A chiral separation membrane based on layered double metal hydroxide and its preparation method and application

Abstract

The present invention discloses a chiral separation membrane based on layered double hydroxide, a preparation method thereof, and an application thereof. By utilizing a two-dimensional layered material LDH to construct a "Z"-shaped mass transfer channel on the membrane surface, the number of theoretical plates for chiral separation is increased, thereby improving the membrane separation performance. The obtained chiral separation membrane can be applied to racemic separation, thereby realizing green and efficient separation of chiral drugs.

Description

Technical Field

[0001] The present invention belongs to the technical field of membrane separation, and in particular relates to a chiral separation membrane based on layered double metal hydroxides, and a preparation method and application thereof. Background Art

[0002] Chiral drugs are drugs that, after introducing a chiral center into their molecular structure, result in a pair of mirror-image enantiomers. Because the two enantiomers in chiral drugs exhibit distinct pharmacokinetic processes, they often exhibit significant differences in their pharmacological activity, metabolic processes, metabolic rates, and toxicity in vivo. Often, only one enantiomer exhibits pharmacological effects, while the other not only lacks pharmacological effects but also produces certain side effects.

[0003] Following the US Food and Drug Administration's (FDA) regulations on chiral drugs, relevant certification bodies in Europe, China, and Japan have subsequently proposed guidelines for chiral drugs, requiring only therapeutically effective enantiomers to be released to the market, and requiring that the pharmacology and metabolic pathways of each enantiomer be studied. Traditional chiral resolution techniques, such as crystallization, chemical methods, extraction, and chromatography, suffer from drawbacks such as low throughput, cumbersome procedures, and high costs. With the recent advancements in chiral separation technology, membrane separation, with its advantages of continuous operation and ease of scalability, has been recognized as a promising new energy-saving technology for large-scale enantiomer separation, demonstrating significant potential application value and scientific research significance. Its fundamental principle is based on the membrane's selective permeability, allowing only the components that meet specific requirements to pass through while retaining the undesirable components of the enantiomers, thereby achieving enantiomeric resolution. Membrane resolution offers advantages such as low cost, low energy consumption, continuous production, and ease of scalability, and holds great promise for future applications.

[0004] Traditional chiral separation technologies such as crystallization, chemical methods, extraction methods, and chromatography have disadvantages such as low processing capacity, complicated operation, and high cost. With the development of chiral separation technology, membrane separation has the advantages of continuous operation and easy scale-up in recent years. It is recognized as a new energy-saving technology with great potential for large-scale separation of enantiomers, showing great potential application value and scientific research significance. Its basic principle is based on the selective permeability of the membrane, which only allows components that meet special requirements to pass through and intercepts components in the enantiomers that do not meet the requirements, thereby achieving enantiomer separation. The membrane separation method has the advantages of low cost, low energy consumption, continuous production, and easy scale-up, and has good application prospects. However, due to the thin selective layer of the traditional chiral separation membrane, the number of theoretical plates for separation of chiral substances is small, so the separation efficiency is low. Therefore, the present invention constructs a "Z"-shaped mass transfer channel through two-dimensional materials to increase the number of theoretical plates for enantiomer separation and improve the separation efficiency. Summary of the Invention

[0005] The purpose of this section is to summarize some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the abstract and title of this application to avoid obscuring the purpose of this section, the abstract and the title of the invention, and such simplifications or omissions should not be used to limit the scope of the present invention.

[0006] In view of the above problems and / or the problems existing in the prior art, the present invention is proposed.

[0007] Therefore, the object of the present invention is to overcome the deficiencies in the prior art and provide a chiral separation membrane based on layered double hydroxides.

[0008] In order to solve the above technical problems, the present invention provides the following technical solutions: comprising:

[0009] Base film, which is a polymer flat film;

[0010] The separation layer is selected, including two-dimensional materials, chiral selectors, and negatively charged polymers as fixatives.

[0011] As a preferred embodiment of the chiral separation membrane based on layered double hydroxide of the present invention, the material of the base membrane includes polyimide, polyethersulfone, polysulfone, sulfonated polysulfone, sulfonated polyethersulfone, polyamide and cellulose acetate.

[0012] As a preferred embodiment of the chiral separation membrane based on layered double hydroxides described in the present invention, the two-dimensional material is a layered double hydroxide, including Mg / Al-LDH, Ni / Fe-LDH, and Ni / Al-LDH.

[0013] As a preferred embodiment of the chiral separation membrane based on layered double hydroxides of the present invention, the chiral selector comprises α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin.

