CN114075162A - Crystal form B of 7, 8-dihydroxyflavone derivative, and preparation method and application thereof - Google Patents

Crystal form B of 7, 8-dihydroxyflavone derivative, and preparation method and application thereof Download PDF

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CN114075162A
CN114075162A CN202010841093.6A CN202010841093A CN114075162A CN 114075162 A CN114075162 A CN 114075162A CN 202010841093 A CN202010841093 A CN 202010841093A CN 114075162 A CN114075162 A CN 114075162A
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crystal form
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dihydroxyflavone
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章志宏
宋金津
胡姣
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Shanghai Braegen Pharmaceutical Co ltd
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Abstract

The invention discloses a crystal form B of a 7, 8-dihydroxyflavone derivative, and a preparation method and application thereof. Which has been subjected to powder X-ray diffraction using a radiation source of Cu-Ka at diffraction angles 2 theta of 7.294 DEG, 9.622 DEG, 11.061 DEG, 17.079 DEG and 22 DEGThe diffraction peaks are characterized at 167 °, 22.404 °, 23.805 °, 26.642 °, 29.188 ° and 32.759 °, and the error range of 2 θ is ± 0.2. The crystal form B has good stability, extremely low hygroscopicity and high bioavailability under high-humidity conditions, is simple in preparation method, and has important value in optimization and development of medicines.
Figure DDA0002641423860000011

Description

Crystal form B of 7, 8-dihydroxyflavone derivative, and preparation method and application thereof
Technical Field
The invention relates to a crystal form B of a 7, 8-dihydroxyflavone derivative, and a preparation method and application thereof.
Background
Brain-derived neurotrophic factor (BDNF) exerts a neurotrophic effect by activating homologous TrkB receptors. The 7, 8-dihydroxyflavone (7, 8-dihydroflavon, 7,8-DHF for short) can simulate the function of BDNF, 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 has short in vivo half-life, low bioavailability and poor drug action. Chinese patent application CN201380062367.X discloses that 7,8-dihydroxy flavone is modified to obtain 7,8-dihydroxy flavone derivatives with structural formula
Figure BDA0002641423840000011
(abbreviated as compound of formula I or compound BrAD-R13). 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 study of drug polymorphism is a leading topic in the pharmaceutical field. Different crystal forms of the drug have differences in internal structure, and may have different physicochemical properties, such as solubility, dissolution rate, etc., which affect the bioavailability of the drug. In addition, the discovery of the new crystal form of the drug can prolong the life cycle of a drug patent and set a technical barrier, and has important significance for the development of solid drugs. Compared with the change of the structure of the medicine, the change of the crystal form of the compound is obviously more practical, safe and economical.
Currently, in the prior art, the 7, 8-dihydroxyflavone derivative shown as formula I only discloses a crystal form a, for example, chinese patent application CN 201910032859.3 discloses a crystal form a of 7, 8-dihydroxyflavone derivative, and its X-ray diffraction pattern is shown in fig. 2.
In view of this, it is very important to develop other crystal forms of the 7, 8-dihydroxyflavone derivatives shown in formula I with advantageous properties.
Disclosure of Invention
The invention provides a 7,8-dihydroxy flavone derivative crystal form B different from the prior art, a preparation method and application. The crystal form has better stability and extremely low hygroscopicity under high humidity, and the preparation method is simple. The crystal form B 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 crystal form B of a 7, 8-dihydroxyflavone derivative shown as a formula I, which has characteristic diffraction peaks at diffraction angles 2 theta (7.294 degrees), 9.622 degrees, 11.061 degrees, 17.079 degrees, 22.167 degrees, 22.404 degrees, 23.805 degrees, 26.642 degrees, 29.188 degrees and 32.759 degrees in a powder X-ray diffraction spectrum using a radiation source Cu-Kalpha, wherein the error range of 2 theta is +/-0.2;
Figure BDA0002641423840000021
preferably, the crystal form B of the 7,8-dihydroxy flavone derivative shown in the formula I has characteristic peaks at 7.294 degrees, 9.622 degrees, 11.061 degrees, 17.079 degrees, 20.035 degrees, 21.889 degrees, 22.167 degrees, 22.404 degrees, 23.805 degrees, 24.177 degrees, 24.733 degrees, 26.642 degrees, 29.188 degrees, 32.759 degrees and 33.091 degrees by X-ray powder diffraction represented by 2 theta angles, and the error range of 2 theta is +/-0.2.
