Crystalline or Amorphous form of Bcl-2/Bcl-xL inhibitor compound or its salts

Abstract

Disclosed herein are a crystalline or amorphous form of a Bcl-2/Bcl-xL inhibitor compound or a salt thereof, and a preparation method and application thereof.

Claims

1. A crystalline or amorphous form of the compound of formula 1 or its salt: ##STR00003##

2. The form of claim 1, wherein the form is the crystalline form I of the fumarate salt of the compound of formula 1; the crystalline form II of the hydrochloride salt of the compound of formula 1; the nicotinate crystalline form III of the compound of formula 1; the sodium salt crystalline form IV of the compound of formula 1; the crystalline form V of the potassium salt of the compound of formula 1; the crystalline form VI of the compound of formula 1; the crystalline form VII of the compound of formula 1; the crystalline form VIII of the compound of formula 1; the adipate salt amorphous form IX of the compound of formula 1; the fumarate amorphous form X of the compound of formula 1; the nicotinic acid salt amorphous form XI of the compound of formula 1; the amorphous form XII of the potassium salt of the compound of formula 1; the amorphous form XIII of the sodium salt of the compound of formula 1; the amorphous form XIV of the compound of formula 1; the amorphous form XV of the maleate salt of the compound of formula 1; or the amorphous form XVI of the meglumine salt of the compound of formula 1.

3. The form of claim 2, wherein the form is the crystalline form I of the fumarate salt of the compound of formula 1, characterized in that it has characteristic peaks at the following positions in an X-ray powder diffraction (XRPD) pattern represented by an angle of 2θ: 18.03±0.2°, 28.81±0.2° and 31.88±0.2°, and wherein the form has one or more of the following: 1) XRPD characteristic peaks at positions substantially similar to Table 1; 2) an XRPD pattern substantially similar to FIG. 1; 3) an endothermic peak at 217.4±2.0° C. measured from modulated differential scanning calorimetry (MDSC); and 4) MDSC endothermic peaks substantially similar to FIG. 2.

4. The form of claim 2, wherein the form is the crystalline form II of the hydrochloride salt of the compound of formula 1, characterized in that it has characteristic peaks at the following positions in the XRPD diagram represented by an angle of 2θ: 13.01±0.2°, 21.55±0.2°, 25.95±0.2°, 31.33±0.2° and 37.34±0.2, and wherein the form has one or more of the following: 1) XRPD characteristic peaks at positions substantially similar to Table 2; 2) an XRPD pattern substantially similar to FIG. 3; 3) an endothermic peak at 148.2±2.0° C. and a glass transition temperature at 139.5±2.0° C. measured from MDSC; and 4) MDSC endothermic peaks substantially similar to FIG. 4.

5. (canceled)

6. The form of claim 2, wherein the form is the nicotinate crystalline form III of the compound of formula 1, characterized in that it has characteristic peaks at the following positions in the XRPD diagram expressed at 2θ angles: 15.46±0.2° and 18.06±0.2°, and wherein the form has one or more of the following: 1) XRPD characteristic peaks at positions substantially similar to Table 3; 2) an XRPD pattern substantially similar to FIG. 5; 3) a glass transition temperature at 127.6±2.0° C. measured by MSDC; and 4) MDSC endothermic peaks substantially similar to FIG. 6.

7. (canceled)

8. The form of claim 2, wherein the form is the sodium salt crystalline form IV of the compound of formula 1, characterized in that it has characteristic peaks at the following positions in the XRPD diagram expressed at 2θ angles: 16.75±0.2°, 32.34±0.2°, 33.48±0.2° and 37.95±0.2°, and wherein the form has one or more of the following: 1) XRPD characteristic peaks at positions substantially similar to Table 4; and 2) an XRPD pattern substantially similar to FIG. 7.

9. (canceled)

10. The form of claim 2, wherein the form is the crystalline form V of the potassium salt of the compound of formula 1, characterized in that it has characteristic peaks at the following positions in the XRPD diagram represented by an angle of 2θ: 24.35±0.2°, 30.10±0.2° and 31.41±0.2°, and wherein the form has one or more of the following: 1) XRPD characteristic peaks at positions substantially similar to Table 5; and 2) an XRPD pattern substantially similar to FIG. 8.

11. (canceled)

12. The form of claim 2, wherein the form is the crystalline form VI of the compound of formula 1, characterized in that it has characteristic peaks at the following positions in the XRPD diagram represented by an angle of 2θ: 3.94±0.2°, 5.09±0.2°, 18.01±0.2°, 19.08±0.2°, 19.70±0.2°, and wherein the form has one or more of the following: 1) XRPD characteristic peaks at positions substantially similar to Table 6; 2) an XRPD pattern substantially similar to FIG. 9; 3) a weight loss of 7.01±0.2% by weight before 160° C. measured by Thermogravimetric Analysis (TGA); 4) endothermic peaks at the peak temperature of 78.8±2.0° C. and −162.5±2.0° C. measured by differential scanning calorimetry (DSC); 5) a TGA diagram substantially similar to FIG. 10; and 6) a DSC chart substantially similar to FIG. 11.

13. (canceled)

14. The form of claim 2, wherein the form is the crystalline form VII of the compound of formula 1, characterized in that it has characteristic peaks at the following positions in the XRPD diagram represented by 2θ angles: 20.18±0.2°, 20.74±0.2°, 29.20±0.2°, 29.28±0.2° and 36.73±0.2°, and wherein the form has one or more of the following: 1) XRPD characteristic peaks at positions substantially similar to Table 7; 2) an XRPD pattern substantially similar to FIG. 12; 3) endothermic peaks at peak temperatures of 77.5±2.0° C. and 195.7±2.0° C. measured by DSC; and 4) a DSC chart substantially similar to FIG. 13.

15. (canceled)

16. The form of claim 2, wherein the form is the crystalline form VIII of the compound of formula 1, characterized in that it has a characteristic peak at the following position in the XRPD diagram represented by an angle of 2θ: 18.11±0.2°, and wherein the form has one of the following: 1) XRPD characteristic peaks at positions substantially similar to Table 8; 2) an XRPD pattern substantially similar to FIG. 14; 3) a weight loss of 7.59±0.2% by weight before 150° C. measured by TGA; 4) endothermic peaks at peak temperatures of 69.3±2.0° C. and 152.1±2.0° C. measured by DSC; 5) a TGA diagram substantially similar to FIG. 15; and 6) a DSC chart substantially similar to FIG. 16.

