Crystal form of nicotinate compound, preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a crystal form of a nicotinate compound, a preparation method therefor and the use thereof. The X-ray powder diffraction pattern measured using Cu-Kα radiation of the crystal form has characteristic peaks at 2θ angles of 5.6±0.20°, 14.7±0.20°, 15.8±0.20°, 20.0±0.20°, 20.9±0.20° and 21.1±0.20°. Formula (I). The crystal form has low hygroscopicity and good stability, and has good druggability.

Description

A nicotinic acid ester compound crystal form and its preparation method and application

[0001] This application claims priority to a prior application, patent application number PCT / CN2023 / 140727, filed with the State Intellectual Property Office of China on December 21, 2023, entitled “A Crystalline 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 a crystal form of a nicotinic acid ester compound, a preparation method and an 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. Summary of the Invention

[0007] The present invention provides a crystalline form of a compound represented by formula (I). The crystalline form uses Cu-Kα radiation, and X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.6±0.20°, 14.7±0.20°, 15.8±0.20°, 20.0±0.20°, 20.9±0.20°, and 21.1±0.20°; further, the crystalline form also has characteristic peaks at 11.1±0.20°, 22.6±0.20°, and / or 24.7±0.20°; further, the crystalline form also has characteristic peaks at 7.5±0.20°, 22.4±0.20°, 25.0±0.20°, 25.4±0.20°, 27.7±0.20°, and / or 29.5±0.20°.

[0008] According to some embodiments of the present invention, the crystalline form has an X-ray powder diffraction pattern expressed in 2θ angles using Cu-Kα radiation at 5.6±0.20°, 7.5±0.20°, 11.1±0.20°, 14.7±0.20°, 15.8±0.20°, 16.6±0.20°, 16.9±0.20°, 18.1±0.20°, 18.9±0.20°, 20.0±0.20°, 20.9±0.20°, 21.1±0.20°, 21.8±0.20°, 22.1±0.20°, 23. 55. According to an embodiment of the present invention, the crystalline form has an XRPD pattern substantially as shown in Figure 55.

[0009] According to an embodiment of the present invention, the crystalline form loses no more than 0.6% of its weight from room temperature to 155°C, for example, loses no more than 0.42% of its weight from room temperature to 150°C.

[0010] According to an embodiment of the present invention, the crystalline form has a TGA / DSC pattern substantially as shown in Figure 56.

[0011] According to an embodiment of the present invention, the crystalline form is an anhydrate.

[0012] The present invention also provides a method for preparing the above-mentioned crystal form, which is prepared from an amorphous form or a solvate of the compound represented by formula (I).

[0013] According to an embodiment of the present invention, the amorphous form of the compound represented by formula (I) is the amorphous form described in patent application PCT / CN2024 / 105186.

[0014] According to one embodiment of the present invention, the preparation method of the crystal form comprises: adding an amorphous form of the compound represented by formula (I) to toluene to form a colloidal solid, separating the obtained colloidal solid, adding n-heptane thereto, suspending and stirring at 60-90°C to obtain a suspension, separating the suspension, and drying to obtain the crystal form.

[0015] According to one embodiment of the present invention, the preparation method of the crystal form comprises: mixing a solvate of the compound represented by formula (I) with cyclohexane, stirring the resulting suspension at 60-90° C. until a solid precipitates, and separating the solid to obtain the crystal form.

[0016] The present invention also provides a pharmaceutical composition containing the crystal form of the compound represented by the above formula (I).

[0017] 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.

[0018] The present invention also provides the use of a crystalline form or a pharmaceutical composition of the compound represented by the above formula (I) in the preparation of a pharmaceutical preparation, wherein the pharmaceutical preparation is used to prevent and / or treat diseases or symptoms caused by androgen deficiency. For example, the diseases or symptoms include acute or chronic muscle wasting, muscle wasting, muscle atrophy, bone-related diseases, 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.

[0019] The present invention also provides a pharmaceutical preparation containing the crystal form or pharmaceutical composition of the compound represented by the above formula (I).

[0020] 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.

[0021] 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.

[0022] The present invention also provides a method for preventing and / or treating diseases or symptoms caused by androgen deficiency, comprising administering to a patient an effective amount of the crystalline form, pharmaceutical composition or pharmaceutical preparation of the compound represented by formula (I). Beneficial effects

[0023] The compound represented by formula (I) easily forms a solvate. The present invention provides a crystalline anhydride of the compound represented by formula (I), and surprisingly found that the crystalline anhydride has low hygroscopicity and good stability.