Further preferably, the crystal form B of the 7, 8-dihydroxyflavone derivative shown in formula I has characteristic peaks at 7.294 °, 9.622 °, 11.061 °, 15.44 °, 17.079 °, 18.104 °, 19.266 °, 20.035 °, 20.686 °, 21.597 °, 21.889 °, 22.167 °, 22.404 °, 23.805 °, 24.177 °, 24.733 °, 25.364 °, 26.642 °, 26.998 °, 27.392 °, 29.188 °, 31.098 °, 32.759 °, 33.091 °, 34.454 ° and 36.585 ° by X-ray powder diffraction represented by 2 θ, and the 2 θ error range is ± 0.2.
Still more preferably, the crystal form B of the 7, 8-dihydroxyflavone derivative shown in formula I has characteristic peaks at 7.294 °, 9.622 °, 11.061 °, 11.932 °, 15.44 °, 17.079 °, 18.104 °, 19.266 °, 20.035 °, 20.686 °, 21.201 °, 21.597 °, 21.889 °, 22.167 °, 22.404 °, 23.805 °, 24.177 °, 24.733 °, 25.364 °, 26.642 °, 26.998 °, 27.392 °, 28.559 °, 27.888 °, 29.188 °, 30.419 °, 31.098 °, 32.759 °, 33.091 °, 33.764 °, 34.454 °, 35.085 °, 36.585 ° and 36.82 ° by X-ray powder diffraction represented by 2 θ, and the error range of 2 θ is ± 0.2.
Still more preferably, the X-ray powder diffraction pattern of the crystal form B of the 7, 8-dihydroxyflavone derivative shown in the formula I is also basically shown in figure 3.
Preferably, in a thermogravimetric analysis (TGA) of the crystalline form B of the 7, 8-dihydroxyflavone derivative represented by formula I, the mass of the weight loss at 100 ± 2 ℃ accounts for 1.978% of the mass before the weight loss, and the "%" is a mass percentage.
Preferably, the crystal form B of the 7, 8-dihydroxyflavone derivative shown in the formula I is solvate-free.
Preferably, the thermogravimetric analysis diagram of the crystalline form B of the 7, 8-dihydroxyflavone derivative represented by formula I is also substantially as shown in figure 5.
Preferably, the 7, 8-dihydroxyflavone derivative of the crystal form B has an absorption peak at 210.9 +/-10 ℃ and a heat of fusion of 317.7J/g in a differential scanning thermal spectrum (DSC) of the crystal form B, and has an absorption peak at 241.87 +/-10 ℃ and a heat of fusion of 17.04J/g in a DSC.
Preferably, in the dynamic moisture adsorption profile (DVS) of the crystal form B of the 7, 8-dihydroxyflavone derivative represented by formula I, the weight gain is less than 2.5%, for example 2.3%, within the range of 10% to 90% of the relative humidity, and the "%" is the mass percentage of the added mass of the crystal form B of the 7, 8-dihydroxyflavone derivative represented by formula I to the initial mass.
Preferably, the dynamic moisture adsorption pattern of the crystal form B of the 7, 8-dihydroxyflavone derivative shown in the formula I is also basically shown in figure 6.
The invention also provides a preparation method of the crystal form B of the 7,8-dihydroxy flavone derivative shown in the formula I, which comprises the following steps: dissolving the crystal form A of the 7, 8-dihydroxyflavone derivative shown as the formula I in a mixed solvent and shaking the mixed solvent to obtain the crystal form A;
the mixed solvent comprises an organic solvent and water; the volume ratio of the organic solvent to the water is 1: (0.05-4); the organic solvent comprises C3～6Ketone solvent, nitrile solvent, C1～4One or more of alcohol solvents and ether solvents.
In the invention, the crystal form A of the 7, 8-dihydroxyflavone derivative shown as the formula I can be prepared by a conventional method in the field. For example, the preparation can be carried out by the examples disclosed in the Chinese patent application CN 109574975A.
