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Abbreviation (ISO4): Prog Chem      Editor in chief: Jincai ZHAO

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Progress in Chemistry >

2024 , Vol. 36 >Issue 5: 667 - 678

DOI: https://doi.org/10.7536/PC230809

Review

Application of New Separation and Purification Technology in Natural Products

  • Wenwei Li 1 ,
  • Ziyu Zhu 1 ,
  • Ruilin Haotian 1 ,
  • Yao Xie , 2, * ,
  • Aiqin Luo , 1, * ,
  • Axin Liang , 1, *
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  • 1 Key Laboratory of Molecular Medicine and Biotherapy, the Ministry of Industry and Information Technology, School of Life Science, Beijing Institute of Technology, Beijing 100081, China
  • 2 Beijing Dawn Aerospace Bio-Tech Co. Ltd, Beijing 100043, China
* e-mail: (Yao Xie);
(Aiqin Luo);
(Axin Liang)

Received date: 2023-08-15

  Revised date: 2023-12-20

  Online published: 2024-03-15

Supported by

National Key R&D Program of China(2019YFA0904104)

Scientific Research Cooperation Program(202221641061A)

Scientific Research Cooperation Program(202321641067A)

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Abstract

natural products are secondary metabolites preserved by natural selection in the long-term evolution process of natural organisms,and are widely used in many fields because of their rich medicinal value.With the development of modern science,the demand for high purity products of natural products is also increasing.Traditional separation methods usually have some disadvantages such as large consumption of organic solvents,poor separation effect,high cost and long cycle,which seriously restrict the development and use of natural products in various fields.the emergence of new separation and purification technology provides a new idea for the extraction,separation and application of natural products.On the basis of summarizing the existing literature,this paper reviews the new methods of separation and purification of natural products,and finally summarizes and discusses the research bottleneck and future development direction of natural product separation and purification。

Contents

1 Introduction

2 Novel chromatographic method

2.1 Counter-current chromatography

2.2 Hydrophilic interaction chromatography

3 Supercritical fluid separation

3.1 Ionic liquid separation

3.2 Deep eutectic solvent separation

3.3 Ionic liquid and deep eutectic solvent cooperation

4 Molecular imprinting technology

4.1 Magnetic molecularly imprinted polymer

4.2 Molecular imprinted solid phase extraction

4.3 Deep eutectic solvent-molecularly imprinted polymer

5 Conclusion and outlook

Key words： natural products; separation; purification

Cite this article

Wenwei Li , Ziyu Zhu , Ruilin Haotian , Yao Xie , Aiqin Luo , Axin Liang . Application of New Separation and Purification Technology in Natural Products[J]. Progress in Chemistry, 2024 , 36(5) : 667 -678 . DOI: 10.7536/PC230809

1 Introduction

natural product(NP)refers to the endogenous chemical components and their metabolites in natural substrates such as plants,terrestrial animals,insects,marine organisms and microorganisms,which are secondary metabolites retained by Natural selection in the long-term evolution of Natural organisms and have a wide range of sources[1]。 natural products not only have the function of maintaining the integrity of tissues and organs and normal growth and development of organisms,but also have a variety of biological activities and medical significance.Many studies have confirmed that Natural products have rich pharmacological effects such as anti-cancer,anti-virus,treatment of leukemia,prevention of neurodegenerative diseases,anti-oxidation,hypoglycemic and so on[2,3][4][5][6][7][8]。 Natural products and their derivatives are classified into four categories according to their respective biosynthetic sources,including plant,animal,microbial,and mineral sources[9]。 the diversity of natural substances is related to a variety of factors,most notably the great biodiversity of aquatic and terrestrial species,which synthesize a variety of molecular structures with a wide range of biological activities.Medicinal natural products of plant origin are usually secondary metabolites,which are the products of gene expression and usually do not require reproduction,growth and development.These secondary metabolites do not play an important role in maintaining the basic life activities of plants.It is formed as a result of environmental adaptation or a potential protective strategy against predators,which can improve the ability of plants to survive and resist external pressures through interaction with the environment[10]。
Because many natural products have high medicinal value,many drugs used in clinic are directly or indirectly derived from natural products,such as morphine,quinine,artemisinin,paclitaxel,penicillin and so on[11]。 drug research and development is a high-cost,time-consuming and high-risk process.in recent years,a number of new technologies and strategies have emerged around the development of new drugs to accelerate the development of new drugs to deal with different diseases.Compared with the direct synthesis of small molecule drugs,Natural products have greater unique advantages in Drug development.natural products are produced in organisms through long-term evolutionary selection in nature,and their specific structures and activities are far beyond people's imagination[12]。 Therefore,although the proportion of synthetic drugs is increasing year by year,natural products are still the main source of drugs or lead compounds[13]。
With the rapid development of chemistry,biology,medicine and other disciplines,various new technologies have been introduced into the development of natural product drugs.Economical and efficient methods are urgently needed for the separation,determination,activity screening and toxicity evaluation of natural products[14]。 in order to use the natural active ingredients in plants as drugs,the first problem to be solved is extraction,separation and purification.Access to potential high-value chemicals is the initial step in natural product research and development.Whether for bioactivity determination,batch preparation,or especially for quality assessment of raw material intermediates or finished products,many analytical laboratories around the world have been looking for efficient,selective,reproducible,low-cost,and environmentally friendly methods[15]。 There are more than 200,000 metabolites in the plant kingdom,including primary metabolites needed for development and reproduction,and secondary metabolites needed for competition in the environment,up to thousands of metabolites in a plant[16]。 Even For the same characteristic structure,the number of representative compounds is very large.for example,more than 400 kinds of ganoderic acid have been found,including ganoderic acid A,Ganoderma acid C2,Ganoderma acid G,etc[17]。
for these reasons,it is very important to explore new technologies For the separation and purification of natural products.the traditional separation and purification methods include fractional precipitation,gel chromatography,fiber column chromatography,preparative liquid chromatography,membrane separation,macroporous resin separation,etc.However,due to the complexity of the matrix of natural products,the traditional methods have the disadvantages of low separation efficiency,high cost,heavy pollution,long preparation cycle,etc.,which seriously restrict the development and application of natural products[18][19][20][21][22][23][24,25]。 At present,many research groups are committed to the development of new separation and purification technologies,as well as the supplement and optimization of traditional methods,resulting in many new technologies that have been successfully applied,such as countercurrent chromatography,hydrophilic interaction chromatography,ionic liquid extraction and molecular imprinting separation[26,27][28,29][30,31][32⇓~34]。 Our research group has completed the separation and purification of many different substances,and successfully designed and synthesized several new chromatographic stationary phases,such as chiral hydrogen-bonded organic frameworks,metal organic cages,β-cyclodextrin covalent organic frameworks,etc.the prepared chromatographic column is combined with methods such as ultraviolet spectroscopy,gas chromatography,ultra-high performance liquid chromatography,mass spectrometry and the like,so that the separation capability,selectivity and sensitivity of various samples are greatly improved[35⇓⇓⇓~39]。
In this review,the new separation and purification methods of natural products(Figure 1)are briefly introduced,and the principles,applications,application scope,advantages and disadvantages of different methods are summarized,and finally the current bottlenecks and future development directions are summarized and prospected。
图1 天然产物新型分离纯化方法概述示意图

