Crystal form of liver specific delivery-based antiviral prodrug nucleoside cyclophosphate compound, preparation method therefor, and use thereof

Abstract

The present invention relates to a crystal form of a liver specific delivery-based antiviral prodrug nucleoside cyclophosphate compound, a preparation method therefor, and a use thereof, and in particular to a polymorph of (2R)-9-{2-[(2R, 4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methoxypropyl}adenine and a salt thereof, a preparation method for the polymorph and a use of the polymorph. The crystal form of the present invention has the characteristics of high bioavailability, significant efficacy, good stability, high yield, high purity and the like, and can be used alone or in combination with other antiviral drugs to treat hepatitis B virus (HBV), hepatitis D virus (HDV), human immunodeficiency viruses (HIV), and diseases caused thereby.

Description

Crystal forms of liver-delivered antiviral prodrug nucleoside cyclic phosphate compounds, methods of making and uses thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicinal chemistry, in particular to polymorphs of the antiviral prodrug (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methoxylpropyl}adenine and salts thereof, methods of making the same, pharmaceutical compositions containing a therapeutically effective amount of the compound and pharmaceutical uses thereof. BACKGROUND

[0002] Viruses such as hepatitis B virus (HBV), hepatitis D virus (HDV), human immunodeficiency virus (HIV) seriously threaten human health. Taking hepatitis B virus as an example, hepatitis B (hepatitis B) is a disease caused by hepatitis B virus, mainly with liver inflammatory lesions, and can cause multiple organ damage.

[0003] The main class of anti-hepatitis B virus drugs is nucleotide drugs, such as adefovir dipivoxil, tenofovir disoproxil (TDF), tenofovir alafenamide (TAF), entecavir, lamivudine, telbivudine, etc. The mechanism of action is to be activated into triphosphate metabolites in cells, which can inhibit the DNA or RNA polymerase activity of the virus, prevent the synthesis of DNA or RNA, and achieve the purpose of inhibiting virus replication.

[0004] Some nucleotide compounds, such as adefovir, tenofovir, etc., are highly negatively charged at physiological pH. Therefore, the transmembrane ability is poor and the bioavailability is low when orally administered; at the same time, the gastrointestinal and renal toxic side effects are increased. However, esterification modification forms ester prodrugs, such as adefovir dipivoxil, tenofovir disoproxil, etc., which can improve bioavailability and tissue distribution. However, ester hydrolase is widely distributed in the body, causing most of the drug to be hydrolyzed into negatively charged bioactive ingredients (adefovir, tenofovir, etc.) before reaching the liver cells, which are not easy to enter the liver cells, but are actively transported to the proximal tubules of the kidney, which is easy to cause renal toxicity.

[0005] (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine is a prodrug of tenofovir. It has a cyclic phosphate (4-aryl-2-oxo-1,3,2-dioxaphosphorinan) precursor structure with good liver-specific delivery performance, and the mechanism is very clear, the 4-aryl substitution position is specifically catalyzed by CYP3A in the cytochrome P450 isozyme family in hepatocytes to generate a hydroxyl group, and then ring-opening to generate a negatively charged phosphate intermediate, which is difficult to pass through the cell membrane and exist in the cell, and under the catalysis of phosphodiesterase, it is hydrolyzed, β-eliminated to generate a nucleotide monophosphate compound, and under the action of nucleotide kinase, it is continuously generated to generate a biologically active nucleotide triphosphate compound, and the metabolic by-product aryl vinyl ketone can be eliminated by 1,4-addition reaction with the abundant antioxidant and free radical glutathione in hepatocytes. No side effects of the addition product have been reported.

[0006] Therefore, there is a need in the art to develop an anti-hepatitis B virus drug with fewer side effects and higher efficacy. SUMMARY

[0007] The present application aims to provide a crystal form of an anti-hepatitis B virus drug with liver-specific delivery (liver delivery) effect to reduce side effects and improve efficacy, and in particular relates to a crystal form of a compound as shown in formula (I) and a preparation method and use thereof.

[0008] In a first aspect of the present application, a crystal form of (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine as shown in formula (I-A) is provided,

[0009] wherein m is 1-10;

[0010] n is 0-20;

[0011] X is selected from the group consisting of water, sulfuric acid, phosphoric acid, fumaric acid, citric acid, hydrochloric acid, maleic acid, oxalic acid, methanesulfonic acid, ethanedisulfonic acid, and saccharin.

[0012] In another preferred embodiment, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0013] In another preferred embodiment, n is 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14.

[0014] In another preferred embodiment, the crystalline form is a crystalline form of free form and a crystalline form of salt;

[0015] wherein the crystalline form of salt is selected from the group consisting of: sulfate Form B, sulfate Form A, phosphate Form A, phosphate Form B, phosphate Form C, fumarate Form A, fumarate Form B, fumarate Form E, citrate Form A, hydrochloride Form A, hydrochloride Form B, maleate Form A, oxalate Form A, oxalate Form B, mesylate Form A, mesylate Form B, edisylate Form A, saccharinate Form A;

[0016] wherein the crystalline form of free form is selected from the group consisting of: anhydrous Form A, anhydrous Form B, hydrate Form C.

[0017] In another preferred embodiment, the X is sulfuric acid, and the crystalline form is sulfate Form B; the XRPD pattern of the sulfate Form B comprises 3 or more 2Θ diffraction peaks selected from the group consisting of: 8.3821 ± 0.20°, 16.8042 ± 0.20°, 21.8664 ± 0.20°, 25.4711 ± 0.20°, 30.3120 ± 0.20°.

[0018] In another preferred embodiment, the XRPD pattern of the sulfate Form B further comprises 2Θ diffraction peaks selected from the group consisting of: 10.0213 ± 0.20°, 18.0850 ± 0.20°, 18.9828 ± 0.20°, 20.2120 ± 0.20°, 21.2977 ± 0.20°, 23.7487 ± 0.20°, 24.8583 ± 0.20°, 28.6460 ± 0.20°, 34.1748 ± 0.20°, 34.6187 ± 0.20°, 37.1125 ± 0.20°, 38.9996 ± 0.20°.

[0019] In another preferred embodiment, the sulfate Form B further has one or more characteristics selected from the group consisting of:

[0020] 1) the XRPD pattern of the sulfate Form B is substantially as characterized in Figure 1;

[0021] 2) the DSC pattern of the sulfate Form B is substantially as characterized in Figure 2;

[0022] 3) the DSC pattern of the sulfate Form B has an endothermic peak in the range of 183.3 °C - 187.3 °C.

[0023] In another preferred embodiment, the method for preparing the sulfate Form B comprises:

[0024] a) mixing a compound of formula (I), concentrated sulfuric acid and ethyl acetate;

[0025] b) stirring at a temperature of 5-50 °C for 2-10 days;

[0026] c) filtering to obtain the sulfate salt Form B.

[0027] In another preferred embodiment, the concentrated sulfuric acid in step a) is in the form of an ethanol solution of concentrated sulfuric acid;

[0028] In another preferred embodiment, the mass volume ratio of the compound of formula (I) and concentrated sulfuric acid is (2-60): 1 (mg / μL); preferably (4-10): 1 (mg / μL), more preferably (5-9): 1 (mg / μL).

[0029] In another preferred embodiment, the method for preparing the sulfate salt Form B comprises: weighing 400.2 mg of the compound of formula (I) and 10 mL of ethyl acetate in a 20 mL vial; adding dropwise 1 mL of an ethanol solution containing 49 μL of concentrated sulfuric acid into the 20 mL vial; stirring at room temperature for 6 days, and filtering to separate the solid to obtain the sulfate salt Form B.

[0030] In another preferred embodiment, the X is sulfuric acid, and the crystal form is the sulfate salt Form A; the XRPD pattern of the sulfate salt Form A comprises 3 or more 2θ diffraction peaks selected from the group consisting of: 3.9666±0.20°, 9.3970±0.20°, 11.6142±0.20°, 19.6179±0.20°, 20.8014±0.20°, 21.6096±0.20°, 23.7426±0.20°.

[0031] In another preferred embodiment, the XRPD pattern of the sulfate salt Form A further comprises 2θ diffraction peaks selected from the group consisting of: 7.8655±0.20°, 15.8718±0.20°, 17.5595±0.20°, 18.2166±0.20°, 18.8666±0.20°, 24.3771±0.20°, 26.3259±0.20°, 27.9095±0.20°, 30.3783±0.20°, 34.7503±0.20°.

[0032] In another preferred embodiment, the sulfate salt Form A further has one or more characteristics selected from the group consisting of:

[0033] 1) the XRPD pattern of the sulfate salt Form A is substantially as characterized in Figure 3;

[0034] 2) the DSC pattern of the sulfate salt Form A is substantially as characterized in Figure 4;

[0035] 3) the DSC pattern of said sulfate Form A has an endothermic peak in the range of 139.1 °C - 143.1 °C.

[0036] In another preferred embodiment, the method for preparing said sulfate Form A comprises:

[0037] a) mixing a compound of formula (I), concentrated sulfuric acid and ethyl acetate;

[0038] b) stirring at a temperature of 5-50 °C for 6-30 h;

[0039] c) stirring at a temperature of 20-80 °C for 1-10 h;

[0040] d) filtering to obtain the sulfate Form A.

[0041] In another preferred embodiment, the mass to volume ratio of said compound of formula (I) and sulfuric acid is (1-15): 1 (mg / μL), preferably (4-12): 1 (mg / μL), more preferably (7-9): 1 (mg / μL).

[0042] In another preferred embodiment, the method for preparing said sulfate Form A comprises: weighing 19.8 mg of compound of formula (I) in a 5 mL vial; adding ethyl acetate 47.5 μL and concentrated sulfuric acid 2.4 μL; after stirring at room temperature for 1 day, transferring to stirring at 50 °C for 3 hours, and then filtering to isolate the solid to obtain the sulfate Form A.

[0043] In another preferred embodiment, said X is phosphoric acid, and said crystal form is phosphate Form A; said phosphate Form A has an XRPD pattern comprising 3 or more diffraction peaks selected from the group consisting of: 6.6968 ± 0.20°, 10.7641 ± 0.20°, 12.6320 ± 0.20°, 13.9813 ± 0.20°, 15.3566 ± 0.20°, 16.6756 ± 0.20°, 20.2549 ± 0.20°, 23.4036 ± 0.20°, 24.3390 ± 0.20°, 26.4374 ± 0.20°.

[0044] In another preferred embodiment, said phosphate Form A further comprises diffraction peaks selected from the group consisting of: 10.1377 ± 0.20°, 12.0216 ± 0.20°, 13.3655 ± 0.20°, 17.2800 ± 0.20°, 17.7165 ± 0.20°, 18.3199 ± 0.20°, 18.5292 ± 0.20°, 18.9808 ± 0.20°, 20.6318 ± 0.20°, 24.9363 ± 0.20°, 27.1449 ± 0.20°, 29.5894 ± 0.20°.

[0045] In another preferred embodiment, the phosphate salt Form A further has one or more characteristics selected from the group consisting of:

[0046] 1) the XRPD pattern of the phosphate salt Form A is substantially as characterized in Figure 5;

[0047] 2) the DSC pattern of the phosphate salt Form A is substantially as characterized in Figure 6;

[0048] 3) the DSC pattern of the phosphate salt Form A has an endothermic peak in the range of 194.8-198.8 °C.

[0049] In another preferred embodiment, the method for preparing the phosphate salt Form A comprises:

[0050] a) mixing the compound of Formula (I), phosphoric acid and ethanol;

[0051] b) stirring at a temperature of 5-50 °C for 2-10 days;

[0052] c) filtering to obtain the phosphate salt Form A.

[0053] In another preferred embodiment, the mass to volume ratio of the compound of Formula (I) and phosphoric acid is (1-20): 1 (mg / μL), preferably (3-9): 1 (mg / μL), more preferably (5-7): 1 (mg / μL).

[0054] In another preferred embodiment, the method for preparing the phosphate salt Form A comprises: weighing 19.8 mg of the compound of Formula (I) in a 5 mL vial, adding 59.7 μL of ethanol and 3.0 μL of concentrated phosphoric acid, and stirring at room temperature for 6 days, and filtering to isolate the solid to obtain the phosphate salt Form A.

[0055] In another preferred embodiment, the X is phosphoric acid, and the crystal form is phosphate salt Form B; the XRPD pattern of the phosphate salt Form B comprises 3 or more diffraction peaks selected from the group consisting of 2Θ: 6.0739 ± 0.20°, 12.1632 ± 0.20°, 12.7958 ± 0.20°, 18.0089 ± 0.20°, 18.9774 ± 0.20°, 19.9173 ± 0.20°, 22.5667 ± 0.20°, 22.7631 ± 0.20°, 24.2184 ± 0.20°, 25.1475 ± 0.20°, 27.0017 ± 0.20°.

[0056] In another preferred embodiment, the phosphate salt Form B further comprises a diffraction peak selected from the group consisting of: 11.2736 ± 0.20°, 11.6591 ± 0.20°, 14.4780 ± 0.20°, 15.7184 ± 0.20°, 15.9997 ± 0.20°, 16.6021 ± 0.20°, 16.8676 ± 0.20°, 18.2901 ± 0.20°, 21.7825 ± 0.20°, 21.9541 ± 0.20°, 24.4914 ± 0.20°, 27.8487 ± 0.20°, 29.8628 ± 0.20°.

[0057] In another preferred embodiment, the phosphate salt Form B further has one or more characteristics selected from the group consisting of:

[0058] 1) the XRPD pattern of the phosphate salt Form B is substantially as characterized in Figure 7;

[0059] 2) the DSC pattern of the phosphate salt Form B is substantially as characterized in Figure 8;

[0060] 3) the DSC pattern of the phosphate salt Form B has endothermic peaks in the range of 117.7 °C - 121.7 °C and 192.1 °C - 196.1 °C.

[0061] In another preferred embodiment, the method for preparing the phosphate salt Form B comprises:

[0062] a) mixing a compound of Formula (I), phosphoric acid and tetrahydrofuran / water;

[0063] b) stirring at a temperature of 5-50 °C for 2-10 days;

[0064] c) filtering to obtain the phosphate salt Form B.

[0065] In another preferred embodiment, the mass to volume ratio of the compound of Formula (I) and phosphoric acid is (1-20): 1 (mg / μL), preferably (3-9): 1 (mg / μL), more preferably (5-7): 1 (mg / μL).

[0066] In another preferred embodiment, the volume ratio of the tetrahydrofuran / water is (5-40): 1, preferably (15-30): 1, more preferably (15-25): 1.

[0067] In another preferred embodiment, the method for preparing the phosphate salt Form B comprises: weighing 19.8 mg of the compound of Formula (I) in a 5 mL vial, adding 59.7 μL of tetrahydrofuran / water (19: 1, v / v) and 3.0 μL of concentrated phosphoric acid, and stirring at room temperature for 6 days, and filtering to separate the solid to obtain the phosphate salt Form B.

[0068] In another preferred embodiment, said X is phosphoric acid, and said crystalline form is phosphate Form C; said phosphate Form C has an XRPD pattern comprising three or more peaks selected from the group consisting of: 8.1420 ± 0.20°, 15.3443 ± 0.20°, 16.6701 ± 0.20°, 17.3849 ± 0.20°, 17.8823 ± 0.20°, 19.0586 ± 0.20°, 20.9589 ± 0.20°, 21.2888 ± 0.20°, 21.7201 ± 0.20°, 23.6176 ± 0.20°, 26.1302 ± 0.20°, 29.4580 ± 0.20°.

[0069] In another preferred embodiment, said phosphate Form C further comprises one or more peaks selected from the group consisting of: 6.8915 ± 0.20°, 11.2010 ± 0.20°, 14.7238 ± 0.20°, 16.3599 ± 0.20°, 18.7616 ± 0.20°, 19.9107 ± 0.20°, 22.5840 ± 0.20°, 25.0331 ± 0.20°, 26.6931 ± 0.20°, 27.0932 ± 0.20°, 27.4451 ± 0.20°, 28.6511 ± 0.20°, 28.9991 ± 0.20°, 33.8533 ± 0.20°, 36.2525 ± 0.20°.

[0070] In another preferred embodiment, said phosphate Form C further has one or more characteristics selected from the group consisting of:

[0071] 1) said phosphate Form C has an XRPD pattern substantially as characterized in Figure 9;

[0072] 2) said phosphate Form C has a DSC pattern substantially as characterized in Figure 10;

[0073] 3) said phosphate Form C has a DSC pattern with an endothermic peak in the range of 202.3 °C to 206.3 °C.

[0074] In another preferred embodiment, a process for preparing said phosphate Form C comprises:

[0075] a) mixing a compound of formula (I), phosphoric acid and ethanol;

[0076] b) stirring at a temperature of 5 to 50 °C for 1 to 5 days;

[0077] c) stirring at a temperature of 20 to 80 °C for 2 to 10 h;

[0078] d) stirring at a temperature of 5 to 50 °C for 5 to 20 days;

[0079] e) filtering to obtain phosphate Form C.

[0080] In another preferred embodiment, the mass volume ratio of the compound of formula (I) and phosphoric acid is (1-15): 1 (mg / μL), preferably (2-10): 1 (mg / μL), more preferably (4-8): 1 (mg / μL).

[0081] In another preferred embodiment, the preparation method of the phosphate salt crystal form C comprises: weighing 400.4 mg of the compound of formula (I) and 4 mL of ethanol into a 20 mL vial; adding dropwise 2 mL of an ethanol solution containing 60 μL of concentrated phosphoric acid into the 20 mL vial; stirring at room temperature for 3 days, then stirring at 50°C for 6 hours, then stirring at room temperature for 10 days, and then filtering to separate the solid to obtain the phosphate salt crystal form C.

