CN107151329B

CN107151329B - Rapid synthesis method of cyclodextrin-metal organic framework material

Info

Publication number: CN107151329B
Application number: CN201610125456.XA
Authority: CN
Inventors: 张继稳; 刘波涛; 李海燕; 吕娜娜; 伍丽; 郭桢
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2016-03-04
Filing date: 2016-03-04
Publication date: 2020-10-16
Anticipated expiration: 2036-03-04
Also published as: WO2017148439A1; CN107151329A

Abstract

The invention provides a rapid synthesis method of a cyclodextrin-metal organic framework material. Specifically, the invention provides a method for rapidly synthesizing cyclodextrin-metal organic frameworks (CD-MOFs) based on Cyclodextrin (CD) by utilizing a solvothermal volatilization/solvothermal/microwave/ultrasonic wave auxiliary method, which comprises the following steps of: preparing aqueous solution of metal salt and cyclodextrin, and pre-adding a part of organic solvent in the aqueous solution; the reactants are quickly reacted by a solvothermal volatilization/solvothermal/microwave/ultrasonic method; after reacting for a certain time, taking the supernatant and adding a size regulator to obtain the cyclodextrin-metal organic framework material. The method is rapid, simple, convenient and safe, has high yield, uses cheap and easily-obtained raw materials and solvents, is beneficial to industrial production, and the obtained CD-MOFs have wide application prospects in the fields of catalysis, adsorption, construction of drug carriers, nano devices and the like.

Description

Rapid synthesis method of cyclodextrin-metal organic framework material

Technical Field

The invention relates to the field of biological materials, in particular to a method for quickly synthesizing cyclodextrin-metal organic framework materials based on cyclodextrin by utilizing a solvothermal volatilization/solvothermal/microwave/ultrasonic wave auxiliary method.

Background

Metal-organic frameworks (MOFs) are crystalline materials formed by connecting inorganic Metal centers by organic bridging ligands through coordination bonds. Due to the ultrahigh porosity and huge specific surface area of the MOFs and the structure consisting of different inorganic and organic components, the structure of the MOFs is diversified and adjustable, so that the MOFs have potential application values in various fields such as gas storage, catalysis, drug carriers and the like.

Cyclodextrin is a generic name for a series of cyclic oligosaccharides produced from amylose by the action of glucosyltransferase, and generally contains 6 to 12D-glucopyranose units. Among them, the more studied and of great practical significance are molecules containing 6, 7, 8 glucose units, called α, β -and γ -cyclodextrins, respectively. Cyclodextrins are ideal host molecules found to date to resemble enzymes and have the properties of an enzyme model in their own right. Therefore, cyclodextrin is very important and widely used in the fields of catalysis, separation, food, medicine, and the like.

Due to the solubility and inclusion ability of cyclodextrin in water, changing the physicochemical properties of cyclodextrin has become one of the important purposes for chemically modifying cyclodextrin. In the pre-tissue receptor, the arrangement of the-OCCO-chelating units, including crown ether and cryptether, facilitates the binding of the complex with the metal ions of the first and second main groups. The cyclodextrin is extracted from starch, and the cyclodextrin presents-OCCO-bidentate theme on the primary and secondary surfaces of the cyclodextrin, so that the cyclodextrin is beneficial to being combined with metal ions of the first and second main groups.

The cyclodextrin-metal organic framework mainly utilizes the fact that cyclodextrin can form a new crystal with first and second main group metal ions in an organic coordination mode in an aqueous solution, and the crystal has the characteristics of being porous, large in surface area, capable of storing gas and the like. The green and porous material can adsorb some medicine with unstable structure, and its huge cavity can protect medicine, so that it can be used for commercial development, in particular, the cyclodextrin-metal organic skeleton is edible derivative, and is suitable for human being.

The cyclodextrin is taken as an organic ligand, and the metal ion is taken as an inorganic metal center, so that a novel cyclodextrin-metal organic framework which has higher safety and is used for medicine, namely CD-MOFs, can be formed.

Angew. chem. int. ed.2012,51, 10566-. The first stage of CD-MOF refers to a process of directly separating out crystals by mixing gamma-CD with KOH, evaporating through methanol vapor and passing through a certain time, namely CD-MOF I; the second stage of micron-sized CD-MOF refers to a process of mixing gamma-CD with KOH, evaporating through methanol vapor, taking out supernatant liquid when no or only a small amount of first stage crystals are generated, adding a surfactant Cetyl Trimethyl Ammonium Bromide (CTAB), and then precipitating crystals, namely CD-MOF II; the second stage Nano-scale CD-MOF is a process of mixing gamma-CD with KOH, evaporating through methanol vapor, taking out supernatant liquid when no or only a small amount of first stage crystals are generated, adding a large amount of methanol according to the volume of the supernatant liquid, adding CTAB, and then separating out Nano-scale crystals, namely CD-MOF Nano.

Stoddart et al (Angew. chem. int. Ed.2010,49,8630-8634) first prepared CD-MOFs with a particle size of several hundred microns in a yield of 66% by a normal temperature methanol vapor evaporation method using gamma-CD and KOH as raw materials for 2-7 days.

Furukawa et al (Angew. chem. int. Ed.2012,51,10566-10569) prepared CD-MOFs of 40-500 μm by normal temperature methanol vapor evaporation for 24h using γ -CD and KOH as raw materials, and further prepared CD-MOFs of 10 μm and nanometer level in the second stage by adding Cetyl Trimethyl Ammonium Bromide (CTAB) as surfactant during 26-32 h.

US9085460B2 and US2012/0070904a1 first dissolve the food grade potassium benzoate and food grade cyclodextrin in an aqueous solution, filter through lint, and slowly evaporate through ethanol into the aqueous solution for several days to obtain a fully edible product.

CN103549635A takes octenyl succinic acid resistant starch ester obtained by esterification reaction of octenyl succinic anhydride and resistant starch as a base material, and adsorbs gamma-CD with a metal organic framework structure on the surface of the octenyl succinic acid resistant starch ester to construct a nutrient carrier with a porous network structure. However, the reaction time of the method is long and lasts for several days, and industrial production is difficult.

