High-potency glucocorticoid polymorph, preparation method therefor and use thereof

Abstract

The present invention relates to a novel polymorph of (8R,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[α]phenanthrene-17-furan-2-carboxylate represented by formula (I), a preparation method therefor and a use thereof.

Description

High-potency glucocorticoid polymorphs, their preparation methods and uses Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry, specifically to polymorphs of highly potent glucocorticoids, their preparation methods, and uses. Background Technology

[0002] Inflammatory and autoimmune diseases, such as asthma, arthritis, lupus, and Crohn's disease, seriously threaten human health and reduce quality of life. Glucocorticoids, such as prednisone, dexamethasone (DEX), and budesonide, are highly effective anti-inflammatory drugs widely used to treat inflammatory and autoimmune diseases. These drugs exert their physiological effects by binding to the glucocorticoid receptor (GR) (a ligand-activated transcription factor of a nuclear receptor superfamily). In the absence of glucocorticoids, GR exists in the cytoplasm and binds to chaperone proteins such as hsp90 and hsp70. Hormone binding leads to a conformational change in GR, causing it to translocate to the nucleus, where it exerts its transcriptional control activity, i.e., activation (transcriptional activation) or repression (transcriptional repression). In transcriptional activation, GR dimers, directly binds to specific glucocorticoid response elements, and then recruits coactivators to activate transcription. In transcriptional repression, the general model is as follows: GR binds to other transcription factors (e.g., NF-KB, AP-1) to indirectly tether its binding site through protein-protein interactions. When tethered near the target promoter, GR represses downstream gene expression. Transcriptional repression is generally considered to not require GR dimerization.

[0003] Transcriptional repression is a major mechanism by which glucocorticoids act as anti-inflammatory drugs. Tethering of the GR (glucocorticoid reductase) to the NF-κB / AP-1 promoter leads to transcriptional repression of major downstream pro-inflammatory factors, including pro-inflammatory cytokines (e.g., TNF-α, IL-113, and IL-6), chemokines (e.g., CCL2, CCL19), and ligands associated with inflammatory events (e.g., COX2, MMP13, and phospholipid A2). Due to their rapid action and sustained effects, glucocorticoids remain the first-line treatment for inflammatory diseases. However, long-term use of glucocorticoids, especially at high doses, has many adverse consequences, including diabetes / glucose intolerance, hypertension, obesity, and osteoporosis. Much of these consequences are attributed to transcriptional activation of the GR. For example, glucocorticoids induce genes encoding rate-limiting enzymes in the hepatic glucose production pathway, glucose-6-phosphate and phosphoenolpyruvate carboxylkinase, thereby increasing de novo glucose synthesis and ultimately leading to weight gain or diabetes. Glucocorticoids also induce the upregulation of Dickkopf-1 (DKKl), a key regulatory gene for bone development, leading to osteoporosis and bone loss. Many side effects of glucocorticoids are commonly observed in association with high-dose use. For example, a “threshold pattern” has been observed with prednisone: at 7.5 mg daily, it causes glaucoma, depression, and hypertension. These side effects are caused by transcriptional activation of the glucocorticoid receptor (GR) and non-target activation of other receptors, such as the mineralocorticoid receptor (MR), which contributes to hypertension.

[0004] Furthermore, the development of insensitivity and resistance to glucocorticoid therapy is a major problem in the treatment of common inflammatory diseases such as chronic obstructive pulmonary disease, rheumatoid arthritis, and inflammatory bowel disease. Glucocorticoid resistance is also an unsolved problem in leukocyte cancers, especially childhood acute leukemia. Several mechanisms of glucocorticoid resistance have been identified or proposed, including alterations in kinase pathways, changes in cofactors, and the loss or mutation of receptors. A common observation is the reduced affinity of ligands for receptors in glucocorticoid-resistant patients. Treatment with high-potency glucocorticoids has shown improvement in these patients, but the efficacy gradually diminishes.

[0005] Therefore, there is an urgent need in this field to develop more potent and selective glucocorticoids to reduce unwanted side effects and improve treatment outcomes. Summary of the Invention

[0006] The present invention aims to provide a more potent and selective glucocorticoid to reduce unwanted side effects and improve therapeutic efficacy, specifically relating to a high-potency polymorph of glucocorticoids, its preparation method and uses.

[0007] In a first aspect of the invention, a polymorph of formula (I) is provided, wherein the polymorph is selected from the group consisting of: amorphous type A, solvate type B, solvate type C, solvate type E, solvate type G, solvate type H, isomorphous solvate type D, and isomorphous solvate type F.

[0008] Where m is 1-10;

[0009] n is 0-20;

[0010] X is selected from the following group: water, methanol, ethanol, acetonitrile, ethyl acetate, ethyl acetate / n-heptane, 1,4-dioxane, 1,4-dioxane / n-heptane, isopropanol, 2-methyltetrahydrofuran, 2-methyltetrahydrofuran / n-heptane, N-methylpyrrolidone, N-methylpyrrolidone / water, tetrahydrofuran, tetrahydrofuran / water, acetone.