[0014] As a preferred embodiment of the chiral separation membrane based on layered double hydroxide of the present invention, the negatively charged polymer as the fixing agent is polyvinyl alcohol with a molecular weight of 10 to 20w.

[0015] Another object of the present invention is to overcome the deficiencies in the prior art and provide a method for preparing a chiral separation membrane based on layered double hydroxides.

[0016] In order to solve the above technical problems, the present invention provides the following technical solutions: comprising:

[0017] Layered bimetallic oxides were synthesized by hydrothermal method and their nanodispersions were prepared as deposition reagents.

[0018] The chiral selector is mixed with polyvinyl alcohol to prepare a cyclodextrin fixative solution;

[0019] dispersing a deposition reagent into a cyclodextrin fixative solution to obtain a membrane-forming solution;

[0020] The membrane-making solution is coated on the surface of the base membrane by vacuum filtration, and the cross-linking agent is fixed to obtain a chiral separation membrane.

[0021] As a preferred embodiment of the method for preparing the chiral separation membrane of the present invention, the concentration of the layered double hydroxide dispersion is 0.01 to 0.5 g / L, the concentration of the chiral selector is 0.1 to 1 g / L, and the concentration of polyvinyl alcohol is 1 g / L, wherein the mass ratio of the chiral selector to the polyvinyl alcohol is 1 to 5:1.

[0022] As a preferred embodiment of the method for preparing the chiral separation membrane of the present invention, the volume ratio of the deposition reagent to the cyclodextrin fixative solution is 6:1.

[0023] As a preferred embodiment of the method for preparing the chiral separation membrane of the present invention, the cross-linking agent is fixed, wherein the cross-linking agent is glutaraldehyde, the cross-linking temperature is 25-70° C., and the cross-linking time is 5-60 min.

[0024] Another object of the present invention is to overcome the deficiencies in the prior art and provide an application of a chiral separation membrane based on layered double hydroxides.

[0025] In order to solve the above technical problems, the present invention provides the following technical solutions: including applying the chiral separation membrane to racemate separation to achieve green and efficient separation of chiral drugs.

[0026] Beneficial effects of the present invention:

[0027] The present invention utilizes two-dimensional layered material double metal hydroxide nanosheets to stack layer by layer on the surface of the base membrane to construct a "Z"-shaped mass transfer channel, and adds a chiral selector between the sheets to increase the number of theoretical plates for chiral separation and improve chiral selectivity. The resulting chiral separation membrane can be used in racemic separation to achieve green and efficient separation of chiral drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for describing the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. Those skilled in the art can also derive other drawings based on these drawings without inventive effort. Among them:

[0029] Figure 1 Schematic diagram of a simple osmotic device for chiral separation experiments of the present invention.

[0030] Figure 2 This is a SEM characterization image of Mg / Al-LDH prepared in Example 1 of the present invention.

[0031] Figure 3 2 is a comparison chart of the separation performance of the chiral membranes prepared in Example 2 of the present invention and Comparative Examples 1 and 2.

[0032] Figure 4 This is a graph showing the effect of cyclodextrin content on membrane separation performance in Example 3 of the present invention.

[0033] Figure 5 This is a graph showing the effect of LDH content on membrane separation performance in Example 4 of the present invention.

[0034] Figure 6 Graph showing the effect of LDH content on the permeation flux of D, L-Trp enantiomers in Example 4 of the present invention.

[0035] Figure 7 This is a diagram showing the effect of different feed concentrations on membrane separation performance in Example 5 of the present invention.

[0036] Figure 8 This is a diagram showing the effect of the amount of filtrate on membrane separation performance in Example 6 of the present invention. DETAILED DESCRIPTION

[0037] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the embodiments of the specification.

[0038] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways different from those described herein. Those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0039] Secondly, the term "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation of the present invention. The phrase "in one embodiment" appearing in various places throughout this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive of other embodiments.

[0040] The chiral separation experiment in the present invention is carried out by Figure 1 The simple osmosis device is completed, which includes a feed pool, a permeation pool and a membrane. The permeate and the original solution are collected from the permeation pool and the feed pool respectively, and then tested by liquid chromatography. The original solution and the permeate after testing are not returned.

