THE CRYSTALLINE FORMS OR AMORPHOUS FORMS OF BISDIAZABICYCLIC COMPOUNDS OR SALTS THEREOF

Abstract

Crystallines form or amorphous forms of bisdiazabicyclic compounds or salts thereof for the treatment and/or prevention of diseases or disorders related to hepatitis virus, and a preparation method and application thereof are provided. The crystalline forms or amorphous forms involved provide important reference value for the development and utilization of drugs in the future.

Claims

1. The crystalline forms or amorphous forms of the compound 1 or its salts: ##STR00003##

2. The form according to claim 1, which is the crystalline form I of compound 1, which has characteristic peaks at the following positions in the XRPD pattern represented by angles 2θ: 7.93±0.2°, 9.60±0.2°, 11.27±0.2°, 15.73±0.2°, 18.63±0.2° and 19.22±0.2°; optionally, which also has one or more characteristic peaks at the following positions in the XRPD pattern represented by angles 2θ:11.92±0.2°, 12.52±0.2° and 16.72±0.2°; or which is the crystalline form II of the compound 1, which has characteristic peaks at the following positions in the XRPD pattern represented by angles 2θ: 5.80±0.2° and 7.68±0.2°; or which is the crystalline form III of compound 1, which has characteristic peaks at the following positions in the XRPD pattern represented by angles 2θ: 7.83±0.2°, 9.78±0.2°, 11.78±0.2°, 19.32±0.2° and 19.68±0.2°; or which is the amorphous form IV of the compound 1 monohydrochloride, has the XRPD pattern substantially as shown in FIG. 10, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 7.9±0.2% by weight before 150° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 184.6±2.0° C.; 3) the TGA plot substantially as shown in FIG. 11; and/or 4) the mDSC curve substantially as shown in FIG. 12; or which is the amorphous form VI of the compound 1 sulfate, has the XRPD pattern substantially as shown in FIG. 16, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 9.6±0.2% by weight before 150° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 207.2±2.0° C.; 3) the TGA plot substantially as shown in FIG. 17; and/or 4) the mDSC curve substantially as shown in FIG. 18; or which is the amorphous form VII of the compound 1 phosphate, has the XRPD pattern substantially as shown in FIG. 19, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 4.5±0.2% by weight before 150° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 176.0±2.0° C.; 3) the TGA plot substantially as shown in FIG. 20; and/or 4) the mDSC curve substantially as shown in FIG. 21; or which is the amorphous form VIII of the compound 1 mesylate, has the XRPD pattern substantially as shown in FIG. 22, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 5.2±0.2% by weight before 150° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 172.7±2.0° C.; 3) the TGA plot substantially as shown in FIG. 23; and/or 4) the mDSC curve substantially as shown in FIG. 24; or which is the amorphous form IX of the compound 1 maleate, has the XRPD pattern substantially as shown in FIG. 25, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 3.7±0.2% by weight before 150° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 163.6±2.0° C.; 3) the TGA plot substantially as shown in FIG. 26; and/or 4) the mDSC curve substantially as shown in FIG. 27; or which is the amorphous form X of the compound 1 tartrate, has the XRPD pattern substantially as shown in FIG. 28, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 8.3±0.2% by weight before 150° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 163.9±2.0° C.; 3) the TGA plot substantially as shown in FIG. 29; and/or 4) the mDSC curve substantially as shown in FIG. 30; or which is the amorphous form XI of the compound 1 benzoate, has the XRPD pattern substantially as shown in FIG. 31, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 9.1±0.2% by weight before 150° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 143.8±2.0° C.; 3) the TGA plot substantially as shown in FIG. 32; and/or 4) the mDSC curve substantially as shown in FIG. 33; or which is the amorphous form XII of the compound 1 succinate, has the XRPD pattern substantially as shown in FIG. 34, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 3.5±0.2% by weight before 150° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 138.9±2.0° C.; 3) the TGA plot substantially as shown in FIG. 35; and/or 4) the mDSC curve substantially as shown in FIG. 36; or which is the amorphous form XIII of the compound 1 acetate, has the XRPD pattern substantially as shown in FIG. 37, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 8.0±0.2% by weight before 150° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 137.9±2.0° C.; 3) the TGA plot substantially as shown in FIG. 38; and/or 4) the mDSC curve substantially as shown in FIG. 39; or which is the amorphous form XV of the compound 1 mono-p-toluenesulfonate, has the XRPD pattern substantially as shown in FIG. 43, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 2.55±0.2% by weight before 127° C.; and a weight loss of 2.51±0.2% by weight between 127° C. and 222° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 150.82±2.0° C.; 3) the TGA plot substantially as shown in FIG. 44; and/or 4) the mDSC curve substantially as shown in FIG. 45; or which is the amorphous form XVI of the compound 1 di-p-toluenesulfonate, has the XRPD pattern substantially as shown in FIG. 46, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 2.97±0.2% by weight before 125° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 168.02±2.0° C.; 3) the TGA plot substantially as shown in FIG. 47; and/or 4) the mDSC curve substantially as shown in FIG. 48; or which is the amorphous form XVII of the compound 1 diphosphate, has the XRPD pattern substantially as shown in FIG. 49, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 1.46±0.2% by weight before 140° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 177.83±2.0° C.; 3) the TGA plot substantially as shown in FIG. 50; and/or 4) the mDSC curve substantially as shown in FIG. 51; or which is the crystalline form XVIII of compound 1 dimethanesulfonate, which has at least one or two characteristic peaks at the following positions in the XRPD pattern represented by angles 2θ: 3.94±0.2°, 5.53±0.2°, 11.45±0.2°, 15.25±0.2°, 20.51±0.2°;

3-8. (canceled)

9. The form according to claim 1, which is the amorphous form V of the compound 1 dihydrochloride, has the XRPD pattern substantially as shown in FIG. 13, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 6.6±0.2% by weight before 150° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 213.0±2.0° C.; 3) the TGA plot substantially as shown in FIG. 14; and/or 4) the mDSC curve substantially as shown in FIG. 15.

