New crystal forms of elacestrant dihydrochloride, and preparation method therefor and use thereof

Abstract

The present invention discloses a plurality of new crystal forms of elacestrant dihydrochloride, wherein the X-ray powder diffraction pattern of the crystal form APTI-I plotted against 2θ angle has characteristic peaks at 9.6°±0.2°, 12.0°±0.2°, 13.5°±0.2°, 20.5°±0.2°, 21.9°±0.2°, and 22.4°±0.2°. The crystal form has a good stability, a yield of up to 92.3%, a purity of up to 99.90%, and a low amount of a residual organic solvent, and the preparation thereof is simple to operate and easy to control, and is more suitable for industrial scale-up production. The purities of the crystal forms APTI-II and APTI-III provided by the present invention can reach 99.92% and 99.95%, respectively, which can provide more options for purification during the production process of elacestrant or the salts thereof.

Description

New crystalline forms of elacestrant dihydrochloride and methods of preparation and uses thereof TECHNICAL FIELD

[0001] The present application relates to a crystalline form of an organic compound, more particularly, to a new crystalline form of elacestrant dihydrochloride and methods of preparation and uses thereof. BACKGROUND

[0002] Breast cancer is one of the most common malignant tumors in women worldwide, and the number of patients is increasing year by year. According to the prediction, the global breast cancer patients will reach 8.25 million cases by 2030. According to clinical statistics, about 60% to 75% of breast cancer patients are positive for estrogen receptor (ER) expression. For ER+ breast cancer, common treatment methods include estrogen receptor modulators, aromatase inhibitors, ovarian function inhibitors, and CDK4 / 6 inhibitors, etc. Among them, the estrogen receptor degrader (SERD) drug can more effectively block the ER receptor signaling pathway and induce its degradation. Elacestrant is a new generation of selective SERD developed by Radius Health and Takeda. The biopharmaceutical company Stemline, a member of the Menarini Group, has been granted priority review and fast track designation by the U.S. Food and Drug Administration (FDA), and was approved for marketing by the FDA in January 2023. In September 2023, Elacestrant was approved for marketing by the European Commission. It is used for ER+ / HER2-, ESR1-mutated, and endocrine therapy after disease progression in patients with metastatic breast cancer. It is the first oral SERD approved by the FDA and the first new therapy approved by the FDA for ER+ / HER2- advanced metastatic breast cancer with ESR1 mutations.

[0003] The chemical name of Elacestrant is (R)-6-{2-{ethyl[4-(2-ethylaminoethyl)benzyl]amino}-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-ol, and it is currently mainly administered in the form of Elacestrant dihydrochloride, and its chemical structure is shown below.

[0004] It is well known that for the same drug molecule, due to different stacking methods in the process of microscopic molecular stacking, polymorphism will occur, and water or solvent is usually involved in the crystal stacking during the formation of solid state, thereby forming hydrate or solvate crystal forms. Crystal form usually affects the physicochemical properties of the drug, such as chemical stability, hygroscopicity, solubility, tabletting performance, etc., and ultimately affects drug storage, transportation, and even drug production and drug efficacy. Therefore, screening a better crystal form can make the drug better exert its efficacy.

[0005] Currently, there are existing technologies that have reported research on the crystalline form of Elacestrant dihydrochloride, for example:

[0006] Prior art WO2018129419A discloses Elacestrant dihydrochloride Form 1, Form 2 and Form 3, wherein Form 1 and Form 2 are anhydrous crystalline forms, which will be converted to Form 3 (hydrate) under certain humidity conditions, and Form 3 will be converted to anhydrous crystalline Form 2 under low humidity, and Form 2 is a metastable crystalline form which will be converted to Form 1 according to DSC and variable temperature XRPD. Therefore, the temperature range of the three crystalline forms is relatively narrow, and there is a risk of crystallization.

[0007] Prior art WO2020010216A discloses Elacestrant dihydrochloride Form 1b, which has good stability, but has the problem of easy agglomeration, which has a certain impact on subsequent preparation.

[0008] Prior art WO2023064519A discloses Form 6, Form 7 and Form 9, wherein Form 6 is a DMSO solvate, Form 7 is a n-propanol solvate. Form 9 is an amorphous form which is converted to a crystalline form by placing under 75% humidity. Form 9 is difficult to prepare on a large scale, and there is a risk of repeatability.

[0009] Prior art WO2023 / 227029A discloses a crystalline form CSII of Elacestrant dihydrochloride, which is obtained by preparation in a chloroform system. Chloroform is a second-class solvent, and the residual solvent limit is low. It is very risky to control the production of drugs.

[0010] It can be seen that the crystalline forms of Elacestrant dihydrochloride reported in the prior art are not ideal, and therefore, a crystalline form of Elacestrant dihydrochloride which is more suitable for industrial production and is suitable for preparing a drug containing Elacestrant dihydrochloride or is suitable for purifying Elacestrant or its salt is needed. SUMMARY

[0011] The purpose of the present application is to provide a new crystalline form of Elacestrant dihydrochloride.

[0012] In a first aspect of the present application, the present application provides a crystalline form APTI-I of Elacestrant dihydrochloride, which has characteristic peaks at 9.6°±0.2°, 12.0°±0.2°, 13.5°±0.2°, 20.5°±0.2°, 21.9°±0.2°, 22.4°±0.2° in terms of 2θ angle using Cu-Kα radiation.

[0013] In another preferred embodiment, the X-ray powder diffraction (XRPD) pattern of the crystalline form APTI-I of Elacestrant dihydrochloride further has one or more characteristic peaks selected from the following:

[0014] 6.1°±0.2°, 7.9°±0.2°, 12.3°±0.2°, 14.1°±0.2°, 17.0°±0.2°, 17.2°±0.2°, 17.5°±0.2°, 17.8°±0.2°, 18.7°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 21.3°±0.2°, 22.2°±0.2°, 22.7°±0.2°, 24.2°±0.2°, 24.5°±0.2°, 24.7°±0.2°, 25.0°±0.2°, 25.3°±0.2°, 26.4°±0.2°, 27.2°±0.2°, 27.4°±0.2°, 27.7°±0.2°, 28.7°±0.2°.

[0015] In another preferred embodiment, the crystalline form APTI-I of elacridar dihydrochloride has a differential scanning calorimetry pattern with endothermic peaks at 71.6±5°C and 197.6±5°C.

[0016] In another preferred embodiment, the crystalline form APTI-I of elacridar dihydrochloride has a thermogravimetric analysis (TGA) pattern with weight loss of about 1.5-3.8% at 30-120°C.

[0017] In another preferred embodiment, the crystalline form APTI-I of elacridar dihydrochloride has a thermogravimetric analysis (TGA) pattern with a step weight loss of about 2.06% at 30-120°C.