In the present invention, before the shaking operation, the crystal form B is generally uniformly mixed, so that the crystal form B can be sufficiently dissolved in the mixed solvent, for example, complete dissolution can be achieved by vortexing for 2 min.
In the present invention, the shaking operation and conditions may be conventional in the art.
In the invention, the shaking temperature is required to be within the range of 30-70 ℃. If the temperature is higher than 70 ℃, the 7, 8-dihydroxyflavone derivatives shown in the formula I can be decomposed or degraded, and if the temperature is lower than 30 ℃, the chemical reaction is insufficient in the shaking process.
In the invention, the shaking time is preferably 20-30 h, such as 24 h. If the shaking time is less than 20 hours, the chemical reaction in the shaking process is insufficient.
In the present invention, the volume ratio of the organic solvent to the water is preferably 1: (0.1 to 3.8), more preferably 1:0.12 to 3.76, for example 1:0.19, 1:0.45, 1:0.72, 1:1, 1:1.5, 1:2 or 1: 3.
In the invention, the concentration of the crystal form A of the 7, 8-dihydroxyflavone derivative shown in the formula I in the mixed solution is preferably 40-60 mg/mL, more preferably 45-55 mg/mL, such as 50 mg/mL. If the concentration is lower than 40mg/mL, the system is too clear, and the crystal transformation of the crystal form A cannot be realized. If the concentration is higher than 60mg/mL, the system is in a slurry state, and the crystal transformation of the crystal form A cannot be realized.
In the present invention, said C3～6The ketone solvent may be C3～4Ketone solvents, such as acetone.
In the present invention, the nitrile solvent may be a nitrile solvent that is conventional in the art, and acetonitrile is preferred.
In the present invention, said C1～4The alcohol may be one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol, preferably methanol and/or ethanol.
In the present invention, the ether solvent may be one or more conventional ether solvents in the art, preferably tetrahydrofuran, 1, 4-dioxane, diethyl ether and methyl tert-butyl ether (MTBE), preferably tetrahydrofuran and/or 1, 4-dioxane.
The invention also provides application of the crystal form B of the 7, 8-dihydroxyflavone derivative shown as the formula I in preparing a medicament for preventing and/or treating diseases related to a tyrosine kinase B (TrkB) receptor.
The invention also provides a pharmaceutical composition, which comprises the crystal form B of the 7,8-dihydroxy flavone derivative shown in the formula I and one or more pharmaceutically available auxiliary materials.
The adjuvants may be selected according to the route of administration and the nature of action, and are usually fillers, diluents, surfactants, binders, wetting agents, disintegrants, preservatives, buffers and isotonicity agents, lubricants, emulsifiers or suspending agents.
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 crystal form B of the 7, 8-dihydroxyflavone derivative shown as the formula I has good stability, extremely low hygroscopicity and high bioavailability under high humidity conditions, and the preparation method is simple and has important value for the optimization and development of medicaments.
Drawings
FIG. 1 is an XRPD pattern of a crystal form D of a 7, 8-dihydroxyflavone derivative shown in a formula I obtained in example 1.
FIG. 2 is an XRPD pattern of the crystal form A of the 7,8-dihydroxy flavone derivative shown in the formula I obtained in example 1.
FIG. 3 is an XRPD pattern of the crystal form B of the 7, 8-dihydroxyflavone derivative shown in the formula I obtained in example 2.
Figure 4 is an XRPD pattern of form B and starting material form a obtained in examples 2-6.
FIG. 5 is a thermogravimetric analysis chart of the crystal form B of the 7, 8-dihydroxyflavone derivative shown in the formula I obtained in example 7.
FIG. 6 is a dynamic water absorption diagram of the crystal form B of the 7, 8-dihydroxyflavone derivative shown in the formula I obtained in example 7.
FIG. 7 is a plot of mass versus humidity as a function of time in a DVS test.
FIG. 8 shows XRPD patterns of wet products obtained in example 8 at different solvent ratios.
FIG. 9 shows the XRPD patterns of the dried products obtained in example 8 with different solvent ratios.