[0024] Definitions and Explanations of Terms

[0025] Unless otherwise stated, the definitions of terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, and specific definitions in embodiments, may be arbitrarily combined and coupled with each other. Such combinations and couplings shall fall within the scope of this specification.

[0026] The term "effective amount" refers to the amount of the crystalline form of the present invention sufficient to achieve the intended application (including but not limited to the treatment of diseases as defined below). The effective amount may vary depending on the following factors: the intended application (in vitro or in vivo), or the subject and disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, and the mode of administration, which can be easily determined by one of ordinary skill in the art. The specific dosage will vary depending on the following factors: the specific active ingredient selected, the dosage regimen based on, whether to be administered in combination with other compounds, the time schedule of administration, the tissue to be administered, and the physical delivery system carried.

[0027] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1. XRPD pattern of the amorphous form of the compound represented by formula (I)

[0029] Figure 2. TGA spectrum of the amorphous form of the compound represented by formula (I);

[0030] Figure 3. DSC spectrum of the amorphous form of the compound represented by formula (I);

[0031] Figure 4. Isothermal adsorption curve of the amorphous form of the compound represented by formula (I);

[0032] Figure 5. XRPD pattern of Form 1 (Form 1) of the compound represented by formula (I);

[0033] Figure 6. TGA spectrum of Form 1 (Form 1) of the compound represented by formula (I);

[0034] Figure 7. DSC spectrum of Form 1 (Form 1) of the compound represented by formula (I);

[0035] Figure 8. XRPD pattern of Form 2 (Form 2) of the compound represented by formula (I);

[0036] Figure 9. TGA spectrum of Form 2 (Form 2) of the compound represented by formula (I);

[0037] Figure 10. DSC spectrum of Form 2 (Form 2) of the compound represented by formula (I);

[0038] Figure 11. XRPD pattern of Form 3 of the compound represented by formula (I);

[0039] Figure 12. TGA spectrum of Form 3 of the compound represented by formula (I);

[0040] Figure 13. DSC spectrum of Form 3 of the compound represented by formula (I);

[0041] Figure 14. XRPD pattern of Form 4 of the compound represented by formula (I);

[0042] Figure 15. TGA spectrum of Form 4 of the compound represented by formula (I);

[0043] Figure 16. DSC spectrum of Form 4 of the compound represented by formula (I);

[0044] Figure 17. XRPD pattern of Form 5 of the compound represented by formula (I);

[0045] Figure 18. TGA spectrum of Form 5 of the compound represented by formula (I);

[0046] Figure 19. DSC spectrum of Form 5 of the compound represented by formula (I);

[0047] Figure 20. XRPD spectrum of Form 6 of the compound represented by formula (I);

[0048] Figure 21. XRPD pattern of Form 7 of the compound represented by formula (I);

[0049] Figure 22. TGA spectrum of Form 7 of the compound represented by formula (I);

[0050] Figure 23. DSC spectrum of Form 7 of the compound represented by formula (I);

[0051] Figure 24. XRPD pattern of Form 8 of the compound represented by formula (I);

[0052] Figure 25. TGA spectrum of Form 8 of the compound represented by formula (I);

[0053] Figure 26. DSC spectrum of Form 8 of the compound represented by formula (I);

[0054] Figure 27. XRPD pattern of Form 9 of the compound represented by Formula (I);

[0055] Figure 28. TGA spectrum of Form 9 of the compound represented by formula (I);

[0056] Figure 29. DSC spectrum of Form 9 of the compound represented by formula (I);

[0057] Figure 30. XRPD pattern of Form 10 (Form 10) of the compound represented by Formula (I);

[0058] Figure 31. TGA spectrum of Form 10 (Form 10) of the compound represented by formula (I);

[0059] Figure 32. DSC spectrum of Form 10 (Form 10) of the compound represented by Formula (I);

[0060] Figure 33. XRPD pattern of Form 11 of the compound of Formula (I);

[0061] Figure 34. XRPD pattern of Form 12 of the compound of Formula (I);

[0062] Figure 35. TGA spectrum of Form 12 of the compound represented by Formula (I);

[0063] Figure 36. DSC spectrum of Form 12 of the compound represented by Formula (I);

[0064] Figure 37. XRPD pattern of Form 13 of the compound of Formula (I);

[0065] Figure 38. TGA spectrum of Form 13 of the compound represented by Formula (I);

