WO2017148439A1 - Rapid synthesis method for cyclodextrin-metal organic frameworks - Google Patents

Abstract

The present invention provides a rapid synthesis method for cyclodextrin-metal organic frameworks. In particular, a method for the rapid synthesis of cyclodextrin-metal organic frameworks (CD-MOFs) based on a cyclodextrin (CD) by using solvent thermal evaporation/solvothermal/ microwave/ultrasound-assisted technology. The present invention comprises the steps of: preparing a solution containing a metal salt and a CD and adding to the solution a portion of an organic solvent; using solvent thermal evaporation/solvothermal/microwave/ultrasound-assisted technology to enable rapid reaction of the reactants; after a fixed period of reaction time, collecting a supernatant and adding thereto a size modulator to obtain the CD-MOFs. The present method is fast, safe, and easy to follow and has a high yield; the raw materials and solvents used are cheap and widely available, thereby making the method ideal for industrial-scale production. The resultant CD-MOFs have wide application potential in fields such as catalysis, adsorption, pharmaceutical carriers, and construction of nanodevices.

Description

Rapid synthesis method of cyclodextrin-metal organic framework material Technical field

The present invention relates to the field of biomaterials, and more particularly to a method for rapidly synthesizing a cyclodextrin-based cyclodextrin-metal organic framework material by a solvent thermal volatilization/solvent heat/microwave/ultrasonic assist method.

Background technique

Metal-organic frameworks (MOFs) are crystalline materials in which an inorganic bridged metal is joined by an organic bridging ligand to form an infinitely extended network-like structure by means of coordinate bonds. Due to the ultra-high porosity and large specific surface area of MOFs, and its structure consisting of inorganic and organic different components, its structure is diverse and adjustable, which makes MOFs potential in many fields such as gas storage, catalysis, drug carriers and other fields. Value.

Cyclodextrin is a general term for a series of cyclic oligosaccharides produced by amylose by glucosyltransferase, usually containing 6 to 12 D-glucopyranose units. Among them, which have been studied more and have practical significance, are molecules containing 6, 7, or 8 glucose units, which are called α, β-, and γ-cyclodextrin, respectively. Cyclodextrins are ideal host molecules similar to those found to date, and have the properties of an enzyme model by themselves. Therefore, cyclodextrin has received great attention and wide application in the fields of catalysis, separation, food, and medicine.

Due to the solubility and encapsulation ability of cyclodextrin in water, changing the physicochemical properties of cyclodextrin has become one of the important purposes of chemically modified cyclodextrin. In pre-tissue receptors, the arrangement of the -OCCO-chelating unit, including crown ethers and hole ethers, contributes to the complexation of the complex with the metal ions of the first and second main groups. While cyclodextrin is extracted from starch, cyclodextrin exhibits the -OCCO-dual ligand theme on its primary and secondary surfaces, which helps it to bind to the metal ions of the first and second main groups.

The cyclodextrin-metal organic skeleton mainly uses cyclodextrin to form a new crystal in an aqueous solution with the first and second main metal ions in an organic coordination manner. The crystal has a porous surface and a large surface area. Features such as storage of gases. This green, porous material is capable of adsorbing some structurally unstable drugs, and its huge cavity can protect the drug, which makes it possible for commercial development, especially due to the cyclodextrin-metal organic framework. Edible derivatives, suitable for human consumption.

Using cyclodextrin as an organic ligand and metal ions as the center of inorganic metal, a new, safe and pharmaceutically acceptable cyclodextrin-metal organic skeleton, namely CD-MOFs, can be formed.

Angew. Chem. Int. Ed. 2012, 51, 10566-10569 describes the division of CD-MOFs into a first stage CD-MOF, a second stage micron-level CD-MOF, and a second stage nano-scale CD-MOF. The first stage CD-MOF refers to the process of mixing γ-CD with KOH, evaporating by methanol vapor, and directly depositing crystals after a certain period of time, namely CD-MOF I; the second stage micro-scale CD-MOF means γ- The CD is mixed with KOH and evaporated by methanol vapor. When a small amount of the first stage crystal has not been produced or is produced, the supernatant is taken out, and the surfactant cetyltrimethylammonium bromide (CTAB) is added, and then The process of crystal precipitation, namely CD-MOF II; The second stage nano-scale CD-MOF refers to mixing γ-CD with KOH and evaporating by methanol vapor. When no or only a small amount of the first-stage crystal is produced, the supernatant is taken out and added in a large amount according to the volume of the supernatant. The process of adding methanol to the CTAB and then depositing nano-sized crystals, namely CD-MOF Nano.

Stoddart et al. (Angew. Chem. Int. Ed. 2010, 49, 8630-8634) first prepared γ-CD and KOH as raw materials by means of evaporation of methanol at room temperature for 2-7 days. One hundred micron CD-MOFs with a yield of 66%.

Furukawa et al. (Angew. Chem. Int. Ed. 2012, 51, 10566-10569) prepared γ-CD and KOH as raw materials, and CD-MOFs of 40-500 μm were prepared by evaporation of methanol at room temperature for 24 hours. The second stage 10 μm and nano-scale CD-MOFs were further prepared by adding the surfactant cetyltrimethylammonium bromide (CTAB) at 26-32 h.

US9085460B2 and US2012/0070904A1 first dissolve food grade potassium benzoate and food grade cyclodextrin in an aqueous solution, filter through cotton wool, and slowly evaporate into the aqueous solution by ethanol for several days to finally obtain a fully edible product.

CN103549635A The octenyl succinic acid-resistant starch ester obtained by the esterification reaction of octenyl succinic anhydride and resistant starch is used as a substrate, and the γ-CD structured by metal organic skeleton is adsorbed on octenyl succinate resistant starch. On the surface of the ester, a nutrient carrier with a porous network structure is constructed. The advantage of this product is that it can embed functional substances such as nutrients in a solid form, effectively avoiding light irradiation, oxygen, acid and alkali damage, and playing a certain role. Slow release effect. However, the above method has a long reaction time and lasts for several days, making it difficult to industrialize production.

CN201380030382.6 mentions a method for preparing MOFs in the form of Mx(L)y(OH)v(H2O)w (M is a metal or a plurality of metals, L is a benzene polycarboxylate linker), mainly L The salt or the aqueous solution thereof is mixed with the metal salt/source solution, and after being sufficiently dissolved, the obtained mixed solution is evaporated by a rotary evaporator or filtered, and the synthesis time is only 30 minutes to 6 hours.

In summary, there is an urgent need in the art to develop a rapid and simple method for synthesizing a cyclodextrin-based cyclodextrin-metal organic framework material.

Summary of the invention

It is an object of the present invention to provide a method for rapidly synthesizing a cyclodextrin-based cyclodextrin-metal organic framework material using a solvent thermal volatilization/solvent heat/microwave/ultrasonic assist method.

In a first aspect of the invention, there is provided a method of preparing a cyclodextrin-metal organic framework material, comprising the steps of:

(1) providing a first mixed solution, the first mixed solution being a solution containing a metal ion and a cyclodextrin;

(2) adding a first organic solvent to the first mixed solution to obtain a second mixed solution,

Wherein the volume ratio of the first organic solvent to the first mixed solution is (0.01-5): 1, preferably (0.1-2): 1, optimally (0.5-1): 1;

(3) pretreating the second mixed solution to obtain a pretreated first mixture, wherein the pretreatment is selected from the group consisting of solvent heat treatment, microwave treatment, ultrasonic treatment, or a combination thereof.

