Crystal form of wedograssex as well as preparation method and application of crystal form

Abstract

The invention relates to the field of chemical medicines, and in particular relates to a crystal form of wedograssex as well as a preparation method and application of the crystal form. The compound I has a crystal form D, the XRPD pattern of the compound I has characteristic peaks at the following diffraction angles 2 theta: 3.7 + / -0.2 degrees, 7.0 + / -0.2 degrees, 15.2 + / -0.2 degrees, 15.4 + / -0.2 degrees and 23.2 + / -0.2 degrees, and further, the XRPD pattern of the crystal form D is basically shown in figure 1. The crystal form D has the advantages in at least one aspect of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in-vivo and in-vitro dissolution, bioavailability and the like, particularly, the stability and hygroscopicity weight gain is small, no organic solvent residue exists, the purity is high, the purification effect is good, the crystal morphology is good, and the problems existing in the prior art are solved. The compound I has very important significance on development of medicines containing the compound I.

Description

[0001] This application claims priority to Chinese Patent Application No. 202411290515.X, filed on September 14, 2024, entitled “Crystal Forms of the Wedegers Group and Their Preparation Methods and Uses,” the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to the field of chemical pharmaceuticals, and in particular to a crystal form of the Wedegrass group, its preparation method, and its uses. Background Technology

[0003] (3S)-3-[6-[4-[[1-[4-[(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl]phenyl]piperidin-4-yl]methyl]piperazin-1-yl]-3-oxo-1H-isoindol-2-yl]piperidin-2,6-dione, also known as Videgracetam, was developed by Arvinas for the treatment of various diseases, including breast cancer, and is currently in Phase III clinical trials. The structural formula of Videgracetam is shown in Formula I:

[0004]

[0005] WO2024049922A1 mentions that vedegrass is a compound with low solubility and low permeability, therefore it is necessary to screen for polymorphic forms. Different polymorphs of the active pharmaceutical ingredient have different physicochemical properties, which may lead to different dissolution and absorption rates in vivo, thus affecting the clinical efficacy of the drug to some extent. This is especially true for some poorly soluble oral solid or semi-solid dosage forms, where the polymorph is crucial to product performance. Furthermore, the physicochemical properties of the polymorph are critical to the manufacturing process.

[0006] Currently, only WO2022056368A1 publicly studies the polymorphic forms of the Wedegrass group. For example, by screening polymorphs through conventional methods such as temperature cycling, evaporation, rapid cooling (2–8°C), rapid cooling (-20°C), and the addition of antisolvents, five solid forms—Form I, Form II, Form III, Form IV, and amorphous—can be obtained. Further research indicates that Form I is a thermodynamically stable, non-solventized form with a high melting point (259°C), excellent stability, good solubility in process-related solvents, improved solubility at lower biorelevant pH levels, and low hygroscopicity (1.7 wt% at 90% RH). However, the preparation method for Form I is complex and time-consuming, which is not conducive to scale-up and meeting the needs of large-scale production. Furthermore, the solid morphology of this form is a flat, plate-like crystal with poor morphology, affecting the physicochemical properties of the API, post-processing, and formulation processes.

[0007] To overcome the shortcomings of existing technologies, a new solid form, particularly a new crystal form, that meets pharmaceutical standards is still needed for the development of drugs containing compound I. After considerable creative effort, crystal form D of compound I described in this invention was unexpectedly discovered. It possesses advantages in at least one aspect regarding solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, flowability, in vitro and in vivo dissolution, and bioavailability. In particular, it exhibits advantages in stability, minimal weight gain due to hygroscopicity, absence of organic solvent residue, high purity, good purification effect, and excellent crystal morphology. This solves the problems existing in the prior art and is of great significance for the development of drugs containing compound I. Summary of the Invention

[0008] The present invention provides a crystal form of compound I, a method for preparing the same, and a pharmaceutical composition comprising the new crystal form.

[0009] According to the purpose of this invention, the present invention provides crystal form D of compound I (hereinafter referred to as "crystal form D").

[0010] On the one hand, using Cu-Kα radiation, the XRPD pattern of the crystal form D has characteristic peaks at the following diffraction angles 2θ: 3.7±0.2°, 7.0±0.2°, 15.2±0.2°, 15.4±0.2°, and 23.2±0.2°.