[0018] In another preferred embodiment, the crystalline form APTI-I of elacridar dihydrochloride has a thermogravimetric analysis (TGA) pattern with weight loss of about 3.76% at 30-120°C.

[0019] In another preferred embodiment, the crystalline form APTI-I of elacridar dihydrochloride has a thermogravimetric analysis (TGA) pattern with weight loss of about 3.76% at 30-120°C.

[0020] In another preferred embodiment, the crystalline form APTI-I of elacridar dihydrochloride has a thermogravimetric analysis (TGA) pattern with weight loss of about 3.76% at 30-120°C.

[0021] In another preferred embodiment, the crystalline form APTI-I of elacridar dihydrochloride provided by the present application has an XRPD pattern with characteristic peaks expressed in angles of 2θ using Cu-Kα radiation at least one of 9.6°±0.2°, 12.0°±0.2°, 20.5°±0.2°. In another preferred embodiment, the XRPD pattern of the crystalline form APTI-I further has one or more characteristic peaks selected from the group consisting of:

[0022] 6.1°±0.2°, 7.9°±0.2°, 12.3°±0.2°, 13.5°±0.2°, 14.1°±0.2°, 17.0°±0.2°, 17.2°±0.2°, 17.5°±0.2°, 17.8°±0.2°, 18.7°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 21.3°±0.2°, 21.9°±0.2°, 22.2°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 24.2°±0.2°, 24.5°±0.2°, 24.7°±0.2°, 25.0°±0.2°, 25.3°±0.2°, 26.4°±0.2°, 27.2°±0.2°, 27.4°±0.2°, 27.7°±0.2°, 28.7°±0.2°.

[0023] In a second aspect of the present application, the present application provides a method for preparing the crystalline form APTI-I of elacridar dihydrochloride, comprising the following steps:

[0024] After stirring elacridar dihydrochloride in a mixture of organic solvent and water, the crystalline form APTI-I is separated and dried.

[0025] In another preferred embodiment, the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetone, 2-butanone, acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof, more preferably acetonitrile or acetone.

[0026] In another preferred embodiment, the volume ratio of the organic solvent to water is 3-9:1, more preferably 7-9:1.

[0027] In another preferred embodiment, the weight / volume ratio of elacridar dihydrochloride to the mixture is 0.05-0.2 g / mL.

[0028] In another preferred embodiment, the temperature of the system is 20-60°C and the stirring time is 8-48 h when elacridar dihydrochloride is stirred in the mixture.

[0029] In another preferred embodiment, the temperature of drying is 40-60°C and the time is 8-24 h.

[0030] In a third aspect of the present application, the present application provides a crystalline form APTI-II of elacridar dihydrochloride, which has characteristic peaks in XRPD pattern expressed in terms of 2θ angle at 7.0°±0.2°, 13.9°±0.2°, 15.8°±0.2°, 21.9°±0.2°, 23.5°±0.2° using Cu-Kα radiation.

[0031] In another preferred embodiment, the XRPD pattern of said crystalline form APTI-II further has one or more characteristic peaks selected from:

[0032] 8.1°±0.2°, 8.8°±0.2°, 11.7°±0.2°, 12.5°±0.2°, 14.9°±0.2°, 17.4°±0.2°, 18.7°±0.2°, 19.5°±0.2°, 20.9°±0.2°, 24.4°±0.2°, 25.3°±0.2°, 26.2°±0.2°, 26.9°±0.2°, 28.0°±0.2°, 28.6°±0.2°, 29.7°±0.2°, 30.9°±0.2°, 38.0°±0.2°.

[0033] In another preferred embodiment, the thermal gravimetric analysis (TGA) pattern of said crystalline form APTI-II has a step weight loss of about 12.7% at 30-170°C.

[0034] In another preferred embodiment, the XRPD pattern of said crystalline form APTI-II is substantially consistent with Figure 6.

[0035] In another preferred embodiment, said crystalline form APTI-II is a 2-ethoxyethanol solvate of elacridar dihydrochloride. In another preferred embodiment, the ratio of elacridar molecules to 2-ethoxyethanol molecules in said crystalline form APTI-II is 1:1.

[0036] In a fourth aspect of the present application, the present application provides a method for preparing the crystalline form APTI-II of elacridar dihydrochloride, comprising the following steps:

[0037] After stirring elacridar dihydrochloride in 2-ethoxyethanol, the system is allowed to stand and separate, and the crystalline form APTI-II is obtained by drying.

[0038] In another preferred embodiment, in the method for preparing the crystalline form APTI-II, the weight-to-volume ratio of elacridar dihydrochloride to 2-ethoxyethanol is 0.05-0.2 g / mL.

[0039] In another preferred embodiment, in the method for preparing the crystalline form APTI-II, the stirring is performed at 40-60°C for 6-10 h, then at 0-40°C for 6-10 h, and finally at 40-60°C for 6-10 h.

[0040] In another preferred embodiment, in the method for preparing the crystalline form APTI-II, the standing process is standing at room temperature for 6-9 days.

[0041] In another preferred embodiment, in the method for preparing the crystalline form APTI-II, the drying temperature is 40-60°C, and the drying time is 8-24 h.

[0042] In a fifth aspect, the present application provides a crystalline form APTI-III of Icarolimus dihydrochloride, which has an XRPD pattern with characteristic peaks at 11.3°±0.2°, 11.8°±0.2°, 13.4°±0.2°, 18.2°±0.2°, 21.2°±0.2°, 25.8°±0.2° in terms of 2θ angle using Cu-Kα radiation.

[0043] In another preferred embodiment, the XRPD pattern of the crystalline form APTI-III further has one or more characteristic peaks selected from the group consisting of:

[0044] 5.6°±0.2°, 10.3°±0.2°, 11.0°±0.2°, 12.5°±0.2°, 14.9°±0.2°, 15.4°±0.2°, 18.8°±0.2°, 19.3°±0.2°, 20.1°±0.2°, 20.5°±0.2°, 22.0°±0.2°, 23.0°±0.2°, 24.0°±0.2°, 26.3°±0.2°, 27.2°±0.2°, 27.6°±0.2°, 29.9°±0.2°;

[0045] In another preferred embodiment, the crystalline form APTI-III has a differential scanning calorimetry pattern with endothermic peaks at 112.5℃±5℃ and 227.8℃±5℃.

[0046] In another preferred embodiment, the XRPD pattern of the crystalline form APTI-III is substantially consistent with Figure 8.

[0047] In another preferred embodiment, the crystalline form APTI-III of Icarolimus dihydrochloride is a DMF solvate of Icarolimus dihydrochloride. In another preferred embodiment, the ratio of Icarolimus molecules to DMF molecules in the crystalline form APTI-III of Icarolimus dihydrochloride is 1:1.

[0048] In a sixth aspect, the present application provides a method for preparing the crystalline form APTI-III of Icarolimus dihydrochloride described above, comprising the following steps:

[0049] adding Icarolimus dihydrochloride into DMF, dissolving after heating and cooling to crystallize, separating and drying to obtain the crystalline form APTI-III.

