Amorphous form and polymorph of nicotinate compound, preparation method therefor and use of same

Abstract

Disclosed in the present invention are an amorphous form and polymorph of a nicotinate compound, a preparation method therefor and the use of same. The amorphous form has an XRPD pattern substantially as shown in figure 20. Unexpectedly, the amorphous form of the present invention has more excellent stability and hygroscopicity and lower solvent residue than the polymorph, and thus has good developability.

Description

Amorphous and polymorphic forms of nicotinate compounds, preparation methods and applications thereof

[0001] This application claims the benefit of priority to a prior application filed with the State Intellectual Property Office of China on July 13, 2023, with patent number 202310861466.X, entitled “Amorphous Form and Polymorphic Form of Nicotinate Ester Compounds, Preparation Methods, and Applications Thereof.” The entire text of the prior application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of compounds, and in particular relates to an amorphous substance and a polymorphic substance of a nicotinic acid ester compound, and a preparation method and application thereof. Background Art

[0003] The androgen receptor (AR) is a steroid nuclear receptor that is a receptor for ligand-induced nuclear transcription factors. It is an important cellular regulatory protein that plays a crucial role in numerous physiological processes through endogenous androgens. With aging, androgen levels in the body decrease, leading to the development of age-related diseases. While androgen therapy can alleviate androgen deficiency to some extent, it is prone to side effects.

[0004] In order to replace androgen therapy, it is urgent to find and develop new drugs that can be used to prevent and / or treat diseases caused by androgen deficiency. In recent years, non-steroidal selective androgen receptor modulators (SARMs) have attracted increasing interest from academia and the pharmaceutical industry.

[0005] CN201410033958.0 discloses the compound (S)-1-(4-cyano-3-(trifluoromethyl)anilino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-nicotinate (also known as "(S)-1-((4-cyano-3-(trifluoromethyl)phenyl)amino)-3-(4-cyanophenoxy)-2-methyl-1-oxopropan-2-ylnicotinate"), with a structure shown in Formula (I). However, the compound's form is not disclosed. Subsequent experiments revealed that the compound of Formula (I) prepared by the column chromatography purification method described in this patent was a mixed phase containing crystals and exhibited poor stability. CN201911320125.1 discloses a method for synthesizing the compound of Formula (I), which is suitable for industrial production and avoids column chromatography purification. Subsequent experiments revealed that the product prepared by this method was also a mixed phase containing crystals.

[0006] In order to meet the further development of drugs, it has become a technical problem that technicians in this field are committed to solving to develop a solid form of the compound suitable for drug formulation, such as a solid form with improved stability, hygroscopicity and / or efficacy, so as to achieve good results in the pharmaceutical preparation and use stages.

[0007] Summary of the Invention

[0008] In order to improve the above technical problems, the present invention provides a solid form of a compound represented by formula (I), including an amorphous form or a polymorphic form.

[0009] According to an embodiment of the present invention, the amorphous form has an XRPD pattern substantially as shown in FIG. 20 .

[0010] According to an embodiment of the present invention, the amorphous material has a weight loss of no more than 3% before 150°C, preferably has a weight loss of no more than 2% before 150°C, for example, has a weight loss of about 1.1% before 150°C.

[0011] According to an embodiment of the present invention, the decomposition temperature of the amorphous substance is 255-270°C, for example, 262±5°C, and exemplarily 262.13°C.

[0012] Illustratively, the amorphous material has a TGA pattern substantially as shown in FIG. 21 .

[0013] According to an embodiment of the present invention, the amorphous substance has an endothermic peak before 100°C, with an onset temperature of 70±5°C, for example, 70.91°C.

[0014] According to an embodiment of the present invention, the glass transition temperature of the amorphous material is not more than 100±5°C, preferably not more than 100±2°C, for example, 95°C.

[0015] Illustratively, the amorphous material has a DSC spectrum substantially as shown in FIG. 22 .

[0016] According to an embodiment of the present invention, the polymorph is a solvate of the compound represented by formula (I).

[0017] According to an embodiment of the present invention, the polymorph is form 2 of the compound represented by formula (I), and the X-ray powder diffraction pattern of form 2 using Cu-Kα radiation is 7.4±0.20°, 7.9±0.20°, 14.5±0.20°, 14.8±0.20°, 18.3±0.20°, 20.0±0.20°, 21.7±0.20°, 22.3±0.2 0° and 26.2±0.20°; preferably, characteristic peaks are present at 4.7±0.20°, 7.4±0.20°, 7.9±0.20°, 14.5±0.20°, 14.8±0.20°, 18.3±0.20°, 20.0±0.20°, 21.7±0.20°, 22.3±0.20°, 23.4±0.20° and 26.2±0.20°.

[0018] According to an embodiment of the present invention, Form 2 has an XRPD pattern substantially as shown in Figure 30.

[0019] According to an embodiment of the present invention, the form 2 is a tetrahydrofuran solvate of the compound represented by formula (I), for example, the molar ratio of the compound represented by formula (I) to tetrahydrofuran is about 1:1.

[0020] According to an embodiment of the present invention, the polymorph is form 5 of the compound represented by formula (I), and the form 5 uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.6±0.20°, 7.5±0.20°, 13.8±0.20°, 14.8±0.20°, and 22.7±0.20°; preferably, it has characteristic peaks at 4.6±0.20°, 7.5±0.20°, 8.0±0.20°, 13.8±0.20°, 14.4±0.20°, 14.8±0.20°, 18.5±0.20°, 19.8±0.20°, 22.3±0.20°, and 22.7±0.20°.

[0021] According to an embodiment of the present invention, Form 5 has an XRPD pattern substantially as shown in Figure 39.

[0022] According to an embodiment of the present invention, the form 5 is a hemimethylcyclohexane solvate of the compound represented by formula (I), that is, the molar ratio of the compound represented by formula (I) to methylcyclohexane is about 1:0.5.

[0023] According to an embodiment of the present invention, the Form 5 loses no more than 10% of its weight before 120° C., for example, loses about 8.8% of its weight.

[0024] According to an embodiment of the present invention, the decomposition temperature of Form 5 is 240-270°C, for example, 258±5°C, and exemplified by 258.65°C.

[0025] Illustratively, Form 5 has a TGA pattern substantially as shown in FIG. 40 .

[0026] According to an embodiment of the present invention, the form 5 has an obvious endothermic peak before 110°C, with an onset temperature of 59±5°C, for example, 59.10°C.

[0027] Illustratively, the Form 5 has a DSC spectrum substantially as shown in FIG41 .

[0028] According to an embodiment of the present invention, the polymorph is form 7 of the compound represented by formula (I), and the form 7 uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed in 2θ angles is 4.6±0.20°, 7.2±0.20°, 7.6±0.20°, 9.5±0.20°, 10.3±0.20°, 14.4±0.20°, 18.2±0.20°, 21.4±0.20°, 21.7±0.2 0° and 29.1±0.20°; preferably, characteristic peaks are present at 4.6±0.20°, 7.2±0.20°, 7.6±0.20°, 9.5±0.20°, 10.3±0.20°, 14.0±0.20°, 14.4±0.20°, 15.1±0.20°, 18.2±0.20°, 21.4±0.20°, 21.7±0.20° and 29.1±0.20°.

[0029] According to an embodiment of the present invention, Form 7 has an XRPD pattern substantially as shown in Figure 43.

[0030] According to an embodiment of the present invention, the form 7 is a hemi-methyl tert-butyl ether solvate of the compound represented by formula (I), that is, the molar ratio of the compound represented by formula (I) to methyl tert-butyl ether is about 1:0.5.

[0031] According to an embodiment of the present invention, the polymorph is form 10 of the compound represented by formula (I), and the form 10 uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles is at 7.5±0.20°, 13.8±0.20°, 15.0±0.20°, 18.4±0.20°, 19.9±0.20°, 22.5±0.20°, and 23.3±0.20°, having characteristic peaks; preferably at 4.6±0.20°, 7.5±0.20°, 7.9±0.20°, 13.8±0.20°, 14.3±0.20°, 15.0±0.20°, and 26.4±0.20°. .20°, 17.2±0.20°, 18.4±0.20°, 19.9±0.20°, 20.3±0.20°, 20.7±0.20°, 22.5±0.20°, 23.3±0.20°, 26.3±0.20°, and 27.9±0.20°; more preferably, at 4.6±0.20°, 7.5±0.20°, 7.9±0.20°, 13.8±0.20°, 14.3±0.20°, 14.7±0.20°, 15.0±0.20°, 17.2±0.20°, 17.8±0.20°, There are characteristic peaks at 18.4±0.20°, 19.9±0.20°, 20.3±0.20°, 20.7±0.20°, 21.4±0.20°, 22.5±0.20°, 23.3±0.20°, 26.3±0.20°, and 27.9±0.20°.

[0032] According to an embodiment of the present invention, Form 10 has an XRPD pattern substantially as shown in Figure 52.

[0033] According to an embodiment of the present invention, the form 10 is a hemi-isopropanol tunnel solvate of the hemihydrate of the compound represented by formula (I), that is, the molar ratio of the compound represented by formula (I) to water and isopropanol is about 1:0.5:0.5.

[0034] According to an embodiment of the present invention, the form 10 loses no more than 10% of its weight before 100° C., such as about 7% of its weight.

[0035] According to an embodiment of the present invention, the decomposition temperature of the form 10 is 240-270°C, for example, 257±5°C, and exemplified by 257.27°C.

[0036] Illustratively, Form 10 has a TGA pattern substantially as shown in FIG. 53 .

[0037] According to an embodiment of the present invention, the form 10 has an obvious endothermic peak with an onset temperature of 104±5°C, for example, 104.72°C.