Fig. 10 is an XRPD spectrum of crystalline form B of the 7, 8-dihydroxyflavone derivative represented by formula I in effect example 1 after being left under different high humidity conditions for seven days.
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.
1. The sources of the raw materials in the following examples are as follows:
TABLE 1
Figure BDA0002641423840000061
Figure BDA0002641423840000071
2. Use instrument and method
X-ray powder diffractometer (XRPD): the manufacturer Bruker, model D8 advance.
The test method comprises the following steps: light pipe: cu: K-Alpha
Figure 2
Light tube voltage current: voltage: 40 kV; current: 40 mA; scanning range: the rotating speed of a 4-40 DEG sample disc is 15rpm, and the scanning speed is 10 deg/min.
Differential Scanning Calorimeter (DSC): manufacturer TA, model Q2000. The test method comprises the following steps: heating from 25 ℃ to 300 ℃ at a heating rate of 10 ℃/min.
Thermogravimetric analyzer (TGA): manufacturer TA, model: q5000 IR. The test method comprises the following steps: heating from 25 ℃ to 300 ℃ at a heating 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: 90% -10% -90%. The criteria are shown in Table 2:
TABLE 2
Figure BDA0002641423840000073
Figure BDA0002641423840000081
Example 1 preparation of the starting crystalline form a of form B
Preparation of crystal form D of 7,8-dihydroxy flavone derivative shown as formula I
Reference is made to the 4-oxo-2 phenyl-4H-chromene-7, 8-diyl bis (dimethylcarbamate) compound R in patent cn201380062367.x7The preparation method comprises the step of replacing dimethyl carbamoyl chloride in the raw materials with methyl carbamoyl chloride to obtain the 7, 8-dihydroxyl flavone derivative shown in the formula I.
Figure BDA0002641423840000082
The XRPD detection shows that the X-ray powder diffraction pattern expressed by 2 theta angle has diffraction peak characteristics at 6.745 +/-0.2 degrees, 7.896 +/-0.2 degrees, 8.212 +/-0.2 degrees, 8.839 +/-0.2 degrees, 9.433 +/-0.2 degrees, 10.201 +/-0.2 degrees, 10.890 +/-0.2 degrees, 13.300 +/-0.2 degrees, 13.500 +/-0.2 degrees, 14.432 +/-0.2 degrees, 15.961 +/-0.2 degrees, 16.814 +/-0.2 degrees, 17.742 +/-0.2 degrees, 18.472 +/-0.2 degrees, 19.224 +/-0.2 degrees, 19.692 +/-0.2 degrees, 20.484 +/-0.2 degrees, 21.078 +/-0.2 degrees, 22.319 +/-0.2 degrees, 22.873 +/-0.2 degrees, 23.542 +/-0.2 degrees, 24.545 +/-0.2 degrees, 25.613 +/-0.2 degrees, 26.146 +/-0.2 degrees and 26.146 +/-0.2 degrees; the XRPD pattern is shown in figure 1.
Preparation of crystal form a of 7, 8-dihydroxyflavone derivatives represented by formula I:
weighing 200mg of the crystal form D of the 7, 8-dihydroxyflavone derivative shown as the formula I into an 8mL glass bottle, adding 4mL of methanol, and shaking for 2 minutes until the mixture is uniformly mixed. After stirring at 50 ℃ for 1 day, the solution was suspended, centrifuged, and dried to obtain 182mg of a solid.
The XRPD detection shows that the X-ray powder diffraction pattern expressed by 2 theta angle 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, 16.814 +/-0.2 degrees, 18.511 +/-0.2 degrees, 20.424 +/-0.2 degrees, 22.910 +/-0.2 degrees, 25.631 +/-0.2 degrees, 26.857 +/-0.2 degrees, 31.064 +/-0.2 degrees, 33.229 +/-0.2 degrees, 35.260 +/-0.2 degrees, 36.131 +/-0.2 degrees, 37.594 +/-0.2 degrees, 38.678 +/-0.2 degrees and 39.470 +/-0.2 degrees, and the XRPD pattern is shown as figure 2.
