WO2017016512A1 - New crystalline form of masitinib mesylate and preparation method therefor - Google Patents

Abstract

The present invention provides a crystalline form A of masitinib mesylate, a preparation method therefor and a medical use thereof. The hygroscopicity of crystalline form A is remarkably reduced. Therefore, it is convenient for medicaments preparation and long-term storage.

Description

New crystal form of masatinib mesylate and preparation method thereof Technical field

The invention relates to the field of chemical medicine, in particular to a new crystal form of macetinib mesylate and a preparation method thereof.

Background technique

Marsetinib (a compound of formula I) is a novel orally administered tyrosine kinase inhibitor developed by AB Sciences that inhibits a limited number of kinase-targeted mast cells and macrophages. Based on its unique mechanism of action, Marsetini has the potential to develop a variety of diseases such as tumors, inflammatory diseases, and central nervous system. The mesylate salt of masatinib is used in clinical research and is currently in clinical phase III. The US FDA granted macitinib (massetinib) to orphan drug status in amyotrophic lateral sclerosis (ALS) in March 2015. And AB Science will submit a conditional marketing approval application to the European Medicines Agency EMA for the treatment of amyotrophic lateral sclerosis (ALS) disease.

Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and may also have different effects on drug stability, bioavailability, and efficacy. Therefore, in the development of drugs, the issue of drug polymorphism should be fully considered.

At present, the patent CN103342701A of AB Science discloses the mesylate salt of the compound of the formula (I). a polymorph (ie, Form I below) characterized by an X-ray diffraction pattern comprising 2θ values at about 7.269, 9.120, 11.038, 13.704, 14.481, 15.483, 15.870, 16.718, 17.087, 17.473, 18.224, 19.248, 19.441, 19.940, 20.441, 21.469, 21.750, 22.111, 23.319, 23.763, 24.120, 24.681, 25.754, 26.777, 28.975, 29.609, 30.073 with characteristic peaks, the crystal form Extremely high humidity, not conducive to drug storage. In addition, U.S. Application No. US20150166524 A1 to SANDOZ AG discloses the crystal form H of the methanesulfonate salt of the compound of the formula (I), which has a complicated preparation process and a long crystallization cycle, and has many limitations in the industrialization process.

Based on the deficiencies of the prior art, the inventors of the present invention surprisingly discovered in the course of the research that there is also a stable, industrially produced crystal form of the macetinib mesylate salt. In order to keep the drug stable during preparation, storage and formulation development, it provides more and better choice for drug development.

Summary of the invention

It is an object of the present invention to provide a novel crystalline form of masatinib mesylate, designated as Form A, which has low hygroscopicity for ease of preparation and long term storage of the drug.

The present invention provides a crystalline form A of a mesylate salt of the compound of the formula (I) (ie, Masitinib mesylate),

The X-ray powder diffraction pattern has characteristic peaks at 2theta values of 20.7 ° ± 0.2 °, 18.2 ° ± 0.2 °, and 21.1 ° ± 0.2 °.

According to a particular aspect of the invention, the X-ray powder diffraction pattern of Form A is still in 2theta The values have characteristic peaks at 20.3 ° ± 0.2 °, 23.6 ° ± 0.2 °, and 11.5 ° ± 0.2 °. Further, the X-ray powder diffraction pattern of Form A also has a characteristic peak at a 2theta value of 19.9 ° ± 0.2 °, 29.6 ° ± 0.2 °, and 10.5 ° ± 0.2 °.

According to still another specific aspect of the invention, the X-ray powder diffraction pattern of Form A also has a characteristic peak at a 2theta value of 10.5 ± 0.2° and/or 11.5 ° ± 0.2°.

According to still another specific aspect of the invention, the X-ray powder diffraction pattern of Form A also has a characteristic peak at a 2theta value of 18.6 ± 0.2° and/or 27.4 ° ± 0.2°.

In a specific embodiment, the X-ray powder diffraction pattern of Form A of the present invention is substantially as shown in FIG.

The crystal form A provided by the present invention is further characterized in that an endothermic peak starts to appear near the temperature of 108 ° C, and an exothermic peak starts to appear near the temperature of 178 ° C, and another endothermic peak starts to appear near the temperature of 232 ° C, and its DSC Basically as shown in Figure 2.

The crystal form A provided by the present invention is further characterized in that it has a weight loss gradient of about 6.44% when heated to 100 ° C, and its TGA is substantially as shown in FIG. It can be calculated from the TGA chart that when heated to 100 ° C, Form A loses about 2 molecules of water.

