CN111961214B - Preparation method of cyclodextrin-metal organic framework crystal material - Google Patents
Preparation method of cyclodextrin-metal organic framework crystal material Download PDFInfo
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- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
Abstract
The invention relates to a preparation method of a cyclodextrin-metal organic framework crystal material. Specifically, the method can obviously reduce the dosage of the organic solvent, and has the advantages of simplicity, rapidness, greenness and safety.
Description
Technical Field
The invention relates to the field of material chemistry and biomedicine, in particular to a preparation method of a cyclodextrin-metal organic framework crystal material.
Background
Metal-Organic Frameworks (MOFs), also known as porous coordination polymers, are formed by coordinatively linking Organic ligands to inorganic centers (Metal ions or ion clusters) to form infinitely extended crystals with a three-dimensional network structure, and have ultrahigh porosity and ultrahigh loading capacity for target molecules, and have received attention from many scientists in various fields worldwide since the end of the 20 th century. MOFs have become a new class of porous materials, and are used in many areas such as molecular recognition, gas storage, separation, catalysis, and drug delivery. In general, they are highly tunable hybrid materials made of metal junctions and organic bridging ligands with predictable extended structures. Since biocompatibility of materials is essential for most biological applications, the MOFs as a carrier for drug delivery require that metal ions and organic ligands have biocompatibility at the same time. Stoddart et al (Angew. chem. int. Ed.2010,49,8630-8634), the university of northwest, USA, for the first time, proposed that gamma-Cyclodextrin (gamma-CD) is used as an organic linker and potassium ions are used as an inorganic metal center to synthesize a Cyclodextrin metal-organic framework (CD-MOF). The potassium ion is the element with the highest content in the necessary metal elements of the life body, the intake safety range is wide, 8 glucose residues in the gamma-CD are arranged into a symmetrical annular structure, the safety is high, the biocompatibility of the CD-MOF taking the potassium ion as a metal center and the gamma-CD as a ligand is good, and the excellent selection is provided for MOFs as a drug delivery carrier.
The synthesis method of CD-MOF proposed by Stoddart et al is to take gamma-CD and potassium metal salt as raw materials, and prepare the compound by methanol vapor evaporation at normal temperature for 2-7 days. The applicant of the invention also develops a rapid synthesis method of CD-MOF (CN 107151329A; WO2017148439A1) by utilizing solvothermal volatilization, solvothermal, microwave and ultrasonic wave assisted methods in earlier stage, shortens the reaction which can be completed by the traditional method in a plurality of days to the reaction which can be completed by a plurality of minutes to a plurality of hours, and improves the yield to a certain extent. However, CD-MOF still has a problem of low production efficiency in the process of requiring large amount of use, and the use of large amount of organic solvent such as methanol limits the environment required for its synthesis.
Disclosure of Invention
The invention aims to provide a method for preparing a cyclodextrin-metal organic framework crystal material, which has high preparation efficiency, low organic solvent dosage proportion, simplicity, rapidness, greenness and safety.
In a first aspect of the present invention, a method for preparing a cyclodextrin-metal organic framework crystal material is provided, which comprises the steps of:
a-1) providing cyclodextrin, metal salt and water, and mixing to obtain a first mixture;
a-2) treating the first mixture by adopting a first treatment mode to obtain a second mixture containing transition state crystals;
a-3) carrying out step a-3-1) or step a-3-2), wherein,
step a-3-1): separating the transition state crystal, adding a crystal transfer solvent into the separated transition state crystal to obtain a third mixture containing the cyclodextrin-metal organic framework crystal material, and further separating to obtain the cyclodextrin-metal organic framework crystal material;
step a-3-2): directly adding a crystal transfer solvent into the second mixture without separating the transition state crystal to obtain a fourth mixture containing the cyclodextrin-metal organic framework crystal material, and further separating to obtain the cyclodextrin-metal organic framework crystal material.
In another preferred example, the method further comprises, after step a-3), the steps of:
a-4) carrying out centrifugal washing and purification by using a first solvent, and drying the obtained product to obtain the cyclodextrin-metal organic framework crystal material.