10-17. (canceled)

18. The form according to claim 1, which is the amorphous form XIV of the compound 1, has the XRPD pattern substantially as shown in FIG. 40, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 4.2±0.2% by weight before 130° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 145.2±2.0° C.; 3) the TGA plot substantially as shown in FIG. 41; and/or 4) the mDSC curve substantially as shown in FIG. 42.

19-23. (canceled)

24. The form according to claim 1, which is the amorphous form XIX of the compound 1 monooxalate, has the XRPD pattern substantially as shown in FIG. 55, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 3.63±0.2% by weight before 105° C.; and a weight loss of 10.4±0.2% by weight between 105° C. and 242° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 100.62±2.0° C.; 3) the TGA plot substantially as shown in FIG. 56; and/or 4) the mDSC curve substantially as shown in FIG. 57.

25. The form according to claim 1, which is the amorphous form XX of the compound 1 dioxalate, has the XRPD pattern substantially as shown in FIG. 58, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 3.52±0.2% by weight before 122° C.; and a weight loss of 11.6±0.2% by weight between 122° C. and 236° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 97.8±2.0° C.; 3) the TGA plot substantially as shown in FIG. 59; and/or 4) the mDSC curve substantially as shown in FIG. 60.

26. The form according to claim 1, which is the amorphous form XXI of the compound 1 dimaleate, has the XRPD pattern substantially as shown in FIG. 61, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 2.29±0.2% by weight before 117° C.; and a weight loss of 8.33±0.2% by weight between 117° C. and 216° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 142.29±2.0° C.; 3) the TGA plot substantially as shown in FIG. 62; and/or 4) the mDSC curve substantially as shown in FIG. 63.

27. The form according to claim 1, which is the amorphous form XXII of the compound 1 ditartrate, has the XRPD pattern substantially as shown in FIG. 64, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 3.14±0.2% by weight before 127.5° C.; and a weight loss of 15.15±0.2% by weight between 127.5° C. and 272.5° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 155.97±2.0° C.; 3) the TGA plot substantially as shown in FIG. 65; and/or 4) the mDSC curve substantially as shown in FIG. 66.

28. The form according to claim 1, which is the amorphous form XXIII of the compound 1 disulfate, has the XRPD pattern substantially as shown in FIG. 67, and optionally has the following characteristics: 1) In the TGA plot, there is a weight loss of 4.77±0.2% by weight before 100° C.; 2) In the mDSC curve, there is a glassy transition temperature at the midpoint temperature of 174.60±2.0° C.; 3) the TGA plot substantially as shown in FIG. 68; and/or 4) the mDSC curve substantially as shown in FIG. 69.

29. The method for preparing the crystalline form of the compound 1 according to claim 1, which comprises the following steps: mixing the compound 1 with a solvent, suspending and stirring at room temperature −50° C., optionally adding the seed crystal of the corresponding crystalline form, the obtained solid is separated and dried, thereby obtaining the crystalline form of the compound 1; and/or the mass-volume ratio of the compound 1 to the solvent is 100 mg: (0.1-10 mL).

30. The preparation method according to claim 29, wherein the solvent is selected from a mixed solvent of IPA/H2O or a mixed solvent of THF/n-heptane.

31. The method for preparing the crystalline form of the compound 1 according to claim 1, which comprises the following steps: mixing the compound 1 with a solvent and an acid, and suspending and stirring at room temperature-50° C., separating the obtained solid, thereby obtaining the amorphous form of the salt of the compound of 1; and/or the mass-volume ratio of the compound 1 to the solvent is 100 mg: (0.1-10 mL).

32. The preparation method according to claim 31, wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, maleic acid, tartaric acid, benzoic acid, succinic acid and acetic acid.

33. The method for preparing the crystalline form of the compound 1 according to claim 1, which comprises the steps of: mixing the compound 1 with a solvent and an acid, separating the resulting solid and drying, thereby the crystalline form of the salt of the compound 1 is obtained; and/or the mass-volume ratio of the compound 1 to the solvent is 100 mg: (0.1-10 mL).

34. The preparation method according to claim 33, wherein the acid is selected from methanesulfonic acid.

35. The method for preparing the amorphous form XIV of the compound 1 according to claim 18, which comprises the following steps: mixing the compound 1 with a solvent to form a solution, and then adding an anti-solvent to the solution to separate the resulting solid, the amorphous form XIV of the compound 1 is thus obtained; optionally the solvent is selected from one or more of ethanol, acetone, IPA, 2-MeTHF, dichloromethane, 1,4-dioxane, THF, DMSO and/or the anti-solvent is selected from one or more of IPAc, MTBE, heptane, toluene, and water.

36. A pharmaceutical composition, which comprising the crystalline form or amorphous form of the compound 1 or its salts, according to claim 1 and pharmaceutically acceptable excipients.

37. A method of preventing and/or treating diseases or disorders related to hepatitis virus, comprising administering a patient in need thereof a therapeutically effective amount of the crystalline form or amorphous form of the compound 1 or its salts according to claim 1.

38. The use according to claim 37, wherein the diseases or disorders related to hepatitis virus is a disease or condition related to hepatitis A virus, hepatitis B virus or hepatitis C virus, preferably, the diseases or conditions is selected from hepatitis A, hepatitis B, hepatitis C and liver cirrhosis

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0221] FIG. 1 is an XRPD pattern of Compound 1 crystalline Form I.