Another object of the present invention is to provide a process for the preparation of Form A comprising the amorphous or solvate of the methanesulfonate salt of the compound of the formula (I) in a cyclic ether, an aromatic hydrocarbon, a halogenated hydrocarbon organic solvent or Crystallization is carried out in a mixed solvent with water.

Further, the cyclic ether solvent is preferably 2-methyltetrahydrofuran. The halogenated hydrocarbon solvent is preferably dichloromethane. The means or manner of crystallization is preferably stirred and crystallized.

According to a preferred aspect of the present invention, the methanesulfonate chloroform solvate of the compound of the formula (I) is suspended in 2-methyltetrahydrofuran, dichloromethane or a mixture of the two, stirred at 10 ° C or less, and centrifuged. The lower layer of solid was dried overnight at a constant temperature to obtain Form A. Preferably, the stirring is carried out at 5 ° C and below, for example 5 ° C.

According to still another aspect of the present invention, Form A can be obtained by subjecting the methanesulfonate chloroform solvate of the compound of the formula (I) to humidity control-induced crystallization (transcrystallization). Further, humidity control induced crystallisation can be performed on an existing dynamic moisture adsorption tester, and the conditions employed can be the usual test conditions. The selected initial humidity may be from 40% relative humidity to 80% relative humidity, and the selected endpoint humidity is from 90% relative humidity to 95% relative humidity. The induction temperature selected is from 0 ° C to 40 ° C, more preferably from 20 ° C to 30 ° C. The residence time of each humidity condition is not higher than 180 minutes, and the humidity change interval is not more than 10% relative humidity.

Further, the preparation method of the present invention further comprises the step of suspending the amorphous methanesulfonate salt of the compound of the formula (I) in chloroform and stirring to obtain a methanesulfonate chloroform solvate of the compound of the formula (I).

Further, the amorphous methanesulfonate of the compound of the formula (I) can be obtained by dissolving a crystalline form such as CN103342701A in a solvent such as methanol, ethanol or a mixed solvent thereof with other solvents, followed by rapid evaporation, and other solvents such as isopropyl. Alcohol, acetonitrile, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl ethyl ketone, ethyl acetate, dichloromethane and the like. Alternatively, it can also be obtained by freeze-drying a product solution containing the methanesulfonate salt of the compound of the formula (I).

In the present invention, "crystal" or "crystal form" refers to the characterization by the X-ray diffraction pattern shown. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ±0.2° is usually allowed. In addition, due to the sample The influence of experimental factors such as height will cause an overall shift in the peak angle, usually allowing a certain offset. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of one crystal form in the present invention need not be identical to the X-ray diffraction pattern in the examples referred to herein. Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention. One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.

"Crystal form" and "polymorph" and other related terms are used in the present invention to mean that a solid compound exists in a specific crystalline state in a crystal structure. The difference in physical and chemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate and the like. In extreme cases, differences in solubility or dissolution rate can cause drug inefficiencies and even toxicity.

In some embodiments, the novel crystalline form of the masatinib mesylate salt in the present invention, Form A, is pure, unitary, and substantially free of any other crystalline form. In the present invention, "substantially free" when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.

It should be noted that the numerical values and numerical ranges recited in the present invention are not to be construed as narrowly construed as a numerical value or a numerical range per se. It will be understood by those skilled in the art that they may vary depending on the specific technical environment without departing from the spirit of the invention. On the basis of the principle, there are fluctuations around specific numerical values. In the present invention, such a floating range which can be foreseen by those skilled in the art is often expressed by the term "about".

Polymorphic forms of the drug can be obtained by methods including, but not limited to, melt recrystallization, melt cooling, solvent recrystallization, solvent loss, rapid volatilization, rapid temperature drop, slow temperature drop, vapor diffusion, and sublimation. Sometimes, different methods may also achieve the same crystallization. Polymorphs can be obtained by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), optical microscopy, Hygroscopicity, etc. to detect, discover and classify. The crystal form adopted by the crystal form of the present invention is a crystal slurry method in which a supersaturated solution of a sample (in the presence of insoluble solids) is stirred and crystallized in a solvent system, and the crystallization time is usually 24-72 hours.

Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of Form A of a compound of formula (I) mesylate and a pharmaceutically acceptable adjuvant. Typically, a therapeutically effective amount of Form A of the methanesulfonate salt of a compound of formula (I) is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation in the pharmaceutical field. Prepared in a manner well known in the art. Furthermore, the pharmaceutical composition may also comprise other crystalline forms or amorphous forms of pharmaceutically acceptable methicinib or a salt thereof, including, but not limited to, the known crystal forms disclosed in, for example, the patents CN103342701A and US20150166524 A1. .