17. (canceled)

18. The form of claim 2, wherein the form is selected from the group consisting of: the adipate salt amorphous form IX of the compound of formula 1, wherein the form has one or more of the following: 1) an XRPD pattern substantially similar to FIG. 17; 2) a glass transition temperature at 113.4±2.0° C. measured by MDSC; and 3) an MDSC chart substantially similar to FIG. 18; the fumarate amorphous form X of the compound of formula 1, wherein the form has one or more of the following: 1) an XRPD pattern substantially similar to FIG. 19; 2) a glass transition temperature at 136.6±2.0° C. measured by MDSC; and 3) an MDSC chart substantially similar to FIG. 20; the nicotinic acid salt amorphous form XI of the compound of formula 1, wherein the form has one or more of the following: 1) an XRPD pattern substantially similar to FIG. 21; 2) a glass transition temperature at 117.9±2.0° C. measured by MDSC; and 3) an MDSC chart substantially similar to FIG. 22; the amorphous form XII of the potassium salt of the compound of formula 1, wherein the form has one or more of the following: 1) an XRPD pattern substantially similar to FIG. 23; 2) a glass transition temperature at 135.7±2.0° C. measured by MDSC; and 3) an MDSC chart substantially similar to FIG. 24; the amorphous form XIII of the sodium salt of the compound of formula 1, wherein the form has one or more of the following: 1) an XRPD pattern substantially similar to FIG. 25; 2) a glass transition temperature at 140.9±2.0° C. measured by MDSC; and 3) an MDSC chart substantially similar to FIG. 26; the amorphous form XIV of the compound of formula 1, wherein the form has one or more of the following: 1) an XRPD pattern substantially similar to FIG. 27; 2) a glass transition temperature at 148.9±2.0° C. measured by MDSC; 3) a weight loss of 6.35±0.2% by weight before 200° C. measured by TGA; 4) an MDSC chart substantially similar to FIG. 28; and 4) a TGA diagram substantially similar to FIG. 29; the amorphous form XV of the maleate salt of the compound of formula 1, wherein the form has one or more of the following: 1) an XRPD pattern substantially similar to FIG. 30; 2) a glass transition temperature at 91.89±2.0° C. measured by MDSC; 3) a weight loss of 8.767±0.2% by weight before 223.63° C. measured by TGA; 4) an MDSC chart substantially similar to FIG. 31; and 5) a TGA diagram substantially similar to FIG. 32; and the amorphous form XVI of the meglumine salt of the compound of formula 1, wherein the form has one or more of the following: 1) an XRPD pattern substantially similar to FIG. 33; 2) a glass transition temperature at 66.19±2.0 measured by MDSC; 3) a weight loss of 2.416±0.2% by weight before 124.19° C. and a weight loss of 2.774±0.2% by weight between 187.71° C. and 124.19° C. measured by TGA; 4) an MDSC chart substantially similar to FIG. 34; and 5) a TGA diagram substantially similar to FIG. 35.

19-25. (canceled)

26. The method for preparing any one of the crystalline forms I-V of the salt of the compound of formula 1 according to claim 2, comprising: mixing the compound of formula 1 with a solvent and an acid or a base, and with volatilization at room temperature; wherein the solvent is selected from one or more of: water, alkane, alcohol, ketone, ester, aromatic hydrocarbon, halogenated hydrocarbon, nitrile, ether, aliphatic hydrocarbons solvents and polar aprotic solvents such as DMF and DMSO; wherein the mass-volume ratio of the compound of formula 1 to the solvent is 100 mg:(0.1-10 mL); wherein the acid is fumaric acid, hydrochloric acid, niacin, or maleic acid; and wherein the base is sodium hydroxide, potassium hydroxide, or meglumine.

27. (canceled)

28. The method according to claim 2, further comprising: dissolving the compound of formula 1 in ethyl acetate, adding L-malic acid, and separating the obtained solid to obtain the crystalline form VII of the compound of formula 1.

29. The method according to claim 2, further comprising: dissolving the compound of formula 1 in acetone, adding methanol, and separating the obtained solid to obtain the crystalline form VI of the compound of formula 1.

30. The method according to claim 2, further comprising: adding the compound of formula 1 to a tetrahydrofuran/n-hexane mixed solvent and separating the obtained solid to obtain the crystalline form VIII of the compound of formula 1.

31. The method for preparing any one of the amorphous forms IX-XIII and XV-XVI of the salt of the compound of formula 1 according to claim 18, wherein the method comprises: mixing the compound of formula 1 with a solvent and an acid or base, and separating the resulting solid to obtain the compound of formula 1 amorphous form of salt; wherein the solvent is selected from one or more of water, alkane, alcohol, ketone, ester, aromatic hydrocarbon, halogenated hydrocarbon, nitrile, ether, aliphatic hydrocarbons solvents, polar aprotic solvents such as DMF and DMSO; wherein the mass-volume ratio of the compound of formula 1 to the solvent is 100 mg:(0.1-10 mL); wherein the acid is fumaric acid, hydrochloric acid, niacin, or maleic acid; and wherein the base is sodium hydroxide, potassium hydroxide, or meglumine.

32. (canceled)

33. The method for preparing the amorphous form XIV of the compound of formula 1 according to claim 18, wherein the method comprises: adding the compound of formula 1 to a solvent to obtain a solution, adding the obtained solution to an anti-solvent, and separating the obtained solid to obtain the amorphous form XIV of compound of formula 1; wherein the solvent is selected from one or more of ethyl acetate, acetone, tetrahydrofuran, acetonitrile, DMSO, 1,4-dioxane, MIBK, dichloromethane, and DMF; and wherein the anti-solvent is selected from one or more of heptane, ethanol, water, IPAc, IPA, butanol, and NPA.

34. A pharmaceutical composition comprising the crystalline or amorphous form of the compound of Formula 1 or its salt according to claim 1, and pharmaceutically acceptable excipients.

35. A method of treating a Bcl-2 or Bcl-xL disease, comprising administering the crystalline form or amorphous form of the compound of formula 1 or its salt according to claim 1 to a patient in need thereof.