[0011] In another preferred embodiment, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0012] In another preferred embodiment, n is 0, 0.5, 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, or 14.

[0013] The polymorph is the crystal form of compound (8R, 9R, 10S, 11S, 13S, 14S, 16R, 17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[α]phenanthrene-17-ylfuran-2-carboxylic acid ester of formula (I-1):

[0014] In another preferred embodiment, n is 0, and the crystal form is amorphous type A.

[0015] In another preferred embodiment, the XRPD pattern of the crystal-agnostic type A has three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the following group: 7.3435±0.2°, 9.7701±0.2°, 12.8476±0.2°, 13.4629±0.2°, 14.6917±0.2°, 14.9150±0.2°, 15.8911±0.2°, and 18.7354±0.2°.

[0016] In another preferred embodiment, the XRPD pattern of the crystal-agnostic type A has 2θ diffraction peaks selected from the group consisting of: 7.3435±0.2°, 9.7701±0.2°, 12.8476±0.2°, 13.4629±0.2°, 14.6917±0.2°, 14.9150±0.2°, 15.8911±0.2°, and 18.7354±0.2°.

[0017] In another preferred embodiment, the crystal-agnostic type A further has one or more 2θ diffraction peaks selected from the group consisting of: 19.6114±0.2°, 20.4651±0.2°, 22.4373±0.2°, 22.6151±0.2°, 24.2667±0.2°, 25.4833±0.2°, 26.7725±0.2°, 27.0642±0.2°, 29.4052±0.2°, and 32.8443±0.2°.

[0018] In another preferred embodiment, the crystal-amorphous type A further has one or more features selected from the group consisting of:

[0019] 1) The XRPD spectrum of the crystal-amorphous type A is basically represented as shown in Figure 1;

[0020] 2) The DSC spectrum of the crystal-amorphous type A is basically as shown in Figure 2;

[0021] 3) The DSC spectrum of the amorphous type A has an endothermic peak in the range of 256.5℃-260.5℃;

[0022] 4) The aqueous type A is an anhydrous compound.

[0023] In another preferred embodiment, the method for preparing the amorphous type A includes:

[0024] a) Mix isomorphous solvate D with ethyl acetate, sonicate to dissolve, filter, and obtain filtrate;

[0025] b) Stir at room temperature, add n-heptane dropwise to the filtrate to obtain the reaction solution;

[0026] c) Transfer the reaction solution to a 45–55°C temperature for suspension and stirring, then filter to separate the solids;

[0027] d) Transfer the solid to a vacuum dryer at 45-55°C, collect the solid, and obtain amorphous type A.

[0028] In another preferred embodiment, the method for preparing the amorphous type A includes:

[0029] a) Mix isomorphous solvate D with ethyl acetate, sonicate to dissolve, filter, and obtain filtrate;

[0030] b) Stir at 20–30°C, add n-heptane dropwise to the filtrate to obtain the reaction solution;

[0031] c) Transfer the reaction solution to 45–55°C and suspend it under stirring for 2–6 hours, then centrifuge to separate the solids;

[0032] d) Transfer the solid to a vacuum dryer at 45-55°C for 1-3 hours, collect the solid, and obtain amorphous type A.

[0033] In another preferred embodiment, the mass-to-volume ratio of the solvate crystal form D to ethyl acetate is (10-50):1 (mg / mL), preferably (20-40):1 (mg / mL).

[0034] In another preferred embodiment, the mass-to-volume ratio of the solvate crystal form D to n-heptane is (5-11):1 (mg / mL), preferably (7-9):1 (mg / mL).

[0035] In another preferred embodiment, X is ethanol, and the crystal form is solvate crystal form B.

[0036] In another preferred embodiment, the XRPD pattern of the solvate crystal form B has three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the following group: 7.8241±0.2°, 8.0677±0.2°, 11.8678±0.2°, 12.0458±0.2°, 14.1289±0.2°, 14.6628±0.2°, 16.1633±0.2°, 18.4062±0.2°, 19.3972±0.2°, 21.1388±0.2°, and 24.3347±0.2°.

[0037] In another preferred embodiment, the XRPD pattern of the solvate crystal form B has 2θ diffraction peaks selected from the group consisting of: 7.8241±0.2°, 8.0677±0.2°, 11.8678±0.2°, 12.0458±0.2°, 14.1289±0.2°, 14.6628±0.2°, 16.1633±0.2°, 18.4062±0.2°, 19.3972±0.2°, 21.1388±0.2°, and 24.3347±0.2°.

[0038] In another preferred embodiment, the solvate crystal form B further has one or more 2θ diffraction peaks selected from the group consisting of: 9.7530±0.2°, 15.6548±0.2°, 16.3717±0.2°, 18.0425±0.2°, 20.4815±0.2°, 21.6118±0.2°, 22.6746±0.2°, 22.9815±0.2°, 23.4008±0.2°, 25.8514±0.2°, and 28.7348±0.2°.