Fig. 1 Overview schematic of new methods for separation and purification of natural products

2 New chromatographic method

chromatography has always been a common method for the separation and analysis of natural products.According to different principles,it can be divided into normal phase chromatography,countercurrent chromatography,reversed phase chromatography,multi-dimensional chromatography,supercritical fluid chromatography and so on.Although the separation effect of traditional chromatographic methods is good,the consumption of solvent is large,the sample injection volume is small,and the separation efficiency is low,so in recent years,new chromatographic methods for the separation of natural products have emerged。

2.1 Countercurrent chromatography

Counter-current chromatography(CCC)is an efficient preparative separation technique based on the partitioning of a sample between two immiscible solvents.Because that distribution coefficient of each component in the solute in the two solvents are different,the liquid-liquid distribution principle can be use to separate the mixture,and the method can continuously distribute the target compound between the immiscible liquid-liquid phases to achieve the purpose of separation without using the traditional solid phase carrier[40][41]。 Traditional separation methods of natural products often require multiple liquid-liquid extraction steps,and then separate and purify the monomeric compounds in the extract by different chromatographic methods,which have the disadvantages of time-consuming,large solvent consumption,and also cause sample denaturation and irreversible adsorption[42]。 High speed counter-current chromatography(HSCCC)avoids the above disadvantages in principle and overcomes the shortcomings of traditional column chromatography separation.It has the advantages of flexible elution method,large sample loading,High product purity and simple operation.It has been widely used in the separation and purification of bioactive compounds in natural plants,such as proteins,polysaccharides,polyphenols and so on[43][44]。
Although countercurrent chromatography has unique advantages,because both The mobile phase and the stationary phase are liquids,any change in the composition of one phase may cause a change in the composition of the other phase,so the optimization of chromatographic conditions has a great impact on the separation results.Yang et al.Established a new linear gradient elution method,prepared biphasic solvent systems containing heptane,ethyl acetate,methanol and water in different proportions,and used them to optimize the countercurrent chromatography separation of methanol isobaric and linear gradient.the optimal system was 3:7:4:6(V/V/V/V),under which complex mixtures with a wide range of polarities in 12 species of Melilotus officinalis roots could be separated[45]。
There are also studies on the combination of extraction and countercurrent chromatography to reduce solvent consumption.Song et al.Established a new method for enrichment of plant extracts by direct continuous injection of countercurrent chromatography.the n-hexane-acetonitrile-water solvent system was pumped into the CCC column respectively,and the extract(45%acetonitrile)was directly and continuously injected.Because the extract was the mobile phase,the consumption of solvent could be greatly reduced.Finally,315.9 G of crude extract of Tussilago farfara was injected,and 6.8 G of sesquiterpene enrichment could be obtained in a single run of 8.5 H.the average recoveries of the three compounds obtained by this method were 96.1%,96.9%and 94.6%,respectively,while the average recoveries of the three compounds obtained by open-column chromatography were 77.7%,66.5%and 58.4%,respectively,which proved that countercurrent chromatography had better ability to enrich target components from natural products than traditional column chromatography,and had the advantages of large processing capacity and less solvent consumption[46]。
Because HSCCC does not require a fixed carrier as a stationary phase,It has high sample loading capacity and high recovery of target analytes,and can easily separate substances with similar skeletons and polarities.However,there is no sufficient theoretical basis for the selection and optimization of the solvent system in this method,and the key issues such as the separation principle,hydrodynamic equilibrium and separation theory,and solvent system need to be further studied.it is necessary to carry out many experiments based on subjective experience to screen out a better solvent system,which has certain randomness and uncertainty;and the separation effect is easily affected by the density difference between the two phases,temperature,volume flow rate,rotating speed,etc;as well as excessive solvent consumption and long separation time,the application of countercurrent chromatography is still restricted and needs to be further improved and perfected。