[0011] Furthermore, using Cu-Kα radiation, the XRPD pattern of crystal form D further includes a characteristic peak at at least one of the following diffraction angle 2θ values: 16.1±0.2°, 17.7±0.2°, 18.3±0.2°, 19.1±0.2°, 20.5±0.2°, and 21.1±0.2°. Preferably, the XRPD pattern of crystal form D further includes a characteristic peak at a diffraction angle 2θ value of 16.1±0.2°, 17.7±0.2°, 18.3±0.2°, 19.1±0.2°, 20.5±0.2°, and 21.1±0.2°.

[0012] Furthermore, using Cu-Kα radiation, the XRPD pattern of crystal form D also includes values ​​for the following diffraction angles 2θ: 7.6±0.2°, 8.7±0.2°, 8.9±0.2°, 13.9±0.2°, 20.0±0.2°, 21.4±0.2°, 22.4±0.2°, 22.9±0.2°, 24.8±0.2°, 25.1±0.2°, 26.6±0.2°, and 26.9±0.2°. At least one characteristic peak is present. Preferably, the XRPD pattern of crystal form D also includes characteristic peaks at diffraction angles 2θ of 7.6±0.2°, 8.7±0.2°, 8.9±0.2°, 13.9±0.2°, 20.0±0.2°, 21.4±0.2°, 22.4±0.2°, 22.9±0.2°, 24.8±0.2°, 25.1±0.2°, 26.6±0.2°, and 26.9±0.2°.

[0013] Furthermore, using Cu-Kα radiation, the XRPD pattern of crystal form D is basically as follows: Figure 1 As shown.

[0014] Furthermore, the crystal form D provided by the present invention exhibits a weight loss gradient of approximately 1.78% when heated to 200°C; preferably, its thermogravimetric analysis diagram is substantially as shown in the figure. Figure 2 As shown.

[0015] Furthermore, the crystal form D provided by the present invention has two endothermic peaks: a broad melting absorption peak in the range of 0–50 °C and a sharp endothermic peak in the range of 200–240 °C, for example, endothermic peaks at 43.6 ± 5 °C and 225 ± 5 °C, respectively; preferably, the differential scanning calorimetry (DSC) chromatogram of the crystal form D is substantially as follows: Figure 3 As shown.

[0016] Furthermore, the crystal form D of the present invention is a short rod-shaped crystal with a particle size of 5-10 μm.

[0017] Preferably, the PLM image of the crystal form D is substantially as follows: Figure 4 As shown.

[0018] Furthermore, the crystal form D is a hydrate crystal form.

[0019] Furthermore, the crystal form D is subjected to KF testing, and its moisture content is 1.6% to 2.4%, for example, about 2.1%.

[0020] According to the purpose of this invention, the present invention also provides a method for preparing the crystal form D, the method comprising:

[0021] 1) The solid compound I was placed in an ether or aromatic hydrocarbon solvent and slurried, and the sample was obtained after separation;

[0022] 2) Add an alcohol solvent, and separate by pulping to obtain crystal D.

[0023] Furthermore, the aromatic hydrocarbon solvent in step 1) is selected from toluene.

[0024] Further, in step 1), the mass-to-volume ratio (mg:mL) of compound I to the ether or aromatic hydrocarbon solvent is 1:10 to 50, preferably 1:15 to 40, more preferably 1:20 to 35, for example 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35.

[0025] Furthermore, the pulping temperature in step 1) is 25±5℃.

[0026] Furthermore, the pulping time in step 1) is 16 to 48 hours, preferably 16 to 24 hours.

[0027] Furthermore, the separation step in step 1) may optionally include: filtration and drying.

[0028] Furthermore, in step 2), the alcohol solvent is selected from methanol.

[0029] Further, in step 2), the mass-to-volume ratio (mg:mL) of compound I to alcohol solvent is 1:10 to 50, preferably 1:15 to 45, more preferably 1:25 to 40, for example 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, 1:31, 1:32, 1:33, 1:34, 1:35, 1:36, 1:37, 1:38, 1:39, 1:40.

[0030] Furthermore, in step 2), the pulping temperature is 20–50°C.

[0031] Furthermore, the pulping time in step 2) is 2 to 18 hours, preferably 2 to 6 hours.

[0032] Furthermore, the separation step in step 2) may optionally include: filtration and drying.