In another preferred embodiment, the cyclodextrin is selected from the group consisting of: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin; and/or
The metal salt is selected from the group consisting of: potassium salt, sodium salt, magnesium salt, calcium salt and zinc salt.
In another preferred embodiment, the potassium salt is selected from the group consisting of: potassium acetate, potassium hydroxide, potassium carbonate, potassium chloride, potassium dihydrogen phosphate.
In another preferred embodiment, the sodium salt is selected from the group consisting of: sodium hydroxide, sodium acetate, sodium chloride and sodium carbonate.
In another preferred embodiment, the magnesium salt is selected from the group consisting of: magnesium sulfate, magnesium acetate, magnesium chloride.
In another preferred embodiment, the calcium salt is selected from the group consisting of: calcium chloride, calcium acetate, calcium iodide, calcium bromide.
In another preferred embodiment, the zinc salt is selected from the group consisting of: zinc sulfate, zinc acetate, and zinc bromide.
In another preferred embodiment, when step a-3) is carried out as step a-3-1), in the first mixture,
the molar ratio of the cyclodextrin to the metal salt is 1: 0.5-20 (preferably 1: 0.8-18, more preferably 1: 1-16); and/or
The mass ratio of the cyclodextrin to the water is 1: 0.5-15 (preferably 1: 0.8-12, more preferably 1: 0.8-10).
In another preferred embodiment, when step a-3) is performed as step a-3-2), in the first mixture,
the molar ratio of the cyclodextrin to the metal salt is 1: 1.2-20 (preferably 1: 1.5-18, more preferably 1: 1.8-16); and/or
The mass ratio of the cyclodextrin to the water is 1: 0.5-15 (preferably 1: 0.8-12, more preferably 1: 0.8-10).
In another preferred embodiment, the first treatment mode is selected from the group consisting of: heating-cooling, sonication, vortexing, or a combination thereof.
In another preferred embodiment, when step a-3) is performed as step a-3-1), the heating-cooling means heating at 35 to 100 ℃ (preferably 40 to 95 ℃, more preferably 50 to 90 ℃) to completely dissolve the cyclodextrin and the metal salt in water, and cooling at 0 to 30 (or 5 to 25 ℃) to crystallize.
In another preferred example, when step a-3) is performed as step a-3-2), the heating-cooling means heating at 80 to 100 ℃ (preferably 85 to 95 ℃) to completely dissolve the cyclodextrin and the metal salt in water, and cooling at 60 to 75 (preferably 65 to 70 ℃).
In another preferred example, the cooling process is also simultaneously carried out with a magnetic stirring treatment.
In another preferred embodiment, the stirring speed of the magnetic stirring process is 250-600rpm, preferably 300-550 rpm.
In another preferred embodiment, the stirring time of the magnetic stirring treatment is 0.5 to 8 hours, preferably 0.8 to 7 hours.
In another preferred example, the ultrasonic treatment time is 1-60 min, preferably 1-10 min.
In another preferred example, the treatment time of the vortex is 1-60 min, preferably 1-10 min.
In another preferred embodiment, the crystallization solvent is selected from the group consisting of: ethanol, acetone, methanol, propanol, butanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, n-hexane.
In another preferred embodiment, the weight ratio of the cyclodextrin in step a-1) to the crystallization solvent in step a-3) is selected from the group consisting of: 1: 0.5-20, 1: 0.8-16, 1: 1-12, 1: 6-10.
In another preferred embodiment, when the metal salt is not a potassium salt, the crystallization solvent further comprises a replacement metal salt, and the replacement metal salt is a potassium salt.
In another preferred embodiment, the first solvent is ethanol; and/or
The drying treatment temperature is 50-80 ℃; and/or
The drying treatment time is 0.5-8 h.
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 a micrograph of dense-type crystals and porous-type crystals in example 1.
FIG. 2 is an X-ray diffraction chart of dense-type crystals and porous-type crystals in example 1.
FIG. 3 is a schematic diagram showing the structural transformation of the dense crystal and the porous crystal in example 1.
FIG. 4 shows the arrangement of cyclodextrin molecules in the dense and porous crystals of example 1.