[0222] FIG. 2 is a TGA plot of Compound 1 crystalline Form I.

[0223] FIG. 3 is a DSC curve of Compound 1 crystalline Form I.

[0224] FIG. 4 is an XRPD pattern of Compound 1 crystalline Form II.

[0225] FIG. 5 is a TGA plot of Compound 1 crystalline Form II.

[0226] FIG. 6 is a DSC curve of Compound 1 crystalline Form II.

[0227] FIG. 7 is an XRPD pattern of Compound 1 crystalline Form III.

[0228] FIG. 8 is a TGA plot of Compound 1 crystalline Form III.

[0229] FIG. 9 is a DSC curve of Compound 1 crystalline Form III.

[0230] FIG. 10 is an XRPD pattern of Compound 1 monohydrochloride amorphous Form IV.

[0231] FIG. 11 is a TGA plot of Compound 1 monohydrochloride amorphous Form IV.

[0232] FIG. 12 is a mDSC curve of Compound 1 monohydrochloride amorphous Form IV.

[0233] FIG. 13 is an XRPD pattern of Compound 1 dihydrochloride amorphous form V.

[0234] FIG. 14 is a TGA plot of Compound 1 dihydrochloride amorphous form V.

[0235] FIG. 15 is a mDSC curve of Compound 1 dihydrochloride amorphous form V.

[0236] FIG. 16 is an XRPD pattern of Compound 1 sulfate amorphous form VI.

[0237] FIG. 17 is a TGA plot of Compound 1 sulfate amorphous form VI.

[0238] FIG. 18 is a mDSC curve of Compound 1 sulfate amorphous form VI.

[0239] FIG. 19 is an XRPD pattern of Compound 1 phosphate amorphous Form VII.

[0240] FIG. 20 is a TGA plot of Compound 1 phosphate amorphous Form VII.

[0241] FIG. 21 is a mDSC curve of Compound 1 phosphate amorphous Form VII.

[0242] FIG. 22 is an XRPD pattern of Compound 1 mesylate amorphous form VIII.

[0243] FIG. 23 is a TGA plot of Compound 1 mesylate amorphous form VIII.

[0244] FIG. 24 is a mDSC curve of Compound 1 mesylate amorphous form VIII.

[0245] FIG. 25 is an XRPD pattern of Compound 1 maleate amorphous form IX.

[0246] FIG. 26 is a TGA plot of Compound 1 maleate amorphous form IX.

[0247] FIG. 27 is a mDSC curve of Compound 1 maleate amorphous form IX.

[0248] FIG. 28 is an XRPD pattern of Compound 1 tartrate amorphous form X.

[0249] FIG. 29 is a TGA plot of Compound 1 tartrate amorphous form X.

[0250] FIG. 30 is a mDSC curve of Compound 1 tartrate amorphous form X.

[0251] FIG. 31 is an XRPD pattern of Compound 1 benzoate amorphous Form XI.

[0252] FIG. 32 is a TGA plot of Compound 1 benzoate amorphous Form XI.

[0253] FIG. 33 is a mDSC curve of Compound 1 benzoate amorphous Form XI.

[0254] FIG. 34 is an XRPD pattern of Compound 1 succinate amorphous form XII.

[0255] FIG. 35 is a TGA plot of Compound 1 succinate amorphous form XII.

[0256] FIG. 36 is a mDSC curve of Compound 1 succinate amorphous form XII.

[0257] FIG. 37 is an XRPD pattern of Compound 1 acetate amorphous Form XIII.

[0258] FIG. 38 is a TGA plot of Compound 1 acetate amorphous Form XIII.

[0259] FIG. 39 is a mDSC curve of Compound 1 acetate amorphous Form XIII.

[0260] FIG. 40 is an XRPD pattern of Compound 1 amorphous Form XIV.

[0261] FIG. 41 is a TGA plot of Compound 1 amorphous Form XIV

[0262] FIG. 42 is a mDSC curve of Compound 1 amorphous Form XIV.

[0263] FIG. 43 is an XRPD pattern of Compound 1 P-toluenesulfonate amorphous Form XV.

[0264] FIG. 44 is a TGA plot of Compound 1 P-toluenesulfonate amorphous Form XV

[0265] FIG. 45 is a mDSC curve of Compound 1 P-toluenesulfonate amorphous Form XV.

[0266] FIG. 46 is an XRPD pattern of Compound 1 di-p-toluenesulfonate amorphous Form XVI.

[0267] FIG. 47 is a TGA plot of Compound 1 di-p-toluenesulfonate amorphous Form XVI

[0268] FIG. 48 is a mDSC curve of Compound 1 di-p-toluenesulfonate amorphous Form XVI.

[0269] FIG. 49 is an XRPD pattern of Compound 1 diphosphate amorphous Form XVII.

[0270] FIG. 50 is a TGA plot of Compound 1 diphosphate amorphous Form XVII.

[0271] FIG. 51 is a mDSC curve of Compound 1 diphosphate amorphous Form XVII.

[0272] FIG. 52 is an XRPD pattern of Compound 1 dimethanesulfonate crystalline Form XVIII.

[0273] FIG. 53 is a TGA plot of Compound 1 dimethanesulfonate crystalline Form XVIII.

[0274] FIG. 54 is a mDSC curve of Compound 1 dimethanesulfonate crystalline Form XVIII.

[0275] FIG. 55 is an XRPD pattern of Compound 1 oxalate amorphous Form XIX.

[0276] FIG. 56 is a TGA plot of Compound 1 oxalate amorphous Form XIX.

[0277] FIG. 57 is a mDSC curve of Compound 1 oxalate amorphous Form XIX.