CN201380030382.6 mentions a method for preparing MOFs in the form of Mx (L) y (OH) v (H2O) w (M is a metal or metals, L is a benzene polycarboxylic acid salt linker), which mainly comprises mixing a salt of L or an aqueous solution thereof with a solution of a metal salt/source, after sufficient dissolution, evaporating water or filtering and recovering the obtained mixed solution by a rotary evaporator, wherein the synthesis time is only 30 minutes to 6 hours.

In view of the foregoing, there is a strong need in the art to develop a rapid and simple method for synthesizing cyclodextrin-metal organic framework materials based on cyclodextrin.

Disclosure of Invention

The invention aims to provide a method for quickly synthesizing cyclodextrin-metal organic framework materials based on cyclodextrin by utilizing a solvothermal volatilization/solvothermal/microwave/ultrasonic wave auxiliary method.

In a first aspect of the present invention, there is provided a process for the preparation of a cyclodextrin-metal organic framework material comprising the steps of:

(1) providing a first mixed solution, wherein the first mixed solution is a solution containing metal ions and cyclodextrin;

(2) adding a first organic solvent into 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, and 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: solvothermal treatment, microwave treatment, ultrasonic treatment, or a combination thereof,

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

(5) when a part or all of the solution is separated from the first mixture, the solution is used as a third mixed solution; adding a second organic solvent and/or a size regulator into the third mixed solution to separate out the cyclodextrin-metal organic framework material; and

(6) optionally separating and/or drying the cyclodextrin-metal-organic framework material precipitated in step (5).

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

in another preferred embodiment, the total time T of step (3) and 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 from 1 minute to 30 minutes, or from 5 minutes to 30 minutes, or from 2 minutes to 25 minutes.

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

In another preferred embodiment, the size-adjusting agent is selected from the group consisting of: polyethylene glycol, povidone, polysorbate, sorbitan monolaurate, polyoxyethylene lauryl ether, emulsifier OP (a polyoxyethylene nonylphenol polyoxyethylene ether condensate), lactofen a (a polyoxyethylene fatty alcohol ether), pluronic (a polyoxyethylene polypropylene glycol condensate), sodium lauryl sulfate, sodium dodecylbenzenesulfonate, dodecyldimethylbenzyl ammonium bromide (benzalkonium bromide), or a combination thereof.

In another preferred embodiment, the size-adjusting agent is polyethylene glycol.

In another preferred embodiment, the polyethylene glycol comprises PEG200, PEG400, PEG600, PEG800, PEG1000, PEG1500, PEG2000, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, or a combination thereof.

In another preferred example, the povidone comprises PVP K12, PVP K15, PVP K17, PVP K25, PVPK30, 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-adjusting agent comprises PEG2000, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, or a combination thereof, preferably PEG 20000.

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

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

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

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

In another preferred embodiment, the radiation frequency of the microwave treatment is 916-2450MHz, preferably 2450 MHz.

In another preferred embodiment, the power of the ultrasonic treatment is 20-1000W, preferably 40W.

In another preferred embodiment, the radiation frequency of the ultrasonic treatment is 22-100KHz, preferably 30-50 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 combinations 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 size: 50nm-50 micron, preferably 100-1000nm (nanometer scale) or 1-10 micron (micron scale);

(ii) in the cyclodextrin-metal organic framework material, the molar ratio of CD to metal ions is 1-1.2: 6-10 (e.g., 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 can have a good protection effect on heat-labile drugs.

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

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

In another preferred embodiment, in step (5), the size-regulating agent is added in an amount of 1-20mg/mL, preferably 5-10 mg/mL.

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

In another preferred embodiment, the rotation speed of the centrifugal treatment is 1000-5000rpm, preferably 2000-3000 rpm.

In another preferred embodiment, the time for the centrifugation treatment is 3-10min, preferably 5-8 min.

In another preferred example, in the step (6), the method comprises the steps of:

(a) centrifuging the pretreated mixed solution to obtain a precipitate;

(b) washing the precipitate; and

(c) and drying the washed precipitate in vacuum to obtain the crystallized cyclodextrin-metal organic framework material.

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

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

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

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

In another preferred example, in the step (1), the metal compound and the cyclodextrin are dissolved in water, thereby obtaining the first mixed solution.

In another preferred embodiment, the metal compound comprises 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 ions in the first mixed solution is 0.05-0.4M, preferably 0.1-0.3M, and more preferably 0.2M.

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

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⁺、Mg²⁺、Cd²⁺、Sn²⁺、Ag⁺、Yb⁺、Ba²⁺、Sr²⁺、Ca²⁺、Pb²⁺、La³⁺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: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl-beta-cyclodextrin, methyl-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, or a combination thereof.

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

In another preferred embodiment, the cyclodextrin-metal organic framework material is used for preparing a product selected from the group consisting of: a catalyst, an adsorbent, and a drug carrier.

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

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, and most preferably (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) carrying out solvent thermal volatilization treatment;

(b) a combination of solvothermal volatilization treatment with any one of the treatment modalities selected from group a, wherein group a comprises solvothermal treatment, microwave treatment, ultrasonication, or a combination thereof;

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

or separating part or all of the solution from the first mixture to serve as a third mixed solution; adding a second organic solvent and/or a size regulator into the third mixed solution to separate out the cyclodextrin-metal organic framework material; and

(5) optionally separating and/or drying the cyclodextrin-metal-organic framework material precipitated in step (4).

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

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

(II) providing an open container II filled with an organic solvent, and putting the open container I and the open container II together into a closed system; and

(III) heating/maintaining the temperature of the organic solvent in the open container II, so that the organic solvent is evaporated and diffused into the mixed solution.

In another preferred example, in the step (III), the closed system is subjected to an overall heating treatment to heat the organic solvent in the open vessel II

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

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

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

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

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

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

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

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

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

FIG. 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 distribution of the particle size of CD-MOF II obtained by the solvent evaporation method in example 2.

FIG. 9 is an optical micrograph of CD-MOF II obtained by the solvothermal method in example 4.

FIG. 10 is an optical micrograph of CD-MOF II obtained by the solvothermal method in example 5.

FIG. 11 is an optical micrograph of CD-MOF II obtained by the solvothermal method in example 6.

FIG. 12 is an optical micrograph of CD-MOF II obtained by the solvothermal method in example 7.

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

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

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

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

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

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

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

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

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

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

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

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

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

FIG. 26 is an optical micrograph of CD-MOF II obtained by ultrasonication in example 11.

