阅读说明：本技术 7,8-二羟基黄酮衍生物的纯化方法 (Purification method of 7,8-dihydroxyflavone derivative ) 是由 章志宏 陈建丽 于 2019-04-15 设计创作，主要内容包括：本发明公开了一种7,8-二羟基黄酮衍生物的纯化方法。其包括以下步骤：将如式I所示的7,8-二羟基黄酮衍生物的溶液滴加至有机溶剂中,或将所述有机溶剂滴加至如式I所示的7,8-二羟基黄酮衍生物的溶液滴中,得混合物,重结晶即可；溶液采用的溶剂包括DMSO、DMF和DMA中的一种或多种；有机溶剂包括C<Sub>3～6</Sub>酯溶剂、C<Sub>1～5</Sub>醇溶剂、C<Sub>3～6</Sub>酮溶剂和C<Sub>4～10</Sub>醚溶剂中的一种或多种。纯化后的7,8-二羟基黄酮衍生物纯度较高,稳定性较好。例如可制得7,8-二羟基黄酮衍生物晶型A,其不仅纯度较高,而且在水中具有较好的溶解度、高湿条件下具有较好的稳定性以及具有极低的吸湿性。<Image he="471" wi="602" file="DDA0002028168350000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a purification method of a 7,8-dihydroxyflavone derivative. Which comprises the following steps: dripping the solution of the 7,8-dihydroxyflavone derivative shown in the formula I into an organic solvent, or dripping the organic solvent into the solution of the 7,8-dihydroxyflavone derivative shown in the formula I to obtain a mixture, and recrystallizing; the solvent adopted by the solution comprises one or more of DMSO, DMF and DMA; the organic solvent comprises C 3～6 Ester solvent, C 1～5 Alcohol solvent, C 3～6 Ketone solvent and C 4～10 One or more of ether solvents. The purified 7,8-dihydroxy flavone derivative has high purity and good stability. For example, the crystal form A of the 7,8-dihydroxyflavone derivative can be prepared, and the crystal form A not only has higher purity, but also has better solubility in water, better stability under high-humidity conditions and extremely low hygroscopicity.)

1. A method for purifying a 7,8-dihydroxyflavone derivative shown as a formula I comprises the following steps:

dripping a solution of the 7,8-dihydroxyflavone derivative shown in the formula I into an organic solvent, or dripping the organic solvent into a solution of the 7,8-dihydroxyflavone derivative shown in the formula I to obtain a mixture, and recrystallizing the mixture;

wherein the solvent adopted by the solution comprises one or more of dimethyl sulfoxide, dimethylformamide and dimethylacetamide; the organic solvent comprises C_3～6Ester solvent, C_1～5Alcohol solvent, C_3～6Ketone solvent and C_4～10One or more of ether solvents;

2. the method for purifying 7,8-dihydroxyflavone derivatives according to claim 1, wherein in the solution of the 7,8-dihydroxyflavone derivatives represented by formula I, the volume-to-mass ratio of the solvent in the solution to the 7,8-dihydroxyflavone derivatives represented by formula I is 1 to 30mL/g, preferably 3 to 15, such as 4mL/g, 5mL/g, 6mL/g, 7mL/g, 8mL/g or 10 mL/g;

and/or the volume-to-mass ratio of the organic solvent to the 7,8-dihydroxyflavone derivative shown in the formula I is (2-50) mL/g, preferably (10-45) mL/g, such as 15mL/g, 20mL/g, 26mL/g, 30mL/g, 32mL/g, 35mL/g, 37mL/g or 42 mL/g.

3. The method of purifying a 7,8-dihydroxyflavone derivative according to claim 1, wherein C is_3～6The ester solvent is one or more of isopropyl acetate, ethyl acetate and propyl acetate;

and/or, said C_1～5The alcohol solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol, preferably methanol or ethanol;

and/or, said C_3～6The ketone solvent is C_3～4Ketone solvents, preferably acetone;

and/or, said C_4～10The ether solvent is one or more of diethyl ether, isopropyl ether, methyl tertiary butyl ether and n-amyl ether, preferably isopropyl ether and/or methyl tertiary butyl ether.

4. The method of purifying a 7,8-dihydroxyflavone derivative according to claim 1, wherein the recrystallization is a step of forming a saturated solution of the 7,8-dihydroxyflavone derivative represented by formula I in the mixture, cooling, and crystallizing.