[0278] FIG. 58 is an XRPD pattern of Compound 1 dioxalate amorphous Form XX.

[0279] FIG. 59 is a TGA plot of Compound 1 dioxalate amorphous Form XX.

[0280] FIG. 60 is a mDSC curve of Compound 1 dioxalate amorphous Form XX.

[0281] FIG. 61 is an XRPD pattern of Compound 1 dimaleate amorphous Form XXI.

[0282] FIG. 62 is a TGA plot of Compound 1 dimaleate amorphous Form XXI.

[0283] FIG. 63 is a mDSC curve of Compound 1 dimaleate amorphous Form XXI.

[0284] FIG. 64 is an XRPD pattern of Compound 1 ditartrate amorphous Form XXII.

[0285] FIG. 65 is a TGA plot of Compound 1 ditartrate amorphous Form XXII

[0286] FIG. 66 is a mDSC curve of Compound 1 ditartrate amorphous Form XXII.

[0287] FIG. 67 is an XRPD pattern of Compound 1 disulfate amorphous Form XXIII.

[0288] FIG. 68 is a TGA plot of Compound 1 disulfate amorphous Form XXIII.

[0289] FIG. 69 is a mDSC curve of Compound 1 disulfate amorphous Form XXIII.

DETAILED DESCRIPTION OF THE INVENTION

Examples

[0290] In the following examples, the experimental methods are completed in accordance with conventional conditions or conventional test conditions, and the compounds used in the examples are commercially available or self-made.

Example 1—Screening and Preparation Experiment of the Crystalline Form of the Compound 1

[0291] The following different experimental methods were used to screen the possible crystalline forms of the compound 1.

[0292] 1.1 Anti-Solvent Addition Experiment of Compound 1

[0293] A total of 16 anti-solvent addition experiments were set up with different solvents. Approximately 15 mg of the compound 1 was weighed into a 20 mL vial, and the solid was dissolved completely with 0.2-2.0 mL of solvent. The anti-solvent was added dropwise to the clear solution while stirring (1000 rpm) until solids were precipitated, or when the total volume of anti-solvent was added to 15 mL, the sample without solids precipitated was suspended and stirred at 5° C. If there was still no solid precipitation, suspended and stirred at −20° C. The clear sample evaporated at room temperature. The precipitated solids were separated and tested by XRPD. The results are shown in Table 5.

TABLE-US-00005 TABLE 5 Test Number Solvent Anti-solvent Solid Form 1 EtOH IPAc Amorphous Form* 2 Acetone Amorphous Form* 3 IPA MTBE Amorphous Form* 4 2-MeTHF Amorphous Form# 5 DCM Amorphous Form 6 1,4-dioxane n-heptane Amorphous Form* 7 THF Amorphous Form 8 DCM Amorphous Form 9 IPA Amorphous Form 10 IPA/IPAc(1:9) Amorphous Form 11 Acetone Amorphous Form* 12 IPA Toluene Amorphous Form* 13 DCM Amorphous Form* 14 IPA H.sub.2O Amorphous Form 15 DMSO Amorphous Form 16 1,4-dioxane Amorphous Form* Notes: Amorphous* was obtained by stirring at −20° C., and amorphous# was obtained by stirring at 5° C.

[0294] 1.2 Slow Evaporation Experiment of Compound 1

[0295] A total of 8 slow evaporation tests were set up with different solvent systems. Approximately 15 mg of the compound 1 was weighed and added into a 3-mL vial, 0.2-1.6 mL of solvent was added to dissolve (the undissolved sample was filtered with a 0.45 μm PTFE filter) respectively, and the vial was sealed with Parafilm® sealing film. Pierce 5 pinholes on it, and place it at room temperature to evaporate slowly. The obtained solid was collected for XRPD test. The results are shown in Table 6.

TABLE-US-00006 TABLE 6 Test Number Solvent Solid Form 1 MeOH Amorphous Form 2 Acetone Amorphous Form 3 IPA Amorphous Form 4 THF Amorphous Form 5 ACN Amorphous Form 6 DCM Amorphous Form 7 EtOAc Amorphous Form 8 2-MeTHF Amorphous Form

[0296] 1.3 Slow Cooling Experiment of Compound 1

[0297] A total of 7 slow cooling tests were set up with different solvent systems. About 15 mg of the compound 1 was weighed and added into a 3-mL vial, 0.6-1.0 mL of solvent was added, stirred and equilibrated at 50° C. for about 2 hours, and then filtered and obtained the supernatant. The obtained supernatant was placed in a biochemical incubator, cooled down from 50° C. to 5° C. at a rate of 0.1° C./min, and then maintain a constant temperature at 5° C. The precipitated solid was collected for XRPD test. Transferred the sample with no solid precipitated to −20° C. and let it stand. If there was still no solid precipitated, transfer to −20° C. for volatilization. The results are shown in Table 7.

TABLE-US-00007 TABLE 7 Test Number Solvent Solid Form 1 IPA Amorphous Form 2 MIBK Amorphous Form 3 EtOAc Amorphous Form# 4 IPA/IPAc (1:9) Amorphous Form* 5 ACN/Toluene (2:23) Amorphous Form# 6 MeOH/MTBE (1:4) Amorphous Form# 7 THF/n-heptane (4:1) Amorphous Form# Notes: Amorphous* was obtained by standing at −20° C., and Amorphous# was obtained by evaporating after standing at −20° C. for 13 days.