[0039] In another preferred embodiment, the solvate crystal form B further has one or more features selected from the group consisting of:

[0040] 1) The XRPD pattern of the solvate crystal form B is basically characterized as shown in Figure 3;

[0041] 2) The DSC spectrum of the solvate crystal form B is basically characterized as shown in Figure 4;

[0042] 3) The DSC spectrum of the solvate crystal form B has endothermic peaks in the ranges of 117.6℃-121.6℃, 146.0℃-150.0℃ and 256.2℃-260.2℃, and exothermic peaks in the range of 197.8℃-201.8℃;

[0043] 4) The solvate crystal form B is an ethanol solvate.

[0044] In another preferred embodiment, the method for preparing the solvate crystal form B includes:

[0045] a) The starting material compound of formula (I-1) was suspended and stirred in ethanol at room temperature;

[0046] b) After centrifugation to separate the solid, it was dried in a humid environment in an open air to obtain solvate crystal form B.

[0047] In another preferred embodiment, the method for preparing the solvate crystal form B includes:

[0048] a) Mix the compound of formula (I-1) with ethanol;

[0049] b) Stir at 20–30°C for 1–5 days;

[0050] c) After centrifugation to separate the solid, dry it in a humid environment for 1 to 3 days, collect the solid, and obtain solvate crystal form B.

[0051] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) to ethanol is (140-180):1 (mg / mL), preferably (150-170):1 (mg / mL).

[0052] In another preferred embodiment, X is 1,4-dioxane, and the crystal form is solvate crystal form C.

[0053] In another preferred embodiment, the XRPD pattern of the solvate crystal form C has three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the group consisting of: 9.3364±0.2°, 10.8253±0.2°, 12.4948±0.2°, 13.1241±0.2°, 14.4081±0.2°, 15.3668±0.2°, 16.4963±0.2°, 17.5285±0.2°, 17.9766±0.2°, 19.0582±0.2°, 19.5076±0.2°, 21.6255±0.2°, and 24.9988±0.2°.

[0054] In another preferred embodiment, the XRPD pattern of the solvate crystal form C has 2θ diffraction peaks selected from the group consisting of: 9.3364±0.2°, 10.8253±0.2°, 12.4948±0.2°, 13.1241±0.2°, 14.4081±0.2°, 15.3668±0.2°, 16.4963±0.2°, 17.5285±0.2°, 17.9766±0.2°, 19.0582±0.2°, 19.5076±0.2°, 21.6255±0.2°, and 24.9988±0.2°.

[0055] In another preferred embodiment, the XRPD pattern of the solvate crystal form C further has one or more 2θ diffraction peaks selected from the group consisting of: 8.1113±0.2°, 13.9482±0.2°, 14.9936±0.2°, 18.7095±0.2°, 22.2902±0.2°, 23.0597±0.2°, 24.2476±0.2°, 26.1344±0.2°, 26.3568±0.2°, 27.0548±0.2°, 28.2364±0.2°, 29.4411±0.2°, 31.0022±0.2°, 31.8382±0.2°, and 37.5931±0.2°.

[0056] In another preferred embodiment, the solvate crystal form C further has one or more features selected from the group consisting of:

[0057] 1) The XRPD pattern of the solvate crystal form C is basically characterized as shown in Figure 5;

[0058] 2) The DSC spectrum of the solvate crystal form C is basically characterized as shown in Figure 6;

[0059] 3) The DSC spectrum of the solvate crystal form C has endothermic peaks in the ranges of 154.2℃-158.2℃, 155.4℃-159.4℃, and 256.1℃-260.1℃;

[0060] 4) The solvate crystal form C is a 1,4-dioxane solvate.

[0061] In another preferred embodiment, the method for preparing the solvate crystal form C includes:

[0062] a) The starting material compound of formula (I-1) was suspended and stirred at room temperature in a mixed solvent of 1,4-dioxane / n-heptane;

[0063] b) After centrifugation to separate the solid, it was dried in a humid environment to obtain solvate crystal form C.

[0064] In another preferred embodiment, the method for preparing the solvate crystal form C includes:

[0065] a) Mix the compound of formula (I-1) with 1,4-dioxane / n-heptane (1:(1-3), v / v);

[0066] b) Stir at 20–30°C for 1–5 days;

[0067] c) After centrifugation to separate the solid, dry it in a humid environment for 1 to 3 days, collect the solid, and obtain the solvate crystal form C.

[0068] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) and 1,4-dioxane / n-heptane (1:(1-3), v / v) is (140-180):1 (mg / mL), preferably (150-170):1 (mg / mL).

[0069] In another preferred embodiment, X is isopropanol, and the crystal form is solvate crystal form E.

[0070] In another preferred embodiment, the XRPD pattern of the solvate crystal form E has three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the following group: 8.0799±0.2°, 9.4158±0.2°, 10.8909±0.2°, 12.4553±0.2°, 13.1421±0.2°, 15.5862±0.2°, 16.7023±0.2°, 17.4834±0.2°, 17.9850±0.2°, 19.2262±0.2°, 19.6761±0.2°, and 21.6316±0.2°.