FIG. 27 is a scanning electron micrograph of CD-MOF II obtained by the ultrasonication in example 11.

FIG. 28 is a scanning electron micrograph of a CD-MOF Nano obtained by the ultrasonication in example 12.

FIG. 29 is an X-ray powder diffraction pattern of CD-MOF II obtained by the ultrasonication in example 11.

FIG. 30 is an X-ray powder diffraction pattern of CD-MOF Nano obtained by the ultrasonication in example 12.

FIG. 31 is an infrared spectrum of IBU on CD-MOF II in example 2 and CD-MOF II in example 13.

FIG. 32 is an infrared spectrum of IBU on CD-MOF Nano in example 3 and CD-MOF Nano in example 14.

FIG. 33 is a graph of the infrared spectra of CD-MOF II in example 2 and LPZ on CD-MOF II in example 15.

FIG. 34 is an infrared spectrum of LPZ on CD-MOF Nano no in example 3 and CD-MOF Nano no in example 16.

FIG. 35 is a graph showing the release profile of IBU from CD-MOF Nano in PBS7.4 in example 14.

FIG. 36 is a graph showing the release profile in PBS7.4 of LPZ-loaded microspheres from CD-MOF Nano in example 16.

Detailed Description

The present inventors have extensively and intensively studied and, for the first time, unexpectedly found a method for rapidly synthesizing a cyclodextrin-based metal-organic framework material using solvothermal volatilization/solvothermal/microwave/ultrasonic-assisted methods. Specifically, the method comprises the following steps: preparing aqueous solution of metal salt and cyclodextrin, and pre-adding a part of organic solvent in the aqueous solution; the reactants are quickly reacted by a solvothermal volatilization/solvothermal/microwave/ultrasonic method; after reacting for a certain time, taking the supernatant and adding a size regulator to obtain the cyclodextrin-metal organic framework material. While the conventional method requires several days to complete the reaction, the method of the present invention requires several minutes to several hours to complete. The method is rapid, simple, convenient and safe, has high yield, uses cheap and easily-obtained raw materials and solvents, is beneficial to industrial production, and the obtained CD-MOFs have wide application prospects in the fields of catalysis, adsorption, construction of drug carriers, nano devices and the like.

Cyclodextrin-metal organic framework material

As used herein, the terms "cyclodextrin-based metal-organic framework material", "cyclodextrin-metal-organic framework compound" are used interchangeably and utilize the ability of cyclodextrin to form a new crystal in an organic coordination with first and second main group metal ions in aqueous solution, such a crystal being porous, having a large surface area, and storing a gas. The green and porous material can adsorb some medicine with unstable structure, and its huge cavity can protect medicine, so that it can be used for commercial development, in particular, the cyclodextrin-metal organic skeleton is edible derivative, and is suitable for human being. The cyclodextrin is taken as an organic ligand, and the metal ion is taken as an inorganic metal center, so that a novel cyclodextrin-metal organic framework which has higher safety and is used for medicine, namely CD-MOFs, can be formed.

As used herein, the term "CD-MOF I" refers to first stage CD-MOF crystals, meaning that γ -CD is mixed with KOH and the resulting crystals are precipitated directly by evaporation from methanol vapor over time; the first stage CD-MOF crystals produced by the process of the invention are about 40 to 500 μm in size.

As used herein, the term "CD-MOF II" refers to second stage CD-MOF crystals, meaning that γ -CD is mixed with KOH, evaporated by methanol vapor, and when no or only a small amount of first stage crystals are produced, the supernatant is removed, size-adjusting agent is added, and then the resulting crystals are re-precipitated; the second stage CD-MOF crystals produced by the process of the invention are about 1-10 μm in size.

As used herein, the term "CD-MOF Nano" refers to Nano-sized CD-MOF crystals, meaning that γ -CD is mixed with KOH, evaporated by methanol vapor, and when no or only a small amount of first stage crystals are produced, the supernatant is taken out, a large amount of methanol is added according to the volume of the supernatant, a size-adjusting agent is added, and then the resulting crystals are separated out; the size of the CD-MOF Nano prepared by the method is about 200-500 nm.

Metal organic framework material

Cyclodextrin

Cyclodextrin is a generic name for a series of cyclic oligosaccharides produced from amylose by the action of glucosyltransferase, and generally contains 6 to 12D-glucopyranose units. Among them, the more studied and of great practical significance are molecules containing 6, 7, 8 glucose units, called α, β -and γ -cyclodextrins, respectively. Cyclodextrins are ideal host molecules found to date to resemble enzymes and have the properties of an enzyme model in their own right.

Pre-adding organic solvent

In the method, a certain amount of organic solvent is added in advance in a reaction system before the reaction, so that the obtained CD-MOFs crystals can be separated out more quickly, meanwhile, the excessive organic solvent cannot be added, otherwise, the dissolved cyclodextrin is easy to be directly separated out, and finally, the obtained CD-MOFs are doped with a part of cyclodextrin.

Pretreatment of

In the method of the present invention, for the purpose of achieving a rapid reaction, a mixed solution containing a metal salt and cyclodextrin, which is pre-added with an organic solvent, is subjected to a pretreatment including a solvothermal treatment, a microwave treatment, and/or an ultrasonic treatment.

The solvothermal method is the optimization of the hydrothermal method, microwave treatment can enable substance molecules to generate high-frequency vibration, so that heat is generated, the temperature is quickly raised, substance transfer is enhanced, reaction activation energy is reduced, the reaction between potassium hydroxide and gamma-cyclodextrin is promoted, heating is uniform, heat conduction time is shortened, and the defect of nonuniform heating in the traditional method is avoided. The ultrasonic treatment is mainly to utilize ultrasonic cavitation to enable the reaction solution to generate a series of actions such as expansion, compression, collapse and the like, and the generated chemical effect and mechanical effect can improve the reaction condition and accelerate the reaction speed. The generation and the closing of the microwave and the ultrasonic energy are instantaneous, have no thermal inertia, are safe and reliable, and are convenient for automatic control.