2.2 Hydrophilic interaction liquid chromatography

Hydrophilic interaction chromatography(HILIC)is a separation technique using a polar stationary phase and an aqueous solution of a polar organic solvent as the mobile phase.Compared with traditional reversed-phase liquid chromatography,HILIC has better separation ability for strongly polar and Hydrophilic compounds[47][48]。 the separation mechanism of HILIC is complex,and the distribution mechanism proposed by Alpert is generally accepted at present:when the mobile phase enters the chromatographic column,the surface of the stationary phase will selectively adsorb the water In the mobile phase,forming a dynamic"water-rich layer"on the surface.the solute is partitioned between the bulk mobile phase and the water-rich layer partially fixed on the surface of the stationary phase.in addition,forces such as adsorption,hydrogen bonding,dipole-dipole interaction,electrostatic interaction,molecular shape selectivity,and hydrophobic interaction between the analyte and the stationary phase may also exist at the same time.Figure 2 illustrates this principle[49][50]。
图2 （a）描述HILIC保留机制的亲水-减水模型；（b）蜘蛛图显示了22个具有代表性的HILIC色谱柱的选择性[50]

Fig. 2 (a) A hydrophilic-subtraction model describing the HILIC retention mechanism; (b) Spider diagram displaying the column selectivity of 22 representative HILIC columns[50]

Like traditional chromatographic separation methods,stationary phases are At the heart of HILIC,and a variety of HILIC stationary phases have been introduced over the past two decades.the most commonly used commercial chromatographic stationary phases include keyless silica,amides,glycols,neutrals,etc.at the same time,There are also many newly developed stationary phases,such as metal-organic frameworks(MOF),covalent organic frameworks(COF),graphene,magnetic elements,etc.,among which MOF shows good chemical stability,high mechanical strength,large specific surface area,and high density of functional groups[51]。 Si et al.Used two-dimensional MOF-FDM-23 nanosheets to modify the surface of silica spheres and prepared core-shell composites,which have good separation properties for sulfonamides,alkaloids,antibiotics,amino acids and other multipolar compounds.in addition,the stationary phase is superior to most reported MOF-based stationary phases In terms of separation performance,preparative reproducibility,and chromatographic stability,which broadens the application of MOF-based composites as chromatographic stationary phases[52]。
Although HILIC shows great advantages in separating polar components,there are still some shortcomings,such as the separation principle of HILIC is not very clear,there are many complex interactions,and the peak shape may be abnormal due to the different degrees of influence of various interactions.Therefore,it is particularly important to optimize the parameters,such as flow rate,column temperature,groups bonded to the stationary phase,pH,type of buffer salt,etc.At the same time,the HILIC column has a long equilibrium time,and if the column equilibrium time is too short,it will lead to the drift of retention time and poor repeatability,which is not suitable for the gradient elution system with too fast changes.in view of the above problems,the research on the separation mechanism of HILIC and the development of new stationary phases are the main development goals in the future。

3 Supercritical fluid separation

Supercritical fluid(SF)has become an excellent alternative to traditional separation methods in the past 10 years,and has been widely used in Bioanalysis,food safety,and environmental monitoring.Table 1 shows the extensive research and application of SF in natural product separation[53][54]。 traditional separation of natural products requires a large amount of organic solvents,which causes great pollution to the environment.Therefore,the use of green solvents instead of Traditional volatile organic solvents is an important way to achieve green extraction of natural products[55]。 ionic liquids and deep eutectic solvents in supercritical fluids have received much attention as new green solvents.Ionic liquids are low-temperature molten salts formed by anions and cations through Ionic bonds,which are liquid at or near room temperature;the deep eutectic solvent is composed of a hydrogen bond donor(HBD)and a hydrogen bond acceptor(HBA)in a certain proportion,and is usually liquid at room temperature due to the formation of hydrogen bonds between the two,resulting in a decrease in freezing point[56]。 Both ionic liquids and deep eutectic solvents have excellent physical and chemical properties,such as wide liquid range,low vapor pressure,non-volatility,high conductivity,good solubility and wide applicability[57]。
表1 Application of Supercritical Fluid in Separation of Natural Products

Table 1 Application of supercritical fluids in the separation of natural products