[0050] In another preferred embodiment, the method for preparing the crystalline form APTI-III, the heating temperature is 80-100℃ and the cooling temperature is 10-30℃.

[0051] In another preferred embodiment, in the preparation method of the crystalline form APTI-III, the weight / volume ratio of elacridar dihydrochloride to DMF is 10-25 mg / mL.

[0052] In another preferred embodiment, in the preparation method of the crystalline form APTI-III, the drying temperature is 40-60 °C, and the drying time is 8-24 h.

[0053] In a sixth aspect of the present application, there is provided the use of the crystalline form APTI-I, the crystalline form APTI-II or the crystalline form APTI-III of elacridar dihydrochloride in the preparation of a medicament containing elacridar dihydrochloride or in the purification of elacridar or a salt thereof. BRIEF DESCRIPTION OF DRAWINGS

[0054] Figure 1 is an XRPD pattern of the crystalline form APTI-I of elacridar dihydrochloride;

[0055] Figure 2 is a DSC pattern of the crystalline form APTI-I of elacridar dihydrochloride;

[0056] Figure 3 is a TGA pattern of the crystalline form APTI-I of elacridar dihydrochloride prepared in Example 1;

[0057] Figure 4 is a PLM pattern of the crystalline form APTI-I of elacridar dihydrochloride prepared in Example 2;

[0058] Figure 5 is a PSD pattern of the crystalline form APTI-I of elacridar dihydrochloride prepared in Example 2;

[0059] Figure 6 is an XRPD pattern of the crystalline form APTI-II of elacridar dihydrochloride;

[0060] Figure 7 is a TGA pattern of the crystalline form APTI-II of elacridar dihydrochloride;

[0061] Figure 8 is an XRPD pattern of the crystalline form APTI-III of elacridar dihydrochloride;

[0062] Figure 9 is a DSC pattern of the crystalline form APTI-III of elacridar dihydrochloride;

[0063] Figure 10 is a TGA pattern of the crystalline form APTI-I of elacridar dihydrochloride prepared in Example 2;

[0064] Figure 11 is an overlay of the XRPD patterns of the crystalline form APTI-I prepared in Example 2 before and after vacuum drying at 80 °C for 24 h;

[0065] Figure 12a is a TGA pattern of the crystalline form APTI-I prepared in Example 2 after vacuum drying at 80 °C for 24 h;

[0066] Figure 12b is a DSC pattern of the crystalline form APTI-I obtained in Example 2 after vacuum drying at 80°C for 24h.

[0067] Figure 13a is an overlay of the XRPD patterns of the crystalline form APTI-I obtained in Example 2 before and after grinding;

[0068] Figure 13b is an overlay of the XRPD patterns of the crystalline form APTI-I obtained in Example 3 before and after grinding;

[0069] Figure 14 is an overlay of the XRPD patterns of the crystalline form APTI-I obtained in Example 2 before and after storage at 25°C / 60%RH and 40°C / 70%RH for 2 weeks;

[0070] Figure 15a is an overlay of the XRPD patterns of the crystalline form APTI-I obtained in Example 2 and the Form 1 of the prior art at different water activities;

[0071] Figure 15b is an overlay of the XRPD patterns of the crystalline form APTI-I obtained in Example 3 and the Form 1 of the prior art at different water activities;

[0072] Figure 16 is an XRPD pattern of Form 1 obtained in Comparative Example 1 according to the prior art WO2018129419A1 ;

[0073] Figure 17 is a PSD pattern of Form 1 obtained in Comparative Example 1 according to the prior art WO2018129419A1 ;

[0074] Figure 18 is an XRPD pattern of Form 2 obtained in Comparative Example 2 according to the prior art WO2018129419A1 ;

[0075] Figure 19 is a DSC pattern of Form 2 obtained in Comparative Example 2 according to the prior art WO2018129419A1 ;

[0076] Figure 20 is an overlay of the XRPD patterns of Form 2 of Comparative Example 2 before and after stirring and trituration;

[0077] Figure 21 is an XRPD pattern of Form 3 obtained in Comparative Example 3 according to the prior art WO2018129419A1 ;

[0078] Figure 22 is an overlay of the XRPD patterns of Form 3 of Comparative Example 3 before and after air drying at room temperature;

[0079] Figure 23 is an overlay of the XRPD patterns of the crystalline form APTI-I obtained in the present application and the Form 1, Form 2, Form 3 of the prior art.

[0080] Figure 24 is an overlay of the XRPD patterns of tablet excipient, tablet of Form APTI-I, and Form APTI-I (from top to bottom);

[0081] Figure 25 is an overlay of the XRPD patterns of Form APTI-I tablet after being exposed to light, 40°C / 75% RH, 25°C / 60% RH for 10 days and the XRPD pattern of freshly prepared Form APTI-I tablet (from top to bottom);

[0082] Figure 26 is an overlay of the XRPD patterns of Form APTI-I tablet after being exposed to light, 40°C / 75% RH, 25°C / 60% RH for 20 days and the XRPD pattern of freshly prepared Form APTI-I tablet (from top to bottom);

[0083] Figure 27 is a comparison of the dissolution rate curves of Form APTI-I tablet and Form 1 tablet in 1.2 pH buffer;

[0084] Figure 28 is a comparison of the dissolution rate curves of Form APTI-I tablet and Form 1 tablet in 4.5 pH buffer;

[0085] Figure 29 is a comparison of the dissolution rate curves of Form APTI-I tablet and Form 1 tablet in 6.8 pH buffer;

[0086] Figure 30 is a comparison of the dissolution rate curves of Form APTI-I tablet and Form 1 tablet in water. DETAILED DESCRIPTION

[0087] To solve the problems in the prior art, the inventors of the present application have conducted in-depth research on the crystalline forms of elasigidum dihydrochloride and unexpectedly found a new crystalline form, Form APTI-I, which has a high yield, a low amount of residual organic solvent, a simple preparation method, and is suitable for scale-up production. In addition, in the water activity competition, surprisingly, the crystalline form has a wider water activity stable range than the crystalline forms disclosed in the prior art (e.g., Form 1 and Form 3 disclosed in WO2018129419), so that the crystalline form has more production operation space and less production and storage risk, and the crystalline form has stable physicochemical properties at high temperature and under different temperature and humidity conditions, and good product flowability, so that it can be used to prepare various formulations. The inventors of the present application have also obtained new crystalline forms APTI-II and APTI-III, which have purities of 99.92% and 99.95%, respectively. These high-purity crystalline forms provide more options for the purification research and application of elasigidum drug substances. On this basis, the present application is completed.

[0088] In the description of the present application, "room temperature" refers to 0-40℃, for example, 5-35℃, 15-28℃, 20-25℃, 28℃, etc. all belong to room temperature.