[0082] In another preferred embodiment, the X is fumaric acid, and the crystal form is fumarate salt crystal form A; the XRPD pattern of the fumarate salt crystal form A contains three or more 2θ diffraction peaks selected from the group consisting of 8.5376±0.20°, 9.3019±0.20°, 13.2247±0.20°, 17.5380±0.20°, 18.9356±0.20°, 22.1653±0.20°.

[0083] In another preferred embodiment, the XRPD pattern of the fumarate salt crystal form A further has 2θ diffraction peaks selected from the group consisting of 4.6110±0.20°, 16.3131±0.20°, 25.4876±0.20°, 26.2282±0.20°.

[0084] In another preferred embodiment, the fumarate salt crystal form A further has one or more characteristics selected from the group consisting of:

[0085] 1) the XRPD pattern of the fumarate salt crystal form A is substantially as characterized in FIG. 11;

[0086] 2) the DSC pattern of the fumarate salt crystal form A is substantially as characterized in FIG. 12;

[0087] 3) the DSC pattern of the fumarate salt crystal form A has endothermic peaks in the range of 92.9-96.9°C and 165.7-169.7°C.

[0088] In another preferred embodiment, the preparation method of the fumarate salt crystal form A comprises:

[0089] a) mixing the compound of formula (I), fumaric acid and ethanol;

[0090] b) stirring at a temperature of 5-50°C for 1-10 days;

[0091] c) filtering to obtain the fumarate salt crystal form A.

[0092] In another preferred embodiment, the mass ratio of the compound of formula (I) and fumaric acid is (1-15): 1, preferably (2-8): 1, more preferably (3-5): 1.

[0093] In another preferred embodiment, the preparation method of the fumarate salt crystal form A comprises: weighing 20 mg of the compound of formula (I) into a 5 mL vial, adding 100.0 μL of ethanol and 5.0 mg of fumaric acid, stirring the sample at room temperature for 6 days, and filtering to separate the solid to obtain the fumarate salt crystal form A.

[0094] In another preferred embodiment, the X is fumaric acid, and the crystal form is fumarate salt crystal form B; the XRPD pattern of the fumarate salt crystal form B comprises 3 or more 2θ diffraction peaks selected from the group consisting of 12.1477±0.20°, 18.2849±0.20°, 19.5748±0.20°, 24.4247±0.20°, 30.7722±0.20°.

[0095] In another preferred embodiment, the XRPD pattern of the fumarate salt crystal form B further has 2θ diffraction peaks selected from the group consisting of 13.1470±0.20°, 14.6236±0.20°, 21.7551±0.20°.

[0096] In another preferred embodiment, the fumarate salt crystal form B further has one or more characteristics selected from the group consisting of:

[0097] 1) the XRPD pattern of the fumarate salt crystal form B is substantially as characterized in Figure 13;

[0098] 2) the DSC pattern of the fumarate salt crystal form B is substantially as characterized in Figure 14;

[0099] 3) the DSC pattern of the fumarate salt crystal form B has an endothermic peak in the range of 134.0-138.0°C.

[0100] In another preferred embodiment, the preparation method of the fumarate salt crystal form B comprises:

[0101] a) mixing the compound of formula (I), fumaric acid and acetone;

[0102] b) stirring at a temperature of 5-50°C for 1-10 days;

[0103] c) filtering to obtain the fumarate salt crystal form B.

[0104] In another preferred embodiment, the mass ratio of the compound of formula (I) and fumaric acid is (1-15): 1, preferably (2-8): 1, more preferably (3-5): 1.

[0105] In another preferred embodiment, the preparation method of the fumarate salt Form B comprises: weighing 20 mg of the compound of Formula (I) into a 5 mL vial, adding 102.0 μL of acetone and 5.1 mg of fumaric acid, stirring the sample at room temperature for 6 days, and isolating the solid by filtration to obtain the fumarate salt Form B.

[0106] In another preferred embodiment, the X is fumaric acid; the crystal form is fumarate salt Form E; and the fumarate salt Form E has an XRPD pattern comprising three or more 2θ diffraction peaks selected from the group consisting of: 9.0304 ± 0.20°, 12.3516 ± 0.20°, 12.6066 ± 0.20°, 17.4018 ± 0.20°, 17.7212 ± 0.20°, 18.0895 ± 0.20°, 18.6941 ± 0.20°, 18.9926 ± 0.20°, 21.0620 ± 0.20°, 29.6237 ± 0.20°.

[0107] In another preferred embodiment, the fumarate salt Form E has an XRPD pattern further comprising 2θ diffraction peaks selected from the group consisting of: 8.7812 ± 0.20°, 17.1753 ± 0.20°, 19.5115 ± 0.20°, 22.8451 ± 0.20°, 25.9343 ± 0.20°, 26.8384 ± 0.20°, 29.8874 ± 0.20°, 30.9541 ± 0.20°, 35.1309 ± 0.20°, 36.5704 ± 0.20°.

[0108] In another preferred embodiment, the fumarate salt Form E has one or more characteristics selected from the group consisting of:

[0109] 1) the XRPD pattern of the fumarate salt Form E is substantially as characterized in Figure 15;

[0110] 2) the DSC pattern of the fumarate salt Form E is substantially as characterized in Figure 16;

[0111] 3) the DSC pattern of the fumarate salt Form E has endothermic peaks in the range of 90.5 °C - 94.5 °C, 114.0 °C - 118.0 °C and 163.7 °C - 167.7 °C.

[0112] In another preferred embodiment, the preparation method of the fumarate salt Form E comprises:

[0113] a) slowly evaporating the fumarate salt Form A in methanol to obtain the fumarate salt Form E.

[0114] In another preferred embodiment, the preparation method of the fumarate salt Form E further comprises the preparation method of the fumarate salt Form A.

[0115] In another preferred embodiment, the preparation method of the fumarate salt Form E comprises: weighing 10.8 mg of the fumarate salt Form A into a 5 mL vial, adding 0.5 mL of methanol, assisting dissolving by shaking, filtering (0.45 μm PTFE filter membrane), taking the filtrate, sealing the vial containing the filtrate with a sealing film and punching 3-5 small holes on the sealing film, and placing in a room temperature to slowly evaporate, thereby obtaining the fumarate salt Form E.

[0116] In another preferred embodiment, the X is citric acid; the crystal form is the citrate salt Form A; the XRPD pattern of the citrate salt Form A comprises three or more 2θ diffraction peaks selected from the group consisting of: 8.0517±0.20°, 12.8847±0.20°, 14.2509±0.20°, 15.2838±0.20°, 16.2119±0.20°, 16.6432±0.20°, 16.9270±0.20°, 18.1427±0.20°, 19.7174±0.20°, 19.9457±0.20°, 21.0868±0.20°, 21.9343±0.20°, 25.0505±0.20°, 26.0073±0.20°.

[0117] In another preferred embodiment, the XRPD pattern of the citrate salt Form A further has one or more 2θ diffraction peaks selected from the group consisting of: 10.3613±0.20°, 10.9422±0.20°, 11.7207±0.20°, 13.8184±0.20°, 20.7297±0.20°, 22.6258±0.20°, 23.2142±0.20°, 23.8911±0.20°, 30.3359±0.20°, 32.5518±0.20°.

[0118] In another preferred embodiment, the citrate salt Form A further has one or more characteristics selected from the group consisting of:

[0119] 1) the XRPD pattern of the citrate salt Form A is substantially as characterized in Figure 17;

[0120] 2) the DSC pattern of the citrate salt Form A is substantially as characterized in Figure 18;

[0121] 3) the DSC pattern of the citrate salt Form A has an endothermic peak in the range of 117.3-121.3 °C.

[0122] In another preferred embodiment, the preparation method of the citrate salt Form A comprises:

[0123] a) mixing the compound of formula (I), citric acid and acetone;

[0124] b) stirring at a temperature of 5-50 °C for 1-10 days.

[0125] c) filtration to obtain the citrate salt Form A.

[0126] In another preferred embodiment, the mass ratio of the compound of formula (I) to citric acid is (1-8): 1, preferably (1-5): 1, more preferably (1-3): 1.

[0127] In another preferred embodiment, the method for preparing the citrate salt Form A comprises: weighing 20 mg of the compound of formula (I) into a 5 mL vial, adding 100 μL of acetone and 9.9 mg of citric acid, stirring to suspend at room temperature for 6 days, and filtering to separate the solid to obtain the citrate salt Form A.

[0128] In another preferred embodiment, the X is hydrochloric acid, and the crystal form is the hydrochloride salt Form A; the XRPD pattern of the hydrochloride salt Form A comprises 3 or more 2θ diffraction peaks selected from the group consisting of: 6.1356±0.20°, 12.3538±0.20°, 14.4219±0.20°, 14.9461±0.20°, 18.0322±0.20°, 23.7243±0.20°, 25.2906±0.20°, 28.0063±0.20°.

[0129] In another preferred embodiment, the XRPD pattern of the hydrochloride salt Form A further comprises 2θ diffraction peaks selected from the group consisting of: 3.2504±0.20°, 16.2942±0.20°, 19.0770±0.20°, 20.7647±0.20°, 21.9281±0.20°, 26.6537±0.20°.

[0130] In another preferred embodiment, the hydrochloride salt Form A further has one or more characteristics selected from the group consisting of:

[0131] 1) the XRPD pattern of the hydrochloride salt Form A is substantially as characterized in Figure 19;

[0132] 2) the DSC pattern of the hydrochloride salt Form A is substantially as characterized in Figure 20;

[0133] 3) the DSC pattern of the hydrochloride salt Form A has endothermic peaks in the range of 93.3-97.3 °C, 145.2-149.2 °C and 155.1-159.1 °C.

[0134] In another preferred embodiment, the method for preparing the hydrochloride salt Form A comprises:

[0135] a) mixing the compound of formula (I), hydrochloric acid and ethyl acetate;

[0136] b) stirring at a temperature of 5-50 °C for 1-10 days;

[0137] c) filtration to obtain the hydrochloride salt Form A.

[0138] In another preferred embodiment, the mass to volume ratio of the compound of formula (I) and hydrochloric acid is (1-10): 1 (mg / μL), preferably (2-8): 1 (mg / μL), more preferably (4-6): 1 (mg / μL).

[0139] In another preferred embodiment, the preparation method of the hydrochloride salt Form A comprises: weighing 20 mg of the compound of formula (I) into a 5 mL vial, adding 75 μL of ethyl acetate and 3.7 μL of concentrated hydrochloric acid, stirring and suspending at room temperature for 6 days, and filtering to separate the solid to obtain the hydrochloride salt Form A.

[0140] In another preferred embodiment, the X is hydrochloric acid, and the crystal form is hydrochloride salt Form B; the XRPD pattern of the hydrochloride salt Form B comprises 3 or more 2θ diffraction peaks selected from the group consisting of: 9.9695±0.20°, 10.5366±0.20°, 13.6933±0.20°, 15.6644±0.20°, 19.3701±0.20°, 20.4795±0.20°, 22.0086±0.20°, 22.8505±0.20°, 23.4011±0.20°, 24.0977±0.20°, 24.9281±0.20°, 26.7713±0.20°.

[0141] In another preferred embodiment, the XRPD pattern of the hydrochloride salt Form B further has one or more 2θ diffraction peaks selected from the group consisting of: 11.5303±0.20°, 13.1608±0.20°, 14.2472±0.20°, 16.8317±0.20°, 17.3360±0.20°, 18.2084±0.20°, 21.2259±0.20°, 29.3613±0.20°, 32.1021±0.20°.

[0142] In another preferred embodiment, the hydrochloride salt Form B further has one or more characteristics selected from the group consisting of:

[0143] 1) the XRPD pattern of the hydrochloride salt Form B is substantially as characterized in Figure 21;

[0144] 2) the DSC pattern of the hydrochloride salt Form B is substantially as characterized in Figure 22;

[0145] 3) the DSC pattern of the hydrochloride salt Form B has an endothermic peak in the range of 117.1-121.1 °C.

[0146] In another preferred embodiment, the preparation method of the hydrochloride salt Form B comprises:

[0147] a) mixing the compound of formula (I), hydrochloric acid and acetone;

[0148] b) stirring at a temperature of 5-50 °C for 1-10 days;

[0149] c) filtering to obtain the hydrochloride salt Form B.

[0150] In another preferred embodiment, the mass volume ratio of the compound of formula (I) and hydrochloric acid is (1-10): 1 (mg / μL), preferably (2-8): 1 (mg / μL), more preferably (4-6): 1 (mg / μL).

[0151] In another preferred embodiment, the method for preparing the hydrochloride salt Form B comprises: weighing 20 mg of the compound of formula (I) into a 5 mL vial, adding 75.1 μL of acetone and 3.7 μL of concentrated hydrochloric acid, stirring at room temperature for 6 days, and filtering to separate the solid to obtain the hydrochloride salt Form B.

[0152] In another preferred embodiment, the X is maleic acid, and the crystal form is maleate salt Form A; the XRPD pattern of the maleate salt Form A comprises 3 or more 2θ diffraction peaks selected from the group consisting of: 5.7857±0.20°, 7.0217±0.20°, 13.0388±0.20°, 13.8432±0.20°, 17.4388±0.20°, 26.2828±0.20°, 27.6029±0.20°.

[0153] In another preferred embodiment, the XRPD pattern of the maleate salt Form A further comprises 2θ diffraction peaks selected from the group consisting of: 10.7438±0.20°, 19.1335±0.20°, 23.6142±0.20°, 25.5992±0.20°.

[0154] In another preferred embodiment, the maleate salt Form A further has one or more characteristics selected from the group consisting of:

[0155] 1) the XRPD pattern of the maleate salt Form A is substantially as characterized in Figure 23;

[0156] 2) the DSC pattern of the maleate salt Form A is substantially as characterized in Figure 24;

[0157] 3) the DSC pattern of the maleate salt Form A has an endothermic peak in the range of 122.6-126.6 °C.

[0158] In another preferred embodiment, the method for preparing the maleate salt Form A comprises:

[0159] a) mixing the compound of formula (I), maleic acid and ethyl acetate;

[0160] b) stirring at a temperature of 5-50 °C for 1-10 days;

[0161] c) filtration to obtain the maleate salt Form A.

[0162] In another preferred embodiment, the mass ratio of the compound of formula (I) to maleic acid is (2-10): 1, preferably (3-6): 1, more preferably (3-5): 1.

[0163] In another preferred embodiment, the method for preparing the maleate salt Form A comprises: weighing 19.8 mg of the compound of formula (I) into a 5 mL vial, adding ethyl acetate 101 μL and 5.1 mg of maleic acid, stirring to suspend at room temperature for 6 days, and filtering to separate the solid to obtain the maleate salt Form A.

[0164] In another preferred embodiment, X is oxalic acid, and the crystal form is oxalate salt Form A; the XRPD pattern of the oxalate salt Form A comprises 3 or more 2θ diffraction peaks selected from the group consisting of: 4.3703 ± 0.20°, 5.6634 ± 0.20°, 9.9038 ± 0.20°, 11.2315 ± 0.20°, 11.5985 ± 0.20°, 13.0284 ± 0.20°, 14.2036 ± 0.20°, 15.3713 ± 0.20°, 19.4759 ± 0.20°, 21.2986 ± 0.20°, 22.3009 ± 0.20°, 22.9207 ± 0.20°.

[0165] In another preferred embodiment, the XRPD pattern of the oxalate salt Form A further has 2θ diffraction peaks selected from the group consisting of: 7.4950 ± 0.20°, 17.2958 ± 0.20°, 20.4756 ± 0.20°, 23.6879 ± 0.20°, 25.4147 ± 0.20°, 26.6737 ± 0.20°, 27.1222 ± 0.20°, 29.9694 ± 0.20°.

[0166] In another preferred embodiment, the oxalate salt Form A further has one or more characteristics selected from the group consisting of:

[0167] 1) the XRPD pattern of the oxalate salt Form A is substantially as characterized in Figure 25;

[0168] 2) the DSC pattern of the oxalate salt Form A is substantially as characterized in Figure 26;

[0169] 3) the DSC pattern of the oxalate salt Form A has an endothermic peak in the range of 159.8-163.8 °C.

[0170] In another preferred embodiment, the method for preparing the oxalate salt Form A comprises:

[0171] a) mixing a compound of formula (I), oxalic acid and tetrahydrofuran / water;

[0172] b) stirring at a temperature of 5-50 °C for 1-10 days;

[0173] c) filtering to obtain the oxalate salt Form A.

[0174] In another preferred embodiment, the mass ratio of the compound of formula (I) and oxalic acid is (2-10): 1, preferably (3-6): 1, more preferably (3-5): 1.

[0175] In another preferred embodiment, the volume ratio of the tetrahydrofuran / water is (5-40): 1, preferably (15-30): 1, more preferably (15-25): 1.

[0176] In another preferred embodiment, the method for preparing the oxalate salt Form A comprises: weighing 20.3 mg of the compound of formula (I) into a 5 mL vial, adding 115.7 μL of tetrahydrofuran / water (19: 1, v / v) and 5.7 mg of oxalic acid, stirring at room temperature for 6 days, and filtering to separate the solid to obtain the oxalate salt Form A.

[0177] In another preferred embodiment, the X is oxalic acid, and the crystal form is oxalate salt Form B; the XRPD pattern of the oxalate salt Form B contains three or more 2Q diffraction peaks selected from the group consisting of: 4.8106±0.20°, 9.6280±0.20°, 10.4874±0.20°, 14.0092±0.20°, 14.4623±0.20°, 18.6248±0.20°, 19.3121±0.20°, 23.4088±0.20°.

[0178] In another preferred embodiment, the XRPD pattern of the oxalate salt Form B further has 2Q diffraction peaks selected from the group consisting of: 7.7977±0.20°, 17.3939±0.20°, 20.5879±0.20°, 25.9818±0.20°, 28.6026±0.20°, 30.4754±0.20°.