[0298] 1.4 The Slurry and Stirring Experiment of Compound 1 at Room Temperature

[0299] About 15 mg of the compound 1 was weighed and added into HPLC glass vials, 0.5 mL of solvent was added, and the resulting turbid liquid was placed under magnetic stirring (1000 rpm) at room temperature. After stirring at room temperature for 5 days, transferred the clear sample to 5° C. After stirring for 20 days at room temperature, the clear sample was transferred to −20° C. and stirred, and the solid was collected by centrifugation (10000 rpm, 2 minutes) for XRPD test. If there was no solid precipitation after stirring, transfer to −20° C. or evaporate at room temperature. The results are shown in Table 8.

TABLE-US-00008 TABLE 8 Test Number Solvent Solid Form 1 MIBK Amorphous Form 2 MeOH/MTBE (1:9) Amorphous Form* 3 MeOH/MTBE (1:19) Amorphous Form 4 IPA/IPAc (1:9) Amorphous Form# 5 EtOAc Amorphous Form# 6 MTBE Amorphous Form 7 n-heptane Amorphous Form 8 Toluene Amorphous Form 9 CHCl.sub.3/n-heptane (1:19) Amorphous Form 10 DCM/Toluene (1:19) Amorphous Form 11 ACN/IPAc (1:19) Amorphous Form 12 THF/n-heptane (3:2) Crystalline Form II* 13 THF/n-heptane (2:1) Amorphous Form 14 IPAc Amorphous Form 15 Acetone/Toluene (2:23) Amorphous Form+ 16 IPA Amorphous Form 17 H.sub.2O Amorphous Form Notes: Amorphous* was obtained by stirring at 5° C.; Amorphous# was obtained by evaporating at −20° C.; Amorphous+ was obtained by evaporating at room temperature.

[0300] 1.5 the Slurry and Stirring Experiment of Compound 1 at 5° C.

[0301] Approximately 15 mg of the compound 1 was weighed and added into HPLC glass vial, 0.3 mL of solvent was added, and the resulting suspension was magnetically stirred at 5° C. (1000 rpm). The clarified sample was transferred to −20° C., stirred, and centrifuged (10000 rpm, 2 minutes). The solids were collected for the XRPD test. If there was still no solid precipitation, transfer to −20° C. or evaporate at room temperature. The results are shown in Table 9.

TABLE-US-00009 TABLE 9 Test Number Solvent Solid Form 1 EtOAc Amorphous Form 2 IPA/IPAc (1:9) Amorphous Form 3 IPA Amorphous Form 4 MIBK Amorphous Form 5 MeOH/MTBE (1:4) Amorphous Form* 6 Acetone/Toluene(2:23) Amorphous Form* 7 CHCl.sub.3/n-heptane (1:9) Amorphous Form 8 THF/n-heptane (4:1) Amorphous Form# Notes: Amorphous* was obtained by evaporating at −20° C. or room temperature, and amorphous # was obtained by stirring at −20° C.

[0302] 1.6 The Slurry and Stirring Experiment of Compound 1 at 50° C.

[0303] 15 mg of the compound 1 was weighed and added into HPLC glass vial, 0.3 mL of solvent was added, the resulting suspension was magnetically stirred at 50° C. (1000 rpm), the clear sample was transferred to room temperature and stirred, if there was still no solid precipitation, then transferred at 5° C. or −20° C. and stirred, centrifugated (10000 rpm, 3 minutes) to collect the solid for XRPD test. In the end, samples that were still clear were transferred to −20° C. to evaporate, and the results are shown in Table 10.

TABLE-US-00010 TABLE 10 Test Number Solvent Solid Form 1 MeOH/MTBE (1:19) Amorphous Form 2 MeOH/MTBE (1:9) Amorphous Form 3 1,4-dioxane/n-heptane(1:19) Amorphous Form 4 n-heptane Amorphous Form 5 Toluene Amorphous Form 6 H2O Amorphous Form 7 IPA/H.sub.2O (1:9) Crystalline Form I 8 MTBE Amorphous Form 9 IPAc Amorphous Form 10 MIBK Amorphous Form 11 THF/n-heptane (3:2) Crystalline Form II* 12 EtOAc Amorphous Form* 13 IPA/H.sub.2O (1:1) Amorphous Form# 14 IPA/IPAc (1:9) Amorphous Form* Notes: Amorphous* was obtained by stirring at 5° C., and amorphous # was obtained by stirring at −20° C.

[0304] 1.7 Gas-Solid Permeation Experiment of Compound 1

[0305] A total of 9 gas-solid diffusion tests were set up with different solvents. 15 mg of the compound 1 was weighed and added into a 3 mL vial, about 2 mL of solvent was added into the 20 mL vial, the 3 mL vial was placed open in the 20 mL vial, and then the 20 mL vial was sealed. After standing at room temperature for 19 days, the solids were collected for XRPD testing. If the sample was dissolved, the solid was collected by evaporating at room temperature. The results are shown in Table 11.

TABLE-US-00011 TABLE 11 Test Number Solvent Solid Form 1 MIBK Amorphous Form 2 IPAc Amorphous Form 3 MTBE Amorphous Form 4 n-heptane Amorphous Form 5 Toluene Amorphous Form 6 H.sub.2O Amorphous Form 7 IPA Amorphous Form* 8 CHCl.sub.3 Amorphous Form* 9 DMSO Amorphous Form* Notes: Amorphous* was obtained by evaporating at room temperature.

[0306] 1.8 Gas-Liquid Diffusion Experiment of Compound 1

[0307] A total of 13 gas-liquid diffusion tests were set up with different solvents. About 15 mg of the compound 1 was weighed and added into a 3 mL vial, 0.2˜1.4 mL of solvent was added to dissolve it (0.45 μm PTFE filter for undissolved solid), Another 20 mL vial was taken and about 3 mL of antisolvent was added into it, After placing the 3 mL vial containing the clear liquid (open) into the 20 mL vial, the 20 mL vial was sealed and allowed to stand at room temperature. Collect solids and perform XRPD testing. If the sample was dissolved, evaporated at room temperature and perform XRPD test for collected solids. The results are shown in Table 12.