Target Source Phase component Separation condition Extraction yield Ref
Flavonoids Eucommia ulmoides leaves [Ch][Try] IL 2.91%，73℃ 78.0% 73
Ginkgo biloba
leaves		 Menthol-acetic acid DES
micellar system		 IL 0.2 g/mL，25℃ 97.29% 74
M. oleifera leaves [ChCl][CA](1:1) 20 mL DES was added to crushed leaves at a ratio of 1:10 (m/v). The mixture was homogenized in a sonicator bath at 50℃ for 1 h. - 75
Alkaloids Scutellaria baicalensis Georgi [C2min]Cl, [C4min]Cl, KPF6 60℃ for 1 h, ultrasound-assisted extraction for 5 min 43.3 mg/g 76
Berberidis Radix [ChCL][LA](1:2) 200 W ultrasonic irradiation at 50℃ for 30 min 75.00% 77
Aqueous solution [C2mim]Cl/PEG 2000 50℃, atmospheric pressure 70.70% 78
Terpenoids Licorice [P4,4,4][PTS] Less than 60℃ for 30 min 9.63 mg/g 79
Panax notoginseng ChCl-ethylene glycol DES/K2HPO4 55℃, pH=5.0 75.79% 80
Polyphenolics Cistanche tubulosa [C4mim]BF4/(NH4)2SO4 sample solution of 2.5 mg/mL,
pH=6.0; 130 min		 99.78% 81

3.1 Ionic liquid separation

ionic liquids(ILs)are organic salts composed of ions,which are liquid at near room temperature,so they are called room temperature molten salts or low temperature molten salts.As an ideal solvent for separation and purification,they are also called"liquid molecular sieves".the physical and chemical properties are affected by the nature of cations and anions,molecular size,the balance between Coulomb and van der Waals forces,hydrogen bonding andπ-πbonding interactions,and the results of these studies are of great benefit for the selection and design of Ionic liquids for specific applications[58]。
Liquid-liquid extraction is one of the most commonly used ionic liquid separation methods.Chen et al.Mixed 1-vinylimidazole and 1-chloromethyl-4-trimethoxysilylbenzene,and the obtained ionic liquid was grafted to the hydroxyl group on the surface of silica to obtain IL@SiO2,which was used to adsorb and separate artemisinene in artemisinin(Figure 3).With only one double bond,the traditional column chromatography method can not achieve complete separation effect,and the ionic liquid-based liquid-liquid extraction method also has some problems,because of the strong electrostatic and hydrogen bonding interaction between ions,the viscosity of ILs is high,which affects the mass transfer of the system and reduces the separation efficiency[59]。 Therefore,considering comprehensively,it is a good choice to graft ionic liquids with functional groups onto solid materials.The introduction of unsaturated bonds(C=C and aromatic rings)in the ionic liquid enhances the n-n conjugate interaction between the SiO2and the artemisene,so that the ionic liquid has affinity for the artemisene,The method overcomes the defect that the traditional column chromatography method cannot completely remove the artemisinin,simultaneously avoids the use of a large amount of organic solvent,the purity of the purified artemisinin can reach 97.97%,and the purified artemisinine still has a certain purification effect after being recycled for six times 。
图3 IL@SiO2分离青蒿烯原理图[59]

Fig. 3 Schematic diagram of separation of artemisene using IL@SiO2 [59]

temperature-responsive ionic liquid(TRIL)is a kind of ionic liquid that can change its state(hydrophilic or lipophilic)by changing the ambient temperature.This temperature-responsive characteristic has great potential in the separation of different polar compounds[60]。 Luo et al.Developed a switchable temperature-responsive ionic liquid-based microemulsion to prepare TRIL from 1-ethyl-3-methylimidazolium tetrafluoroborate,1,2-propanediol,and water.Then the TRIL was introduced into the microemulsion as an oil phase to form a novel surfactant-free microemulsion(TRIL-SFME)with temperature response,which can be demulsified without additional chemical demulsifier.Compared with the traditional ILs separation,the extraction rate is increased by 1.50 to 5.79 times,and the hydrophilic compounds(phenolic acids)and lipophilic compounds(alkaloids)can be separated and enriched in situ within 3 minutes.It overcomes the problems of low mass transfer rate and low extraction efficiency of TRIL as a solvent in the extraction process,and is an efficient and green separation strategy,which can simultaneously extract,separate and enrich natural active compounds with different polarities from plant substrates in situ[61]。 They adopted the DPD method to simulate the extraction process,and Fig.4 shows the schematic diagram of TRIL-SFME and the components of six target compounds over time。
图4 TRIL-SFME对目标化合物提取过程的DPD模拟：（a）初始态，（b）平衡态[61]

Fig. 4 DPD simulation for extraction process of targeted compounds by TRIL-SFME. (a) Initial state and (b) equilibrium state.[61]

ILs have a good prospect in the field of natural product separation,but there are also many problems to be solved,such as:1)Although the research and application of ILs are deepening,However,there is still a lack of basic research on its mechanism.At present,many studies focus on imidazolium ionic liquids,and there is no systematic summary of the change of ILs properties caused by the different composition of anions and cations;2)Compared with traditional organic solvents,ILs have greatly reduced vapor pressure and are not easy to volatilize,but they still have certain biological toxicity;3)the structure,preparation process and purification process of ILs are more complex than traditional organic solvents,and the production cost of using ILs for separation is higher,so trying to recover and recycle them is a major challenge for the future application of ILs。