[0038] Illustratively, the Form 10 has a DSC spectrum substantially as shown in FIG. 54 .

[0039] According to an embodiment of the present invention, the polymorph is form 12 of the compound represented by formula (I), and the form 12 uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles is 4.6±0.20°, 7.5±0.20°, 13.8±0.20°, 14.4±0.20°, 14.8±0.20°, 18.4±0.20°, 19.8±0.20°, 22.6±0.20°, 23.0±0.20°, and 23.3±0.20° having characteristic peaks; preferably at 4.6±0.20°, 7.5±0.20°, 8.0±0.20°, 13.8±0.20°, 14.4±0.20°, 14.8±0.20°, 18.4±0.20°, 19.8±0.20°, 22.6±0.20°, 23.0±0.20°, and 23.3±0.20°; .20°, 9.6±0.20°, 10.7±0.20°, 13.8±0.20°, 14.4±0.20°, 14.8±0.20°, 17.1±0.20°, 18.4±0.20°, 19.8±0.20°, 20.1±0.20°, 20.7±0.20°, 22.6±0.20°, 23.0±0.20°, 23.3±0.20°, 24.0±0.20°, 26.4±0.20°, 26.9±0.20°, 28.0±0.20°, and 30.9±0.20°, and there are characteristic peaks.

[0040] According to an embodiment of the present invention, Form 12 has an XRPD pattern substantially as shown in Figure 56.

[0041] According to an embodiment of the present invention, the form 12 is a semi-toluene solvate of the compound represented by formula (I), that is, the molar ratio of the compound represented by formula (I) to toluene is about 1:0.5.

[0042] According to an embodiment of the present invention, the polymorph is form 13 of the compound represented by formula (I), and the form 13 uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles is at 4.6±0.20°, 7.5±0.20°, 13.8±0.20°, 15.0±0.20°, 17.9±0.20°, 18.4±0.20°, 19.9±0.20°, 22.5±0.20°, 26.3±0.20°, and 28.0±0.20° having characteristic peaks; preferably at 4.6±0.20°, 7.5±0.20°, 9.6±0.20°, 13.8±0.20°, 15.0±0.20°, 17.9±0.20°, 18.4±0.20°, 19.9±0.20°, 22.5±0.20°, 26.3±0.20°, and 28.0±0.20°; .20°, 10.5±0.20°, 13.1±0.20°, 13.8±0.20°, 14.3±0.20°, 15.0±0.20°, 16.6±0.20°, 17.9±0.20°, 18.4±0.20°, 19.2±0.20°, 19.9±0.20°, 20.7±0.20°, 22.5±0.20°, 23.3±0.20°, 24.0±0.20°, 26.3±0.20°, 26.6±0.20°, 28.0±0.20°, and 30.9±0.20°, and there are characteristic peaks.

[0043] According to an embodiment of the present invention, Form 13 has an XRPD pattern substantially as shown in Figure 59.

[0044] According to an embodiment of the present invention, the form 13 is a hemiacetone solvate of the hemihydrate of the compound represented by formula (I), that is, the molar ratio of the compound represented by formula (I) to water and acetone is about 1:0.5:0.5.

[0045] According to an embodiment of the present invention, the polymorph is form 16 of the compound represented by formula (I), and the form 16 uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.6±0.20°, 7.5±0.20°, 13.8±0.20°, 14.8±0.20°, 19.8±0.20°, and 22.7±0.20°; preferably, it has characteristic peaks at 4.6±0.20°, 7.5±0.20°, 8.0±0.20°, 13.8±0.20°, 14.3±0.20°, 14.8±0.20°, 18.4±0.20°, 19.8±0.20°, 22.7±0.20°, and 23.3±0.20°.

[0046] According to an embodiment of the present invention, Form 16 has an XRPD pattern substantially as shown in Figure 66.

[0047] According to an embodiment of the present invention, the form 16 is an isopropyl ether solvate of the compound represented by formula (I), for example, the molar ratio of the compound represented by formula (I) to isopropyl ether is about 1:1.

[0048] According to an embodiment of the present invention, the form 16 loses no more than 18% of its weight before 100° C., such as about 14% of its weight.

[0049] According to an embodiment of the present invention, the decomposition temperature of Form 16 is 240-270°C, for example, 258±5°C, and exemplified by 258.78°C.

[0050] Illustratively, Form 16 has a TGA pattern substantially as shown in FIG. 67 .

[0051] According to an embodiment of the present invention, the form 16 has an obvious endothermic peak with an onset temperature of 70±5°C, for example, 70°C.

[0052] Illustratively, the Form 16 has a DSC spectrum substantially as shown in FIG. 68 .

[0053] The present invention also provides a method for preparing the amorphous form of the compound represented by formula (I), wherein the preparation method is selected from any one of the following methods 1 to 8:

[0054] Method 1: The compound represented by formula (I) is mixed with water, slurried, the precipitated solid is filtered, and dried to obtain the amorphous substance;

[0055] Preferably, the compound represented by formula (I) is prepared by the synthesis method provided in Chinese patent application No. 201911320125.1;

[0056] Preferably, the beating temperature is 5-40°C, such as 10°C, 25°C, or 30°C;

[0057] Preferably, the beating time is not less than 40 hours, for example, 40-100 hours;

[0058] Method 2: Form 2 of the compound of formula (I) is heated to obtain the amorphous form, wherein Form 2 has the definitions as described above, and preferably Form 2 has an XRPD pattern substantially as shown in Figure 30; preferably, the heating temperature is 70-80°C, for example 75°C;

[0059] Method 3: Form 5 of the compound of formula (I) is heated to obtain the amorphous form, wherein Form 5 has the definitions as described above, preferably Form 5 has an XRPD pattern substantially as shown in Figure 39; preferably, the heating temperature is 85-95°C, for example 90°C;

[0060] Method 4: Form 7 of the compound of formula (I) is heated to obtain the amorphous form, wherein Form 7 has the definitions as described above, preferably Form 7 has an XRPD pattern substantially as shown in Figure 43; preferably, the heating temperature is 75-85°C, for example 80°C;

[0061] Method 5: Form 10 of the compound of formula (I) is heated to obtain the amorphous form, wherein Form 10 has the above-defined characteristics, preferably Form 10 has an XRPD pattern substantially as shown in FIG. 52 ; preferably, the heating temperature is 75-85° C., for example, 80° C.;

[0062] Method 6: Form 12 of the compound of formula (I) is heated to obtain the amorphous form, wherein Form 12 has the definitions as described above, and preferably, Form 12 has an XRPD pattern substantially as shown in Figure 56; preferably, the heating temperature is 85-95°C, for example, 90°C;

[0063] Method 7: Form 13 of the compound of formula (I) is heated to obtain the amorphous form, wherein Form 13 has the definitions as described above, and preferably Form 13 has an XRPD pattern substantially as shown in Figure 59; preferably, the heating temperature is 75-85°C, for example 80°C;

[0064] Method eight: Form 16 of the compound represented by formula (I) is heated to obtain the amorphous material, and the form 16 has the limitations as shown above, and preferably the form 16 has an XRPD spectrum basically as shown in Figure 66; preferably, the heating temperature is 85-95°C, for example 90°C.

[0065] The present invention also provides a method for preparing the polymorph, comprising mixing an amorphous form of the compound represented by formula (I) with a solvent to prepare the polymorph.

[0066] According to an embodiment of the present invention, when the polymorph is form 5 of the compound represented by formula (I), its preparation method includes mixing the amorphous form of the compound represented by formula (I) with isopropyl acetate and methylcyclohexane to form a suspension, stirring, centrifuging, filtering, and drying to obtain the form 5.

[0067] According to an embodiment of the present invention, when the polymorph is form 10 of the compound represented by formula (I), its preparation method comprises mixing the amorphous form of the compound represented by formula (I) with isopropanol and water, and centrifuging, filtering, and drying the precipitated solid to obtain the form 10.

[0068] According to an embodiment of the present invention, when the polymorph is form 16 of the compound represented by formula (I), its preparation method includes mixing the amorphous form of the compound represented by formula (I) with isopropyl ether to form a suspension, stirring, centrifuging, filtering, and drying to obtain the form 16.

[0069] The present invention also provides the use of a solid form of a compound represented by formula (I) in the preparation and / or purification of an amorphous substance such as the above-mentioned one, wherein the solid form is a polymorph, preferably a solvate of the compound represented by formula (I), for example, form 2, form 5, form 7, form 10, form 12, form 13 or form 16 of the compound represented by formula (I).

[0070] The present invention also provides a pharmaceutical composition comprising a solid form of the compound represented by formula (I), preferably comprising an amorphous form and a polymorphic form of the compound represented by formula (I).

[0071] According to an embodiment of the present invention, the pharmaceutical composition further contains pharmaceutically acceptable excipients, such as, but not limited to, one or more of excipients, fillers, lubricants, binders, disintegrants, inorganic salts, solvents, dissolution aids, suspending agents, isotonic agents, buffers, preservatives, antioxidants, colorants, foaming agents and flavoring agents.

[0072] The present invention also provides a solid form of a compound represented by formula (I) or a pharmaceutical composition for use in the preparation of a pharmaceutical preparation for preventing and / or treating diseases caused by androgen deficiency. For example, the diseases include acute or chronic muscle wasting, muscle wasting, muscle atrophy, bone-related conditions, cancer (such as prostate cancer, breast cancer, etc.), AIDS, kidney disease, muscle wasting / muscle wasting / muscle atrophy caused by burns, anemia, obesity, diabetes, changes in mood and cognition in the elderly, urinary incontinence (such as stress urinary incontinence), heart failure, dry eye, new coronavirus infectious diseases, etc.