Example 2 preparation of crystalline form B of a 7, 8-dihydroxyflavone derivative according to formula I:
50mg of the crystal form A of the 7, 8-dihydroxyflavone derivative shown in the formula I prepared in the example 1 is placed in a 2ml glass bottle, 1ml of mixed solvent (tetrahydrofuran: water volume ratio is 1:1) is added, vortex is carried out for 2min, and the mixture is uniformly mixed. Shaking at 50 deg.C for 24 hr to obtain suspension, and centrifuging and drying to obtain crystal form B.
According to XRPD detection, an X-ray powder diffraction pattern expressed by 2 theta angles shows that the diffraction peaks of 7.294 + -0.2 degrees, 15.44 + -0.2 degrees, 7.294 + -0.72 + -0 degree, 7.294 + -0.2 degrees, 7.294 + -0.72 + -0 degrees, 7.294 + -0.72 + -0.2 degrees, 7.294 + -0.72 + -0 degrees, 7.294 + -0.72 degrees, 7.294 + -0.2 degrees, 7.294 + -0.72 degrees, 7.294 + -0 degrees, 7.294 + -0.72 degrees, and 7.294 + -0.72 degrees, are shown in a diffraction peak value of a 7.294 + -0 degree, a chart (shown in a chart of a peak error (shown in a chart of the XRPD error, a chart of the XRPD error, a chart of the same as shown in the same as a chart, a.
Table 37, PXRD characteristic peaks of crystalline form B of 8-dihydroxyflavone derivative
Figure BDA0002641423840000091
Figure BDA0002641423840000101
Figure 4 is an XRPD pattern of form B and starting material form a obtained in examples 2-6. In fig. 4, the starting compound refers to form a of the starting material.
The weight loss at 100 +/-2 ℃ is 1.978 percent of the weight before the weight loss through TGA detection, and the TGA spectrum is shown in figure 5.
It has an absorption peak at 210.9 + -10 deg.C and a heat of fusion of 317.7J/g as determined by DSC, and an absorption peak at 241.87 + -10 deg.C and a heat of fusion of 17.04J/g.
In the dynamic water absorption Diagram (DVS) of the crystal form B of the 7, 8-dihydroxyflavone derivative shown in the formula I, the weight is increased by 2.3 percent within the relative humidity range of 10-90 percent, and the DVS diagram is shown in figure 6.
FIG. 7 is a plot of mass versus humidity as a function of time in a DVS test.
Example 3 preparation of crystalline form B of a 7, 8-dihydroxyflavone derivative according to formula I:
in this example, the operation and conditions were the same as in example 1 except that the solvent in example 2 was replaced with 1ml of a mixed solvent (acetonitrile: water volume ratio: 1), thereby obtaining crystal form B. The identification data are as in example 2.
Example 4 preparation of crystalline form B of a 7, 8-dihydroxyflavone derivative according to formula I:
in this example, the operation and conditions were the same as in example 1 except that the solvent in example 2 was replaced with 1ml of the mixed solvent (acetone: water volume ratio: 1), to obtain crystal form B. The identification data are as in example 2.
Example 5 preparation of crystalline form B of a 7, 8-dihydroxyflavone derivative according to formula I:
in this example, the operation and conditions were the same as in example 1 except that the solvent in example 2 was replaced with 1ml of the mixed solvent (ethanol: water volume ratio: 1), to obtain crystalline form B. The identification data are as in example 2.
Example 6 preparation of crystalline form B of a 7, 8-dihydroxyflavone derivative according to formula I:
in this example, the operation and conditions were the same as in example 1 except that the solvent in example 2 was replaced with 1ml of the mixed solvent (methanol: water volume ratio: 1), to obtain crystalline form B. The identification data are as in example 2.
Example 750 ℃ suspension method magnification test
An amplification test was performed by a suspension method at 50 ℃ in a mixed solvent (ethanol: water ═ 1: 1). 500mg of the crystal form A of the 7, 8-dihydroxyflavone derivative shown in the formula I prepared in example 1 was weighed into a 40mL glass bottle, 10mL of a mixed solvent was added, and shaking was carried out for 2 minutes until uniform mixing was achieved. Stirring for 1 day at 50 deg.C to obtain suspension, centrifuging, and drying to obtain crystal form B. Identification data the same as in example 2
Example 855 ℃ suspension method
50mg of the crystalline form A of the 7, 8-dihydroxyflavone derivative represented by the formula I obtained in example 1 was weighed into a 2mL glass bottle, 1mL of a solvent (as shown in Table 4) was added, and then vortexed for about 2 minutes, and mixed well. Followed by shaking at 55 ℃ for 1 day. After shaking, the mixture is observed to be in a suspension state, and vacuum drying is carried out overnight at the temperature of 30 ℃ to obtain a dry crystal form B. The characterization results are shown in table 4 and fig. 8-9, and crystal form B is generated in mixed solvents of acetone/11, 16, 31, 42, and 79% water.