FIG. 5 is a micrograph of crystalline material of cyclodextrin-metal organic framework of examples 17-20.
FIG. 6 is a comparison of the powder X-ray diffraction patterns of the cyclodextrin-metal-organic framework materials obtained in example 5 and example 17.
FIG. 7 is a micrograph of crystalline material of cyclodextrin-metal organic frameworks formed from different metal salts of examples 22, 26-28.
FIG. 8 is an X-ray diffraction pattern of crystal powders produced by the different transcrystallizing solvents of examples 29 to 30.
FIG. 9 is a powder X-ray diffraction pattern of the cyclodextrin-metal-organic framework materials of examples 46, 48-50.
Detailed Description
Through long-term and intensive research, the cyclodextrin-metal organic framework crystal material can be prepared by a simple, convenient, rapid, green and safe preparation process with higher efficiency and obviously reduced organic solvent dosage ratio through adjusting the preparation process. On this basis, the inventors have completed the present invention.
Preparation method
The invention aims to develop a CD-MOF synthesis method which avoids the use of a second organic solvent, is less in use and has rapid crystal growth. The CD-MOF can form a special compact CD-MOF transition state crystal in water, and can be induced to be transformed into the target porous CD-MOF through organic solvents such as ethanol and the like, thereby providing a synthesis method which is not only quick, but also high in efficiency and safety. The synthesis method of the invention is different from the traditional hydrothermal method in the synthesis of metal organic frameworks, and does not involve high pressure; compared with the growth speed of the synthesized crystal of the CD-MOF by an organic solvent diffusion method (Stoddart and the like), the method greatly reduces the usage amount of the organic solvent required by the same yield of the CD-MOF compared with the method (CN 107151329A; WO2017148439A1) of the inventor in the previous period. The commonly used second organic solvent methanol is developed into a usable third organic solvent ethanol, acetone and the like, so that the safety of the synthesis process is obviously improved.
The invention discloses a preparation method of a cyclodextrin-metal organic framework crystal material, which is characterized in that cyclodextrin and alkali metal salt are dissolved in a pure water environment in a heating-cooling or ultrasonic or vortex mode to generate a transition state crystal, and then the transition state crystal is induced by ethanol or other solvents to generate the cyclodextrin-metal organic framework crystal material. The preparation method provided by the invention is green and safe, high in efficiency, good in stability, suitable for large-scale production, and applicable to the fields of material chemistry, biomedicine and the like.
The transition crystal can realize the loading of the drug in the drug solution with the crystal transition solvent.
Compared with the prior art, the invention has the following main advantages:
(1) the preparation method has the advantages of few steps, short time consumption and easy control and realization of preparation conditions.
(2) The preparation method provided by the invention is completed in water in the first step, does not involve the use of an organic solvent, and is green and safe. And in the second step, ethanol and the like with higher safety in the organic solvent are used for realizing the conversion of the target crystal, the stability of the preparation process is good, and the large-scale industrial production is easy to realize.
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 according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
Examples 1 to 8
As shown in the following table 1, according to the molar ratio of gamma-CD to potassium acetate of 1:8, gamma-CD and potassium acetate are weighed and placed in a beaker, pure water is added according to the weight ratio of gamma-CD to water of 1:3.9, the mixture is heated in a water bath to be completely dissolved into solution (mother solution), and then the solution is cooled to separate out crystals. And (3) centrifugally separating out precipitates, adding 40mL of ethanol (the weight ratio of gamma-CD to ethanol is 1:3.1) to convert the precipitated crystal forms, centrifugally washing and purifying by using ethanol (40mL multiplied by 2 times), and drying the obtained solid in a 60-DEG C forced air drying oven for 4 hours to obtain 6.6g of the cyclodextrin-metal organic framework material. The yield is 82.5g/L, and the calculation method comprises the following steps: 6.6g CD-MOF/(40mL water +40mL ethanol).
The lower the cooling temperature, the faster the crystal precipitation rate and the higher the yield, the crystals before ethanol crystal transformation were columnar crystals with a particle size of 10-300 μm and amorphous particles after drying, and the crystals obtained after ethanol crystal transformation were both cubic before and after drying with a particle size of 1-10 μm (fig. 1).