3.2 Deep eutectic solvent separation

Deep eutectic solvent(DES)was discovered by Abbott et al.In 2003.The basic form of DES is Deep eutectic solvent,in which Cat+can be ammonium,sulfonic acid or phosphorus,X-is Lewis base,Y is Lewis acid or Brønsted acid,Y can form a complex with X-,Z represents the number of Y molecules bound to anions,and these substances form a eutectic mixture through interaction[62][63]。 According to the difference of hydrogen bond donor and hydrogen bond acceptor,DES can be divided into several main types:TypeⅠDES is mainly formed by the combination of metal chloride and quaternary ammonium salt,typeⅡDES is composed of metal chloride hydrate and quaternary ammonium salt,and typeⅢDES is formed by the combination of carboxylic acid,amide,or polyol with quaternary ammonium salt.type IV is formed by the combination of a metal chloride hydrate and a hydrogen bond donor(acid,amine,or alcohol).Recently,the synthesis of ternary DES has been reported.Compared with binary DES,ternary DES has lower viscosity and melting point[64]。 the extraction capacity of DES depends on various physicochemical parameters,such as conductivity,density,polarity,and viscosity,which can be adjusted by changing The components of HBD and HBA.The synthetic raw materials of IL and DES are quite different.IL is a salt composed of anions and cations.DES contains not only salts,but also carbohydrates,amino acids and polyols.Its molecules do not interact through covalent bonds or ionic bonds,but through intermolecular forces.Therefore,the scope of application of DES and IL is also different[65]。
1,8-cineole is widely distributed in plant aromatic oils and has a variety of physiological activities.However,1,8-cineole is usually mixed with monoterpenoids in plant essential oils,which is difficult to separate by distillation due to its close boiling point.Liu et al.Invented a series of deep eutectic solvents(LaDESs)based on lactic acid(LA).New LaDESs synthesized from LA and tyrosine(Tyr)were developed and used for the liquid-liquid separation of 1,8-cineole and monoterpene olefins.the purity of 1,8-cineole in the final product reached 99%.This method has the advantages of low energy consumption,high selectivity and safety[66][67][68]。 At LA/Tyr/1,8-cineole=1:1:1,there is a strong attraction between the carboxyl hydrogen of LA and the oxygen of 1,8-cineole,and the N—H…O and O—H…O bond lengths of Tyr-LA are 2.0808Åand 1.9292Å,respectively,and the O—H..O length of 1,8-ceteole-LA is 1.5959Å,all of which are smaller than the H…O van der Waals radius of 2.7272Åand larger than the length of O—;Both∠N—H…O and∠O—H…O are greater than 90°,and the length and angle are within the hydrogen bond criteria.the hydrogen bond of 1,8-cineole and LaDES is shorter than that of 1,8-cineole and LA,indicating that the bond energy is increased,which explains that the extraction performance of LaDES is better than that of pure LA to some extent,because there is no competitive relationship between Tyr and 1,8-eudesmol,so the addition of Tyr can enhance the interaction between 1,8-eudesmol and LA。
At present,a variety of DESs have been proved to have the advantages of biocompatibility,low toxicity,environmental friendliness and high selectivity,and have many advantages in separation compared with traditional organic solvents.However,on the one hand,the high viscosity and weak volatility of DES limit its application in the separation of natural products,and the low vapor pressure makes it difficult to effectively remove and recover DES by vacuum distillation or vacuum drying;on the other hand,many potential applications of DES have not been fully studied,such as the impact of DES residues in water on the environment and organisms,the degradability of DES in nature,and the impact of DOS on the biological activity of natural products in the separation process,which have not been studied in depth。

3.3 Synergism of ionic liquid and deep eutectic solvent

Under the action of inorganic salts or polymers,ILs/DESs can form aqueous two-phase systems(ATPS)[69]。 Based on the principle of natural product separation by ATPS,IL is in a stable dispersion state in water,however,DESs are unstable in water because of the strong ability of H2O molecules to form hydrogen bonds,which will destroy the hydrogen bonds between HBA and HBD[70]。 Therefore,ATPS constructed from DESs need to control the concentration of water.For ATPS containing inorganic salts,salting-out is the main force affecting phase separation and extraction,and the adsorption capacity of salt and ILs/DESs for water molecules is different.When the added salt contains co-moving ions,the order of H2O molecules around it is more regular and the free energy is lower due to the polarization of co-moving ions[71]。
Wang et al.Developed a new green solvothermal switching solvent system,deep eutectic solvent/ionic liquid/water mixture(DIWM),and this new method was proposed based on their previously reported temperature-responsive extraction system.Namely,a temperature-responsive ionic liquid solvent system,the method is capable of simultaneously extracting hydrophilic and hydrophobic compounds at 65°C,and the extracted compounds can be separated in situ simply by cooling the extract to room temperature[72]。 Compared with this method,thermal switch DIWM has a lower phase transition temperature(60℃),and the extracted target compounds are cooled to 25℃for in-situ separation.The solvent system consists of ChCl:LA/[BMIM]PF6/H2O（v/v/v=1/2/1）.Rosmarinic acid(RA)and carnosic acid(CA)in rosemary leaves were successfully extracted and separated in situ by this method.Under the optimum conditions,the target compound was extracted and cooled from 60℃to 25℃.At this time,the extraction solution was converted from single-phase system to two-phase system.RA was mainly distributed in the upper phase,and the recovery rate was 88.97%.CA was mainly distributed in the lower phase,and the recovery rate was 97.46%.It has the advantages of mild extraction conditions,low energy consumption,simple operation and high extraction efficiency,and has great potential in the comprehensive extraction of natural products 。