[0089] Crystalline form APTI-I of Elacridar dihydrochloride

[0090] The crystalline form APTI-I of Elacridar dihydrochloride provided by the present application has an XRPD pattern expressed by 2θ angle using Cu-Kα radiation with characteristic peaks at 9.6°±0.2°, 12.0°±0.2°, 13.5°±0.2°, 20.5°±0.2°, 21.9°±0.2°, 22.4°±0.2°, or an XRPD pattern expressed by 2θ angle using Cu-Kα radiation with characteristic peaks at 9.6°±0.2°, 12.0°±0.2°, 20.5°±0.2°.

[0091] Further, the crystalline form APTI-I of Elacridar dihydrochloride provided by the present application has an XRPD pattern expressed by 2θ angle using Cu-Kα radiation with characteristic peaks at 6.1°±0.2°, 7.9°±0.2°, 9.6°±0.2°, 12.0°±0.2°, 12.3°±0.2°, 13.5°±0.2°, 14.1°±0.2°, 17.0°±0.2°, 17.2°±0.2°, 17.5°±0.2°, 17.8°±0.2°, 18.7°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 20.5°±0.2°, 21.3°±0.2°, 21.9°±0.2°, 22.2°±0.2°, 22.4°±0.2°, 22.7°±0.2°, 24.2°±0.2°, 24.5°±0.2°, 24.7°±0.2°, 25.0°±0.2°, 25.3°±0.2°, 26.4°±0.2°, 27.2°±0.2°, 27.4°±0.2°, 27.7°±0.2°, 28.7°±0.2°.

[0092] Further, the crystalline form APTI-I of Elacridar dihydrochloride provided by the present application has an XRPD pattern expressed by 2θ angle using Cu-Kα radiation with characteristic peaks as shown in Table 1:

[0093] Table 1

[0094] Further, the crystalline form APTI-I of Elacridar dihydrochloride provided by the present application has an XRPD pattern expressed by 2θ angle using Cu-Kα radiation consistent with Figure 1.

[0095] Further, the DSC pattern of the elacridar dihydrochloride crystal form APTI-I provided by the present application is consistent with Figure 2.

[0096] Further, the TGA pattern of the elacridar dihydrochloride crystal form APTI-I provided by the present application is consistent with Figure 3.

[0097] Further, the TGA pattern of the elacridar dihydrochloride crystal form APTI-I provided by the present application is consistent with Figure 10.

[0098] Further, the PLM observation result of the elacridar dihydrochloride crystal form APTI-I provided by the present application shows that the crystal morphology is in block shape, uniformly distributed, and without agglomeration phenomenon.

[0099] Further, the PLM observation result of the elacridar dihydrochloride crystal form APTI-I provided by the present application is shown in Figure 4.

[0100] Further, the elacridar dihydrochloride crystal form APTI-I provided by the present application is an elacridar dihydrochloride hydrate.

[0101] Further, the water content of the elacridar dihydrochloride crystal form APTI-I provided by the present application is 1.5% to 3.8% (by weight). In some specific embodiments, the ratio of elacridar dihydrochloride molecules to water molecules in the elacridar dihydrochloride crystal form APTI-I provided by the present application is 1:1. In some specific embodiments, the ratio of elacridar dihydrochloride molecules to water molecules in the elacridar dihydrochloride crystal form APTI-I provided by the present application is 1:0.5. In some specific embodiments, the ratio of elacridar dihydrochloride molecules to water molecules in the elacridar dihydrochloride crystal form APTI-I provided by the present application is 1:0.6.

[0102] In some specific embodiments, the preparation method of the elacridar dihydrochloride crystal form APTI-I provided by the present application comprises the steps of: stirring elacridar dihydrochloride in a mixed solution of an organic solvent and water, separating, and drying to obtain the crystal form APTI-I. Wherein the weight / volume ratio of elacridar dihydrochloride to the mixed solution is 0.05 to 0.2 g / mL, the volume ratio of the organic solvent to water is 3 to 9:1, the system temperature during stirring is 20 to 60°C, the stirring time is 8 to 48 h, the drying temperature is 40 to 60°C, and the drying time is 8 to 24 h.

[0103] The organic solvent includes but is not limited to methanol, ethanol, n-propanol, isopropanol, acetone, 2-butanone, acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0104] New crystalline form of elacridar dihydrochloride APTI-II

[0105] The present application provides a crystalline form of elacridar dihydrochloride APTI-II, which has an XRPD pattern expressed in terms of 2θ angles using Cu-Kα radiation with characteristic peaks at 7.0°±0.2°, 13.9°±0.2°, 15.8°±0.2°, 21.9°±0.2°, 23.5°±0.2°.

[0106] Further, the XRPD pattern expressed in terms of 2θ angles using Cu-Kα radiation of the crystalline form of elacridar dihydrochloride APTI-II provided by the present application has characteristic peaks at 7.0°±0.2°, 8.1°±0.2°, 8.8°±0.2°, 11.7°±0.2°, 12.5°±0.2°, 13.9°±0.2°, 14.9°±0.2°, 15.8°±0.2°, 17.4°±0.2°, 18.7°±0.2°, 19.5°±0.2°, 20.9°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.4°±0.2°, 25.3°±0.2°, 26.2°±0.2°, 26.9°±0.2°, 28.0°±0.2°, 28.6°±0.2°, 29.7°±0.2°, 30.9°±0.2°, 38.0°±0.2°.

[0107] Further, the XRPD pattern expressed in terms of 2θ angles using Cu-Kα radiation of the crystalline form of elacridar dihydrochloride APTI-II provided by the present application has characteristic peaks at 7.0°±0.2°, 8.1°±0.2°, 8.8°±0.2°, 11.7°±0.2°, 12.5°±0.2°, 13.9°±0.2°, 14.9°±0.2°, 15.8°±0.2°, 17.4°±0.2°, 18.7°±0.2°, 19.5°±0.2°, 20.9°±0.2°, 21.9°±0.2°, 23.5°±0.2°, 24.4°±0.2°, 25.3°±0.2°, 26.2°±0.2°, 26.9°±0.2°, 28.0°±0.2°, 28.6°±0.2°, 29.7°±0.2°, 30.9°±0.2°, 38.0°±0.2°.

[0108] Table 2

[0109] Further, the XRPD pattern of the crystalline form of elacridar dihydrochloride APTI-II provided by the present application is consistent with that of FIG. 6.

[0110] Further, the crystalline form of elacridar dihydrochloride APTI-II provided by the present application has a thermogravimetric analysis (TGA) pattern with a step weight loss of about 12.7% at 170°C.

[0111] Further, the TGA pattern of the crystalline form of elacridar dihydrochloride APTI-II provided by the present application is consistent with that of FIG. 7.