[0033] According to the purpose of this invention, the present invention also provides a method for treating a disease or condition in a subject in need, the method comprising administering a therapeutically effective amount of crystal form D to the subject. In some embodiments, the disease or condition is associated with targeting estrogen receptor (ER) activity, excessive activity, intrinsic activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is associated with ER activity. In some embodiments, the disease or condition is associated with excessive ER activity; in some embodiments, the disease or condition is associated with intrinsic ER activity; in some embodiments, the disease or condition is associated with ER expression; in some embodiments, the disease or condition is associated with ER overexpression. In some embodiments, the disease or condition is associated with ER accumulation and aggregation.

[0034] In some embodiments, the disease or condition is a cancer or neoplasia associated with ER activity, excessive activity, inherent activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. In some embodiments, the disease or condition is endometriosis.

[0035] According to the purpose of this invention, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of crystal form D, wherein the composition is effective in treating or improving at least one symptom of a disease or condition. In some embodiments, the disease or condition is causally related to ER activity, excessive activity, inherent activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is cancer or neoplasia causally related to ER activity, excessive activity, inherent activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. In some embodiments, the disease or condition is endometriosis.

[0036] According to the purpose of this invention, the present invention also provides the use of crystal form D in the preparation of a medicament for treating a disease or condition. In some embodiments, the disease or condition is associated with ER activity, excessive activity, inherent activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is cancer or neoplasia associated with ER activity, excessive activity, inherent activity, expression, overexpression, or accumulation and aggregation. In some embodiments, the disease or condition is breast cancer, ovarian cancer, endometrial cancer, or uterine cancer. In some embodiments, the disease or condition is endometriosis.

[0037] The crystal form D provided by this invention has at least one of the following beneficial effects:

[0038] 1. Crystal form D can be stored for at least two weeks under three different humidity and temperature conditions (25℃ / 60%RH, 40℃ / 75%RH or 25℃ / 92.5%RH), and no crystal transformation occurs. The physical form and chemical purity still have good stability.

[0039] 2. Crystal form D does not transform into crystals even at high temperatures (e.g., ≥40℃) or under light conditions, exhibiting good stability and can be stored stably for a long time.

[0040] 3. Crystal form D has a good solid morphology as short rod-shaped crystals with a particle size of 5-10 μm. It has a regular shape, is easy to filter, does not aggregate, and is convenient for controlling impurities and solvent residues during the later process scale-up and for formulation preparation. In contrast, crystal form I disclosed in the WO2022056368A1 example has an encapsulation phenomenon and is irregularly lamellar, with poor flowability, making it difficult for later formulation preparation.

[0041] 4. Crystal form D remains stable under different humidity conditions and has good hygroscopicity. It can remain stable without strict humidity control during drug production and storage. It has low requirements for preparation process and storage conditions and has strong medicinal value.

[0042] 5. Crystal form D has high oral bioavailability.

[0043] Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0044] The crystal form D described in this invention is different from existing crystal forms and has the advantage of better powder flowability compared to existing crystal forms. However, it is difficult to obtain through conventional crystallization ideas and methods (such as cooling, adding antisolvent, salt formation reaction crystallization, etc.). The method of this invention can prepare crystal form D, and its process is stable and controllable. The prepared crystal form D product has high chemical purity and crystal form purity, good flowability, and the process can be scaled up to meet the needs of large-scale production.

[0045] The crystal form D particles of this invention have more complete morphology and more uniform particle size, resulting in better flowability and easier filtration of the target product particles.

[0046] The crystal form D of this invention has advantages in at least one aspect, including solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, flowability, in vivo and in vitro dissolution, and bioavailability. In particular, it has advantages in stability, low weight gain due to hygroscopicity, no organic solvent residue, high purity, good purification effect, and good crystal morphology. It solves the problems existing in the prior art and is of great significance for the development of drugs containing compound I. Attached Figure Description

[0047] Figure 1 The XRPD pattern of crystal form D is shown.

[0048] Figure 2 The TGA spectrum of crystal form D is shown.

[0049] Figure 3 The DSC spectrum of crystal form D is shown.

[0050] Figure 4 A PLM image of crystal form D is shown.

[0051] Figure 5 The XRPD comparison diagrams of the stability experiment of crystal form D are shown (a is the XRPD diagram before placement; b, c, and d are the XRPD diagrams after two weeks of placement at 25℃ / 60% RH, 40℃ / 75% RH, and 25℃ / 92.5% RH, respectively).