The X-ray diffraction results show (fig. 2), the crystals before and after the ethanol crystal transformation are two cyclodextrin-metal organic framework crystals with different structures, the cyclodextrin-metal organic framework crystal generated before the ethanol crystal transformation is a compact structure, and the cyclodextrin-metal organic framework crystal generated after the ethanol crystal transformation is a porous structure (fig. 3 and fig. 4). Compact crystals are simple orthorhombic structures, P2 12121(19)，
α ═ β ═ γ ═ 90 °; the porous ring crystal is of a body-centered cubic structure, I432(211),
α＝β＝γ＝90°。
explanation of crystal-to-molecule mechanism: the energy of the cyclodextrin unit structure on the dense crystal is-258 cal/mol, while the energy of the cyclodextrin unit structure on the porous crystal is lower and is-488 cal/mol. That is, crystals of a dense structure are easily converted into crystals of a porous structure having lower energy. C on sugar ring of gamma-CD2And C3The ESP (electrostatic potential) charge on the hydroxyl group is O: -0.48 (H: +0.34), and C6ESP charge of hydroxyl group at position is O: 0.57 (H: +0.41), ESP charge of hydroxyl group in ethanol is O: -0.59 (H: + 0.36). The formation of dense crystals relies mainly on the electrostatic force of the hydroxyl groups on gamma-CD, which is known from the crystal structure and mainly composed of C2Hydroxy and C in position3The hydroxyl groups at the sites interact with one another and the presence of ethanol occupies the electrostatic interaction sites, resulting in a transformation of the crystal structure.
It should be understood that the above mechanism explanation is only for illustrating the present invention, and does not set any limit to the contents of the present invention.
The characteristic peaks of the cyclodextrin-metal organic framework materials obtained in examples 1-8 are basically completely consistent with the characteristic peaks of the publicly reported cyclodextrin-metal organic framework material (CN201610125456.X), and are the same cyclodextrin-metal organic framework material.
γ -CD-MOF was prepared according to the solvothermal method of the published patent (CN201610125456.X) (example 4), disclosing a yield of 87%, the resulting product was calculated to be (163.0mg γ -CD +56.0mg KOH) × 87% ═ 190.53mg CD-MOF. Corresponding to the third mixture of example 1 of the present application, the yield of patent publication example 4 was only 24g/L, calculated as 190.53mg CD-MOF/(5mL water +3mL methanol), i.e., a large proportion of methanol was consumed.
The yield of the preparation of example 1 is increased by a factor of 3.4 compared to the solvothermal process, while the consumption of organic solvent is reduced in large proportion (solvothermal process consumes 15.8mL of methanol per 1g of target product prepared, and the method of the invention consumes only 6.0mL of ethanol per 1g of target product prepared).
TABLE 1 EXAMPLES 1-8
Examples 9 to 12
Weighing gamma-CD and potassium acetate according to a molar ratio of gamma-CD to potassium acetate of 1:8, placing the gamma-CD and the potassium acetate into a beaker, adding pure water according to a weight ratio of gamma-CD to water of 1:3.9, heating in a water bath at 75 ℃ to completely dissolve the gamma-CD and the potassium acetate into a solution, and performing magnetic stirring at 25 ℃ (see the following table 2). And (3) centrifugally separating out precipitates, converting the precipitated crystal forms by using 40mL of ethanol (the weight ratio of gamma-CD to ethanol is 1:3.1), centrifugally washing and purifying by using ethanol (40mL multiplied by 2 times), and drying the obtained solid in a 60-DEG C forced air drying oven for 4 hours to obtain the cyclodextrin-metal organic framework material.
Compared with the standing at 25 ℃ in examples 1-3 (complete precipitation within 1-6 h), the stirring in examples 9-12 accelerates the cooling speed, further accelerates the precipitation of crystals (complete precipitation within 1 h), and ensures that the crystals have a particle size of 1-10 μm and are cubic crystals, and PXRD results show that the crystals are not changed.