TABLE 4
Figure BDA0002641423840000121
Wherein: the mixture in the table refers to a mixture of the crystal form A and the crystal form B. ② acetone/3% water means that the parts of acetone and water are 100 parts, 97 parts of acetone and 3 parts of water.
FIG. 8 shows XRPD patterns of wet products obtained in example 8 at different solvent ratios. Wherein the starting compound is form a.
FIG. 9 shows the XRPD patterns of the dried products obtained in example 8 with different solvent ratios. Wherein the starting compound is form a.
Effect example 1 stability of Crystal form B of 7, 8-dihydroxyflavone derivative represented by formula I under high humidity conditions
An appropriate amount of the crystalline form B sample of the 7, 8-dihydroxyflavone derivative represented by formula I prepared in example 5 was placed on a petri dish and left open under high humidity conditions of 25 ℃/60% RH and 40 ℃/75% RH, respectively. The sample was taken for 7 days for X-ray powder diffraction characterization, with specific results in fig. 10, table 5.
As can be seen from the X-ray powder diffraction pattern of FIG. 10, the crystal form B of the 7, 8-dihydroxyflavone derivative shown in the formula I is respectively placed at 25 ℃/60% RH and 40 ℃/75% RH for 7 days, the crystal form has no crystal transformation phenomenon, hardly generates any change, and is relatively stable under high humidity conditions.
TABLE 5
Figure BDA0002641423840000131
Effect example 2 hygroscopicity of crystalline form B of 7, 8-dihydroxyflavone derivative represented by formula I
Taking about 10-15 mg of the crystal form B sample of the 7, 8-dihydroxyflavone derivative shown in the formula I prepared in the example 2, drying the sample for 120 minutes under the condition of humidity of 0% RH, testing the moisture absorption characteristic of the sample when the humidity is changed from 90% RH to 10% RH and the moisture removal characteristic of the sample when the humidity is changed from 10% RH to 90% RH, wherein the humidity change step length is 10% RH, the weight change rate is less than 0.01%/min within 5min of the equilibrium standard, and the longest equilibrium time is 180 minutes.
The results show that: the crystal form B of the 7, 8-dihydroxyflavone derivative shown in the formula I has the increased mass compared with the initial mass, the weight of a sample is increased by 2.3% from 10% RH to 90% RH, and the crystal form B has hygroscopicity, which is shown in fig. 6.
Comparative example 1
11 groups of experiments are carried out in parallel, crystal form A of the 7, 8-dihydroxyflavone derivative is respectively prepared, and the preparation method comprises the following steps:
50mg of the 7, 8-dihydroxyflavone derivative crystal form A shown in the formula I prepared in the example 1 is placed in a 2ml glass bottle, added into 1ml of solvent (wherein the solvent is respectively isopropanol, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, toluene or 1, 4-dioxane), vortexed for 2min and mixed uniformly. Shaking at 50 deg.C for 24 hr, observing to obtain suspension, and centrifuging to obtain solid.
The identification data is the same as the XRPD pattern of the crystal form A in example 1, so that the crystal form A of the 7, 8-dihydroxyflavone derivative is still prepared by a suspension method by using the solvent.
Wherein, when the solvent is isobutanol, the crystallinity of the obtained form A is enhanced. When acetone is used as the solvent, the crystallinity of the obtained crystal form A is reduced.