[0071] In another preferred embodiment, the XRPD pattern of the solvate crystal form E has 2θ diffraction peaks selected from the group consisting of: 8.0799±0.2°, 9.4158±0.2°, 10.8909±0.2°, 12.4553±0.2°, 13.1421±0.2°, 15.5862±0.2°, 16.7023±0.2°, 17.4834±0.2°, 17.9850±0.2°, 19.2262±0.2°, 19.6761±0.2°, and 21.6316±0.2°.

[0072] In another preferred embodiment, the solvate crystal form E further has one or more 2θ diffraction peaks selected from the group consisting of: 13.3591±0.2°, 13.9946±0.2°, 14.4352±0.2°, 15.0316±0.2°, 18.3663±0.2°, 18.7598±0.2°, 18.9295±0.2°, 21.8673±0.2°, 22.3063± 0.2°, 24.5835±0.2°, 25.1068±0.2°, 25.3157±0.2°, 25.7008±0.2°, 26.4426±0.2°, 27.1314±0.2°, 28.1896±0.2°, 28.5237±0.2°, 29.9213±0.2°, 35.9890±0.2°, 37.5706±0.2°.

[0073] In another preferred embodiment, the solvate crystal form E further has one or more features selected from the group consisting of:

[0074] 1) The XRPD pattern of the solvate crystal form E is basically characterized as shown in Figure 7;

[0075] 2) The DSC spectrum of the solvate crystal form E is basically characterized as shown in Figure 8;

[0076] 3) The DSC spectrum of the solvate crystal form E has endothermic peaks in the ranges of 129.2℃-133.2℃ and 256.3℃-260.3℃;

[0077] 4) The solvate crystal form E is an isopropanol solvate.

[0078] In another preferred embodiment, the method for preparing the solvate crystal form E includes:

[0079] a) The starting material compound of formula (I-1) was suspended and stirred in isopropanol at room temperature;

[0080] b) After centrifugation to separate the solid, it is air-dried in a humid environment to obtain the crystal form E of the target solvate.

[0081] In another preferred embodiment, the method for preparing the solvate crystal form E includes:

[0082] a) Mix the compound of formula (I-1) with isopropanol;

[0083] b) Stir at 20–30°C for 1–5 days;

[0084] c) After centrifugation to separate the solid, dry it under humid conditions in a room for 8-10 hours, collect the solid, and obtain the solvate crystal form E.

[0085] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) to isopropanol is (140-180):1 (mg / mL), preferably (150-170):1 (mg / mL).

[0086] In another preferred embodiment, X is 2-methyltetrahydrofuran, and the crystal form is solvate crystal form G.

[0087] In another preferred embodiment, the XRPD pattern of the solvate crystal form G has three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the group consisting of: 9.3084±0.2°, 10.7288±0.2°, 12.2027±0.2°, 14.1646±0.2°, 15.3382±0.2°, 16.4599±0.2°, 17.0935±0.2°, 17.5680±0.2°, and 19.4359±0.2°.

[0088] In another preferred embodiment, the XRPD pattern of the solvate crystal form G has 2θ diffraction peaks selected from the group consisting of: 9.3084±0.2°, 10.7288±0.2°, 12.2027±0.2°, 14.1646±0.2°, 15.3382±0.2°, 16.4599±0.2°, 17.0935±0.2°, 17.5680±0.2°, and 19.4359±0.2°.

[0089] In another preferred embodiment, the solvate crystal form G further has one or more 2θ diffraction peaks selected from the group consisting of: 7.9625±0.2°, 12.8501±0.2°, 14.8697±0.2°, 18.6017±0.2°, 18.9050±0.2°, 21.2465±0.2°, 21.5707±0.2°, 24.7033±0.2°, and 26.9966±0.2°.

[0090] In another preferred embodiment, the solvate crystal form G further has one or more features selected from the group consisting of:

[0091] 1) The XRPD pattern of the solvate crystal form G is basically characterized as shown in Figure 9;

[0092] 2) The DSC spectrum of the solvate crystal form G is basically characterized as shown in Figure 10;

[0093] 3) The DSC spectrum of the solvate crystal form G has endothermic peaks in the ranges of 90.8℃-94.8℃ and 256.3℃-260.3℃;

[0094] 4) The solvate crystal form G is a 2-methyltetrahydrofuran solvate.

[0095] In another preferred embodiment, the method for preparing the solvate crystal form G includes:

[0096] a) Mix the compound of formula (I-1) with 2-methyltetrahydrofuran / n-heptane;

[0097] b) Stir at 40–60°C, filter using a filter membrane with a pore size of 0.3–0.5 μm, and collect the supernatant;

[0098] c) Cool the supernatant from 40-60°C to 2-7°C at a rate of 0.05-0.5°C / min, and maintain the temperature at 2-7°C for 1-3 days;

[0099] d) After centrifugation to separate the solid, it was dried under humid conditions in a room to obtain the solvate crystal form G.