36. The method of claim 35, wherein the Bcl-2 or Bcl-xL disease is selected from the group consisting of bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, prostate cancer, testicular cancer, genitourinary tract cancer, lymphatic system cancer, rectal cancer, Laryngeal cancer, pancreatic cancer, esophageal cancer, gastric cancer, gallbladder cancer, cervical cancer, thyroid cancer, skin cancer, hematopoietic tumors of the lymphatic system, including leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymph Tumor, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hair cell lymphoma, histiocytic lymphoma and Burketts lymphoma; hematopoietic tumors of the bone marrow line, including acute and chronic myelogenous leukemia, bone marrow Dysplasia syndrome, myelogenous leukemia and promyelocytic leukemia; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannoma; tumors of mesenchymal origin, Including fibrosarcoma, rhabdomyosarcoma and osteosarcoma; and other tumors, including melanoma, xeroderma pigmentosum, keratoacanthoma, seminoma, thyroid follicular carcinoma, teratoma, renal cell carcinoma (RCC), Myeloma, myelogenous and lymphoblastic leukemia, neuroblastoma and glioblastoma.

Description

DESCRIPTION OF THE DRAWINGS

[0134] FIG. 1 is the XPRD pattern of the crystalline form I of the fumarate salt of formula 1.

[0135] FIG. 2 is the MDSC chart of the crystalline form I of the fumarate salt of formula 1.

[0136] FIG. 3 is the XPRD pattern of the crystalline form II of the hydrochloride salt of formula 1.

[0137] FIG. 4 is the MDSC chart of the crystalline form II of the hydrochloride salt of formula 1.

[0138] FIG. 5 is the XPRD pattern of the crystalline form III of the Nicotinate of formula 1.

[0139] FIG. 6 is the MDSC chart of the crystalline form III of the Nicotinate of formula 1.

[0140] FIG. 7 is the XPRD pattern of the crystalline form IV of the sodium salt of formula 1.

[0141] FIG. 8 is the XPRD pattern of the crystalline form V of the potassium salt of formula 1.

[0142] FIG. 9 is the XPRD pattern of the crystalline form VI of formula 1.

[0143] FIG. 10 is the TGA diagram of the crystalline form VI of formula 1.

[0144] FIG. 11 is a DSC chart of the crystalline form VI of formula 1.

[0145] FIG. 12 is the XPRD pattern of the crystalline form VII of formula 1.

[0146] FIG. 13 is a DSC chart of the crystalline form VII of formula 1.

[0147] FIG. 14 is the XPRD pattern of the crystalline form VIII of formula 1.

[0148] FIG. 15 is the TGA diagram of the crystalline form VIII of formula 1.

[0149] FIG. 16 is a DSC chart of the crystalline form VIII of formula 1.

[0150] FIG. 17 is the XPRD pattern of the amorphous form IX of the adipate salt of formula 1.

[0151] FIG. 18 is the MDSC chart of the amorphous form IX of the adipate salt of formula 1.

[0152] FIG. 19 is the XPRD pattern of the fumarate amorphous form X of formula 1.

[0153] FIG. 20 is the MDSC chart of the fumarate amorphous form X of formula I.

[0154] FIG. 21 is the XPRD pattern of the amorphous form XI of the nicotinate of formula 1.

[0155] FIG. 22 is an MDSC chart of amorphous form XI of the nicotinate of formula 1.

[0156] FIG. 23 is the XPRD pattern of the amorphous form XII of the potassium salt of formula 1.

[0157] FIG. 24 is the MDSC chart of the amorphous form XII of the potassium salt of formula 1.

[0158] FIG. 25 is the XPRD pattern of the amorphous form XIII of the sodium salt of formula 1.

[0159] FIG. 26 is the MDSC chart of the amorphous form XIII of the sodium salt of formula 1.

[0160] FIG. 27 is the XPRD pattern of the amorphous form XIV of formula 1.

[0161] FIG. 28 is the MDSC chart of the amorphous form XIV of formula 1.

[0162] FIG. 29 is the TGA chart of the amorphous form XIV of formula 1.

[0163] FIG. 30 is the XPRD pattern of the amorphous form XV of the maleate salt of formula 1.

[0164] FIG. 31 is the MDSC chart of the amorphous form XV of the maleate salt of formula 1.

[0165] FIG. 32 is the TGA chart of the amorphous form XV of the maleate salt of formula 1.

[0166] FIG. 33 is the XPRD pattern of the amorphous form XVI of the meglumine salt of formula 1.

[0167] FIG. 34 is the MDSC chart of the amorphous form XVI of the meglumine salt of formula 1.

[0168] FIG. 35 is the TGA graph of the amorphous form XVI of the meglumine salt of formula 1.

SPECIFIC IMPLEMENTATION

Example

[0169] In the following examples, the experimental methods are completed according to conventional conditions or conventional test conditions, and the compounds used in the examples are obtained by commercially available or self-made methods.

Example 1: Preparation of Crystalline Form I of the Fumarate Salt of the Compound of Formula 1

[0170] Weigh 208 mg of the compound of formula 1, add 4.2 mL of acetonitrile to prepare an acetonitrile solution, weigh 1.2 mg of fumaric acid into a glass vial, add 0.2 mL of the above-prepared acetonitrile solution, and after stirring the solution for 24 hours, it is observed that the sample is turbid. Continue to stir overnight, centrifuge to obtain a supernatant solution, and slowly evaporate the supernatant at room temperature to obtain the fumarate crystalline form I of the compound of formula 1.

Example 2: Preparation of Crystalline Form II of the Hydrochloride Salt of the Compound of Formula 1

[0171] Weigh 212 mg of the compound of formula 1, add 5.2 mL of methanol to prepare a methanol solution, add 6.5 μL of concentrated hydrochloric acid aqueous solution to a glass vial, and add 0.2 mL of the above-prepared methanol solution to obtain a clear solution. The above clear solution was slowly volatilized at room temperature to obtain the crystalline form II of the hydrochloride salt of the compound of formula 1.

Example 3: Preparation of Crystalline Form III of Nicotinate of Formula 1

[0172] Weigh 213 mg of the compound of formula 1, add 4.2 mL of acetone/water (19/1, v/v) to prepare an acetone/water (19/1, v/v) solution, weigh 0.9 mg of niacin and add it to a glass vial, add 0.2 mL of the acetone/water (19/1, v/v) solution prepared above. After stirring the solution for 24 hours, it is observed that the sample is clear. Stirring is continued overnight, and the above liquid is slowly volatilized at room temperature to obtain the crystalline form III of nicotinate of formula 1.