[0179] In another preferred embodiment, the oxalate salt Form B further has one or more characteristics selected from the group consisting of:

[0180] 1) the XRPD pattern of the oxalate salt Form B is substantially as characterized in Figure 27;

[0181] 2) the DSC pattern of the oxalate salt Form B is substantially as characterized in Figure 28;

[0182] 3) the DSC pattern of the oxalate salt Form B has an endothermic peak in the range of 142.3-146.3 °C and 156.8-160.8 °C, and an exothermic peak in the range of 144.6-148.6 °C.

[0183] In another preferred embodiment, the method for preparing the oxalate salt Form B comprises:

[0184] a) mixing the compound of Formula (I), oxalic acid and ethanol;

[0185] b) stirring at a temperature of 5-50 °C for 1-10 days;

[0186] c) filtering to obtain the oxalate salt Form B.

[0187] In another preferred embodiment, the mass ratio of the compound of Formula (I) and oxalic acid is (2-10): 1, preferably (3-6): 1, more preferably (3-5): 1.

[0188] In another preferred embodiment, the method for preparing the oxalate salt Form B comprises: weighing 20.3 mg of the compound of Formula (I) into a 5 mL vial, adding 115.7 μL of ethanol and 5.7 mg of oxalic acid, and stirring at room temperature for 6 days, and filtering to separate the solid to obtain the oxalate salt Form B.

[0189] In another preferred embodiment, the X is methanesulfonic acid, and the crystal form is a methanesulfonate salt Form A; the XRPD pattern of the methanesulfonate salt Form A comprises 3 or more 2Q diffraction peaks selected from the group consisting of: 10.3356 ± 0.20°, 10.7840 ± 0.20°, 12.2938 ± 0.20°, 16.0821 ± 0.20°, 18.3298 ± 0.20°, 18.7459 ± 0.20°, 21.2257 ± 0.20°, 21.6146 ± 0.20°, 23.9924 ± 0.20°, 24.7225 ± 0.20°.

[0190] In another preferred embodiment, the XRPD pattern of the methanesulfonate salt Form A further comprises 2Q diffraction peaks selected from the group consisting of: 12.0276 ± 0.20°, 13.8679 ± 0.20°, 17.9565 ± 0.20°, 19.1032 ± 0.20°, 20.3166 ± 0.20°, 21.9117 ± 0.20°, 25.9337 ± 0.20°, 26.7897 ± 0.20°, 27.4909 ± 0.20°, 28.0534 ± 0.20°, 28.3905 ± 0.20°, 32.7796 ± 0.20°.

[0191] In another preferred embodiment, the methanesulfonate salt Form A further has one or more characteristics selected from the group consisting of:

[0192] 1) The XRPD pattern of said mesylate salt Form A is substantially as characterized in Figure 29;

[0193] 2) The DSC pattern of said mesylate salt Form A is substantially as characterized in Figure 30;

[0194] 3) The DSC pattern of said mesylate salt Form A has an endothermic peak in the range of 179.9-183.9 °C.

[0195] In another preferred embodiment, the method for preparing said mesylate salt Form A comprises:

[0196] a) mixing a compound of Formula (I), methanesulfonic acid and ethyl acetate;

[0197] b) stirring at a temperature of 5-50 °C for 6-48 h;

[0198] c) stirring at a temperature of 0-15 °C for 1-10 days;

[0199] d) filtering to obtain the mesylate salt Form A.

[0200] In another preferred embodiment, the mass ratio of said compound of Formula (I) and methanesulfonic acid is (2-10): 1, preferably (3-7): 1, more preferably (4-6): 1.

[0201] In another preferred embodiment, the method for preparing said mesylate salt Form A comprises: weighing 19.8 mg of compound of Formula (I) into a 5 mL vial, adding 81.2 μL of ethyl acetate and 4.1 mg of methanesulfonic acid, suspending and stirring the sample at room temperature for 1 day, transferring to 5 °C for stirring for 5 days, and filtering to isolate the solid to obtain the mesylate salt Form A.

[0202] In another preferred embodiment, said X is methanesulfonic acid, and said crystal form is mesylate salt Form B; said mesylate salt Form B has an XRPD pattern comprising 3 or more 2Θ diffraction peaks selected from the group consisting of: 8.2704 ± 0.20°, 14.7351 ± 0.20°, 15.4662 ± 0.20°, 16.5097 ± 0.20°, 18.0449 ± 0.20°, 18.9187 ± 0.20°, 21.4777 ± 0.20°, 21.7910 ± 0.20°, 23.3194 ± 0.20°, 26.2673 ± 0.20°.

[0203] In another preferred embodiment, the XRPD pattern of said mesylate salt Form B further comprises one or more 2Θ diffraction peaks selected from the group consisting of: 6.8124 ± 0.20°, 9.8841 ± 0.20°, 13.6902 ± 0.20°, 16.9916 ± 0.20°, 17.4977 ± 0.20°, 20.5367 ± 0.20°, 21.1464 ± 0.20°, 24.5932 ± 0.20°, 25.2006 ± 0.20°, 27.1578 ± 0.20°, 27.5874 ± 0.20°, 29.6628 ± 0.20°.

[0204] In another preferred embodiment, said mesylate salt Form B further comprises one or more characteristics selected from the group consisting of:

[0205] 1) the XRPD pattern of said mesylate salt Form B is substantially as characterized in Figure 31;

[0206] 2) the DSC pattern of said mesylate salt Form B is substantially as characterized in Figure 32;

[0207] 3) the DSC pattern of said mesylate salt Form B has an endothermic peak in the range of 136.6 °C - 140.6 °C.

[0208] In another preferred embodiment, the process for preparing said mesylate salt Form B comprises:

[0209] a) mixing a compound of formula (I), methanesulfonic acid and ethanol;

[0210] b) stirring at a temperature of 5-50 °C for 1-10 days;

[0211] c) filtering to obtain the mesylate salt Form B.

[0212] In another preferred embodiment, the mass ratio of said compound of formula (I) and methanesulfonic acid is (2-10): 1, preferably (3-7): 1, more preferably (4-6): 1.

[0213] In another preferred embodiment, the process for preparing said mesylate salt Form B comprises: weighing 19.8 mg of compound of formula (I) into a 5 mL vial, adding 89.1 μL of ethanol and 4.5 mg of methanesulfonic acid, suspending and stirring the sample at room temperature for 6 days, and filtering to isolate the solid to obtain the mesylate salt Form B.

[0214] In another preferred embodiment, the X is ethanesulfonic acid, and the crystalline form is ethanesulfonate Form A; the ethanesulfonate Form A has an XRPD pattern comprising three or more 20 diffraction peaks selected from the group consisting of: 10.4848 ± 0.20°, 14.4489 ± 0.20°, 16.3296 ± 0.20°, 18.2904 ± 0.20°, 18.9269 ± 0.20°, 23.0329 ± 0.20°.

[0215] In another preferred embodiment, the ethanesulfonate Form A has an XRPD pattern further comprising 20 diffraction peaks selected from the group consisting of: 12.1929 ± 0.20°, 20.3472 ± 0.20°, 24.5934 ± 0.20°, 25.2132 ± 0.20°.

[0216] In another preferred embodiment, the ethanesulfonate Form A further has one or more characteristics selected from the group consisting of:

[0217] 1) the XRPD pattern of the ethanesulfonate Form A is substantially as characterized in Figure 33;

[0218] 2) the DSC pattern of the ethanesulfonate Form A is substantially as characterized in Figure 34;

[0219] 3) the DSC pattern of the ethanesulfonate Form A has an endothermic peak in the range of 121.8 °C to 125.8 °C.

[0220] In another preferred embodiment, the ethanesulfonate Form A is prepared by a process comprising:

[0221] a) mixing a compound of Formula (I), ethanesulfonic acid and ethanol;

[0222] b) stirring at a temperature of 5 to 50 °C for 1 to 10 days;

[0223] c) filtering to obtain the ethanesulfonate Form A.

[0224] In another preferred embodiment, the mass ratio of the compound of Formula (I) and ethanesulfonic acid is (1 to 8): 1, preferably (1 to 4): 1, more preferably (1 to 3): 1.

[0225] In another preferred embodiment, the ethanesulfonate Form A is prepared by a process comprising: weighing 20.2 mg of the compound of Formula (I) into a 5 mL vial, adding 202.0 μL of ethanol and 10.0 mg of ethanesulfonic acid, and stirring the sample at room temperature for 6 days, and filtering to isolate the solid to obtain the ethanesulfonate Form A.

[0226] In another preferred embodiment, the X is saccharin, and the crystalline form is saccharin salt Form A; the XRPD pattern of the saccharin salt Form A comprises three or more 2Q diffraction peaks selected from the group consisting of: 5.2825 ± 0.20°, 10.6586 ± 0.20°, 14.8562 ± 0.20°, 15.4501 ± 0.20°, 16.0266 ± 0.20°, 19.9548 ± 0.20°, 21.4317 ± 0.20°.

[0227] In another preferred embodiment, the XRPD pattern of the saccharin salt Form A further comprises 2Q diffraction peaks selected from the group consisting of: 8.9153 ± 0.20°, 18.6848 ± 0.20°, 25.0597 ± 0.20°, 27.0087 ± 0.20°.

[0228] In another preferred embodiment, the saccharin salt Form A further has one or more characteristics selected from the group consisting of:

[0229] 1) the XRPD pattern of the saccharin salt Form A is substantially as characterized in Figure 35;

[0230] 2) the DSC pattern of the saccharin salt Form A is substantially as characterized in Figure 36;

[0231] 3) the DSC pattern of the saccharin salt Form A has endothermic peaks in the range of 68.9 °C - 72.9 °C and 113.1 °C - 117.1 °C.

[0232] In another preferred embodiment, the saccharin salt Form A is prepared by a process comprising:

[0233] a) mixing a compound of Formula (I), saccharin and ethanol;

[0234] b) stirring at a temperature of 5-50 °C for 1-10 days;

[0235] c) filtering to obtain the saccharin salt Form A.

[0236] In another preferred embodiment, the mass ratio of the compound of Formula (I) and saccharin is (1-8): 1, preferably (1-4): 1, more preferably (2-3): 1.

[0237] In another preferred embodiment, the saccharin salt Form A is prepared by a process comprising: weighing 20.2 mg of the compound of Formula (I) into a 5 mL vial, adding 164.8 μL of ethanol and 8.2 mg of saccharin, and suspending the sample at room temperature for 6 days with stirring, and filtering to isolate the solid to obtain the saccharin salt Form A.

[0238] In another preferred embodiment, said n is 0, and said crystalline form is anhydrous Form A; said anhydrous Form A has an XRPD pattern comprising three or more peaks selected from the group consisting of: 13.2515 ± 0.20°, 14.2931 ± 0.20°, 17.0618 ± 0.20°, 17.8271 ± 0.20°, 18.1358 ± 0.20°, 20.8501 ± 0.20°, 26.3927 ± 0.20°, 27.5533 ± 0.20°.

[0239] In another preferred embodiment, said anhydrous Form A further has one or more peaks selected from the group consisting of: 11.6785 ± 0.20°, 14.9559 ± 0.20°, 18.9979 ± 0.20°, 21.9771 ± 0.20°, 23.4646 ± 0.20°, 25.2559 ± 0.20°, 25.9502 ± 0.20°, 28.7384 ± 0.20°, 29.5701 ± 0.20°.

[0240] In another preferred embodiment, said anhydrous Form A further has one or more peaks selected from the group consisting of:

[0241] 1) said anhydrous Form A has an XRPD pattern substantially as characterized in Figure 37;

[0242] 2) said anhydrous Form A has a DSC pattern substantially as characterized in Figure 38;

[0243] 3) said anhydrous Form A has a DSC pattern with an endothermic peak in the range of 135.6 °C - 139.6 °C;

[0244] 4) said anhydrous Form A is an anhydrate.

[0245] In another preferred embodiment, said anhydrous Form A is prepared by a process comprising:

[0246] a) mixing a compound of formula (I) with methyl tert-butyl ether;

[0247] b) stirring at a temperature of 5-50 °C for 2-10 days;

[0248] c) filtering to obtain anhydrous Form A.

[0249] In another preferred embodiment, said compound of formula (I) and methyl tert-butyl ether are in a mass to volume ratio of (5-50): 1 (mg / mL).

[0250] In another preferred embodiment, said anhydrous Form A is prepared by a process comprising: weighing 15.4 mg of a compound of formula (I) into a 5 mL vial, adding 0.5 mL of methyl tert-butyl ether, and stirring the solution at room temperature for 6 days, and filtering to isolate the solid to obtain anhydrous Form A as a free form.

[0251] In another preferred embodiment, n is 0, and the crystalline form is anhydrous Form B; the XRPD pattern of the anhydrous Form B comprises three or more peaks selected from the group consisting of: 12.9724 ± 0.20°, 15.7653 ± 0.20°, 17.6842 ± 0.20°, 17.9933 ± 0.20°, 18.8267 ± 0.20°, 19.9255 ± 0.20°, 20.4975 ± 0.20°, 21.0044 ± 0.20°, 21.6138 ± 0.20°, 22.0878 ± 0.20°, 23.4309 ± 0.20°, 23.7649 ± 0.20°.

[0252] In another preferred embodiment, the XRPD pattern of the anhydrous Form B has peaks selected from the group consisting of: 8.5267 ± 0.20°, 9.5010 ± 0.20°, 10.7164 ± 0.20°, 11.0407 ± 0.20°, 13.3675 ± 0.20°, 13.8571 ± 0.20°, 14.2765 ± 0.20°, 19.7264 ± 0.20°, 22.6385 ± 0.20°, 22.9612 ± 0.20°, 25.4361 ± 0.20°, 25.8280 ± 0.20°, 27.0352 ± 0.20°, 27.6250 ± 0.20°, 28.0903 ± 0.20°, 28.4441 ± 0.20°, 31.4666 ± 0.20°.

[0253] In another preferred embodiment, the anhydrous Form B further has one or more characteristics selected from the group consisting of:

[0254] 1) the XRPD pattern of the anhydrous Form B is substantially as characterized in Figure 39;

[0255] 2) the DSC pattern of the anhydrous Form B is substantially as characterized in Figure 40;

[0256] 3) the DSC pattern of the anhydrous Form B has an endothermic peak in the range of 155.4 °C to 159.4 °C;

[0257] 4) the anhydrous Form B is an anhydrate.

[0258] In another preferred embodiment, the method of preparing the anhydrous Form B comprises:

[0259] a) mixing a compound of Formula (I) and ethyl acetate;

[0260] b) stirring at a temperature of 5 to 50 °C for 2 to 10 days;

[0261] c) filtering to obtain the anhydrous Form B.

[0262] In another preferred embodiment, the mass to volume ratio of the compound of formula (I) and ethyl acetate is (5-50): 1 (mg / mL).

[0263] In another preferred embodiment, the method of preparing the anhydrous Form B comprises: weighing 15.4 mg of the compound of formula (I) into a 5 mL vial, adding 0.5 mL of ethyl acetate, suspending and stirring the solution at room temperature for 6 days, and isolating the solid by filtration to obtain the anhydrous Form B.

[0264] In another preferred embodiment, the X is water, and the hydrate Form C; the XRPD pattern of the hydrate Form C comprises 3 or more 2Θ diffraction peaks selected from the group consisting of: 14.2748 ± 0.20°, 17.5137 ± 0.20°, 17.9790 ± 0.20°, 19.7111 ± 0.20°, 19.9345 ± 0.20°, 20.5161 ± 0.20°, 21.4440 ± 0.20°, 22.2261 ± 0.20°, 23.0594 ± 0.20°, 23.7822 ± 0.20°, 28.7022 ± 0.20°.

[0265] In another preferred embodiment, the XRPD pattern of the hydrate Form C has one or more peaks selected from the group consisting of: 8.5152 ± 0.20°, 10.6904 ± 0.20°, 11.1007 ± 0.20°, 11.4605 ± 0.20°, 13.0405 ± 0.20°, 13.8461 ± 0.20°, 15.5683 ± 0.20°, 18.4703 ± 0.20°, 18.8372 ± 0.20°, 20.9938 ± 0.20°, 23.4274 ± 0.20°, 24.6210 ± 0.20°, 25.0432 ± 0.20°, 25.6011 ± 0.20°, 27.0241 ± 0.20°, 28.0774 ± 0.20°, 29.9035 ± 0.20°, 31.9933 ± 0.20°, 33.2859 ± 0.20°.

[0266] In another preferred embodiment, the hydrate Form C further has one or more characteristics selected from the group consisting of:

[0267] 1) the XRPD pattern of the hydrate Form C is substantially as characterized in FIG. 41;

[0268] 2) the DSC pattern of the hydrate Form C is substantially as characterized in FIG. 42;

[0269] 3) the DSC pattern of the hydrate Form C has an endothermic peak in the range of 155.7 °C - 159.7 °C;

[0270] 4) the hydrate crystal form C is a hydrate.

[0271] In another preferred embodiment, the method for preparing the hydrate crystal form C comprises:

[0272] a) mixing the compound of formula (I) and water;

[0273] b) stirring at a temperature of 5-50 °C for 2-10 days;

[0274] c) filtering to obtain the hydrate crystal form C.

[0275] In another preferred embodiment, the mass to volume ratio of the compound of formula (I) and water is (5-50): 1 (mg / mL).

[0276] In another preferred embodiment, the method for preparing the hydrate crystal form C comprises: weighing 15.8 mg of the compound of formula (I) into a 5 mL vial, adding 0.6 mL of water, suspending and stirring the solution at room temperature for 6 days, and filtering to separate the solid to obtain the hydrate crystal form C.

[0277] In a second aspect of the present application, a pharmaceutical composition comprising the crystal form of formula (I) according to the first aspect of the present application is provided, optionally further comprising a pharmaceutically acceptable carrier.

[0278] In another preferred embodiment, the pharmaceutical composition further comprises other antiviral drugs.

