounds content and in vitro antioxidant of Caryophylli Flos extracts obtained by natural deep eutectic solvents

In this study, a simple, green and efficient method based on ultrasound-assisted NADESs was used to extract ellagic acid, isoquercitrin, myricetin, luteolin and eugenol from Caryophylli Flos. Nine different NADESs were synthesized and screened, and 1,3-butanediol-levulinic acid (molar ratio 1: 3) was selected as the topgallant solvent for maximizing target compounds extraction yields. Single factor experiments combined with response surface methodology and genetic algorithm were applied for efficient optimization of the main variables in the extraction procedure. The optimum experimental conditions were as follows: water content in NADES 29%, liquid-solid ratio 21 mL/g and extraction time 30 min. After the optimization of several main variables, an extract obtained showed higher extraction yields and DPPH and ABTS radical scavenging rate than conventional organic solvents extracts which were used for comparison. Consequently, this study provides a suitable strategy for efficiently extracting bioactive compounds from Caryophylli Flos, and NADESs can be employed as green extraction media for obtaining other natural products.     

天然低共熔溶剂在药剂学中的应用

天然低共熔溶剂是一种由生物相容性好的天然物质作为氢键供体和受体所构成的低共熔溶剂,如胆碱、氨基酸和糖等,具有低成本、易制备及环境友好等优点,已在许多领域中有着广泛的应用。由于其生物相容性好,使用较为安全,特别适用于医药领域。本文首先从天然低共熔溶剂的形成原理出发,对目前所采用的分子模拟设计方法进行了综述;然后对目前天然低共熔溶剂所使用材料和制备方法进行了总结,并阐述了其理化性质;最后对其目前在药剂学中的应用进行了总结,包括增加药物溶解度、促进药物渗透性、促进药物口服吸收等,并对其在药剂学中的应用前景进行展望。     

Ultrasound-assisted extraction of antioxidant phenolic compounds from Lavandula angustifolia flowers using natural deep eutectic solvents: An experimental design approach

In this study, the green extraction of antioxidant phenolic compounds from Lavandula angustifolia was investigated using ultrasound-assisted extraction coupled with natural deep eutectic solvents (NADESs). One variable at a time, fractional factorial design, steepest ascent/descent method, and central composite design were used to optimize the extraction conditions. Eighteen NADESs based on choline chloride, organic acids, and sugars were tested by one variable at a time approach. The NADES composed of choline chloride and glycerol with a molar ratio of 1:2 showed higher extraction performance than other NADESs and benchmark solvents (70 % ethanol and 80 % methanol). After solvent selection, other extraction parameters including ultrasound amplitude (20–100 %), temperature (40–70 °C), time (5–30 min), liquid to solid ratio (10–50 mL/g), and water content in NADES (10–50 %) were screened using fractional factorial design. Subsequently, the steepest ascent/descent method was applied to approach the suitable level of the selected parameters. Finally, response surface methodology was used to determine the optimal extraction conditions. The optimum conditions were ultrasound amplitude of 60 %, temperature of 60 °C, time of 17.5 min, liquid to solid ratio of 31.7 mL/g, and water content in NADES of 33.5 % with the predicted phenolic content of 50.50 mg gallic acid equivalent/g, flavonoid content of 35.79 mg catechin equivalent/g, antioxidant capacity (AC)_DPPH of 41.60 mg Trolox equivalent (TE)/g, AC_ABTS of 77.13 mg TE/g, and AC_CUPRAC of 163.33 mg TE/g. Phenolics and volatiles were analyzed by HPLC and GC-MS, respectively. The results showed a sustainable, green, and effective extraction of antioxidant phenolic compounds from L. angustifolia.     

Microwave-assisted hydrodistillation extraction based on microwave-assisted preparation of deep eutectic solvents coupled with GC-MS for analysis of essential oils from clove buds

In recent years, deep eutectic solvents (DESs) as green and sustainable solvents have been widely used in the effective extraction of natural products. Usually, DESs are synthesized by heating and stirring method which takes a long time and energy. In this case, a microwave assisted preparation technique was used to form DESs for saving time and energy. And the DESs as pretreatment solvents were combined with microwave-assisted hydrodistillation (MAHD) for the extraction of essential oils (EOs) from the clove buds in this work. The maximum essential oils yield of 4.60% was obtained with the microwave power of 600 W, the pretreatment time of 5 min and the hydrodistillation time of 40 min using a deep eutectic solvent composed of choline chloride and lactic acid (molar ratio with 1:2). In addition, the essential oil was analyzed by gas chromatography-mass spectrometry (GC-MS), a total of 40 compounds were identified. Compared with MAHD, water-based MAHD and traditional hydrodistillation (HD), the content and composition of essential oil extracted by DES-based MAHD were higher. Thus, the combination of deep eutectic solvents with a microwave-assisted technique in this study provided an eco-friendly way of extracting essential oils.     