[0112] Further, the crystalline form of elacridar dihydrochloride APTI-II provided by the present application is a 2-ethoxyethanol solvate of elacridar dihydrochloride. In some embodiments, the ratio of elacridar molecules to 2-ethoxyethanol molecules in the crystalline form APTI-II is 1:1.

[0113] In some embodiments, the present application provides a method for preparing the crystalline form APTI-II of elacridar dihydrochloride according to the present application, which comprises: stirring elacridar dihydrochloride (solid) in 2-ethoxyethanol, then standing and separating, and drying to obtain the crystalline form APTI-II. The weight / volume ratio of elacridar dihydrochloride to 2-ethoxyethanol is 0.05-0.2 g / mL; during stirring, the system is first stirred at 40-60 °C for 6-10 h, then stirred at 0-40 °C for 6-10 h, and finally stirred at 40-60 °C for 6-10 h; the standing process is to place at room temperature for 6-9 days. The drying temperature is 40-60 °C, and the drying time is 8-24 h.

[0114] A new crystalline form APTI-III of elacridar dihydrochloride.

[0115] The crystalline form APTI-III of elacridar dihydrochloride according to the present application has an XRPD pattern expressed by 2θ angles using Cu-Kα radiation, which has characteristic peaks at 11.3±0.2°, 11.8±0.2°, 13.4±0.2°, 18.2±0.2°, 21.2±0.2°, 25.8±0.2°.

[0116] Further, the XRPD pattern expressed by 2θ angles of the crystalline form APTI-III of elacridar dihydrochloride according to the present application using Cu-Kα radiation has characteristic peaks at 5.6±0.2°, 10.3±0.2°, 11.0±0.2°, 11.3±0.2°, 11.8±0.2°, 12.5±0.2°, 13.4±0.2°, 14.9±0.2°, 15.4±0.2°, 18.2±0.2°, 18.8±0.2°, 19.3±0.2°, 20.1±0.2°, 20.5±0.2°, 21.2±0.2°, 22.0±0.2°, 23.0±0.2°, 24.0±0.2°, 25.8±0.2°, 26.3±0.2°, 27.2±0.2°, 27.6±0.2°, 29.9±0.2°.

[0117] Further, the XRPD pattern expressed by 2θ angles of the crystalline form APTI-III of elacridar dihydrochloride according to the present application using Cu-Kα radiation has characteristic peaks as shown in Table 3:

[0118] Table 3

[0119] Further, the XRPD pattern expressed by 2θ angles of the crystalline form APTI-III of elacridar dihydrochloride according to the present application using Cu-Kα radiation is consistent with that of FIG. 8.

[0120] Further, the DSC pattern of the elacridar dihydrochloride crystal form APTI-III provided by the present application is consistent with that of Figure 9.

[0121] Further, the elacridar dihydrochloride crystal form APTI-III provided by the present application is a N,N-dimethylformamide (DMF) solvate of elacridar dihydrochloride. In some specific embodiments, the ratio of elacridar molecules to DMF molecules in the crystal form APTI-III is 1:1.

[0122] In some specific embodiments, the present application provides a method for preparing the crystal form APTI-III of elacridar dihydrochloride, which comprises the following steps:

[0123] The elacridar dihydrochloride is added into DMF, heated to dissolve, then cooled to crystallize, separated, and dried to obtain the crystal form APTI-III. The heating temperature is 80-100℃, the cooling temperature is 0-30℃, the drying temperature is 40-60℃, and the drying time is 8-24h. The weight / volume ratio of elacridar dihydrochloride to DMF is 10-25mg / mL.

[0124] Compared with the prior art, the elacridar dihydrochloride crystal form of the present application has the following advantages:

[0125] 1. The crystal form APTI-I provided by the present application has a wider preparation water activity range, is simple and easy to control in operation, has a high yield and high purity, is more suitable for large-scale production in industry, is stable at different temperatures and humidities, and is more conducive to storage. Moreover, the crystal form has good crystalline dispersibility and flowability, which is conducive to the use of the later preparation. Therefore, the crystal form APTI-I shows better practicability in the early production, mid-term storage, and later preparation.

[0126] 2. The crystal form APTI-II and the crystal form APTI-III prepared by the present application have high purity, which provides more options for the purification of elacridar or its salt in the production process.

[0127] The present application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not used to limit the scope of the present application. The experimental methods in the following examples, if not otherwise specified, are usually carried out according to the conventional conditions or the conditions suggested by the manufacturers. Unless otherwise specified, the percentages and parts are weight percentages and weight parts.

[0128] General method

[0129] 1. XRPD pattern determination method

[0130] X-ray powder diffraction instrument: BRUKER AXS D2 PHASER X-ray powder diffractometer; radiation source: Intensity ratio a1 / a2: 0.5; Generator kv: 30.0 kv; Generator mA: 10.0 mA; scanning range: 3.0-40.0°.

[0131] 2. DSC measurement method

[0132] METTLEER DSC1 differential scanning calorimeter Temperature program: 30-250°C, 10°C / min.

[0133] 3. TGA measurement method

[0134] Instrument model: METTLEER TGA / DSC1 thermogravimetric analyzer Temperature program: 30-300°C, 10°C / min.

[0135] Comparative Example 1: Preparation of Form 1 disclosed in prior art WO2018129419A1

[0136] The aqueous solution of elacezumab dihydrochloride was rotary evaporated at 50°C to obtain amorphous elacezumab dihydrochloride, 20 mL of ethanol was added and stirred at 50°C for 4 h, filtered under reduced pressure, and vacuum dried at 50°C for 16 h to obtain 4.2 g of white solid, which was Form 1 disclosed in prior art WO2018129419A1 (see Figure 16 for its XRPD pattern), with a purity of 99.77%, the product was filtered and agglomerated, and the PSD results are shown in Figure 17, which showed that the D90 was 355.9 pm, and the agglomeration was not easy to disperse, which was not conducive to subsequent preparation.

[0137] Comparative Example 2: Preparation of Form 2 disclosed in prior art WO2018129419A1

[0138] Take 200 mg of elacridar dihydrochloride (solid), add 2 mL of methanol at 50°C, cool to room temperature, then add dropwise to 6 mL of ethyl acetate, a large amount of white solid is precipitated, filter under reduced pressure, and take samples for detection. The Form 2 disclosed in the prior art WO2018129419A1 (see Figure 18 for its XRPD pattern) is obtained. The DSC results (see Figure 19) show that after melting at 163°C, recrystallization occurs at 170°C, which is consistent with the Form 2 data disclosed in the prior art WO2018129419A1. The Form 2 is continued to be slurried in the methanol / ethyl acetate system at 50°C for 1 h, and then converted to the Form 1 disclosed in the prior art WO2018129419A1. Form 2 is a metastable anhydrous crystal form, and there is a risk of recrystallization. It is not easy to repeat (see the comparison of the XRPD patterns of Form 2 and the product obtained after 1 h of slurry (stirring) at 50°C in the methanol / ethyl acetate system shown in Figure 20).