Comparative example 2 antisolvent experiment
N, N-dimethylformamide and dimethyl sulfoxide are selected as solvents, 20mg of the 7, 8-dihydroxyflavone derivative crystal form A shown in the formula I prepared in the example 1 is weighed into a 40mL glass bottle, 1mL of the solvent is added for vortex and complete dissolution, then 1-10mL of an anti-solvent is gradually added until the compound is completely separated out, and the type and the dosage of the anti-solvent are shown in Table 6. XRPD characterization after centrifugation confirmed the crystalline state as shown in table 6. This comparative example illustrates that the anti-solvent process does not produce form B.
TABLE 6
Figure BDA0002641423840000141
Wherein "N/A" means a state without any crystal form.
Comparative example 360 ℃ heating and cooling method
Heating and cooling experiments were performed in different solvents. Selecting the solvent in the table 7, weighing 10mg of the crystal form A of the 7, 8-dihydroxyflavone derivative shown in the formula I prepared in the example 1 into a 2mL glass bottle, adding 1.8mL of the solvent, vortexing for 2 minutes to form a supersaturated solution, shaking for one day at 60 ℃, observing that acetonitrile, acetone, methyl ethyl ketone and 1, 4-dioxane are clear solutions, and cooling to room temperature to precipitate in the acetonitrile and the 1, 4-dioxane. XRPD results indicated precipitation as initial form a.
TABLE 7
Figure BDA0002641423840000142
Figure BDA0002641423840000151
Wherein "N/A" means a state without any crystal form.
Comparative example 4 grinding method
A small amount of the 7, 8-dihydroxyflavone derivative crystal form A prepared in example 1 and shown in formula I is ground in a mortar for 20 minutes, and XRPD characterization is carried out on the sample. XRPD characterization results show that after grinding, the crystal form of the compound is kept unchanged and still is the crystal form A, and the crystallinity is reduced.

Claims (10)

1. A crystal form B of a 7, 8-dihydroxyflavone derivative shown as a formula I is characterized in that in a powder X-ray diffraction spectrum using a radiation source of Cu-Kalpha, characteristic diffraction peaks exist at diffraction angles 2 theta of 7.294 degrees, 9.622 degrees, 11.061 degrees, 17.079 degrees, 22.167 degrees, 22.404 degrees, 23.805 degrees, 26.642 degrees, 29.188 degrees and 32.759 degrees, and the error range of 2 theta is +/-0.2;
Figure FDA0002641423830000011
2. the crystalline form B of a 7, 8-dihydroxyflavone derivative according to claim 1, which is represented by formula I, characterized in that it has characteristic peaks at 7.294 °, 9.622 °, 11.061 °, 17.079 °, 20.035 °, 21.889 °, 22.167 °, 22.404 °, 23.805 °, 24.177 °, 24.733 °, 26.642 °, 29.188 °, 32.759 ° and 33.091 ° by X-ray powder diffraction at an angle of 2 θ;
and/or in a thermogravimetric analysis map of the crystal form B of the 7,8-dihydroxy flavone derivative shown in the formula I, the weight loss at 100 +/-2 ℃ accounts for 1.978% of the weight before weight loss, and the "%" is the mass percentage;
and/or the crystal form B of the 7, 8-dihydroxyflavone derivative shown in the formula I is a solvate-free crystal form.
3. The crystalline form B of a 7, 8-dihydroxyflavone derivative according to claim 1, which is characterized by having characteristic peaks at 7.294 °, 9.622 °, 11.061 °, 15.44 °, 17.079 °, 18.104 °, 19.266 °, 20.035 °, 20.686 °, 21.597 °, 21.889 °, 22.167 °, 22.404 °, 23.805 °, 24.177 °, 24.733 °, 25.364 °, 26.642 °, 26.998 °, 27.392 °, 29.188 °, 31.098 °, 32.759 °, 33.091 °, 34.454 ° and 36.585 ° by X-ray powder diffraction at an angle of 2 Θ;
and/or, in the differential scanning heat map of the crystal form B of the 7,8-dihydroxy flavone derivative shown in the formula I, an absorption peak with the heat of fusion of 317.7J/g is at 210.9 +/-10 ℃, and an absorption peak with the heat of fusion of 17.04J/g is at 241.87 +/-10 ℃;
and/or in the dynamic moisture adsorption pattern of the crystal form B of the 7,8-dihydroxy flavone derivative shown in the formula I, the weight gain is less than 2.5 percent, such as 2.3 percent, within the relative humidity range of 10-90 percent, and the "%" is the mass percentage of the added mass of the crystal form B of the 7,8-dihydroxy flavone derivative shown in the formula I in the initial mass.