[0052] Figure 6 The XRPD superimposed spectra before and after illumination of crystal form D are shown.

[0053] Figure 7 The DVS diagram of crystal form D is shown.

[0054] Figure 8 The XRPD spectra of crystal form D before and after DVS detection are shown.

[0055] Figure 9 The XRPD patterns of crystal form D after 24 h of storage in FaSSGF solution (pH 1.5), FeSSIF solution (pH 4.5), FaSSIF solution (pH 6.8), and water are shown. Detailed Implementation

[0056] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. Obviously, the described embodiments are merely some embodiments of this invention, and not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this invention are within the scope of protection of this invention.

[0057] Unless otherwise specified, the reagents described are used directly without purification. All solvents were purchased from commercial suppliers and are ready for use without treatment.

[0058] The abbreviations used in this invention are explained as follows:

[0059] XRPD: X-ray powder diffraction

[0060] DSC: Differential Scanning Calorimetry

[0061] DVS: Dynamic Moisture Adsorption

[0062] KF: Karl Fischer method

[0063] Test method:

[0064] (1) X-ray powder diffraction analysis

[0065] The XRPD spectra of this invention were acquired using a Bruker D8 ADVANCE diffractometer. The X-ray powder diffraction method parameters are as follows: X-ray reflection parameters: Cu, Kα; tube voltage: 40 kV; tube current: 40 mA; slits: #2 scattering slit: 1°, #3 anti-scattering slit: 1°, #4 receiving slit: 0.3 mm; scanning mode: stepping; step angle: 0.02°; sampling time: 0.2 s; scanning range: from 3.0 to 40.0 degrees.

[0066] (2) Dynamic moisture adsorption (DVS)

[0067] Approximately 5-16 mg of sample was weighed and placed in a metal container, which was then placed in the Intrinsic DVSAdvantage instrument. The sample underwent two consecutive adsorption-desorption cycles, each run at 40%-0%-95%-0%-40% relative humidity (%RH). One cycle consisted of 10 steps, with each step between 0-95%RH differing by 10%RH. At each stage, the following equilibrium criteria were used: dm / dt < 0.002% over 5 minutes, where dm is the mass change and dt is the time change, and the minimum and maximum times at each stage were 10 and 360 minutes, respectively.

[0068] (3) Differential Scanning Calorimetry (DSC)

[0069] The digital scanning calorimetry (DSC) images described in this invention are acquired using a DSC250, and the method parameters are as follows:

[0070] Scan rate: 10℃ / min;

[0071] Protective gas: Nitrogen.

[0072] (4) Thermogravimetric analysis (TGA)

[0073] The thermogravimetric analysis (TGA) graph described in this invention was acquired using Discovery 55, and the method parameters are as follows:

[0074] Scan rate: 10℃ / min;

[0075] Protective gas: Nitrogen.

[0076] Example 1:

[0077] 0.5 g of amorphous compound I was added to 15 mL of toluene and stirred at room temperature for 24 h. The mixture was then filtered, and the filter cake was vacuum dried at room temperature for 2 h. 20 mL of methanol was added to the dried sample, and the mixture was stirred at room temperature for another 6 h. The mixture was then vacuum filtered, and the filter cake was vacuum dried at room temperature for 2 h. A sample was taken for analysis to obtain crystal form D. The XRPD pattern of crystal form D is shown below. Figure 1 As shown; its TGA spectrum is as follows Figure 2 As shown, when heated to 200℃, it exhibits a weight loss gradient of approximately 1.78%; its DSC spectrum is as follows. Figure 3 As shown, there are two endothermic peaks: a broad melting endothermic peak in the 0–50℃ range and a sharp endothermic peak in the 200–240℃ range, for example, endothermic peaks at 43.6±5℃ and 225±5℃ respectively; KF analysis shows approximately 2.1% water, indicating that crystal form D is a hydrate; its PLM image is shown below. Figure 4 As shown, crystal form D has a short rod-like morphology with a particle size of 5-10 μm. It has a regular shape, is easy to filter, and is more conducive to the control of impurities and solvent residues during subsequent process scale-up. In contrast, crystal form I disclosed in the WO2022056368A1 example has an encapsulation phenomenon and is irregularly lamellar, with poor flowability, making it difficult to prepare formulations in the later stages.