4 Molecular imprinting technique

Molecular imprinting technology(MIT)is a new recognition technology,which promotes the specific recognition of template molecules by mimicking the mutual recognition between enzymes and substrates,antibodies and antigens,intracellular receptors and hormones.Molecularly imprinted polymers(MIPs)are synthetic binders that can capture a specific template molecule by targeting the binding site.the preparation method of MIPs is mainly divided into two steps:(1)in the presence of the template molecule,the functional monomer and the crosslinking monomer are copolymerized to embed the template molecule in the rigid polymer material[82]; (2)the template molecule is eluted from the polymer material by a certain method,and a three-dimensional hole matching the size,shape and structure of the template molecule is formed on the polymer material,which can specifically recognize and combine with the template molecule[83]。 MIT has been paid more and more attention by the academic community because of its outstanding advantages such as high selectivity,stability,practicability and low cost,and has been widely used in the separation of natural products.Table 2 shows the application of molecular imprinting technology in the separation of natural products in recent years[84]。
表2 Application of molecular imprinting technique in natural product separation in recent years

Table 2 Application of molecular imprinting technique in separation of natural products in recent years

Template molecule Functional monomers Cross-linkers Extraction yield Ref
Magnetic molecularly imprinted polymer Chlorogenic acid Acrylamide (AM) Ethylene glycol dimethacrylate (EGDMA) 3.86 μg/mL 87
Chrysin Methacrylic acid (MAA) EGDMA 35.27 mg/g 99
Ferulic acid MAA Polyvinylpolypyrrolidone (PVPP) 50 mg/g 100
Rutin 4-vinylpyridine(4-VP), 4-vinylphenylboronic acid (4-VPBA) Divinylbenzene (DVB) 11.9 mg/g 89
Molecular imprinted solid phase extraction Chlorogenic acid MAA, AM, 2-VP EGDMA 75.15% 94
(E)-resveratrol 4-VP EGDMA 96% 101
Harmaline MAA Ethylene glycol dimethacrylate
(EDMA)		 45.31 mg/g 102
Fsesquiterpene coumarins MAA, methacrylamide (MAAM), 4-VP EDGMA 0.8 μg/g 103
DESs-MIP Quercetagetin 2-VP EGDMA 27.2 mg/g 98
Catechins DESs were formed from
ChCl/MAA (molar ratio 1:2) and betaine/MAA/H2O (molar
ratio 1:2:1)		 EDMA 13.1 mg/g 104
Paclitaxel DESs EGDMA 87.08 mg/g 105
Gallic Acid DES EGDMA 87.85 % 106

4.1 Magnetic molecularly imprinted polymer

With the development of nanoparticle molecular imprinting technology,magnetic molecularly imprinted polymers(MMIPs)have attracted much attention because of their excellent magnetic response,specific selectivity,fast mass transfer rate and high affinity.MMIPs can be prepared by coating on the magnetic nanoparticle core,enabling more recognition sites on the surface of the material,and at the same time,MMIPs can be rapidly separated from the sample using an external magnetic device without any filtration or centrifugation steps[85]。 Based on the above characteristics,MMIPs are widely used in different fields such as chromatographic separation,cell recognition,targeted drug delivery,sensors and food analysis[86]。
Lysozyme(Lyz)is a small single-chain protein,which can dissolve a variety of bacterial cell walls to achieve bactericidal effect,and the efficient separation and detection of Lys has important clinical significance.Our research group prepared a kind of L-cysteine-capped Mn2+doped ZnS quantum dots for Lyz adsorption,and coated L-cysteine on the surface of the Mn2+doped ZnS quantum dots.Increases water dispersibility,reduces cytotoxicity,and provides a carboxylic acid group that binds to the amino group of the template protein,enabling it to adsorb Lyz in a liquid biological sample without causing damage to the sample[87]。 the prepared quantum dots were embedded into a molecularly imprinted membrane(MIM),which has the advantages of large specific surface area and fast mass transfer,and can improve the adsorption capacity.Lyz in actual biological samples(such as egg white)was adsorbed,and the concentration of Lyz in the diluted sample was 1.02μmol/L,the recovery rate was 93%-103%,and the RSD was 1.9%-3.5%.This experiment provides a new idea for the development of an efficient,specific,sensitive and recoverable method for the separation of target proteins from biological samples。
Traditional separation extraction is usually carried out in organic solvents.in order to use MIP extraction in highly polar solvents(such as methanol,ethanol,boiling water and alkaline water),it is necessary to consider that highly polar solvents weaken the hydrogen bond between the functional monomer and the imprinted template,which will lead to the reduction of the recognition ability of MIP[88]。 Zhang et al.Combined micelles with MIP to provide a larger hydrophobic environment,and prepared magnetic micellar nanoparticles(MMNP)with stable structure and good chemical properties by using Fe3O4magnetic nanoparticles as carriers,and isolated rutin in a strong polar solvent[89]。 4-Vinyl-pyridine(4-VP)is bound to the template molecule rutin through hydrogen bonds,and boric acid and rutin containing cis-diols form cyclic borate compounds in alkaline solution,which can quickly break the ester bond Under acidic conditions to achieve reversible molecular recognition.After the template functional monomer is synthesized,the prepolymer is doped into the micelle by hydrophobic interaction,and then the prepolymer is crosslinked with a crosslinking agent by ultraviolet light,that is,the double bond of the functional monomer is fixed on the micelle to form a positively charged MIP,and the MMIP is adsorbed on the modified magnetic nano surface by electrostatic adsorption to form a core-shell MM NIP microsphere.under the optimized elution conditions,the adsorption capacity of MMNIP for separating rutin from crude extract was 16.58 mg/G.Compared with other methods,magnetic micellar molecular imprinting has the following advantages:1)the hydrophobic/hydrophilic core/shell structure avoids the weakening effect in strong polar solvents;2)the hydrophobic/hydrophilic core/shell structure has a large specific surface area,and the imprinted holes are located on the surface,which is beneficial to the adsorption and elution of the template。
MMIPs have been widely used In the separation of a variety of natural products due to their high selectivity and superparamagnetism,but At the same time,MMIPs also face many problems,such as limited types of functional monomers,low precision,poor reproducibility,and low success rate of preparation.the applicability of MMIPs depends on the recognition ability of the template molecule and its dispersibility in the solvent.the molecular recognition ability of MMIPs in aqueous medium and polar environment is low.in the future,we should screen from the existing compounds,synthesize new ligands,graft hydrophilic groups,etc.,to make them more suitable for hydrophilic polymerization;at the same time,MMIPs with multiple recognition sites can be prepared by using multiple functional monomers,which broadens the application range,improves the imprinting accuracy and reduces the interference;It can also optimize the preparation process,simplify the preparation process,and reduce the problems of magnetic response performance decline and particle agglomeration caused by multi-step reaction。