TABLE 2 examples 9 to 12
Examples 13 to 16
As shown in the following table 3, according to different molar ratios of gamma-CD to potassium acetate, weighing gamma-CD and potassium acetate, placing the gamma-CD and the potassium acetate into a beaker, adding pure water according to the weight ratio of gamma-CD to water of 1:3.9, heating in a water bath at 70 ℃ to completely dissolve the gamma-CD and the potassium acetate into a solution, cooling at 25 ℃ for 1h to precipitate crystals (wherein, the cooling temperature of example 13 and example 14 at 25 ℃ for 1h does not precipitate crystals (because the saturated state is not reached), cooling the temperature to 5 ℃ for continuous cooling, and collecting the crystals in a transition state). And (2) centrifuging to separate out a precipitate, converting the precipitated crystal form by using 40mL of ethanol (the weight ratio of gamma-CD to ethanol is 1:3.1) (wherein 40mL of ethanol is used in example 16, the residual amount of potassium acetate is high, and the effect is good when 80mL of ethanol is used), centrifuging, washing and purifying by using ethanol (40mL multiplied by 2 times), and drying the obtained solid in a 60-DEG C forced air drying oven for 4 hours to obtain the cyclodextrin-metal organic framework material.
PXRD results show that the crystals obtained in examples 13-16 are the same as those obtained in example 1.
TABLE 3 examples 13 to 16
Examples 17 to 21
As shown in the following table 4, according to the molar ratio of gamma-CD to metal ions of 1:8, gamma-CD and different amounts of metal salts are weighed and placed in conical flasks, pure water is added according to the weight ratio of gamma-CD to water of 1:3.9, the mixture is heated in a water bath at 80 ℃ to be completely dissolved into a solution, and then the mixture is cooled at 25 ℃ to precipitate crystals. And (3) centrifugally separating out precipitates, converting the precipitated crystal forms by using 40mL of ethanol (the weight ratio of gamma-CD to ethanol is 1:3.1), centrifugally washing and purifying by using ethanol (40mL multiplied by 2 times), and drying the obtained solid in a 60-DEG C forced air drying oven for 4 hours to obtain cyclodextrin-metal organic framework materials of different salt types.
The metal salt has different crystal forms with the cyclodextrin-metal organic framework formed by cyclodextrin. Since the crystal has self-plasticity and the crystal morphology shows the internal arrangement of the crystal, different metal salts can be presumed from the aspect of morphology to obtain cyclodextrin-metal organic framework materials with different salt forms (fig. 5), and PXRD results show that: example 17 cyclodextrin-metal organic framework material prepared with potassium carbonate is different from the cyclodextrin-metal organic framework material prepared with potassium acetate in example 5 (fig. 6).
TABLE 4 examples 17 to 21
Examples 22 to 28
As shown in the following table 5, according to the molar ratio of gamma-CD to metal ions of 1:2, gamma-CD and different amounts of metal salts are weighed and placed in conical flasks, pure water is added according to the weight ratio of gamma-CD to water of 1:0.8, the mixture is heated in a water bath at 90 ℃ to be completely dissolved into a solution, and then the mixture is cooled at 25 ℃ to precipitate crystals. And (3) centrifuging to separate out precipitates, using 10mL of ethanol (the weight ratio of gamma-CD to ethanol is 1:6.1), stirring at 300rpm at 25 ℃ for 12h to convert the precipitated crystal forms, then using ethanol (10mL multiplied by 2 times) to carry out centrifugal washing and purification, and drying the obtained solid in a blast drying oven at 60 ℃ for 4h to obtain cyclodextrin-metal organic framework materials with different salt forms.
The metal salt has different crystal forms with the cyclodextrin-metal organic framework formed by cyclodextrin. Because the crystal has self-plasticity and the crystal form shows the internal arrangement of the crystal, different metal salts can be presumed from the form angle to obtain cyclodextrin-metal organic framework materials with different salt forms.