[0279] In another preferred embodiment, the composition is suitable for oral and injection administration routes.

[0280] In another preferred embodiment, the composition is suitable for oral administration route.

[0281] In another preferred embodiment, the composition can be prepared into tablets, capsules, dispersions and suspensions.

[0282] In another preferred embodiment, the composition can be prepared into tablets.

[0283] In a third aspect of the present application, the use of the crystal form according to the first aspect of the present application for the preparation of a medicament for the treatment of hepatitis B virus (HBV), hepatitis D virus (HDV) and human immunodeficiency virus (HIV) and diseases caused by them, alone or in combination with other antiviral drugs, is provided.

[0284] It should be understood that, within the scope of the present application, the above technical features of the present application and the technical features specifically described in the following (such as the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they are not listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0285] Figure 1 shows a DSC pattern of sulfate Form B.

[0286] Figure 2 shows an XRPD pattern of sulfate Form B.

[0287] Figure 3 shows an XRPD pattern of sulfate Form A.

[0288] Figure 4 shows a DSC pattern of sulfate Form A.

[0289] Figure 5 shows an XRPD pattern of phosphate Form A.

[0290] Figure 6 shows a DSC pattern of phosphate Form A.

[0291] Figure 7 shows an XRPD pattern of phosphate Form B.

[0292] Figure 8 shows a DSC pattern of phosphate Form B.

[0293] Figure 9 shows an XRPD pattern of phosphate Form C.

[0294] Figure 10 shows a DSC pattern of phosphate Form C.

[0295] Figure 11 shows a DSC pattern of fumarate Form A.

[0296] Figure 12 shows an XRPD pattern of fumarate Form A.

[0297] Figure 13 shows a DSC pattern of fumarate Form B.

[0298] Figure 14 shows an XRPD pattern of fumarate Form B.

[0299] Figure 15 shows a DSC pattern of fumarate Form E.

[0300] Figure 16 shows an XRPD pattern of fumarate Form E.

[0301] Figure 17 shows an XRPD pattern of citrate Form A.

[0302] Figure 18 shows a DSC pattern of citrate Form A.

[0303] Figure 19 shows an XRPD pattern of hydrochloride Form A.

[0304] Figure 20 shows a DSC pattern of hydrochloride Form A.

[0305] Figure 21 shows an XRPD pattern of hydrochloride Form B.

[0306] Figure 22 shows a DSC pattern of hydrochloride Form B.

[0307] Figure 23 shows the XRPD pattern of the maleate salt Form A.

[0308] Figure 24 shows the DSC pattern of the maleate salt Form A.

[0309] Figure 25 shows the DSC pattern of the oxalate salt Form A.

[0310] Figure 26 shows the XRPD pattern of the oxalate salt Form A.

[0311] Figure 27 shows the DSC pattern of the oxalate salt Form B.

[0312] Figure 28 shows the XRPD pattern of the oxalate salt Form B.

[0313] Figure 29 shows the DSC pattern of the mesylate salt Form A.

[0314] Figure 30 shows the XRPD pattern of the mesylate salt Form A.

[0315] Figure 31 shows the DSC pattern of the mesylate salt Form B.

[0316] Figure 32 shows the DSC pattern of the mesylate salt Form B.

[0317] Figure 33 shows the XRPD pattern of the disulfonate salt Form A.

[0318] Figure 34 shows the DSC pattern of the disulfonate salt Form A.

[0319] Figure 35 shows the XRPD pattern of the saccharinate salt Form A.

[0320] Figure 36 shows the DSC pattern of the saccharinate salt Form A.

[0321] Figure 37 shows the XRPD pattern of the anhydrous Form A.

[0322] Figure 38 shows the DSC pattern of the anhydrous Form A.

[0323] Figure 39 shows the XRPD pattern of the anhydrous Form B.

[0324] Figure 40 shows the DSC pattern of the anhydrous Form B.

[0325] Figure 41 shows the XRPD pattern of the hydrate Form C.

[0326] Figure 42 shows the DSC pattern of the hydrate Form C.

[0327] Figure 43 shows the XRPD comparison of the free Form A / B at different temperature suspension competition test.

[0328] Figure 44 shows the XRPD comparison of the free Form A / B / C at different temperature suspension competition test.

[0329] Figure 45 shows the XRPD comparison of the sample before and after stability evaluation of the free form of crystalline form A.

[0330] Figure 46 shows the XRPD comparison of the sample before and after stability evaluation of the free form of crystalline form B.

[0331] Figure 47 shows the XRPD comparison of the sample before and after stability evaluation of the free form of crystalline form C.

[0332] Figure 48 shows the XRPD comparison of the remaining solid of the solubility test of the free form of crystalline form.

[0333] Figure 49 shows the XRPD comparison of the phosphate crystalline form A before and after storage.

[0334] Figure 50 shows the XRPD comparison of the fumarate crystalline form A before and after storage.

[0335] Figure 51 shows the XRPD comparison of the citrate crystalline form A before and after storage.

[0336] Figure 52 shows the XRPD comparison of the sulfate crystalline form B before and after storage. DETAILED DESCRIPTION

[0337] The present inventors, through extensive and in-depth research, through a large number of experimental screening, for the first time accidentally developed a precursor drug against hepatitis B virus (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine and its salt polymorphs and a preparation method thereof, the crystal form of the salt polymorph is selected from the group consisting of sulfate crystalline form B, sulfate crystalline form A, phosphate crystalline form A, phosphate crystalline form B, phosphate crystalline form C, fumarate crystalline form A, fumarate crystalline form B, fumarate crystalline form E, citrate crystalline form A, hydrochloride crystalline form A, hydrochloride crystalline form B, maleate crystalline form A, oxalate crystalline form A, oxalate crystalline form B, mesylate crystalline form A, mesylate crystalline form B, ethanedisulfonate crystalline form A, or saccharin salt crystalline form A; the crystal form of the free form of the polymorph is selected from the group consisting of anhydrous crystalline form A, anhydrous crystalline form B, or hydrate crystalline form C. The polymorphs of the anti-hepatitis B virus drug of the present application (especially sulfate crystalline form B) have the characteristics of high bioavailability, significant drug efficacy, good stability, high yield, and high purity, which can reduce side effects during treatment and improve treatment effect. On this basis, the present application is completed.

[0338] TERMS

[0339] Polymorphs of the liver-delivered antiviral precursor drug nucleoside cyclic phosphate compound and its salt of the present application

[0340] The (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine of the present application, i.e., the compound of formula (I), has the following structure:

[0341] At present, polymorphism of drugs has become an important part in the process of drug research and the process of quality control and detection of finished pharmaceutical products. The research on polymorphism of drugs is helpful to select the biological activity of new drug compounds, improve the bioavailability, enhance the clinical efficacy, select and design the drug administration route, and determine the process parameters of drug preparation, thereby improving the production quality of drugs. The bioavailability of the same drug may differ significantly due to different crystal forms. For the same drug, some crystal forms may have higher biological activity than other crystal forms. Obtaining a crystal form with higher biological activity and more suitable for medical application is a technical problem that has been expected to be solved in the medical field.

[0342] The present application provides a polymorph of (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine and salts thereof.

[0343] In the present application, (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine is a cyclic phosphate ester of an antiviral nucleotide drug. Because the cyclic phosphate ester (4-aryl-2-oxo-1,3,2-dioxaphosphorinane) precursor structure has good liver-specific delivery performance, the mechanism is very clear. The present inventors have obtained a new type of anti-hepatitis B virus drug based on the design of the structure, and obtained a class of prodrugs with liver-specific delivery (liver delivery) effect, so that the efficacy is higher and the side effects are smaller.

[0344] In another preferred embodiment, the polymorph is sulfate Form B, wherein the XRPD pattern of the sulfate Form B contains at least diffraction peaks at 2θ±0.20° of 8.3821, 16.8042, 21.8664, 30.3120.

[0345] Preferably, the XRPD pattern of the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2- fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine sulfate salt Form B comprises at least the diffraction peaks at 2-theta ± 0.20° of 8.3821, 16.8042, 21.8664, 25.4711, 30.3120. More preferably, it further comprises the diffraction peaks at 2-theta ± 0.20° of 10.0213, 18.0850, 18.9828, 20.2120, 21.2977, 23.7487, 24.8583, 28.6460, 34.1748, 34.6187, 37.1125, 38.9996.

[0346] Particularly preferably, the sulfate salt Form B has an XRPD pattern substantially as shown in Figure 1.

[0347] In another preferred embodiment, the polymorph is the sulfate salt Form B, which has a differential thermal analysis result showing an endothermic peak at 185.3 °C (peak temperature).

[0348] In another preferred embodiment, the polymorph is the sulfate salt Form B, which has a DSC pattern substantially as shown in Figure 2.

[0349] In one specific embodiment of the present application, a method for preparing the sulfate salt Form B is also provided, comprising: a) dissolving the starting material in ethyl acetate, and adding dropwise an ethanol solution containing concentrated sulfuric acid, and stirring at room temperature; b) after separating the solid by suction filtration, the target sulfate salt Form B is obtained.

[0350] In another preferred embodiment, the polymorph is the sulfate salt Form A, wherein the XRPD pattern of the sulfate salt Form A comprises at least the diffraction peaks at 2-theta ± 0.20° of 3.9666, 9.3970, 11.6142, 20.8014, 21.6096.

[0351] Preferably, the XRPD pattern of the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2- fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine sulfate salt Form A comprises at least the diffraction peaks at 2-theta ± 0.20° of 3.9666, 9.3970, 11.6142, 19.6179, 20.8014, 21.6096, 23.7426. More preferably, it further comprises the diffraction peaks at 2-theta ± 0.20° of 7.8655, 15.8718, 17.5595, 18.2166, 18.8666, 24.3771, 26.3259, 27.9095, 30.3783, 34.7503.

[0352] Particularly preferred, the sulfate Form A has an XRPD pattern substantially as shown in Figure 3.

[0353] In another preferred embodiment, the polymorph is the sulfate Form A, and the differential thermal analysis of the sulfate Form A shows an endothermic peak at 141.1 °C (peak temperature).

[0354] In another preferred embodiment, the polymorph is the sulfate Form A, and the sulfate Form A has a DSC pattern substantially as shown in Figure 4.

[0355] In another preferred embodiment, the polymorph is the phosphate Form A, and the differential thermal analysis of the phosphate Form A shows an endothermic peak at 196.8 °C (peak temperature).

[0356] In another preferred embodiment, the polymorph is the phosphate Form A, and the XRPD pattern of the phosphate Form A comprises at least the following diffraction peaks: 2Θ ± 0.20°: 6.6968, 10.7641, 12.6320, 16.6756, 20.2549, 23.4036, 26.4374.

[0357] Preferably, the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2- dioxaphosphorinan-2-yl]methyloxypropyl}adenine phosphate Form A has an XRPD pattern comprising at least the following diffraction peaks: 2Θ ± 0.20°: 6.6968, 10.7641, 12.6320, 13.9813, 15.3566, 16.6756, 20.2549, 23.4036, 24.3390, 26.4374. More preferably, it further comprises the following diffraction peaks: 2Θ ± 0.20°: 10.1377, 12.0216, 13.3655, 17.2800, 17.7165, 18.3199, 18.5292, 18.9808, 20.6318, 24.9363, 27.1449, 29.5894.

[0358] Particularly preferred, the phosphate Form A has an XRPD pattern substantially as shown in Figure 5.

[0359] In another preferred embodiment, the polymorph is the phosphate Form A, and the differential thermal analysis of the phosphate Form A shows an endothermic peak at 196.8 °C (peak temperature).

[0360] In another preferred embodiment, the polymorph is the phosphate Form A, and the phosphate Form A has a DSC pattern substantially as shown in Figure 6.

[0361] In one embodiment of the present application, there is further provided a method for preparing the phosphate salt Form A, comprising: a) suspending and stirring the starting material and concentrated phosphoric acid in ethanol at room temperature; b) after separating the solid by suction filtration, obtaining the target phosphate salt Form A.

[0362] In another preferred embodiment, the polymorph is phosphate salt Form B, wherein the XRPD pattern of the phosphate salt Form B comprises at least the following diffraction peaks: 6.0739, 12.1632, 18.0089, 19.9173, 22.5667, 22.7631, 24.2184, 27.0017 at 2Θ ± 0.20°.

[0363] Preferably, the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2- dioxaphosphorinan-2-yl]methyloxypropyl}adenine phosphate salt Form B has an XRPD pattern comprising at least the following diffraction peaks: 6.0739, 12.1632, 12.7958, 18.0089, 18.9774, 19.9173, 22.5667, 22.7631, 24.2184, 25.1475, 27.0017 at 2Θ ± 0.20°. More preferably, it further comprises the following diffraction peaks: 11.2736, 11.6591, 14.4780, 15.7184, 15.9997, 16.6021, 16.8676, 18.2901, 21.7825, 21.9541, 24.4914, 27.8487, 29.8628 at 2Θ ± 0.20°.

[0364] Particularly preferably, the phosphate salt Form B has an XRPD pattern substantially as shown in Figure 7.

[0365] In another preferred embodiment, the polymorph is phosphate salt Form B, and the differential thermal analysis of the phosphate salt Form B shows endothermic peaks at 119.7 °C (peak temperature) and 194.1 °C (peak temperature).

[0366] In another preferred embodiment, the polymorph is phosphate salt Form B, and the phosphate salt Form B has a DSC pattern substantially as shown in Figure 8.

[0367] In one embodiment of the present application, there is further provided a method for preparing the phosphate salt Form B, comprising: a) suspending and stirring the starting material and concentrated phosphoric acid in tetrahydrofuran / water (19:1, v / v) at room temperature; b) after separating the solid by suction filtration, obtaining the target phosphate salt Form B.

[0368] In another preferred embodiment, the polymorph is the phosphate Form C, wherein the XRPD pattern of the phosphate Form C comprises at least the following diffraction peaks: 8.1420, 16.6701, 17.3849, 19.0586, 20.9589, 21.2888, 23.6176, 26.1302, 29.4580 of 2q ± 0.20°.

[0369] Preferably, the XRPD pattern of the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2- fluorophenyl)-2-oxo-l,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine phosphate Form C comprises at least the following diffraction peaks: 8.1420, 15.3443, 16.6701, 17.3849, 17.8823, 19.0586, 20.9589, 21.2888, 21.7201, 23.6176, 26.1302, 29.4580 of 2q ± 0.20°. More preferably, it further comprises the following diffraction peaks: 6.8915, 11.2010, 14.7238, 16.3599, 18.7616, 19.9107, 22.5840, 25.0331, 26.6931, 27.0932, 27.4451, 28.6511, 28.9991, 33.8533, 36.2525 of 2q ± 0.20°.

[0370] Particularly preferably, the phosphate Form C has an XRPD pattern substantially as shown in Figure 9.

[0371] In another preferred embodiment, the polymorph is the phosphate Form C, and the differential thermal analysis of the phosphate Form C shows an endothermic peak at 204.3 °C (peak temperature).

[0372] In another preferred embodiment, the polymorph is the phosphate Form C, and the phosphate Form C has a DSC pattern substantially as shown in Figure 10.

[0373] In one embodiment of the present application, a method for preparing the phosphate Form C is also provided, comprising: a) stirring the starting material and concentrated phosphoric acid in ethanol at room temperature, and then transferring to stirring at 50 °C; b) separating the solid by suction filtration to obtain the target phosphate Form C.

[0374] In another preferred embodiment, the polymorph is the fumarate Form A, wherein the XRPD pattern of the fumarate Form A comprises at least the following diffraction peaks: 8.5376, 9.3019, 13.2247, 17.5380 of 2q ± 0.20°.

[0375] Preferably, the XRPD pattern of the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2- fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine fumarate crystal form A comprises at least the following diffraction peaks: 8.5376, 9.3019, 13.2247, 17.5380, 18.9356, 22.1653 at 2q ± 0.20°. More preferably, it further comprises the following diffraction peaks: 4.6110, 16.3131, 25.4876, 26.2282 at 2q ± 0.20°.

[0376] Particularly preferably, the fumarate crystal form A has an XRPD pattern substantially as shown in Figure 11.

[0377] In another preferred embodiment, the polymorph is the fumarate crystal form A, and the fumarate crystal form A has a differential thermal analysis result showing endothermic peaks at 94.9 °C (peak temperature) and 167.0 °C (peak temperature).

[0378] In another preferred embodiment, the polymorph is the fumarate crystal form A, and the fumarate crystal form A has a DSC pattern substantially as shown in Figure 12.

[0379] In one embodiment of the present application, there is also provided a method for preparing the fumarate crystal form A, comprising: a) suspending and stirring the starting material and fumaric acid in ethanol at room temperature; b) separating the solid after suction filtration to obtain the target fumarate crystal form A.

[0380] In another preferred embodiment, the polymorph is the fumarate crystal form B, and the XRPD pattern of the fumarate crystal form B comprises at least the following diffraction peaks: 12.1477, 18.2849, 24.4247, 30.7722 at 2q ± 0.20°.

[0381] Preferably, the XRPD pattern of the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2- fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine fumarate crystal form B comprises at least the following diffraction peaks: 12.1477, 18.2849, 19.5748, 24.4247, 30.7722 at 2q ± 0.20°. More preferably, it further comprises the following diffraction peaks: 13.1470, 14.6236, 21.7551 at 2q ± 0.20°.

[0382] Particularly preferably, the fumarate crystal form B has an XRPD pattern substantially as shown in Figure 13.

[0383] In another preferred embodiment, the polymorph is Form B fumarate salt, which has a differential thermal analysis result showing an endothermic peak at 136.0 °C (peak temperature).

[0384] In another preferred embodiment, the polymorph is Form B fumarate salt, which has a DSC pattern substantially as shown in Figure 14.

[0385] In another preferred embodiment, the polymorph is Form B fumarate salt, which has a DSC pattern substantially as shown in Figure 14.

