Enzastaurin crystalline forms and methods of preparation thereof

Abstract

The application relates to a crystal form of entrectinib and a preparation method thereof, in particular to a crystal form A and a crystal form B of entrectinib. The crystal forms have better solubility, chemical and crystal form stability, no static electricity, good fluidity, easy to be prepared on a large scale, can be better applied to preparation of a pharmaceutical preparation and large-scale production, and have a wide application prospect.

Description

[0001] This application claims priority to the prior application filed on February 3, 2021 with the China National Intellectual Property Office, Patent Application No. 202110150771.9, entitled "Entrectinib Crystal Form and Preparation Method Thereof". The prior application is incorporated herein by reference in its entirety. TECHNICAL FIELD

[0002] The present application belongs to the technical field of pharmaceutical chemistry, and specifically relates to a new crystal form of entrectinib, and a preparation method and use of the new crystal form. BACKGROUND

[0003] Entrectinib, chemical name N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-[(tetrahydro-2H-pyran-4-yl)amino]benzamide, is used for treating adult and pediatric patients with advanced recurrent solid tumors positive for neurotrophic tyrosine receptor kinase (NTRK) fusion. Rozlytrek is the first drug approved in Japan for targeting NTRK gene fusion tumors, approved for use in a series of difficult-to-treat solid tumor types, including pancreatic, thyroid, salivary, breast, colorectal and lung cancer, etc.

[0004]

[0005] A plurality of crystal forms of entrectinib have been disclosed in prior art documents. For example: International Patent Application WO2013174876 of the original research company discloses entrectinib crystal forms 1, 2 and 3, wherein crystal form 3 is a solvate of ethyl acetate and n-hexane; International Patent Application WO2017202674 discloses entrectinib crystal form 4; Chinese Patent Application CN111171009A discloses 9 crystal forms AZT-A to AZT-I, wherein the preferred crystal forms are crystal form AZT-A, crystal form AZT-B and crystal form AZT-E.

[0006] The crystal forms 1, 2 and 4 are crystallized by using a mixed solvent of ethanol and water, and mixed crystals are prone to occur in the crystallization process, and very precise control is required to ensure that no mixed crystals occur, so that the industrial production is difficult. In addition, studies have shown that the crystal form 1 contains a large amount of amorphous substance, the crystallization system is viscous, and the filtration is difficult, which is not conducive to large-scale production, and the crystal form is unstable and is prone to convert into other crystal forms, so it is not suitable for medicinal use; the crystal form 3 is a solvate of ethyl acetate and n-hexane, and the solvent content exceeds the limit required by the ICH guideline, so it is not suitable for medicinal use; the crystallization solvent of the crystal form 4 is the same as that of the crystal form 2, and the crystal form 2 is prone to be obtained in the preparation process, so that there is a risk in production; encorafenib is a BCS classification 2, which belongs to a low-solubility-high-permeability drug, the solubility of the crystal form 2 is poor, and the particle size is large, so that micronization is required, and the micronized sample has problems of serious static electricity and poor flowability, which affects the preparation production; the particle size of the crystal forms AZT-A, AZT-B and AZT-E is large, so that micronization is required, and the micronized sample has problems of serious static electricity and poor flowability, that is, the uniformity of the mixed powder of the raw material is affected, and the preparation production is also adversely affected.

[0007] Therefore, there is an urgent need to find a new crystal form of encorafenib which has good stability, better solubility, no static electricity, good flowability, easy to realize large-scale production in the production process of the raw material and the preparation, and the production process is stable and will not be converted into other crystal forms or mixed crystals, so as to make up for the defects of the prior art.

[0008] In order to overcome the deficiencies of the existing crystal form technology of encorafenib, the inventors have made more in-depth and extensive research on the crystal form of encorafenib. In the process, new crystal forms of encorafenib are obtained, which have good stability, high purity and good solubility, do not need to be crushed, do not produce static electricity, the preparation method is suitable for large-scale production, and has strong practicability, which solves the deficiencies of the prior art. SUMMARY

[0009] The purpose of the present application is to provide new crystal forms of encorafenib which have good stability, high purity, simple preparation process and strong practicability, and a method for preparing the new crystal forms.