5. The method for purifying a 7,8-dihydroxyflavone derivative according to claim 4, wherein the temperature of the saturated solution is 15 to 40 ℃, preferably 15 to 30 ℃;

and/or, before the cooling step, stirring the mixture for 0.5-2 h, for example 1 h;

and/or stirring for 12-24 hours in the cooling and crystallization process;

and/or the temperature after cooling is (-20 ℃) to-10 ℃, such as-10 ℃, -5 ℃ or 0 ℃.

6. The method of purifying a 7,8-dihydroxyflavone derivative according to claim 1, wherein when the organic solvent is C_3～6Ester solvent, said C_3～6When the ester solvent is one or more of isopropyl acetate, ethyl acetate and propyl acetate, the 7,8-dihydroxy flavone derivative crystal form A shown in the formula I is prepared by the purification method;

when the organic solvent is C_1～5Alcohol solvent and/or C_3～6In the case of ketone solvents, the 7,8-dihydroxyflavone derivative crystal form A is prepared by the purification method;

when the organic solvent is C_4～10Ether solvent, said C_4～10When the ether solvent is one or more of ethyl ether, isopropyl ether, methyl tertiary butyl ether and n-amyl ether, the 7,8-dihydroxyflavone derivative crystal form A is prepared by the purification method;

the crystal form A has characteristic diffraction peaks at 6.710 +/-0.2 degrees, 8.821 +/-0.2 degrees, 10.203 +/-0.2 degrees, 13.537 +/-0.2 degrees, 14.267 +/-0.2 degrees, 16.814 +/-0.2 degrees, 18.511 +/-0.2 degrees, 20.424 +/-0.2 degrees, 22.910 +/-0.2 degrees, 23.542,24.590 degrees, 25.631 +/-0.2 degrees, 26.857 +/-0.2 degrees, 27.351 +/-0.2 degrees, 28.830 +/-0.2 degrees, 31.064 +/-0.2 degrees and 31.854 +/-0.2 degrees by X-ray powder diffraction represented by a 2 theta angle.

7. The method for purifying a 7,8-dihydroxyflavone derivative according to claim 6, wherein the form A of the 7,8-dihydroxyflavone derivative represented by formula I has characteristic peaks at 6.710 ± 0.2 °, 8.821 ± 0.2 °, 10.203 ± 0.2 °, 13.537 ± 0.2 °, 14.267 ± 0.2 °, 16.814 ± 0.2 °, 18.511 ± 0.2 °, 20.424 ± 0.2 °, 22.910 ± 0.2 °, 23.542 ± 0.2 °,24.590 ± 0.2 °, 25.631 ± 0.2 °, 26.857 ± 0.2 °, 27.351 ± 0.2 °, 28.830 ± 0.2 °, 31.064 ± 0.2 °, 31.854 ± 0.2 °, 33.229 ± 0.2 ° and 35.260 ± 0.2 ° by X-ray powder diffraction at an angle of 2 θ;

and/or in a thermogravimetric analysis map of the crystal form A of the 7,8-dihydroxy flavone derivative shown in the formula I, the weight loss mass at 100 +/-3 ℃ accounts for 0.07092% of the mass before weight loss, and the "%" is the mass percentage;

and/or, in the differential scanning thermal spectrum of the crystal form A of the 7,8-dihydroxy flavone derivative shown in the formula I, an absorption peak with the melting heat of 223.9J/g is at 193.99 +/-10 ℃, and an absorption peak with the melting heat of 320.9J/g is at 221.1 +/-10 ℃;

and/or in the dynamic moisture adsorption pattern of the crystal form A of the 7,8-dihydroxy flavone derivative shown in the formula I, the weight gain is less than 0.2% within the relative humidity range of 0-90%, and the "%" is the mass percentage of the increased mass of the crystal form A of the 7,8-dihydroxy flavone derivative shown in the formula I in the initial mass.

8. The method of claim 6, wherein the form A of the 7,8-dihydroxyflavone derivative represented by formula I has characteristic peaks at 6.710 + -0.2 °, 8.821 + -0.2 °, 10.203 + -0.2 °, 13.537 + -0.2 °, 14.267 + -0.2 °, 16.814 + -0.2 °, 18.511 + -0.2 °, 20.424 + -0.2 °, 22.910 + -0.2 °, 23.542 + -0.2 °,24.590 + -0.2 °, 25.631 + -0.2 °, 26.857 + -0.2 °, 27.351 + -0.2 °, 28.830 + -0.2 °, 31.064 + -0.2 °, 31.854 + -0.2 °, 33.229 + -0.2 °, 35.260 + -0.2 °, 36.131 + -0.2 ° and 37.594 + -0.2 ° by X-ray powder diffraction at 2 θ;

and/or the thermogravimetric analysis diagram of the crystal form A of the 7,8-dihydroxyflavone derivative shown in the formula I is basically shown in figure 2;

and/or the differential scanning thermal map spectrum of the crystal form A of the 7,8-dihydroxyflavone derivative shown in the formula I is basically shown in figure 3;

and/or the dynamic moisture adsorption pattern of the crystal form A of the 7,8-dihydroxyflavone derivative shown in the formula I is basically shown in figure 4.