[0066] Figure 39. DSC spectrum of Form 13 of the compound represented by Formula (I);

[0067] Figure 40. XRPD pattern of Form 14 of the compound of Formula (I);

[0068] Figure 41. XRPD pattern of Form 15 of the compound of formula (I);

[0069] Figure 42. TGA spectrum of Form 15 of the compound represented by Formula (I);

[0070] Figure 43. DSC spectrum of Form 15 of the compound represented by Formula (I);

[0071] Figure 44. XRPD pattern of Form 16 of the compound of Formula (I);

[0072] Figure 45. TGA spectrum of Form 16 of the compound represented by Formula (I);

[0073] Figure 46. DSC spectrum of Form 16 of the compound represented by Formula (I);

[0074] Figure 47. XRPD pattern of Form 17 (Form 17) of the compound represented by Formula (I);

[0075] Figure 48. XRPD pattern of Form 18 (Form 18) of the compound represented by Formula (I);

[0076] Figure 49. TGA spectrum of Form 18 (Form 18) of the compound represented by Formula (I);

[0077] Figure 50. DSC spectrum of Form 18 (Form 18) of the compound represented by Formula (I);

[0078] Figure 51. XRPD pattern of Form 19 (Form 19) of the compound represented by Formula (I);

[0079] Figure 52. TGA spectrum of Form 19 (Form 19) of the compound represented by Formula (I);

[0080] Figure 53. DSC spectrum of Form 19 of the compound represented by Formula (I);

[0081] Figure 54. XRPD pattern of Form 20 of the compound of Formula (I);

[0082] Figure 55. XRPD pattern of Form 21 of the compound of formula (I);

[0083] Figure 56. TGA / DSC overlay of Form 21 of the compound of Formula (I);

[0084] Figure 57. DVS spectrum of Form 21 of the compound represented by Formula (I);

[0085] Figure 58. XRPD overlay of Form 21 (Form 21) sample A of the compound of Formula (I) before and after accelerated stability (40°C / 75% RH);

[0086] Figure 59. XRPD overlay of Form 21 (Form 21) of the compound of Formula (I) before and after accelerated stability (40°C / 75% RH) of jet milled sample B.

[0087] Figure 60. XRPD overlay of Form 21 of the compound of Formula (I) before and after the study of factors affecting stability;

[0088] Figure 61. XRPD overlay of Form 21 of the compound of Formula (I) before and after the study of factors affecting stability. DETAILED DESCRIPTION

[0089] Instruments, parameters, characterization and test methods used in the examples

[0090] Instrument information and test method parameters used in test method 1

[0091] 1) XRPD patterns were collected on an X-ray powder diffraction analyzer produced by PANalytacal, and the scanning parameters are shown in Table A.

[0092] Table A XRPD test parameters

[0093] 2) Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) / modulated differential scanning calorimetry (mDSC) images were collected on a TA Discovery TGA 5500 thermogravimetric analyzer and a TA Discovery DSC 2500 differential scanning calorimeter, respectively. The test parameters are listed in Tables B and C.

[0094] Table B TGA and DSC test parameters

[0095] Table C mDSC test parameters

[0096] 3) Dynamic moisture sorption (DVS) curves were collected on an SMS (Surface Measurement Systems) DVS Intrinsic. Relative humidity at 25°C was calibrated using the deliquescent points of LiCl, Mg(NO₃)₂, and KCl. DVS test parameters are listed in Table D.

[0097] Table D DVS test parameters

[0098] 4) Liquid-state NMR spectra were collected on a Bruker 400M NMR instrument, and DMSO-d6 was used as the NMR test solvent.

[0099] 5) The purity of the samples in the project was determined by ultra-high performance liquid chromatography (UPLC) using Waters. The specific instrument and test parameters are shown in Table E.

[0100] Table E UPLC parameters

[0101] The instrument information and test method parameters used in test method 2 are shown in Table F.

[0102] Table F

[0103] In previous research, the applicant discovered crystal forms Form 1-Form 20, which were recorded in patent application PCT / CN2024 / 105186. In the latest research, the applicant further discovered anhydrous crystal form Form 21.

[0104] Example 1

[0105] Repeat the synthesis method of Example 1 in CN201911320125.1 to obtain a white solid, which is the compound represented by formula (I).