The present invention also provides the use of the crystalline form A of the methanesulfonate salt of the compound of the formula (I) for the preparation of a pharmaceutical preparation for treating various diseases such as tumors, inflammatory diseases, and central nervous system.

The present invention also provides the use of the crystalline form A of the mesylate salt of the compound of the formula (I) or a pharmaceutical composition comprising the same for the treatment of diseases such as tumors, inflammatory diseases, central nervous system and the like.

The crystal form A of the compound of the formula (I) provided by the invention has a significantly lower wettability than the existing crystal form, and is convenient for preparation and long-term storage of the medicine, and has higher industrial application value.

DRAWINGS

Figure 1 is an XRPD pattern of the mesylate salt form A of the compound of formula (I)

Figure 2 is a DSC chart of the methanesulfonate salt form A of the compound of formula (I);

Figure 3 is a TGA diagram of the methanesulfonate salt form A of the compound of formula (I);

Figure 4 is a ¹ H-NMR chart of the methanesulfonate salt form A of the compound of the formula (I);

Figure 5 is an infrared spectrum of the methanesulfonate crystal form A of the compound of the formula (I);

Figure 6 is a DVS dynamic moisture adsorption diagram of the methanesulfonate salt form A of the compound of formula (I);

Figure 7 is an XRPD pattern of the methanesulfonate crystal form A of the compound of the formula (I) before and after DVS (the upper graph is an XRPD pattern before DVS, and the lower graph is an XRPD pattern after DVS);

Figure 8 is an XRPD pattern of the methanesulfonate salt form A of the compound of the formula (I) before and after being placed at 5 ° C for 270 days (the upper graph is obtained before the test, and the lower graph is obtained after the test);

Figure 9 is an XRPD diagram of the compound (I) mesylate salt Form A before and after 270 days of standing at 25 ° C, 60% relative humidity. The figure is the pre-placement test, the lower figure is the test after placement;

Figure 10 is an XRPD pattern of the compound (I) mesylate salt form A before and after being placed at 40 ° C, 75% relative humidity for 270 days. The figure above shows the pre-placement test, and the lower figure shows the test after placement.

detailed description

The invention is further illustrated by the following examples, but is not intended to limit the scope of the invention. Improvements in the method of preparation and use of the apparatus may be made by those skilled in the art within the scope of the claims, and such modifications are also considered to be within the scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.

In the following examples, the test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer. The starting material is the methanesulfonate salt of the compound of formula (I).

The abbreviations used in the present invention are explained as follows:

XRPD: X-ray powder diffraction; DSC: differential scanning calorimetry

TGA: thermogravimetric analysis; ¹ H NMR: liquid nuclear magnetic resonance spectrum

The X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer. The method parameters of the X-ray powder diffraction described in the present invention are as follows:

X-ray reflection parameters: Cu, Kα

1.540598;

1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 volts (kV); current: 40 milliamperes (mA); scanning range: from 3.0 to 40.0 degrees.

The differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000. The method parameters of differential scanning calorimetry (DSC) according to the present invention are as follows: scan rate: 10 ° C / min; protective gas: nitrogen.

The thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000. The method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows: scan rate: 10 ° C / min; protective gas: nitrogen.

Example 1

Preparation of the amorphous form of the compound of formula (I) mesylate:

495.6 mg of the starting material of the compound of the formula (I) methanesulfonate was dissolved in 20 mL of methanol and rapidly evaporated at 50 ° C. The obtained solid was an amorphous form of the compound of the formula (I) methanesulfonate.

Example 2

Preparation of the compound mesylate salt solvate of formula (I):

The solid obtained in Example 1 was suspended in 15.0 mL of chloroform, stirred at 5 ° C for 24 hours, and the lower solid was removed by centrifugation, and dried at 25 ° C overnight. The obtained solid was a chloroform solvate of the methanesulfonate salt of the compound of the formula (I). The solvate temperature of the chloroform solvate is 130-150 °C.

Example 3

Preparation method of the compound (I) mesylate salt form A:

Taking 100.3 mg of the chloroform solvate of the compound of the formula (I) methanesulfonate suspended in 3.0 mL of 2-methyl The mixture was stirred at 5 ° C for 15 minutes in tetrahydrofuran, and the lower solid was collected by centrifugation, and dried at 25 ° C overnight. The obtained solid was crystal form A.

The XRPD pattern of the crystal form A obtained in this example is shown in Fig. 1, and the X-ray powder diffraction data is shown in Table 1.