[0010] The first aspect of the present application provides a new crystal form A of encorafenib, which has characteristic diffraction peaks at 7.1°±0.2°, 7.7°±0.2°, 8.5°±0.2°, 10.5°±0.2°, 13.9°±0.2°, 15.6°±0.2° and 21.5°±0.2° in X-ray powder diffraction expressed by 2θ angle using Cu-Kα radiation.

[0011] Specifically, the X-ray powder diffraction of the entrectinib crystalline form A has characteristic diffraction peaks at 7.1°±0.2°, 7.7°±0.2°, 8.5°±0.2°, 10.5°±0.2°, 13.2°±0.2°, 13.9°±0.2°, 14.4°±0.2°, 15.6°±0.2°, 21.5°±0.2°, 22.6°±0.2°, 23.5°±0.2°, 24.6°±0.2°, 25.8°±0.2°, using Cu-Kα radiation, expressed in terms of 2θ angle.

[0012] More specifically, the X-ray powder diffraction of the entrectinib crystalline form A has characteristic diffraction peaks at 7.1°±0.2°, 7.7°±0.2°, 8.5°±0.2°, 10.5°±0.2°, 13.2°±0.2°, 13.9°±0.2°, 14.4°±0.2°, 15.6°±0.2°, 17.2°±0.2°, 18.9°±0.2°, 19.6°±0.2°, 21.5°±0.2°, 22.6°±0.2°, 23.5°±0.2°, 24.6°±0.2°, 25.8°±0.2°, using Cu-Kα radiation, expressed in terms of 2θ angle.

[0013] In a preferred embodiment of the present application, the entrectinib crystalline form A has the following characteristic peaks and relative intensities in powder X-ray diffraction:

[0014]

[0015]

[0016] In a preferred embodiment of the present application, the entrectinib crystalline form A has an X-ray powder diffraction pattern substantially as shown in Figure 1 .

[0017] It has been determined that the DSC pattern of the entrectinib crystalline form A has endothermic peaks in the range of 122.0-159.8℃, 193.2-206.4℃, respectively; specifically, the peak values of the endothermic peaks are 147.1±2℃, 198.0±0.1℃, respectively; more specifically, in an embodiment of the present application, the entrectinib crystalline form A has a DSC pattern substantially as shown in Figure 2 .

[0018] In an embodiment of the present application, the entrectinib crystalline form A has a TGA pattern substantially as shown in Figure 2 .

[0019] The second aspect of the present application provides a method for preparing the entrectinib crystalline form A, comprising the following steps:

[0020] The crude amorphous form of entrectinib is added into a mixed solvent of water and acetone, dissolved by heating and refluxing, and then gradually cooled to -5-20℃ under ultrasonic oscillation to crystallize, filtered, and dried at room temperature to obtain the entrectinib crystal form A.

[0021] The volume ratio of acetone to water is 1:0.1-2.0, preferably 1:0.8-1.5, and more preferably 1:1. The mass-volume ratio of the crude amorphous form of entrectinib to acetone is 1:5-40, preferably 1:7-20, and more preferably 1:8-15, unit: mg / mL.

[0022] The third aspect of the present application provides another method for preparing the entrectinib crystal form A, which comprises the following steps:

[0023] The crude amorphous form of entrectinib is added into an organic solvent, dissolved by heating, water and crystal seeds of the crystal form A are added, and then cooled to crystallize, filtered, and dried to obtain the entrectinib crystal form A.

[0024] The organic solvent is selected from one of isopropyl alcohol, acetone, acetonitrile, or any mixed solvent thereof.

[0025] The volume ratio of the organic solvent to water is 1:0.1-2.0, preferably 1:0.8-1.5, and more preferably 1:1. The mass-volume ratio of the crude amorphous form of entrectinib to the organic solvent is 1:5-40, preferably 1:7-30, and more preferably 1:8-15, unit: mg / mL.