Particularly preferred pretreatment methods are microwave/ultrasonic methods which can effectively utilize the molecular resonance generated by the absorption of microwaves or ultrasonic waves by the material to be treated to realize rapid and uniform temperature rise, and simultaneously ultrasonic cavitation, impact and microjet effects greatly accelerate the mass transfer effect, so that the potassium hydroxide can be promoted to react with the gamma-cyclodextrin by cooperating with the size regulator even at a lower temperature.

Preparation method

The invention also provides a method for preparing the cyclodextrin-based metal-organic framework material.

Typically, the method of the invention comprises the steps of: mixing a metal salt solution and a cyclodextrin aqueous solution in an open container, pre-adding a part of organic solvent in the mixed solution, placing the open container in a closed system filled with the organic solvent, diffusing the vapor-state organic solvent into the open container by an organic solvent evaporation method at a certain temperature, reacting for a certain time, absorbing a large amount of organic solvent by the mixed solution system, taking out a supernatant, and adding a size regulator to obtain the cyclodextrin-based metal-organic framework material; or mixing a metal salt solution and a cyclodextrin aqueous solution, adding a part of organic solvent in advance, placing the mixture in a closed container, heating a reaction medium by using solvothermal/microwave/ultrasonic waves to enable reactants to react quickly, taking out supernatant after reacting for a certain time, and adding a size regulator to obtain the cyclodextrin-based metal organic framework material.

In another preferred embodiment, the pre-solvent is added in the beginning of pre-addition and size adjustment. When the initial stage is preset, the volume of the organic solvent is preset to be 0.001-5 times of the mixed solution of the metal salt and the cyclodextrin. Preferably 0.6 times. The size is adjusted by adding organic solvent in an amount of 0.001-5 times of the volume of the obtained supernatant. Preferably 1 fold.

A preferred method for preparing a cyclodextrin-metal organic based framework comprises the following steps: mixing a metal salt solution and a cyclodextrin aqueous solution, then adding a part of organic solvent in advance, reacting for a certain time at a certain temperature (higher than room temperature) by a solvent vapor diffusion method, and then adding a size regulator to obtain the cyclodextrin-based metal-organic framework material; or mixing a metal salt solution with a cyclodextrin aqueous solution, pre-adding a part of organic solvent, vibrating a reaction medium by using solvothermal/microwave/ultrasonic wave to enable reactants to react quickly, and adding a size regulator after reacting for a certain time to obtain the cyclodextrin-based metal-organic framework material.

Wherein the cyclodextrin comprises alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl-beta-cyclodextrin, methyl-beta-cyclodextrin and carboxymethyl-beta-cyclodextrin, preferably gamma-cyclodextrin.

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

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

The metal salt comprises Li⁺、K⁺、Rb⁺、Cs⁺、Na⁺、Mg²⁺、Cd²⁺、Sn²⁺、Ag⁺、Yb⁺、Ba²⁺、Sr²⁺、Ca²⁺、Pb²⁺、La³⁺Preferably K⁺。

The pre-solvent is added in the initial pre-adding stage and the size adjusting stage. When the initial stage is preset, the volume of the organic solvent is preset to be 0.001-5 times of the mixed solution of the metal salt and the cyclodextrin. Preferably 0.6 times. The size is adjusted by adding organic solvent in an amount of 0.001-5 times of the volume of the obtained supernatant. Preferably 1 fold.

The methods include methods for rapidly preparing first and second stage cyclodextrin-metal organic frameworks. The first stage is mainly a process of directly separating out cyclodextrin-metal salt solution by evaporating cyclodextrin metal-organic frameworks through organic solvent steam by a solvent thermal volatilization method. In the second stage, four methods of solvothermal volatilization, solvothermal, microwave and ultrasonic wave assistance are available, namely a process of taking supernatant after reaction of the reaction solution for a period of time, adding a size regulator into the supernatant, and then separating out the cyclodextrin-metal organic framework. The second stage can be subdivided into micron-level/nanometer-level cyclodextrin-metal organic frameworks, wherein the micron-level cyclodextrin-metal organic frameworks are a process of firstly preparing metal salt and cyclodextrin aqueous solution, pre-adding a part of organic solvent, taking supernatant liquid and adding a size regulator through a solvothermal volatilization/solvothermal/microwave/ultrasonic method, and then separating out the cyclodextrin-metal organic frameworks; the nanometer level cyclodextrin-metal organic skeleton is prepared through compounding metal salt and cyclodextrin aqua, adding partial organic solvent, treating with solvothermal volatilization, solvothermal treatment, microwave treatment and ultrasonic treatment, taking supernatant, adding partial organic solvent, adding size regulator and final separating out cyclodextrin-metal organic skeleton. In addition, the method also comprises the steps of centrifuging the reaction solution after the reaction is finished, collecting and washing the precipitate and drying in vacuum.

The size regulator comprises one or more of polyethylene glycol (

PEG

200, 400, 600, 800, 1000, 1500, 2000, 4000, 6000, 8000, 10000, 20000), polyvidone (PVP K12, K15, K17, K25, K30, K60, K90, K120), polysorbate (

Tween

20, 40, 60, 80, 85), sorbitan monolaurate (

span

20, 40, 60, 80), polyoxyethylene lauryl ether, emulsifier OP (polyoxyethylene nonyl phenol condensate), lactofen A (polyoxyethylene fatty alcohol ether), pluronic (polyoxyethylene polypropylene glycol condensate), sodium dodecyl sulfate, sodium dodecyl benzene sulfonate, Cetyl Trimethyl Ammonium Bromide (CTAB), dodecyl dimethyl benzyl ammonium bromide (benzalkonium bromide) and derivatives thereof, and a combination of the size regulators. Preferably, the pharmaceutical adjuvant PEG2000, 4000, 6000, 8000, 10000, 20000, specifically PEG 20000.

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

The second-stage cyclodextrin-metal organic framework comprises that PEG20000 is directly added into the obtained supernatant without adding organic solvent, or 0.05-10ml of organic solvent/5 ml of supernatant is added, and then PEG20000 is added. The added amount of PEG20000 comprises 1-16mg PEG 20000/ml supernatant, preferably 8mg PEG 20000/ml supernatant.

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

The solvent thermal volatilization method has the temperature of room temperature-100 ℃ and the reaction time of 4-24h, preferably 50 ℃ and 6 h.

The solvent thermal method comprises the steps of reacting at room temperature to 100 ℃ for 1min to 24h, preferably at 50 ℃ for 20 min.