[0386] In another preferred embodiment, the polymorph is Form E fumarate salt, wherein the Form E fumarate salt has an XRPD pattern comprising at least diffraction peaks at 2Q ± 0.20° of: 12.3516, 12.6066, 17.4018, 17.7212, 18.0895, 21.0620, 29.6237.

[0387] Preferably, the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2- dioxaphosphorinan-2-yl]methyloxypropyl}adenine Form E fumarate salt has an XRPD pattern comprising at least diffraction peaks at 2Q ± 0.20° of: 9.0304, 12.3516, 12.6066, 17.4018, 17.7212, 18.0895, 18.6941, 18.9926, 21.0620, 29.6237. More preferably, it further comprises diffraction peaks at 2Q ± 0.20° of: 8.7812, 17.1753, 19.5115, 22.8451, 25.9343, 26.8384, 29.8874, 30.9541, 35.1309, 36.5704.

[0388] Particularly preferably, the Form E fumarate salt has an XRPD pattern substantially as shown in Figure 15.

[0389] In another preferred embodiment, the polymorph is Form E fumarate salt, which has a differential thermal analysis result showing endothermic peaks at 92.5 °C (peak temperature), 116.0 °C (peak temperature) and 165.7 °C (peak temperature).

[0390] In another preferred embodiment, the polymorph is Form E fumarate salt, which has a DSC pattern substantially as shown in Figure 16.

[0391] In one embodiment of the present application, there is further provided a preparation method of the fumarate salt crystal form E, comprising: slowly evaporating the fumarate salt crystal form A in methanol to obtain the target fumarate salt crystal form E.

[0392] In another preferred embodiment, the polymorph is the citrate salt crystal form A, wherein the XRPD pattern of the citrate salt crystal form A comprises at least diffraction peaks at 2θ±0.20° of: 12.8847, 14.2509, 15.2838, 16.6432, 16.9270, 18.1427, 19.7174, 19.9457, 21.0868, 21.9343, 26.0073.

[0393] Preferably, the XRPD pattern of the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine citrate salt crystal form A comprises at least diffraction peaks at 2θ±0.20° of: 8.0517, 12.8847, 14.2509, 15.2838, 16.2119, 16.6432, 16.9270, 18.1427, 19.7174, 19.9457, 21.0868, 21.9343, 25.0505, 26.0073. More preferably, it further comprises diffraction peaks at 2θ±0.20° of: 10.3613, 10.9422, 11.7207, 13.8184, 20.7297, 22.6258, 23.2142, 23.8911, 30.3359, 32.5518.

[0394] Particularly preferably, the citrate salt crystal form A has an XRPD pattern substantially as shown in Figure 17.

[0395] In another preferred embodiment, the polymorph is the citrate salt crystal form A, and the differential thermal analysis result of the citrate salt crystal form A shows an endothermic peak at 119.3°C (peak temperature).

[0396] In another preferred embodiment, the polymorph is the citrate salt crystal form A, and the citrate salt crystal form A has a DSC pattern substantially as shown in Figure 18.

[0397] In one embodiment of the present application, there is further provided a preparation method of the citrate salt crystal form A, comprising: a) suspending and stirring the starting material and citric acid in acetone at room temperature; b) after separating the solid by suction filtration, obtaining the target citrate salt crystal form A.

[0398] In another preferred embodiment, the polymorph is the hydrochloride salt Form A, wherein the XRPD pattern of the hydrochloride salt Form A comprises at least the following diffraction peaks: 6.1356, 12.3538, 14.4219, 18.0322, 23.7243 at 2Θ ± 0.20°.

[0399] Preferably, the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2- dioxaphosphorinan-2-yl]methyloxypropyl}adenine hydrochloride salt Form A has an XRPD pattern comprising at least the following diffraction peaks: 6.1356, 12.3538, 14.4219, 14.9461, 18.0322, 23.7243, 25.2906, 28.0063 at 2Θ ± 0.20°. More preferably, it further comprises the following diffraction peaks: 3.2504, 16.2942, 19.0770, 20.7647, 21.9281, 26.6537 at 2Θ ± 0.20°.

[0400] Particularly preferably, the hydrochloride salt Form A has an XRPD pattern substantially as shown in Figure 19.

[0401] In another preferred embodiment, the polymorph is the hydrochloride salt Form A, and the differential thermal analysis of the hydrochloride salt Form A shows endothermic peaks at 95.3 °C (peak temperature), 147.2 °C (peak temperature) and 157.1 °C (peak temperature).

[0402] In another preferred embodiment, the polymorph is the hydrochloride salt Form A, and the hydrochloride salt Form A has a DSC pattern substantially as shown in Figure 20.

[0403] In one embodiment of the present application, there is also provided a method for preparing the hydrochloride salt Form A, comprising: a) suspending and stirring the starting material and concentrated hydrochloric acid in ethyl acetate at room temperature; b) separating the solid by suction filtration to obtain the target hydrochloride salt Form A.

[0404] In another preferred embodiment, the polymorph is the hydrochloride salt Form B, wherein the XRPD pattern of the hydrochloride salt Form B comprises at least the following diffraction peaks: 9.9695, 10.5366, 13.6933, 15.6644, 19.3701, 20.4795, 22.8505, 23.4011, 24.0977, 24.9281 at 2Θ ± 0.20°.

[0405] Preferably, the XRPD pattern of the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2- fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine hydrochloride salt Form B comprises at least the following diffraction peaks: 9.9695, 10.5366, 13.6933, 15.6644, 19.3701, 20.4795, 22.0086, 22.8505, 23.4011, 24.0977, 24.9281, 26.7713 at 2Θ ± 0.20°. More preferably, it further comprises the following diffraction peaks: 11.5303, 13.1608, 14.2472, 16.8317, 17.3360, 18.2084, 21.2259, 29.3613, 32.1021 at 2Θ ± 0.20°.

[0406] Particularly preferably, the hydrochloride salt Form B has an XRPD pattern substantially as shown in Figure 21.

[0407] In another preferred embodiment, the polymorph is the hydrochloride salt Form B, which has a differential thermal analysis result showing an endothermic peak at 119.1 °C (peak temperature).

[0408] In another preferred embodiment, the polymorph is the hydrochloride salt Form B, which has a DSC pattern substantially as shown in Figure 22.

[0409] In one specific embodiment of the present application, there is also provided a method for preparing the hydrochloride salt Form B, comprising: a) suspending and stirring the starting material and concentrated hydrochloric acid in acetone at room temperature; b) separating the solid after suction filtration to obtain the target hydrochloride salt Form B.

[0410] In another preferred embodiment, the polymorph is the maleate salt Form A, wherein the maleate salt Form A has an XRPD pattern comprising at least the following diffraction peaks: 5.7857, 13.0388, 13.8432, 17.4388, 27.6029 at 2Θ ± 0.20°.

[0411] Preferably, the XRPD pattern of the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2- fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine maleate salt Form A comprises at least the following diffraction peaks: 5.7857, 7.0217, 13.0388, 13.8432, 17.4388, 26.2828, 27.6029 at 2Θ ± 0.20°. More preferably, it further comprises the following diffraction peaks: 10.7438, 19.1335, 23.6142, 25.5992 at 2Θ ± 0.20°.

[0412] Particularly preferred, the maleate salt Form A has an XRPD pattern substantially as shown in Figure 23.

[0413] In another preferred embodiment, the polymorph is maleate salt Form A, and the maleate salt Form A has a differential thermal analysis result showing an endothermic peak at 124.6 °C (peak temperature).

[0414] In another preferred embodiment, the polymorph is maleate salt Form A, and the maleate salt Form A has a DSC pattern substantially as shown in Figure 24.

[0415] In another preferred embodiment, the polymorph is maleate salt Form A, and the maleate salt Form A has a DSC pattern substantially as shown in Figure 24.

[0416] In another preferred embodiment, the polymorph is oxalate salt Form A, and the oxalate salt Form A has an XRPD pattern comprising at least diffraction peaks at 2Θ ± 0.20° of: 4.3703, 5.6634, 9.9038, 11.2315, 11.5985, 14.2036, 15.3713, 19.4759, 21.2986, 22.9207.

[0417] Preferably, the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2- dioxaphosphorinan-2-yl]methyloxypropyl}adenine oxalate salt Form A has an XRPD pattern comprising at least diffraction peaks at 2Θ ± 0.20° of: 4.3703, 5.6634, 9.9038, 11.2315, 11.5985, 13.0284, 14.2036, 15.3713, 19.4759, 21.2986, 22.3009, 22.9207. More preferably, it further comprises diffraction peaks at 2Θ ± 0.20° of: 7.4950, 17.2958, 20.4756, 23.6879, 25.4147, 26.6737, 27.1222, 29.9694.

[0418] Particularly preferred, the oxalate salt Form A has an XRPD pattern substantially as shown in Figure 25.

[0419] In another preferred embodiment, the polymorph is oxalate salt Form A, and the oxalate salt Form A has a differential thermal analysis result showing endothermic peaks at 106.2 °C (peak temperature) and 161.8 °C (peak temperature).

[0420] In another preferred embodiment, the polymorph is oxalate salt Form A, and the oxalate salt Form A has a DSC pattern substantially as shown in Figure 26.

[0421] In one embodiment of the present application, there is further provided a method for preparing oxalate Form A, comprising: a) suspending and stirring the starting material and oxalic acid in tetrahydrofuran / water (19:1, v / v) at room temperature; b) after separating the solid by suction filtration, obtaining the target oxalate Form A.

[0422] In another preferred embodiment, the polymorph is oxalate Form B, wherein the XRPD pattern of the oxalate Form B comprises at least the following diffraction peaks: 4.8106, 9.6280, 10.4874, 14.0092, 14.4623, 19.3121, 2θ ± 0.20°.

[0423] Preferably, the XRPD pattern of (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo- 1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine oxalate Form B comprises at least the following diffraction peaks: 4.8106, 9.6280, 10.4874, 14.0092, 14.4623, 18.6248, 19.3121, 23.4088, 2θ ± 0.20°. More preferably, it further comprises the following diffraction peaks: 7.7977, 17.3939, 20.5879, 25.9818, 28.6026, 30.4754, 2θ ± 0.20°.

[0424] Particularly preferably, the oxalate Form B has an XRPD pattern substantially as shown in Figure 27.

[0425] In another preferred embodiment, the polymorph is oxalate Form B, wherein the differential thermal analysis of the oxalate Form B shows endothermic peaks at 144.3 °C (peak temperature) and 158.8 °C (peak temperature), and an exothermic peak at 146.6 °C (peak temperature).

[0426] In another preferred embodiment, the polymorph is oxalate Form B, wherein the differential thermal analysis of the oxalate Form B shows endothermic peaks at 144.3 °C (peak temperature) and 158.8 °C (peak temperature), and an exothermic peak at 146.6 °C (peak temperature).

[0427] In one embodiment of the present application, there is further provided a method for preparing oxalate Form B, comprising: a) suspending and stirring the starting material and oxalic acid in ethanol at room temperature; b) after separating the solid by suction filtration, obtaining the target oxalate Form B.

[0428] In another preferred embodiment, the polymorph is methanesulfonate Form A, wherein the XRPD pattern of the methanesulfonate Form A comprises at least the following diffraction peaks: 10.3356, 12.2938, 18.3298, 18.7459, 21.2257, 23.9924, 24.7225, 2θ ± 0.20°.

[0429] Preferably, the XRPD pattern of the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2- fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine mesylate salt Form A comprises at least the following diffraction peaks: 10.3356, 10.7840, 12.2938, 16.0821, 18.3298, 18.7459, 21.2257, 21.6146, 23.9924, 24.7225 of 2q ± 0.20°. More preferably, it further comprises the following diffraction peaks: 12.0276, 13.8679, 17.9565, 19.1032, 20.3166, 21.9117, 25.9337, 26.7897, 27.4909, 28.0534, 28.3905, 32.7796 of 2q ± 0.20°.

[0430] Particularly preferably, the mesylate salt Form A has an XRPD pattern substantially as shown in Figure 29.

[0431] In another preferred embodiment, the polymorph is mesylate salt Form A, and the differential thermal analysis of the mesylate salt Form A shows an endothermic peak at 181.9 °C (peak temperature).

[0432] In another preferred embodiment, the polymorph is mesylate salt Form A, and the mesylate salt Form A has a DSC pattern substantially as shown in Figure 30.

[0433] In one specific embodiment of the present application, there is also provided a method for preparing the mesylate salt Form A, comprising: a) stirring the starting material and methanesulfonic acid in ethyl acetate at room temperature, and then transferring to stirring at 5 °C; b) separating the solid by suction filtration to obtain the target mesylate salt Form A.

[0434] In another preferred embodiment, the polymorph is mesylate salt Form B, and the XRPD pattern of the mesylate salt Form B comprises at least the following diffraction peaks: 14.7351, 15.4662, 16.5097, 18.9187, 21.4777, 21.7910, 23.3194, 26.2673 of 2q ± 0.20°.

[0435] Preferably, the XRPD pattern of the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2- fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine mesylate Form B comprises at least the following diffraction peaks: 8.2704, 14.7351, 15.4662, 16.5097, 18.0449, 18.9187, 21.4777, 21.7910, 23.3194, 26.2673 at 2θ±0.20°. More preferably, it further comprises the following diffraction peaks: 6.8124, 9.8841, 13.6902, 16.9916, 17.4977, 20.5367, 21.1464, 24.5932, 25.2006, 27.1578, 27.5874, 29.6628 at 2θ±0.20°.

[0436] Particularly preferably, the mesylate salt Form B has an XRPD pattern substantially as shown in Figure 31.

[0437] In another preferred embodiment, the polymorph is mesylate salt Form B, and the mesylate salt Form B has a differential thermal analysis result showing an endothermic peak at 138.6 °C (peak temperature).

[0438] In another preferred embodiment, the polymorph is mesylate salt Form B, and the mesylate salt Form B has a DSC pattern substantially as shown in Figure 32.

[0439] In one specific embodiment of the present application, there is also provided a method for preparing the mesylate salt Form B, comprising: a) suspending and stirring the starting material and methanesulfonic acid in ethanol at room temperature; and b) separating the solid after suction filtration to obtain the target mesylate salt Form B.

[0440] In another preferred embodiment, the polymorph is ethanedisulfonate salt Form A, and the ethanedisulfonate salt Form A has an XRPD pattern comprising at least the following diffraction peaks: 10.4848, 14.4489, 18.2904, 18.9269, 23.0329 at 2θ±0.20°.

[0441] Preferably, the XRPD pattern of the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2- fluorophenyl)-2-oxo-1,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine ethanedisulfonate salt Form A comprises at least the following diffraction peaks: 10.4848, 14.4489, 16.3296, 18.2904, 18.9269, 23.0329 at 2θ±0.20°. More preferably, it further comprises the following diffraction peaks: 12.1929, 20.3472, 24.5934, 25.2132 at 2θ±0.20°.

[0442] Particularly preferred, the ethanedisulfonate salt Form A has an XRPD pattern substantially as shown in Figure 33.

[0443] In another preferred embodiment, the polymorph is ethanedisulfonate salt Form A, and the ethanedisulfonate salt Form A has a differential thermal analysis result showing an endothermic peak at 123.8 °C (peak temperature).

[0444] In another preferred embodiment, the polymorph is ethanedisulfonate salt Form A, and the ethanedisulfonate salt Form A has a DSC pattern substantially as shown in Figure 34.

[0445] In one embodiment of the present application, a preparation method of ethanedisulfonate salt Form A is also provided, comprising: a) suspending and stirring starting materials and ethanedisulfonic acid in ethanol at room temperature; b) after separating the solid by suction filtration, obtaining the target ethanedisulfonate salt Form A.

[0446] In another preferred embodiment, the polymorph is saccharinate salt Form A, and the saccharinate salt Form A has an XRPD pattern comprising at least diffraction peaks at 2Q ± 0.20° of: 5.2825, 10.6586, 16.0266, 19.9548.

[0447] Preferably, the saccharinate salt Form A of (2R)-9-{2-[(2R,4S)-4-(5-chloro-2- fluorophenyl)-2-oxo-l,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine has an XRPD pattern comprising at least diffraction peaks at 2Q ± 0.20° of: 5.2825, 10.6586, 14.8562, 15.4501, 16.0266, 19.9548, 21.4317. More preferably, it further comprises diffraction peaks at 2Q ± 0.20° of: 8.9153, 18.6848, 25.0597, 27.0087.

[0448] Particularly preferred, the saccharinate salt Form A has an XRPD pattern substantially as shown in Figure 35.

[0449] In another preferred embodiment, the polymorph is saccharinate salt Form A, and the saccharinate salt Form A has a differential thermal analysis result showing endothermic peaks at 70.9 °C (peak temperature) and 115.1 °C (peak temperature).

[0450] In another preferred embodiment, the polymorph is saccharinate salt Form A, and the saccharinate salt Form A has a DSC pattern substantially as shown in Figure 36.

[0451] In one embodiment of the present application, a preparation method of saccharinate salt Form A is also provided, comprising: a) suspending and stirring starting materials and saccharin in ethanol at room temperature; b) after separating the solid by suction filtration, obtaining the target saccharinate salt Form A.

[0452] In another preferred embodiment, the polymorph is the free anhydrous crystalline Form A, wherein the XRPD pattern of the Form A comprises at least the following diffraction peaks: 13.2515, 14.2931, 17.0618, 17.8271, 18.1358, 27.5533 at 2Θ ± 0.20°.

[0453] Preferably, the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2- dioxaphosphorinan-2-yl]methyloxypropyl}adenine anhydrous crystalline Form A has an XRPD pattern comprising at least the following diffraction peaks: 13.2515, 14.2931, 17.0618, 17.8271, 18.1358, 20.8501, 26.3927, 27.5533 at 2Θ ± 0.20°. More preferably, it further comprises the following diffraction peaks: 11.6785, 14.9559, 18.9979, 21.9771, 23.4646, 25.2559, 25.9502, 28.7384, 29.5701 at 2Θ ± 0.20°.