The results in FIG. 7 show that different metal salt forms have different transition crystal morphologies: the cyclodextrin-metal organic framework based on potassium chloride is mainly columnar crystal; the cyclodextrin-metal organic framework based on sodium acetate, magnesium sulfate and calcium chloride is columnar and flaky, most of the cyclodextrin-metal organic framework is flaky crystals, and the flaky degree is different.
PXRD results show that: the PXRD results for examples 22-24, all potassium salts, show that the diffraction peak positions of the final crystals after crystal transformation are consistent with those of typical potassium-cyclodextrin-metal-organic framework materials. The cyclodextrin-metal organic framework material obtained has different pH values (pH of potassium chloride type about 6, pH of potassium hydroxide type about 14, pH of potassium acetate type about 8, pH of potassium carbonate type about 11) due to different anion types of metal salts, and is suitable for drugs with different properties.
TABLE 5 examples 22 to 28
Examples 29 to 30
Weighing gamma-CD and potassium acetate according to the molar ratio of gamma-CD to potassium acetate of 1:8, placing the gamma-CD and the potassium acetate into a beaker, adding pure water according to the weight ratio of gamma-CD to water of 1:3.9, heating in a water bath at 70 ℃ to completely dissolve the gamma-CD and the potassium acetate into a solution, and cooling at 25 ℃ to separate out crystals. And (3) centrifugally separating out precipitates, converting crystal forms of the precipitates by using different solvents (shown in table 6) according to the weight ratio of gamma-CD to crystal transformation solvent of 1:0.8, centrifugally washing and purifying by using ethanol (40mL multiplied by 2 times), and drying the obtained solid in a 60-DEG C forced air drying oven for 4 hours to obtain the cyclodextrin-metal organic framework material.
The results of fig. 8 show that the porous cyclodextrin-metal organic framework material having the same crystal form as that of the compact transition state crystal washed with ethanol can be obtained by washing the compact transition state crystal with methanol and acetone, respectively.
TABLE 6 examples 29 to 30
Example 31
According to the molar ratio of gamma-CD to potassium acetate of 1:8, 10.24g of gamma-CD and 6.20g of potassium acetate are weighed and placed in a beaker, 40mL of pure water is added according to the weight ratio of gamma-CD to water of 1:3.9, the mixture is heated in a water bath at 70 ℃ to be completely dissolved into a solution, and then the solution is cooled at 25 ℃ to precipitate crystals. And (3) centrifugally separating out a precipitate, drying the precipitate in a 60 ℃ forced air drying oven for 12 hours, converting the precipitated crystal form by using 40mL of ethanol (the weight ratio of gamma-CD to ethanol is 1:3.1), centrifugally washing and purifying the precipitate by using ethanol (40mL multiplied by 2 times), and drying the obtained solid in the 60 ℃ forced air drying oven for 4 hours to obtain the cyclodextrin-metal organic framework material.
The PXRD results show that the crystal obtained in example 31 is the same as the crystal obtained in example 1.
Examples 32 to 33
As shown in the following table 7, according to the molar ratio of beta-CD to potassium ion of 1:8, beta-CD and potassium salt are weighed and placed in a beaker, pure water is added according to the weight ratio of beta-CD to water of 1:10, the mixture is heated in a water bath at 70 ℃ to be completely dissolved into a solution, and then the solution is cooled at 25 ℃ and magnetically stirred at 300rpm for 6 hours to precipitate crystals. Centrifuging to separate out precipitates, converting the precipitated crystal forms by using 40mL of ethanol (the weight ratio of beta-CD to ethanol is 1:16.0), centrifuging, washing and purifying by using ethanol (40mL multiplied by 2 times), and drying the obtained solid in a 60 ℃ forced air drying oven for 4 hours to obtain the cyclodextrin-metal organic framework material which is square under a microscope, has obvious polarization phenomenon and is different from the simple beta-CD and metal salt microscopic forms; the corresponding metal organic framework material can be prepared by preliminarily judging the beta-CD.