(4) Optionally, when the precipitated cyclodextrin-metal organic framework material is contained in the first mixture, the precipitated cyclodextrin-metal organic framework material is separated from the first mixture;

(5) when a part or all of the solution is separated from the first mixture as a third mixed solution; and a second organic solvent and/or a size adjuster is added to the third mixed solution to precipitate a cyclodextrin Fine-metal organic framework material; and

(6) Optionally, the cyclodextrin-metal organic framework material precipitated in the step (5) is separated and/or dried.

In another preferred embodiment, the pretreatment is microwave treatment or ultrasonic treatment;

In another preferred embodiment, the total time T of the step (3) and the step (5) is from 1 minute to 12 hours, more preferably from 1 minute to 3 hours, most preferably from 1 minute to 1 hour, or 1 - 30 minutes, or 5-30 minutes, or 2-25 minutes.

Alternatively, the total time T of the step (3) and the step (5) is from 5 minutes to 12 hours, more preferably from 5 minutes to 3 hours, most preferably from 10 minutes to 1 hour.

In another preferred embodiment, the size modifier is selected from the group consisting of polyethylene glycol, povidone, polysorbate, sorbitan monolaurate, polyoxyethylene lauryl ether, emulsifier OP (nonylphenol polyoxyethylene ether condensate), lactulin A (polyoxyethylene fatty alcohol ether), pulilol (polyoxyethylene polypropylene glycol condensate), sodium lauryl sulfate, dodecyl Sodium benzenesulfonate, dodecyldimethylbenzylammonium bromide (benzapium bromide), or a combination thereof.

In another preferred embodiment, the size modifier is polyethylene glycol.

In another preferred embodiment, the polyethylene glycol comprises PEG 200, PEG 400, PEG 600, PEG 800, PEG 1000, PEG 1500, PEG 2000, PEG 4000, PEG 6000, PEG 8000, PEG 10000, PEG 20000, or a combination thereof.

In another preferred embodiment, the povidone comprises PVP K12, PVP K15, PVP K17, PVP K25, PVP K30, PVP K60, PVP K90, PVP K120, or a combination thereof.

In another preferred embodiment, the polysorbate comprises Tween 20, Tween 40, Tween 60, Tween 80, Tween 85, or a combination thereof.

In another preferred embodiment, the sorbitan monolaurate comprises Span 20, Span 40, Span 60, Span 80, or a combination thereof.

In another preferred embodiment, the size modifier comprises PEG2000, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, or a combination thereof, preferably PEG 20000.

In another preferred embodiment, the temperature of the pretreatment is from 25 to 100 ° C, preferably from 30 to 80 ° C, more preferably from 40 to 60 ° C.

In another preferred embodiment, the pretreatment time is from 10 min to 24 h, preferably from 15 min to 1 h, more preferably from 20 to 30 min.

In another preferred embodiment, the solvent heat treatment is a water bath heating or an oil bath heating of the mixed solution.

In another preferred embodiment, the microwave processing power is 20-1000 W, preferably 25-100 W.

In another preferred embodiment, the microwave treatment has a radiation frequency of 916 to 2450 MHz, preferably 2450 MHz.

In another preferred embodiment, the ultrasonic treatment has a power of 20 to 1000 W, preferably 40 W.

In another preferred embodiment, the ultrasonic treatment has a radiation frequency of 22 to 100 kHz, preferably 30 to 50 kHz.

In another preferred embodiment, the first organic solvent and the second organic solvent are each independently selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile, or a combination thereof.

In another preferred embodiment, the first organic solvent and the second organic solvent are the same or different.

In another preferred embodiment, the first organic solvent and the second organic solvent are methanol.

In another preferred embodiment, the step (4) may or may not be performed.

In another preferred embodiment, the prepared cyclodextrin-metal organic framework material has one or more characteristics selected from the group consisting of:

(i) average particle diameter: 50 nm to 50 μm, preferably 100 to 1000 nm (nanoscale) or 1-10 micrometer (micrometer);

(ii) in the cyclodextrin-metal organic framework material, the molar ratio of CD to metal ion is 1 to 1.2: 6-10 (such as 1:6-10, or about 1:8);

(iii) the cyclodextrin-metal organic framework material is a pharmaceutically acceptable carrier;

(iv) The cyclodextrin-metal organic framework material has a good protective effect on heat labile drugs.

In another preferred embodiment, in the step (5), the volume ratio of the second organic solvent to the third mixed liquid is (0.01-5):1, preferably (0.5-2):1, more The good land is 1:1.

In another preferred embodiment, the third mixed solution is a supernatant.

In another preferred embodiment, the amount of the size modifier added in the step (5) is from 1 to 20 mg/mL, preferably from 5 to 10 mg/mL.

In another preferred embodiment, in the step (5), the first mixture is subjected to centrifugation to separate a part of the solution from the first mixture.

In another preferred embodiment, the centrifugal process has a rotational speed of from 1000 to 5000 rpm, preferably from 2000 to 3000 rpm.

In another preferred embodiment, the centrifugation time is from 3 to 10 min, preferably from 5 to 8 min.

In another preferred embodiment, in step (6), the steps are included:

(a) centrifuging the pretreated mixed solution, never obtaining a precipitate;

(b) washing the precipitate; and

(c) The washed precipitate was vacuum dried to obtain a crystalline cyclodextrin-metal organic framework material.

In another preferred embodiment, in step (b), the precipitate is washed with ethanol.

In another preferred embodiment, in step (c), the vacuum drying temperature is 40-60 °C.

In another preferred embodiment, in step (c), the vacuum drying time is 6-24 h.

In another preferred embodiment, in the step (1), an aqueous solution of a metal compound and an aqueous solution of a cyclodextrin are mixed to obtain the first mixed solution.

In another preferred embodiment, in the step (1), the metal compound and the cyclodextrin are dissolved in water to obtain the first mixed solution.

In another preferred embodiment, the metal compound includes a metal salt and a metal base.

In another preferred embodiment, the metal compound is KOH.

In another preferred embodiment, the concentration of the metal ion in the first mixed solution is from 0.05 to 0.4 M, preferably from 0.1 to 0.3 M, more preferably 0.2 M.

In another preferred embodiment, the concentration of the cyclodextrin in the first mixed solution is from 0.013 to 0.05 M, preferably from 0.02 to 0.03 M, more preferably 0.025 M.

In another preferred embodiment, the molar ratio of cyclodextrin to metal ion in the first mixed solution is 1: (6-10), preferably 1:8.

In another preferred embodiment, the metal ion is selected from the group consisting of Li ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ , Na ⁺ , Mg ²⁺ , Cd ²⁺ , Sn ²⁺ , Ag ⁺ , Yb ⁺ , Ba ²⁺ , Sr ²⁺ , Ca ²⁺ , Pb ²⁺ , La ³⁺ , or a combination thereof.

In another preferred embodiment, the metal ion is K ⁺ .

In another preferred embodiment, the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl- --cyclodextrin, methyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, or a combination thereof.

In another preferred embodiment, the cyclodextrin is γ-cyclodextrin.

In another preferred embodiment, the cyclodextrin-metal organic framework material is used to prepare a product selected from the group consisting of a catalyst, an adsorbent, and a pharmaceutical carrier.

In a second aspect of the invention, there is provided a method of preparing a cyclodextrin-metal organic framework material, comprising the steps of:

(1) providing a first mixed solution, the first mixed solution being a solution containing a metal ion and a cyclodextrin;

(2) adding a first organic solvent to the first mixed solution to obtain a second mixed solution,

Wherein the volume ratio of the first organic solvent to the first mixed solution is (0.01-0.5): 1, preferably (0.03-0.3): 1, optimally (0.05-0.2): 1 ;

(3) pretreating the second mixed solution to obtain a pretreated first mixture, wherein the pretreatment is selected from the group consisting of:

(a) solvent thermal evaporation treatment;

(b) a combination of a solvent thermal volatilization treatment and any treatment selected from the group consisting of solvent heat treatment, microwave treatment, ultrasonic treatment, or a combination thereof;

(4) when the first mixture contains the precipitated cyclodextrin-metal organic framework material, the precipitated cyclodextrin-metal organic framework material is separated from the first mixture;

Or separating part or all of the solution from the first mixture as a third mixed solution; and adding a second organic solvent and/or a size adjuster to the third mixed solution to precipitate a cyclodextrin-metal Organic framework material; and

(5) Optionally, the cyclodextrin-metal organic framework material precipitated in the step (4) is separated and/or dried.