[0454] Particularly preferably, the free anhydrous crystalline Form A has an XRPD pattern substantially as shown in Figure 37.

[0455] In another preferred embodiment, the polymorph is the free anhydrous crystalline Form A, wherein the differential thermal analysis of the anhydrous Form A shows an endothermic peak at 137.6 °C (peak temperature).

[0456] In another preferred embodiment, the polymorph is the free anhydrous crystalline Form A, wherein the anhydrous Form A has a DSC pattern substantially as shown in Figure 38.

[0457] In one embodiment of the present application, a process for preparing the free anhydrous crystalline Form A is also provided, comprising: a) suspending and stirring the starting material in methyl tert-butyl ether at room temperature; b) separating the solid by suction filtration to obtain the target anhydrous Form A.

[0458] In another preferred embodiment, the polymorph is the free anhydrous crystalline Form B, wherein the XRPD pattern of the Form B comprises at least the following diffraction peaks: 17.6842, 17.9933, 18.8267, 19.9255, 20.4975, 21.0044, 21.6138, 22.0878, 23.4309 at 2Θ ± 0.20°.

[0459] Preferably, the XRPD pattern of the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2- fluorophenyl)-2-oxo-l,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine anhydrate Form B comprises at least the diffraction peaks at 2Q ± 0.20° of: 12.9724, 15.7653, 17.6842, 17.9933, 18.8267, 19.9255, 20.4975, 21.0044, 21.6138, 22.0878, 23.4309, 23.7649. More preferably, it further comprises the diffraction peaks at 2Q ± 0.20° of: 8.5267, 9.5010, 10.7164, 11.0407, 13.3675, 13.8571, 14.2765, 19.7264, 22.6385, 22.9612, 25.4361, 25.8280, 27.0352, 27.6250, 28.0903, 28.4441, 31.4666.

[0460] Particularly preferably, the free anhydrate Form B has an XRPD pattern substantially as shown in Figure 39.

[0461] In another preferred embodiment, the polymorph is the free anhydrate Form B, which has a differential thermal analysis result showing an endothermic peak at 157.4 °C (peak temperature).

[0462] In another preferred embodiment, the polymorph is the free anhydrate Form B, which has a DSC pattern substantially as shown in Figure 40.

[0463] In one specific embodiment of the present application, there is also provided a method for preparing the free anhydrate Form B, comprising: a) suspending and stirring the starting material in ethyl acetate at room temperature; b) separating the solid by suction filtration to obtain the target anhydrate Form B.

[0464] In another preferred embodiment, the polymorph is the free hydrate Form C, wherein the XRPD pattern of the Form C comprises at least the diffraction peaks at 2Q ± 0.20° of: 14.2748, 17.5137, 17.9790, 19.7111, 19.9345, 20.5161, 21.4440, 22.2261.

[0465] Preferably, the XRPD pattern of the (2R)-9-{2-[(2R,4S)-4-(5-chloro-2- fluorophenyl)-2-oxo-l,3,2-dioxaphosphorinan-2-yl]methyloxypropyl}adenine hydrate Form C comprises at least the following diffraction peaks: 2Θ ± 0.20°: 14.2748, 17.5137, 17.9790, 19.7111, 19.9345, 20.5161, 21.4440, 22.2261, 23.0594, 23.7822, 28.7022. More preferably, it further comprises the following diffraction peaks: 2Θ ± 0.20°: 8.5152, 10.6904, 11.1007, 11.4605, 13.0405, 13.8461, 15.5683, 18.4703, 18.8372, 20.9938, 23.4274, 24.6210, 25.0432, 25.6011, 27.0241, 28.0774, 29.9035, 31.9933, 33.2859.

[0466] Particularly preferably, the free hydrate Form C has an XRPD pattern substantially as shown in Figure 41.

[0467] In another preferred embodiment, the polymorph is the free hydrate Form C, and the hydrate Form C has a differential thermal analysis result showing an endothermic peak at 157.7 °C (peak temperature).

[0468] In another preferred embodiment, the polymorph is the free hydrate Form C, and the hydrate Form C has a DSC pattern substantially as shown in Figure 42.

[0469] In one embodiment of the present application, there is also provided a method for preparing the free hydrate Form C, comprising: a) suspending and stirring the starting material in water at room temperature; b) separating the solid by suction filtration to obtain the target hydrate Form C.

[0470] In the present application, there is also provided a pharmaceutical composition comprising an effective amount of the crystal form, and optionally, the composition further comprises a pharmaceutically acceptable carrier.

[0471] The composition of the present application includes those suitable for oral and injection administration routes. Preferably, the oral administration route. The dosage forms include tablets, capsules, dispersions and suspensions, preferably tablets.

[0472] In the present application, there is also provided the use of the crystal form and the pharmaceutical composition containing the crystal form in the treatment of hepatitis B virus (HBV), hepatitis D virus (HDV) and human immunodeficiency virus (HIV) and diseases caused by them, alone or in combination with other antiviral drugs.

[0473] Compared with the prior art, the application has the following beneficial effects:

[0474] The new polymorph of the application has the characteristics of significant drug effect, good stability, high yield and high purity. The new polymorph of the application is helpful for the selection and design of drug administration routes and the determination of drug preparation process parameters, thereby improving the production quality of drugs.

[0475] The application will be further described below in combination with specific embodiments. It should be understood that the embodiments are only used for illustrating the application and are not used for limiting the scope of the application. The experimental methods in the following examples are generally carried out according to conventional conditions or according to the conditions recommended by the manufacturers unless the specific conditions are indicated. Unless otherwise specified, the percentages and parts are calculated by weight.

[0476] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art. In addition, any method and material similar or equivalent to those described herein can be used in the present application.

[0477] The experimental materials and reagents used in the following examples can be obtained from commercial channels unless otherwise specified.

[0478] Example 1: Preparation of sulfate salt Form B

[0479] 400.2 mg of the starting sample and 10 mL of ethyl acetate were weighed into a 20 mL vial, 1 mL of an ethanol solution containing 49 μL of concentrated sulfuric acid was added dropwise into the 20 mL vial, and the sample was stirred at room temperature for 6 days, and then the solid was separated by filtration to obtain sulfate salt Form B.

[0480] The obtained solid was subjected to X-ray powder diffraction test, and the X-ray powder diffraction pattern thereof was consistent with that of FIG. 1, proving that the obtained solid was sulfate salt Form B. The powder diffraction data of sulfate salt Form B are shown in Table 1.

[0481] Table 1: Powder diffraction data of sulfate salt Form B

[0482] Example 2: Preparation of sulfate salt Form A

[0483] 19.8 mg of the starting sample was weighed into a 5 mL vial, 47.5 μL of ethyl acetate and 2.4 μL of concentrated sulfuric acid were added, and the sample was stirred at room temperature for 1 day, then transferred to 50°C for stirring for 3 hours, and then the solid was separated by filtration to obtain sulfate salt Form A.

[0484] The obtained solid was subjected to X-ray powder diffraction test, and the X-ray powder diffraction pattern thereof was consistent with that of FIG. 3, proving that the obtained solid was sulfate salt Form A. The powder diffraction data of sulfate salt Form A are shown in Table 2.

[0485] Table 2: Powder Diffraction Data for Sulfate Form A

[0486] Example 3: Preparation of Phosphate Form A

[0487] A 19.9 mg sample of the starting material was weighed into a 5 mL vial, 59.7 μL of ethanol and 3.0 μL of concentrated phosphoric acid were added, and the sample was stirred with suspension at room temperature for 6 days. The solid was isolated by filtration to give Phosphate Form A.

[0488] The resulting solid was tested by X-ray powder diffraction, and the X-ray powder diffraction pattern was consistent with Figure 5, confirming that the resulting solid was Phosphate Form A. The powder diffraction data for Phosphate Form A are shown in Table 3.

[0489] Table 3: Powder Diffraction Data for Phosphate Form A

[0490] Example 4: Preparation of Phosphate Form B

[0491] A 19.9 mg sample of the starting material was weighed into a 5 mL vial, 59.7 μL of tetrahydrofuran / water (19:1, v / v) and 3.0 μL of concentrated phosphoric acid were added, and the sample was stirred with suspension at room temperature for 6 days. The solid was isolated by filtration to give Phosphate Form B.

[0492] The resulting solid was tested by X-ray powder diffraction, and the X-ray powder diffraction pattern was consistent with Figure 7, confirming that the resulting solid was Phosphate Form B. The powder diffraction data for Phosphate Form B are shown in Table 4.

[0493] Table 4: Powder Diffraction Data for Phosphate Form B

[0494] Example 5: Preparation of Phosphate Form C

[0495] A 400.4 mg sample of the starting material was weighed into a 20 mL vial, 4 mL of ethanol was added, and a solution of 60 μL of concentrated phosphoric acid in 2 mL of ethanol was added dropwise. The sample was stirred with suspension at room temperature for 3 days, then at 50 °C for 6 hours, and then at room temperature for 10 days. The solid was isolated by filtration to give Phosphate Form C.

[0496] The resulting solid was tested by X-ray powder diffraction, and the X-ray powder diffraction pattern was consistent with Figure 9, confirming that the resulting solid was Phosphate Form C. The powder diffraction data for Phosphate Form C are shown in Table 5.

[0497] Table 5: Powder Diffraction Data for Phosphate Form C

[0498] Example 6: Preparation of fumarate salt Form A

[0499] A 20.0 mg starting sample was weighed into a 5 mL vial, 100.0 μL of ethanol and 5.0 mg of fumaric acid were added, the sample was stirred under suspension at room temperature for 6 days, the solid was separated by filtration to obtain fumarate salt Form A.

[0500] The obtained solid was subjected to X-ray powder diffraction test, the X-ray powder diffraction pattern thereof was consistent with that of Figure 11, proving that the obtained was fumarate salt Form A, and the powder diffraction data of fumarate salt Form A are shown in Table 6.

[0501] Table 6: Powder diffraction data of fumarate salt Form A

[0502] Example 7: Preparation of fumarate salt Form B

[0503] A 20.0 mg starting sample was weighed into a 5 mL vial, 102.0 μL of acetone and 5.1 mg of fumaric acid were added, the sample was stirred under suspension at room temperature for 6 days, the solid was separated by filtration to obtain fumarate salt Form B.

[0504] The obtained solid was subjected to X-ray powder diffraction test, the X-ray powder diffraction pattern thereof was consistent with that of Figure 13, proving that the obtained was fumarate salt Form B, and the powder diffraction data of fumarate salt Form B are shown in Table 7.

[0505] Table 7: Powder diffraction data of fumarate salt Form B

[0506] Example 8: Preparation of fumarate salt Form E

[0507] A 10.8 mg fumarate salt Form A was weighed into a 5 mL vial, 0.5 mL of methanol was added, after being dissolved by shaking and filtration (0.45 μm PTFE filter membrane), the filtrate was taken, the vial containing the filtrate was sealed with sealing film and 3-5 small holes were punched on it, and was placed at room temperature for slow evaporation to obtain the target fumarate salt Form E.

[0508] The obtained solid was subjected to X-ray powder diffraction test, the X-ray powder diffraction pattern thereof was consistent with that of Figure 15, proving that the obtained was fumarate salt Form E, and the powder diffraction data of fumarate salt Form E are shown in Table 8.

[0509] Table 8: Powder diffraction data of fumarate salt Form E

[0510] Example 9: Preparation of citrate salt Form A

[0511] A 20.1 mg sample of the starting material was weighed into a 5 mL vial, 100.0 μL of acetone and 9.9 mg of citric acid were added, and the sample was stirred with suspension at room temperature for 6 days. The solid was separated by filtration to give citrate Form A.

[0512] The X-ray powder diffraction pattern of the obtained solid was consistent with that of Figure 17, demonstrating that the obtained was citrate Form A. The powder diffraction data of citrate Form A are shown in Table 9.

[0513] Table 9: Powder diffraction data of citrate Form A

[0514] Example 10: Preparation of hydrochloride Form A

[0515] A 20.3 mg sample of the starting material was weighed into a 5 mL vial, 75.1 μL of ethyl acetate and 3.7 μL of concentrated hydrochloric acid were added, and the sample was stirred with suspension at room temperature for 6 days. The solid was separated by filtration to give hydrochloride Form A.

[0516] The X-ray powder diffraction pattern of the obtained solid was consistent with that of Figure 19, demonstrating that the obtained was hydrochloride Form A. The powder diffraction data of hydrochloride Form A are shown in Table 10.

[0517] Table 10: Powder diffraction data of hydrochloride Form A

[0518] Example 11: Preparation of hydrochloride Form B

[0519] A 20.0 mg sample of the starting material was weighed into a 5 mL vial, 75.1 μL of acetone and 3.7 μL of concentrated hydrochloric acid were added, and the sample was stirred with suspension at room temperature for 6 days. The solid was separated by filtration to give hydrochloride Form B.

[0520] The X-ray powder diffraction pattern of the obtained solid was consistent with that of Figure 21, demonstrating that the obtained was hydrochloride Form B. The powder diffraction data of hydrochloride Form B are shown in Table 11.

[0521] Table 11: Powder diffraction data of hydrochloride Form B

[0522] Example 12: Preparation of maleate Form A

[0523] A 19.8 mg sample of the starting material was weighed into a 5 mL vial, 101.0 μL of ethyl acetate and 5.1 mg of maleic acid were added, and the sample was stirred with suspension at room temperature for 6 days. The solid was separated by filtration to give maleate Form A.

[0524] The resulting solid was tested by X-ray powder diffraction, which gave a pattern consistent with Figure 23, confirming that the resulting was the maleate salt Form A. The powder diffraction data for the maleate salt Form A is shown in Table 12.

[0525] Table 12: Powder diffraction data for the maleate salt Form A

[0526] Example 13: Preparation of oxalate salt Form A

[0527] A 20.3 mg sample of the starting material was weighed into a 5 mL vial, 115.7 μL of tetrahydrofuran / water (19: 1, v / v) and 5.7 mg of oxalic acid were added, and the sample was stirred with suspension at room temperature for 6 days. The solid was isolated by filtration to give the oxalate salt Form A.

[0528] The resulting solid was tested by X-ray powder diffraction, which gave a pattern consistent with Figure 25, confirming that the resulting was the oxalate salt Form A. The powder diffraction data for the oxalate salt Form A is shown in Table 13.

[0529] Table 13: Powder diffraction data for the oxalate salt Form A

[0530] Example 14: Preparation of oxalate salt Form B

[0531] A 20.3 mg sample of the starting material was weighed into a 5 mL vial, 115.7 μL of tetrahydrofuran / water (19: 1, v / v) and 5.7 mg of oxalic acid were added, and the sample was stirred with suspension at room temperature for 6 days. The solid was isolated by filtration to give the oxalate salt Form A.

[0532] The resulting solid was tested by X-ray powder diffraction, which gave a pattern consistent with Figure 27, confirming that the resulting was the oxalate salt Form B. The powder diffraction data for the oxalate salt Form B is shown in Table 14.

[0533] Table 14: Powder diffraction data for the oxalate salt Form B

[0534] Example 15: Preparation of methanesulfonate salt Form A

[0535] A 19.8 mg sample of the starting material was weighed into a 5 mL vial, 81.2 μL of ethyl acetate and 4.1 mg of methanesulfonic acid were added, and the sample was stirred with suspension at room temperature for 1 day. The sample was then transferred to a 5 °C stirring for 5 days. The solid was isolated by filtration to give the methanesulfonate salt Form A.

[0536] The resulting solid was tested by X-ray powder diffraction, which gave a pattern consistent with Figure 29, confirming that the resulting was the methanesulfonate salt Form A. The powder diffraction data for the methanesulfonate salt Form A is shown in Table 15.

[0537] Table 15: Powder Diffraction Data for Mesylate Form A

[0538] Example 16: Preparation of Mesylate Form B

[0539] A 19.8 mg sample of the starting material was weighed into a 5 mL vial, 89.1 μL of ethanol and 4.5 mg of methanesulfonic acid were added, and the sample was stirred with suspension at room temperature for 6 days. The solid was separated by filtration to obtain mesylate Form B.

[0540] The obtained solid was tested by X-ray powder diffraction, and the X-ray powder diffraction pattern thereof was consistent with that of FIG. 31, proving that the obtained was mesylate Form B. The powder diffraction data of mesylate Form B are shown in Table 16.

[0541] Table 16: Powder Diffraction Data for Mesylate Form B

[0542] Example 17: Preparation of Edisylate Form A

[0543] A 20.2 mg sample of the starting material was weighed into a 5 mL vial, 202.0 μL of ethanol and 10.0 mg of edisylate were added, and the sample was stirred with suspension at room temperature for 6 days. The solid was separated by filtration to obtain edisylate Form A.

[0544] The obtained solid was tested by X-ray powder diffraction, and the X-ray powder diffraction pattern thereof was consistent with that of FIG. 33, proving that the obtained was edisylate Form A. The powder diffraction data of edisylate Form A are shown in Table 17.

[0545] Table 17: Powder Diffraction Data for Edisylate Form A

[0546] Example 18: Preparation of Saccharinate Form A

[0547] A 20.1 mg sample of the starting material was weighed into a 5 mL vial, 164.8 μL of ethanol and 8.2 mg of saccharin were added, and the sample was stirred with suspension at room temperature for 6 days. The solid was separated by filtration to obtain saccharinate Form A.

[0548] The obtained solid was tested by X-ray powder diffraction, and the X-ray powder diffraction pattern thereof was consistent with that of FIG. 35, proving that the obtained was saccharinate Form A. The powder diffraction data of saccharinate Form A are shown in Table 18.