The microwave radiation frequency is 916-.

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

Compared with the prior art, the method has the main advantages that:

1. the reaction is rapid and simple, the time is saved, a plurality of complicated procedures are saved, and the reaction time is reduced from 2 to 7 days to minutes to hours.

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

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

4. The obtained CD-MOFs comprise first-stage CD-MOF (CD-MOF I) and second-stage CD-MOF, wherein the second-stage CD-MOF is divided into micron-scale and nanometer-scale CD-MOF (CD-MOF I) with the size of 1-20 μm, the second-stage nanometer-scale CD-MOF (CD-MOF Nano) with the size of 100-1000nm, the yield of the first stage in the literature is lower than 70%, and the yield of the second stage is lower. The yield of the method can reach 70-90%.

5. The cyclodextrin-based metal organic framework material prepared by the method has regular size and high yield. The medicinal auxiliary materials are used for regulating the size of the crystal, the safety is high, the crystal can be used for medicine, if the size regulator is not added, almost no crystal or a small amount of crystal can be obtained, the shape and the size are irregular, and the size is generally dozens of micrometers.

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

7. The invention can effectively control the size of the CD-MOFs. The size control of CD-MOFs is beneficial to the application of metal organic framework compounds in the aspects of catalysis, adsorption, drug carriers and the like and the preparation of some nanometer devices such as gas sensors, thin film separation devices, capillary chromatographic columns, dry powder inhalation and the like. The method has important significance and wide application prospect in the aspects of expanding the application of metal organic framework compounds and researching the MOFs forming mechanism, particularly in the research fields of drug carriers and the like.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

Example 1

Preparation of first-stage CD-MOF crystals by solvothermal volatilization method

163.0mg of γ -CD and 56.0mg of KOH mixture (molar ratio of γ -CD to KOH: 0.125) were dissolved in 5mL of water, sonicated for 10 minutes to allow sufficient dissolution, and filtered through a 0.45 μm filter. Then 0.5mL of methanol is added into the mixed solution of the gamma-CD and the KOH in advance, and the methanol is heated in a closed container at the temperature of 50 ℃ (the whole closed container is heated), so that the methanol steam is evaporated into the mixed system of the gamma-CD and the KOH. And (3) generating a small amount of crystals after reacting for 6 hours, obtaining a large amount of colorless transparent crystals after reacting for 24 hours, discarding supernatant, centrifuging for 5min at 3000rpm, washing with ethanol (10mL multiplied by 3), and vacuum-drying the obtained crystals for 12 hours at 50 ℃ to obtain the first-stage CD-MOF crystals (CD-MOF I) which can be stored for a long time, wherein the size of the first-stage CD-MOF crystals is 40-500 mu m, and the yield is 76.3% as shown in figures 1 and 5.

Example 2

Method for preparing second-stage micron-sized CD-MOF crystals by solvothermal volatilization method

163.0mg of γ -CD and 56.0mg of KOH mixture (molar ratio of γ -CD to KOH: 0.125) were weighed out and dissolved in 5mL of water, sonicated for 10 minutes to dissolve it thoroughly, and filtered through a 0.45 μm filter. Then 0.5mL of methanol is added into the mixed solution of the gamma-CD and the KOH in advance, and the methanol is heated in a closed container at the temperature of 50 ℃ (the whole closed container is heated), so that the methanol steam is evaporated into the mixed system of the gamma-CD and the KOH. After 6 hours of reaction, taking out the supernatant, adding PEG20000 according to the proportion of 8mg/mL of the supernatant, standing for half an hour, centrifuging for 5min at 3000rpm, respectively washing with ethanol (10mL multiplied by 2) and dichloromethane (10mL multiplied by 2), and vacuum drying the obtained crystals for 12 hours at 50 ℃ to obtain second-stage micron-sized CD-MOF crystals (CD-MOF II) which can be stored for a long time and have the size of 1-10 mu m, such as figure 2, figure 3, figure 6 and figure 8, wherein the yield is 85.1%.

Example 3

Method for preparing second-stage nanoscale CD-MOF crystals by solvothermal volatilization method

163.0mg of γ -CD and 56.0mg of KOH mixture (molar ratio of γ -CD to KOH: 0.125) were dissolved in 5mL of water, sonicated for 10 minutes to allow sufficient dissolution, and filtered through a 0.45 μm filter. Then 0.5mL of methanol is added into the mixed solution of the gamma-CD and the KOH in advance, and the methanol is heated in a closed container at the temperature of 50 ℃ (the whole closed container is heated), so that the methanol steam is evaporated into the mixed system of the gamma-CD and the KOH. After 6 hours of reaction, taking out the supernatant, adding methanol with the same volume, adding PEG20000 according to the proportion of 8mg/mL of the supernatant, standing for half an hour, centrifuging at 3000rpm for 5min, respectively washing with ethanol (10mL multiplied by 2) and dichloromethane (10mL multiplied by 2), and vacuum drying the obtained crystal for 1 hour at 50 ℃ to obtain the second-stage nanoscale CD-MOF crystal (CD-MOF Nano) with the size of 200 plus 500nm, as shown in figures 4 and 7, the yield is 90.3%.

Example 4

Solvothermal method for preparing second-stage micron-sized CD-MOF crystals

And directly heating a mixed system of the gamma-cyclodextrin, KOH aqueous solution and a part of organic solvent by using a solvothermal mode. Weighing 163.0mg of gamma-CD and 56.0mg of KOH mixture (the molar ratio of the gamma-CD to the KOH is 0.125) to be dissolved in 5mL of water, adding 3mL of methanol into the mixed solution in advance, heating in a water bath at 50 ℃ for 20min, taking out the solution, adding 64mg of PEG20000, standing for half an hour, centrifuging at 3000rpm for 5min, washing with ethanol (10mL multiplied by 2) and dichloromethane (10mL multiplied by 2) respectively, and drying the obtained crystals in vacuum at 50 ℃ for 12h to obtain second-stage micron-sized CD-MOF crystals (CD-MOF II) with the size of 1-10 mu m, as shown in the figure 9, the figure 13, the figure 15 and the figure 17, wherein the yield is 87.0%.