In another preferred embodiment, in the step (3), the solvent thermal evaporation treatment comprises the steps of:

(I) placing the mixed solution in an open container I;

(II) providing an open container II containing an organic solvent, and placing the open container I and the open container II together in a closed system;

(III) Heating/insulating the organic solvent in the open vessel II such that the organic solvent is evaporated and diffused into the mixed solution.

In another preferred embodiment, in the step (III), the closed system is subjected to an integral heat treatment to heat the organic solvent in the open vessel II.

In another preferred embodiment, in the step (III), the heat treatment includes water bath heating, and oil bath heating.

In another preferred embodiment, in the step (III), the heat treatment temperature is 25 to 100 ° C, preferably 30 to 80 ° C, more preferably 40 to 60 ° C.

In another preferred embodiment, in the step (III), the heat treatment time is 4 to 48 h, preferably 6 to 24 h.

It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.

DRAWINGS

1 is an optical micrograph of CD-MOF I prepared by the solvent evaporation method in Example 1.

2 is an optical micrograph of CD-MOF II obtained by the solvent evaporation method in Example 2.

Figure 3 is a scanning electron micrograph of CD-MOF II obtained by the solvent evaporation method in Example 2.

4 is a scanning electron micrograph of the CD-MOF Nano obtained by the solvent evaporation method in Example 3.

Figure 5 is an X-ray powder diffraction pattern of CD-MOF I obtained by the solvent evaporation method in Example 1.

Figure 6 is an X-ray powder diffraction pattern of CD-MOF II obtained by the solvent evaporation method in Example 2.

Fig. 7 is an X-ray powder diffraction pattern of CD-MOF Nano obtained by the solvent evaporation method in Example 3.

Fig. 8 is a graph showing the particle size distribution of CD-MOF II obtained by the solvent evaporation method in Example 2.

Figure 9 is an optical micrograph of CD-MOF II obtained by solvothermal method in Example 4.

Figure 10 is an optical micrograph of CD-MOF II obtained by solvothermal method in Example 5.

Figure 11 is an optical micrograph of CD-MOF II obtained by solvothermal method in Example 6.

Figure 12 is an optical micrograph of CD-MOF II obtained by solvothermal method in Example 7.

Figure 13 is a scanning electron micrograph of the CD-MOF II obtained by the solvothermal method in Example 4.

Figure 14 is a scanning electron micrograph of the CD-MOF Nano obtained by the solvothermal method in Example 8.

Figure 15 is an X-ray powder diffraction pattern of the CD-MOF II obtained by the solvothermal method in Example 4.

Figure 16 is an X-ray powder diffraction pattern of the CD-MOF Nano obtained by the solvothermal method in Example 8.

Figure 17 is a graph showing the particle size distribution of CD-MOF II obtained by the solvothermal method in Example 4.

Figure 18 is a graph showing the particle size distribution of CD-MOF II obtained by the solvothermal method in Example 5.

Figure 19 is a graph showing the particle size distribution of CD-MOF II obtained by the solvothermal method in Example 6.

Figure 20 is a graph showing the particle size distribution of CD-MOF II obtained by the solvothermal method in Example 7.

Figure 21 is an optical micrograph of CD-MOF II obtained by the microwave method in Example 9.

Figure 22 is a scanning electron micrograph of CD-MOF II obtained by the microwave method in Example 9.

Figure 23 is a scanning electron micrograph of the CD-MOF Nano obtained by the microwave method in Example 10.

Figure 24 is an X-ray powder diffraction pattern of CD-MOF II obtained by the microwave method in Example 9.

Figure 25 is an X-ray powder diffraction pattern of the CD-MOF Nano obtained by the microwave method in Example 10.

Figure 26 is an optical micrograph of CD-MOF II obtained by the ultrasonic method in Example 11.

Figure 27 is a scanning electron micrograph of the CD-MOF II obtained by the ultrasonic method in Example 11.

Figure 28 is a scanning electron micrograph of the CD-MOF Nano obtained by the ultrasonic method in Example 12.

Figure 29 is an X-ray powder diffraction pattern of CD-MOF II obtained by the ultrasonic method in Example 11.

Figure 30 is an X-ray powder diffraction pattern of the CD-MOF Nano obtained by the ultrasonic method in Example 12.

Figure 31 is an infrared spectrum of CD-MOF II in Example 2 and CD-MOF II-loaded IBU in Example 13.

32 is an infrared spectrum diagram of CD-MOF Nano in Example 3 and CD-MOF Nano-loaded IBU in Example 14.

Figure 33 is a graph showing the infrared spectrum of CD-MOF II in Example 2 and CD-MOF II-loaded LPZ in Example 15.

Figure 34 is an infrared spectrum of CD-MOF Nano in Example 3 and CD-MOF Nano-loaded LPZ in Example 16.

Figure 35 is a graph showing the release of microspheres made by CD-MOF Nano-loaded IBU in PBS7.4 in Example 14.

Figure 36 is a graph showing the release profile of microspheres made by CD-MOF Nano-loaded LPZ in PBS7.4 in Example 16.

Figure 37 is a scanning electron micrograph of the CD-MOF Nano obtained by the microwave method in Example 18.

detailed description

The inventors have extensively and intensively studied, and for the first time, unexpectedly discovered a method for rapidly synthesizing a cyclodextrin-based metal organic framework material by a solvent thermal evaporation/solvent heat/microwave/ultrasonic assist method. Specifically, the method comprises the steps of: formulating a metal salt and a cyclodextrin aqueous solution, and pre-adding a part of the organic solvent therein; allowing the reactant to react rapidly by a solvothermal volatilization/solvent heat/microwave/ultrasonic method; After the supernatant is added to the size regulator, a cyclodextrin-metal organic framework material is obtained. The conventional method takes several days to complete the reaction, and the method used in the present invention can be completed in a few minutes to several hours. The method of the invention is fast, simple, safe, high in yield, and the raw materials and solvents used are cheap and easy to obtain, which is beneficial to industrial production, and the obtained CD-MOFs have broad application prospects in the fields of catalysis, adsorption, drug carrier and nano device construction.

Cyclodextrin-metal organic framework material

As used herein, the terms "cyclodextrin-based metal-organic framework material", "cyclodextrin-metal organic framework material", "cyclodextrin-metal organic framework compound" are used interchangeably and are made by using cyclodextrin in water. The liquid can form a new crystal with the first and second main metal ions in an organic coordination manner, and the crystal has the characteristics of porous, large surface area and storage gas. This green, porous material is capable of adsorbing some structurally unstable drugs, and its huge cavity can protect the drug, which makes it possible for commercial development, especially due to the cyclodextrin-metal organic framework. Edible derivatives, suitable for human consumption. Using cyclodextrin as an organic ligand and metal ions as the center of inorganic metal, a new, safe and pharmaceutically acceptable cyclodextrin-metal organic skeleton, namely CD-MOFs, can be formed.

As used herein, the term "CD-MOF I" refers to a first stage CD-MOF crystal, which refers to a crystal obtained by mixing γ-CD with KOH and evaporating by methanol vapor, and directly decomposing over a certain period of time; The size of the first stage CD-MOF crystal obtained is about 40-500 μm.