[0078] Example 2

[0079] The crystal form D obtained in Example 1 was placed under different temperatures and humidity conditions for two weeks. Samples were taken to determine the XRPD comparison crystal form and to compare the chemical purity by HPLC. The results are shown in Table 1 below.

[0080] Table 1. Experimental results on the stability of crystal form D

[0081]

[0082] Table 1 shows that the crystal form D described in this invention can be stored for at least two weeks under the three different humidity and temperature conditions (25℃ / 60%RH, 40℃ / 75%RH, or 25℃ / 92.5%RH) described in Table 1. Figure 5 As shown, the stability of crystal form D obtained by this invention remained unchanged before and after placement, as indicated by X-ray powder diffraction. Crystal form D of compound I of this invention exhibits good stability. It maintains good stability in both physical form and chemical purity even under high temperature and high humidity conditions.

[0083] Example 3

[0084] The crystal form D prepared in Example 1 was placed in a light stability chamber until the total illuminance reached 1.2 × 10⁻⁶. 6 Lux·hr, XRPD and HPLC were taken out and placed for 10 days. The experimental results are shown in Table 2:

[0085] Table 2. Results of illumination experiments for crystal form D

[0086]

[0087] Table 2 and Figure 6 The results showed that the chemical purity changed significantly after the light exposure ended, but XRPD showed no crystal transformation phenomenon. Crystal form D has a certain degree of light stability and can be stored stably for a long time.

[0088] Example 4

[0089] Approximately 20 mg of crystal form D prepared in Example 1 was tested for adsorption and desorption of water under a 40-0-95-0-40% RH program. Its hygroscopicity was measured using a dynamic water adsorption (DVS) instrument. The experimental results are shown in Table 3.

[0090] Table 3. Hygroscopicity test results of crystal form D

[0091]

[0092] The DVS spectrum of the hygroscopicity test is as follows: Figure 7 As shown, the XRPD comparison spectra of the sample before and after testing are as follows: Figure 8 As shown.

[0093] Figure 7 and Figure 8 The results showed that the crystal form D of this application increased in weight by less than 2% under 40-90% humidity, and there was no change in crystal form D after the DVS test. This indicates that crystal form D of this application can remain stable under different humidity conditions, has good hygroscopicity, and can remain stable without strict humidity control during drug production and storage. It has low requirements for preparation process and storage conditions and has strong medicinal value.

[0094] Example 5

[0095] At 37°C, crystal form D prepared in Example 1 was added to buffer solutions of FaSSGF solution (gastric juice in an empty stomach), FeSSIF solution (artificial intestinal juice in a fed state), and FaSSIF solution (artificial intestinal juice in an empty stomach), and water, respectively. The content of compound I in the solutions was determined by high-performance liquid chromatography (HPLC) after 2 hours and 24 hours, respectively. The experimental results are shown in Table 4.

[0096] Table 4. Study on the dynamic solubility of crystal form D

[0097]

[0098] The results showed that, regarding solubility, the solubility of crystal form D decreased with increasing pH. Surprisingly, the solubility of the new crystal form D was superior to that of crystal form I, especially in FaSSGF and FeSSIF solutions, where the final solubility was greater than 0.3 mg / mL, indicating high oral bioavailability and a significant advantage in solubility. Furthermore, the solubility of crystal form D at pH 4.5 was 0.38 mg / mL, while crystal form I, reported in WO2022056368A1, transformed into an amorphous form with a solubility <0.05 mg / mL at pH 4. It is also worth noting that the solubility of crystal form D at pH 4.5 was approximately 8 times higher than that of crystal form I at pH 4. For detailed XRPD patterns of the present invention after 24 hours of incubation in FaSSGF solution (pH 1.5), FeSSIF solution (pH 4.5), FaSSIF solution (pH 6.8), and water, please refer to [link to XRPD data]. Figure 9 XRPD map.

[0099] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A crystalline form D of the compound of formula I: characterized in that which has characteristic peaks in the XRPD pattern at 2Θ values of 3.7 ± 0.2°, 7.0 ± 0.2°, 15.2 ± 0.2°, 15.4 ± 0.2°, 23.2 ± 0.2°.