TABLE-US-00012 TABLE 12 Test Number Solvent Anti-solvent Solid Form 1 IPA n-heptane Amorphous Form* 2 Acetone Amorphous Form 3 2-MeTHF Amorphous Form 4 DCM Amorphous Form 5 ACN Amorphous Form 6 1,4-dioxane Amorphous Form 7 CHCl.sub.3 Toluene Amorphous Form 8 Acetone Amorphous Form 9 IPA/IPAc (1:9) MTBE Amorphous Form 10 ACN Amorphous Form* 11 IPA H.sub.2O Amorphous Form 12 THF Amorphous Form 13 Acetone Amorphous Form Notes: Amorphous* was obtained by evaporating at room temperature.

[0308] 1.9 Polymorph Screening Test of Compound 1 Dimethylsulfonate

[0309] 40 mg of the compound was taken and added into a 2 mL glass bottle, a stir bar and then 400 μL of solvent were added (as shown in Table 13 below). If the sample was dissolved, let it stand at room temperature and evaporated. Other suspensions were stirring for 2 days at 40° C., quickly centrifuge (6000 rpm, 10 min), and the remaining solid was taken out and dried in a vacuum drying oven (−0.1 Mpa, 25° C.). The results are shown in Table 13.

TABLE-US-00013 TABLE 13 Test number Solvent XRPD results — Initial Crystalline Form Crystalline Form XVIII 1 Ethanol Crystalline Form XVIII 2 Isopropanol Crystalline Form XVIII 3 Acetonitrile Crystalline Form XVIII 4 Ethyl acetate Crystalline Form XVIII 5 Isopropyl acetate Crystalline Form XVIII 6 Tert-butyl methyl ether Crystalline Form XVIII 7 Tetrahydrofuran Crystalline Form XVIII 8 Methyltetrahydrofuran Crystalline Form XVIII 9 Dichloromethane Crystalline Form XVIII 10 N-heptane Crystalline Form XVIII 11 Acetone/ethyl acetate = 2/1 Crystalline Form XVIII

[0310] 1.10 Stability Test of Salts of Compound 1

[0311] 30 mg of the compound was weighed and added into an 8 mL glass bottle, and then was placed under the condition of room temperature (25° C., closed), high humidity (room temperature/75% RH, open) and light (25° C. closed, white light: 5000 Lux, ultraviolet 282 μW/cm2). samples were taken on the 5th, 10th, and 30th day for detection (HPLC, XRD).

TABLE-US-00014 TABLE 14 Time Test point TRS Sample conditions (day) (%) XPRD compound 1 Initial sample 0 0.73 Amorphous dihydrochloride 25° C. closed 5 0.72 Amorphous amorphous 10 0.77 Amorphous form V 30 0.83 Amorphous 25° C./75% 5 0.81 Amorphous RH open 10 0.77 Amorphous 30 0.79 Amorphous Illumination 5 1.81 Amorphous 5K lux 10 2.54 Amorphous closed compound 1 Initial sample 0 1.96 Amorphous disulfate 25° C. 5 2.45 Amorphous amorphous form 10 2.72 Amorphous XXIII 30 4.83 Amorphous 25° C./75% 5 2.69 Amorphous RH 10 3.14 Amorphous 30 5.13 Amorphous illumination 5 3.66 Amorphous 5K lux 10 5.50 Amorphous Compound 1 Initial sample 0 2.44 Crystalline dimethanesulfonate Form XVIII crystalline Form 25° C. 5 2.51 Crystalline Form XVIII XVIII 10 2.57 Crystalline Form XVIII 30 2.55 Crystalline Form XVIII illumination 5 2.63 Crystalline 5K lux Form XVIII 10 2.64 Crystalline Form XVIII Compound 1 Initial sample 0 1.66 Amorphous di-p- 25° C. 5 1.66 Amorphous toluenesulfonate 10 1.71 Amorphous amorphous Form 30 1.80 Amorphous XVI. 25° C./75% 5 1.56 Amorphous RH 10 1.66 Amorphous 30 1.88 Amorphous illumination 5 1.89 Amorphous 5K lux 10 2.40 Amorphous

Example 2: The Preparation Method of Crystalline Form I of Compound 1

[0312] 150 mg compound 1 was weighed and added in 5.0 mL of mixed solvent IPA/H2O (1:9, v/v), suspended and stirred at 50° C. for 5 days. After centrifugation, the solid was dried under vacuum at room temperature for 1 day, and about 80 mg solid was taken out and dried under vacuum at 50° C. for 2 hours.

Example 3: The Preparation Method of Crystalline Form II of Compound 1

[0313] 150 mg compound 1 was weighed and added in 5.0 mL mixed solvent THF/n-heptane (3:2, v/v), suspended and stirred at room temperature for 3 days, transferred to 50° C. and suspended and stirred for 2 days, about 3 mg of the seed crystals of crystalline form II obtained in the above screening test were added, then suspended and stirred at 50° C. for 2 days, centrifuged, and the solid was dried under vacuum at room temperature for 1 day.

Example 4: The Preparation Method of Crystalline Form III of Compound 1

[0314] 150 mg of the compound 1 was weighed and added in 5.0 mL of mixed solvent IPA/H2O (1:9, v/v), suspended and stirred at 50° C. for 5 days. After centrifugation, the solid was dried under vacuum at room temperature for 4 hours.