Example 4: Preparation of Crystalline Form IV of the Sodium Salt of the Compound of Formula 1

[0173] Weigh 212 mg of the compound of formula 1 and add 5.2 mL of methanol to prepare a methanol solution. Weigh 0.54 mg of sodium hydroxide into a glass vial, add 0.2 mL of the methanol solution prepared above, and the solution is clear after stirring for 24 hours. The clear solution is slowly volatilized at room temperature to obtain the crystalline form IV of the sodium salt of the compound of formula 1

Example 5: Preparation of the Crystalline Form V of the Potassium Salt of the Compound of Formula 1

[0174] Weigh 208 mg of the compound of formula 1, add 4.2 mL of acetonitrile to prepare the acetonitrile solution of the compound of formula 1, weigh 0.4 mg of potassium hydroxide into a glass vial, add 0.2 mL of the above-prepared acetonitrile solution, and observe after stirring the solution for 24 hours When the solid precipitated, the sample was centrifuged after continuing to stir overnight, and the supernatant was placed at room temperature to slowly volatilize to obtain the crystalline form V of potassium salt of the compound of formula 1.

Example 6: Preparation of Crystalline Form VII of the Compound of Formula 1

[0175] Weigh 110 mg of the compound of formula 1, add 5.25 mL of ethyl acetate to prepare the ethyl acetate solution of the compound of formula 1, weigh 1.6 mg of L-malic acid into a glass vial, and add 0.75 mL of the prepared ethyl acetate solution. After the solution was stirred for 3 days, turbidity of the sample was observed, and the above sample was centrifuged to obtain the crystalline form VII of the compound of formula 1.

Example 7: Preparation of Crystalline Forms VIII of the Compound of Formula 1

[0176] In order to prepare the above crystalline form of the compound of formula 1, the crystallization process was screened as follows:

[0177] (1) Slow Volatilization Test of Compound of Formula 1

[0178] The slow volatilization test is carried out by selecting the compound of formula 1 and 8 different solvents or mixed solvents. In the experiment, weigh about 10 mg of the solid compound of formula 1 into a 1 mL glass bottle, add the corresponding solvent to dissolve to obtain a clear solution, then seal with Parafilm™ membrane and pierce 4 small holes with a needle, and place it at room temperature to slowly volatilize and crystallize. After the solid has precipitated, take out the solid to test XRPD (See Table 9).

TABLE-US-00009 TABLE 9 Experiment number Solvent temperature form 1 EtOAc Room temperature Amorphous formXIV 2 acetone Room temperature Amorphous XIV 3 THF Room temperature Amorphous XIV 4 Acetonitrile Room temperature Amorphous XIV 5 DCM Room temperature Amorphous XIV 6 MeOH Room temperature Amorphous XIV 7 THF/H.sub.2O (9/1, v/v) Room temperature Amorphous XIV 8 THF/acetone (9/1, v/v), Room temperature Amorphous fXIV Contains L-tartaric acid * * The molar ratio of compound to tartaric acid is 1:1.

[0179] (2) Suspension Stirring Test of Compound of Formula 1

[0180] The suspension stirring test selects the compound of formula 1 to be carried out under a variety of different conditions.

[0181] In the experiment, approximately 15 mg of the solid compound of formula 1 was weighed and placed in a 1 mL glass vial containing 0.5 mL of solvent, and the suspension was stirred at room temperature and 50° C. for 3 days. If there is precipitation, the solid is obtained after centrifugal separation and tested for XRPD. If there is no precipitation, use a slow volatilization method to precipitate solids (see Table 10).

TABLE-US-00010 TABLE 10 Experiment number Solvent temperature form 1 Heptane Room Crystal form VIII/Crystal form VIII temperature/50° C. 2 IPAc Room Amorphous XIV/_Amorphous XIV temperature/50° C. 3 IPA Room Amorphous XIV/Crystalline form VIII temperature/50° C. 4 EtOH Room Amorphous XIV/Crystalline form VIII temperature/50° C. 5 Butanol Room Amorphous XIV/Amorphous XIV temperature/50° C. 6 EtOAc/Heptane Room Crystalline form (1/19, v/v) temperature/50° C. VIII/Crystalline form VIII 7 EtOAc/IPA Room Amorphous XIV/Amorphous XIV (1/19, v/v) temperature/50° C. 8 Acetone/ Room Amorphous XIV/Crystalline form VIII Heptane(1/19, v/v) temperature/50° C. 9 Acetone/IPAc Room Amorphous XIV/Amorphous XIV (1/19, v/v) temperature/50° C. 10 Acetone/EtOH Room Amorphous XIV/Amorphous XIV (1/19, v/v) temperature/50° C. 11 Acetone/H.sub.2O Room Amorphous XIV/Crystal formVIII (1/19, v/v) temperature/50° C. 12 THF/Hexane Room Crystal form VIII/Crystal form VIII (1/19, v/v) temperature/50° C. 13 THF/IPAc Room Amorphous XIV/Amorphous XIV (1/19, v/v) temperature/50° C. 14 THF/H.sub.2O Room Amorphous XIV/Amorphous XIV (1/19, v/v) temperature/50° C. 15 THF/Butanol Room Amorphous XIV/Amorphous XIV (1/19, v/v) temperature/50° C. 16 Acetonitrile/IPAc Room Amorphous XIV/Amorphous XIV (1/19, v/v) temperature/50° C. 17 Acetonitrile/H.sub.2O Room Amorphous XIV/Crystal formVIII (1/19, v/v) temperature/50° C. 18 Acetonitrile/NPA Room Amorphous XIV/Amorphous XIV (1/19, v/v) temperature/50° C. 19 DMSO/IPAc Room Amorphous XIV/Amorphous XIV (1/19, v/v) temperature/50° C. 20 DMSO/EtOH Room Amorphous XIV/Amorphous XIV (1/19, v/v) temperature/50° C. 21 DMSO/H.sub.2O Room Amorphous XIV/Crystal form VIII (1/19, v/v) temperature/50° C. 22 MIBK/Heptane Room Crystal form VIII/Crystal form VIII (1/19, v/v) temperature/50° C. 23 MIBK/IPAc Room Amorphous XIV/Amorphous XIV (1/19, v/v) temperature/50° C. 24 MIBK/IPA Room Amorphous XIV/Amorphous XIV (1/19, v/v) temperature/50° C. 25 DCM/Heptane Room Crystal form VIII/Crystal form VIII (1/19) temperature/50° C. 26 DCM/IPAc Room Amorphous XIV/Amorphous XIV (1/19) temperature/50° C. 27 DCM/EtOH Room Amorphous XIV/Amorphous XIV (1/19) temperature/50° C. 28 pH = 1.0 Room temperature Amorphous XIV Buffer.sup.a 29 pH = 4.0 Room temperature Amorphous XIV Buffer.sup.b 30 pH = 6.8 Room temperature Amorphous XIV Buffer.sup.c .sup.aPreparation method: Pipette 50 mL of 0.2M potassium chloride solution into a 200-mL volumetric flask, add 134 mL of 0.2M hydrochloric acid solution, and mix well. Add purified water close to the graduation line and adjust the pH to 1.0. .sup.bPreparation method: Pipette 50 mL of 0.2M potassium hydrogen phthalate solution into a 200-mL volumetric flask, add 0.1 mL of 0.2M hydrochloric acid solution, and mix well. Add purified water close to the graduation line and adjust the pH to 4.0. .sup.cPreparation method: Pipette 25 mL of 0.2M potassium dihydrogen phosphate (KH2PO4) solution and 11.2 mL of 0.2M sodium hydroxide solution into a 100-mL volumetric flask. Add purified water close to the graduation line and adjust the pH to 6.8.