疏水性低共熔溶剂对水中5种非甾体抗炎药物的萃取研究

目的 建立一种以疏水性低共熔溶剂为萃取溶剂的分散液液微萃取方法,以提取水中的酮洛芬、布洛芬、洛索洛酚钠、萘普生、双氯酚酸钠五种非甾体抗炎药物。方法 以五种非甾体抗炎类药物的萃取率为指标,考察了疏水性低共熔溶剂种类和体积、氢受体/氢供体比例、分散剂的种类和体积及氯化钠的浓度对萃取效率的影响,确定了最佳萃取条件。结果 通过条件筛选,得到的最佳萃取条件为以DES（甲基三辛基氯化铵/癸酸比例=1：5）为萃取溶剂,以乙腈为分散剂,DES的体积为300μL,乙腈的体积为650μL,氯化钠的浓度为13.5%。结论 在最佳条件下,酮洛芬、布洛酚、洛索洛芬钠、萘普生、双氯酚酸钠的萃取率为89.7%,80.3%,77.1%,92.6%和91.4%。     

Sustainable eutectic mixture-based ultrasound assisted multifaceted valorisation of pineapple waste for bromelain and bioethanol production

A large number of pineapple residues like peels, leaves and stems generated during processing remains underutilized. The current investigation provides one-pot task-specific valorisation of these residues by sequential extraction of bromelain and saccharification of cellulose residue for bioethanol production. Employing natural deep eutectic solvents (NADES) prepared by mixing ammonium salts with imidazole and glycerol has guaranteed sustainable extraction of bromelain. Ultrasound-assisted liquid phase microextraction (UA-LPME) was performed and NADES with moderate density (TBC:I:G/sodium sulphate) was observed to have a higher bromelain yield and purity. Response Surface Methodology-based optimization of UA-LPME was carried out and solid: liquid ratio (25 ml/g), ultrasound time (17.5 min) and ultrasound temperature (45 °C) were observed to be influential variables resulting in an optimal bromelain yield of (87%). Sequential fractionation of the enzyme concentrate with gel filtration chromatography and anion exchange chromatography has resulted in a corresponding purity fold of 89.27. The cellulose-rich residue remaining after bromelain extraction was enzymatically saccharified (Cellic CTec2) for bioethanol production (12.7 g/L). This novel approach guarantees sustainable valorisation of pineapple waste using NADES as a sustainable extraction medium.     

Green,rapid and efficient synthesis of new antibacterial pyridopyrimidinone mediated by eutectic mixture of Urea/CuCl2

An eco-friendly, efficient and green one-pot multicomponent preparation of pyridopyrimidine is reported. A mixture of urea/CuCl₂ was prepared and used as efficient catalyst to synthesize a various derivative of pyridopyrimidine with excellent yields in short times of reaction using microwave irradiation. All product were obtained with excellent yields (94-98%) in short time of reaction (few minutes). This green deep eutectic solvents was recycled and reutilized for many cycles without showing any significant loss of performance. The synthesized compounds were assessed for their activity against some bacterial strains. Therefore, just 6 compounds were showed active against the targeted bacterial strains.     

Non-taxane compounds from the bark of Taxus yunnanensis

From the bark of Taxus yunnanensis , 15 non-taxane compounds were isolated. Through spectroscopic methods such as 1D and 2D NMR and MS experiments, one of them was determined as a new abietane-type diterpenoid named taxayunnin ( 1 ). The other 14 known compounds were identified as taxamairin C ( 2 ), taxamairin A ( 3 ), 3 g -hydroxy-sandaracopimaric acid ( 4 ), (+)-3-hydroxy-isodrimenin ( 5 ), rubrosterone ( 6 ), ponasterone A ( 7 ), ecdysterone ( 8 ), 20-hydroxy-echysone-20,22-monoacetonide ( 9 ), 7-oxositosterol ( 10 ), stigmast-4-en-6 g -ol-3-one ( 11 ), 5 f ,6 g -dihydroxy-daucosterol ( 12 ), g -sitosterol ( 13 ), daucosterol ( 14 ), 1- O - g - d -glucopyranosyl-(2 S , 3 R , 4 E , 8 Z )-2- N -(2'-hydroxypalmitoyl)-octadeca-sphinga-4,8-dienine ( 15 ), respectively. Compounds 4 - 6 , 9 - 12 and 15 were isolated from Taxus plants for the first time.     