Example 5: The Preparation Method of Amorphous Form IV of Compound 1 Monohydrochloride

[0315] 15 mg of the compound 1 was weighed and added into an HPLC vial, 0.5 mL of solvent MIBK was added, and 1.1 μL of concentrated hydrochloric acid was added, suspended at room temperature and stirred for 3 days, and centrifuged.

Example 6: The Preparation Method of Amorphous Form V of Compound 1 Dihydrochloride

[0316] 15 mg of the compound 1 was weighed and added into an HPLC vial, 0.5 mL of solvent EtOAc was added, 2.2 μL of concentrated hydrochloric acid was added, suspended and stirred at room temperature for 3 days, and centrifuged.

Example 7: The Preparation Method of Amorphous Form VI of Compound 1 Sulfate

[0317] 15 mg of the compound 1 was weighed and added into an HPLC vial, 0.5 mL of mixed solvent MeOH/MTBE (1:9, v/v) was added, 0.8 μL of concentrated sulfuric acid was added, suspended and stirred at room temperature for 3 days, and centrifuged.

Example 8: The Preparation Method of Amorphous Form VII of Compound 1 Phosphate

[0318] 15.0 mg of the compound 1 was weighed and added into an HPLC vial, 0.5 mL of mixed solvent MeOH/MTBE (1:9, v/v) was added, 0.86 μL of concentrated phosphoric acid was added, suspended and stirred at room temperature for 3 days, and centrifuged.

Example 9: The Preparation Method of Amorphous Form VIII of Compound 1 Mesylate

[0319] 15 mg of the compound 1 was weighed and added into an HPLC vial, 0.5 mL of solvent MIBK was added, 0.83 μL of methanesulfonic acid was added, suspended and stirred at room temperature for 3 days, and centrifuged.

Example 10: The Preparation Method of Amorphous Form IX of Compound 1 Maleate

[0320] 15 mg of the compound 1 was weighed and added into an HPLC vial, 0.5 mL of mixed solvent MeOH/MTBE (1:9, v/v) was added, 1.6 mg of maleic acid was added, suspended and stirred at room temperature for 3 days, and centrifuged.

Example 11: The Preparation Method of Amorphous Form X of Compound 1 Tartrate

[0321] 15.0 mg of the compound 1 was weighed and added into an HPLC vial, 0.5 mL of solvent MIBK was added, 2.1 mg of tartaric acid was added, suspended and stirred at room temperature for 3 days, and centrifuged.

Example 12: The Preparation Method of Amorphous Form XI of Compound 1 Benzoate

[0322] 15.0 mg of the compound 1 was weighed into an HPLC vial, 0.5 mL of mixed solvent MeOH/MTBE (1:9, v/v) was added, 1.6 mg of benzoic acid was added, suspended and stirred at room temperature for 3 days, and centrifuged.

Example 13: The Preparation Method of Amorphous Form XII of Compound 1 Succinate

[0323] 15.0 mg of the compound 1 was weighed and added into an HPLC vial, 0.5 mL of solvent MIBK was added, 1.6 mg of succinic acid was added, suspended and stirred at room temperature for 3 days, and centrifuged.

Example 14: The Preparation Method of Amorphous Form XIII of Compound 1 Acetate

[0324] 15.0 mg of the compound 1 was weighed and added into an HPLC vial, 0.5 mL of solvent MIBK was added, 0.6 μL of glacial acetic acid was added, suspended and stirred at room temperature for 3 days, and centrifuged.

Example 15: The Preparation Method of Amorphous Form XIV of Compound 1

[0325] About 15 mg of the compound 1 was weighed and added into a 20 mL vial, then the solid was dissolved completely with 0.2-2.0 mL of EtOH. IPAc was added dropwise to the clear solution while stirring (1000 rpm) until solid precipitated, and if there is no solid precipitation, suspended and stirred at 5° C. If there is still no solid precipitation, transferred to −20° C. for suspension and stirring. The clear sample evaporated at room temperature. Then the precipitated solid was separated.

Example 16—the Preparation Method of Amorphous Form XV of the Compound 1 Mono-p-Toluenesulfonate

[0326] 200 mg of the compound 1 was weighed and added into a 20 mL glass bottle, a stir bar and 2 mL of acetone were added, and then 0.19 mL of 1M p-toluenesulfonic acid in ethanol was added to dissolve the sample, the sample directly turned into oil. After stirring for 2 days, no solids were precipitated. The sample solution evaporated. The remaining solids were taken out and dried in a vacuum drying oven (−0.1 Mpa, 25° C.).

Example 17—the Preparation Method of Amorphous Form XVI of the Compound 1 Di-p-Toluenesulfonate

[0327] 1000 mg of the compound 1 was weighed and added into a 40 mL glass bottle, a stir bar and 20 mL of acetone were added, and then 1.9 mL of 1M p-toluenesulfonic acid in ethanol was added, the sample directly turned into oil. The n-heptane was added. No solids were precipitated. After stirring for 2 days, the sample solution was concentrated, and the remaining solid was dried in a vacuum drying oven (−0.1 Mpa, 25° C.).

Example 18—the Preparation Method of Amorphous Form XVII of Compound 1 Diphosphate

[0328] 1000 mg of the compound 1 was weighed and added into a 40 mL glass bottle, a stir bar and 20 mL of acetone were added, and then 1.9 mL of 1M phosphoric acid in ethanol was added, solids were precipitated. After stirring for 2 days, centrifugated (6000 rpm 10 min), the residual solids was taken out and dried in a vacuum drying oven (−0.1 Mpa, 25° C.).