[0182] (3) The Reverse Anti-Solvent Addition Test of the Compound of Formula 1

[0183] The reverse anti-solvent addition experiment used the compound of formula 1 as the starting material and selected 19 different solvent/anti-solvent systems.

[0184] In the experiment, weigh about 15 mg of the compound of formula 1 and add 0.1-1.0 mL of the corresponding solvent to obtain a clear solution. The above solutions were added to 2.0 mL of anti-solvent under magnetic stirring conditions, and stirred at room temperature for 70 hours. If there is precipitation, the solid is obtained after centrifugal separation and tested for XRPD. If there is no precipitation, use a slow volatilization method to precipitate solids (see Table 11).

TABLE-US-00011 TABLE 11 Experiment number Solvent Anti-solvent form 1 EtOAc Heptane Amorphous XIV 2 EtOAc EtOH Amorphous XIV 3 acetone EtOH Amorphous XIV 4 acetone H.sub.2O Amorphous XIV 5 acetone IPAc Amorphous XIV 6 THF Heptane Crystal form VIII 7 THF IPA Amorphous XIV 8 Acetonitrile Butanol Amorphous XIV 9 Acetonitrile IPAc Amorphous XIV 10 DMSO IPA Amorphous XIV 11 DMSO IPAc Amorphous XIV 12 1,4-dioxane Heptane Amorphous XIV 13 1,4-dioxane IPA Amorphous XIV 14 1,4-dioxane H.sub.2O Amorphous XIV 15 MIBK EtOH Amorphous XIV 16 DCM Heptane Amorphous XIV 17 DCM IPAc Amorphous XIV 18 DMF H.sub.2O Amorphous XIV 19 DMF NPA Amorphous XIV

[0185] (4) Slow Cooling Test of Compound of Formula 1

[0186] The slow cooling test used the compound of formula 1 as the starting material, and a total of 9 different solvents or mixed solvents were selected. In the experiment, weigh about 15 mg of the compound of formula 1 into a 1 mL glass vial, and then add 0.6 mL of the corresponding solvent. All the obtained suspensions were placed in a 50° C. thermostat to equilibrate for 30 minutes. If the sample was dissolved, the solids were added continuously until a suspension at that temperature was obtained. Filter all the suspension with a syringe (filter membrane pore size is 0.45 μm), place the filtered clear filtrate in a 50° C. thermostat, and cool to 5° C. at a rate of 0.1° C./min. If there is precipitation, centrifuge to obtain a solid and test for XRPD. If there is no precipitation, use a slow volatilization method to precipitate solids (see Table 12).

TABLE-US-00012 TABLE 12 Experiment number Solvent Form 1 MeOH Amorphous XIV 2 EtOAc/Heptane (1/4, v/v) Oily 3 Acetonitrile/IPA (1/4, v/v) Amorphous XIV 4 MIBK/Hexane (1/4, v/v) Oily 5 acetone/H2O (1/4, v/v) Oily 6 THF/EtOH (1/4, v/v) Amorphous XIV 7 DCM/IPAc (1/4, v/v) Oily 8 1,4-Dioxane/EtOH (1/4, v/v) Amorphous XIV 9 DMF/IPA (1/4, v/v) Oily

[0187] (5) Gas Phase Permeation Test of Compound of Formula 1

[0188] The gas-phase permeation test uses the compound of formula 1 as the starting material, and a total of 2 different solvent/antisolvent systems are selected. In the experiment, weigh about 10 mg of the compound of formula 1 into a 3 mL glass vial, and add a solvent to dissolve it until it is clear. Take 3 mL of anti-solvent into a 20-mL glass bottle, put the 3 mL glass vial containing the sample solution into the 20 mL glass bottle, and close the bottle cap tightly. Observe the phenomenon after standing for one week. If there is a solid precipitation, the solid is obtained after centrifugal separation and XRPD test is performed. If there is no precipitation, use a slow volatilization method to precipitate solids. The results in Table 13 show that only Amorphous was obtained in the test.

TABLE-US-00013 TABLE 13 Experiment number Solvent Anti-solvent Form 1 1,4-Dioxane Heptane Amorphous XIV 2 DCM IPAc Amorphous XIV

[0189] (6) Gas-Solid Permeability Test of Compound of Formula 1

[0190] The gas-solid permeation test used the compound of formula 1 as the starting material, and a total of 3 different solvents were selected. In the experiment, weigh about 10 mg of the compound of formula 1 into a 3 mL glass vial, take 2 mL of the corresponding solvent into a 20 mL glass bottle, then put the 3 mL glass vial containing the sample into the 20 mL glass bottle, and close the bottle cap tightly. After standing for one week, observe the phenomenon, if there is solid, take it out for XRPD test. If the solid has been completely dissolved, the solid will be precipitated out using a slow volatilization method. The results in Table 14 show that only amorphous was obtained in the test.

TABLE-US-00014 TABLE 14 Experiment number Solvent Form 1 MeOH Amorphous XIV 2 EtOAc Amorphous XIV 3 Acetonitrile Amorphous XIV

[0191] The preparation methods of the crystalline forms VIII of the compound of formula 1 obtained through the above-mentioned crystal form screening experiment are as follows:

[0192] The crystalline form VIII of the compound of formula 1: Weigh 196 mg of the compound of formula 1, add 8 mL of tetrahydrofuran/n-hexane (1/19, v/v) mixed solvent, stir at 800 rpm at 50° C. for 48 hours, then centrifuge to obtain the crystalline form VIII of the compound of formula 1

Example 8: Optimization and Preparation Method of the Crystalline Form VI of the Compound of Formula 1

[0193] The crystalline form VI was found during the salt formation screening with fumaric acid, so the preparation method of the crystalline form VI of the compound of formula 1 is as follows:

[0194] The compound of formula 1 (15 mg) and fumaric acid (1.37 mg) at a molar ratio of 1:1 were suspended and stirred in 0.5 mL of methanol at room temperature to obtain the crystalline form VI of the compound of formula 1.