9. The method for purifying a 7,8-dihydroxyflavone derivative according to claim 6, wherein the form A of the 7,8-dihydroxyflavone derivative represented by formula I has characteristic peaks at 6.710 ± 0.2 °, 8.821 ± 0.2 °, 10.203 ± 0.2 °, 13.537 ± 0.2 °, 14.267 ± 0.2 °, 16.814 ± 0.2 °, 18.511 ± 0.2 °, 20.424 ± 0.2 °, 22.910 ± 0.2 °, 23.542 ± 0.2 °,24.590 ± 0.2 °, 25.631 ± 0.2 °, 26.857 ± 0.2 °, 27.351 ± 0.2 °, 28.830 ± 0.2 °, 31.064 ± 0.2 °, 31.854 ± 0.2 °, 33.229 ± 0.2 °, 35.260 ± 0.2 °, 36.131 ± 0.2 °, 37.594 ± 0.2 °, 38.678 ± 0.2 ° and 39.470 ± 0.2 ° by X-ray powder diffraction at an angle of 2 θ.

10. The method of purifying a 7,8-dihydroxyflavone derivative according to claim 6, wherein the X-ray powder diffraction pattern of the crystalline form a of the 7,8-dihydroxyflavone derivative according to formula I is substantially as shown in figure 1.

Technical Field

The invention relates to a purification method of 7,8-dihydroxyflavone derivatives.

Background

7,8-dihydroxyflavone (7, 8-dihydroflavon, 7,8-DHF for short) is a specific agonist of a tyrosine kinase B (TrkB) receptor and can activate the TrkB receptor. In vitro and in vivo experiments prove that the 7,8-DHF has curative effects on neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, depression, psychiatric disorders, post-traumatic stress disorder, autism spectrum disorder, apoplexy, Raet syndrome and the like, and plays an important biological role. However, 7,8-DHF is easily metabolized into a biphasic metabolite in vivo and is eliminated from the body, and the in vivo half-life period is short, the bioavailability is low, and the drug property is poor.

The Chinese patent application CN201380062367.X discloses that 7,8-DHF is modified to obtain 7,8-dihydroxy flavone derivatives with the structural formula

(Compound of formula I or compound R13 for short). In-vivo non-clinical tests show that the compound of the formula I has the half-life and the bioavailability which are obviously improved compared with 7,8-DHF, and has stronger drug property. The compound of the formula I prepared by the Chinese patent application CN201380062367.X has lower purity and poorer stability, and the important significance is provided for how to obtain the compound of the formula I with high purity and good stability.

Disclosure of Invention

The invention provides a purification method of a 7,8-dihydroxyflavone derivative. The purified 7,8-dihydroxy flavone derivative has high purity and good stability. For example, the 7,8-dihydroxyflavone derivative crystal form A can be prepared by the purification method, and has high purity, good solubility in water, good stability under high-humidity conditions and extremely low hygroscopicity. The crystal form A of the 7,8-dihydroxyflavone derivative has important value for the optimization and development of medicaments.

The invention solves the technical problems through the following technical scheme.

The invention provides a purification method of a 7,8-dihydroxy flavone derivative shown as a formula I, which comprises the following steps:

dripping a solution of the 7,8-dihydroxyflavone derivative shown in the formula I into an organic solvent, or dripping the organic solvent into a solution of the 7,8-dihydroxyflavone derivative shown in the formula I to obtain a mixture, and recrystallizing the mixture;

wherein the solvent adopted by the solution comprises one or more of dimethyl sulfoxide DMSO, dimethylformamide DMF and dimethylacetamide DMA; the organic solvent comprises C_3～6Ester solvent, C_1～5Alcohol solvent, C_3～6Ketone solvent and C_4～10One or more of ether solvents;

in the invention, in the solution of the 7,8-dihydroxyflavone derivative shown in the formula I, the volume-to-mass ratio of the solvent in the solution to the 7,8-dihydroxyflavone derivative shown in the formula I can be conventional in the art, and is preferably 1-30 mL/g, more preferably 3-15, such as 4mL/g, 5mL/g, 6mL/g, 7mL/g, 8mL/g or 10 mL/g.