[0073] The present invention also provides a pharmaceutical preparation containing the solid form or pharmaceutical composition of the compound represented by the above formula (I).

[0074] According to an embodiment of the present invention, the pharmaceutical preparation can be in the form of powder, tablet (e.g., coated tablet, sustained-release or controlled-release tablet), lozenge, capsule (e.g., soft capsule or hard capsule), granule, pill, dispersible powder, suspension, solution, emulsion, elixir, syrup, aerosol, cream, ointment, gel, injection, lyophilized powder injection or suppository.

[0075] According to an embodiment of the present invention, the pharmaceutical preparation can be administered in any of the following ways: orally, buccal administration, sublingually, inhaled, topically applied, parenterally administered intravenously, subcutaneously, at acupuncture points or intramuscularly, or rectally.

[0076] The present invention also provides a method for preventing and / or treating diseases caused by androgen deficiency, comprising administering a therapeutically effective amount of a solid form, pharmaceutical composition or pharmaceutical preparation of the compound represented by formula (I) to a patient in need of such treatment.

[0077] According to an embodiment of the present invention, the disease has the same definition as above. Beneficial effects

[0078] It is well known in the art that drug polymorphs can be classified into stable, metastable and unstable types based on stability. Generally, the entropy value of the stable crystal form is small, the melting point is high, and the chemical stability is the best, while the amorphous drug has the lowest stability. During the preparation and storage of drugs, metastable and unstable crystal forms are easy to become stable forms. Therefore, in the research of drug products, stable crystal forms are usually selected as the research object. Sometimes, metastable crystal forms are selected for product development for certain reasons (such as increasing bioavailability) (see: "Pharmaceutics 4th Edition" edited by Tang Xing, China Medical Science and Technology Press, page 56, December 2019). Amorphous forms are not suitable for drug formulation due to poor stability, high hygroscopicity, high solvent residues and other reasons.

[0079] During the development of a pharmaceutical solid form suitable for the compound of formula (I), the inventors discovered that the compound readily forms solvates, while obtaining an unsolvated solid form is difficult. The present inventors unexpectedly discovered an amorphous unsolvated form of the compound of formula (I). This amorphous form is difficult to obtain using conventional methods and, contrary to common knowledge, exhibits excellent stability, hygroscopicity, and low residual solvent, offering promising drug development prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0080] Figure 1. XRPD pattern of the compound represented by formula (I);

[0081] Figure 2. Spatial structure diagram of Form A of the compound represented by formula (I);

[0082] Figure 3. XRPD simulation of Form A of the compound represented by formula (I);

[0083] Figure 4. XRPD pattern of Form A of the compound represented by formula (I) after storage at room temperature for 80 days;

[0084] Figure 5. DSC graph of Form A of the compound represented by formula (I) after 80 days at room temperature;

[0085] Figure 6. XRPD pattern of Form B of the compound represented by formula (I);

[0086] Figure 7. DSC spectrum of Form B of the compound represented by formula (I);

[0087] Figure 8. XRPD pattern of Form C of the compound represented by formula (I);

[0088] Figure 9. DSC spectrum of Form C of the compound represented by formula (I);

[0089] Figure 10. XRPD pattern of Form D of the compound represented by formula (I);

[0090] Figure 11. DSC spectrum of Form D of the compound represented by formula (I);

[0091] Figure 12. XRPD pattern of Form E of the compound represented by formula (I);

[0092] Figure 13. DSC spectrum of Form E of the compound represented by formula (I);

[0093] Figure 14. XRPD pattern of Form F of the compound represented by formula (I);

[0094] Figure 15. DSC spectrum of Form F of the compound represented by formula (I);

[0095] Figure 16 is an XRPD pattern of the volatile, enlarged crystals obtained in Example 8 under a volume ratio of isopropyl alcohol to water of 4 / 3.

[0096] Figure 17. XRPD patterns of the precipitated crystals of Examples 9 to 11;

[0097] Figure 18. XRPD pattern of the precipitated crystals of Example 12-13;

[0098] Figure 19. XRPD pattern of the precipitated crystals of Example 14-15;

[0099] Figure 20. XRPD pattern of the amorphous form of the compound represented by formula (I)

[0100] Figure 21. TGA spectrum of the amorphous form of the compound represented by formula (I);

[0101] Figure 22. DSC spectrum of the amorphous form of the compound represented by formula (I);

[0102] Figure 23. DVS spectrum of the amorphous form of the compound represented by formula (I);

[0103] Figure 24. Isothermal adsorption curve of the amorphous form of the compound represented by formula (I);

[0104] Figure 25. XRPD pattern of the precipitated crystals of Examples 19-24;

[0105] Figure 26. XRPD pattern of the precipitated crystals of Examples 25-27;

[0106] Figure 27. XRPD pattern of Form 1 of the compound of formula (I);

[0107] Figure 28. TGA spectrum of Form 1 (Form 1) of the compound represented by formula (I);

[0108] Figure 29. DSC spectrum of Form 1 (Form 1) of the compound represented by formula (I);

[0109] Figure 30. XRPD pattern of Form 2 of the compound represented by formula (I);

[0110] Figure 31. TGA spectrum of Form 2 of the compound represented by formula (I);

[0111] Figure 32. DSC spectrum of Form 2 (Form 2) of the compound represented by formula (I);

[0112] Figure 33. XRPD pattern of Form 3 of the compound represented by formula (I);

[0113] Figure 34. TGA spectrum of Form 3 of the compound represented by formula (I);

[0114] Figure 35. DSC spectrum of Form 3 of the compound represented by formula (I);

[0115] Figure 36. XRPD pattern of Form 4 of the compound represented by formula (I);

[0116] Figure 37. TGA spectrum of Form 4 of the compound represented by formula (I);

[0117] Figure 38. DSC spectrum of Form 4 of the compound represented by formula (I);

[0118] Figure 39. XRPD pattern of Form 5 of the compound represented by formula (I);

[0119] Figure 40. TGA spectrum of Form 5 of the compound represented by formula (I);

[0120] Figure 41. DSC spectrum of Form 5 of the compound represented by formula (I);

[0121] Figure 42. XRPD spectrum of Form 6 of the compound represented by formula (I);

[0122] Figure 43. XRPD pattern of Form 7 of the compound represented by Formula (I);

[0123] Figure 44. TGA spectrum of Form 7 of the compound represented by formula (I);

[0124] Figure 45. DSC spectrum of Form 7 of the compound represented by formula (I);

[0125] Figure 46. XRPD pattern of Form 8 of the compound of formula (I);

[0126] Figure 47. TGA spectrum of Form 8 of the compound represented by formula (I);

[0127] Figure 48. DSC spectrum of Form 8 of the compound represented by formula (I);

[0128] Figure 49. XRPD pattern of Form 9 of the compound of formula (I);

[0129] Figure 50. TGA spectrum of Form 9 of the compound represented by formula (I);

[0130] Figure 51. DSC spectrum of Form 9 of the compound represented by formula (I);

[0131] Figure 52. XRPD pattern of Form 10 (Form 10) of the compound represented by Formula (I);

[0132] Figure 53. TGA spectrum of Form 10 (Form 10) of the compound represented by Formula (I);

[0133] Figure 54. DSC spectrum of Form 10 (Form 10) of the compound represented by Formula (I);

[0134] Figure 55. XRPD pattern of Form 11 of the compound of Formula (I);

[0135] Figure 56. XRPD pattern of Form 12 of the compound of Formula (I);

[0136] Figure 57. TGA spectrum of Form 12 of the compound represented by Formula (I);

[0137] Figure 58. DSC spectrum of Form 12 of the compound represented by Formula (I);

[0138] Figure 59. XRPD pattern of Form 13 of the compound of Formula (I);

[0139] Figure 60. TGA spectrum of Form 13 of the compound represented by Formula (I);

[0140] Figure 61. DSC spectrum of Form 13 of the compound represented by Formula (I);

[0141] Figure 62. XRPD pattern of Form 14 of the compound of Formula (I);

[0142] Figure 63. XRPD pattern of Form 15 of the compound of Formula (I);

[0143] Figure 64. TGA spectrum of Form 15 of the compound represented by Formula (I);

[0144] Figure 65. DSC spectrum of Form 15 of the compound of Formula (I);

[0145] Figure 66. XRPD pattern of Form 16 of the compound of Formula (I);

[0146] Figure 67. TGA spectrum of Form 16 of the compound represented by Formula (I);

[0147] Figure 68. DSC spectrum of Form 16 of the compound of Formula (I);

[0148] Figure 69. XRPD pattern of Form 17 (Form 17) of the compound represented by Formula (I);

[0149] Figure 70. XRPD pattern of Form 18 (Form 18) of the compound represented by Formula (I);

[0150] Figure 71. TGA spectrum of Form 18 (Form 18) of the compound represented by Formula (I);

[0151] Figure 72. DSC spectrum of Form 18 (Form 18) of the compound represented by Formula (I);

[0152] Figure 73. XRPD pattern of Form 19 of the compound of Formula (I);

[0153] Figure 74. TGA spectrum of Form 19 (Form 19) of the compound represented by Formula (I);

[0154] Figure 75. DSC spectrum of Form 19 of the compound of Formula (I);

[0155] Figure 76. XRPD pattern of Form 20 of the compound of Formula (I);

[0156] Figure 77. XRPD pattern of Form 10 (Form 10) crystal stability test - open;

[0157] Figure 78. XRPD pattern of Form 10 (Form 10) crystal stability test - sealed;

[0158] Figure 79. XRPD pattern of Form 16 (Form 16) crystal stability test - open;

[0159] Figure 80. XRPD pattern of Form 16 (Form 16) crystal stability test - sealed;

[0160] Figure 81. XRPD pattern of Form 5 (Form 5) crystal stability test - open;

[0161] Figure 82. XRPD pattern of Form 5 (Form 5) crystal stability test - sealed;

[0162] Figure 83. TGA spectrum of Form 10 (Form 10) crystal stability test - open;

[0163] Figure 84. TGA spectrum of Form 10 (Form 10) crystal stability test - sealed;

[0164] Figure 85. TGA spectrum of Form 16 (Form 16) crystal stability test - open;

[0165] Figure 86. TGA spectrum of Form 16 (Form 16) crystal stability test - sealed;

[0166] Figure 87. TGA spectrum of Form 5 (Form 5) crystal stability test - open;

[0167] Figure 88. TGA spectrum of Form 5 crystal stability test - sealed. DETAILED DESCRIPTION

[0168] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0169] Unless otherwise indicated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. Those skilled in the art will appreciate that V represents the mass-to-volume ratio (1 g / mL). For example, when the starting material is 1 g and 1 V of solvent is added, 1 mL of solvent is added.