[0195] But the residual fumaric acid in the obtained crystalline form VI sample is difficult to remove, which affects the purity of the crystalline form VI. Therefore, this Example optimizes the preparation method of crystalline form VI. Table 15 is a summary of optimization experiments on the preparation method of crystalline form VI.

[0196] First of all, the method of adding anti-solvent is used instead of suspension stirring to realize the possibility of solid precipitation from a clear solution. Secondly, compared with methanol, acetone can dissolve the compound of formula 1 well without wall hanging, so the solvent containing acetone is selected as the positive solvent. In addition, it can be seen from the test results in Table 15 that the crystalline form VI can only be obtained in a solvent system containing methanol, and fumaric acid may not be added. Therefore, considering the simplicity of operation, the anti-solvent methanol was added dropwise to the acetone solution of the free base of the compound of formula 1 as an optimized method for preparing the crystalline form VI. Specifically, 100 mg of the compound of formula 1 was weighed and dissolved in 1.0 mL of acetone, and 5.0 mL of methanol was added dropwise under magnetic stirring (1000 rpm), stirred at room temperature for 48 hours, and centrifuged to obtain the crystalline form VI of compound of formula 1.

TABLE-US-00015 TABLE 15 Whether Experiment Anti- to add number Solvent solvent fumaric acid Form 1 acetone MeOH yes Crystal form VI 2 acetone MeOH No Crystal form VI 3 acetone Heptane yes Amorphous XIV 4 acetone Heptane No Amorphous XIV 5 acetone/MeOH Heptane yes Crystal form VI (1:1, v/v) 6 acetone/MeOH Heptane No Crystal form VI (1:1, v/v)

Example 9: Investigation on the Physicochemical Stability of the Crystalline Form VI of the Compound of Formula 1

[0197] After placing the crystalline form VI of formula 1 at 25° C./60% RH and 40° C./75% RH for one week, the purity and crystal form did not change significantly (See table 16), indicating that the crystalline form VI The physical and chemical properties are stable when stored for one week under the conditions of 25° C./60% RH and 40° C./75% RH.

TABLE-US-00016 TABLE 16 Crystal form VI (one week) Condition HPLC purity (Peak area %) Solid crystal form Initial sample 99.02 Crystal form VI 25° C./60% RH 99.01 Crystal form VI 40° C./75% RH 99.06 Crystal form VI

Example 10: Preparation of Amorphous Form IX of Adipate Compound of Formula 1

[0198] Weigh 195 mg of the compound of formula 1 and 22.6 mg of adipic acid, and add 2 mL of tetrahydrofuran/water (19/1, v/v). The above sample was stirred at room temperature for 3 days, and then centrifuged to separate solid and liquid. The supernatant was taken out and added with 2 mL of n-heptane for addition of the anti-solvent, and precipitated to obtain the Amorphous Form IX of the adipate compound of Formula 1

Example 11: Preparation of Amorphous Form X of Fumarate Compound of Formula 1

[0199] Weigh 21.0 mg of the compound of formula 1 and 1.6 mg of fumaric acid, add 0.2 mL of acetonitrile, stir the above sample at 5° C. for 2 days, then place it at −20° C. for 2 days, and precipitate to obtain the Amorphous Form X of Fumarate Compound of Formula 1

Example 12: Preparation of Amorphous Form XI of Nicotinate Compound of Formula 1

[0200] Weigh 209 mg of the compound of formula 1, add 4.2 mL of tetrahydrofuran/water (19/1, v/v) to prepare a tetrahydrofuran/water (19/1, v/v) solution, weigh 0.84 mg of niacin and add it to a glass vial, add 0.2 mL of the above-prepared tetrahydrofuran/water (19/1, v/v) solution. After stirring the solution for 24 hours, the sample is observed to be clear. Continue stirring overnight, and slowly evaporate the above liquid at room temperature to obtain the Amorphous Form XI of Nicotinate Compound of Formula 1.

Example 13: Preparation of Amorphous Form XII of the Potassium Salt of the Compound of Formula 1

[0201] Weigh 19.6 mg of the compound of formula 1, add 1.1 mg of potassium hydroxide and 0.2 mL of acetonitrile, stir the above sample at 5° C. for 2 days, then place it at −20° C. for 2 days, and precipitate to obtain the Amorphous form XII of the potassium salt of the compound of formula 1.

Example 14: Preparation of Amorphous Form XIII of Sodium Salt of the Compound of Formula 1

[0202] Weigh 19.8 mg of the compound of formula 1, add 0.8 mg sodium hydroxide and 0.2 mL acetonitrile. After stirring the above sample at 5° C. for 2 days, it was placed at −20° C. and allowed to stand for 2 days. The solid precipitated out to obtain the sodium salt Amorphous form XIII of the compound of formula 1.

Example 15: Preparation of Amorphous Form XIV of Compound of Formula 1

[0203] Weigh about 15 mg of the compound of formula 1, and add 0.1-1.0 mL of EtOAc to obtain a clear solution. The above solution was added to 2.0 mL of heptane under magnetic stirring, and stirred at room temperature for 70 hours. The precipitate is separated by centrifugation, and the Amorphous form XIV of the compound of formula 1 is obtained.

Example 16: Hygroscopicity Test of the Amorphous Form XIV of the Compound of Formula 1 (DVS)

[0204] Take about 10 mg of the Amorphous form XIV sample of the compound of formula I for dynamic water adsorption (DVS) test. The conclusions are described in Table 17 below:

TABLE-US-00017 TABLE 17 Name Moisture gain (80% RH) Amorphous XIV 4.83% (Hygroscopic)

[0205] The above results indicate that Amorphous samples easily absorb water during storage and need to be kept tightly closed.

Example 17: Stability Test of the Amorphous Form XIV of the Compound of Formula 1

[0206] Pack the amorphous sample with nitrogen, shading, and moisture-proof, and place it under 40° C., high humidity 92.5% RH, light conditions, and take samples at 0 days/5 days/10 days to investigate its content, related substances and crystal forms (light conditions: total illuminance ≥1.2×106 Lux.Math.hr, near ultraviolet energy ≥200 w.Math.hr/m2). The results are shown in Table 18.