TABLE 7 examples 32 to 33
Examples 34 to 39
Weighing gamma-CD and potassium acetate respectively, placing the gamma-CD and the potassium acetate into a beaker, adding pure water, performing ultrasonic treatment for 10min, taking out the mixture, converting the precipitated crystal form by using 2mL of ethanol (the weight ratio of the gamma-CD to the ethanol is 1:1.2), performing centrifugal washing and purification by using ethanol (10m L multiplied by 2 times), and drying the obtained solid in a 60-DEG C forced air drying oven for 4h to obtain the cyclodextrin-metal organic framework material.
The PXRD results of examples 34-39 show that the characteristic peaks of crystalline PXRD after washing are consistent with the crystalline form of the cyclodextrin-metal organic framework material obtained in example 1.
TABLE 8 examples 34 to 39
The yield of the process according to example 36 was about 316.7g, an improvement of about 13-fold over the solvothermal preparation, with a large reduction in the consumption of organic solvent (0.6 mL of ethanol per 1g of product prepared using this process).
Example 40
1.280g of gamma-CD and 0.193g of potassium acetate were weighed into a beaker, and 1.5mL of pure water was added thereto and vortexed. The sample subjected to vortex treatment has small particle size and high aggregation, and the generation of the potassium acetate-MOF is judged through the polarization phenomenon of an aggregation surface. The sample obtained by heating, dissolving and re-precipitating has large crystal particles with obvious polarization and small crystal particles with large volume difference, which are compact crystals. Therefore, the crystal generation is not influenced by the processing mode. After the crystal is induced by an organic reagent, the crystal is transformed into a porous crystal, and PXRD results show that the crystal structure of the crystal is consistent with the porous crystal structure obtained in example 1.
Examples 41 to 44
Weighing gamma-CD and different metal salts according to the molar ratio of gamma-CD to metal salt of 1:2, placing the gamma-CD and the different metal salts in a beaker, adding 1.5mL of pure water according to the weight ratio of gamma-CD to water of 1:1.2, heating in a water bath at 80 ℃ to completely dissolve the gamma-CD and the water to form a solution, and cooling and standing at 25 ℃ to separate out crystals. And (3) converting the precipitated crystal form by using 10mL of a replacement metal salt-crystal transformation solvent (0.197mol/mL) and stirring at 300rpm at 25 ℃ for 12h, then carrying out centrifugal washing and purification by using ethanol (10mL multiplied by 2 times), and drying the obtained solid in a 60 ℃ forced air drying oven for 4h to obtain the cyclodextrin-metal organic framework material.
TABLE 9 examples 41 to 44
PXRD results show that the crystal after crystal transformation of examples 41-44 is the same as that obtained in example 1.
Example 45
Preparing two 25mL portions of valsartan ethanol solution with the concentration of 0.25g/mL, respectively adding 1.0g of the porous cyclodextrin-metal organic framework crystal material and the transition state crystal (namely the compact structure) thereof prepared in the embodiment 1, carrying out magnetic stirring drug loading, carrying out suction filtration after 24h of drug loading at the water bath temperature of 40 ℃ and the rotating speed of 400rpm, placing the filter cake in an air blast drying oven for drying at 60 ℃ for 4h, carrying out centrifugal drying, and respectively measuring the drug loading amount of the transition state crystal and the porous cyclodextrin-metal organic framework crystal material on valsartan.
The content of valsartan is measured at 250nm by an ultraviolet spectrophotometer, and the result is that: the drug loading of the transition crystal to the valsartan is 33.5 +/-1.5%, and the drug loading of the porous cyclodextrin-metal organic framework crystal material to the valsartan is 30.2 +/-1.3%. The transition crystal and the cyclodextrin-metal organic framework crystal material can be used as carrier materials of the valsartan. Although the transition state crystal has a compact structure, in the drug loading process, due to the existence of a drug loading solvent (ethanol), the transition state crystal can be used for loading drugs while being in a porous structure in the drug loading process, and thus the transition state crystal has a potential drug loading function.