[0170] Instruments, parameters, characterization and test methods used in the examples

[0171] Instrument information and test method parameters used in test method 1

[0172] 1) XRPD patterns were collected on a PANalytacal X-ray powder diffraction analyzer. The XRPD parameters are shown in the table below.

[0173] XRPD test parameters

[0174] 2) Differential scanning calorimetry (DSC) was performed on a TAQ200 / 2000 differential scanning calorimeter. The test parameters are listed in the table below.

[0175] DSC test parameters

[0176] 3) High Performance Liquid Chromatography (HPLC) was performed on an Agilent 1200 HPLC or other equivalent HPLC system. Specific instrumentation and test parameters are shown in the table below.

[0177] HPLC test parameters

[0178] 4) H NMR spectrum ( 1 H NMR) and liquid-state H NMR spectra were collected on a Bruker 400M NMR spectra with CDCl3 as the solvent.

[0179] Instrument information and test method parameters used in test method 2

[0180] Example 1

[0181] The synthesis method of Example 1 in CN201911320125.1 was repeated to obtain a white solid, which is the compound represented by formula (I). The obtained white solid was subjected to XRPD using detection method 1, and the results are shown in Figure 1. As can be seen from Figure 1, the compound represented by formula (I) is a mixed state containing crystals, and it was used as the starting sample for subsequent crystal form screening research.

[0182] Example 2 Preparation and Characterization of Form A Crystalline Form

[0183] 0.2 g of the compound of formula (I) obtained in Example 1 was weighed into a beaker, and acetone and water (volume ratio of 35:30, total 50V) were added to dissolve the sample to obtain a clear solution. The solution was sealed with a sealing film at room temperature, pierced with 4 to 5 small holes, and then allowed to evaporate naturally for 60 days. The resulting solid was filtered and dried at 20-30°C to obtain single crystal Form A. Its spatial structure is shown in Figure 2. As can be seen from the figure, Form A is a tunnel acetone solvate of the monohydrate of the compound of formula (I).

[0184] The obtained Form A single crystal was subjected to XRPD analysis using detection method 1, and the obtained XRPD pattern is shown in FIG3 .

[0185] The obtained Form A single crystal was placed at room temperature for 80 days and subjected to XRPD and DSC analysis using detection method 1. The obtained XRPD spectrum is shown in FIG4 , and the DSC spectrum is shown in FIG5 .

[0186] Form A and Form A after 80 days of storage were tested using NMR and KF in test method 1. The results are shown in Table 1.

[0187] Table 1

[0188] Example 3 Preparation and Characterization of Form B Crystalline Form

[0189] 0.2 g of the compound of formula (I) obtained in Example 1 was weighed into a beaker, and isopropanol and water (volume ratio 40:10, total 50V) were added to dissolve the sample to obtain a clear solution. The solution was sealed with a sealing film at room temperature, pierced with 4 to 5 small holes, and allowed to evaporate naturally for 80 days. The resulting solid was filtered and dried at 20-30°C to obtain crystalline Form B.

[0190] The obtained Form B crystalline form was subjected to XRPD and DSC analysis using detection method 1. The obtained XRPD spectrum is shown in FIG6 , and the DSC spectrum is shown in FIG7 .

[0191] Form B was tested using NMR and KF in detection method 1. The results showed that Form B contained 0.7 eq of isopropanol and no water.

[0192] Example 4 Preparation and Characterization of Form C Crystalline Form

[0193] 0.2 g of the compound of formula (I) obtained in Example 1 was weighed into a beaker, and tetrahydrofuran and n-heptane (volume ratio of 25:20, total 45V) were added to dissolve the sample to obtain a clear solution. The solution was sealed with a sealing film at room temperature, pierced with 4 to 5 small holes, and allowed to evaporate naturally for 80 days. The resulting solid was filtered and dried at 20-30°C to obtain crystalline Form C.

[0194] The obtained Form C crystalline form was subjected to XRPD and DSC analysis using detection method 1. The obtained XRPD pattern is shown in FIG8 , and the DSC pattern is shown in FIG9 .

[0195] Form C was tested using NMR and KF in detection method 1. The results showed that Form C contained 0.7 eq of tetrahydrofuran and 0.2 eq of n-heptane.

[0196] Example 5 Preparation and Characterization of Form D Crystalline Form

[0197] 0.2 g of the compound of formula (I) obtained in Example 1 was weighed into a beaker, and ethyl acetate and n-heptane (volume ratio 70:60, total 130 V) were added to dissolve the sample to obtain a clear solution. The solution was sealed with a sealing film at room temperature, pierced with 4 to 5 small holes, and allowed to evaporate naturally for 80 days. The resulting solid was filtered and dried at 20-30°C to obtain crystalline Form D.

[0198] The obtained Form D crystal form was subjected to XRPD and DSC analysis using detection method 1. The obtained XRPD spectrum is shown in Figure 10, and the DSC spectrum is shown in Figure 11.

[0199] Form D was tested using NMR and KF in detection method 1. The results showed that Form D contained 0.2 eq of n-heptane.

[0200] Example 6 Preparation and Characterization of Form E Crystalline Form

[0201] 0.2 g of the compound represented by formula (I) obtained in Example 1 was weighed into a beaker, and ethyl acetate and methyl tert-butyl ether (volume ratio of 10:40, total 50V) were added to dissolve the sample to obtain a clear solution. The solution was sealed with a sealing film at room temperature, pierced with 4 to 5 small holes, and allowed to evaporate naturally for 80 days. The resulting solid was filtered and dried at 20-30°C to obtain crystalline Form E.

[0202] The obtained Form E crystal form was subjected to XRPD and DSC analysis using detection method 1. The obtained XRPD pattern is shown in FIG12 , and the DSC pattern is shown in FIG13 .

[0203] Form E was tested using nuclear magnetic resonance and KF in detection method 1. The results showed that Form E contained 0.2 eq of ethyl acetate and 0.7 eq of methyl tert-butyl ether.

[0204] Example 7 Preparation and Characterization of Form F Crystalline Form

[0205] Weigh 0.2 g of the compound of formula (I) obtained in Example 1 into a beaker, and add ethyl acetate, methyl tert-butyl ether, and n-heptane (volume ratio of 10:10:20, total 40V) to dissolve the sample to obtain a clear solution. The solution was sealed with a sealing film at room temperature, pierced with 4 to 5 small holes, and allowed to evaporate naturally for 3 days. The resulting solid was filtered and dried at 20-30°C to obtain crystalline Form F.

[0206] The obtained Form F crystalline form was subjected to XRPD and DSC analysis using detection method 1. The obtained XRPD pattern is shown in FIG14 , and the DSC pattern is shown in FIG15 .

[0207] Example 8

[0208] Weigh 0.2 g of the compound represented by formula (I) obtained in Example 1 into a beaker, add isopropanol and water (volume ratio 4:3, total 7V) to dissolve the sample to obtain a clear solution, place it at room temperature, seal it with a sealing film, pierce 4 to 5 small holes, and let it evaporate naturally for 1 hour. Filter the precipitated solid and dry it at 20-30°C.

[0209] The obtained solid was subjected to XRPD using detection method 1, and the obtained XRPD pattern is shown in FIG16 .

[0210] The obtained solid was detected by nuclear magnetic resonance and KF in detection method 1. The results showed that the solid did not contain isopropanol and contained 0.6eq of water.

[0211] The above-mentioned solvent crystallization method was used to investigate various solvents, including acetone / water, IPA / water, THF / n-heptane, ethyl acetate / n-heptane, ethyl acetate / MTBE, and ethyl acetate / MTBE / n-heptane. All solvents produced crystals, but NMR confirmed that crystals from all solvents except IPA / water contained significant amounts of solvent, likely representing solvates. Crystallization from IPA / water, on the other hand, produced a mixture of amorphous and crystalline products, with only minimal residual IPA. Therefore, the IPA / water solvent system was selected for further crystallization optimization.

[0212] Examples 9-11

[0213] 1 g of the compound of formula (I) obtained in Example 1 was weighed into a beaker, and isopropyl alcohol (IPA) and water (7V in total) were added to dissolve the sample to obtain a clear solution, which was left to evaporate at room temperature. The precipitated solid was filtered and dried.

[0214] The obtained solid was subjected to XRPD using detection method 1. The obtained XRPD pattern is shown in FIG17 , and the results are shown in Table 2.

[0215] Table 2

[0216] Conclusion: The crystallization of IPA / water system with different crystallization times all produced a mixed state containing crystals.