[0549] Table 18: Powder Diffraction Data for Saccharinate Form A

[0550] Example 19: Preparation of free anhydrous Form A

[0551] A 15.4 mg starting sample was weighed into a 5 mL vial, 0.5 mL of methyl tert-butyl ether was added, the sample was stirred with suspension at room temperature for 6 days, and the solid was separated by filtration to obtain free anhydrous Form A.

[0552] The obtained solid was tested by X-ray powder diffraction, and the X-ray powder diffraction pattern thereof was consistent with that of FIG. 37, proving that the obtained was free anhydrous Form A. The powder diffraction data of anhydrous Form A are shown in Table 19.

[0553] Table 19: Powder diffraction data of free anhydrous Form A

[0554] Example 20: Preparation of free anhydrous Form B

[0555] A 15.4 mg starting sample was weighed into a 5 mL vial, 0.5 mL of ethyl acetate was added, the sample was stirred with suspension at room temperature for 6 days, and the solid was separated by filtration to obtain free anhydrous Form B.

[0556] The obtained solid was tested by X-ray powder diffraction, and the X-ray powder diffraction pattern thereof was consistent with that of FIG. 39, proving that the obtained was free anhydrous Form B. The powder diffraction data of anhydrous Form B are shown in Table 20.

[0557] Table 20: Powder diffraction data of free anhydrous Form B

[0558] Example 21: Preparation of free hydrate Form C

[0559] A 15.8 mg starting sample was weighed into a 5 mL vial, 0.6 mL of water was added, the sample was stirred with suspension at room temperature for 6 days, and the solid was separated by filtration to obtain free hydrate Form C.

[0560] The obtained solid was tested by X-ray powder diffraction, and the X-ray powder diffraction pattern thereof was consistent with that of FIG. 41, proving that the obtained was free hydrate Form C. The powder diffraction data of hydrate Form C are shown in Table 21.

[0561] Table 21: Powder diffraction data of free hydrate Form C

[0562] Example 22: Study on transition relationship of free anhydrous forms

[0563] The results of the study of the free anhydrous crystal form showed that crystal form B and crystal form A were a single variable relationship. From the DSC results (Figures 38 and 40), it can be seen that the melting point and melting enthalpy of crystal form B are higher, indicating that the thermodynamic stability of crystal form B is higher than that of crystal form A. To further confirm, a suspension competition test was set up at 5°C, room temperature and 50°C in methyl ethyl ketone, respectively. According to the comparison results in Figure 43, crystal form B was obtained at different temperatures.

[0564] Table 22: Summary of suspension competition results of free crystal forms A and B

[0565] Example 23: Study on the conversion relationship between free anhydrous crystal form and hydrate crystal form

[0566] To study the critical water activity of the conversion between free anhydrous crystal form A / B and hydrate crystal form C, a suspension competition test of crystal forms A / B / C at room temperature under different water activity conditions was set up. As shown in Table 23, first, a saturated solution of crystal form A in different water activity systems was prepared by room temperature beating, and crystal forms A / B / C were added to 0.4 milliliters of the saturated solution in equal mass ratio to form a suspension, which was stirred at room temperature (about 500 rpm) for 1 day, and then sampled for XRPD test. According to the comparison results in Figure 44, crystal form B was obtained under the condition of water activity ≤0.4, and crystal form C was obtained under the condition of water activity 1.0. Since the solubility of crystal form A in water activity 0.6 and 0.8 systems is high (>800 milligrams / milliliter), it is difficult to prepare a saturated solution, and the suspension results under this condition are not obtained. The results are summarized in Table 23.

[0567] To further narrow the range of conversion water activity, a rough solubility test of crystal forms B / C in water activity 0.5 system at room temperature was set up. The results are shown in Table 24. The solubility of crystal form B is higher than that of crystal form C in water activity 0.5 system at room temperature, indicating that crystal form C has higher stability in water activity 0.5 system. Based on the above studies, crystal form B is more stable under the condition of water activity ≤0.4 at room temperature, and crystal form C is more stable under the condition of water activity ≥0.5.

[0568] Table 23: Summary of suspension competition results of free crystal forms A, B and C

[0569] NA: Since the solubility of crystal form A in water activity 0.6 and 0.8 systems is high (>800 milligrams / milliliter), it is difficult to prepare a saturated solution, and the suspension results under this condition are not obtained.

[0570] Table 24: Rough solubility of free crystal forms B and C under water activity 0.5

[0571] Example 24: Solid-state stability of free crystal form

[0572] To evaluate the solid state stability of the free form of Form A / B / C, aliquots of samples were placed open at 25°C / 60% RH and 40°C / 75% RH for one week, while another set of samples was placed sealed at 80°C for 24 hours. The samples after storage were characterized by XRPD and HPLC to detect the change of crystal form and chemical purity. The results are summarized in Table 25, which shows that Form A did not observe purity and crystal form change under the test conditions. Form B and C also have good chemical stability. But Form B and C were observed to have crystal transformation under high humidity and high temperature conditions, respectively. The XRPD comparison graphs are shown in Figures 45, 46 and 47.

[0573] Table 25: Summary of free form of Form A / B / C solid state stability evaluation results

[0574] Example 25: Solubility determination of free form of Form

[0575] The solubility of free form of Form A / B / C in water was collected at room temperature for 2 hours and 24 hours. The corresponding Form samples were weighed into water to prepare a suspension, after stirring at room temperature for 24 hours, the sample was centrifuged, the solid was used for XRPD test, and the supernatant was used for solubility test. The results of Figure 48 show that Form A / B / C all transformed into Form C in water at room temperature within 2 hours, the solubility was 4-6 mg / mL, see Table 26 for details.

[0576] Table 26: Summary of solubility data of free form of Form A / B / C in water

[0577] Example 26: Solubility determination of the preferred salt form

[0578] The solubility of the two preferred salt forms of phosphate Form A in SGF, sulfate Form B in H2O, artificial gastric juice with surfactant (SGF), artificial gastric juice under fasting conditions (FaSSIF) and artificial gastric juice under feeding conditions (FeSSIF) was further evaluated. The results are shown in Table 27, compared with the free form, both salt forms showed higher solubility in the corresponding system (≥15 vs, 8-12 mg / mL).

[0579] Table 27: Rough solubility evaluation of phosphate A and sulfate B

[0580] Example 27: Physicochemical stability

[0581] Four candidate salt forms were subjected to physical and chemical stability studies by placing samples at 25 °C / 60% RH (open) and 40 °C / 75% RH (open) for one week. The samples after the placement were tested by XRPD and HPLC to evaluate their physical and chemical stability, respectively. The XRPD comparison plots are shown in Figures 49-52, and the results are summarized in Table 28.

[0582] The fumarate Form A sample showed no change in purity and crystal form, but a decrease in crystallinity after being placed at 25 °C / 60% RH and 40 °C / 75% RH open for one week (Figure 50). The phosphate Form A, citrate Form A, and sulfate Form B showed no change in purity or crystal form after being placed at 25 °C / 60% RH and 40 °C / 75% RH open for one week, demonstrating better physical and chemical stability.

[0583] Table 28: Summary of one week stability test results WP: white powder. FC: form change.

[0584] All documents referred to in this disclosure are incorporated herein by reference as if each were individually incorporated by reference. In addition, it is to be understood that the application can be carried out by specifically different embodiments and that embodiments can be practiced without the specific details that are set forth above. Further, it should be noted that various modifications and alternatives can be apparent to one of ordinary skill in the art having the benefit of this disclosure, without departing from the scope of the application.

Claims

1. A crystal form of (2R)-9-{2-[(2R,4S)-4-(5-chloro-2-fluorophenyl)-2-oxo-1,3,2-dioxaphosphanecyclohexane-2-yl]methoxypropyl}adenine as shown in formula (IA), in, m is 1-10; n is 0-20; X is selected from the following group: water, sulfuric acid, phosphoric acid, fumaric acid, citric acid, hydrochloric acid, maleic acid, oxalic acid, methanesulfonic acid, ethanedisulfonic acid, saccharin.

2. The crystal form as described in claim 1, characterized in that, X is sulfuric acid, and the crystal form is sulfate crystal form B; the XRPD pattern of sulfate crystal form B contains three or more 2θ diffraction peaks selected from the following group: 8.3821±0.20°, 16.8042±0.20°, 21.8664±0.20°, 25.4711±0.20°, 30.3120±0.20°.

3. The crystal form as described in claim 2, characterized in that, The XRPD pattern of the sulfate crystal form B also includes 2θ diffraction peaks selected from the following group: 10.0213±0.20°, 18.0850±0.20°, 18.9828±0.20°, 20.2120±0.20°, 21.2977±0.20°, 23.7487±0.20°, 24.8583±0.20°, 28.6460±0.20°, 34.1748±0.20°, 34.6187±0.20°, 37.1125±0.20°, 38.9996±0.20°.

4. The crystal form as described in claim 2, characterized in that, The sulfate crystal form B also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the sulfate crystal form B is basically characterized as shown in Figure 1; 2) The DSC spectrum of the sulfate crystal form B is basically characterized as shown in Figure 2; 3) The DSC spectrum of the sulfate crystal form B has an endothermic peak in the range of 183.3℃-187.3℃.

5. The crystal form as described in claim 1, characterized in that, X is sulfuric acid, and the crystal form is sulfate crystal form A; the XRPD pattern of sulfate crystal form A contains three or more 2θ diffraction peaks selected from the following group: 3.9666±0.20°, 9.3970±0.20°, 11.6142±0.20°, 19.6179±0.20°, 20.8014±0.20°, 21.6096±0.20°, 23.7426±0.20°.

6. The crystal form as described in claim 5, characterized in that, The XRPD pattern of the sulfate crystal form A also includes 2θ diffraction peaks selected from the following group: 7.8655±0.20°, 15.8718±0.20°, 17.5595±0.20°, 18.2166±0.20°, 18.8666±0.20°, 24.3771±0.20°, 26.3259±0.20°, 27.9095±0.20°, 30.3783±0.20°, 34.7503±0.20°.

7. The crystal form as described in claim 5, characterized in that, The sulfate crystal form A also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the sulfate crystal form A is basically characterized as shown in Figure 3; 2) The DSC spectrum of the sulfate crystal form A is basically characterized as shown in Figure 4; 3) The DSC spectrum of the sulfate crystal form A has an endothermic peak in the range of 139.1℃-143.1℃.

8. The crystal form as described in claim 1, characterized in that, X is phosphoric acid, and the crystal form is phosphate crystal form A; the XRPD pattern of phosphate crystal form A contains three or more 2θ diffraction peaks selected from the following group: 6.6968±0.20°, 10.7641±0.20°, 12.6320±0.20°, 13.9813±0.20°, 15.3566±0.20°, 16.6756±0.20°, 20.2549±0.20°, 23.4036±0.20°, 24.3390±0.20°, 26.4374±0.20°.

9. The crystal form as described in claim 8, characterized in that, The phosphate crystal form A further includes 2θ diffraction peaks selected from the following group: 10.1377±0.20°, 12.0216±0.20°, 13.3655±0.20°, 17.2800±0.20°, 17.7165±0.20°, 18.3199±0.20°, 18.5292±0.20°, 18.9808±0.20°, 20.6318±0.20°, 24.9363±0.20°, 27.1449±0.20°, 29.5894±0.20°.

10. The crystal form as described in claim 8, characterized in that, The phosphate crystal form A also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the phosphate crystal form A is basically characterized as shown in Figure 5; 2) The DSC spectrum of the phosphate crystal form A is basically characterized as shown in Figure 6; 3) The DSC spectrum of the phosphate crystal form A has an endothermic peak in the range of 194.8℃-198.8℃.

11. The crystal form as described in claim 1, characterized in that, X is phosphoric acid, and the crystal form is phosphate crystal form B; the XRPD pattern of phosphate crystal form B contains three or more 2θ diffraction peaks selected from the following group: 6.0739±0.20°, 12.1632±0.20°, 12.7958±0.20°, 18.0089±0.20°, 18.9774±0.20°, 19.9173±0.20°, 22.5667±0.20°, 22.7631±0.20°, 24.2184±0.20°, 25.1475±0.20°, 27.0017±0.20°.

12. The crystal form as described in claim 11, characterized in that, The phosphate crystal form B also contains 2θ diffraction peaks selected from the following group: 11.2736±0.20°, 11.6591±0.20°, 14.4780±0.20°, 15.7184±0.20°, 15.9997±0.20°, 16.6021±0.20°, 16.8676±0.20°, 18.2901±0.20°, 21.7825±0.20°, 21.9541±0.20°, 24.4914±0.20°, 27.8487±0.20°, 29.8628±0.20°.

13. The crystal form as described in claim 11, characterized in that, The phosphate crystal form B also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the phosphate crystal form B is basically characterized as shown in Figure 7; 2) The DSC spectrum of the phosphate crystal form B is basically characterized as shown in Figure 8; 3) The DSC spectrum of the phosphate crystal form B has endothermic peaks in the ranges of 117.7℃-121.7℃ and 192.1℃-196.1℃.

14. The crystal form as described in claim 1, characterized in that, X is phosphoric acid, and the crystal form is phosphate crystal form C; the XRPD pattern of phosphate crystal form C contains three or more 2θ diffraction peaks selected from the following group: 8.1420±0.20°, 15.3443±0.20°, 16.6701±0.20°, 17.3849±0.20°, 17.8823±0.20°, 19.0586±0.20°, 20.9589±0.20°, 21.2888±0.20°, 21.7201±0.20°, 23.6176±0.20°, 26.1302±0.20°, 29.4580±0.20°.

15. The crystal form as described in claim 14, characterized in that, The phosphate crystal form C also contains 2θ diffraction peaks selected from the following group: 6.8915±0.20°, 11.2010±0.20°, 14.7238±0.20°, 16.3599±0.20°, 18.7616±0.20°, 19.9107±0.20°, 22.5840±0.20°, 25.0331±0.20°, 26.6931±0.20°, 27.0932±0.20°, 27.4451±0.20°, 28.6511±0.20°, 28.9991±0.20°, 33.8533±0.20°, 36.2525±0.20°.

16. The crystal form as described in claim 14, characterized in that, The phosphate crystal form C also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the phosphate crystal form C is basically characterized as shown in Figure 9; 2) The DSC spectrum of the phosphate crystal form C is basically characterized as shown in Figure 10; 3) The DSC spectrum of the phosphate crystal form C has an endothermic peak in the range of 202.3℃-206.3℃.

17. The crystal form as described in claim 1, characterized in that, X is fumaric acid, and the crystal form is fumarate crystal form A; the XRPD pattern of fumarate crystal form A contains three or more 2θ diffraction peaks selected from the following group: 8.5376±0.20°, 9.3019±0.20°, 13.2247±0.20°, 17.5380±0.20°, 18.9356±0.20°, 22.1653±0.20°.

18. The crystal form as described in claim 17, characterized in that, The XRPD pattern of the fumarate crystal form A also has 2θ diffraction peaks selected from the following group: 4.6110±0.20°, 16.3131±0.20°, 25.4876±0.20°, 26.2282±0.20°.

19. The crystal form as described in claim 17, characterized in that, The fumarate crystal form A also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the fumarate crystal form A is basically characterized as shown in Figure 11; 2) The DSC spectrum of the fumarate crystal form A is basically characterized as shown in Figure 12; 3) The DSC spectrum of the fumarate crystal form A has endothermic peaks in the ranges of 92.9℃-96.9℃ and 165.7℃-169.7℃.

20. The crystal form as described in claim 1, characterized in that, X is fumaric acid, and the crystal form is fumarate crystal form B; the XRPD pattern of fumarate crystal form B contains three or more 2θ diffraction peaks selected from the following group: 12.1477±0.20°, 18.2849±0.20°, 19.5748±0.20°, 24.4247±0.20°, 30.7722±0.20°.

21. The crystal form as described in claim 20, characterized in that, The XRPD pattern of the fumarate crystal form B also has 2θ diffraction peaks selected from the following group: 13.1470±0.20°, 14.6236±0.20°, 21.7551±0.20°.

22. The crystal form as described in claim 20, characterized in that, The fumarate crystal form B also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the fumarate crystal form B is basically characterized as shown in Figure 13; 2) The DSC spectrum of the fumarate crystal form B is basically characterized as shown in Figure 14; 3) The DSC spectrum of the fumarate crystal form B has an endothermic peak in the range of 134.0℃-138.0℃.

23. The crystal form as described in claim 1, characterized in that, X is fumaric acid; the crystal form is fumarate crystal form E; the XRPD pattern of fumarate crystal form E contains three or more 2θ diffraction peaks selected from the following group: 9.0304±0.20°, 12.3516±0.20°, 12.6066±0.20°, 17.4018±0.20°, 17.7212±0.20°, 18.0895±0.20°, 18.6941±0.20°, 18.9926±0.20°, 21.0620±0.20°, 29.6237±0.20°.

24. The crystal form as described in claim 23, characterized in that, The XRPD pattern of the fumarate crystal form E also has 2θ diffraction peaks selected from the following group: 8.7812±0.20°, 17.1753±0.20°, 19.5115±0.20°, 22.8451±0.20°, 25.9343±0.20°, 26.8384±0.20°, 29.8874±0.20°, 30.9541±0.20°, 35.1309±0.20°, 36.5704±0.20°.

25. The crystal form as described in claim 23, characterized in that, The fumarate crystal form E also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the fumarate crystal form E is basically characterized as shown in Figure 15; 2) The DSC spectrum of the fumarate crystal form E is basically characterized as shown in Figure 16; 3) The DSC spectrum of the fumarate crystal form E has endothermic peaks in the ranges of 90.5℃-94.5℃, 114.0℃-118.0℃ and 163.7℃-167.7℃.