[0100] In another preferred embodiment, the method for preparing the solvate crystal form G includes:

[0101] a) Mix the compound of formula (I-1) with 2-methyltetrahydrofuran / n-heptane (1:(0.5-3), v / v);

[0102] b) Stir at 40–60°C for 3–5 hours, filter using a filter membrane with a pore size of 0.3–0.5 μm, and collect the supernatant;

[0103] c) Cool the supernatant from 40-60°C to 2-7°C at a rate of 0.05-0.5°C / min, and maintain the temperature at 2-7°C for 1-3 days;

[0104] d) After centrifugation to separate the solid, dry it in a humid environment for 1-2 days and collect the solid to obtain solvate crystal form G.

[0105] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) and 2-methyltetrahydrofuran / n-heptane (1:(0.5-3), v / v) is (20-40):1 (mg / mL), preferably (20-30):1 (mg / mL).

[0106] In another preferred embodiment, X is N-methylpyrrolidone, and the crystal form is solvate crystal form H.

[0107] In another preferred embodiment, the XRPD pattern of the solvate crystal form H has three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the following group: 10.8332±0.2°, 12.0361±0.2°, 12.8852±0.2°, 14.1461±0.2°, 15.7442±0.2°, 16.8217±0.2°, 17.4163±0.2°, 19.7156±0.2°, 21.0801±0.2°, 21.7331±0.2°, and 24.7468±0.2°.

[0108] In another preferred embodiment, the XRPD pattern of the solvate crystal form H has 2θ diffraction peaks selected from the group consisting of: 10.8332±0.2°, 12.0361±0.2°, 12.8852±0.2°, 14.1461±0.2°, 15.7442±0.2°, 16.8217±0.2°, 17.4163±0.2°, 19.7156±0.2°, 21.0801±0.2°, 21.7331±0.2°, and 24.7468±0.2°.

[0109] In another preferred embodiment, the solvate crystal form H further has one or more 2θ diffraction peaks selected from the group consisting of: 7.8983±0.2°, 9.4784±0.2°, 13.9427±0.2°, 14.9085±0.2°, 18.3991±0.2°, 18.9884±0.2°, 19.1454±0.2°, 21.9545±0.2°, 23.7319±0.2°, 25.4235±0.2°, 25.8434±0.2°, 27.4457±0.2°, 28.0745±0.2°, 30.3708±0.2°, 35.3259±0.2°, and 36.5337±0.2°.

[0110] In another preferred embodiment, the solvate crystal form H further has one or more features selected from the group consisting of:

[0111] 1) The XRPD pattern of the solvate crystal form H is basically characterized as shown in Figure 11;

[0112] 2) The DSC spectrum of the solvate crystal form H is basically characterized as shown in Figure 12;

[0113] 3) The DSC spectrum of the solvate crystal form H has an endothermic peak in the range of 151.9℃-155.9℃;

[0114] 4) The solvate crystal form H is an N-methylpyrrolidone solvate.

[0115] In another preferred embodiment, the method for preparing the solvate crystal form H includes:

[0116] a) The starting material compound of formula (I-1) was suspended and stirred in an N-methylpyrrolidone / water mixed solvent at room temperature;

[0117] b) After centrifugation to separate the solid, it was dried in a humid environment in an open air to obtain the solvate crystal form H.

[0118] In another preferred embodiment, the method for preparing the solvate crystal form H includes:

[0119] a) Mix the compound of formula (I-1) with N-methylpyrrolidone / water (1:(2-6), v / v);

[0120] b) Stir at 20–30°C for 1–5 days;

[0121] c) Dry the solid in a humid environment for 1-3 days, collect the solid, and obtain the solvate crystal form H.

[0122] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) and N-methylpyrrolidone / water (1:(2-6), v / v) is (140-180):1 (mg / mL), preferably (150-170):1 (mg / mL).

[0123] In another preferred embodiment, X is acetone or tetrahydrofuran, and the crystal form is isomorphous solvate crystal form D.

[0124] In another preferred embodiment, the XRPD pattern of the isomorphous solvate crystal form D has three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the following group: 8.0939±0.2°, 11.0035±0.2°, 12.4283±0.2°, 13.1918±0.2°, 14.4935±0.2°, 15.8641±0.2°, 17.4204±0.2°, and 17.9797±0.2°.

[0125] In another preferred embodiment, the XRPD pattern of the isomorphous solvate crystal form D has 2θ diffraction peaks selected from the group consisting of: 8.0939±0.2°, 11.0035±0.2°, 12.4283±0.2°, 13.1918±0.2°, 14.4935±0.2°, 15.8641±0.2°, 17.4204±0.2°, and 17.9797±0.2°.

[0126] In another preferred embodiment, the isomorphous solvate crystal form D further has one or more 2θ diffraction peaks selected from the group consisting of: 9.5504±0.2°, 14.1043±0.2°, 15.1282±0.2°, 16.9629±0.2°, 18.9617±0.2°, 19.4353±0.2°, 19.9097±0.2°, 21.6488±0.2°, 22.0686±0.2°, 24.9683±0.2°, 25.2690±0.2°, 25.6853±0.2°, 26.5393±0.2°, 27.2064±0.2°, 28.0602±0.2°, and 31.2955±0.2°.