4.2 Molecularly imprinted solid phase extraction

Solid-phase extraction(SPE)is a common separation technique in the process of liquid-Solid matrix sample preparation,which can separate,concentrate and purify the target analyte from the fluid medium,and has the advantages of simple operation,high recovery rate,automation and low solvent consumption[90]。 adsorbents for SPE are the decisive factor for extraction,so the development of new SPE adsorbents is also of great interest to researchers,and the high selectivity of MIPs for specific structures,together with their low cost,high stability and reusability,make them ideal adsorbents for SPE[91]。 the molecularly imprinted solid phase extraction device consists of a frit and a MIP.Fig.5 shows The procedure of molecularly imprinted solid phase extraction。
图5 分子印迹固相萃取(MISPE)程序[91]

Fig. 5 Molecular imprinted solid phase extraction (MISPE) procedure[91]

chlorogenic acid(CGA)is a highly effective phenolic antioxidant and preservative in Eucommia ulmoides,which is synthesized from caffeic acid and quinic acid,and has the effect of prolonging the shelf life of food by improving the oxidation resistance of fat.Because of the low vapor pressure and strong miscibility of deep eutectic solvents,the recovery of Chlorogenic acid from deep eutectic solvent extraction products is challenging.the pretreatment process of traditional adsorbents is complex,and the adsorption and elution time is long.MIP can significantly improve the poor selectivity of this method in actual samples,and has a high recovery rate[92][93]。 Liu et al.used MIPs as a filler for solid phase extraction to recover the target component chlorogenic acid from the deep eutectic solvent extract of Eucommia ulmoides leaves,and Used chlorogenic acid as a template molecule to form MIP by bulk polymerization.the interaction between MAA,acrylamide and 2-vinylpyridine and chlorogenic acid was simulated by calculation,and the results showed that the binding energy of MAA and chlorogenic acid was the largest(-282.48 kJ/mol).MAA was mainly connected by hydrogen bonds formed by hydroxyl oxygen atoms and carbonyl oxygen atoms in chlorogenic acid,and the simulation showed that CGA-MAA with larger binding energy could produce more specific recognition sites in the imprinting process,and the MIPs formed had higher adsorption capacity(120.70 mg/G)and selectivity(IF=3.72),which provided a new idea for extracting chlorogenic acid from extracts[94]。
Although molecularly imprinted solid phase extraction has the advantages of simple operation,strong specific recognition,good selectivity and good reproducibility,it is mainly suitable for rigid small molecules.Biomacromolecules with large volume,complex conformation and diverse functional groups are less involved,Because the elution process will cause irreversible damage to the conformation of some target molecules,resulting in the loss of target products;At the same time,the eluent is usually organic solvent,which limits the application range of molecularly imprinted solid phase extraction;because most of the MIPs are connected with the target molecules by hydrogen bonds,the reaction is limited to non-polar or weak polar solvents,and the selectivity in aqueous solution is poor,so it is necessary to find a new functional monomer suitable for strong polar solvents such as water;the cost of this technology in practical application is high,and there is still a certain distance from the realization of large-scale industrial production and application。