[0026] The amount of the crystal seeds added is 0.1-1% of the amount of the crude amorphous form of entrectinib.

[0027] The crystallization temperature is -10-20℃, and preferably -5-5℃.

[0028] The fourth aspect of the present application provides another new entrectinib crystal form B, which has X-ray powder diffraction peaks at 8.5°±0.2°, 9.5°±0.2°, 10.4°±0.2°, 11.3°±0.2°, 14.4°±0.2°, 16.0°±0.2°, 18.5°±0.2°, 19.3°±0.2°, 20.5°±0.2°, 22.3°±0.2°, using Cu-Kα radiation, expressed by 2θ angle.

[0029] Preferably, the X-ray powder diffraction of the entrectinib Form B has diffraction peaks expressed in terms of 2θ angle using Cu-Kα radiation at 8.5°±0.2°, 9.5°±0.2°, 10.4°±0.2°, 11.3°±0.2°, 12.9°±0.2°, 13.8°±0.2°, 14.4°±0.2°, 16.0°±0.2°, 16.6°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 19.3°±0.2°, 20.5°±0.2°, 22.3°±0.2°, 22.8°±0.2°, 23.9°±0.2°, 24.2°±0.2°, 25.5°±0.2°, 30.1°±0.2°.

[0030] In a preferred embodiment of the present application, the entrectinib Form B has the following characteristic peaks and relative intensities in powder X-ray diffraction:

[0031] 2 theta Relative intensity 8.5°±0.2° 91％ 9.5°±0.2° 36％ 10.4°±0.2° 75％ 11.3°±0.2° 11％ 12.9°±0.2° 9％ 13.8°±0.2° 25％ 14.4°±0.2° 74％ 16.0°±0.2° 16％ 16.6°±0.2° 16％ 17.4°±0.2° 35％ 18.5°±0.2° 56％ 19.3°±0.2° 84％ 20.5°±0.2° 93％ 22.3°±0.2° 100％ 22.8°±0.2° 88％ 23.9°±0.2° 44％ 24.2°±0.2° 32％ 25.5°±0.2° 29％ 30.1°±0.2° 16％

[0032] In a preferred embodiment of the present application, the entrectinib Form B has an X-ray powder diffraction pattern substantially as shown in Figure 3 In a preferred embodiment of the present application, the entrectinib Form B has an X-ray powder diffraction pattern substantially as shown in

[0033] In a preferred embodiment of the present application, the entrectinib Form B has a DSC pattern substantially as shown in Figure 4 In a preferred embodiment of the present application, the entrectinib Form B has a DSC pattern substantially as shown in

[0034] In a preferred embodiment of the present application, the entrectinib Form B has a TGA pattern substantially as shown in Figure 4 In a preferred embodiment of the present application, the entrectinib Form B has a TGA pattern substantially as shown in

[0035] The fifth aspect of the present application provides a method for preparing the entrectinib Form B, which comprises the following steps:

[0036] The crude amorphous entrectinib is dissolved in dioxane by heating to 80℃, and then purified water is added. The mixture is cooled to -5-20℃ and kept for crystallization. The mixture is filtered and dried to obtain the entrectinib Form B.

[0037] Preferably, the volume ratio of dioxane to water is 1:0.2-2.0, preferably 1:0.6-1.4, and more preferably 1:0.8. The mass-volume ratio of the crude amorphous entrectinib to dioxane is 1:5-30, preferably 1:8-20, and more preferably 1:10-15, unit: mg / mL.