[0127] In another preferred embodiment, the isomorphous solvate crystal form D further has one or more features selected from the group consisting of:

[0128] 1) The XRPD pattern of the isomorphous solvate crystal form D is basically characterized as shown in Figure 13;

[0129] 2) The DSC spectrum of the isomorphous solvate crystal form D is basically characterized as shown in Figure 14;

[0130] 3) The DSC spectrum of the isomorphous solvate crystal form D has endothermic peaks in the ranges of 161.3℃-165.3℃, 161.9℃-165.9℃ and 256.7℃-260.7℃, and exothermic peaks in the range of 194.2℃-198.2℃;

[0131] 4) The crystal form D of the isomorphous solvate is an isomorphous solvate.

[0132] In another preferred embodiment, the method for preparing the isomorphous solvate crystal form D includes:

[0133] a) The starting material compound of formula (I-1) was suspended and stirred in acetone at room temperature;

[0134] b) After centrifugation to separate the solid, it was dried in a humid environment in an open air to obtain isomorphous solvate crystal form D.

[0135] In another preferred embodiment, the method for preparing the isomorphous solvate crystal form D includes:

[0136] a) Mix the compound of formula (I-1) with acetone;

[0137] b) Stir at 20–30°C for 1–5 days;

[0138] c) After centrifugation to separate the solid, dry it in a humid environment for 1-3 days, collect the solid, and obtain the solvate crystal form D.

[0139] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) to acetone is (140-180):1 (mg / mL), preferably (150-170):1 (mg / mL).

[0140] In another preferred embodiment, the method for preparing the isomorphous solvate crystal form D includes:

[0141] a) The starting material compound of formula (I-1) was suspended and stirred in a tetrahydrofuran / water mixed solvent at room temperature;

[0142] b) After centrifugation to separate the solid, it was dried in a humid environment to obtain isomorphous solvate crystal form D.

[0143] In another preferred embodiment, the method for preparing the isomorphous solvate crystal form D includes:

[0144] a) Mix the compound of formula (I-1) with tetrahydrofuran / water (1:(0.5-3), v / v);

[0145] b) Stir at 20–30°C for 1–5 days;

[0146] c) After centrifugation to separate the solid, dry it in a humid environment for 1-3 days, collect the solid, and obtain the solvate crystal form D.

[0147] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) and tetrahydrofuran / water (1:(0.5-3), v / v) is (140-180):1 (mg / mL), preferably (150-170):1 (mg / mL).

[0148] In another preferred embodiment, X is methanol or acetonitrile, and the crystal form is isomorphous solvate crystal form F.

[0149] In another preferred embodiment, the XRPD pattern of the isomorphous solvate crystal form F has three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the following group: 7.3652±0.2°, 9.6556±0.2°, 12.5755±0.2°, 14.4123±0.2°, 14.7320±0.2°, 18.4093±0.2°, 19.1579±0.2°, 21.6671±0.2°.

[0150] In another preferred embodiment, the XRPD pattern of the isomorphous solvate crystal form F has 2θ diffraction peaks selected from the group consisting of: 7.3652±0.2°, 9.6556±0.2°, 12.5755±0.2°, 14.4123±0.2°, 14.7320±0.2°, 18.4093±0.2°, 19.1579±0.2°, and 21.6671±0.2°.

[0151] In another preferred embodiment, the isomorphous solvate crystal form F further has one or more 2θ diffraction peaks selected from the group consisting of: 13.5773±0.2°, 15.7837±0.2°, 16.8104±0.2°, 20.6120±0.2°, 22.1919±0.2°, 24.1664±0.2°, 28.6021±0.2°, 31.8928±0.2°, and 36.4652±0.2°.

[0152] In another preferred embodiment, the isomorphous solvate crystal form F further has one or more features selected from the group consisting of:

[0153] 1) The XRPD pattern of the isomorphous solvate crystal form F is basically characterized as shown in Figure 15;

[0154] 2) The DSC spectrum of the isomorphous solvate crystal form F is basically characterized as shown in Figure 16;

[0155] 3) The DSC spectrum of the isomorphous solvate crystal form F has an endothermic peak in the range of 256.6℃-260.6℃;

[0156] 4) The crystal form F of the isomorphous solvate is an isomorphous solvate.

[0157] In another preferred embodiment, the method for preparing the isomorphous solvate crystal form F includes:

[0158] a) Place the compound of formula (I-1) in a sealed environment containing methanol;

[0159] b) After standing at 20-30°C for 6-8 days, the isomorphous solvate crystal form F is obtained.

[0160] In another preferred embodiment, the method for preparing the isomorphous solvate crystal form F includes:

[0161] a) The compound of formula (I-1) is placed in a sealed container containing methanol, and the compound of formula (I-1) and methanol are not in direct contact;

[0162] b) After standing at 20-30°C for 6-8 days, the isomorphous solvate crystal form F is obtained.

[0163] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) to methanol is (2-8):1 (mg / mL), preferably (4-6):1 (mg / mL).

[0164] In another preferred embodiment, the method for preparing the isomorphous solvate crystal form F includes:

[0165] a) Place the compound of formula (I-1) in a sealed environment containing acetonitrile;

[0166] b) After standing at 20-30°C for 6-8 days, the isomorphous solvate crystal form F is obtained.