In the present invention, the amount of the organic solvent may be an amount conventionally used in recrystallization operations in the art, and preferably, the volume-to-mass ratio of the organic solvent to the 7,8-dihydroxyflavone derivative represented by formula I is preferably (2 to 50) mL/g, more preferably (10 to 45) mL/g, such as 15mL/g, 20mL/g, 26mL/g, 30mL/g, 32mL/g, 35mL/g, 37mL/g or 42 mL/g.

In the present invention, said C_3～6The ester solvent may be ester solvent with 3-6 carbon atoms, which is conventional in recrystallization operation in the art, and preferably one or more of isopropyl acetate, ethyl acetate and propyl acetate. The esters generally refer to a class of organic compounds formed by the reaction of an acid (a carboxylic acid or an inorganic oxyacid) with an alcohol. Low molecular weight esters are colorless, volatile aromatic liquids.

In the present invention, said C_1～5The alcohol solvent generally refers to an alcohol solvent containing 1-5 carbon atoms, and may be one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol, preferably methanol or ethanol.

In the present invention, said C_3～6The ketone solvent is generally a ketone solvent having 3 to 6 carbon atoms, preferably C_3～4Ketone solvents, such as acetone.

In the present invention, said C_4～10The ether solvent may be one containing 4-10 carbon atoms in recrystallization, preferably C_5～6An ether solvent. Said C is_4～10The ether solvent can be one or more of diethyl ether, isopropyl ether, methyl tertiary butyl ether and n-amyl ether, and preferably isopropyl ether and/or methyl tertiary butyl ether.

In the present invention, the recrystallization may be a conventional recrystallization in the art, and it is preferable that the mixture, i.e., the 7,8-dihydroxyflavone derivative represented by formula I, is formed into a saturated solution, cooled, and crystallized.

In the present invention, the temperature of the saturated solution is generally room temperature, for example, 15 to 40 ℃, preferably 15 to 30 ℃, for example, 20 ℃.

In the present invention, the mixture is generally stirred for 0.5 to 2 hours, for example, 1 hour, before the cooling step.

In the invention, the cooling is generally stirred for 12-24 hours in the process of crystallization so as to ensure that crystals are fully precipitated.

In the present invention, the temperature after cooling may be conventional in the art, and is typically (-20 ℃) to-10 ℃, for example, -10 ℃, -5 ℃ or 0 ℃.

In the invention, after the recrystallization is finished, the method can further comprise the following operation steps: and separating, washing and drying the product obtained in the recrystallization process.

Wherein, the separation mode can be carried out by adopting a conventional separation mode in the field, and centrifugation or filtration is preferred. The washing mode can be performed by adopting a conventional washing mode in the field, and the washing mode is generally performed by 2-4 times, for example 3 times, by using the organic solvent. The kind of the organic solvent is as described above. The drying can be carried out by conventional methods in the art, such as drying under atmospheric pressure or reduced pressure, e.g., vacuum drying at 50 ℃ for 20 h.

In the present invention, it is preferable that when the organic solvent is C_3～6Ester solvent, said C_3～6When the ester solvent is one or more of isopropyl acetate, ethyl acetate and propyl acetate, the product is prepared by the purification methodObtaining the crystal form A of the 7,8-dihydroxy flavone derivative shown in the formula I.

In the present invention, it is preferable that when the organic solvent is C_1～5Alcohol solvent and/or C_3～6And in the case of ketone solvents, preparing the crystal form A of the 7,8-dihydroxyflavone derivative shown in the formula I by the purification method.

In the present invention, it is preferable that when the organic solvent is C_4～10Ether solvent, said C_4～10When the ether solvent is one or more of ethyl ether, isopropyl ether, methyl tertiary butyl ether and n-amyl ether, the 7,8-dihydroxy flavone derivative crystal form A shown in the formula I is prepared by the purification method.