4.3 Deep eutectic solvent-molecularly imprinted polymer

Functional monomer and cross-linking agent are two key factors affecting the formation of MIPs,which determine the formation of imprinting sites and the recognition specificity and sensitivity of MIPs to bioactive substances[95]。 However,traditional functional monomers and crosslinking agents are often limited by poor functionality and toxicity.In contrast,deep eutectic solvents as functional monomers and crosslinking agents have good environmental performance.at the same time,When the deep eutectic solvent is used alone to separate the mixture,some components with similar polarity and physicochemical properties to the target substance will be extracted At the same time,so the adsorption performance of MIP will also be improved by introducing DES into MIP[96]。
Sinapinic acid is a natural phenolic acid with antioxidant and anti-inflammatory effects,which is widely distributed in plants[97]。 Sun et al.Prepared a layered porous support framework(CRP)by roasting rape pollen at high temperature to remove external organic matter,and successfully constructed a highly efficient MIP(CRPD-MIP)by combining with different kinds of chlorocholine-based DESs as functional monomers and cross-linking agents(Fig.6)[98]。 the results showed that the adsorption capacity of this method For sinapic acid was 154 mg/G,and it had good selectivity(IF=3.24)and fast kinetic adsorption equilibrium(60 min).for the extraction of sinapic acid from real samples,CRPD-MIPs had ideal precision and good practical feasibility.The proposal of this study could also promote the recycling of biological waste resources。
图6 CRPD-MIPs的构建方案及其在选择性提取辛酸中的应用[98]

Fig. 6 Scheme of constructing CRPD-MIPs and their application in selectively extracting sinapic acids[98]

the use of deep eutectic solvent and MIPs is a new technology in the separation of natural products,and its separation principle and the selection of synthetic raw materials are not yet fully understood,and the study of the interaction between the two materials is even more lacking.Because both of them have their own unique advantages in separation and purification,the combination of them can integrate their advantages and achieve the effect of learning from each other,which is of great benefit to the development of new separation technologies for natural products。

5 Conclusion and prospect

extraction and separation of natural products from animals and plants are the main source of most drugs.the commonly used separation methods of natural products include liquid chromatography,column chromatography,solvent extraction,membrane separation and recrystallization.These methods have the advantages of high separation efficiency,wide application range and mature technology,but there are still bottlenecks in many aspects:most of the traditional separation systems have shortcomings such as long extraction time,large solvent loss and low extraction rate.At the same time,the selectivity is also poor,which limits the further development of traditional methods in the separation of natural products and restricts the practical application of natural products in social and economic life.Based On this,the following prospects are put forward in this paper:①on the basis of traditional chromatographic methods,new instruments and substances can be used to create easier conditions for substance separation,such as phase change,high temperature,high pressure,supercritical fluid,etc;(2)to explore the application of supercritical fluid and molecular imprinting technology in natural product separation technology,design and adjust the synthesis system of supercritical fluid and molecular imprinting polymer by software simulation,and further expand the technical spectrum of natural product separation and purification methods.(3)Combining a variety of separation and purification technologies to optimize and improve the separation methods of natural products and extend the depth of research and development。
In summary,new natural product separation and purification techniques have been widely used for a variety of compounds,and Table 3 shows a comparison of different natural product separation methods.It is a very important task to continuously improve the separation and purification strategies and methods of active ingredients of natural products,which can improve the utilization efficiency of natural products,and at the same time,It is of great benefit to the development of new drugs,which can help people solve the challenges of many diseases.It is believed that with the continuous development and improvement of science and technology,the separation and purification of natural products will enter a higher level of development。
表3 Comparison of Different Separation Methods for Natural Products

Table 3 Comparison of different natural products separation methods

Techique Principles Advantages Disadvantages Range of application Ref
Fractional
precipitation		 Like dissolves like Simplicity of operator, solvent environmental protection Poor separation, need to be repeated several times. Substances of very different polarity 18
Gel chromatography Different molecular sizes High purification, high separation efficiency, mild conditions High cost, complex conditions Substances with different molecular weights 19
Cellulose
column
chromatography (DEAE)		 Eluted in descending order of water solubility. Good purification effect, large amount of separation Complex operation, slow separation Substances with different molecular weights 20
Preparative high Performance liquid chromatography The difference in the distribution coefficient. High purification, high precision, high stability, good reproducibility High cost, complex process, long time Substances of different polarity 21
Separation membrane Different molecular sizes. Little damage to polysaccharide activity, good separation effect Poor separation effect for substances with similar molecular weight. Substances with different molecular weights 22
Macroporous resin The difference of adsorption force and molecular weight. Good selectivity, easy regeneration treatment, mild desorption conditions, long service life Pretreatment requirements are strict Substances of different polarity 23
High-speed
Counter-current Chromatography (HSCCC)		 The difference in the distribution coefficient. Small sample loss, large amount of preparation, can separate structurally similar substances Low separation efficiency, large solvent consumption Suitable for separation of polar substances 26~27,40⇓⇓⇓⇓⇓ ~46
Hydrophilic interaction chromatography（HILIC） Uses the charge and hydrophilicity on the molecular surface to control the separation of molecules. Good ability to separate polar compounds, separation without affecting sample properties Large influence of parameters For the simultaneous separation of both polar and small polar compounds 28~29,47⇓⇓⇓⇓ ~52
Ionic liquids（IL）/ Deep eutectic solvent (DES) Design molecular structures to separate different substances. Eco-Friendly, good solubility, high electrical conductivity, low toxicity Hard to be separated from the sample, high cost Liquid mixture 30~31,53⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ ~81
Molecular imprinting technique (MIT) “Antigen-antibody” specific binding Strong specificity, long service life, good stability, low cost The selectivity is poor in aqueous solution. Mainly in the field of small molecules 32⇓~34,82⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓ ~106

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