[0106] Weigh 1 g of the resulting white solid into a beaker, add 4 mL of purified water, and slurry the mixture at 10°C to 30°C for 40 hours. Filter the suspended white solid and dry it. XRPD, hot-stage XRPD, TGA, DSC, and DVS analyses were performed using Detection Method 2. The results are shown in Table 1 below. The white solid was amorphous.

[0107] Table 1

[0108] Example 2 Preparation and Characterization of Form 1 Crystalline Form

[0109] Single solvent evaporation crystallization

[0110] 5 mg of amorphous starting sample was weighed into a 3 mL vial, and 0.025 mL of isopropyl acetate was 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 until a solid precipitated. The obtained solid was filtered and dried to obtain crystalline Form 1. XRPD analysis was performed using detection method 2. The obtained XRPD pattern is shown in Figure 5.

[0111] The obtained Form 1 crystal form was subjected to TGA analysis using detection method 2, and the obtained spectrum is shown in Figure 6.

[0112] The obtained Form 1 crystal form was subjected to DSC analysis using detection method 2, and the obtained spectrum is shown in Figure 7.

[0113] Example 3 Preparation and Characterization of Form 2 Crystalline Form

[0114] Single solvent evaporation crystallization

[0115] 5 mg of amorphous starting sample was weighed into a 3 mL vial, and 0.025 mL of tetrahydrofuran was 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 until a solid precipitated. The obtained solid was filtered and dried to obtain crystalline Form 2. XRPD analysis was performed using detection method 2. The obtained XRPD pattern is shown in Figure 8.

[0116] The obtained Form 2 crystal form was subjected to TGA analysis using detection method 2, and the obtained spectrum is shown in Figure 9.

[0117] The obtained Form 2 crystal form was subjected to DSC analysis using detection method 2, and the obtained spectrum is shown in Figure 10.

[0118] Example 4 Preparation and Characterization of Form 3 Crystalline Form

[0119] Mixed solvent evaporation crystallization

[0120] Weigh 7 mg of the amorphous 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 crystalline Form 3. XRPD analysis was performed using detection method 2, and the obtained XRPD spectrum is shown in Figure 11.

[0121] The obtained Form 3 crystal form was subjected to TGA analysis using detection method 2, and the obtained spectrum is shown in Figure 12.

[0122] The obtained Form 3 crystal form was subjected to DSC analysis using detection method 2, and the obtained spectrum is shown in Figure 13.

[0123] Example 5 Preparation and Characterization of Form 4 Crystalline Form

[0124] Mixed solvent evaporation crystallization

[0125] 7 mg of amorphous starting sample was weighed into a 3 mL vial, 1,4-dioxane / water (0.4 mL / 0.2 mL) was added and the sample was dissolved to obtain a clear solution, which was sealed with a sealing film at room temperature. After piercing 4 to 5 small holes, the solution was allowed to evaporate naturally until a solid precipitated. The obtained solid was filtered and dried to obtain crystalline Form 4. XRPD analysis was performed using detection method 2. The obtained XRPD spectrum is shown in Figure 14.

[0126] The obtained Form 4 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 15.

[0127] The obtained Form 4 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 16.

[0128] Example 6 Preparation and Characterization of Form 5 Crystalline Form

[0129] Mixed solvent slurry crystallization

[0130] 15 mg of the amorphous starting sample was weighed into a 5 mL vial, and isopropyl acetate / methylcyclohexane (0.1 mL / 1 mL) was added to obtain a suspension. The suspension was stirred at 40° C. for 3 days. The suspension was centrifuged, and the obtained solid was filtered and dried to obtain crystalline Form 5. XRPD analysis was performed using detection method 2. The obtained XRPD pattern is shown in Figure 17.

[0131] The obtained Form 5 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 18.

[0132] The obtained Form 5 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 19.

[0133] Example 7

[0134] Single solvent slurry crystallization

[0135] 15 mg of the amorphous 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.

[0136] 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 6, indicating that the obtained crystal was Form 5.

[0137] Example 8 Preparation and Characterization of Form 6 Crystalline Form

[0138] 7 mg of amorphous starting sample was weighed into a 3 mL vial, and isopropanol / water (0.8 mL / 0.2 mL) was added to dissolve the sample to obtain a clear solution. The solution was sealed with a sealing film at room temperature, and 4 to 5 small holes were pierced and allowed to evaporate naturally until a solid precipitated. The obtained solid was filtered and dried to obtain crystalline Form 6. XRPD analysis was performed using detection method 2. The obtained XRPD spectrum is shown in Figure 20.