As used herein, the term "CD-MOF II" refers to a second stage CD-MOF crystal, which means mixing γ-CD with KOH, by evaporation of methanol vapor, when a small amount of the first stage crystal has not been produced or is produced, The supernatant is taken out, a size modifier is added, and the resulting crystals are precipitated; the second stage CD-MOF crystal obtained by the method of the present invention has a size of about 1-10 μm.

As used herein, the term "CD-MOF Nano" refers to a nano-sized CD-MOF crystal, meaning that gamma-CD is mixed with KOH and evaporated by methanol vapor, when no or only a small amount of the first-stage crystal is produced. The supernatant was taken out, a large amount of methanol was added according to the volume of the supernatant, and then a size adjusting agent was added, and then the obtained crystal was precipitated; the size of the CD-MOF Nano obtained by the method of the present invention was about 200 to 500 nm.

Metal organic framework material

Metal-organic frameworks (MOFs) are crystalline materials in which an inorganic bridged metal is joined by an organic bridging ligand to form an infinitely extended network-like structure by means of coordinate bonds. Due to the ultra-high porosity and large specific surface area of MOFs, and its structure consisting of inorganic and organic different components, its structure is diverse and adjustable, which makes MOFs potential in many fields such as gas storage, catalysis, drug carriers and other fields. Value.

Cyclodextrin

Cyclodextrin is a general term for a series of cyclic oligosaccharides produced by amylose by glucosyltransferase, usually containing 6 to 12 D-glucopyranose units. Among them, which have been studied more and have practical significance, are molecules containing 6, 7, or 8 glucose units, which are called α, β-, and γ-cyclodextrin, respectively. Cyclodextrins are ideal host molecules similar to those found to date, and have the properties of an enzyme model by themselves.

Pre-addition of organic solvent

In the method of the present invention, before the reaction, a certain amount of an organic solvent is preliminarily added to the reaction system, so that the obtained CD-MOFs crystal can be precipitated faster, and at the same time, an excessive amount of the organic solvent cannot be added, otherwise the dissolved ring is easily formed. The dextrin is directly precipitated, and the resulting CD-MOFs are doped with a part of the cyclodextrin.

Pretreatment

In the method of the present invention, a mixture containing a metal salt and a cyclodextrin and pre-added with an organic solvent is pretreated for the purpose of rapid reaction, the pretreatment including solvent heat treatment, microwave treatment, and/or Or ultrasonic treatment.

The solvothermal method is the optimization of hydrothermal method. Microwave treatment can cause high-frequency vibration of material molecules, which not only generates heat, but also increases the temperature rapidly. At the same time, it enhances the substance transfer, reduces the activation energy of the reaction, and promotes potassium hydroxide and γ- The cyclodextrin reacts to make the heating uniform, shorten the heat conduction time, and does not have the disadvantage of the conventional method of uneven heating. Ultrasonic treatment mainly uses ultrasonic cavitation to cause a series of actions such as expansion, compression and collapse of the reaction solution. The chemical and mechanical effects produced can improve the reaction conditions and speed up the reaction. The generation and shutdown of microwave and ultrasonic energy are instantaneous, without thermal inertia, safe and reliable, and easy to automate control.

A particularly preferred pretreatment method is a microwave/ultrasonic method, which can effectively utilize the absorbed matter of the treated material to absorb microwaves or ultrasonic waves to achieve rapid and uniform temperature rise, while the ultrasonic cavitation, impact and micro-jet effects greatly accelerate the mass transfer effect. Therefore, the synergistic size modifier can promote the reaction of potassium hydroxide with γ-cyclodextrin even at a lower temperature.

Preparation

A method of preparing a cyclodextrin-based metal organic framework material is also provided in the present invention.

Typically, the method of the present invention comprises the steps of: mixing a metal salt solution with an aqueous cyclodextrin solution in an open vessel, pre-adding a portion of the organic solvent to the mixed solution, and placing the open vessel in a closed atmosphere containing an organic solvent. In the system, at a certain temperature, the organic solvent in the vapor state is diffused into the open vessel by evaporation of the organic solvent. After the reaction for a certain period of time, the mixed solution system absorbs a large amount of the organic solvent, and the supernatant is taken out, and then the size adjustment is performed. The cyclodextrin-based metal organic framework material is obtained; or the metal salt solution is mixed with the cyclodextrin aqueous solution, a part of the organic solvent is pre-charged, placed in a closed container, and the reaction is carried out by solvothermal/microwave/ultrasonic reaction. The medium is subjected to heat treatment, so that the reactant reacts rapidly, and after the reaction for a certain period of time, the supernatant is taken out, and then a size adjusting agent is added to obtain the metal organic based on cyclodextrin. Skeleton material.

In another preferred embodiment, the pre-dosing agent is added to the initial stage pre-addition and the size adjustment. When the initial stage is pre-added, the volume of the pre-added organic solvent is 0.001 to 5 times that of the mixed solution of the metal salt and the cyclodextrin. Preferably 0.6 times. When the size is adjusted, the volume of the organic solvent is 0.001 to 5 times the volume of the resulting supernatant. It is preferably 1 time.

A preferred method for preparing a cyclodextrin-metal organic framework comprises the steps of: mixing a metal salt solution with a cyclodextrin aqueous solution, pre-adding a portion of the organic solvent, and passing the solvent vapor at a certain temperature (above room temperature). a diffusion method, reacting for a certain period of time, adding a size adjusting agent to obtain the cyclodextrin-based metal organic framework material; or mixing the metal salt solution with the cyclodextrin aqueous solution, pre-adding a part of the organic solvent, using solvent heat/microwave / Ultrasonic vibration of the reaction medium, so that the reactants react rapidly, and after the reaction for a certain period of time, a size adjusting agent is added to obtain the cyclodextrin-based metal organic skeleton material.

Wherein the cyclodextrin comprises α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, methyl-β - cyclodextrin, carboxymethyl-β-cyclodextrin, preferably γ-cyclodextrin.

The concentration of the metal salt in the metal salt solution is from 0.05 to 0.4 M, preferably 0.2 M.

The concentration of the cyclodextrin in the aqueous cyclodextrin solution is from 0.013 to 0.05 M, preferably 0.025 M.

The metal salt includes Li ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ , Na ⁺ , Mg ²⁺ , Cd ²⁺ , Sn ²⁺ , Ag ⁺ , Yb ⁺ , Ba ²⁺ , Sr ²⁺ , Ca ²⁺ , Pb ²⁺ , La ³⁺ , preferably K ⁺ .

The pre-dosing is divided into a start-stage pre-addition and a size adjustment. When the initial stage is pre-added, the volume of the pre-added organic solvent is 0.001 to 5 times that of the mixed solution of the metal salt and the cyclodextrin. Preferably 0.6 times. When the size is adjusted, the volume of the organic solvent is 0.001 to 5 times the volume of the resulting supernatant. It is preferably 1 time.