TABLE-US-00018 TABLE 18 Condition Content(%) Total impurities(%) 0 Days 99.5 0.39 5 Days-high humidity 100.7 0.37 5 Days-light 100.4 0.43 5 Days-40° C. 100.3 0.59 10 Days-high humidity 99.7 0.39 10 Days-light 100.1 0.41 10 Days-40° C. 99.7 0.64

[0207] The results show that the amorphous sample is packed with nitrogen, shading, and moisture-proof, and is stable under high humidity and light conditions; but it is sensitive to heat and needs to be stored at low temperature and protected from light.

Example 18: Polymorphic Screening Test of the Potassium Salt of the Compound of Formula 1

[0208] Weigh about 50 mg of the potassium salt amorphous form XII into a 4 mL glass bottle, and gradually add 0.4 mL of a single or mixed solvent (see Table 19) to prepare a suspension sample in the glass bottle, and add the magnets at 40° C. After stirring for 3 days, it was centrifuged, and the remaining solid was dried in a vacuum drying oven at 25° C.

TABLE-US-00019 TABLE 19 Experiment Number Solvent Form — Initial form Amorphous XII 1 Methanol Basically Amorphous XII 2 Ethanol Amorphous XII 3 Acetonitrile Amorphous XII 4 Acetone Amorphous XII 5 Ethyl acetate Amorphous XII 6 Tetrahydrofuran Oily 7 n-Heptane Amorphous XII 8 1,4-Dioxane Amorphous XII 9 Water Amorphous XII 10 Methanol:Water 3:1(v:v) Amorphous XII 11 Ethanol:Water 3:1(v:v) Amorphous XII 12 Acetonitrile:Water 1:1(v:v) Amorphous XII 13 Acetone:Water 1:2(v:v) Amorphous XII

Example 19: Polymorph Screening Test of the Sodium Salt of the Compound of Formula 1

[0209] Weigh about 50 mg of the sodium salt amorphous form XIII into a 4 mL glass bottle, and gradually add 0.4 mL of a single or mixed solvent (see Table 20) to prepare a suspension sample in the glass bottle. After adding the magnet, it is heated at 40° C. After stirring for 3 days, it was centrifuged, and the remaining solid was dried in a vacuum drying oven at 25° C.

TABLE-US-00020 TABLE 20 Experiment Number Solvent Form — Initial form Amorphous XIII 1 Methanol Basically Amorphous XIII 2 Ethanol Amorphous XIII 3 Acetonitrile Amorphous XIII 4 Acetone Oily 5 Ethyl acetate Amorphous XIII 6 Tetrahydrofuran Oily 7 n-Heptane Amorphous XIII 8 1,4-Dioxane Oily 9 Water Amorphous XIII 10 Methanol:Water 3:1(v:v) Amorphous XIII 11 Ethanol:Water 3:1(v:v) Amorphous XIII 12 Acetonitrile:Water 1:1(v:v) Amorphous XIII

Example 20: Preparation of the Amorphous Form XV of the Maleate Salt of the Compound of Formula 1

[0210] Weigh 19.2 g of the compound of formula 1 and place it in a 40 mL glass bottle, add 30 mL of acetone for ultrasonic solubilization, add a magnet and stir on a stirrer, then add 19.2 g of maleic acid. After stirring overnight at room temperature, it becomes slightly turbid. After adding 20 mL of n-hexane, a precipitate was precipitated. After stirring overnight, the amorphous form XV of the maleate salt of the compound of formula 1 was obtained after centrifugal separation.

Example 21: Polymorphic Screening Test of Maleate Compound of Formula 1

[0211] Weigh about 50 mg of the maleate amorphous form XV into a 4 mL glass bottle, and gradually add 0.4 mL of a single or mixed solvent (see Table 21) to prepare a suspension sample in the glass bottle. After adding the magnet after stirring for 3 days at 40° C., it was centrifuged, and the remaining solid was placed in a vacuum drying oven at 25° C. to dry.

TABLE-US-00021 TABLE 21 Experiment Number Solvent Form — Initial form Amorphous XV 1 Methanol Crystal form VI 2 Ethanol Amorphous XV 3 Acetonitrile Amorphous XV 4 Acetone Oily 5 Ethyl acetate Amorphous XV 6 Tetrahydrofuran Mixed with maleic acid 7 n-Heptane Amorphous XV 8 1,4-Dioxane Mixed with maleic acid 9 Water Amorphous XV 10 Methanol:Water 3:1(v:v) Amorphous XV 11 Ethanol:Water 3:1(v:v) Amorphous XV 12 Acetonitrile:Water 1:1(v:v) Amorphous XV 13 Acetone:Water 1:2(v:v) Amorphous XV

Example 22: Preparation of the Amorphous Form XVI of the Meglumine Salt of the Compound of Formula 1

[0212] Weigh 19.2 g of the compound of formula 1 and place it in a 40 mL glass bottle, add 30 mL of acetone for ultrasonic solubilization, add a magnet and stir on a stirrer, and then add 19.2 g of meglumine. After stirring overnight at room temperature, it becomes slightly turbid. After adding 30 mL of n-hexane, a precipitate was precipitated. After stirring overnight, the amorphous form XVI of the meglumine salt of the compound of formula 1 was obtained after centrifugal separation.

Example 23: Polymorph Screening Test of Meglumine Salt of the Compound of Formula 1

[0213] (1) Weigh about 50 mg of the amorphous form of meglumine salt XVI in a 4 mL glass bottle, and gradually add 0.4 mL of single or mixed solvent (see Table 22) to prepare a suspension sample in the glass bottle, and add magnet After the seeds were stirred at 40° C. for 3 days and then centrifuged, the remaining solid was placed in a vacuum drying oven at 25° C. to dry.

TABLE-US-00022 TABLE 22 Experiment Number Solvent Form — Initial form Amorphous XVI 1 Methanol Amorphous XVI 2 Ethanol Amorphous XVI 3 Acetonitrile Amorphous XVI 4 Acetone Oily 5 Ethyl acetate Oily 6 Tetrahydrofuran Oily 7 n-Heptane Amorphous XVI 8 1,4-Dioxane Oily 9 Water Amorphous XVI 10 Methanol:Water 3:1(v:v) Amorphous XVI 11 Ethanol:Water 3:1(v:v) Amorphous XVI 12 Acetonitrile:Water 1:1(v:v) Amorphous XVI 13 Acetone:Water 1:2(v:v) Amorphous XVI

[0214] (2) Weigh about 50 mg of meglumine salt amorphous form XVI in a 1.5 mL glass bottle, and gradually add 0.3 mL of single or mixed solvent (see Table 23) to prepare a suspension sample in the glass bottle, and add magnet After the seeds were stirred at room temperature for 3 days and then centrifuged, the remaining solid was placed in a vacuum drying oven at 25° C. to dry.