2. The crystalline Form D of claim 1, characterized by, The XRPD pattern of said crystalline form D further comprises characteristic peaks at 2Θ values of at least one of 16.1 ± 0.2°, 17.7 ± 0.2°, 18.3 ± 0.2°, 19.1 ± 0.2°, 20.5 ± 0.2°, 21.1 ± 0.2°; Preferably, the XRPD pattern of said crystalline form D further comprises characteristic peaks at 2Θ values of 16.1 ± 0.2°, 17.7 ± 0.2°, 18.3 ± 0.2°, 19.1 ± 0.2°, 20.5 ± 0.2°, 21.1 ± 0.2°.

3. The crystalline Form D of claim 1, characterized by, The XRPD pattern of said crystalline form D further comprises characteristic peaks at 2Θ values of at least one of 7.6 ± 0.2°, 8.7 ± 0.2°, 8.9 ± 0.2°, 13.9 ± 0.2°, 20.0 ± 0.2°, 21.4 ± 0.2°, 22.4 ± 0.2°, 22.9 ± 0.2°, 24.8 ± 0.2°, 25.1 ± 0.2°, 26.6 ± 0.2°, 26.9 ± 0.2°; Preferably, the XRPD pattern of said crystalline form D further comprises characteristic peaks at 2Θ values of 7.6 ± 0.2°, 8.7 ± 0.2°, 8.9 ± 0.2°, 13.9 ± 0.2°, 20.0 ± 0.2°, 21.4 ± 0.2°, 22.4 ± 0.2°, 22.9 ± 0.2°, 24.8 ± 0.2°, 25.1 ± 0.2°, 26.6 ± 0.2°, 26.9 ± 0.2°.

4. The crystalline Form D of claim 1, characterized by, The XRPD pattern of said crystalline form D is substantially as shown in Figure 1.

5. The crystalline Form D of any one of claims 1-4, characterized by, Said crystalline form D has a weight loss gradient of about 1.78% when heated to 200°C; Preferably, the TGA pattern of said crystalline form D is substantially as shown in Figure 2; Said crystalline form D has two endothermic peaks, one broad melting absorption peak at 0-50°C and one sharp endothermic peak at 200-240°C; Preferably, the differential scanning calorimetry pattern of said crystalline form D is substantially as shown in Figure 3; and / or, said crystalline form D is short rod-like crystal with a particle size of 5-10 μm; Preferably, the PLM image of said crystalline form D is substantially as shown in Figure 4; and / or, said crystalline form D is a hydrate crystalline form; and / or, said crystalline form D has a KF test moisture value of 1.6-2.4%, preferably 2.1%.

6. A method of preparing the crystalline Form D according to any one of claims 1 to 5, characterized in that, comprising the following steps: 1) beating the compound I solid in an ether or aromatic hydrocarbon solvent, and separating to obtain the sample; 2) adding an alcohol solvent, and beating and separating to obtain the crystal D.

7. The production method according to claim 6, wherein The aromatic hydrocarbon solvent in step 1) is selected from toluene; and / or, the mass-volume mg:mL ratio of compound I to the ether or aromatic hydrocarbon solvent in step 1) is 1:10-50, preferably 1:15-40, more preferably 1:20-35; and / or, the beating temperature in step 1) is 25 ± 5°C; and / or, the beating time in step 1) is 16-48h, preferably 16-24h; and / or, the separation step in step 1) can optionally include: suction filtration, drying.

8. The preparation method according to claim 6, characterized in that, the alcohol solvent in step 2) is selected from methanol; and / or, the mass-volume mg:mL ratio of compound I to the alcohol solvent in step 2) is 1:10-50, preferably 1:15-45, more preferably 1:25-40; and / or, the beating temperature in step 2) is 20-50°C; and / or, the beating time in step 2) is 2-18h, preferably 2-6h; and / or, the separation step in step 2) can optionally include: suction filtration, drying.

9. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof. It comprises administering to the subject a therapeutically effective amount of crystalline Form D as claimed in any one of claims 1-5, the disease or condition being causally related to targeting estrogen receptor activity, overactivity, inherent activity, expression, overexpression, or accumulation and aggregation.

10. A pharmaceutical composition, characterized by, It comprises a therapeutically effective amount of crystalline Form D as claimed in any one of claims 1-5, wherein the composition is effective in treating or ameliorating at least one symptom of a disease or condition, preferably the disease or condition being causally related to targeting estrogen receptor activity, overactivity, inherent activity, expression, overexpression, or accumulation and aggregation.

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