The method includes a method of rapidly preparing a first stage and a second stage cyclodextrin-metal organic framework. The first stage is mainly the process of directly desorbing the cyclodextrin metal organic skeleton from the cyclodextrin-metal salt solution by vapor evaporation of the solvent. The second stage can be carried out by solvent thermal volatilization/solvent heat/microwave/ultrasonic assistance. After the reaction solution is reacted for a period of time, the supernatant is added to the size regulator, and then the cyclodextrin-metal organic skeleton is precipitated. process. The second stage can be subdivided into micron/nano-scale cyclodextrin-metal organic framework. The micron-level cyclodextrin-metal organic framework is prepared by first preparing a metal salt and a cyclodextrin aqueous solution, and pre-adding a part of the organic solvent through the solvent. Thermal volatilization/solvent heat/microwave/ultrasonic method, the supernatant is added to the size regulator, and then the cyclodextrin-metal organic skeleton is precipitated; the nano-scale cyclodextrin-metal organic skeleton is prepared by first preparing a metal salt and a ring. An aqueous solution of dextrin, pre-added a part of organic solvent, treated with solvothermal volatilization/solvent heat/microwave/ultrasonic method, taking the supernatant, adding a part of organic solvent, then adding size regulator, and finally separating cyclodextrin-metal organic The process of the skeleton. Further, the method further comprises the steps of centrifuging the reaction liquid after the end of the reaction, collecting the precipitate and washing, and vacuum drying.

The size regulator includes polyethylene glycol ( PEG 200, 400, 600, 800, 1000, 1500, 2000, 4000, 6000, 8000, 10000, 20000), povidone (PVP K12, K15, K17, K25, K30, K60, K90, K120), polysorbate ( Tween 20, 40, 60, 80, 85), sorbitan monolaurate (division) Plates 20, 40, 60, 80), polyoxyethylene lauryl ether, emulsifier OP (decylphenol polyoxyethylene ether condensate), lactulin A (polyoxyethylene fatty alcohol ether), Pluronic ( Polyoxyethylene polypropylene glycol condensate), sodium lauryl sulfate, sodium dodecylbenzenesulfonate, cetyltrimethylammonium bromide (CTAB), dodecyldimethylbenzyl bromide One or more of ammonium (benzapium bromide) and their derivatives, as well as combinations of several size modifiers. Preferred pharmaceutical excipients are PEG 2000, 4000, 6000, 8000, 10000, 20000, specifically PEG 20000.

The organic solvent includes, but is not limited to, methanol, ethanol, acetone, isopropanol, acetonitrile, and specifically may be methanol.

The second stage cyclodextrin-metal organic skeleton comprises directly adding PEG 20000 to the obtained supernatant without adding an organic solvent, or adding 0.05-10 ml of an organic solvent/5 ml of the supernatant, and then adding PEG 20000. The PEG 20000 addition amount includes 1-16 mg of PEG 20000/ml supernatant, preferably 8 mg of PEG 20000/ml supernatant.

The molar ratio of the cyclodextrin to the aqueous metal salt solution is from 0.06:0.5 to 0.25:2, preferably 0.125:1.

The solvent thermal evaporation method, the temperature includes room temperature -100 ° C, reaction time 4-24h, preferably 50 ° C, 6h.

The solvothermal method comprises a temperature of from room temperature to 100 ° C and a reaction time of from 1 min to 24 h, preferably 50 ° C, for 20 min.

The microwave radiation frequency is 912-4250 MHz, the power is 20-1000 W, the temperature is set at 25-100 ° C, the reaction time is 1 min-24 h, preferably 2450 MHz, 25 W, 50 ° C, 20 min.

The ultrasonic radiation frequency is 22-40 KHz, the power is 100-1000 W, the temperature is set at 25-100 ° C, the reaction time is 1 min-24 h, preferably 30 KHz, 300 W, 50 ° C, 20 min.

The main advantages of the present invention over existing methods include:

1, the reaction is quick and easy, saves time, saves a lot of cumbersome procedures, the reaction time is reduced from 2-7 days to several minutes - a few hours.

2. The method of the present invention can avoid waste of organic solvents. Especially when the solvothermal/microwave/ultrasonic method is adopted, the waste of the organic solvent in the solvent evaporation process can be effectively avoided.

3. CD-MOF prepared by solvothermal/microwave/ultrasonic method can completely realize industrial production, and common solvent evaporation method is difficult to implement.

4. The obtained CD-MOFs have a first-stage CD-MOF (CD-MOF I) and a second-stage CD-MOF, wherein the second-stage CD-MOF is further divided into micro-scale and nano-scale, and the second-stage micro-scale CD- The MOF (CD-MOF I) size is 1-20 μm, the second stage nano-scale CD-MOF (CD-MOF Nano) size is 100-1000 nm, and the yield of the first stage in the literature is less than 70%, the second The yield of the stage is lower. The process of the invention can achieve a yield of 70-90%.

5. The size rule of the cyclodextrin-based metal organic framework material obtained by the method of the present invention has a high yield. The use of medicinal excipients to adjust the size of the crystal is safe and medicinal, and if no size regulator is added, Almost no crystals or only a small amount of crystals are obtained, and the morphology and size are very irregular, generally several tens of micrometers.

6. The method of the invention avoids the leakage of the solvent in the volatilization process caused by the traditional solvent evaporation method, and is more safe and reliable.

7. The present invention can effectively control the size of CD-MOFs. The size control of CD-MOFs is beneficial to the application of metal-organic framework compounds in catalysis, adsorption, drug carriers, etc. and some nano-devices such as gas sensors, membrane separation devices, capillary column preparation, dry powder inhalation, etc. The method has important significance and broad application prospects for the application of extended metal organic framework compounds and the formation mechanism of MOFs, especially in the research field of drug carriers.

The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

Example 1

Preparation of the first stage CD-MOF crystal by solvothermal evaporation method

163.0 mg of γ-CD and 56.0 mg of KOH mixture (γ-CD and KOH molar ratio of 0.125) were dissolved in 5 mL of water, thoroughly dissolved by sonication for 10 minutes, and filtered through a 0.45 μm filter. Then, 0.5 mL of methanol was preliminarily added to the mixed solution of γ-CD and KOH, and methanol (heated in a closed vessel) was heated in a closed vessel at 50 ° C to evaporate methanol vapor into a mixed system of γ-CD and KOH. A small amount of crystals began to be formed after 6 hours of reaction. After 24 hours of reaction, a large amount of colorless transparent crystals were obtained. The supernatant was discarded, centrifuged at 3000 rpm for 5 min, washed with ethanol (10 mL×3), and the obtained crystals were dried under vacuum at 50 ° C for 12 h. The first stage CD-MOF crystal (CD-MOF I), which has a long-term storage, has a size of 40-500 μm. As shown in Figures 1 and 5, the yield is 76.3%.

Example 2

Preparation of second-stage micron-sized CD-MOF crystals by solvothermal evaporation method

A mixture of 163.0 mg of γ-CD and 56.0 mg of KOH (γ-CD and KOH molar ratio of 0.125) was weighed and dissolved in 5 mL of water, solubilized by ultrasonication for 10 minutes, and filtered through a 0.45 μm filter. Then, 0.5 mL of methanol was preliminarily added to the mixed solution of γ-CD and KOH, and methanol (heated in a closed vessel) was heated in a closed vessel at 50 ° C to evaporate methanol vapor into a mixed system of γ-CD and KOH. After 6 hours of reaction, remove it. The supernatant was added to PEG 20000 at a ratio of 8 mg/mL of the supernatant, and after standing for half an hour, it was centrifuged at 3000 rpm for 5 min, and washed with ethanol (10 mL × 2) and dichloromethane (10 mL × 2), respectively, and the obtained crystal was 50 ° C. After drying in vacuum for 12 h, the second-stage micron-sized CD-MOF crystal (CD-MOF II) can be stored for a long time, and the size is 1-10 μm. As shown in Fig. 2, Fig. 3, Fig. 6 and Fig. 8, the yield is 85.1%. .