[0038] Advantages

[0039] The present application provides the crystal form A and the crystal form B of entrectinib, which have higher purity, excellent chemical stability and crystal form stability, and better solubility, and are more suitable for process production. The existing experimental data shows that the crystal form A and the crystal form B provided by the present application have obvious improvement and promotion in one or several aspects of particle size, static electricity, fluidity and dissolution rate, overcome the defects of the prior art, and are easy to be made into medicine and industrialized preparation, simple to operate, and have good controllability. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 X-RPD spectrum of the entrectinib crystal form A obtained in Example 2;

[0041] Figure 2 DSC-TGA spectrum of the entrectinib crystal form A obtained in Example 2;

[0042] Figure 3 X-RPD spectrum of the entrectinib crystal form B obtained in Example 5;

[0043] Figure 4 DSC-TGA spectrum of the entrectinib crystal form B obtained in Example 5;

[0044] Figure 5 Scanning electron microscope image of the entrectinib crystal form A obtained in Example 2;

[0045] Figure 6 Scanning electron microscope image of the entrectinib crystal form B obtained in Example 5;

[0046] Figure 7 Scanning electron microscope image of the crystal form 2 obtained in Reference Example 2;

[0047] Figure 8 Scanning electron microscope image of the crystal form AZT-A obtained in Reference Example 4;

[0048] Figure 9 Scanning electron microscope image of the crystal form AZT-B obtained in Reference Example 5;

[0049] Figure 10 Scanning electron microscope image of the crystal form AZT-E obtained in Reference Example 6. DETAILED DESCRIPTION

[0050] The above content of the present application will be further explained in detail through specific embodiments, but this should not be understood as any limitation to the protection subject of the present application. Any technical solution realized based on the above content of the present application belongs to the scope of the present application. The present application generally and / or specifically describes the materials used in the test and the test method; except for special description, the "room temperature" described in the present application has the common meaning in the art, specifically referring to 15-35℃, preferably 20-30℃, more preferably 20-25℃.

[0051] Instruments and methods used in the present application:

[0052] (1) X-ray powder diffractometer

[0053] Instrument model: PANalytical X-ray powder diffractometer

[0054] Test method: Fill the finely ground sample (100 mg) in the groove of a glass plate, and use a glass slide to align the plane of the sample with the glass surface, then place the sample in the PANalytical X-ray powder diffractometer, use a copper X-ray source with 40 kV and 40 mA, the scanning range is 3-45° (2θ), the scanning speed is 8° / min. The scanning error is usually ±0.2 degrees (2θ).

[0055] (2) TGA / DSC1 simultaneous thermal analyzer

[0056] Instrument model: METTLER TGA / DSC1.

[0057] Test method: Place 10 mg of sample in a sealed aluminum pan with a small pinhole, keep balance at 30℃, then heat to 250℃ at a scanning rate of 10℃ / min. Dry nitrogen is used as the purge gas.

[0058] (3) Electron microscope scanning

[0059] Instrument model: ZEISS Sigma 300 scanning electron microscope

[0060] Test method: Take an appropriate amount of test product, evenly spread it on a conductive tape, spray gold, and observe under the field of view of the electron microscope.

[0061] Reference Example 1: Preparation of entrectinib crystal form 1

[0062] Reference Example 1 : Preparation of crystalline Form 1 of Entrectinib

[0063] Reference Example 2: Preparation of crystalline Form 2 of Entrectinib

[0064] Reference Example 1 : Preparation of crystalline Form 1 of Entrectinib

[0065] Reference Example 3: Preparation of crystalline Form 4 of Entrectinib

[0066] Reference Example 1 : Preparation of crystalline Form 1 of Entrectinib

[0067] Reference Example 4: Reference to Example 1-1 of Chinese patent application CN111171009A

[0068] Reference Example 1 : Preparation of crystalline Form 1 of Entrectinib

[0069] Reference Example 5: Reference to Example 2-2 of Chinese patent application CN111171009A

[0070] Reference Example 1 : Preparation of crystalline Form 1 of Entrectinib

[0071] Reference Example 6: Reference to Example 5-2 of Chinese patent application CN111171009A

[0072] At room temperature, 0.3 g of entrectinib crystal form AZT-A obtained in Reference Example 4 was added into 1 ml of a mixed solvent of ethanol and purified water in a ratio of 3:1, and stirred at 5 °C for 24 h to obtain a solid, which is named as crystal form AZT-E in Chinese Patent Application CN111171009A.