Example 19—the Preparation Method of Crystalline Form XVIII of the Compound 1 Dimethylsulfonate

[0329] 1000 mg of the compound 1 was weighed and added into a 40 mL glass bottle, a stir bar and 20 mL of acetone were added, and then 1.9 mL of 1M methanesulfonic acid in ethanol was added, the solid was immediately precipitated. After stirring for 2 days, centrifugated (6000 rpm 10 min), the remaining solids was taken out and dried in a vacuum drying oven (−0.1 Mpa, 25° C.).

Example 20—the Preparation Method of Amorphous Form XIX Compound 1 Monooxalate

[0330] 200 mg of the compound 1 was weighed and added into a 40 mL glass bottle, a stir bar and 20 mL of acetone were added, and then 1.9 mL of 1M oxalic acid in ethanol was added. Solids were precipitated. After stirring for 2 days, centrifugated (6000 rpm. 10 min), the residual solids was taken out and dried in a vacuum drying oven (−0.1 Mpa, 25° C.).

Example 21—the Preparation Method of Amorphous Form XX of Compound 1 Dioxalate

[0331] 1000 mg of the compound 1 was weighed and added into a 40 mL glass bottle, a stir bar and 20 mL of acetone were added, and then 1.9 mL of 1M oxalic acid in ethanol was added. Solids were precipitated. After stirring for 2 days, centrifugated (6000 rpm. 10 min), the residual solids were taken out and dried in a vacuum drying oven (−0.1 Mpa, 25° C.).

Example 22—the Preparation Method of the Amorphous Form XXI of the Compound 1 Dimaleate

[0332] 1000 mg of the compound 1 was weighed and added into a 40 mL glass bottle, a stir bar and 20 mL of acetone were added, and then 1.9 mL of 1M maleic acid in ethanol was added. No solid precipitated. The anti-solvent n-heptane was added, there was still no precipitation. After stirring for 2 days, the sample solution was directly concentrated, and the remaining solids was dried in a vacuum drying oven (−0.1 Mpa, 25° C.).

Example 23—the Preparation Method of Amorphous Form XXII of Compound 1 Ditartrate

[0333] 1000 mg of the compound 1 was weighed and added into a 40 mL glass bottle, a stir bar and 20 mL of acetone were added, and then 1.9 mL of 1M tartaric acid in ethanol was added. Solids were precipitated. After stirring for 2 days, centrifugated (6000 rpm 10 min), the remaining solids were taken out and dried in a vacuum drying oven (−0.1 Mpa, 25° C.).

Example 24—the Preparation Method of Amorphous Form XXIII of Compound 1 Disulfate

[0334] 1000 mg of the compound 1 was weighed and added into a 40 mL glass bottle, a stir bar and 20 mL of acetone were added, and then 1.9 mL of 1M sulfuric acid in ethanol was added. The sample directly turned into oil. The n-heptane was added, there was still no precipitation. After stirring for 2 days, the sample solution was concentrated, and the remaining solids were dried in a vacuum drying oven (−0.1 Mpa, 25° C.).

Example 25—the DVS Test of Compound 1 Solid Form V/XIV/XVIII

[0335] About 10 mg of the solid form of the compound 1 was taken for dynamic water adsorption (DVS) test. The conclusions are described in Table 15 below:

TABLE-US-00015 TABLE 15 Sample XRPD after DVS XIV No change V No change XVIII No change

Example 26: Identification and Characterization of Various Forms of Compound 1

[0336] The used instruments and their parameters are described as follows:

[0337] 1. XRPD X-Ray Powder Diffraction

[0338] X-ray powder diffraction analyzer (PANalytacal)

TABLE-US-00016 Parameters Instruments X rays X′ Pert3 Cu, Kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.544426 Kα2/Kα1intensity ratio: 0.50 Setting of X-ray tube 45 kV, 40 mA Divergence slit ⅛° Scan patterns Continuous Scanning range (2θ) 3°-40° Scanning time per step (s) 46.665   Scanning step size (2θ) 0.0263° Test Time ~5 min

[0339] 2. TGA Thermogravimetric Analysis and DSC Differential Scanning Calorimetry

[0340] TA Q500/5000 thermogravimetric analyzer and TA Q200/2000 differential scanning calorimeter

TABLE-US-00017 Parameter TGA DSC Method Linear temperature Linear temperature Sample plate Platinum plate, open Aluminum plate, gland Temperature range Room temperature-set the 25° C.- set the end end temperature temperature Scanning rate (° C./ 10 10 min) Shielding gas Nitrogen Nitrogen

[0341] 3. mDSC—Modulated Differential Scanning Calorimetry

TABLE-US-00018 Parameter Set value Test mode Conventional mDSC Amplitude (° C.) 1.0 Modulation period (sec.) 60 Scanning rate (° C./Minute) 3.0 Shielding gas Nitrogen

[0342] 4. IC—Ion Chromatography

TABLE-US-00019 Parameter Ion Chromatography (Thermo ICS1100) chromatographic column IonPac AS18 Analytical Column (4 × 250 mm) Mobile phase 25 mM NaOH Injection volume 25 μL Flow rate 1.0 mL/min Cell temperature 35° C. Column temperature 35° C. Currrent 80 mA Run time Cl.sup.−: 6.0 min; PO.sub.4.sup.3−: 12.0 min; SO.sub.4.sup.2−: 8.0 min

[0343] For the identification and characterization results of the above XPRD, TGA, DSC, mDSC, etc., please refer to FIG. 1-69, Table 1-4 and related text description.

[0344] Each reference, including all patents, patent applications and publications referenced in this application, is incorporated herein by reference in its entirety as if each of them is incorporated separately. In addition, it is understood that in the teaching of the present invention, the technicians in the art may make certain changes or modifications to the present invention and that these equivalents will remain within the scope of the present invention as limited by the claims appended to the application.