[0041] The enantiomer concentration in the test solution was detected by liquid chromatography. The specific chromatographic method was as follows:

[0042] Chromatographic column: Crownpak CR (+) chiral HPLC separation column (5 μm, 150 mm × 4 mm);

[0043] Mobile phase: A and B dual-channel mixed mobile phase, volume ratio of 15:85, where channel A is chromatographic-grade methanol, and channel B is 0.01 mol / L HClO4 solution (previously filtered with a 0.45 μm pore size filter membrane and ultrasonically degassed);

[0044] Flow rate: 0.8 mL / min;

[0045] Column temperature: 20°C;

[0046] Detector: Ultraviolet (UV) detector, detection wavelength is 220nm;

[0047] Injection volume: 10 μL.

[0048] Example 1

[0049] This embodiment provides a method for synthesizing layered bimetallic oxides (LDHs).

[0050] 2.27 g of magnesium nitrate and 1.66 g of aluminum nitrate were dissolved in 100 ml of deionized water, recorded as solution A; 10 g of urea was added to solution A, stirred evenly, and placed in a tetrafluoroethylene-lined autoclave. After reacting at 140°C for 10 h, the mixture was filtered, washed with water, and the filter cake was dried to obtain Mg / Al-LDH.

[0051] Figure 2 This is the SEM image of the prepared Mg / Al-LDH.

[0052] Example 2

[0053] This embodiment provides a method for preparing a chiral separation membrane coupled with layered double hydroxide and cyclodextrin.

[0054] 5 mg of Mg / Al-LDH was added to 30 ml of formamide solvent and ultrasonicated for 2 h to obtain LDH formamide nanodispersion;

[0055] 50 mg of polyvinyl alcohol (PVA) and 40 mg of β-cyclodextrin (β-CD) were dissolved in 50 ml of deionized water and stirred at 90°C for 3 h to obtain a PVA-β-CD aqueous solution, where the mass ratio of PVA to β-CD was 5:4;

[0056] 30 ml of LDH formamide nanodispersion was mixed with 5 ml of PVA-β-CD aqueous solution to obtain a membrane solution. After reacting for 12 h, the solution was diluted to 100 ml with deionized water. The polyimide film was used as the base film and the PVA-β-CD-LDH membrane was obtained by vacuum filtration.

[0057] The LDH-PVA-β-CD membrane was heat-treated at 60°C for 10 min and then immersed in a 25 mg / ml glutaraldehyde (GA) aqueous solution for cross-linking, ultimately obtaining a PVA-β-CD-LDH membrane, i.e., a chiral separation membrane coupled with layered double hydroxide and cyclodextrin.

[0058] Comparative Example 1

[0059] 50 mg of polyvinyl alcohol (PVA) and 40 mg of β-cyclodextrin (β-CD) were dissolved in 50 ml of deionized water and stirred at 90°C for 3 h to obtain a PVA-β-CD aqueous solution, where the mass ratio of PVA to β-CD was 5:4;

[0060] Take 5 ml of PVA-β-CD aqueous solution and dilute it to 100 ml with deionized water. Use polyimide film as the base film and obtain PVA-β-CD membrane by vacuum filtration.

[0061] The PVA-β-CD membrane was heat-treated at 60° C. for 10 min and then immersed in a 25 mg / ml glutaraldehyde (GA) aqueous solution for cross-linking, thereby finally obtaining a PVA-β-CD membrane.

[0062] Comparative Example 2

[0063] 5 mg of Mg / Al-LDH was added to 30 ml of formamide solvent and ultrasonicated for 2 h to obtain LDH formamide nanodispersion;

[0064] Take 5 ml of 1 mg / ml PVA solution and 30 ml of LDH formamide nanodispersion, mix them, dilute to 100 ml with deionized water, and use polyimide film as the base film to obtain PVA-LDH membrane by vacuum filtration;

[0065] The PVA-LDH membrane was heat-treated at 60° C. for 10 min and then immersed in a 25 mg / ml glutaraldehyde (GA) aqueous solution for cross-linking, thereby finally obtaining a PVA-LDH membrane.

[0066] A 0.1 mmol / L D,L-Trp solution was prepared as the stock solution for the permeation experiment. The separation effects of the chiral membranes prepared in Example 2 and Comparative Examples 1 and 2 were tested by chiral separation experiments. The results are shown in FIG. Figure 3 As shown, the enantiomeric selectivity of the PVA-β-CD-LDH membrane is 25%, which is better than the membrane without β-CD and the separation membrane without LDH.

[0067] Example 3

[0068] This example investigates the effect of the mass ratio of polyvinyl alcohol to chiral selector on the separation performance of chiral membranes.