As mentioned above, the X-ray powder diffraction of the crystal form A expressed by the angle of 2 theta has characteristic diffraction peaks at 6.710 +/-0.2 degrees, 8.821 +/-0.2 degrees, 10.203 +/-0.2 degrees, 13.537 +/-0.2 degrees, 14.267 +/-0.2 degrees, 16.814 +/-0.2 degrees, 18.511 +/-0.2 degrees, 20.424 +/-0.2 degrees, 22.910 +/-0.2 degrees, 23.542 degrees, 24.590 degrees, 25.631 +/-0.2 degrees, 26.857 +/-0.2 degrees, 27.351 +/-0.2 degrees, 28.830 +/-0.2 degrees, 31.064 +/-0.2 degrees and 31.854 +/-0.2 degrees.

Further preferably, the crystal form A of the 7,8-dihydroxy flavone derivative shown in formula I has characteristic peaks at 6.710 + -0.2 °, 8.821 + -0.2 °, 10.203 + -0.2 °, 13.537 + -0.2 °, 14.267 + -0.2 °, 16.814 + -0.2 °, 18.511 + -0.2 °, 20.424 + -0.2 °, 22.910 + -0.2 °, 23.542 + -0.2 °,24.590 + -0.2 °, 25.631 + -0.2 °, 26.857 + -0.2 °, 27.351 + -0.2 °, 28.830 + -0.2 °, 31.064 + -0.2 °, 31.854 + -0.2 °, 33.229 + -0.2 ° and 35.260 + -0.2 ° by X-ray powder diffraction represented by an angle of 2 theta.

More preferably, the crystal form A of the 7,8-dihydroxy flavone derivative shown in formula I has characteristic peaks at 6.710 + -0.2 °, 8.821 + -0.2 °, 10.203 + -0.2 °, 13.537 + -0.2 °, 14.267 + -0.2 °, 16.814 + -0.2 °, 18.511 + -0.2 °, 20.424 + -0.2 °, 22.910 + -0.2 °, 23.542 + -0.2 °,24.590 + -0.2 °, 25.631 + -0.2 °, 26.857 + -0.2 °, 27.351 + -0.2 °, 28.830 + -0.2 °, 31.064 + -0.2 °, 31.854 + -0.2 °, 33.229 + -0.2 °, 35.260 + -0.2 °, 36.131 + -0.2 ° and 37.594 + -0.2 ° by X-ray powder diffraction represented by 2 theta.

Still further preferably, the crystal form a of the 7,8-dihydroxyflavone derivative shown in formula I has characteristic peaks at 6.710 ± 0.2 °, 8.821 ± 0.2 °, 10.203 ± 0.2 °, 13.537 ± 0.2 °, 14.267 ± 0.2 °, 16.814 ± 0.2 °, 18.511 ± 0.2 °, 20.424 ± 0.2 °, 22.910 ± 0.2 °, 23.542 ± 0.2 °,24.590 ± 0.2 °, 25.631 ± 0.2 °, 26.857 ± 0.2 °, 27.351 ± 0.2 °, 28.830 ± 0.2 °, 31.064 ± 0.2 °, 31.854 ± 0.2 °, 33.229 ± 0.2 °, 35.260 ± 0.2 °, 36.131 ± 0.2 °, 37.594 ± 0.2 °, 38.678 ± 0.2 ° and 39.470 ± 0.2 ° by X-ray powder diffraction expressed by 2 θ.

Still more preferably, the X-ray powder diffraction pattern of the crystal form A of the 7,8-dihydroxyflavone derivative shown in the formula I is also basically shown in figure 1.

The X-ray powder diffraction was measured using the K α line of the Cu target.

Preferably, in a thermogravimetric analysis (TGA) of the crystalline form a of the 7,8-dihydroxyflavone derivative represented by the formula I, the mass lost at 100 ± 3 ℃ accounts for 0.07092% of the mass before weight loss, and the "%" is a mass percentage.

Preferably, the crystal form A of the 7,8-dihydroxyflavone derivative shown in the formula I is solvate-free.

Preferably, the thermogravimetric analysis diagram of the crystalline form a of the 7,8-dihydroxyflavone derivative represented by the formula I is also substantially as shown in fig. 2.

Preferably, the 7,8-dihydroxyflavone derivative of the formula I has a Differential Scanning Calorimetry (DSC) of the crystal form A with an absorption peak at 193.99 + -10 ℃ and a heat of fusion of 223.9J/g, and has an absorption peak at 221.1 + -10 ℃ and a heat of fusion of 320.9J/g.

Preferably, the differential scanning thermal spectrum of the crystal form A of the 7,8-dihydroxyflavone derivative shown in the formula I is also basically shown in figure 3.