[0217] Examples 12-13

[0218] 5 g of the compound represented by formula (I) obtained in Example 1 was weighed into a beaker, and isopropanol and water were added to dissolve the sample to obtain a clear solution, which was left to evaporate at room temperature. The precipitated solid was filtered and dried.

[0219] The obtained solid was subjected to XRPD using detection method 1. The obtained XRPD pattern is shown in FIG18 , and the results are shown in Table 3.

[0220] Table 3

[0221] Conclusion: Crystallization of IPA / water system with different IPA volume ratios all produces a mixed state containing crystals.

[0222] Examples 14-18

[0223] 1 g of the compound represented by formula (I) obtained in Example 1 was weighed into a beaker, 4 mL of purified water was added to slurry, and the precipitated solid was filtered and dried.

[0224] The obtained solid was subjected to XRPD detection using detection method 1, and the obtained spectrum is shown in Figure 19. The experimental results are shown in Table 4. Examples 14 and 15 precipitated a mixed state of crystals and amorphous phases.

[0225] Table 4

[0226] Conclusion: Using pure water for beating can effectively remove residual IPA in the sample. When beating for more than 40 hours, the amorphous product can be stably obtained. If beating for less than 40 hours, the crystallization may not be complete.

[0227] The amorphous phase obtained in Example 16 was analyzed by XRPD, hot stage XRPD, TGA, DSC, and DVS using detection method 2. The results are shown in Table 5 below.

[0228] Table 5

[0229] Examples 19-24

[0230] Weigh 1 g of the starting material into a beaker, add isopropanol and water (4 mL in total), slurry, filter the precipitated solid, and dry.

[0231] The obtained solid was subjected to XRPD detection using detection method 1, and the obtained spectrum is shown in Figure 25. The experimental results are shown in Table 6. The precipitated solids of Examples 19 to 24 were a mixture of crystals and amorphous.

[0232] Table 6

[0233] Conclusion: When amorphous or crystalline / amorphous mixtures are used as starting materials and slurried in an aqueous solution containing IPA (wherein the volume ratio of IPA to water is 1:4 to 4:1), the products obtained are all crystalline / amorphous mixtures.

[0234] Examples 25-27

[0235] Weigh 1 g of the starting material into a beaker, add isopropanol and water (4 mL in total), slurry, filter the precipitated solid, and dry.

[0236] The obtained solid was subjected to XRPD detection using detection method 1, and the obtained spectrum is shown in Figure 26. The experimental results are shown in Table 7. The precipitated solids of Examples 25 to 27 were a mixture of crystals and amorphous.

[0237] Table 7

[0238] Conclusion: When using amorphous or crystalline / amorphous mixture as the starting material and beating in an IPA / water solution (4 / 3) for more than 20 hours, the products obtained are all crystalline / amorphous mixtures.

[0239] Examples 28-64 used the amorphous material obtained in Example 16 as a starting sample to prepare Form 1 to Form 20.

[0240] Example 28 Preparation and Characterization of Form 1 Crystalline Form

[0241] Single solvent evaporation crystallization

[0242] Weigh 5 mg of the starting sample into a 3 mL vial, add 0.025 mL of isopropyl acetate to dissolve the sample to obtain a clear solution, place it at room temperature, seal it with a sealing film, pierce 4 to 5 small holes, and then allow it to evaporate naturally until a solid precipitates. Filter the obtained solid and dry it to obtain crystal Form 1. XRPD analysis was performed using detection method 2. The obtained XRPD spectrum is shown in Figure 27.

[0243] The obtained Form 1 crystal form was subjected to TGA analysis using detection method 2, and the obtained spectrum is shown in Figure 28.

[0244] The obtained Form 1 crystal form was subjected to DSC analysis using detection method 2, and the obtained spectrum is shown in Figure 29.

[0245] Example 29 Preparation and Characterization of Form 2 Crystalline Form

[0246] Single solvent evaporation crystallization

[0247] Weigh 5 mg of the starting sample into a 3 mL vial, add 0.025 mL of tetrahydrofuran to dissolve the sample to obtain a clear solution, place it at room temperature and seal it with a sealing film, pierce 4 to 5 small holes and then allow it to evaporate naturally until a solid precipitates. Filter the obtained solid and dry it to obtain crystal Form 2. XRPD analysis was performed using detection method 2. The obtained XRPD spectrum is shown in Figure 30.

[0248] The obtained Form 2 crystal form was subjected to TGA analysis using detection method 2, and the obtained spectrum is shown in Figure 31.

[0249] The obtained Form 2 crystal form was subjected to DSC analysis using detection method 2. The obtained spectrum is shown in Figure 32, and the XRPD peak list is shown in Table A.

[0250] Table A. XRPD peak list of Form 2

[0251] Example 30

[0252] Mixed solvent evaporation crystallization

[0253] Weigh 7 mg of the starting sample into a 3 mL vial, add tetrahydrofuran / isopropyl ether (0.4 mL / 0.4 mL) and dissolve the sample to obtain a clear solution, place it at room temperature and seal it with a sealing film, pierce 4 to 5 small holes and allow it to evaporate naturally until a solid precipitates. Filter the obtained solid and dry it.

[0254] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 2 in Example 29, indicating that the obtained crystal was Form 2.

[0255] Example 31

[0256] Antisolvent crystallization

[0257] Weigh 15 mg of the starting sample into a 5 mL vial, add tetrahydrofuran (0.1 mL), add water (0.6 mL) under stirring, continue stirring for about 5 minutes after solid precipitates, centrifuge, filter, and dry to obtain a solid.

[0258] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 2 in Example 29, indicating that the obtained crystal was Form 2.

[0259] Example 32 Preparation and Characterization of Form 3 Crystalline Form

[0260] Mixed solvent evaporation crystallization

[0261] Weigh 7 mg of the starting sample into a 3 mL vial, add ethyl acetate / n-heptane (0.4 mL / 0.4 mL) and dissolve the sample to obtain a clear solution, place it at room temperature and seal it with a sealing film, pierce 4 to 5 small holes and let it evaporate naturally until a solid precipitates, filter the obtained solid, and dry it to obtain crystal Form 3. XRPD analysis was performed using detection method 2, and the obtained XRPD spectrum is shown in Figure 33.

[0262] The obtained Form 3 crystal form was subjected to TGA analysis using detection method 2, and the obtained spectrum is shown in Figure 34.

[0263] The obtained Form 3 crystal form was subjected to DSC analysis using detection method 2, and the obtained spectrum is shown in Figure 35.

[0264] Example 33

[0265] Antisolvent crystallization

[0266] Weigh 15 mg of the starting sample into a 5 mL vial, add tetrahydrofuran (0.1 mL), and add n-heptane (2 mL) under stirring. After the solid precipitates, continue stirring for about 5 minutes, centrifuge, filter, and dry to obtain a solid.

[0267] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 3 in Example 32, indicating that the obtained crystal was Form 3.

[0268] Example 34

[0269] Gas-liquid diffusion crystallization

[0270] About 7 mg of the starting sample was placed in a centrifuge tube, 0.2 mL of ethanol was added, and then the tube was placed in an n-heptane atmosphere at room temperature. After the solid precipitated, the tube was directly sampled.

[0271] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 3 in Example 32, indicating that the obtained crystal was Form 3.

[0272] Example 35

[0273] Gas-solid diffusion crystallization

[0274] About 7 mg of the starting sample was placed in a centrifuge tube, which was then placed in an n-heptane atmosphere at room temperature. After 3 days, the solid was directly taken out.

[0275] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 3 in Example 32, indicating that the obtained crystal was Form 3.

[0276] Example 36 Preparation and Characterization of Form 4 Crystalline Form

[0277] Mixed solvent evaporation crystallization

[0278] Weigh 7 mg of the starting sample into a 3 mL vial, add 1,4-dioxane / water (0.4 mL / 0.2 mL) and dissolve the sample to obtain a clear solution, place it at room temperature and seal it with a sealing film, pierce 4 to 5 small holes and let it evaporate naturally until a solid precipitates, filter the obtained solid, and dry it to obtain crystal Form 4. XRPD analysis was performed using detection method 2, and the obtained XRPD spectrum is shown in Figure 36.

[0279] The obtained Form 4 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 37.

[0280] The obtained Form 4 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 38.

[0281] Example 37

[0282] Antisolvent crystallization

[0283] Weigh 15 mg of the starting sample into a 5 mL vial, add 1,4-dioxane (0.1 mL), add water (0.3 mL) under stirring, continue stirring for about 5 minutes after solid precipitates, centrifuge, filter, and dry to obtain a solid.

[0284] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 4 in Example 36, indicating that the obtained crystal was Form 4.

[0285] Example 38

[0286] Cooling crystallization

[0287] Weigh 16 mg of the starting sample into a 5 mL vial, add 1,4-dioxane / water (1.0 mL / 0.5 mL) in a 50 °C water bath, stir to dissolve, keep warm for 30 minutes, turn off the heating, cool to room temperature by self-heating, stir overnight, precipitate the solid, centrifuge, filter, and dry to obtain crystals.

[0288] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 4 in Example 36, indicating that the obtained crystal was Form 4.

[0289] Example 39

[0290] Gas-liquid diffusion crystallization

[0291] Take about 7 mg of the starting sample, place it in a centrifuge tube, add 0.2 mL of 1,4-dioxane, and then place it in a water atmosphere at room temperature. After the solid precipitates, take a sample directly.

[0292] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 4 in Example 36, indicating that the obtained crystal was Form 4.