[0073] Example 1 Preparation of entrectinib crystal form A

[0074] The crude amorphous 5.0 g of entrectinib was added into 70 ml of acetone and 70 ml of purified water, and dissolved by heating to reflux. Crystallization was carried out by gradually cooling to -5-20 °C under ultrasonic oscillation, and then filtered and air-dried at room temperature to obtain 4.7 g of entrectinib crystal A.

[0075] It was determined that the X-RPD pattern thereof was substantially consistent with Figure 1 , and the DSC-TGA pattern thereof was substantially consistent with Figure 2 .

[0076] Example 2 Preparation of entrectinib crystal form A

[0077] The crude amorphous 5 kg of entrectinib was added into 50 L of acetone, and dissolved by heating to reflux. After cooling to 50-55 °C, 20 L of purified water and 2 g of crystal seed of form A were added. Slow cooling to -5-5 °C was carried out for crystallization. Centrifugation and washing with purified water were carried out, and air-drying at 80±5 °C was carried out to obtain 4.5 kg of entrectinib crystal form A with a HPLC purity of 99.92%.

[0078] It was determined that the X-RPD pattern thereof was as shown in Figure 1 , and the DSC-TGA pattern thereof was as shown in Figure 2 .

[0079] Example 3 Preparation of entrectinib crystal form A

[0080] The crude amorphous 5.0 g of entrectinib was added into 110 ml of isopropyl alcohol, and dissolved by heating to reflux. After cooling to 50-60 °C, 11 ml of purified water and 5 mg of crystal seed of form A were added. Slow cooling to -5-5 °C was carried out for crystallization. Filtration and washing with purified water were carried out, and air-drying at 80±5 °C was carried out to obtain 4.4 g of entrectinib crystal form A with a HPLC purity of 99.91%.

[0081] It was determined that the X-RPD pattern thereof was substantially consistent with Figure 1 , and the DSC-TGA pattern thereof was substantially consistent with Figure 2 .

[0082] Example 4 Preparation of entrectinib crystal form A

[0083] The crude amorphous form of entrectinib 5.0 g was added to 140 ml of acetonitrile and dissolved by heating under reflux. After cooling to 50-60 °C, 14 ml of purified water and 5 mg of crystal seed of Form A were added. Slow cooling to -5-5 °C was performed and the crystals were allowed to precipitate. Filtration under suction, washing with purified water and drying at 80±5 °C with air blowing gave 4.3 g of entrectinib Form A with a HPLC purity of 99.90%.

[0084] It was determined that the X-RPD pattern thereof was substantially consistent with Figure 1 the DSC-TGA pattern thereof was substantially consistent with Figure 2 .

[0085] Example 5 Preparation of entrectinib Form B

[0086] The crude amorphous form of entrectinib 5.0 g was added to 50 ml of dioxane and dissolved by heating to 80 °C. After cooling to 75 °C, 40 ml of purified water was added and the temperature was slowly lowered to -5-5 °C to allow the crystals to precipitate. Filtration under suction, washing with purified water and drying at 80±5 °C with air blowing gave 4.3 g of entrectinib Form B with a HPLC purity of 99.91%.

[0087] It was determined that the X-RPD pattern thereof was as shown in Figure 3 the DSC-TGA pattern thereof was as shown in Figure 4 .

[0088] Example 6 Preparation of entrectinib Form B

[0089] The crude amorphous form of entrectinib 5.0 g was added to 25 ml of dioxane and dissolved by heating to 80 °C. After cooling to 75 °C, 15 ml of purified water was added and the temperature was slowly lowered to 0-10 °C to allow the crystals to precipitate. Filtration under suction, washing with purified water and drying at room temperature gave 4.2 g of entrectinib Form B with a HPLC purity of 99.90%.