[0139] Comparative Example 3: Preparation of Form 3 (Form 3) disclosed in the prior art WO2018129419A1

[0140] Take 1 g of elacridar dihydrochloride, add 3 mL of water, stir at room temperature for 1 day, and filter to obtain 267 mg of white solid, which is Form 3 disclosed in the prior art WO2018129419A1 (see Figure 21 for its XRPD pattern). The product is dried at room temperature, and recrystallizes to become crystal form APTI-I (see the comparison of the XRPD patterns of Form 3 and the crystal form it becomes after drying at room temperature shown in Figure 22). The crystal form is unstable, and the yield is less than 26.7% due to the high solubility of elacridar dihydrochloride in water.

[0141] Example 1: Preparation of elacridar dihydrochloride crystal form APTI-I

[0142] Add 200 mg of elacridar dihydrochloride (solid) to a reaction bottle, add 2 mL of acetonitrile:H2O (volume ratio 8:1) mixed solvent (mixed solution), and stir at 50°C for 2 days (48 hours). Filter and dry at 50°C under vacuum for 16 h to obtain 182 mg of solid with a purity of 99.81%. The XRPD detection result is consistent with Figure 1. The DSC detection result is consistent with Figure 2. The TGA result is consistent with Figure 3. The KF detection result of the product is 1.95%, i.e. each molecule of crystal form APTI-I contains about 0.6 water. The yield after deducting the water content is 89%. The organic solvent residue detection result shows that the acetonitrile residue in the product is 41 ppm, which is much lower than the ICH limit (the ICH limit for acetonitrile is 410 ppm).

[0143] Example 2: Preparation of elacridar dihydrochloride crystal form APTI-I

[0144] Into a reaction bottle, add 1.60 g of elacridar dihydrochloride solid, add 15 mL of a mixed solvent (mixture) of acetone:H20 (volume ratio 9:1), stir at 50°C for 2 (48 hours), filter, and dry at 50°C under vacuum for 6 h to obtain 1.53 g of solid with a purity of 99.90%. The obtained solid is detected by XRPD, and the result is consistent with that in FIG. 1; the result of DSC detection is consistent with that in FIG. 2; and the result of TGA detection is consistent with that in FIG. 10. The product is detected by KF, and the result is 3.3%, that is, about 1 water molecule is contained in each molecule of the crystal form APTI-I, and the moisture yield after deduction is 92.3%. The result of detection of residual organic solvents shows that the residual acetone in the product is 89 ppm, which is much lower than the ICH limit (the ICH limit of acetone is 5000 ppm). The prepared material is detected by polarized light PLM, and the result is shown in FIG. 4. The product is blocky crystal, and the particle size distribution is uniform, which is more conducive to granulation and tabletting in preparation, and the detection of PSD will show that the product is basically normally distributed (see FIG. 5). Compared with Form 1 (see FIG. 17), the particle distribution is more uniform.

[0145] Example 3: High-temperature stability experiment of elacridar dihydrochloride crystal form APTI-I

[0146] The elacridar dihydrochloride crystal form APTI-I prepared in Example 2 is placed in a vacuum dryer at 80°C for 24 h, and the product is sampled and detected. The XRPD pattern of the product is consistent with that before drying (see the superimposed XRPD patterns before and after 24 h of drying at 80°C under vacuum shown in FIG. 11), the TGA detection result of the crystal form is shown in FIG. 12a, the DSC result is shown in FIG. 12b, the KF result shows that the water content is about 1.65%, about 0.5 water molecules, the purity before and after is 99.90%, and no chemical degradation is observed. Based on this, the crystal form can be subjected to high-temperature granulation in the preparation process, and there is no influence of high-temperature dehydration on the crystal form.

[0147] The crystal form of Example 1, the crystal form of Example 2, and the crystal form of Example 3 (Example 2 crystal form APTI-I dried at 80°C under vacuum for 24 h) are obtained, and the XRPD pattern and DSC detection result of the obtained crystal form are consistent, and only the TGA data and water content are different. It is inferred that the obtained elacridar dihydrochloride crystal form APTI-I is a channel-type hydrate, and each molecule contains 0.5-1 water molecules.

[0148] Example 4: Grinding stability experiment of elacridar dihydrochloride crystal form APTI-I

[0149] XRPD of 200 mg of the crystalline form of Elacridar dihydrochloride salt Form APTI-I (HPLC purity 99.90%) prepared in Example 2 was detected after manual dry grinding in an agate mortar for 30 min, and compared with the XRPD before dry grinding. The results are shown in Figure 13a. It was found that the crystalline form did not change before and after grinding, and the purity was 99.87%, which did not change significantly.

[0150] XRPD of 200 mg of the crystalline form of Elacridar dihydrochloride salt Form APTI-I (HPLC purity 99.90%) prepared in Example 2 was detected after manual dry grinding in an agate mortar for 30 min, and compared with the XRPD before dry grinding. The results are shown in Figure 13a. It was found that the crystalline form did not change before and after grinding, and the purity was 99.87%, which did not change significantly.

[0151] Example 5: Temperature and humidity stability experiment of Elacridar dihydrochloride salt Form APTI-I

[0152] The Elacridar dihydrochloride salt Form APTI-I of Example 2 was packaged with PE bags and aluminum foil bags and placed at 25°C / 60% RH and 40°C / 70% RH for 2 weeks, respectively, and the XRPD thereof was detected, and compared with the XRPD of the crystalline form before placement. The superimposed XRPD patterns of the crystalline form APTI-I before and after placement are shown in Figure 14.

[0153] The parameters of the grinding stability and temperature and humidity stability experiments of the Elacridar dihydrochloride salt Form APTI-I of Example 2 and the purity results of the obtained products are shown in Table 4.

[0154] Table 4

[0155] It can be seen from Figure 14 and Table 4 that the crystalline form and purity of the Elacridar dihydrochloride salt Form APTI-I of Example 2 did not change significantly after being ground for 30 minutes and being placed at 25°C / 60% RH and 40°C / 70% RH for 2 weeks.

[0156] Example 6: Water activity suspension competition experiment of Elacridar dihydrochloride salt Form APTI-I

[0157] The same amount of the crystalline form APTI-I of elacezium dihydrochloride obtained in Example 2 and Form 1 obtained according to the prior art WO2018129419 were weighed out, and after magnetic stirring at room temperature for 2 days in a single or mixed saturated solution of acetone / water with water activity of 0, 0.2, 0.3, 0.4, 0.6, 0.7, 0.8, 1, XRPD was detected, and the results are shown in Figure 15a. The results show that the water activity is 0-0.2, Form 1, 0.3-0.7, crystalline form APTI-I, and 0.8-1, Form 3. The crystalline form APTI-I has a wider water activity preparation interval.