[0293] Example 40 Preparation and Characterization of Form 5 Crystalline Form

[0294] Mixed solvent slurry crystallization

[0295] Weigh 15 mg of the starting sample into a 5 mL vial, add isopropyl acetate / methylcyclohexane (0.1 mL / 1 mL) to obtain a suspension, and stir at 40°C for 3 days. The suspension is centrifuged, and the resulting solid is filtered and dried to obtain crystalline Form 5. XRPD analysis is performed using detection method 2. The resulting XRPD spectrum is shown in Figure 39, and the XRPD peak list is shown in Table B.

[0296] Table B. XRPD peak list of Form 5

[0297] The obtained Form 5 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 40.

[0298] The obtained Form 5 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 41.

[0299] Example 41

[0300] Single solvent slurry crystallization

[0301] 15 mg of the starting sample was weighed into a 5 mL vial, and methylcyclohexane (1 mL) was added to obtain a suspension. The suspension was stirred at 40° C. for 5 days, and the suspension was centrifuged, filtered, and dried.

[0302] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 5 in Example 40, indicating that the obtained crystal was Form 5.

[0303] Example 42 Preparation and Characterization of Form 6 Crystalline Form

[0304] Weigh 7 mg of the starting sample into a 3 mL vial, add isopropanol / water (0.8 mL / 0.2 mL) and dissolve the sample to obtain a clear solution, place it at room temperature and seal it with a sealing film, pierce 4 to 5 small holes and let it evaporate naturally until a solid precipitates, filter the obtained solid, and dry it to obtain crystalline Form 6. XRPD analysis was performed using detection method 2, and the obtained XRPD spectrum is shown in Figure 42.

[0305] Example 43 Preparation and Characterization of Form 7 Crystalline Form

[0306] Single solvent evaporation crystallization

[0307] Weigh 16 mg of the starting sample into a 5 mL vial, add methyl tert-butyl ether (0.6 mL) in a 50°C water bath, stir to dissolve, keep warm for 30 minutes, turn off the heating, cool to room temperature by self-heating, stir overnight, precipitate the solid, centrifuge, filter, and dry to obtain crystalline Form 7. XRPD analysis was performed using detection method 2. The resulting XRPD spectrum is shown in Figure 43.

[0308] The obtained Form 7 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 44.

[0309] The obtained Form 7 crystal form was subjected to differential thermal analysis using detection method 2. The obtained spectrum is shown in Figure 45, and the XRPD peak list is shown in Table C.

[0310] Table C. XRPD peak list of Form 7

[0311] Example 44

[0312] Cooling crystallization experiment

[0313] Weigh 16 mg of the starting sample into a 5 mL vial, add methyl tert-butyl ether (0.6 mL) in a 50 ° C water bath, stir to dissolve, keep warm for 30 minutes, turn off the heating, cool to room temperature by self-heating, stir overnight, precipitate solid, centrifuge, filter, and dry to obtain crystals.

[0314] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 7 in Example 43, indicating that the obtained crystal was Form 7.

[0315] Example 45

[0316] Gas-solid diffusion crystallization

[0317] About 7 mg of the starting sample was placed in a centrifuge tube, which was then placed in a methyl tert-butyl ether atmosphere at room temperature. After 3 days, the solid was directly taken out.

[0318] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 7 in Example 17, indicating that the obtained crystal was Form 7.

[0319] Example 46 Preparation and Characterization of Form 8 Crystalline Form

[0320] Single solvent slurry crystallization

[0321] Weigh 15 mg of the starting sample into a 5 mL vial, add toluene (0.2 mL) to obtain a suspension, and stir at room temperature for 3 days. The suspension is centrifuged, filtered, and dried to obtain crystal Form 8. XRPD analysis is performed using detection method 2. The resulting XRPD spectrum is shown in Figure 46.

[0322] The obtained Form 8 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 47.

[0323] The obtained Form 8 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 48.

[0324] Example 47 Preparation and Characterization of Form 9 Crystalline Form

[0325] Antisolvent crystallization

[0326] Weigh 15 mg of the starting sample into a 5 mL vial, add acetonitrile (0.1 mL), and add water (0.45 mL) under stirring. After the solid precipitates, continue stirring for about 5 minutes, centrifuge, filter, and dry to obtain crystalline Form 9. XRPD analysis is performed using detection method 2. The resulting XRPD spectrum is shown in Figure 49.

[0327] The obtained Form 9 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 50.

[0328] The obtained Form 9 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 51.

[0329] Example 48 Preparation and Characterization of Form 10 Crystalline Form

[0330] Antisolvent crystallization

[0331] 15 mg of the starting sample was weighed into a 5 mL vial, isopropanol (0.4 mL) was added, and water (0.9 mL) was added with stirring. After the solid precipitated, stirring was continued for about 5 minutes. The mixture was centrifuged, filtered, and dried to obtain crystalline Form 10. XRPD analysis was performed using detection method 2. The resulting XRPD pattern is shown in Figure 52, and the XRPD peak list is shown in Table D.

[0332] Table D. XRPD peak list of Form 10

[0333] The obtained Form 10 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 53.

[0334] The obtained Form 10 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 54.

[0335] Example 49 Preparation and Characterization of Form 11 Crystalline Form

[0336] Antisolvent crystallization

[0337] Weigh 15 mg of the starting sample into a 5 mL vial, add acetone (0.1 mL), add water (0.45 mL) under stirring, continue stirring for about 5 minutes after the solid precipitates, centrifuge, filter, and dry to obtain crystal Form 11. XRPD analysis is performed using detection method 2. The resulting XRPD spectrum is shown in Figure 55.

[0338] Example 50

[0339] Polymer template crystallization experiment

[0340] Take about 10 mg of the starting sample, add 0.2 mL of acetone and 0.8 mL of water, sonicate to dissolve the clear solution, then add about 1-2 mg of HPC (hydroxypropyl cellulose), sonicate for 2 minutes, punch a small hole, evaporate at room temperature, and collect the precipitated solid.

[0341] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 11 in Example 49, indicating that the obtained crystal was Form 11.

[0342] Example 51

[0343] Cooling crystallization

[0344] Weigh 16 mg of the starting sample into a 5 mL vial, add acetone / water (0.6 mL / 0.5 mL) in a 50 °C water bath, stir to dissolve, keep warm for 30 minutes, turn off the heating, cool to room temperature by self-heating, stir overnight, precipitate the solid, centrifuge, filter, and dry to obtain crystals.

[0345] The obtained crystals were subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 11 in Example 49, indicating that the obtained crystals were Form 11.

[0346] Example 52 Preparation and Characterization of Form 12 Crystalline Form

[0347] Cooling crystallization

[0348] Weigh 16 mg of the starting sample into a 5 mL vial, add toluene (0.8 mL) in a 50°C water bath, stir to dissolve, keep warm for 30 minutes, turn off the heating, cool to room temperature by self-heating, stir overnight, precipitate the solid, centrifuge, filter, and dry to obtain crystalline Form 12. XRPD analysis was performed using detection method 2. The resulting XRPD spectrum is shown in Figure 56.

[0349] The obtained Form 12 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 57.

[0350] The obtained Form 12 crystal form was subjected to differential thermal analysis using detection method 2. The obtained spectrum is shown in Figure 58, and the XRPD peak list is shown in Table E.

[0351] Table E. XRPD Peak List for Form 12

[0352] Example 53

[0353] Gas-solid diffusion crystallization

[0354] Weigh 7 mg of the starting sample and place it in a centrifuge tube, then place it in a toluene atmosphere at room temperature, and directly take out the solid after 3 days.

[0355] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 12 in Example 52, indicating that the obtained crystal was Form 12.

[0356] Example 54 Preparation and Characterization of Form 13 Crystalline Form

[0357] Mixed solvent slurry

[0358] Weigh 15 mg of the starting sample into a 5 mL vial, add acetone / water (0.1 mL / 0.5 mL) to obtain a suspension, stir at room temperature for 3 days, centrifuge the suspension, filter the obtained solid, and dry to obtain crystalline Form 13. XRPD analysis was performed using detection method 2, and the obtained XRPD spectrum is shown in Figure 59.

[0359] The obtained Form 13 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 60.

[0360] The obtained Form 13 crystal form was subjected to differential thermal analysis using detection method 2. The obtained spectrum is shown in Figure 61, and the XRPD peak list is shown in Table F.

[0361] Table F. XRPD peak list for Form 13

[0362] Example 55 Preparation and Characterization of Form 14 Crystalline Form

[0363] Single solvent evaporation crystallization

[0364] Weigh 5 mg of the starting sample into a 3 mL vial, add 0.025 mL of ethanol to dissolve the sample to obtain a clear solution, place it at room temperature and seal it with a sealing film, pierce 4 to 5 small holes and let it evaporate naturally until a solid precipitates, filter the obtained solid, and dry it to obtain crystalline Form 14. XRPD analysis was performed using detection method 2, and the obtained XRPD spectrum is shown in Figure 62.

[0365] Example 56

[0366] Mixed solvent evaporation crystallization

[0367] Weigh 7 mg of the starting sample into a 3 mL vial, add ethanol / water (0.8 mL / 0.2 mL) and dissolve the sample to obtain a clear solution, place it at room temperature and seal it with a sealing film, pierce 4 to 5 small holes and let it evaporate naturally until a solid precipitates. Filter the obtained solid and dry it to obtain crystals.

[0368] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 14 in Example 55, indicating that the obtained crystal was Form 14.

[0369] Example 57

[0370] Polymer template crystallization

[0371] Take about 10 mg of the starting sample, add 0.2 mL of water and 0.8 mL of ethanol, sonicate to dissolve the clear solution, then add about 1-2 mg of PVP (povidone K30), sonicate for 2 minutes, punch a small hole, evaporate at room temperature, and collect the precipitated solid.