[0090] It was determined that the X-RPD pattern thereof was substantially consistent with Figure 3 the DSC-TGA pattern thereof was substantially consistent with Figure 4 .

[0091] Example 7 Preparation of entrectinib Form B

[0092] The crude amorphous form of entrectinib 5.0 g was added to 100 ml of dioxane and dissolved by heating to 80 °C. After cooling to 75 °C, 200 ml of purified water was added and the temperature was slowly lowered to 10-20 °C to allow the crystals to precipitate. Filtration under suction, washing with purified water and drying at room temperature gave 4.4 g of entrectinib Form B with a HPLC purity of 99.89%.

[0093] It was determined that the X-RPD pattern thereof was substantially consistent with Figure 3 the DSC-TGA pattern thereof was substantially consistent with Figure 4Consistent.

[0094] Stability test

[0095] The samples of the crystalline form A of entrectinib prepared in Example 2, the crystalline form B of entrectinib prepared in Example 5, the crystalline form 1 (Reference Example 1), the crystalline form 2 (Reference Example 2), and the crystalline form 4 (Reference Example 3) were respectively placed under the influence factor conditions, and the stability after 10 days of placement was investigated, and the test results are shown in Table 1.

[0096] The specific stability test method can refer to the determination by high performance liquid chromatography in Chinese Pharmacopoeia 2015 Edition Volume IV General Chapter 0512.

[0097] Table 1: Results of chemical stability test

[0098]

[0099] Table 2: Results of crystalline form stability test

[0100]

[0101] As can be seen from Table 1, after 10 days of influence factor test, the crystalline form A and the crystalline form B of the present application have good chemical stability.

[0102] After 10 days of influence factor test, the crystalline form A and the crystalline form B of entrectinib prepared in the present application have good crystalline form stability, while the crystalline form 1 in Reference Example 1 is unstable and crystalline form conversion occurs under high temperature conditions.

[0103] Comparison of solubility of crystals

[0104] The solubility of the crystalline form A, the crystalline form B, the crystalline form 2 (Reference Example 2), and the crystalline form 4 (Reference Example 3) of the present application was compared under the condition of 25℃ in 95% ethanol and pH = 1 aqueous solution, respectively.

[0105] Investigation conditions:

[0106] Dissolution temperature: 25℃

[0107] Dissolution time: 20 min

[0108] The investigation results are as follows:

[0109] Table 3: Comparison of solubility of entrectinib crystalline form A, crystalline form B, and crystalline form 2 and crystalline form 4 of Reference Example

[0110]

[0111] The above data show that the crystal form A, B has better solubility in 95% ethanol, pH = 1 aqueous solution compared with the crystal form 2 and crystal form 4 in the reference examples, and thus is more advantageous to the dissolution in solid preparations.

[0112] Crystal form preparation stability study

[0113] The crystal form A obtained in Example 2 was mixed and milled with the crystal form 2, crystal form 4, crystal form AZT-A, AZT-B, AZT-E obtained in the reference examples, respectively, to investigate the crystal form conversion.

[0114] Mixing and milling method: 0.1 g of each of the two crystal forms to be mixed was added to a single-mouth bottle, 2 ml of acetone and 1 ml of water were added, and stirring and milling were carried out at room temperature for 10 h, followed by filtration, drying at room temperature, to obtain crystals, and X-RPD determination of the crystal form, with the results shown in the following table.

[0115] Table 4 Crystal form preparation stability comparison

[0116] Sample mixing Transformed crystal form Example 2 Form A mixed with Reference Example 2 Form 2 Form A Example 2 Form A mixed with Reference Example 3 Form 4 Form A Example 2 Form A mixed with Reference Example 4 Form AZT-A Form A Example 2 Form A mixed with Reference Example 5 Form AZT-B Form A Example 2 Form A mixed with Reference Example 6 Form AZT-E Form A

[0117] The experimental results show that when the crystal form A is mixed with other crystal forms and milled at room temperature in an acetone / water system for 10 h, the mixed crystal forms are all converted into crystal form A, indicating that under this system, the crystal form A does not undergo crystal transformation, while the other crystal forms undergo crystal transformation, and the crystal form A is more stable and is advantageous for preparation.