[0158] The same amount of the crystalline form APTI-I of elacezium dihydrochloride obtained in Example 2 and Form 1 obtained according to the prior art WO2018129419 were weighed out, and after magnetic stirring at room temperature for 2 days in a single or mixed saturated solution of acetone / water with water activity of 0, 0.2, 0.3, 0.4, 0.6, 0.7, 0.8, 1, XRPD was detected, and the results are shown in Figure 15a. The results show that the water activity is 0-0.2, Form 1, 0.3-0.7, crystalline form APTI-I, and 0.8-1, Form 3. The crystalline form APTI-I has a wider water activity preparation interval.

[0159] Example 7: Flowability of crystalline form APTI-I of elacezium dihydrochloride

[0160] In the preparation process, the compressibility coefficient c is usually used to evaluate the flowability of the powder or granules, and the compressibility coefficient is calculated as c=(p f-p 0) / p f, wherein p f is the tap density and p 0 is the loose density. According to the evaluation standard of USP General Charpters: <1174> Powder Flow, the flowability of the crystalline form APTI-I of Example 2 of the present application was evaluated, and the results showed that the product loose density p 0 was 0.231 g / mL, the tap density was 0.269 mg / mL, the compressibility coefficient c was 14.1, and the product flowability was good (11-15).

[0161] Example 8: Preparation of crystalline form APTI-II of elacezium dihydrochloride

[0162] A reaction bottle was added with 1 g of elacezium dihydrochloride (solid), 30 mL of 2-ethoxyethanol, and after 8 h of beater at 50°C, the temperature was lowered to room temperature for 8 h of beater, then the temperature was raised to 50°C for 8 h of beater, and then the temperature was lowered to room temperature for 7 days of standing. After filtration and drying, 1.02 g of solid was obtained, which was consistent with the XRPD test of Figure 6, and was crystalline form APTI-II. The TGA results were consistent with Figure 7, and the nuclear magnetic resonance spectrum results showed that in this crystalline form, the ratio of the number of molecules of elacezium dihydrochloride to 2-ethoxyethanol was 1:1, and the purity was 99.92%.

[0163] Example 9: Preparation of Elacridar dihydrochloride Form APTI-III

[0164] Into a reaction bottle, elacridar dihydrochloride (solid) 200 mg was added, DMF 12 mL was added, and the temperature was raised to 90°C. After stirring until the solid was dissolved, the temperature was slowly lowered to 25°C. White solid was precipitated, filtered, and dried to obtain 172 mg of solid. XRPD test was consistent with Figure 8, and DSC results were consistent with Figure 9. The nuclear magnetic resonance hydrogen spectrum showed that the ratio of elacridar dihydrochloride to DMF molecules in this crystal form was 1:1. The purity of the product was 99.95%.

[0165] Example 10: Preparation of tablets of elacridar dihydrochloride Form APTI-I and tablets of Form 1 disclosed in prior art WO2018129419A1

[0166] The components of the tablets of Form 1 and Form APTI-I and the preparation processes thereof are shown in Tables 5 and 6, respectively.

[0167] Table 5: Composition and amount of components of tablets

[0168] In Table 5, “API” refers to Form 1 or Form APTI-I.

[0169] Table 6: Preparation process of tablets

[0170] Example 11: Stability study of tablets of elacridar dihydrochloride Form APTI-I

[0171] The excipients, tablets of Form APTI-I, and Form APTI-I were detected by XRPD. The superimposed XRPD patterns are shown in Figure 24.

[0172] The tablets of Form APTI-I were left open to light, 40°C / 75% RH, and 25°C / 60% RH for 10 days or 20 days, and then sampled for XRPD detection. The results are shown in Table 7 and Figures 25 and 26. From the test results, it can be seen that the tablets of Form APTI-I did not change significantly after being left open under these conditions, indicating that the tablets have stable physicochemical properties.

[0173] Table 7

[0174] Example 12: Dissolution study of tablets of elacridar dihydrochloride Form APTI-I and tablets of Form 1

[0175] The tablets of the crystal form APTI-I and the tablets of Form 1 were placed in buffers of different pH and water, and the concentration of elacridar was detected at 10, 15, 20, 30, 45, 60, 90, 120 min, respectively, and the dissolution curves were drawn (see Figures 27-30). The results showed that the dissolution rates of the two crystal forms were relatively high, and the crystal form APTI-I did not affect the drug release.

[0176] In summary, the crystal form APTI-I of elacridar dihydrochloride obtained by the present application is a new crystal form different from the existing disclosed crystal form, and has a brand-new XRPD pattern. Compared with Form 1 and Form 3 obtained by the original research, the crystal form has a wider water activity stable interval, and thus has better crystal form stability and is easier to scale up. Moreover, compared with Form 2 obtained by the original research, the crystal form APTI-I has no risk of crystal transformation in solution, and compared with Form 3, the crystal form APTI-I is stable in drying and has no risk of crystal transformation. In addition, the crystal form APTI-I has good stability of physicochemical properties under the conditions of 25℃ / 60% RH and 40℃ / 75% RH and grinding, the product crystal is blocky, the particle size distribution is uniform, the purity and yield are relatively high, the crystal form preparation solvent has high selectivity, the residual solvent is easy to control, and as a solid drug, the crystal form APTI-I exhibits excellent performance in production, storage, transportation and later preparation processing, thereby providing a better choice for the selection of crystal form in drug development.

[0177] The crystal forms APTI-II and APTI-III of elacridar dihydrochloride obtained by the present application are also new crystal forms different from the existing disclosed crystal forms, and have higher purity, thereby providing more choices for product purification.

Claims

1. A crystalline form of Ipatilumab dihydrochloride, Form APTI-I, characterized by, XRPD pattern, expressed in terms of 2θ angle using Cu-Kα radiation, has characteristic peaks at 9.6°±0.2°, 12.0°±0.2°, 13.5°±0.2°, 20.5°±0.2°, 21.9°±0.2°, 22.4°±0.2°.

2. The crystalline form APTI-I of elacestrant dihydrochloride according to claim 1, characterized in that, The crystalline form APTI-I also has one or more of the following characteristics: (i) its XRPD pattern also has one or more of the following characteristic peaks: 6.1°±0.2°、7.9°±0.2°、12.3°±0.2°、14.1°±0.2°、17.0°±0.2°、17.2°±0.2°、17.5°±0.2°、 17.8°±0.2°、18.7°±0.2°、19.1°±0.2°、19.8°±0.2°、21.3°±0.2°、22.2°±0.2°、22.7°±0.2°、24.2°±0.2°、24.5°±0.2°、24.7°±0.2°、25.0°±0.2°、25.3°±0.2°、26.4°±0.2°、27.2°±0.2°、27.4°±0.2°、27.7°±0.2°、28.7±0.2°。 (ii) its differential scanning calorimetry pattern has endothermic peaks at 71.6±5°C and 197.6±5°C, (iii) its thermogravimetric analysis (TGA) pattern has a weight loss of about 1.5-3.8% at 30-120°C, (iv) its XRPD pattern is substantially in accordance with Figure 1, (v) its differential scanning calorimetry pattern is substantially in accordance with Figure 2, (vi) its thermogravimetric analysis pattern is substantially in accordance with Figure 3 or Figure 10.