Example 5

Solvothermal method for preparing second-stage micron-sized CD-MOF crystals

And directly heating a mixed system of the gamma-cyclodextrin, KOH aqueous solution and a part of organic solvent by using a solvothermal mode. Weighing 163.0mg of gamma-CD and 56.0mg of KOH mixture (the molar ratio of the gamma-CD to the KOH is 0.125) to be dissolved in 5mL of water, adding 3mL of methanol into the mixed solution in advance, heating in a water bath at 50 ℃ for 20min, taking out the solution, adding 16mg of PEG20000, standing for half an hour, centrifuging at 3000rpm for 5min, washing with ethanol (10mL multiplied by 2) and dichloromethane (10mL multiplied by 2) respectively, and drying the obtained crystals in vacuum at 50 ℃ for 12h to obtain second-stage micron-sized CD-MOF crystals (CD-MOF II) with the size of 1-10 mu m, as shown in the graph 10 and the graph 18, wherein the yield is 58.3%.

Example 6

Solvothermal method for preparing second-stage micron-sized CD-MOF crystals

And directly heating a mixed system of the gamma-cyclodextrin, KOH aqueous solution and a part of organic solvent by using a solvothermal mode. Weighing 163.0mg of gamma-CD and 56.0mg of KOH mixture (the molar ratio of the gamma-CD to the KOH is 0.125), dissolving in 5mL of water, adding 3mL of methanol into the mixed solution, heating in a water bath at 50 ℃ for 20min, taking out the solution, adding 64mg of PEG2000, standing for half an hour, centrifuging at 3000rpm for 5min, washing with ethanol (10mL multiplied by 2) and dichloromethane (10mL multiplied by 2), respectively, and drying the obtained crystals in vacuum at 50 ℃ for 12h to obtain second-stage micron-sized CD-MOF crystals (CD-MOF II) with the size of 1-10 mu m, as shown in FIGS. 11 and 19, and the yield is 83.0%.

Example 7

Solvothermal method for preparing second-stage micron-sized CD-MOF crystals

And directly heating a mixed system of the gamma-cyclodextrin, KOH aqueous solution and a part of organic solvent by using a solvothermal mode. Weighing 163.0mg of gamma-CD and 56.0mg of KOH mixture (the molar ratio of the gamma-CD to the KOH is 0.125), dissolving in 5mL of water, adding 3mL of methanol into the mixed solution, heating in a water bath at 50 ℃ for 20min, taking out the solution, adding 64mg of PEG10000, standing for half an hour, centrifuging at 3000rpm for 5min, washing with ethanol (10mL multiplied by 2) and dichloromethane (10mL multiplied by 2), respectively, and drying the obtained crystals in vacuum at 50 ℃ for 12h to obtain second-stage micron-sized CD-MOF crystals (CD-MOF II) with the size of 1-10 mu m, as shown in figures 12 and 20, the yield is 87.4%.

Example 8

Solvothermal method for preparing second-stage nanoscale CD-MOF crystals

And directly heating a mixed system of the gamma-cyclodextrin, KOH aqueous solution and a part of organic solvent by using a solvothermal mode. 163.0mg of gamma-CD and 56.0mg of KOH mixture (the molar ratio of gamma-CD to KOH is 0.125) are weighed and dissolved in 5mL of water, 3mL of methanol is added into the mixed solution in advance, after the mixture is heated in a water bath at 50 ℃ for 20min, the solution is taken out, methanol with the same volume is added, 64mg of PEG20000 is added, after the mixture is kept still for half an hour, the mixture is centrifuged at 3000rpm for 5min, the mixture is respectively washed by ethanol (10mL multiplied by 2) and dichloromethane (10mL multiplied by 2), and the obtained crystals are dried in vacuum at 50 ℃ for 12h to obtain second-stage nano-scale CD-MOF crystals (CD-MOano), the size of which is 200 and 500nm, as shown in figures 14 and 16, the yield is 90.

Example 9

Microwave method for preparing second-stage micron-sized CD-MOF crystals

And (3) microwave heating is carried out on the mixed system of the gamma-cyclodextrin, KOH aqueous solution and a part of organic solvent by using a microwave mode. Weighing 163.0mg of gamma-CD and 56.0mg of KOH mixture (the molar ratio of the gamma-CD to the KOH is 0.125), dissolving in 5mL of water, adding 3mL of methanol into the mixed solution, setting the power of a microwave reactor at 2450MHz to 25W, setting the temperature to 50 ℃, reacting for 20min, taking out the solution, adding 64mg of PEG20000, standing for half an hour, centrifuging at 3000rpm for 5min, washing with ethanol (10mL multiplied by 2) and dichloromethane (10mL multiplied by 2), respectively, and vacuum-drying the obtained crystals at 50 ℃ for 12h to obtain second-stage micron-sized CD-MOF crystals (CD-MOF II) with the size of 1-10 mu m, as shown in figure 21, figure 22 and figure 24, wherein the yield is 82.2%.

Example 10

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

And (3) microwave heating is carried out on the mixed system of the gamma-cyclodextrin, KOH aqueous solution and a part of organic solvent by using a microwave mode. 163.0mg of gamma-CD and 56.0mg of KOH mixture (the molar ratio of gamma-CD to KOH is 0.125) are weighed and dissolved in 5mL of water, 3mL of methanol is added into the mixed solution in advance, a microwave reactor with 2450MHz is used, the power is set to 25W, the temperature is set to 50 ℃, after 20min of reaction, the solution is taken out, methanol with the same volume is added, 64mg of PEG20000 is added, after standing for half an hour, the solution is centrifuged at 3000rpm for 5min, the solution is respectively washed by ethanol (10mL multiplied by 2) and dichloromethane (10mL multiplied by 2), and the obtained crystals are dried in vacuum at 50 ℃ for 12h to obtain second-stage nanoscale CD-MOF crystals (CD-MOF Nano), the size of which is 200-500nm, as shown in figures 23 and 25, the yield of 90.1%.