[0167] In another preferred embodiment, the method for preparing the isomorphous solvate crystal form F includes:

[0168] a) The compound of formula (I-1) is placed in a sealed container containing acetonitrile, and the compound of formula (I-1) and acetonitrile are not in direct contact;

[0169] b) After standing at 20-30°C for 6-8 days, the isomorphous solvate crystal form F is obtained.

[0170] In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) to acetonitrile is (2-8):1 (mg / mL), preferably (4-6):1 (mg / mL).

[0171] In a second aspect of the invention, a pharmaceutical composition is provided comprising a polymorph of formula (I) as described in the first aspect, optionally further comprising a pharmaceutically acceptable carrier and / or excipient.

[0172] In another preferred embodiment, the composition is suitable for oral, injection, nasal spray, oral inhalation aerosol, and topical skin application routes of administration.

[0173] In another preferred embodiment, the composition is suitable for administration via nasal spray, oral inhalation aerosol, and topical skin application.

[0174] In another preferred embodiment, the composition can be formulated as tablets, injections, syringes, sprays, aerosols, and creams.

[0175] In another preferred embodiment, the composition can be formulated as a spray, aerosol, or cream.

[0176] In a third aspect of the invention, there is provided the use of the polymorph as described in the first aspect for preparing a medicament for treating or preventing rhinitis, asthma, or neurodermatitis.

[0177] In another preferred embodiment, it is used to prepare a drug for treating or preventing rhinitis, asthma, or neurodermatitis.

[0178] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0179] Figure 1 shows the XRPD plot of crystal-agnostic type A.

[0180] Figure 2 shows the DSC diagram of crystal-agnostic type A.

[0181] Figure 3 shows the XRPD diagram of solvate crystal form B.

[0182] Figure 4 shows the DSC diagram of solvate crystal form B.

[0183] Figure 5 shows the XRPD diagram of solvate crystal form C.

[0184] Figure 6 shows the DSC diagram of solvate crystal form C.

[0185] Figure 7 shows the XRPD diagram of solvate crystal form E.

[0186] Figure 8 shows the DSC diagram of solvate crystal form E.

[0187] Figure 9 shows the XRPD diagram of solvate crystal form G.

[0188] Figure 10 shows the DSC diagram of solvate crystal form G.

[0189] Figure 11 shows the XRPD diagram of solvate crystal form H.

[0190] Figure 12 shows the DSC diagram of solvate crystal form H.

[0191] Figure 13 shows the XRPD diagram of crystal form D of the isomorphous solvate.

[0192] Figure 14 shows the DSC diagram of isomorphous solvate crystal form D.

[0193] Figure 15 shows the XRPD diagram of crystal form F of the isomorphous solvate.

[0194] Figure 16 shows the DSC diagram of crystal form F of the isomorphous solvate.

[0195] Figure 17 shows the DVS diagram of crystal-amorphous type A.

[0196] Figure 18 shows the XRPD overlay of crystal-free type A before and after the DVS test.

[0197] Figure 19 shows the XRPD overlay of the solid after the solubility test of the non-crystalline type A.

[0198] Figure 20 shows the XRPD overlay of the crystal-amorphous A-type stability evaluation sample.

[0199] Figure 21 shows the XRPD overlay of the crystal-free A-type light stability evaluation sample. Detailed Implementation

[0200] Through extensive and in-depth research and numerous experimental screenings, the inventors have unexpectedly developed, for the first time, a polymorph of a glucocorticoid drug (8R, 9R, 10S, 11S, 13S, 14S, 16R, 17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[α]phenanthrene-17-ylfuran-2-carboxylic acid ester and its preparation method. The polymorph is selected from the following group: amorphous type A, solvate type B, solvate type C, solvate type E, solvate type G, solvate type H, isomorphous solvate type D, and isomorphous solvate type F. The polymorphs of glucocorticoids of the present invention (especially amorphous A) have higher potency and selectivity, and can reduce side effects during treatment and improve therapeutic efficacy. The present invention was completed based on this.

[0201] the term

[0202] As used in this article, the term "n or more 2θ values ​​selected from the following group" refers to any positive integer including n and greater than n (e.g., n, n+1, ...), where the upper limit Nup is the number of all 2θ peaks in the group. For example, "1 or more" includes not only the positive integers of the upper limit Nup (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ...), but also ranges such as "2 or more", "3 or more", "4 or more", "5 or more", "6 or more", "7 or more", "8 or more", "9 or more", and "10 or more". For example, "3 or more" not only includes the positive integers up to the upper limit Nup of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, ..., but also includes the ranges of "4 or more", "5 or more", "6 or more", "7 or more", "8 or more", "9 or more", "10 or more".

[0203] As used in this article, the term "multiple" refers to 2, 3, 4, 5, or 6.

[0204] As used in this article, the terms "free anhydrous crystalline form" and "anhydrous crystalline form" are synonymous.

[0205] As used in this article, the term "isomorphic" refers to crystals with similar or nearly identical chemical compositions that, under the same thermodynamic conditions, form crystals with the same structure.