4. The crystal form B of the 7,8-dihydroxy flavone derivative shown in the formula I according to claim 1, wherein the crystal form B of the 7,8-dihydroxy flavone derivative shown in the formula I has characteristic peaks at 7.294 °, 9.622 °, 11.061 °, 11.932 °, 15.44 °, 17.079 °, 18.104 °, 19.266 °, 20.035 °, 20.686 °, 21.201 °, 21.597 °, 21.889 °, 22.167 °, 22.404 °, 23.805 °, 24.177 °, 24.733 °, 25.364 °, 26.642 °, 26.998 °, 27.392 °, 28.559 °, 27.888 °, 29.188 °, 30.419 °, 31.098 °, 32.759 °, 33.091 °, 33.764 °, 34.454 °, 35.085 °, 36.585 ° and 36.82 ° by X-ray powder diffraction represented by an angle of 2 θ.
5. The crystalline form B of a 7, 8-dihydroxyflavone derivative according to claim 1, which is represented by formula I, wherein the X-ray powder diffraction pattern of the crystalline form B of a 7, 8-dihydroxyflavone derivative according to formula I is represented by figure 3;
and/or the thermogravimetric analysis graph of the crystal form B of the 7, 8-dihydroxyflavone derivative shown in the formula I is shown in figure 5;
and/or the dynamic moisture adsorption pattern of the crystal form B of the 7, 8-dihydroxyflavone derivative shown in the formula I is shown in figure 6.
6. A process for the preparation of crystalline form B of a 7, 8-dihydroxyflavone derivative according to formula I, as defined in any one of claims 1 to 5, characterized in that it comprises the following steps: dissolving the crystal form A of the 7, 8-dihydroxyflavone derivative shown as the formula I in a mixed solvent and shaking the mixed solvent to obtain the crystal form A;
the mixed solvent comprises an organic solvent and water; the volume ratio of the organic solvent to the water is 1: (0.05-4); the organic solvent comprises C3～6Ketone solvent, nitrile solvent, C1～4One or more of alcohol solvents and ether solvents.
7. The preparation method of the crystal form B of the 7,8-dihydroxy flavone derivative shown in the formula I as claimed in claim 6, wherein the shaking temperature is 30-70 ℃;
and/or the shaking time is 20-30 h, such as 24 h;
and/or the volume ratio of the organic solvent to the water is 1: (0.1 to 3.8), preferably 1:0.12 to 3.76, such as 1:0.19, 1:0.45, 1:0.72, 1:1, 1:1.5, 1:2 or 1: 3;
and/or the concentration of the crystal form A of the 7, 8-dihydroxyflavone derivative shown in the formula I in the mixed solution is 40-60 mg/mL, preferably 45-55 mg/mL, such as 50 mg/mL.
8. Preparation method of crystal form B of 7, 8-dihydroxyflavone derivative shown as formula I in claim 7Method characterized in that C is3～6The ketone solvent is C3～4Ketone solvents, preferably acetone;
and/or, the nitrile solvent is acetonitrile;
and/or, said C1～4The alcohol is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol, preferably methanol and/or ethanol;
and/or the ether solvent is one or more of tetrahydrofuran, 1, 4-dioxane, diethyl ether and methyl tert-butyl ether, and is preferably tetrahydrofuran and/or 1, 4-dioxane.
9. The application of the crystal form B of the 7, 8-dihydroxyflavone derivative shown as the formula I in any one of claims 1 to 5 in preparing medicines for preventing and/or treating diseases related to tyrosine kinase B receptors.
10. A pharmaceutical composition, which comprises the crystal form B of the 7, 8-dihydroxyflavone derivative shown in the formula I as claimed in any one of claims 1 to 5 and one or more pharmaceutically acceptable auxiliary materials.
CN202010841093.6A 2020-08-20 2020-08-20 Crystal form B of 7, 8-dihydroxyflavone derivative, and preparation method and application thereof Pending CN114075162A (en)

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