Example 3

Preparation of second-stage nano-scale CD-MOF crystal by solvothermal evaporation method

163.0 mg of γ-CD and 56.0 mg of KOH mixture (γ-CD and KOH molar ratio of 0.125) were dissolved in 5 mL of water, thoroughly dissolved by sonication for 10 minutes, and filtered through a 0.45 μm filter. Then, 0.5 mL of methanol was preliminarily added to the mixed solution of γ-CD and KOH, and methanol (heated in a closed vessel) was heated in a closed vessel at 50 ° C to evaporate methanol vapor into a mixed system of γ-CD and KOH. After reacting for 6 hours, the supernatant was taken out, an equal volume of methanol was added, and PEG 20000 was added in a ratio of 8 mg/mL of the supernatant, and allowed to stand for half an hour, and then centrifuged at 3000 rpm for 5 minutes, respectively, using ethanol (10 mL × 2), dichloro The methane (10 mL×2) was washed, and the obtained crystal was dried under vacuum at 50 ° C for 1 h to obtain a second-stage nano-scale CD-MOF crystal (CD-MOF Nano) having a size of 200-500 nm, as shown in FIG. 4 and FIG. It is 90.3%.

Example 4

Preparation of second-stage micron-sized CD-MOF crystals by solvothermal method

The γ-cyclodextrin and the aqueous KOH solution and a part of the organic solvent mixture system are directly heated by a solvothermal method. Weigh 163.0mg γ-CD and 56.0mg KOH mixture (γ-CD and KOH molar ratio is 0.125) dissolved in 5mL water, pre-add 3mL methanol to the mixed solution, heated in 50 ° C water bath for 20min, remove the solution, then add 64mg PEG After standing for half an hour, the mixture was centrifuged at 3000 rpm for 5 min, washed with ethanol (10 mL × 2), dichloromethane (10 mL × 2), and the obtained crystal was vacuum dried at 50 ° C for 12 h to obtain a second-stage micron-sized CD-MOF. The crystal (CD-MOF II), having a size of 1-10 μm, was as shown in Fig. 9, Fig. 13, Fig. 15 and Fig. 17, and the yield was 87.0%.

Example 5

Preparation of second-stage micron-sized CD-MOF crystals by solvothermal method

Mix γ-cyclodextrin with KOH aqueous solution and a part of organic solvent directly by solvothermal method The system is heated. Weigh 163.0mg γ-CD and 56.0mg KOH mixture (γ-CD and KOH molar ratio is 0.125) dissolved in 5mL water, pre-add 3mL methanol to the mixed solution, heated in 50 °C water bath for 20min, then take out the solution, then add 16mg PEG After standing for half an hour, the mixture was centrifuged at 3000 rpm for 5 min, washed with ethanol (10 mL × 2), dichloromethane (10 mL × 2), and the obtained crystal was vacuum dried at 50 ° C for 12 h to obtain a second-stage micron-sized CD-MOF. The crystal (CD-MOF II), having a size of 1-10 μm, as shown in Fig. 10 and Fig. 18, yielded 58.3%.

Example 6

Preparation of second-stage micron-sized CD-MOF crystals by solvothermal method

The γ-cyclodextrin and the aqueous KOH solution and a part of the organic solvent mixture system are directly heated by a solvothermal method. Weigh 163.0mg γ-CD and 56.0mg KOH mixture (γ-CD and KOH molar ratio is 0.125) dissolved in 5mL water, pre-add 3mL methanol to the mixed solution, heated in 50 ° C water bath for 20min, remove the solution, then add 64mg PEG After standing for half an hour, it was centrifuged at 3000 rpm for 5 min, washed with ethanol (10 mL × 2), dichloromethane (10 mL × 2), and the obtained crystal was vacuum dried at 50 ° C for 12 h to obtain a second-stage micron-sized CD-MOF. The crystal (CD-MOF II), having a size of 1-10 μm, as shown in Figures 11 and 19, yielded 83.0%.

Example 7

Preparation of second-stage micron-sized CD-MOF crystals by solvothermal method

The γ-cyclodextrin and the aqueous KOH solution and a part of the organic solvent mixture system are directly heated by a solvothermal method. Weigh 163.0mg γ-CD and 56.0mg KOH mixture (γ-CD and KOH molar ratio is 0.125) dissolved in 5mL water, pre-add 3mL methanol to the mixed solution, heated in 50 ° C water bath for 20min, remove the solution, then add 64mg PEG 10000, after standing for half an hour, centrifuge at 3000 rpm for 5 min, wash with ethanol (10 mL × 2), dichloromethane (10 mL × 2), and dry the obtained crystal at 50 ° C for 12 h to obtain the second stage micron-sized CD-MOF. The crystal (CD-MOF II), having a size of 1-10 μm, as shown in Fig. 12 and Fig. 20, had a yield of 87.4%.

Example 8

Preparation of second-stage nano-scale CD-MOF crystal by solvothermal method

The γ-cyclodextrin and the aqueous KOH solution and a part of the organic solvent mixture system are directly heated by a solvothermal method. Weigh 163.0mg γ-CD and 56.0mg KOH mixture (γ-CD and KOH molar ratio is 0.125) dissolved in 5mL water, pre-add 3mL methanol to the mixed solution, after heating in 50°C water bath for 20min, remove the solution and add equal volume. Methanol, then added 64 mg PEG 20000, allowed to stand for half an hour, centrifuged at 3000 rpm for 5 min, washed with ethanol (10 mL × 2), dichloromethane (10 mL × 2), and the obtained crystals were dried under vacuum at 50 ° C for 12 h to obtain a second. The stage nano-scale CD-MOF crystal (CD-MOF Nano) has a size of 200-500 nm, as shown in Fig. 14 and Fig. 16, the yield is 90.5%.

Example 9

Preparation of second-stage micron-sized CD-MOF crystals by microwave method

The γ-cyclodextrin and the KOH aqueous solution and a part of the organic solvent mixed system were microwave-heated by means of microwaves. Weigh 163.0mg γ-CD and 56.0mg KOH mixture (γ-CD and KOH molar ratio is 0.125) dissolved in 5mL water, pre-add 3mL methanol to the mixed solution, 2450MHz microwave reactor, power setting 25W, temperature setting 50 °C After reacting for 20 min, the solution was taken out, and then 64 mg of PEG 20000 was added thereto. After standing for half an hour, it was centrifuged at 3000 rpm for 5 min, washed with ethanol (10 mL × 2), dichloromethane (10 mL × 2), and the obtained crystal was vacuum dried at 50 ° C. At 12 h, a second stage micron-sized CD-MOF crystal (CD-MOF II) having a size of 1-10 μm, as shown in Fig. 21, Fig. 22 and Fig. 24, yielded 82.2%.

Example 10

Preparation of second-stage nanoscale CD-MOF crystals by microwave method

The γ-cyclodextrin and the KOH aqueous solution and a part of the organic solvent mixed system were microwave-heated by means of microwaves. Weigh 163.0mg γ-CD and 56.0mg KOH mixture (γ-CD and KOH molar ratio is 0.125) dissolved in 5mL water, pre-add 3mL methanol to the mixed solution, 2450MHz microwave reactor, power setting 25W, temperature setting 50 °C After reacting for 20 min, the solution was taken out, an equal volume of methanol was added, and 64 mg of PEG 20000 was added thereto. After standing for half an hour, it was centrifuged at 3000 rpm for 5 min, and washed with ethanol (10 mL × 2) and dichloromethane (10 mL × 2), respectively. The obtained crystal was dried under vacuum at 50 ° C for 12 h to obtain a second-stage nano-scale CD-MOF crystal (CD-MOF Nano) having a size of 200-500 nm, as shown in Fig. 10 and Fig. 23, with a yield of 90.1%.