[0139] Example 9 Preparation and Characterization of Form 7 Crystalline Form

[0140] Single solvent evaporation crystallization

[0141] Weigh 16 mg of amorphous 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 21.

[0142] The obtained Form 7 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 22.

[0143] The obtained Form 7 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 23.

[0144] Example 10

[0145] Cooling crystallization experiment

[0146] Weigh 16 mg of amorphous 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.

[0147] 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 9, indicating that the obtained crystal was Form 7.

[0148] Example 11

[0149] Gas-solid diffusion crystallization

[0150] About 7 mg of the amorphous 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.

[0151] 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 9, indicating that the obtained crystal was Form 7.

[0152] Example 12 Preparation and Characterization of Form 8 Crystalline Form

[0153] Single solvent slurry crystallization

[0154] 15 mg of the amorphous starting sample was weighed into a 5 mL vial, and toluene (0.2 mL) was added to obtain a suspension. The suspension was stirred at room temperature for 3 days. The suspension was centrifuged, filtered, and dried to obtain crystalline Form 8. XRPD analysis was performed using detection method 2. The obtained XRPD spectrum is shown in Figure 24.

[0155] The obtained Form 8 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 25.

[0156] The obtained Form 8 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 26.

[0157] Example 13 Preparation and Characterization of Form 9 Crystalline Form

[0158] Antisolvent crystallization

[0159] Weigh 15 mg of the amorphous 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 pattern is shown in Figure 27.

[0160] The obtained Form 9 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 28.

[0161] The obtained Form 9 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 29.

[0162] Example 14 Preparation and Characterization of Form 10 Crystalline Form

[0163] Antisolvent crystallization

[0164] 15 mg of the amorphous 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 30.

[0165] The obtained Form 10 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 31.

[0166] The obtained Form 10 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 32.

[0167] Example 15 Preparation and Characterization of Form 11 Crystalline Form

[0168] Antisolvent crystallization

[0169] Weigh 15 mg of the amorphous starting sample into a 5 mL vial, add acetone (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 11. XRPD analysis is performed using detection method 2. The resulting XRPD spectrum is shown in Figure 33.

[0170] Example 16

[0171] Polymer template crystallization experiment

[0172] Take about 10 mg of amorphous 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.

[0173] 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 15, indicating that the obtained crystal was Form 11.

[0174] Example 17

[0175] Cooling crystallization

[0176] Weigh 16 mg of amorphous 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 solid, centrifuge, filter, and dry to obtain crystals.

[0177] 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 15, indicating that the obtained crystals were Form 11.

[0178] Example 18 Preparation and Characterization of Form 12 Crystalline Form

[0179] Cooling crystallization

[0180] Weigh 16 mg of amorphous 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 34.

[0181] The obtained Form 12 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 35.

[0182] The obtained Form 12 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 36.

[0183] Example 19

[0184] Gas-solid diffusion crystallization

[0185] 7 mg of the amorphous starting sample was weighed and placed in a centrifuge tube, which was then placed in a toluene atmosphere at room temperature. After 3 days, the solid was directly taken out.

[0186] 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 18, indicating that the obtained crystal was Form 12.

[0187] Example 20 Preparation and Characterization of Form 13 Crystalline Form

[0188] Mixed solvent slurry

[0189] Weigh 15 mg of the amorphous starting sample into a 5 mL vial, add acetone / water (0.1 mL / 0.5 mL) to obtain a suspension, and stir at room temperature for 3 days. The suspension is centrifuged, and the resulting solid is filtered and dried to obtain crystalline Form 13. XRPD analysis is performed using detection method 2, and the resulting XRPD pattern is shown in Figure 37.

[0190] The obtained Form 13 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 38.

[0191] The obtained Form 13 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 39.

[0192] Example 21 Preparation and Characterization of Form 14 Crystalline Form

[0193] Single solvent evaporation crystallization

[0194] Weigh 5 mg of amorphous 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 40.

[0195] Example 22

[0196] Mixed solvent evaporation crystallization

[0197] Weigh 7 mg of the amorphous 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.

[0198] 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 21, indicating that the obtained crystal was Form 14.

[0199] Example 23

[0200] Polymer template crystallization

[0201] Take about 10 mg of amorphous 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.

[0202] 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 21, indicating that the obtained crystal was Form 14.

[0203] Example 24 Preparation and Characterization of Form 15 Crystalline Form

[0204] Single solvent slurry crystallization

[0205] Weigh 15 mg of the amorphous 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 crystalline Form 15. XRPD analysis is performed using detection method 2. The resulting XRPD spectrum is shown in Figure 41.