Rapid and eco-friendly high yield synthesis of dihydroquinazolinones mediated by urea/zinc chloride eutectic mixture

In this contribution an efficient and environmentally friendly one-pot multicomponent synthesis of dihydroquinazolinones is reported. Several deep eutectic solvents were studied as alternative reaction media for the three-component reaction between isatoic anhydride, amines and aldehydes or ketones. Among the low melting mixtures, the mixture urea/zinc chloride efficiently catalyzed the reaction affording a variety of dihydroquinazolinones in excellent yields with short reaction times. In addition, this alternative solvent was recycled and reused in three cycles showing a good performance in the catalytic activity. The versatility of the eutectic solvent was further explored for the obtention of the biologically active compounds methaqualone, mecloqualone and the natural alkaloid tryptanthrin giving an excellent yield.     

Deep eutectic solvents comprising active pharmaceutical ingredients in the development of drug delivery systems

Introduction: Deep eutectic solvents comprising or acting as solvents of active pharmaceutical ingredients (API-DES) emerged as promising alternatives to improve therapeutic efficiency, with the additional possibility to integrate them in (bio)polymer-based systems to enhance their delivery.

Areas covered: A critical review of the API-DES field evolution is herein presented, namely on the capacity of DES to integrate APIs in their composition and on the use of DES as solvents for APIs. These strategies avoid a current major concern related to drugs and APIs, i.e. polymorphism, and increase the solubility and bioavailability of the target API which leads to increased bioavailability. Owing to their composition versatility, polymerizable API-DES can also be prepared. Finally, the incorporation of API-DES in (bio)polymer-based systems to improve drug delivery is presented and discussed.

Expert opinion: The relatively easy preparation of API-DES and their capacity to tune the API’s release profile when incorporated in (bio)polymer-based systems represent an effective alternative to improve the APIs therapeutic action and to develop controlled drug delivery systems. Given the potential and progress demonstrated so far, the authors foresee further research on novel API-DES and on their delivery routes, envisaging the development of alternative therapies and final approval as therapeutics.     

Ultrasound- and heat-assisted extraction of glycyrrhizin from licorice by two glycerol-based DESs - Modeling and optimization as per response surface methodology

Glycyrrhizin is an important bioactive compound of licorice (Glycyrrhiza glabra) having many pharmaceutical properties. The present study explored the extraction of glycyrrhizin from licorice in two glycerol-based deep eutectic solvents glycerol-ammonium acetate (GAA) and glycerol-choline chloride (GCC) and by two different techniques heat-assisted extraction (HAE) and ultrasound-assisted extraction (UAE). For optimization, response surface methodology (RSM) as per CCD (central composite design) was applied. Quantification of the compound was done by HPLC (high performance liquid chromatography). In GAA-HAE, the highest yield 36.96 mg/g was at 80 °C temperature, 25 min time, and 50% DES concentration and in GCC-HAE, the highest yield was 35.26 mg/g that was at temperature 80 °C, time 65 min and 50% DES concentration. In GAA-UAE, the highest yield 35.41 mg/g was at temperature 60 °C, time 79 min and 70% DES concentration, and in GCC-UAE, the highest yield 31.37 mg/g was at temperature 80 °C, time 25 min and 50% DES concentration. UAE-methanol gave the highest yield 31.36 mg/g that was at temperature 60 °C, time 45 min and 70% methanol. The predicted models had high fitness each having a significant p-value (<0.05) and a nonsignificant lack of fit p-value. The R² values were about 94%, 98%, 93%, 95% and 95% for GAA-UAE, GCC-UAE, GAA-HAE, GCC-HAE and methanol-UAE models, respectively, which also indicated high adequacy of the models. In terms of yield, HAE and UAE were comparable but UAE has the advantage of being more environmentally friendly, and GAA was more powerful than GCC as extracting medium. As a result, GAA-UAE should be a viable option for extracting glycyrrhizin from licorice as an efficient and environmentally friendly method.