TABLE-US-00023 TABLE 23 Experiment Number Solvent Form — Initial form Amorphous XVI 1 Isopropanol Amorphous XVI 2 N-Butanol Amorphous XVI 3 Isopropyl acetate Amorphous XVI 4 Methyl tert-butyl ether Amorphous XVI 5 N-heptane Basically Amorphous XVI 6 Cyclohexane Amorphous XVI 7 N-heptane-ethanol (1:1, v:v) Amorphous XVI 8 N-heptane-ethyl acetate Amorphous XVI (1:1, v:v) 9 N-heptane-tetrahydrofuran Basically Amorphous XVI (9:1, v:v) 10 N-Heptane-Acetone (9:1, v:v) Amorphous XVI 11 N-heptane-dichloromethane Basically Amorphous XVI (9:1, v:v) 12 Cyclohexane-methanol Amorphous XVI (9:1, v:v) 13 Cyclohexane-acetonitrile Amorphous XVI (1:1, v:v) 14 Cyclohexane-N- Amorphous XVI methylpyrrolidone (9:1, v:v) 15 Cyclohexane-1,4-dioxane Amorphous XVI (9:1, v:v)

[0215] (3) Weigh about 30 mg of meglumine salt amorphous form XVI in a 1.5 mL glass bottle, gradually add the corresponding solvent (see Table 24) to dissolve it, and then filter it with a 0.22 μm organic filter membrane into a rinsed glass bottle, seal it with aluminum foil paper, pierce the hole, and place it at room temperature to evaporate slowly.

TABLE-US-00024 TABLE 24 Experiment Number Solvent Form — Initial form Amorphous XVI 1 Methanol/2 mL Amorphous XVI 2 Acetone/2 mL Amorphous XVI 3 Dichloromethane/2 mL Amorphous XVI 4 Tetrahydrofuran/2 mL Amorphous XVI 5 2-methyltetrahydrofuran/4 mL Amorphous XVI

[0216] (4) Weigh about 30 mg of meglumine salt amorphous form XVI in an 8 mL glass bottle, first add a good solvent (see Table 25) to dissolve it, and then gradually add 5 mL of anti-solvent n-heptane to obtain a suspension After centrifugation, the residual solid of the sample was dried in a vacuum drying oven at 25° C.

TABLE-US-00025 TABLE 25 Number Solvent Form 1 Dichloromethane/0.2 mL Amorphous XVI 2 Methanol/0.3 mL Amorphous XVI 3 Tetrahydrofuran/0.2 mL Amorphous XVI 4 2-methyltetrahydrofuran/0.5 mL Amorphous XVI 5 Dimethyl sulfoxide/0.2 mL Amorphous XVI 6 N-methylpyrrolidone/0.2 mL Amorphous XVI

Example 24: Stability Test of Salt Form Screening

[0217] Take an appropriate amount of the compound into an 8 mL glass bottle, and then place it at room temperature (25° C., open), high humidity (room temperature/75% RH, open) and light (room temperature, white light: 6980 lux, UV 282 μW/cm2). Take samples for testing on the 5th, 10th, and 30th day (HPLC, XRPD).

TABLE-US-00026 TABLE 26 Total impurities (%) Amorphous Amorphous Amorphous Amorphous Test form XII of form XIII of form XV of form XVI of conditions Time potassium salt sodium salt maleate salt meglumine salt Initial 0 Days 1.40 1.65 0.73 0.83 25° C. 5 Days 1.63 1.89 0.79 0.95 R.T./75% RH 2.25 2.45 1.59 1.36 Light 2.09 2.20 1.33 1.33 25° C. 10 Days 1.58 1.94 0.89 0.89 R.T./75% RH 2.98 3.08 2.59 1.86 Light 2.69 3.55 1.94 1.74 25° C. 30 Days 1.86 2.29 1.23 0.88 R.T./75% RH 6.11 6.31 7.00 4.95

[0218] The results showed that the XRPD of the salt form was unchanged under the above conditions.

Example 25: Identification and Characterization of Compound Form I-XVI of Formula 1

[0219] The instruments used and their parameters are as follows:

[0220] 1. XPRD—X-Ray Powder Diffraction

TABLE-US-00027 X Rays Cu, kα, Kα1 (Å): 1.540598, Cu, Kα, Kα2 (Å): 1.544426 Kα2/Kα1 Intensity ratio: 0.50 X-ray tube setting 45 kV, 40 mA Divergent slit automatic Scan mode continuous Scan range (°2Theta) 3°-40° Scan step (°2Theta) 0.013 Scan rate (°/min) about 10

[0221] 2. Differential Scanning Calorimetry (DSC)

[0222] Instrument: TA Q200/Q2000 differential scanning calorimeter provided by TA Instruments

[0223] Test method: The sample is placed in an aluminum pan, and the temperature is increased from room temperature to the set temperature at a rate of 10° C./min under N.sub.2 protection after pressing the lid.

[0224] 3. Modulation Differential Scanning Calorimetry (MDSC)

[0225] Instrument: TA Q200/Q2000 differential scanning calorimeter provided by TA Instruments

[0226] Measurement method: The sample is placed in an aluminum pan, and after pressing the cover, it is heated from room temperature to the set temperature at a rate of 10° C./min under the protection of N2, and then kept at a constant temperature for 10 minutes, and then cooled to 35° C. at a rate of 15° C./min. The temperature is raised to the specified temperature with a heating rate of 3° C./min, a modulation period of 60 s, and a modulation amplitude of ±1° C.

[0227] 4. Thermogravimetric Analysis (TGA)

[0228] Instrument: TA Q500/Q5000 thermogravimetric analyzer provided by TA Instruments

[0229] Measurement method: The sample is placed in an alloy pan, and the opening is heated from room temperature to the set temperature at a rate of 10° C./min under the protection of N.sub.2.

[0230] For the identification and characterization results of XPRD, TGA and (M)DSC, please refer to FIG. 1-35, Table 1-8 and related text description.

[0231] Each reference, including all patents, patent applications, and publications cited in this application, is incorporated herein by reference in its entirety, as if each of them were individually incorporated. In addition, it will be understood that in the above teachings of the present invention, those skilled in the art can make certain changes or modifications to the present invention, and these equivalents will still fall within the scope of the present invention defined by the appended claims of the application.