[0206] The obtained Form 15 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 42.

[0207] The obtained Form 15 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 43.

[0208] Example 25

[0209] Gas-solid diffusion crystallization

[0210] Weigh 7 mg of the amorphous starting sample, place it in a centrifuge tube, and then place it in an ether atmosphere at room temperature. After 3 days, directly take out the solid.

[0211] 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 24, indicating that the obtained crystal was Form 15.

[0212] Example 26 Preparation and Characterization of Form 16 Crystalline Form

[0213] Single solvent slurry crystallization

[0214] Weigh 15 mg of the amorphous 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 44.

[0215] The obtained Form 16 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 45.

[0216] The obtained Form 16 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 46.

[0217] Example 27 Preparation and Characterization of Form 17 Crystalline Form

[0218] 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 47.

[0219] Example 28 Preparation and Characterization of Form 18 Crystalline Form

[0220] Gas-liquid diffusion crystallization

[0221] Weigh 7 mg of the amorphous starting sample into a centrifuge tube, add 0.2 mL of chloroform, and then place it in an n-heptane atmosphere 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 48.

[0222] The obtained Form 18 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 49.

[0223] The obtained Form 18 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 50.

[0224] Example 29 Preparation and Characterization of Form 19 Crystalline Form

[0225] Weigh 5 mg of amorphous 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 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 19. XRPD analysis was performed using detection method 2, and the obtained XRPD spectrum is shown in Figure 51.

[0226] The obtained Form 19 crystal form was subjected to thermogravimetric analysis using detection method 2, and the obtained spectrum is shown in Figure 52.

[0227] The obtained Form 19 crystal form was subjected to differential thermal analysis using detection method 2, and the obtained spectrum is shown in Figure 53.

[0228] Example 30 Preparation and Characterization of Form 20 Crystalline Form

[0229] During the hot stage XRPD analysis of 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 54.

[0230] Example 31 Preparation and Characterization of Form 21 Crystalline Form

[0231] 3.0227 g of the amorphous starting sample was weighed into a 60 mL glass bottle. After adding 20 mL of Toluene, the solid became colloidal. After being suspended and stirred (600 rpm) at room temperature for about 2 days, a colloidal solid was still obtained.

[0232] The obtained gummy solid was separated, 31 mL of n-Heptane was added thereto, and the mixture was suspended and stirred (1000 rpm) at 80° C. for about 1 day to obtain a white suspension.

[0233] The suspension was filtered at room temperature to separate the solid, which was then dried under vacuum at room temperature for approximately 2 days to obtain Form 21 as a white powder (2007.1 mg). XRPD analysis was performed using Detection Method 1. The resulting XRPD pattern is shown in Figure 55, and the XRPD peak list is shown in Table 2.

[0234] The obtained Form 21 crystal form was subjected to thermogravimetric analysis and differential thermal analysis using detection method 1, and the obtained spectrum is shown in Figure 56. Combined with the small TGA weight loss of the sample (0.42%) and the lack of obvious thermal signal of DSC before 100°C, it is speculated that Form 21 is an anhydrous crystal form.

[0235] The obtained Form 21 crystal form was subjected to DVS analysis using detection method 1, and the obtained spectrum is shown in Figure 57. After the DVS test, XRPD analysis was performed using detection method 1, and the results showed that the crystal form did not change.

[0236] Table 2

[0237] Table 3 is a summary of the properties of crystal forms Form 1 to Form 19. The applicant found that the compound represented by formula (I) can form a variety of solvates, and these solvates have common characteristics: a) in a dry environment and other solvent environments, the tunnel molecules are easily detached from the unit cell or replaced, resulting in a test result of an unstable ratio of solvent molecules; b) the unit cell parameters of the crystals formed after the solvent in the solvate crystals is detached or replaced will change slightly, and the XRPD pattern shows that some diffraction peaks are slightly shifted, resulting in very similar XRPD patterns. However, when the unit cell contains both crystallization solvent molecules and tunnel solvent molecules, it is relatively difficult to completely remove the tunnel molecules and maintain the original unit cell model under normal conditions. The process of removing solvent molecules by high temperature or beating can also easily lead to the removal of crystallization solvent molecules, and may eventually result in an amorphous or weakly crystalline state containing a small number of diffraction peaks.

[0238] Table 3 “—” means not determined.