[0118] Crystal micro-morphology, static electricity, flowability

[0119] The crystal form A obtained in Example 2, the crystal form B obtained in Example 5, the crystal form 2 of Example 2, the crystal form AZT-A of Example 4, the crystal form AZT-B of Example 5, and the crystal form AZT-E of Example 6 were subjected to scanning electron microscope determination of their micro-morphology, and the pulverization and flowability were investigated, with the determination results as follows.

[0120] Table 5 Comparison of the crystal form A and crystal form B of entrectinib with other crystal forms in terms of micro-morphology, static electricity, and flowability

[0121]

[0122] The above results show that the crystal form A and crystal form B of the present application have fine particles, do not need to be pulverized, and have good flowability; the crystal form 2 has non-uniform particle size with large particles, has strong static electricity after pulverization, and has poor flowability; the crystal form AZT-A, AZT-B, and AZT-E have too large particles, have strong static electricity after pulverization, and have poor flowability. Since the crystal forms in the reference examples all have strong static electricity and poor flowability, these characteristics not only affect the uniformity of the raw material powder, but also have a very adverse effect on the preparation of solid preparations.

[0123] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, and the like made within the spirit and principle of the present application should be included in the scope of protection of the present application.

Claims

1. Form B of entrectinib as shown in Formula I, characterized in that: X-ray powder diffraction has diffraction peaks at 8.5°±0.2°, 9.5°±0.2°, 10.4°±0.2°, 11.3°±0.2°, 12.9°±0.2°, 13.8°±0.2°, 14.4°±0.2°, 16.0°±0.2°, 16.6°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 19.3°±0.2°, 20.5°±0.2°, 22.3°±0.2°, 22.8°±0.2°, 23.9°±0.2°, 24.2°±0.2°, 25.5°±0.2°, 30.1°±0.2°, using Cu-Ka radiation, expressed in terms of 2θ angle.

2. The entrectinib crystal form B according to claim 1, characterized in that, The form B of entrectinib has an X-ray powder diffraction pattern substantially as shown in Figure 3.

3. The entrectinib crystal form B according to claim 1, characterized in that, The DSC pattern thereof has an obvious endothermic peak in the range of 182.3-207.4°C.

4. The entrectinib crystal form B according to claim 1, characterized in that, The DSC pattern thereof has an endothermic peak at 196.5°C.

5. The entrectinib crystal form B according to claim 1, characterized in that, The form B of entrectinib has a DSC pattern substantially as shown in Figure 4.

6. The entrectinib crystal form B according to claim 1, characterized in that, The TGA pattern of the form B of entrectinib has no obvious weight loss before product degradation.

7. The entrectinib crystal form B according to claim 1, characterized in that, The form B of entrectinib has a TGA pattern substantially as shown in Figure 4.

8. A method for preparing the form B of entrectinib according to any one of claims 1-7, comprising the following steps: adding crude amorphous entrectinib into dioxane, heating to 80°C for dissolution, purifying water, cooling to -5-20°C for crystallization; suction filtration, drying to obtain the form B of entrectinib.

9. The method of claim 8, wherein, The volume ratio of dioxane to water is 1:0.2-2.0; the mass-volume ratio of the crude amorphous entrectinib to dioxane is 1:5-30, unit: mg / mL.

10. The method of claim 8, wherein, The volume ratio of dioxane to water is 1:0.6-1.

4.

11. The method of claim 8, wherein, The volume ratio of dioxane to water is 1:0.

8.

12. The method of claim 8, wherein, The mass-volume ratio of the crude amorphous entrectinib to dioxane is 1:8-20, unit: mg / mL.

13. The method of claim 8, wherein, The mass-volume ratio of the crude amorphous entrectinib to dioxane is 1:10-15, unit: mg / mL.

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