Example 11

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

And (3) ultrasonically heating a mixed system of the gamma-cyclodextrin, KOH aqueous solution and a part of organic solvent by using an ultrasonic mode. Weighing 163.0mg of gamma-CD and 56.0mg of KOH mixture (the molar ratio of the gamma-CD to the KOH is 0.125), dissolving in 5mL of water, adding 3mL of methanol into the mixed solution in advance, using a 40KHz ultrasonic reactor with the power set at 40W and the temperature of 50 ℃, taking out supernatant after 20min of reaction, adding 64mg of PEG20000, standing for half an hour, centrifuging for 5min at 3000rpm, washing with ethanol (10mL multiplied by 2) and dichloromethane (10mL multiplied by 2), respectively, and drying the obtained crystals in vacuum at 50 ℃ for 12h to obtain second-stage micron-sized CD-MOF crystals (CD-MOF II) with the size of 1-10 mu m, as shown in figures 26, 27 and 29, and the yield is 79.7%.

Example 12

Rapid synthesis of nano-scale CD-MOF crystal by ultrasonic method

And (3) ultrasonically heating a mixed system of the gamma-cyclodextrin, KOH aqueous solution and a part of organic solvent by using an ultrasonic mode. 163.0mg of gamma-CD and 56.0mg of KOH mixture (the molar ratio of gamma-CD to KOH is 0.125) are weighed and dissolved in 5mL of water, 3mL of methanol is added into the mixed solution in advance, a 40KHz ultrasonic reactor is used, the power is set to 40W, the temperature is 50 ℃, the supernatant is taken out after 20min of reaction, 8mL of methanol is added, 64mg of PEG20000 is added, after the mixture is kept stand for half an hour, the mixture is centrifuged at 3000rpm for 5min, ethanol (10mL multiplied by 2) and dichloromethane (10mL multiplied by 2) are respectively used for washing, and the obtained crystals are dried in vacuum at 50 ℃ for 12h to obtain second-stage nanoscale CD-MOF crystals (CD-MOF Nano), wherein the size is 200 and 500nm, and the yield is 85.2% as shown in FIGS. 28 and 30.

Example 13

Second-stage preparation of micron-sized CD-MOF crystal-loaded Ibuprofen (IBU)

100.0mg of the dried powder of CD-MOF II prepared in example 2 was weighed and added to 2.5mL of IBU ethanol solution (40 mg. mL)^-1) In the preparation method, incubation is carried out for 4d in a shaker at 37 ℃ and 150rpm, centrifugation is carried out for 5min at 3000rpm, the crystals are washed by ethanol (3mL × 3), vacuum drying is carried out on the obtained crystals at 35 ℃ for 12h, and the drug loading rate can reach 12.0% (w/w), as shown in an infrared spectrogram of IBU loaded on CD-MOF II.

Example 14

Second-stage preparation of nanoscale CD-MOF crystal-loaded Ibuprofen (IBU) and microspheres thereof

100.0mg of the dried powder of CD-MOF Nano prepared in example 3 was weighed and added to 2.5mL of IBU ethanol solution (40 mg. mL)^-1) In the preparation method, incubation is carried out for 4d in a shaker at 37 ℃ and 150rpm, centrifugation is carried out for 5min at 3000rpm, ethanol (3mL × 3) is used for washing, the obtained crystals are dried for 12h in vacuum at 35 ℃, and the drug loading rate can reach 13.0% (w/w).

Weighing 50mg of drug-loaded CD-MOF Nano, uniformly dispersing in 3mL of acetone solution, adding 450mg of Uygiz RS100, performing ultrasonic treatment for 10min to dissolve the drug-loaded CD-MOF Nano, adding 120mg of aluminum stearate, and performing ultrasonic treatment for 5min to uniformly disperse the drug-loaded CD-MOF Nano. Adding the dispersed phase containing aluminum stearate into liquid paraffin (ice-cooled to 10 ℃), magnetically stirring the suspension at 10 ℃ in an ice-water bath for 30S (500rpm), and dispersing by a dispersion machine (10000rpm, 5min) to obtain an S/O/O type emulsion. Placing the emulsion on a magnetic stirrer, slowly heating to 35 ℃ from 10 ℃ under the stirring condition of 500rpm, continuing stirring for 3h (500rpm, 35 ℃), and removing most of acetone. Transferring the liquid into a 50mL centrifuge tube, centrifuging (2000rpm, 5min), and discarding the liquid paraffin (upper layer); the lower solid was washed 2 times with 30mL n-hexane, centrifuged at 2000rpm for 5 min. After washing, the column was allowed to dry overnight in a fume hood, as shown in FIG. 32, which is an infrared spectrum of IBU loaded on CD-MOF Nano, and FIG. 35, which shows that the IBU loaded microspheres showed significant sustained release in PBS 7.4.

Example 15

Second stage preparation of micron-sized CD-MOF crystal-supported Lansoprazole (LPZ)

200.0mg of the dried powder of CD-MOF II prepared in example 2 was weighed and added to a 3.6mLLPZ ethanol solution (14 mg. mL)^-1) In the preparation method, the crystal is incubated for 4 days at 37 ℃ and 150rpm in a shaking table, centrifuged for 5min at 3000rpm, washed by ethanol (3mL × 3), and vacuum-dried for 12h at 35 ℃ to obtain the crystal with the drug loading rate of 9.4% (w/w), as shown in FIG. 33, which is an infrared spectrogram of LPZ loaded on CD-MOF II.

Example 16

Second-stage nanoscale CD-MOF crystal-supported Lansoprazole (LPZ) and preparation of microspheres thereof

200.0mg of the dried powder of CD-MOF Nano prepared in example 3 was weighed and added to 3.6mL of LPZ ethanol solution (14 mg. mL)^-1) In the preparation method, incubation is carried out for 4d in a shaker at 37 ℃ and 150rpm, centrifugation is carried out for 5min at 3000rpm, ethanol (3mL × 3) is used for washing, the obtained crystals are dried for 12h in vacuum at 35 ℃, and the drug loading rate can reach 1.6% (w/w).