[0239] Test Example 1: Moisture Absorption

[0240] The DVS test results of Examples 1 and 31 herein show that the hygroscopicity of amorphous and Form 21 is summarized as follows. The following results show that Form 21 has lower hygroscopicity.

[0241] 1) The weight change of the amorphous sample in the range of 0% RH to 80% RH is about 0.8%, indicating slight hygroscopicity.

[0242] 2) Form 21 has a water adsorption of 0.054% at 25°C / 80% RH, indicating almost no hygroscopicity. The crystal form remains unchanged after DVS testing.

[0243] Test Example 2 Dynamic Solubility

[0244] The dynamic solubility of the amorphous form and Form 21 in water and two biosolvents (SGF / FaSSIF) was evaluated. The biosolvents were prepared as follows:

[0245] 1) Preparation of simulated gastric fluid (SGF)

[0246] Weigh 100 mg of NaCl and 50 mg of Trinaton X-100 into a 50-mL volumetric flask and dissolve in purified water. Add 816 μL of 1 M hydrochloric acid and adjust the pH to 1.8 with 1 M hydrochloric acid or 1 M NaOH solution. Bring to volume with purified water.

[0247] 2) Preparation of simulated fasting intestinal fluid (FaSSIF)

[0248] Weigh 340 mg of anhydrous NaH2PO4 and 620 mg of NaCl into a 100-mL volumetric flask. Dissolve with purified water, then add 55.44 μL of 50% NaOH solution. Adjust the pH to 6.5 with 1 M hydrochloric acid or 1 M NaOH solution. Bring to volume with purified water. Next, weigh 110 mg of SIF powder into a 50-mL volumetric flask and dissolve with the above solution to bring to volume.

[0249] The solubility of each sample in water, SGF, and FaSSIF (1, 2, and 4 hours) was measured at room temperature using rotary mixing (25 rpm) at a feed concentration of 10 mg / mL. Samples at each time point were centrifuged (0.22 μm PTFE filter) and the filtrate concentration and pH were determined by HPLC. The solid sample after centrifugation was then analyzed by XRPD.

[0250] The solubility test results are summarized in Table 4. The results show that the solubility of Form 21 in water is below the limit of quantification (LOQ). In FaSSIF, the solubility of Form 21 and the amorphous form is similar. In SGF, the solubility of Form 21 is higher than that of the amorphous form. The crystalline form of the sample remains unchanged after the solubility test.

[0251] Table 4 S: solubility (mg / mL); FC: crystal form change; LOQ = 0.26 μg / mL.

[0252] Test Example 3 Mechanical Stability Study

[0253] Mechanical stability studies were conducted on amorphous and Form 21, including compressibility, adhesion, and compressive stability. The compressibility and adhesion test steps are as follows:

[0254] 1) Add approximately 100 mg of sample to a 6 mm round flat punch and press into round tablets using a 10 kN pressure.

[0255] 2) Record the loaded mass (ML) and tablet mass (MT), and then calculate the mass percentage of powder adhering to the punch (ma) using the formula ma = (ML - MT) / ML × 100%;

[0256] 3) Place the compressed tablets in a desiccator for 24 hours to allow for elastic recovery;

[0257] 4) After elastic recovery, measure the diameter (D) and thickness (t) of the tablet using a vernier caliper;

[0258] 5) Using a tablet hardness tester to measure the radial crushing force (hardness, H) and simultaneously measuring the XRPD of the crushed sample;

[0259] 6) Use the formula T = 2H / πDt to calculate the tensile strength of the powder at different hardness levels.

[0260] The results of the compressibility and adhesion tests are summarized in Table 5. The results show that Form 21 has advantages in compressibility and low adhesion. The crystal form of Form 21 remains unchanged after tableting, and the amorphous form remains amorphous after tableting.

[0261] Table 5 Summary of compressibility and adhesion tests *: The amorphous sample broke after tableting, so no data were collected.

[0262] Test Example 4

[0263] Stability test 1

[0264] Starting with Form 21 crystallized sample A and jet-milled sample B, accelerated stability testing was conducted at 40°C / 75% RH for 1, 2, 3, and 6 months. Following the testing, the samples were tested for physical and chemical stability using XRPD and HPLC (areal and gravimetric purity), and for particle size and water content using PSD and KF. The accelerated stability results are summarized in Table 6 below, and the XRPD results are shown in Figures 58-59.