Examples 46 to 50
A one-step method: weighing 200g of gamma-CD, keeping the amount of the gamma-CD unchanged according to different molar ratios of the gamma-CD to potassium acetate, adding potassium acetate with different amounts, placing the potassium acetate into a beaker, adding 200mL of pure water according to the weight ratio of the gamma-CD to the water of 1:1, heating in a water bath at 90 ℃ to completely dissolve the potassium acetate into a solution, directly adding 400mL of ethanol (the weight ratio of the gamma-CD to the ethanol of 1:1.6) when the temperature is reduced to about 70 ℃, stopping heating, stirring at 500rpm and cooling until crystals are completely precipitated, then performing suction filtration, washing and purification by using ethanol (200mL multiplied by 2 times), drying the obtained solid in a blast drying oven at 60 ℃ for 4 hours to obtain the porous cyclodextrin-metal organic framework material.
TABLE 10 examples 46 to 50
As in example 46, the yield was 345.3g, which is a 14-fold improvement over the solvothermal preparation, and the consumption of organic solvent was reduced in a relatively large proportion (1.9 mL of ethanol was consumed per 1g of product prepared using this method).
PXRD results (FIG. 9) show that the crystal structures obtained by using the same concentration of gamma-CD aqueous solution and the gamma-CD/potassium acetate ratios of 1:1.5, 1:2 and 1:3 are the same as those of example 1. When the ratio of the gamma-CD to the potassium acetate is 1:1, the crystal purity is reduced, and partial gamma-CD is recrystallized (the preparation method is the same, only the potassium acetate is not added) to be separated out and doped. Example 46 compares with 47 to show that increased ethanol usage increases the conversion efficiency of the crystals, which in turn increases the yield.
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 (10)
1. A preparation method of a cyclodextrin-metal organic framework crystal material is characterized by comprising the following steps:
a-1) providing cyclodextrin, metal salt and water, and mixing to obtain a first mixture;
a-2) treating the first mixture by adopting a first treatment mode to obtain a second mixture containing transition state crystals;
a-3) carrying out step a-3-1) or step a-3-2), wherein,
step a-3-1): separating the transition state crystal, adding a crystal transfer solvent into the separated transition state crystal to obtain a third mixture containing the cyclodextrin-metal organic framework crystal material, and further separating to obtain the cyclodextrin-metal organic framework crystal material;
step a-3-2): directly adding a crystal transfer solvent into the second mixture without separating the transition state crystal to obtain a fourth mixture containing the cyclodextrin-metal organic framework crystal material, and further separating to obtain the cyclodextrin-metal organic framework crystal material;
the first treatment mode is selected from the group consisting of: heating-cooling, sonication, vortexing, or a combination thereof.
2. The method of claim 1, wherein the method further comprises, after step a-3), the steps of:
a-4) carrying out centrifugal washing and purification by using a first solvent, and drying the obtained product to obtain the cyclodextrin-metal organic framework crystal material.
3. The method of claim 1, wherein the cyclodextrin is selected from the group consisting of: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin; and/or
The metal salt is selected from the group consisting of: potassium salt, sodium salt, magnesium salt, calcium salt and zinc salt.
4. The method of claim 1, wherein, when step a-3) is performed in step a-3-1), in the first mixture,
the molar ratio of the cyclodextrin to the metal salt is 1: 0.5-20; and/or
The mass ratio of the cyclodextrin to the water is 1: 0.5-15.
5. The method of claim 1, wherein, when step a-3) is performed in step a-3-2), in the first mixture,
the molar ratio of the cyclodextrin to the metal salt is 1: 1.2-20; and/or
The mass ratio of the cyclodextrin to the water is 1: 0.5-15.
6. The method of claim 1, wherein the first treatment is heating-cooling.
7. The method of claim 1, wherein the transcrystalline solvent is selected from the group consisting of: ethanol, acetone, methanol, propanol, butanol, isopropanol, n-butanol, tert-butanol, ethyl acetate, n-hexane.
8. The method of claim 1, wherein the weight ratio of the cyclodextrin of step a-1) to the crystallization solvent of step a-3) is 1: 0.5-20.
9. The method of claim 1, wherein when the metal salt is not a potassium salt, the transcrystalline solvent further comprises a replacement metal salt, the replacement metal salt being a potassium salt.
10. The method of claim 2, wherein the first solvent is ethanol; and/or
The drying treatment temperature is 50-80 ℃; and/or
The drying treatment time is 0.5-8 h.
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