[0069] 5 mg of Mg / Al-LDH was added to 30 ml of formamide solvent and ultrasonicated for 2 h to obtain LDH formamide nanodispersion;

[0070] 50 mg of polyvinyl alcohol (PVA) was dissolved with 10, 20, 30, 40, and 50 mg of β-cyclodextrin (β-CD) in 50 ml of deionized water and stirred at 90 °C for 3 h to obtain PVA-β-CD aqueous solutions, where the mass ratios of PVA and β-CD were 5:1, 5:2, 5:3, 5:4, and 5:5, respectively.

[0071] 30 ml of LDH formamide nanodispersion was mixed with 5 ml of PVA-β-CD aqueous solution to obtain a membrane solution. After reacting for 12 h, the solution was diluted to 100 ml with deionized water. The polyimide film was used as the base film and the PVA-β-CD-LDH membrane was obtained by vacuum filtration.

[0072] The LDH-PVA-β-CD membrane was heat-treated at 60°C for 10 min and then immersed in a 25 mg / ml glutaraldehyde (GA) aqueous solution for cross-linking, finally obtaining PVA-β-CD-LDH membranes with different PVA and β-CD mass ratios.

[0073] A 0.1 mmol / L D,L-Trp solution was prepared as the stock solution for the permeation experiment. The separation effect of the chiral membrane prepared in this embodiment was tested by the chiral separation experiment. The results are as follows: Figure 4 As shown in the figure, with the increase of cyclodextrin content, the chiral separation performance of the membrane is improved, and the performance is optimal when the cyclodextrin content is 4 mg, that is, when the mass ratio of PVA and β-CD is 5:4.

[0074] Example 4

[0075] This example investigates the effect of the layered double hydroxide content on the separation performance of chiral membranes.

[0076] 1, 3, 5, and 7 mg of Mg / Al-LDH were added to 30 ml of formamide solvent, and then ultrasonicated for 2 h to obtain LDH formamide nanodispersions.

[0077] 50 mg of polyvinyl alcohol (PVA) and 40 mg of β-cyclodextrin (β-CD) were dissolved in 50 ml of deionized water and stirred at 90 °C for 3 h to obtain a PVA-β-CD aqueous solution, where the mass ratio of PVA to β-CD was 5:4;

[0078] 30 ml of LDH formamide nanodispersion was mixed with 5 ml of PVA-β-CD aqueous solution to obtain a membrane solution. After reacting for 12 h, the solution was diluted to 100 ml with deionized water. The polyimide film was used as the base film and the PVA-β-CD-LDH membrane was obtained by vacuum filtration.

[0079] The LDH-PVA-β-CD film was heat-treated at 60°C for 10 min and then immersed in a 25 mg / ml glutaraldehyde (GA) aqueous solution for cross-linking, ultimately obtaining PVA-β-CD-LDH films with different LCD contents.

[0080] A 0.1 mmol / L D,L-Trp solution was prepared as the stock solution for the permeation experiment. The separation effect of the chiral membrane prepared in this embodiment was tested by the chiral separation experiment. The results are as follows: Figure 5 and Figure 6 As shown in the figure, with the increase of LDH content, the chiral selectivity of the membrane gradually improved, and the performance was optimal when the LDH content was 5 mg.

[0081] Example 5

[0082] 5 mg of Mg / Al-LDH was added to 30 ml of formamide solvent and ultrasonicated for 2 h to obtain LDH formamide nanodispersion;

[0083] 50 mg of polyvinyl alcohol (PVA) and 40 mg of β-cyclodextrin (β-CD) were dissolved in 50 ml of deionized water and stirred at 90°C for 3 h to obtain a PVA-β-CD aqueous solution, where the mass ratio of PVA to β-CD was 5:4;

[0084] 30 ml of LDH formamide nanodispersion was dispersed in 5 ml of PVA-β-CD aqueous solution to obtain a membrane solution. After reacting for 12 h, the solution was diluted to 100 ml with deionized water. The polyimide membrane was used as the base membrane and the PVA-β-CD-LDH membrane was obtained by vacuum filtration.

[0085] The LDH-PVA-β-CD membrane was heat-treated at 60°C for 10 min and then immersed in a 25 mg / ml glutaraldehyde (GA) aqueous solution for cross-linking, ultimately obtaining a PVA-β-CD-LDH membrane, i.e., a chiral separation membrane coupled with layered double hydroxide and cyclodextrin.

[0086] 0.05, 0.1, 0.2, 0.4 mmol / L D, L-Trp solutions were prepared respectively as stock solutions for permeation experiments. The separation effect of the chiral membrane prepared in this embodiment was tested by chiral separation experiments. The results are shown in FIG. Figure 7 As shown in Figure 3, as the enantiomer concentration in the feed solution increases, the separation performance of the membrane decreases, which is due to the adsorption saturation of the chiral selector.