3. A crystalline form of Ipatilumeb dihydrochloride, Form APTI-I, characterized by: XRPD pattern, expressed in terms of 2θ angle using Cu-Kα radiation, has characteristic peaks at 9.6°±0.2°, 12.0°±0.2°, 20.5°±0.2°.

4. The crystalline form APTT-I of elacestrant dihydrochloride according to claim 3, characterized in that, The crystalline form APTI-I also has one or more of the following characteristics: (i) its XRPD pattern also has one or more of the following characteristic peaks: 6.1°±0.2°、7.9°±0.2°、12.3°±0.2°、13.5°±0.2°、14.1°±0.2°、17.0°±0.2°、17.2°±0.2°、 17.5°±0.2°、17.8°±0.2°、18.7°±0.2°、19.1°±0.2°、19.8°±0.2°、21.3°±0.2°、21.9°±0.2°、22.2°±0.2°、22.4°±0.2°、22.7°±0.2°、24.2°±0.2°、24.5°±0.2°、24.7°±0.2°、25.0°±0.2°、25.3°±0.2°、26.4°±0.2°、27.2°±0.2°、27.4°±0.2°、27.7°±0.2°、28.7±0.2°， (ii) its differential scanning calorimetry pattern has endothermic peaks at 71.6±5°C and 197.6±5°C, (iii) its thermogravimetric analysis (TGA) pattern has a weight loss of about 1.5-3.8% at 30-120°C, (iv) its XRPD pattern is substantially in accordance with Figure 1, (v) its differential scanning calorimetry pattern is substantially in accordance with Figure 2, (vi) its thermogravimetric analysis pattern is substantially in accordance with Figure 3 or Figure 10.

5. A process for the preparation of crystalline Form APTI-I of Elacridar dihydrochloride according to any one of claims 1-4, characterized in that, The preparation method comprises the following steps: The crystalline form APTI-I is obtained by stirring elacridar dihydrochloride in a mixture of an organic solvent and water, separating and drying.

6. The method of preparing elacestrant dihydrochloride according to claim 5, characterized by, The organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, acetone, 2-butanone, acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, or a combination thereof, more preferably acetonitrile or acetone, and / or The volume ratio of the organic solvent to water is 3-9:1, more preferably 7-9:1, and / or The weight-to-volume ratio of elacridar dihydrochloride to the mixture is 0.05-0.2 g / mL, and / or The temperature of the system during stirring is 20-60°C, and the stirring time is 8-48 h, and / or The temperature of drying is 40-60°C, and the time is 8-24 h.

7. A crystalline form of Elacridar dihydrochloride, Form APTI-II, characterized by, XRPD pattern, expressed in terms of 2θ angle using Cu-Kα radiation, has characteristic peaks at 7.0°±0.2°, 13.9°±0.2°, 15.8°±0.2°, 21.9°±0.2°, 23.5°±0.2°.

8. The crystalline form APTT-II of elacestrant dihydrochloride according to claim 7, characterized in that, The crystalline form APTI-II also has one or more of the following characteristics: (i) its XRPD pattern also has one or more of the following characteristic peaks: 8.1°±0.2°、8.8°±0.2°、11.7°±0.2°、12.5°±0.2°、14.9°±0.2°、17.4°±0.2°、18.7°± 0.2°、19.5°±0.2°、20.9°±0.2°、24.4°±0.2°、25.3°±0.2°、26.2°±0.2°、26.9°±0.2°、28.0°±0.2°、28.6°±0.2°、29.7°±0.2°、30.9°±0.2°、38.0°±0.2°， (ii) its thermogravimetric analysis pattern has a step at 30-170°C, with a weight loss of about 12.7%, (ii) its XRPD pattern is substantially in accordance with Figure 6.

9. A process for preparing the crystalline form APTT-II of elamsigum dihydrochloride according to claim 7 or 8, characterized in that, The preparation method comprises the following steps: After stirring the elacridar dihydrochloride in 2-ethoxyethanol, standing and separating, drying to obtain the crystal form APTI-II, Preferably, the weight / volume ratio of elacridar dihydrochloride to 2-ethoxyethanol is 0.05-0.2 g / mL, and / or Preferably, when stirring, the system is first stirred at 40-60°C for 6-10 h, then stirred at 0-40°C for 6-10 h, and finally stirred at 40-60°C for 6-10 h, and / or Preferably, the standing is at room temperature for 6-9 days, and / or Preferably, the drying temperature is 40-60°C, and the drying time is 8-24 h.

10. A crystalline form of elacestrant dihydrochloride salt, APTI-III, characterized by, The XRPD pattern using Cu-Kα radiation has characteristic peaks at 11.3±0.2°, 11.8±0.2°, 13.4±0.2°, 18.2±0.2°, 21.2±0.2°, 25.8±0.2° in terms of 2θ angle.

11. Elacridar dihydrochloride in a new crystalline form APTI-III according to claim 10, characterized by The crystal form APTI-III also has one or more characteristics selected from the following: (i) its XRPD pattern also has one or more characteristic peaks selected from the following: 5.6±0.2°、10.3±0.2°、11.0±0.2°、12.5±0.2°、14.9±0.2°、15.4±0.2°、18.8±0.2°、19.3±0.2°、 20.1±0.2°、20.5±0.2°、22.0±0.2°、23.0±0.2°、24.0±0.2°、26.3±0.2°、27.2±0.2°、27.6±0.2°、29.9±0.2°， (ii) its differential scanning calorimetry pattern has endothermic peaks present at 112.5±5°C and 227.8±5°C, (iii) its XRPD pattern is substantially consistent with FIG.

8.

12. A process for preparing the crystalline form APTI-III of elamsigum dihydrochloride according to claim 10 or 11, characterized in that, The preparation method comprises the following steps: After stirring the elacridar dihydrochloride in 2-ethoxyethanol, standing and separating, drying to obtain the crystal form APTI-II, Preferably, the heating temperature is 80-100°C, and the cooling temperature is 0-30°C, and / or Preferably, the weight / volume ratio of elacridar dihydrochloride to N,N-dimethylformamide is 10-25 mg / mL, and / or Preferably, the drying temperature is 40-60°C, and the drying time is 8-24 h.

13. Use of the crystal form APTI-I, the crystal form APTI-II or the crystal form APTI-III of elacridar dihydrochloride in the preparation of a drug containing elacridar dihydrochloride or in the purification of elacridar or a salt thereof.

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