[0265] Table 6 Summary of accelerated stability (40°C / 75% RH) results for Form 21 samples

[0266] The test results showed that no area purity or weight purity changes were observed for all samples before and after the test, XRPD showed that the crystal form remained unchanged, KF showed that the water content of the samples did not change much before and after stabilization, and PSD showed that the particle size distribution did not change much.

[0267] Stability test 2

[0268] Starting with Form 21 jet-milled sample B, the stability of the samples was investigated after exposure to high temperature (60°C / closed-cup), high humidity (25°C / 90% RH), and light (4500 lx, UV / visible light). Following the experiments, the physical and chemical stability of the samples was assessed by XRPD and HPLC (areal and gravimetric purity), while particle size and water content were determined by PSD and KF. The results of the factors influencing stability are summarized in Table 7 below, and the XRPD results are shown in Figures 60-61.

[0269] Table 7 Summary of factors affecting Form 21 sample stability

[0270] The test results showed that no area purity or weight purity changes were observed for all samples before and after the test, XRPD showed that the crystal form remained unchanged, KF showed that the water content of the samples did not change much before and after stabilization, and PSD showed that the particle size distribution did not change much.

[0271] 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. A crystalline form of a compound represented by formula (I), wherein: The crystal form uses Cu-Kα radiation, and the X-ray powder diffraction expressed in 2θ angles has characteristic peaks at 5.6±0.20°, 14.7±0.20°, 15.8±0.20°, 20.0±0.20°, 20.9±0.20°, and 21.1±0.20°; 2. The crystal form according to claim 1, wherein The crystalline form also has characteristic peaks at 11.1±0.20°, 22.6±0.20° and / or 24.7±0.20° in X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation.

3. The crystal form according to claim 1 or 2, wherein The crystalline form also has characteristic peaks at 7.5±0.20°, 22.4±0.20°, 25.0±0.20°, 25.4±0.20°, 27.7±0.20° and / or 29.5±0.20° in X-ray powder diffraction expressed in 2θ angle using Cu-Kα radiation.

4. The crystal form according to any one of claims 1 to 3, wherein The crystalline form has an XRPD pattern substantially as shown in Figure 55; and / or, the crystalline form loses no more than 0.6% of weight from room temperature to 155°C; And / or, the crystalline form has a TGA / DSC spectrum substantially as shown in Figure 56.

5. The crystal form according to claim 1, wherein The crystalline form is an anhydrate.

6. The method for preparing the crystal form according to any one of claims 1 to 5, wherein: Prepared from an amorphous substance or a solvate of the compound represented by formula (I); Preferably, the amorphous form of the compound represented by formula (I) is the amorphous form described in patent application PCT / CN2024 / 105186.

7. A pharmaceutical composition, wherein: The pharmaceutical composition contains the crystal form according to any one of claims 1 to 5.

8. The pharmaceutical composition according to claim 7, wherein The pharmaceutical composition also contains pharmaceutically acceptable excipients.

9. Use of the crystalline form according to any one of claims 1 to 5 or the pharmaceutical composition according to any one of claims 7 to 8 in the preparation of a pharmaceutical preparation for preventing and / or treating diseases or symptoms caused by androgen deficiency; Preferably, the diseases or symptoms include acute or chronic muscle wasting, muscle emaciation, muscle atrophy, bone-related diseases, cancer, AIDS, kidney disease, muscle wasting / muscle wasting / muscle atrophy caused by burns, anemia, obesity, diabetes, senile mood and cognitive changes, urinary incontinence, heart failure, dry eyes, and new coronavirus infectious diseases.

10. A pharmaceutical preparation, wherein The pharmaceutical preparation contains the crystal form according to any one of claims 1 to 5 or the pharmaceutical composition according to any one of claims 7 to 8.

11. A method for preventing and / or treating diseases or symptoms caused by androgen deficiency, wherein: The method comprises administering to the patient an effective amount of the crystalline form of the compound represented by formula (I) according to any one of claims 1 to 5, the pharmaceutical composition according to any one of claims 7 to 8, or the pharmaceutical preparation according to claim 10.

12. The method according to claim 11, wherein: The diseases or symptoms include acute or chronic muscle wasting, muscle emaciation, muscle atrophy, bone-related diseases, cancer, AIDS, kidney disease, muscle wasting / muscle wasting / muscle atrophy caused by burns, anemia, obesity, diabetes, senile mood and cognitive changes, urinary incontinence, heart failure, dry eyes, and diseases caused by the new coronavirus.

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