Preferably, in the dynamic moisture adsorption profile (DVS) of the crystal form a of the 7,8-dihydroxyflavone derivative represented by the formula I, the weight gain is less than 0.2%, for example, 0.1%, within the range of 0% to 90% of the relative humidity, and the "%" is the mass percentage of the added mass of the crystal form a of the 7,8-dihydroxyflavone derivative represented by the formula I to the initial mass.

Preferably, the dynamic moisture adsorption pattern of the crystal form A of the 7,8-dihydroxyflavone derivative shown in the formula I is also basically shown in figure 4.

The crystal form A of the 7,8-dihydroxyflavone derivative shown in the formula I prepared by the preparation method can be applied to preparation of medicines for preventing and/or treating diseases related to tyrosine kinase B (TrkB) receptors.

It is known to those skilled in the art that the intensity and/or condition of the peaks in X-ray powder diffraction may vary depending on the experimental conditions. Meanwhile, due to different accuracies of the instruments, the measured 2 theta value has an error of about +/-0.2 degrees. The relative intensity values of the peaks depend more on certain properties of the measured sample, such as the size of the crystals and the purity than the position of the peaks, so that the measured peak intensities may deviate by about + -20%. One skilled in the art can obtain sufficient information to identify each crystal form from the X-ray powder diffraction data provided herein, despite experimental errors, instrumental errors, and orientation preference, etc. On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows:

the purified 7,8-dihydroxy flavone derivative has high purity (up to 98.9%) and high stability.

The purification method can prepare the crystal form A of the 7,8-dihydroxyflavone derivative, and the crystal form A not only has higher purity, but also has better solubility in water, better stability under high-humidity conditions and extremely low hygroscopicity. The crystal form A of the 7,8-dihydroxyflavone derivative has important value for the optimization and development of medicaments.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of a crystal form A of the 7,8-dihydroxyflavone derivative shown in formula I obtained in example 1.

FIG. 2 is a thermogravimetric analysis chart of the crystal form A of the 7,8-dihydroxyflavone derivative shown in the formula I obtained in example 1.

FIG. 3 is a differential scanning thermogram of the crystal form A of the 7,8-dihydroxyflavone derivative shown in formula I obtained in example 1.

FIG. 4 is a dynamic water absorption diagram of the crystal form A of the 7,8-dihydroxy flavone derivative shown in formula I obtained in example 1.

FIG. 5 is an X-ray powder diffraction pattern of the 7,8-dihydroxyflavone derivative shown in formula I obtained in comparative example 1.

FIG. 6 is an X-ray powder diffraction pattern of the crystal form A of the 7,8-dihydroxyflavone derivative represented by the formula I in Effect example 2 after being left for seven days under different high humidity conditions.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Test method

Powder X-ray diffraction

The instrument comprises the following steps: bruker, D8 advance

The test method comprises the following steps: the light source is CuK, the X-ray intensity is 40KV/40mA, the scanning mode is Theta-Theta, the scanning angle range is 4-40 degrees, the rotating speed of the sample disc is 15rpm, and the scanning speed is 10 deg/min.

Thermogravimetric analysis

The instrument comprises the following steps: TA, Q5000 IR.

The test method comprises the following steps: heating from 25 ℃ to 300 ℃ at a heating rate of 10 ℃/min.

Differential Scanning Calorimetry (DSC)

The instrument comprises the following steps: TA, Q2000.

The test method comprises the following steps: the sample was equilibrated at 25 ℃ and then heated from 25 ℃ to 300 ℃ at a ramp rate of 10 ℃/min.

Dynamic moisture sorption analysis (DVS)

The instrument comprises the following steps: SMS, DVS Advantage-1.

And (3) testing conditions are as follows: using 10-15 mg of sample for DVS detection; balance dm/dt: 0.01%/min: (time: 10min max. 180 min); and (3) drying: 0% RH, 120minRH (%); measuring the gradient: 10% RH (%); measuring the gradient range: 0 to 90 to 0 percent. The criteria are shown in Table 1:

TABLE 1

Moisture-inducing classification	Dampness-inducing weight increase
		Deliquescence	Absorb sufficient water to form liquid
Has moisture absorption property	The moisture-drawing weight gain is not less than 15 percent
		Has moisture absorption effect	The moisture-drawing weight gain is less than 15 percent but not less than 2 percent
Slightly hygroscopic	The moisture-drawing weight gain is less than 2 percent but not less than 0.2 percent
		No or almost no hygroscopicity	The moisture-attracting weight gain is less than 0.2 percent