[0372] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 14 in Example 55, indicating that the obtained crystal was Form 14.

[0373] Example 58 Preparation and Characterization of Form 15 Crystalline Form

[0374] Single solvent slurry crystallization

[0375] Weigh 15 mg of the starting sample into a 5 mL vial, add ether (0.2 mL) to obtain a suspension, and stir at room temperature for 3 days. The suspension is centrifuged, filtered, and dried to obtain crystal Form 15. XRPD analysis is performed using detection method 2. The resulting XRPD spectrum is shown in Figure 63.

[0376] The obtained Form 15 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 64.

[0377] The obtained Form 15 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 65.

[0378] Example 59

[0379] Gas-solid diffusion crystallization

[0380] Weigh 7 mg of the starting sample, place it in a centrifuge tube, then place it in an ether atmosphere at room temperature, and directly take the solid after 3 days.

[0381] The obtained solid was subjected to XRPD, TGA, and DSC analysis using detection method 2, and the obtained spectrum was basically consistent with Form 15 in Example 58, indicating that the obtained crystal was Form 15.

[0382] Example 60 Preparation and Characterization of Form 16 Crystalline Form

[0383] Single solvent slurry crystallization

[0384] Weigh 15 mg of the starting sample into a 5 mL vial, add isopropyl ether (1 mL) to obtain a suspension, and stir at 40°C for 3 days. The suspension is centrifuged, filtered, and dried to obtain crystalline Form 16. XRPD analysis is performed using detection method 2. The resulting XRPD spectrum is shown in Figure 66, and the XRPD peak list is shown in Table G.

[0385] Table G. XRPD peak list for Form 16

[0386] The obtained Form 16 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 67.

[0387] The obtained Form 16 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 68.

[0388] Example 61 Preparation and Characterization of Form 17 Crystalline Form

[0389] Form 16 crystal form was converted to Form 17 at 55°C, and the XRPD pattern obtained by XRPD analysis using detection method 2 is shown in Figure 69.

[0390] Example 62 Preparation and Characterization of Form 18 Crystalline Form

[0391] Gas-liquid diffusion crystallization

[0392] Weigh 7 mg of the starting sample into a centrifuge tube, add 0.2 mL of chloroform, and then place it in an n-heptane atmosphere and leave it at room temperature. After the solid precipitates, filter it and dry it to obtain crystalline Form 18. XRPD analysis is performed using detection method 2. The resulting XRPD spectrum is shown in Figure 70.

[0393] The obtained Form 18 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 71.

[0394] The obtained Form 18 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 72.

[0395] Example 63 Preparation and Characterization of Form 19 Crystalline Form

[0396] Weigh 5 mg of the starting sample into a 15 mL vial, add 5 mL of ether to dissolve the sample to obtain a clear solution, place it at room temperature, seal it with a sealing film, pierce 4 to 5 small holes, and let it evaporate naturally until a solid precipitates. Filter the obtained solid and dry it to obtain crystalline Form 19. XRPD analysis was performed using detection method 2. The obtained XRPD spectrum is shown in Figure 73.

[0397] The obtained Form 19 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 74.

[0398] The obtained Form 19 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 75.

[0399] Example 64 Preparation and Characterization of Form 20 Crystalline Form

[0400] During the hot stage XRPD analysis on Form 9, the temperature was switched to Form 20 at 80°C and XRPD analysis was performed using detection method 2. The resulting XRPD pattern is shown in Figure 76.

[0401] Table 8 summarizes the properties of crystal forms Form 1 to Form 19.

[0402] Table 8

[0403] “-” means not determined.

[0404] Stability test 1

[0405] The crystal form (XRPD detection) and thermal properties (TGA detection) involved in this experiment were all detected using detection method 2.

[0406] Storage conditions: long-term conditions (temperature 25℃±2℃, humidity 60%RH±10%RH, open storage and sealed storage); accelerated conditions (temperature 40℃±2℃, humidity 75%RH±10%RH, open storage and sealed storage).

[0407] Experimental operation: Take appropriate amount of samples and evenly disperse them in culture dishes (the sealing condition is to directly place the samples in 5mL vials and seal them with a cover), place them under different conditions, and take samples on the 0th and 7th days to detect the appearance (visual inspection, take appropriate amount of samples and place them under indoor fluorescent lights, and compare them with white qualitative filter paper (source: Fushun Dongyang Industry and Trade Co., Ltd.), record the sample color and other noteworthy phenomena, such as agglomeration, deliquescence, etc.), crystal form (XRD detection), and thermal properties (TGA detection).

[0408] Appearance (visual inspection)

[0409] Uncovered: Compared to day 0, the appearance of Form 5, Form 10, and Form 16 samples under long-term and accelerated conditions for 7 days showed no significant change to off-white powder.

[0410] Sealing: Compared to the test at day 0, the Form 5, Form 10, and Form 16 samples remained white powders after 7 days under long-term and accelerated conditions, with no significant changes in appearance.

[0411] Crystal form (XRPD detection)

[0412] Exposure: Compared with 0 days, after 7 days of storage under long-term conditions and accelerated conditions, the Form 10, Form 16 and Form 5 crystal forms remained basically unchanged, but the crystallinity decreased to varying degrees.

[0413] Sealing: Compared with the time at day 0, after 7 days of storage under long-term and accelerated conditions, the crystal forms of Form 10, Form 16, and Form 5 remained basically unchanged, but the crystallinity decreased to varying degrees.

[0414] The relevant spectra are shown in Figures 77-82. The XRPD test results of the crystal stability show that the crystallinity of Form 10, Form 16 and Form 5 crystal forms decreases over time.

[0415] Thermal properties (TGA test)

[0416] Exposure: After 7 days of exposure under long-term and accelerated conditions, the weight loss of Form 10, Form 16, and Form 5 decreased.

[0417] Sealing: After 7 days of storage under long-term and accelerated conditions, the weight loss of Form 10 and Form 5 decreased; while the weight loss of Form 16 remained basically unchanged under long-term conditions, and decreased under accelerated conditions.

[0418] Table 9 Crystal stability TGA weight loss

[0419] See Figures 83-88 for related graphs.

[0420] Stability test 2

[0421] This experiment investigated the effects of high temperature and humidity (60℃, 75%±5%RH), light (25℃, 4500Lx±500Lx, near-ultraviolet 0.9w / m 2 ) for one month under 37°C. At the same time, the accelerated stability (40±2°C, 75±5% RH, 6 months) and long-term stability (25±2°C, 60±5% RH, 24 months) of the amorphous substance were further investigated using Test Method 1. The experimental results are shown in Tables 10-12 below.

[0422] Table 10 Stability test results of amorphous materials under high temperature, high humidity and light conditions

[0423] Table 11 Results of accelerated stability test (40±2°C, 75±5% RH) of amorphous material

[0424] - indicates not detected.

[0425] Table 12 Results of long-term stability test of amorphous substance (25±2°C, 60±5% RH)

[0426] - indicates not detected.

[0427] Conclusion: When the amorphous material was placed under accelerated test conditions (40℃±2℃ / 75%±5% RH) for 6 months and under long-term test conditions (25℃±2℃ / 60%±5% RH) for 24 months, the quality indicators showed no significant changes compared with those at 0 months, and no crystal transformation occurred, indicating that the product is stable.

[0428] In summary, the amorphous form of the compound represented by formula (I) has a moisture absorption capacity of approximately 0.8% within the range of 0% to 80% RH; its residual solvent content is low; and after 6 months of storage under accelerated test conditions (40°C±2°C / 75%±5% RH) and 24 months under long-term test conditions (25°C±2°C / 60%±5% RH), its quality indicators showed no significant change compared to the 0-month storage period, and no crystal transformation occurred. This indicates that the amorphous form has excellent stability, hygroscopicity, and low residual solvent content, and has good prospects for drug development.

[0429] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. The solid form of the compound represented by formula (I), including amorphous or polymorphic forms, 2. The solid form according to claim 1, wherein The amorphous material has an XRPD pattern substantially as shown in FIG. 20 .

3. The solid form according to claim 1, wherein The amorphous material has a weight loss of no more than 3% before 150°C; and / or, the decomposition temperature of the amorphous material is 255-270°C; and / or, the amorphous substance has an endothermic peak before 100° C., with an onset temperature of 70±5° C.; And / or, the glass transition temperature of the amorphous material is not more than 100±5°C.

4. The solid form according to claim 1, wherein The polymorph is a solvate of the compound represented by formula (I), for example, form 2, form 5, form 7, form 10, form 12, form 13 or form 16 of the compound represented by formula (I).

5. The solid form according to claim 4, wherein The form 5 uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.6±0.20°, 7.5±0.20°, 13.8±0.20°, 14.8±0.20°, and 22.7±0.20°; preferably, it has characteristic peaks at 4.6±0.20°, 7.5±0.20°, 8.0±0.20°, 13.8±0.20°, 14.4±0.20°, 14.8±0.20°, 18.5±0.20°, 19.8±0.20°, 22.3±0.20°, and 22.7±0.20°. Preferably, Form 5 has an XRPD pattern substantially as shown in Figure 39. Preferably, the form 5 is a hemimethylcyclohexane solvate of the compound represented by formula (I), that is, the molar ratio of the compound represented by formula (I) to methylcyclohexane is about 1:0.