Example 11

Preparation of second-stage micron-sized CD-MOF crystals by ultrasonic method

Ultrasonic heating of a mixed system of γ-cyclodextrin with an aqueous solution of KOH and a part of an organic solvent was carried out by means of ultrasonic waves. Weigh 163.0mg γ-CD and 56.0mg KOH mixture (γ-CD and KOH molar ratio is 0.125) dissolved in 5mL water, pre-add 3mL methanol to the mixed solution, use 40KHz ultrasonic reactor, power setting 40W, temperature 50 °C After 20 min of reaction, the supernatant was taken out, and then 64 mg of PEG 20000 was added. After standing for half an hour, it was centrifuged at 3000 rpm for 5 min, and washed with ethanol (10 mL × 2) and dichloromethane (10 mL × 2), respectively, and the obtained crystal was vacuumed at 50 ° C. After drying for 12 h, a second stage micron-sized CD-MOF crystal (CD-MOF II) having a size of 1-10 μm, as shown in Figures 26, 27 and 29, yielded 79.7%.

Example 12

Rapid Synthesis of Nano-scale CD-MOF Crystals by Ultrasonic Method

Ultrasonic heating of a mixed system of γ-cyclodextrin with an aqueous solution of KOH and a part of an organic solvent was carried out by means of ultrasonic waves. Weigh 163.0mg γ-CD and 56.0mg KOH mixture (γ-CD and KOH molar ratio is 0.125) dissolved in 5mL water, pre-add 3mL methanol to the mixed solution, use 40KHz ultrasonic reactor, power setting 40W, temperature 50 °C After 20 min of reaction, the supernatant was taken out, 8 mL of methanol was added, and 64 mg of PEG 20000 was added thereto. After standing for half an hour, it was centrifuged at 3000 rpm for 5 min, and washed with ethanol (10 mL × 2) and dichloromethane (10 mL × 2), respectively. The crystal was dried under vacuum at 50 ° C for 12 h to obtain a second-stage nano-scale CD-MOF crystal (CD-MOF Nano) having a size of 200-500 nm. As shown in Fig. 28 and Fig. 30, the yield was 85.2%.

Example 13

Preparation of the second stage micron-sized CD-MOF crystal loaded with ibuprofen (IBU)

Weigh 100.0 mg of the dried CD-MOF II powder prepared in Example 2, add it to 2.5 mL of IBU ethanol solution (40 mg·mL ^-1 ), incubate for 4 days at 37 ° C, 150 rpm shaker, centrifuge at 3000 rpm for 5 min, with ethanol. (3mL × 3) washing, the resulting crystals were dried under vacuum at 35 ° C for 12 h, the drug loading rate can reach 12.0% (w / w), as shown in the figure is the infrared spectrum of CD-MOF II IBU.

Example 14

Preparation of the second stage nano-scale CD-MOF crystal carrying ibuprofen (IBU) and its microspheres

Weigh 100.0 mg of the CD-MOF Nano dry powder prepared in Example 3, add it to 2.5 mL of IBU ethanol solution (40 mg·mL ^-1 ), incubate for 4 days at 37 ° C, 150 rpm shaker, centrifuge at 3000 rpm for 5 min, with ethanol. (3 mL × 3) washing, the obtained crystal was dried under vacuum at 35 ° C for 12 h, and the drug loading rate was 13.0% (w/w).

Weigh 50 mg of drug-loaded CD-MOF Nano, uniformly disperse it in 3 mL of acetone solution, add 450 mg of Eudragit RS100, dissolve it by sonication for 10 min, add 120 mg of aluminum stearate, and disperse evenly for 5 min. The dispersed phase containing aluminum stearate was added to liquid paraffin (ice bath to 10 ° C), and the suspension was magnetically stirred at 10 ° C for 30 s (500 rpm) in a 10 ° C ice bath, dispersed in a disperser (10000 rpm, 5min), get S / O / O type emulsion. The above emulsion was placed on a magnetic stirrer, and the temperature was slowly raised from 10 ° C to 35 ° C under stirring at 500 rpm, and stirring was continued for further 3 hours (500 rpm, 35 ° C) to remove most of the acetone. The above liquid was transferred to a 50 mL centrifuge tube, centrifuged (2000 rpm, 5 min), and liquid paraffin (upper layer) was discarded; the lower layer solid was washed twice with 30 mL of n-hexane, centrifuged at 2000 rpm for 5 min. After the end of the washing, the hood was dried overnight, as shown in Fig. 32 for the infrared spectrum of the CD-MOF Nano-loaded IBU, and Figure 35 shows that the IBU-loaded microspheres had a significant sustained release effect in PBS7.4.

Example 15

Preparation of the second stage micron-sized CD-MOF crystal loaded with lansoprazole (LPZ)

200.0 mg of the dried CD-MOF II powder prepared in Example 2 was weighed, added to 3.6 mL of LPZ ethanol solution (14 mg·mL ^-1 ), incubated at 37 ° C for 45 d in a 150 rpm shaker, centrifuged at 3000 rpm for 5 min, and used ethanol ( 3mL×3) washing, the obtained crystal was vacuum dried at 35 ° C for 12 h, the drug loading rate can reach 9.4% (w / w), as shown in Figure 33 is the infrared spectrum of CD-MOF II loaded LPZ.

Example 16

Preparation of Lansoprazole (LPZ) and Its Microspheres in the Second Stage Nano-CD-MOF Crystal

Weigh 200.0 mg of the CD-MOF Nano dry powder prepared in Example 3, add it to 3.6 mL of LPZ ethanol solution (14 mg·mL ^-1 ), incubate for 4 days at 37 ° C, 150 rpm shaker, centrifuge at 3000 rpm for 5 min, with ethanol. (3 mL × 3) washing, the obtained crystals were dried under vacuum at 35 ° C for 12 h, and the drug loading rate was 1.6% (w/w).

Weigh 50 mg of drug-loaded CD-MOF Nano, uniformly disperse it in 3 mL of acetone solution, add 450 mg of Eudragit RS100, dissolve it by sonication for 10 min, add 120 mg of aluminum stearate, and disperse evenly for 5 min. Adding the dispersed phase containing aluminum stearate to liquid paraffin (ice bath to 10 ° C), the above suspension is 10 Under the condition of °C ice water bath, the magnetic stirring was carried out for 30 s (500 rpm), and the disperser was dispersed (10000 rpm, 5 min) to obtain an S/O/O type emulsion. The above emulsion was placed on a magnetic stirrer, and the temperature was slowly raised from 10 ° C to 35 ° C under stirring at 500 rpm, and stirring was continued for further 3 hours (500 rpm, 35 ° C) to remove most of the acetone. The above liquid was transferred to a 50 mL centrifuge tube, centrifuged (2000 rpm, 5 min), and liquid paraffin (upper layer) was discarded; the lower layer solid was washed twice with 30 mL of n-hexane, centrifuged at 2000 rpm for 5 min. After the washing was completed, it was dried overnight in a fume hood. Figure 34 shows the infrared spectrum of CD-MOF Nano loaded LPZ, while Figure 36 shows that the loaded LPZ microspheres have a significant sustained release effect in PBS7.4.

Example 17

By repeating Examples 4, 9, and 11, CD-MOFs crystals of the desired size were still obtained, with the difference being that the heating time was changed as follows:

Example 18

The γ-cyclodextrin and the KOH aqueous solution and a part of the organic solvent mixed system were microwave-heated by means of microwaves. Weigh 324.0mg γ-CD and 112.0mg KOH mixture (γ-CD and KOH molar ratio is 0.124) dissolved in 10mL water, pre-add 6mL methanol to the mixed solution, 2450MHz microwave reactor, power setting 100W, temperature setting 50 °C After reacting for 10 min, the solution was taken out, 16 mL of methanol was added, and 128 mg of PEG 20000 was added thereto. After standing for half an hour, it was centrifuged at 3000 rpm for 5 min, and washed with ethanol (10 mL × 2) and dichloromethane (10 mL × 2), respectively. The crystal was dried under vacuum at 50 ° C for 12 h to obtain a second-stage nano-scale CD-MOF crystal (CD-MOF Nano) having a size of 100-300 nm, as shown in Fig. 37, and a yield of 93.2%.