Table 1

2theta	d interval	strength%
10.52	8.41	29.07
11.55	7.66	41.97
14.75	6.01	13.25
15.54	5.70	27.64
16.90	5.25	24.96
17.55	5.05	23.32
18.22	4.87	65.92
18.69	4.75	18.63
19.88	4.47	32.86
20.34	4.37	54.34
20.68	4.30	100.00
21.12	4.21	58.98
21.55	4.12	29.34
21.86	4.07	24.59
22.66	3.92	12.32
23.57	3.78	50.20
24.39	3.65	27.61
25.64	3.47	33.49
25.98	3.43	31.04

26.59	3.35	23.49
27.35	3.26	18.22
28.49	3.13	7.61
29.60	3.02	32.01
31.91	2.80	8.90
34.12	2.63	15.03
35.31	2.54	6.23
36.95	2.43	8.66

The DSC chart of Form A is shown in Fig. 2, the TGA chart is shown in Fig. 3, the NMR spectrum is shown in Fig. 4, and the infrared spectrum is shown in Fig. 5. among them:

The NMR data are as follows: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 9.47 (s, 1H), 9.34 (s, 1H), 9.18 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.50 (dd, J ₁ = 4.8 Hz, J ₂ = 1.4 Hz, 1H), 8.36 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.52 - 7.41 (m, 4H), 7.36 (dd, J ₁ = 8.2, J ₂ = 2.0 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 3.66 (s) , 2H), 3.10-2.89 (m, 4H), 2.79 (s, 3H), 2.40-2.23 (m, 8H).

The infrared spectrum peaks (cm ^-1 , ± 2 cm ^-1 ) are as follows: 410.06, 456.14, 528.31, 582.75, 624.26, 675.17, 722.83, 762.33, 779.69, 806.04, 821.41, 858.11, 883.70, 916.75, 982.61, 1006.59, 1027.47, 1123.50 ,1176.82,1217.89,1277.78,1316.66,1357.31,1406.30,1448.99,1527.63,1558.05,1599.06,1665.09,2789.99,3260.24,3415.16.

Example 4

Preparation method of the compound (I) mesylate salt form A:

9.6 mg of the chloroform solvate of the compound of the formula (I) methanesulfonate was suspended in 0.4 mL of dichloromethane, stirred at 5 ° C for 10 minutes, centrifuged to remove the solid, and dried at 25 ° C overnight to obtain a solid. The X-ray powder diffraction data is shown in Table 2, indicating that the solid is Form A.

Table 2

2theta	d interval	strength%
5.00	17.67	4.19
10.61	8.34	31.26
11.60	7.63	25.91
12.33	7.18	6.90
14.94	5.93	11.55
15.14	5.85	18.92
15.63	5.67	21.85
16.44	5.39	11.72
16.96	5.23	16.34
18.28	4.85	31.57
18.55	4.78	21.26
19.86	4.47	32.40
20.33	4.37	100.00
20.68	4.29	53.24
21.13	4.20	54.03
21.40	4.15	34.18
21.89	4.06	13.02
23.22	3.83	14.67
23.60	3.77	29.18
24.62	3.62	21.63
25.43	3.50	22.72
26.06	3.42	13.00

26.63	3.35	11.02
27.46	3.25	8.17
28.07	3.18	7.60
28.47	3.14	6.68
29.64	3.01	15.82
30.68	2.91	12.29
31.87	2.81	6.46
34.16	2.62	7.79
35.42	2.53	3.34
37.01	2.43	3.09

Example 5

Preparation method of the compound (I) mesylate salt form A:

The methanesulfonate crystal form A is induced by the humidity control to induce the chloroform solvate of the compound mesylate salt. The specific operation is as follows: 60.2 mg of the chloroform solvate of the methanesulfonate salt of the compound of the formula (I) is placed in the dynamic moisture. In the adsorption apparatus (DVS), the experiment was started according to a preset humidity cycle, and the X-ray powder diffraction data of the solid obtained after the completion of the experiment are shown in Table 3, indicating that the solid was the crystal form A.

table 3

2theta	d interval	strength%
5.22	16.94	4.43
9.92	8.92	7.04
10.27	8.61	1.75
10.49	8.43	12.24
11.53	7.68	38.48
13.41	6.60	0.31

13.90	6.37	2.36
14.64	6.05	11.43
14.86	5.96	4.18
15.55	5.70	16.83
16.31	5.44	1.08
16.65	5.33	5.52
16.89	5.25	5.90
17.55	5.05	6.51
17.92	4.95	19.18
18.23	4.87	34.84
18.70	4.75	7.87
19.53	4.55	9.44
19.88	4.47	10.18
20.31	4.37	69.00
20.68	4.30	21.30
21.11	4.21	100.00
21.55	4.12	7.89
21.82	4.07	9.93
23.27	3.82	3.88
23.58	3.77	11.69
24.08	3.70	5.11
24.37	3.65	6.60
25.14	3.54	15.41
25.63	3.48	9.98
25.96	3.43	15.40
26.48	3.37	11.65