5. Preferably, the Form 2 has an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation at 7.4±0.20°, 7.9±0.20°, 14.5±0.20°, 14.8±0.20°, 18.3±0.20°, 20.0±0.20°, 21.7±0.20°, 22.3±0.20°, 26.2±0.20° Preferably, the peaks are at 4.7±0.20°, 7.4±0.20°, 7.9±0.20°, 14.5±0.20°, 14.8±0.20°, 18.3±0.20°, 20.0±0.20°, 21.7±0.20°, 22.3±0.20°, 23.4±0.20°, 26.2±0.20°. peak; Preferably, Form 2 has an XRPD pattern substantially as shown in Figure 30. Preferably, the form 2 is a tetrahydrofuran solvate of the compound represented by formula (I), that is, the molar ratio of the compound represented by formula (I) to tetrahydrofuran is about 1:

1. Preferably, the Form 7 has an X-ray powder diffraction pattern in 2θ angles using Cu-Kα radiation at 4.6±0.20°, 7.2±0.20°, 7.6±0.20°, 9.5±0.20°, 10.3±0.20°, 14.4±0.20°, 18.2±0.20°, 21.4±0.20°, 21.7±0.20°, 29.1±0.20° It has characteristic peaks; preferably at 4.6±0.20°, 7.2±0.20°, 7.6±0.20°, 9.5±0.20°, 10.3±0.20°, 14.0±0.20°, 14.4±0.20°, 15.1±0.20°, 18.2±0.20°, 21.4±0.20°, 21.7±0.20°, and 29.1±0.20°. Preferably, Form 7 has an XRPD pattern substantially as shown in Figure 43. Preferably, the form 7 is a half-methyl tert-butyl ether solvate of the compound represented by formula (I), that is, the molar ratio of the compound represented by formula (I) to methyl tert-butyl ether is about 1:0.

5. Preferably, the form 10 uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angle is 7.5±0.20°, 13.8±0.20°, 15.0±0.20°, 18.4±0.20°, 19.9±0.20°, 22.5±0.20°, and 23.3±0.20°, preferably 4.6±0.20°, 7.5±0.20°, 7.9±0.20°, 13.8±0.20°, 14.3±0.20°, 15.0±0.20°, 17.2±0.20°, 18.4±0.20°, 19.9±0.20°, 20.3±0.20°, 20.7±0.20°, 22.5±0.20°, 23.3±0.20°, 24.5±0.20°, 25. The invention relates to a method for preparing the present invention that has characteristic peaks at 20°, 23.3±0.20°, 26.3±0.20°, and 27.9±0.20°; more preferably, the method has characteristic peaks at 4.6±0.20°, 7.5±0.20°, 7.9±0.20°, 13.8±0.20°, 14.3±0.20°, 14.7±0.20°, 15.0±0.20°, 17.2±0.20°, 17.8±0.20°, 18.4±0.20°, 19.9±0.20°, 20.3±0.20°, 20.7±0.20°, 21.4±0.20°, 22.5±0.20°, 23.3±0.20°, 26.3±0.20°, and 27.9±0.20°. Preferably, the Form 10 has an XRPD pattern substantially as shown in Figure 52. Preferably, the form 10 is a semi-isopropanol tunnel solvate of a semi-hydrate of the compound represented by formula (I), that is, the molar ratio of the compound represented by formula (I) to water and isopropanol is about 1:0.5:0.

5. Preferably, the form 12 uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angle is 4.6±0.20°, 7.5±0.20°, 13.8±0.20°, 14.4±0.20°, 14.8±0.20°, 18.4±0.20°, 19.8±0.20°, 22.6±0.20°, 23.0±0.20°, 23.3±0.20°, preferably 4.6±0.20°, 7.5±0.20°, 8.0±0.20°, 9.6±0.20°. , 10.7±0.20°, 13.8±0.20°, 14.4±0.20°, 14.8±0.20°, 17.1±0.20°, 18.4±0.20°, 19.8±0.20°, 20.1±0.20°, 20.7±0.20°, 22.6±0.20°, 23.0±0.20°, 23.3±0.20°, 24.0±0.20°, 26.4±0.20°, 26.9±0.20°, 28.0±0.20°, and 30.9±0.20°, have characteristic peaks. Preferably, Form 12 has an XRPD pattern substantially as shown in Figure 56. Preferably, the form 12 is a semi-toluene solvate of the compound represented by formula (I), that is, the molar ratio of the compound represented by formula (I) to toluene is about 1:0.

5. Preferably, the form 13 uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles is 4.6±0.20°, 7.5±0.20°, 13.8±0.20°, 15.0±0.20°, 17.9±0.20°, 18.4±0.20°, 19.9±0.20°, 22.5±0.20°, 26.3±0.20°, and 28.0±0.20°, preferably 4.6±0.20°, 7.5±0.20°, 9.6±0.20°, 10.5±0.20°. , 13.1±0.20°, 13.8±0.20°, 14.3±0.20°, 15.0±0.20°, 16.6±0.20°, 17.9±0.20°, 18.4±0.20°, 19.2±0.20°, 19.9±0.20°, 20.7±0.20°, 22.5±0.20°, 23.3±0.20°, 24.0±0.20°, 26.3±0.20°, 26.6±0.20°, 28.0±0.20°, and 30.9±0.20°, have characteristic peaks. Preferably, the Form 13 has an XRPD pattern substantially as shown in Figure 59. Preferably, the form 13 is a semi-acetone solvate of the semi-hydrate of the compound represented by formula (I), that is, the molar ratio of the compound represented by formula (I) to water and acetone is about 1:0.5:0.

5. Preferably, the form 16 uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 4.6±0.20°, 7.5±0.20°, 13.8±0.20°, 14.8±0.20°, 19.8±0.20°, and 22.7±0.20°; preferably, it has characteristic peaks at 4.6±0.20°, 7.5±0.20°, 8.0±0.20°, 13.8±0.20°, 14.3±0.20°, 14.8±0.20°, 18.4±0.20°, 19.8±0.20°, 22.7±0.20°, and 23.3±0.20°. Preferably, Form 16 has an XRPD pattern substantially as shown in Figure 66. Preferably, the form 16 is an isopropyl ether solvate of the compound represented by formula (I), that is, the molar ratio of the compound represented by formula (I) to isopropyl ether is about 1:

1.

6. A method for preparing an amorphous substance of a compound represented by formula (I) according to any one of claims 1 to 3, wherein: The preparation method is selected from any one of the following methods 1 to 8: Method 1: The compound represented by formula (I) is mixed with water, slurried, and the precipitated solid is filtered and dried to obtain the amorphous substance; Method 2: Form 2 of the compound represented by formula (I) is heated to obtain the amorphous substance; the form 2 is the form 2 in claim 5, preferably having an XRPD pattern substantially as shown in FIG. 30; Method 3: Form 5 of the compound represented by formula (I) is heated to obtain the amorphous substance; the form 5 is the form 5 in claim 5, preferably having an XRPD pattern substantially as shown in FIG. 39; Method 4: Form 7 of the compound represented by formula (I) is heated to obtain the amorphous substance, wherein the form 7 is the form 7 in claim 5, preferably having an XRPD pattern substantially as shown in FIG. 43; Method 5: Form 10 of the compound represented by formula (I) is heated to obtain the amorphous substance, wherein the form is form 10 in claim 5, preferably 10 has an XRPD pattern substantially as shown in FIG. 52; Method 6: Form 12 of the compound represented by formula (I) is heated to obtain the amorphous substance, wherein the form 12 is the form 12 in claim 5, preferably having an XRPD pattern substantially as shown in FIG. 56; Method 7: Form 13 of the compound represented by formula (I) is heated to obtain the amorphous substance, wherein the form 13 is the form 13 in claim 5, preferably having an XRPD pattern substantially as shown in FIG. 59 ; Method eight: Form 16 of the compound represented by formula (I) is heated to obtain the amorphous substance, wherein the form 16 is the form 16 in claim 5, and preferably has an XRPD spectrum substantially as shown in Figure 66.

7. The method for preparing a polymorph according to any one of claims 1 to 5, wherein: The preparation method comprises mixing an amorphous substance of the compound represented by formula (I) with a solvent to prepare the polymorphic substance; Preferably, when the polymorph is form 5 of the compound represented by formula (I), the preparation method comprises mixing the amorphous form of the compound represented by formula (I) with isopropyl acetate and methylcyclohexane to form a suspension, stirring, centrifuging, filtering, and drying to obtain the form 5; When the polymorph is form 10 of the compound represented by formula (I), the preparation method comprises mixing the amorphous form of the compound represented by formula (I) with isopropanol and water, and centrifuging, filtering and drying the precipitated solid to obtain the form 10; When the polymorph is form 16 of the compound represented by formula (I), its preparation method includes mixing the amorphous form of the compound represented by formula (I) with isopropyl ether to form a suspension, stirring, centrifuging, filtering, and drying to obtain the form 16.

8. A pharmaceutical composition or pharmaceutical preparation, wherein: The pharmaceutical composition comprises a solid form of the compound of formula (I) according to any one of claims 1 to 5, preferably an amorphous form and a polymorphic form of the compound of formula (I); Preferably, the pharmaceutical composition further contains pharmaceutically acceptable excipients; The pharmaceutical preparation contains a solid form of a compound represented by formula (I) according to any one of claims 1 to 5 or the pharmaceutical composition; Preferably, the pharmaceutical composition or the pharmaceutical preparation is used for preventing and / or treating diseases caused by androgen deficiency.

9. Use of a solid form of a compound represented by formula (I) in the preparation and / or purification of an amorphous substance as claimed in claim 2, wherein: The solid form is as defined in claim 4 or 5.

10. A method for preventing and / or treating a disease caused by androgen deficiency, comprising administering a therapeutically effective amount of a solid form of a compound of formula (I) according to any one of claims 1 to 5, a pharmaceutical composition or a pharmaceutical preparation according to claim 8 to a patient in need of such treatment.

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