26. The crystal form as described in claim 1, characterized in that, X is citric acid; the crystal form is citrate crystal form A; the XRPD pattern of citrate crystal form A contains three or more 2θ diffraction peaks selected from the following group: 8.0517±0.20°, 12.8847±0.20°, 14.2509±0.20°, 15.2838±0.20°, 16.2119±0.20°, 16.6432±0.20°, 16.9270±0.20°, 18.1427±0.20°, 19.7174±0.20°, 19.9457±0.20°, 21.0868±0.20°, 21.9343±0.20°, 25.0505±0.20°, 26.0073±0.20°.

27. The crystal form as described in claim 26, characterized in that, The XRPD pattern of the citrate crystal form A also has 2θ diffraction peaks selected from the following group: 10.3613±0.20°, 10.9422±0.20°, 11.7207±0.20°, 13.8184±0.20°, 20.7297±0.20°, 22.6258±0.20°, 23.2142±0.20°, 23.8911±0.20°, 30.3359±0.20°, 32.5518±0.20°.

28. The crystal form as described in claim 26, characterized in that, The citrate crystal form A also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the citrate crystal form A is basically characterized as shown in Figure 17; 2) The DSC spectrum of the citrate crystal form A is basically characterized as shown in Figure 18; 3) The DSC spectrum of the citrate crystal form A has an endothermic peak in the range of 117.3℃-121.3℃.

29. The crystal form as described in claim 1, characterized in that, X is hydrochloric acid, and the crystal form is hydrochloride crystal form A; the XRPD pattern of the hydrochloride crystal form A contains three or more 2θ diffraction peaks selected from the following group: 6.1356±0.20°, 12.3538±0.20°, 14.4219±0.20°, 14.9461±0.20°, 18.0322±0.20°, 23.7243±0.20°, 25.2906±0.20°, 28.0063±0.20°.

30. The crystal form as described in claim 29, characterized in that, The XRPD pattern of the hydrochloride crystal form A also has 2θ diffraction peaks selected from the following group: 3.2504±0.20°, 16.2942±0.20°, 19.0770±0.20°, 20.7647±0.20°, 21.9281±0.20°, 26.6537±0.20°.

31. The crystal form as described in claim 29, characterized in that, The hydrochloride crystal form A also has one or more features selected from the group consisting of: 1) The XRPD pattern of the hydrochloride crystal form A is basically characterized as shown in Figure 19; 2) The DSC spectrum of the hydrochloride crystal form A is basically characterized as shown in Figure 20; 3) The DSC spectrum of the hydrochloride crystal form A has endothermic peaks in the ranges of 93.3℃-97.3℃, 145.2℃-149.2℃ and 155.1℃-159.1℃.

32. The crystal form as described in claim 1, characterized in that, X is hydrochloric acid, and the crystal form is hydrochloride crystal form B; the XRPD pattern of the hydrochloride crystal form B contains three or more 2θ diffraction peaks selected from the following group: 9.9695±0.20°, 10.5366±0.20°, 13.6933±0.20°, 15.6644±0.20°, 19.3701±0.20°, 20.4795±0.20°, 22.0086±0.20°, 22.8505±0.20°, 23.4011±0.20°, 24.0977±0.20°, 24.9281±0.20°, 26.7713±0.20°.

33. The crystal form as described in claim 32, characterized in that, The XRPD pattern of the hydrochloride crystal form B also has 2θ diffraction peaks selected from the following group: 11.5303±0.20°, 13.1608±0.20°, 14.2472±0.20°, 16.8317±0.20°, 17.3360±0.20°, 18.2084±0.20°, 21.2259±0.20°, 29.3613±0.20°, 32.1021±0.20°.

34. The crystal form as described in claim 32, characterized in that, The hydrochloride crystal form B also has one or more features selected from the group consisting of: 1) The XRPD pattern of the hydrochloride crystal form B is basically characterized as shown in Figure 21; 2) The DSC spectrum of the hydrochloride crystal form B is basically characterized as shown in Figure 22; 3) The DSC spectrum of the hydrochloride crystal form B has an endothermic peak in the range of 117.1℃-121.1℃.

35. The crystal form as described in claim 1, characterized in that, X is maleic acid, and the crystal form is maleate crystal form A; the XRPD pattern of maleate crystal form A contains three or more 2θ diffraction peaks selected from the following group: 5.7857±0.20°, 7.0217±0.20°, 13.0388±0.20°, 13.8432±0.20°, 17.4388±0.20°, 26.2828±0.20°, 27.6029±0.20°.

36. The crystal form as described in claim 35, characterized in that, The XRPD pattern of the maleate crystal form A also has 2θ diffraction peaks selected from the following group: 10.7438±0.20°, 19.1335±0.20°, 23.6142±0.20°, 25.5992±0.20°.

37. The crystal form as described in claim 35, characterized in that, The maleate crystal form A also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the maleate crystal form A is basically characterized as shown in Figure 23; 2) The DSC spectrum of the maleate crystal form A is basically characterized as shown in Figure 24; 3) The DSC spectrum of the maleate crystal form A has an endothermic peak in the range of 122.6℃-126.6℃.

38. The crystal form as described in claim 1, characterized in that, X is oxalic acid, and the crystal form is oxalate crystal form A; the XRPD pattern of oxalate crystal form A contains three or more 2θ diffraction peaks selected from the following group: 4.3703±0.20°, 5.6634±0.20°, 9.9038±0.20°, 11.2315±0.20°, 11.5985±0.20°, 13.0284±0.20°, 14.2036±0.20°, 15.3713±0.20°, 19.4759±0.20°, 21.2986±0.20°, 22.3009±0.20°, 22.9207±0.20°.

39. The crystal form as described in claim 38, characterized in that, The XRPD pattern of the oxalate crystal form A also has 2θ diffraction peaks selected from the following group: 7.4950±0.20°, 17.2958±0.20°, 20.4756±0.20°, 23.6879±0.20°, 25.4147±0.20°, 26.6737±0.20°, 27.1222±0.20°, 29.9694±0.20°.

40. The crystal form as described in claim 38, characterized in that, The oxalate crystal form A also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the oxalate crystal form A is basically characterized as shown in Figure 25; 2) The DSC spectrum of the oxalate crystal form A is basically characterized as shown in Figure 26; 3) The DSC spectrum of the oxalate crystal form A has an endothermic peak in the range of 159.8℃-163.8℃.

41. The crystal form as described in claim 1, characterized in that, X is oxalic acid, and the crystal form is oxalate crystal form B; the XRPD pattern of oxalate crystal form B contains three or more 2θ diffraction peaks selected from the following group: 4.8106±0.20°, 9.6280±0.20°, 10.4874±0.20°, 14.0092±0.20°, 14.4623±0.20°, 18.6248±0.20°, 19.3121±0.20°, 23.4088±0.20°.

42. The crystal form as described in claim 41, characterized in that, The XRPD pattern of the oxalate crystal form B also has 2θ diffraction peaks selected from the following group: 7.7977±0.20°, 17.3939±0.20°, 20.5879±0.20°, 25.9818±0.20°, 28.6026±0.20°, 30.4754±0.20°.

43. The crystal form as described in claim 41, characterized in that, The oxalate crystal form B also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the oxalate crystal form B is basically characterized as shown in Figure 27; 2) The DSC spectrum of the oxalate crystal form B is basically characterized as shown in Figure 28; 3) The DSC spectrum of the oxalate crystal form B has endothermic peaks in the ranges of 142.3℃-146.3℃ and 156.8℃-160.8℃, and exothermic peaks in the range of 144.6℃-148.6℃.

44. The crystal form as described in claim 1, characterized in that, X is methanesulfonic acid, and the crystal form is methanesulfonate crystal form A; the XRPD pattern of methanesulfonate crystal form A contains three or more 2θ diffraction peaks selected from the following group: 10.3356±0.20°, 10.7840±0.20°, 12.2938±0.20°, 16.0821±0.20°, 18.3298±0.20°, 18.7459±0.20°, 21.2257±0.20°, 21.6146±0.20°, 23.9924±0.20°, 24.7225±0.20°.

45. The crystal form as described in claim 44, characterized in that, The XRPD pattern of the methanesulfonate crystal form A also has 2θ diffraction peaks selected from the following group: 12.0276±0.20°, 13.8679±0.20°, 17.9565±0.20°, 19.1032±0.20°, 20.3166±0.20°, 21.9117±0.20°, 25.9337±0.20°, 26.7897±0.20°, 27.4909±0.20°, 28.0534±0.20°, 28.3905±0.20°, 32.7796±0.20°.

46. ​​The crystal form as described in claim 44, characterized in that, The methanesulfonate crystal form A also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the methanesulfonate crystal form A is basically characterized as shown in Figure 29; 2) The DSC spectrum of the methanesulfonate crystal form A is basically characterized as shown in Figure 30; 3) The DSC spectrum of the methanesulfonate crystal form A has an endothermic peak in the range of 179.9℃-183.9℃.

47. The crystal form as described in claim 1, characterized in that, X is methanesulfonic acid, and the crystal form is methanesulfonate crystal form B; the XRPD pattern of methanesulfonate crystal form B contains three or more 2θ diffraction peaks selected from the following group: 8.2704±0.20°, 14.7351±0.20°, 15.4662±0.20°, 16.5097±0.20°, 18.0449±0.20°, 18.9187±0.20°, 21.4777±0.20°, 21.7910±0.20°, 23.3194±0.20°, 26.2673±0.20°.

48. The crystal form as described in claim 47, characterized in that, The XRPD pattern of the methanesulfonate crystal form B also exhibits 2θ diffraction peaks selected from the following group: 6.8124±0.20°, 9.8841±0.20°, 13.6902±0.20°, 16.9916±0.20°, 17.4977±0.20°, 20.5367±0.20°, 21.1464±0.20°, 24.5932±0.20°, 25.2006±0.20°, 27.1578±0.20°, 27.5874±0.20°, 29.6628±0.20°.

49. The crystal form as described in claim 47, characterized in that, The methanesulfonate crystal form B also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the methanesulfonate crystal form B is basically characterized as shown in Figure 31; 2) The DSC spectrum of the methanesulfonate crystal form B is basically characterized as shown in Figure 32; 3) The DSC spectrum of the methanesulfonate crystal form B has an endothermic peak in the range of 136.6℃-140.6℃.

50. The crystal form as described in claim 1, characterized in that, X is ethanedisulfonic acid, and the crystal form is ethanedisulfonate crystal form A; the XRPD pattern of ethanedisulfonate crystal form A contains three or more 2θ diffraction peaks selected from the following group: 10.4848±0.20°, 14.4489±0.20°, 16.3296±0.20°, 18.2904±0.20°, 18.9269±0.20°, 23.0329±0.20°.

51. The crystal form as described in claim 50, characterized in that, The XRPD pattern of the ethylene disulfonate crystal form A also has 2θ diffraction peaks selected from the following group: 12.1929±0.20°, 20.3472±0.20°, 24.5934±0.20°, 25.2132±0.20°.

52. The crystal form as described in claim 50, characterized in that, The ethylene disulfonate crystal form A also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the ethylene disulfonate crystal form A is basically characterized as shown in Figure 33; 2) The DSC spectrum of the ethylene disulfonate crystal form A is basically characterized as shown in Figure 34; 3) The DSC spectrum of the ethylene sulfonate crystal form A has an endothermic peak in the range of 121.8℃-125.8℃.

53. The crystal form as described in claim 1, characterized in that, X is saccharin, and the crystal form is saccharin salt crystal form A; the XRPD pattern of saccharin salt crystal form A contains three or more 2θ diffraction peaks selected from the following group: 5.2825±0.20°, 10.6586±0.20°, 14.8562±0.20°, 15.4501±0.20°, 16.0266±0.20°, 19.9548±0.20°, 21.4317±0.20°.

54. The crystal form as described in claim 53, characterized in that, The XRPD pattern of the saccharin salt crystal form A also has 2θ diffraction peaks selected from the following group: 8.9153±0.20°, 18.6848±0.20°, 25.0597±0.20°, 27.0087±0.20°.

55. The crystal form as described in claim 53, characterized in that, The saccharin salt crystal form A also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the saccharin salt crystal form A is basically characterized as shown in Figure 35; 2) The DSC spectrum of the saccharin salt crystal form A is basically characterized as shown in Figure 36; 3) The DSC spectrum of the saccharin salt crystal form A has endothermic peaks in the ranges of 68.9℃-72.9℃ and 113.1℃-117.1℃.

56. The crystal form as described in claim 1, characterized in that, The n is 0, and the crystal form is free-state amorphous type A; the XRPD pattern of the amorphous type A contains three or more 2θ diffraction peaks selected from the following group: 13.2515±0.20°, 14.2931±0.20°, 17.0618±0.20°, 17.8271±0.20°, 18.1358±0.20°, 20.8501±0.20°, 26.3927±0.20°, 27.5533±0.20°.

57. The crystal form as described in claim 56, characterized in that, The amorphous type A also has 2θ diffraction peaks selected from the following group: 11.6785±0.20°, 14.9559±0.20°, 18.9979±0.20°, 21.9771±0.20°, 23.4646±0.20°, 25.2559±0.20°, 25.9502±0.20°, 28.7384±0.20°, 29.5701±0.20°.

58. The crystal form as described in claim 56, characterized in that, The amorphous type A also has one or more features selected from the group consisting of: 1) The XRPD spectrum of the crystal-amorphous type A is basically represented as shown in Figure 37; 2) The DSC spectrum of the crystal-amorphous type A is basically represented as shown in Figure 38; 3) The DSC spectrum of the amorphous type A exhibits an endothermic peak in the range of 135.6℃-139.6℃; 4) The aqueous type A is an anhydrous compound.

59. The crystal form as described in claim 1, characterized in that, When n is 0, the crystal form is amorphous type B; the XRPD pattern of amorphous type B contains three or more 2θ diffraction peaks selected from the following group: 12.9724±0.20°, 15.7653±0.20°, 17.6842±0.20°, 17.9933±0.20°, 18.8267±0.20°, 19.9255±0.20°, 20.4975±0.20°, 21.0044±0.20°, 21.6138±0.20°, 22.0878±0.20°, 23.4309±0.20°, 23.7649±0.20°.

60. The crystal form as described in claim 59, characterized in that, The XRPD pattern of the crystal-agnostic type B exhibits 2θ diffraction peaks selected from the following group: 8.5267±0.20°, 9.5010±0.20°, 10.7164±0.20°, 11.0407±0.20°, 13.3675±0.20°, 13.8571±0.20°, 14.2765±0.20°, 19.7264± 0.20°, 22.6385±0.20°, 22.9612±0.20°, 25.4361±0.20°, 25.8280±0.20°, 27.0352±0.20°, 27.6250±0.20°, 28.0903±0.20°, 28.4441±0.20°, 31.4666±0.20°.

61. The crystal form as described in claim 59, characterized in that, The crystal-amorphous type B also has one or more features selected from the group consisting of: 1) The XRPD spectrum of the crystal-agnostic type B is basically represented as shown in Figure 39; 2) The DSC spectrum of the crystal-amorphous type B is basically represented as shown in Figure 40; 3) The DSC spectrum of the crystal-amorphous type B exhibits an endothermic peak in the range of 155.4℃-159.4℃; 4) The aqueous type B is an anhydrous compound.

62. The crystal form as described in claim 1, characterized in that, X is water, and the hydrate crystal form is crystal form C; the XRPD pattern of the hydrate crystal form C contains three or more 2θ diffraction peaks selected from the following group: 14.2748±0.20°, 17.5137±0.20°, 17.9790±0.20°, 19.7111±0.20°, 19.9345±0.20°, 20.5161±0.20°, 21.4440±0.20°, 22.2261±0.20°, 23.0594±0.20°, 23.7822±0.20°, 28.7022±0.20°.

63. The crystal form as described in claim 62, characterized in that, The XRPD pattern of the hydrate crystal form C exhibits 2θ diffraction peaks selected from the following group: 8.5152±0.20°, 10.6904±0.20°, 11.1007±0.20°, 11.4605±0.20°, 13.0405±0.20°, 13.8461±0.20°, 15.5683±0.20°, 18.4703±0.20°, 18.8372 ±0.20°, 20.9938±0.20°, 23.4274±0.20°, 24.6210±0.20°, 25.0432±0.20°, 25.6011±0.20°, 27.0241±0.20°, 28.0774±0.20°, 29.9035±0.20°, 31.9933±0.20°, 33.2859±0.20°.

64. The crystal form as described in claim 62, characterized in that, The hydrate crystal form C also has one or more features selected from the group consisting of: 1) The XRPD pattern of the hydrate crystal form C is basically characterized as shown in Figure 41; 2) The DSC spectrum of the hydrate crystal form C is basically characterized as shown in Figure 42; 3) The DSC spectrum of the hydrate crystal form C has an endothermic peak in the range of 155.7℃-159.7℃; 4) The hydrate crystal form C is a hydrate.

65. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the crystal form of formula (I) as described in any one of claims 1-64, and optionally further comprises a pharmaceutically acceptable carrier.

66. The pharmaceutical composition according to claim 65, characterized in that, The composition is suitable for oral and injectable administration.

67. The pharmaceutical composition of claim 65, characterized in that, The composition is suitable for oral administration.

68. The pharmaceutical composition of claim 65, characterized in that, The composition can be formulated into tablets, capsules, dispersants, and suspensions.

69. The pharmaceutical composition according to claim 65, characterized in that, The composition can be formulated into tablets.

70. The use of the crystal form according to any one of claims 1-64, characterized in that, This is used to prepare drugs for the treatment, alone or in combination with other antiviral drugs, of hepatitis B virus (HBV), hepatitis D virus (HDV), and human immunodeficiency virus (HIV) and the diseases they cause.

71. The use of the pharmaceutical composition according to any one of claims 65-69, characterized in that, This is used to prepare drugs for the treatment, alone or in combination with other antiviral drugs, of hepatitis B virus (HBV), hepatitis D virus (HDV), and human immunodeficiency virus (HIV) and the diseases they cause.

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