[0087] Example 6

[0088] 5 mg of Mg / Al-LDH was added to 30 ml of formamide solvent and ultrasonicated for 2 h to obtain LDH formamide nanodispersion;

[0089] 50 mg of polyvinyl alcohol (PVA) and 40 mg of β-cyclodextrin (β-CD) were dissolved in 50 ml of deionized water and stirred at 90°C for 3 h to obtain a PVA-β-CD aqueous solution, where the mass ratio of PVA to β-CD was 5:4;

[0090] 30 ml of LDH formamide nanodispersion was mixed with 5 ml of PVA-β-CD aqueous solution to obtain a membrane solution. After reacting for 12 h, the mixture was diluted to 100 ml with deionized water. The same method was used to prepare membrane solutions with fixed concentrations and different volumes of 50 ml, 100 ml, 200 ml, and 300 ml, respectively. The polyimide membrane was used as the base membrane, and the PVA-β-CD-LDH membrane was obtained by vacuum filtration.

[0091] The LDH-PVA-β-CD membrane was heat-treated at 60°C for 10 min and then immersed in a 25 mg / ml glutaraldehyde (GA) aqueous solution for cross-linking, ultimately obtaining a PVA-β-CD-LDH membrane, i.e., a chiral separation membrane coupled with layered double hydroxide and cyclodextrin.

[0092] A 0.1 mmol / L D,L-Trp solution was prepared as the stock solution for the permeation experiment. The separation effect of the chiral membrane prepared in this embodiment was tested by the chiral separation experiment. The results are as follows: Figure 8 As shown in the figure, as the amount of liquid pumped increases, the membrane layer becomes thicker, the amount of chiral selector increases, and the chiral separation performance of the membrane improves.

[0093] The chiral separation membrane coupled with layered double hydroxide and cyclodextrin of the present invention has high chiral separation performance. By utilizing the two-dimensional layered material LDH to construct a "Z"-shaped mass transfer channel on the membrane surface, the number of theoretical plates for chiral separation is increased, thereby improving the membrane separation performance. As a chiral membrane material, it has practical application value in the separation of chiral drug intermediates and chiral drugs.

[0094] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents without departing from the spirit and scope of the technical solutions of the present invention, which should all be included in the scope of the claims of the present invention.

Claims

1. A chiral separation membrane based on layered double hydroxide, characterized in that: include, Base film, which is a polymer flat film; Selecting a separation layer, including a two-dimensional material, a chiral selector, and a negatively charged polymer as a fixative; The two-dimensional material is Mg / Al-LDH, the chiral selector is β-cyclodextrin, and the negatively charged polymer immobilizer is polyvinyl alcohol; The preparation method of the chiral separation membrane is: Layered bimetallic oxides were synthesized by hydrothermal method and their nanodispersions were prepared as deposition reagents. The chiral selector is mixed with polyvinyl alcohol to prepare a cyclodextrin fixative solution; dispersing a deposition reagent into a cyclodextrin fixative solution to obtain a membrane-forming solution; The membrane-making solution is coated on the surface of the base membrane by vacuum filtration, and the cross-linking agent is fixed to obtain a chiral separation membrane.

2. The chiral separation membrane based on layered double hydroxide according to claim 1, wherein: The materials of the base film include polyimide, polyethersulfone, polysulfone, sulfonated polysulfone, sulfonated polyethersulfone, polyamide and cellulose acetate.

3. The chiral separation membrane based on layered double hydroxide according to claim 1, wherein: The concentration of the layered double hydroxide dispersion is 0.01-0.5 g / L, the concentration of the chiral selector is 0.1-1 g / L, and the concentration of polyvinyl alcohol is 1 g / L, wherein the mass ratio of the chiral selector to the polyvinyl alcohol is 1-5:

1.

4. The chiral separation membrane based on layered double hydroxide according to claim 1, wherein: The volume ratio of the deposition reagent to the cyclodextrin fixative solution is 6:

1.

5. The chiral separation membrane based on layered double hydroxide according to claim 1, wherein: The cross-linking agent is fixed, wherein the cross-linking agent is glutaraldehyde, the cross-linking temperature is 25-70° C., and the cross-linking time is 5-60 min.

6. The use of a chiral separation membrane based on a layered double hydroxide as claimed in claim 1, characterized in that: Including, it is used in racemic separation to achieve green and efficient separation of chiral drugs.

Images