As described in the above embodiments, the method of the present invention can be completed in a few minutes to several hours, and has the advantages of being fast, simple, safe, and high in yield.

The dimensions and yield data for some of the products made in the above examples are summarized in the table below.

* Size regulator added in 8mg/mL supernatant ratio

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (22)

1. A method for preparing a cyclodextrin-metal organic framework material, comprising the steps of:

   (1) providing a first mixed solution, the first mixed solution being a solution containing a metal ion and a cyclodextrin;

   (2) adding a first organic solvent to the first mixed solution to obtain a second mixed solution,

   Wherein the volume ratio of the first organic solvent to the first mixed solution is (0.01-5):1, preferably (0.1-2):1, most preferably (0.5-1):1 ;

   (3) pretreating the second mixed solution to obtain a pretreated first mixture, wherein the pretreatment is selected from the group consisting of solvent heat treatment, microwave treatment, ultrasonic treatment, or a combination thereof.

   (4) Optionally, when the precipitated cyclodextrin-metal organic framework material is contained in the first mixture, the precipitated cyclodextrin-metal organic framework material is separated from the first mixture;

   (5) when a part or all of the solution is separated from the first mixture as a third mixed solution; and a second organic solvent and/or a size adjuster is added to the third mixed solution to precipitate a cyclodextrin Fine-metal organic framework material; and

   (6) Optionally, the cyclodextrin-metal organic framework material precipitated in the step (5) is separated and/or dried.
2. The method of claim 1 wherein the total time T of steps (3) and (5) is from 1 minute to 12 hours, more preferably from 1 minute to 3 hours, most preferably 1 minute - 1 hour.
3. The method of claim 1 wherein said size modifier is selected from the group consisting of polyethylene glycol, povidone, polysorbate, sorbitan monolaurate, polyoxyethylene laurel. Alcohol ether, emulsifier OP, lactulin A, Pluronic, sodium lauryl sulfate, sodium dodecylbenzenesulfonate, dodecyldimethylbenzylammonium bromide, or a combination thereof.
4. The method of claim 1 wherein said size modifier comprises PEG 2000, PEG 4000, PEG 6000, PEG 8000, PEG 10000, PEG 20000, or a combination thereof, preferably PEG 20000.
5. The method of claim 1 wherein said pretreatment has a temperature of from 25 to 100 ° C, preferably from 30 to 80 ° C, more preferably from 40 to 60 ° C.
6. The method of claim 1 wherein said pretreatment is for a period of from 10 min to 24 h, preferably from 15 min to 1 h, more preferably from 20 to 30 min.
7. The method of claim 1 wherein said first organic solvent and said second organic solvent are each independently selected from the group consisting of methanol, ethanol, isopropanol, acetone, acetonitrile, or a combination thereof.
8. The method of claim 1 wherein said prepared cyclodextrin-metal organic framework The material has one or more characteristics selected from the group consisting of:

   (i) average particle diameter: 50 nm to 50 μm, preferably 100 to 1000 nm (nanoscale) or 1-10 micrometer (micrometer);

   (ii) in the cyclodextrin-metal organic framework material, the molar ratio of CD to metal ions is 1 to 1.2: 6-10;

   (iii) the cyclodextrin-metal organic framework material is a pharmaceutically acceptable carrier;

   (iv) The cyclodextrin-metal organic framework material has a protective effect on heat labile drugs.
9. The method according to claim 1, wherein in the step (5), the volume ratio of the second organic solvent to the third mixed liquid is (0.01-5):1, preferably (0.5- 2): 1, more preferably 1:1.
10. The method of claim 1 wherein in step (5), the amount of size modifier added is from 1 to 20 mg/mL, preferably from 5 to 10 mg/mL.
11. The method of claim 1 wherein in step (6), the method comprises the steps of:

    (a) centrifuging the pretreated mixed solution, never obtaining a precipitate;

    (b) washing the precipitate; and

    (c) The washed precipitate was vacuum dried to obtain a crystalline cyclodextrin-metal organic framework material.
12. The method according to claim 1, wherein said first mixed solution has a metal ion concentration of from 0.05 to 0.4 M, preferably from 0.1 to 0.3 M, more preferably 0.2 M;

    The molar ratio of the cyclodextrin to the metal ion in the first mixed solution is 1: (6-10), preferably 1:8.
13. The method according to claim 1, wherein the concentration of the cyclodextrin in the first mixed solution is from 0.013 to 0.05 M, preferably from 0.02 to 0.03 M, more preferably 0.025 M.
14. The method of claim 1 wherein said metal ion is selected from the group consisting of Li ⁺ , K ⁺ , Rb ⁺ , Cs ⁺ , Na ⁺ , Mg ²⁺ , Cd ²⁺ , Sn ²⁺ , Ag ⁺ , Yb ⁺ , Ba ²⁺ , Sr ²⁺ , Ca ²⁺ , Pb ²⁺ , La ³⁺ , or a combination thereof.
15. The method of claim 1 wherein said cyclodextrin is selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin. Refined, sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, carboxymethyl-β-cyclodextrin, or a combination thereof.
16. The method of claim 1 wherein said cyclodextrin-metal organic framework material is used to prepare a product selected from the group consisting of a catalyst, an adsorbent, and a pharmaceutical carrier.
17. A method for preparing a cyclodextrin-metal organic framework material, comprising the steps of:

    (1) providing a first mixed solution, the first mixed solution being a solution containing a metal ion and a cyclodextrin;

    (2) adding a first organic solvent to the first mixed solution to obtain a second mixed solution,

    Wherein the volume ratio of the first organic solvent to the first mixed solution is (0.01-0.5): 1, preferably (0.03-0.3): 1, optimally (0.05-0.2): 1 ;

    (3) pretreating the second mixed solution to obtain a pretreated first mixture, wherein the pretreatment is selected from the group consisting of:

    (a) solvent thermal evaporation treatment;

    (b) a combination of a solvent thermal volatilization treatment and any treatment selected from the group consisting of solvent heat treatment, microwave treatment, ultrasonic treatment, or a combination thereof;

    (4) when the first mixture contains the precipitated cyclodextrin-metal organic framework material, the precipitated cyclodextrin-metal organic framework material is separated from the first mixture;

    Or separating part or all of the solution from the first mixture as a third mixed solution; and adding a second organic solvent and/or a size adjuster to the third mixed solution to precipitate a cyclodextrin-metal Organic framework material; and

    (5) Optionally, the cyclodextrin-metal organic framework material precipitated in the step (4) is separated and/or dried.
18. The method according to claim 17, wherein in the step (3), the solvent thermal evaporation treatment comprises the steps of:

    (I) placing the mixed solution in an open container I;

    (II) providing an open container II containing an organic solvent, and placing the open container I and the open container II together in a closed system;

    (III) Heating/insulating the organic solvent in the open vessel II such that the organic solvent is evaporated and diffused into the mixed solution.
19. The method according to claim 18, wherein in the step (II), the closed system is subjected to an integral heat treatment to heat the organic solvent in the open vessel II.
20. The method according to claim 18, wherein in the step (III), the heat treatment comprises water bath heating, and oil bath heating.
21. The method according to claim 18, wherein in the step (III), the temperature of the heat treatment is 25 to 100 ° C, preferably 30 to 80 ° C, more preferably 40 to 60 ° C.
22. The method according to claim 18, wherein in the step (III), the heat treatment time is 4 to 48 h, preferably 6 to 24 h.

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