27.37	3.26	8.83
28.05	3.18	0.89
28.47	3.14	6.25
28.95	3.08	3.17
29.61	3.02	17.26
30.56	2.93	2.10
31.62	2.83	7.49
31.89	2.81	11.42
32.27	2.77	1.45
34.10	2.63	4.31
35.35	2.54	4.39
36.85	2.44	3.46
37.47	2.40	0.51
39.24	2.30	1.68

The dynamic moisture adsorption (DVS) experiment of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.), and the parameters used are shown in Table 4.

Table 4

Example 6

Taking about 10 mg of the methanesulfonate salt form A of the compound of the formula (I) of the present invention for dynamic moisture adsorption (DVS) After the test, the samples after the test were subjected to XRPD test, and the results are shown in Fig. 6, Fig. 7 and Table 5.

The dynamic moisture adsorption (DVS) test was carried out on the methanesulfonate crystal form disclosed in CN103342701A, and the moisture content at 80% relative humidity and 95% relative humidity is shown in Table 5.

table 5

The results show that the crystal form A of the present invention is placed under the condition of 80% relative humidity, and the weight gain after equilibrium is only 2.40%, and the wettability is lower, which is obviously superior to the mesylate salt form I disclosed in CN103342701A, which is convenient for medicine. Long-term storage. On the other hand, since the crystal form has low wettability, no special drying conditions are required in the preparation process, and the preparation and post-treatment process of the methanesulfonate of the compound of the formula (I) is simplified to some extent, and it is easy to industrialize.

Example 7

The methanesulfonate crystal form A of the compound of the formula (I) of the present invention is placed at 5 ° C; 25 ° C, 60% relative humidity; and 40 ° C, 75% relative humidity, respectively, for 270 days, and X before and after the sample is placed. Ray powder diffraction test, the results are shown in Figure 8-10.

The results show that the crystalline form A of the present invention is stable under normal storage conditions.

The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (12)

1. Form A of a mesylate salt of a compound of formula (I),

   

   It is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 20.7°±0.2°, 18.2°±0.2°, and 21.1°±0.2°.
2. The crystal form A according to claim 1, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 20.3 ° ± 0.2 °, 23.6 ° ± 0.2 °, and 11.5 ° ± 0.2 °.
3. The crystal form A according to claim 2, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 19.9 ° ± 0.2 °, 29.6 ° ± 0.2 °, and 10.5 ° ± 0.2 °.
4. The crystal form A according to claim 1, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 10.5 ± 0.2° and/or 11.5 ° ± 0.2°.
5. The crystal form A according to claim 1, wherein the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 18.6 ± 0.2° and/or 27.4 ° ± 0.2°.
6. Process for the preparation of a crystalline form A of a mesylate salt of a compound of the formula (I), characterized in that the methanesulfonate salt of the compound of the formula (I) is amorphous or solvate in cyclic ethers, aromatic hydrocarbons, halogenated A hydrocarbon organic solvent or a reaction mixture thereof with water is obtained by reaction crystallization.
7. The process according to claim 6, wherein the cyclic ether solvent comprises 2-methyltetrahydrofuran, and the halogenated hydrocarbon solvent comprises dichloromethane.
8. The preparation method according to claim 6, wherein the reaction crystallization means is stirring and crystallization.
9. The process according to claim 6, wherein the methanesulfonate chloroform solvate of the compound of the formula (I) is suspended in 2-methyltetrahydrofuran, dichloromethane or a mixture of the two, and stirred at 10 ° C or lower. The solid is removed by centrifugation and dried to obtain crystal form A; or crystal form A is obtained by subjecting the compound of formula (I) to the chloroform solvate of the methanesulfonate to induce crystallization.
10. The method according to claim 9, wherein the method further comprises suspending the amorphous methanesulfonate salt of the compound of the formula (I) in chloroform, and stirring to obtain the methanesulfonate salt of the compound of the formula (I). The step of the chloroform solvate.
11. A pharmaceutical composition comprising an effective amount of the crystalline form A of the methanesulfonate salt of the compound of formula (I) according to any one of claims 1 to 5, and a pharmaceutically acceptable excipient.
12. Use of Form A of the methanesulfonate salt of the compound of formula (I) according to any one of claims 1 to 5 for the preparation of a pharmaceutical preparation for the treatment of tumors, inflammatory diseases, central nervous system diseases.

Images