Weighing 50mg of drug-loaded CD-MOF Nano, uniformly dispersing in 3mL of acetone solution, adding 450mg of Uygiz RS100, performing ultrasonic treatment for 10min to dissolve the drug-loaded CD-MOF Nano, adding 120mg of aluminum stearate, and performing ultrasonic treatment for 5min to uniformly disperse the drug-loaded CD-MOF Nano. Adding the dispersed phase containing aluminum stearate into liquid paraffin (ice-cooled to 10 ℃), magnetically stirring the suspension at 10 ℃ in an ice-water bath for 30S (500rpm), and dispersing by a dispersion machine (10000rpm, 5min) to obtain an S/O/O type emulsion. Placing the emulsion on a magnetic stirrer, slowly heating to 35 ℃ from 10 ℃ under the stirring condition of 500rpm, continuing stirring for 3h (500rpm, 35 ℃), and removing most of acetone. Transferring the liquid into a 50mL centrifuge tube, centrifuging (2000rpm, 5min), and discarding the liquid paraffin (upper layer); the lower solid was washed 2 times with 30mL n-hexane, centrifuged at 2000rpm for 5 min. After washing was complete, the hood was dried overnight. For example, FIG. 34 is an infrared spectrum of LPZ-loaded CD-MOF Nano, while FIG. 36 shows that LPZ-loaded microspheres have significant sustained release effect in PBS 7.4.

Example 17

By repeating examples 4, 9 and 11, it is possible to obtain CD-MOFs crystals of the desired size, with the difference that the heating time is varied, as shown below:

as described in the above examples, the method of the present invention can be completed in a few minutes to a few hours, and has the advantages of rapidness, simplicity, safety, high yield, etc.

The dimensional and yield data for the portions of the product produced in the above examples are summarized in the table below.

Adding size regulator according to the supernatant ratio of 8mg/mL

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

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

wherein the volume ratio of the first organic solvent to the first mixed solution is (0.01-5) to 1;

(5) separating a part or all of the solution from the first mixture to obtain a third mixed solution; adding a second organic solvent and/or a size regulator into the third mixed solution to separate out the cyclodextrin-metal organic framework material; and

2. The method of claim 1, wherein the total time T of steps (3) and (5) is from 1 minute to 12 hours.

3. The method of claim 1, wherein in step (2), the volume ratio of the first organic solvent to the first mixed solution is (0.1-2): 1.

4. The method according to claim 1, wherein in step (2), the volume ratio of the first organic solvent to the first mixed solution is (0.5-1): 1.

5. The method of claim 1, wherein the size-modifying agent is selected from the group consisting of: polyethylene glycol, povidone, polysorbate, sorbitan monolaurate, polyoxyethylene lauryl ether, an emulsifier OP, lactolin A, pluronic, sodium lauryl sulfate, sodium dodecylbenzenesulfonate, dodecyldimethylbenzyl ammonium bromide, or a combination thereof.

6. The method of claim 1, wherein the size-modifying agent comprises PEG2000, PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, or a combination thereof.

7. The method of claim 1, wherein the temperature of the pretreatment is from 25 ℃ to 100 ℃.

8. The method of claim 1, wherein the temperature of the pretreatment is 30-80 ℃.

9. The method of claim 1, wherein the time for the pre-treatment is 10min to 24 h.

10. The method of claim 1, wherein the time for the pre-treatment is 15min to 1 h.

11. The method of claim 1, wherein the first organic solvent and the second organic solvent are each independently selected from the group consisting of: methanol, ethanol, isopropanol, acetone, acetonitrile, or combinations thereof.

12. The method of claim 1, wherein the cyclodextrin-metal organic framework material produced by the method has one or more characteristics selected from the group consisting of:

(i) average particle size: 50nm-50 microns;

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

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

13. The method according to claim 1, wherein in step (5), the volume ratio of the second organic solvent to the third mixed solution is (0.01-5): 1.

14. The method according to claim 1, wherein in step (5), the volume ratio of the second organic solvent to the third mixed solution is (0.5-2): 1.

15. The method of claim 1, wherein in step (5), the size-adjusting agent is added in an amount of 1-20 mg/mL.

16. The method as claimed in claim 1, wherein in step (6), the method comprises the steps of:

and (5) after the reaction in the step (5) is finished, centrifuging the reaction solution, collecting and washing the precipitate, and drying in vacuum.

17. The method according to claim 1, wherein the concentration of the metal ions in the first mixed solution is 0.05 to 0.4M; and is

The molar ratio of cyclodextrin to metal ions in the first mixed solution is 1: (6-10).

18. The method of claim 17, wherein the concentration of metal ions in the first mixed solution is between 0.1M and 0.3M.

19. The method of claim 1, wherein the concentration of cyclodextrin in the first mixed solution is 0.013 to 0.05M.

20. The method of claim 1, wherein the concentration of cyclodextrin in the first mixed solution is 0.02 to 0.03M.

21. The method of claim 1, wherein the metal ion is selected from the group consisting of: li⁺、K⁺、Rb⁺、Cs⁺、Na⁺、Mg²⁺、Cd²⁺、Sn²⁺、Ag⁺、Yb⁺、Ba²⁺、Sr²⁺、Ca²⁺、Pb²⁺、La³⁺Or a combination thereof.

22. The method of claim 1, wherein the cyclodextrin is selected from the group consisting of: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl-beta-cyclodextrin, methyl-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, or a combination thereof.

23. The method of claim 1, wherein the cyclodextrin-metal organic framework material prepared by the method has an average size of 100 nm or 1-10 μm.

24. The method of claim 1, wherein the total time T of steps (3) and (5) is from 1 minute to 3 hours.

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

wherein the volume ratio of the first organic solvent to the first mixed solution is (0.01-0.5) to 1;

(a) carrying out solvent thermal volatilization treatment;

(b) a combination of solvothermal volatilization treatment with any one of the treatments selected from group a, wherein group a comprises microwave treatment, sonication, or a combination thereof;

26. The method of claim 25, wherein in step (2), the volume ratio of the first organic solvent to the first mixed solution is (0.03-0.3): 1.

27. The method of claim 25, wherein in step (3), said solvothermal volatilization process comprises the steps of:

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

28. The method of claim 27, wherein in step (III), the closed system of step (II) is subjected to an overall heating process to heat the organic solvent in the open container II.

29. The method of claim 27, wherein in step (III), the heating treatment comprises water bath heating or oil bath heating.

30. The method of claim 27, wherein in step (III), the temperature of the heat treatment is 25-100 ℃.

31. The method of claim 27, wherein in step (III), the temperature of the heat treatment is 30-80 ℃.

32. The method of claim 27, wherein in step (III), the heat treatment is performed for a time period of 4 to 48 hours.

33. The method of claim 27, wherein in step (III), the heat treatment is performed for a period of 6 to 24 hours.