[0206] As used in this article, the term "room temperature" refers to 20–30°C.

[0207] As used in this article, the term "room humidity" refers to 40-80%.

[0208] As used in this article, “starting material” refers to the compound of formula (I-1).

[0209] The present invention provides a high-potency polymorph of glucocorticoids.

[0210] (8R,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopentano[α]phenanthrene-17-ylfuran-2-carboxylic acid ester (I-1) has the following structure:

[0211] Potency and efficacy are two key pharmacokinetic parameters of glucocorticoids. While efficacy is the maximum activity achievable with a given drug, potency is typically the concentration of a given drug required to achieve half-maximal activity (EC50) at maximum concentrations. For two glucocorticoids with the same efficacy, the more potent glucocorticoid will require a lower dose to achieve the same therapeutic effect. Importantly, glucocorticoids can have different efficacies for transcriptional activation and inhibition. For example, gene induction of GR via DEX requires 5 to 6 times higher glucocorticoid concentrations than gene inhibition. This differential response provides an opportunity to develop highly potent glucocorticoids that can be used at low doses to achieve complete suppression of inflammatory signaling with minimal transcriptional activation activity and side effects.

[0212] Currently, drug polymorphism has become an essential component of drug research and quality control / testing of finished products. Research on drug polymorphism helps in the selection of the biological activity of new drug compounds, improves bioavailability, enhances clinical efficacy, aids in the selection and design of drug delivery routes, and determines drug formulation process parameters, thereby improving drug production quality. Different polymorphs of the same drug can exhibit significantly different bioavailability. For the same drug, some polymorphs may possess higher biological activity than others. Obtaining a polymorph with higher biological activity and better suitability for pharmaceutical applications has been a long-standing technical challenge in the pharmaceutical field.

[0213] This invention provides a polymorph of (8R,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[α]phenanthrene-17-ylfuran-2-carboxylic acid ester, the structure of which is shown in formula (I):

[0214] Where m is 1-10;

[0215] n is 0-20;

[0216] X is selected from the following group: water, methanol, ethanol, acetonitrile, ethyl acetate, ethyl acetate / n-heptane, 1,4-dioxane, 1,4-dioxane / n-heptane, isopropanol, 2-methyltetrahydrofuran, 2-methyltetrahydrofuran / n-heptane, N-methylpyrrolidone, N-methylpyrrolidone / water, tetrahydrofuran, tetrahydrofuran / water, acetone.

[0217] In this invention, (8R,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[α]phenanthrene-17-ylfuran-2-carboxylic acid ester is a novel, highly potent glucocorticoid. Because the X-ray structure of the glucocorticoid receptor (GR) ligand-binding domain (LBD) of cortisol and mometasone furoate (MF) was determined, the inventors obtained a novel glucocorticoid with significantly enhanced efficacy based on structural design. This highly potent glucocorticoid minimizes side effects and achieves the same therapeutic effect at lower doses.

[0218] In another preferred embodiment, the polymorph is amorphous type A, wherein the XRPD pattern of type A contains at least 2θ±0.20° diffraction peaks at 12.8476, 14.6917, 14.9150, and 18.7354.

[0219] Preferably, the XRPD pattern of the (8R,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[α]phenanthrene-17-ylfuran-2-carboxylic acid ester (amorphous form A) contains at least the following diffraction peaks at 2θ±0.20°: 7.3435, 9.7701, 12.8476, 13.4629, 14.6917, 14.9150, 15.8911, and 18.7354. More preferably, it also includes diffraction peaks at 2θ±0.20° of: 19.6114, 20.4651, 22.4373, 22.6151, 24.2667, 25.4833, 26.7725, 27.0642, 29.4052, and 32.8443.

[0220] Particularly preferred is that the crystal-amorphous type A has an XRPD pattern as shown in Figure 1.

[0221] In another preferred embodiment, the polymorph is amorphous type A, and the differential thermal analysis results of amorphous type A show that there is an endothermic peak at 258.5℃ (peak temperature).

[0222] In another preferred embodiment, the polymorph is amorphous type A, which has a DSC pattern as shown in Figure 2.

[0223] In one specific embodiment of the present invention, a method for preparing amorphous A is also provided, comprising: a) mixing solvate crystal form D and ethyl acetate, ultrasonically dissolving and filtering; b) stirring at room temperature, slowly adding n-heptane solvent to the filtrate, resulting in a turbid sample; c) transferring the reaction solution to 50°C for suspension stirring, and centrifuging to separate the solid; d) transferring the solid to 50°C for vacuum drying, and collecting the solid to obtain amorphous A.

[0224] In another preferred embodiment, the polymorph is solvate crystal form B, wherein the XRPD pattern of crystal form B contains at least the following diffraction peaks at 2θ±0.20°: 7.8241, 8.0677, 14.1289, 14.6628, 16.1633, and 18.4062.

[0225] Preferably, the XRPD pattern of the (8R, 9R, 10S, 11S, 13S, 14S, 16R, 17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[α]phenanthrene-17-ylfuran-2-carboxylic acid ester crystal form B contains at least the following diffraction peaks at 2θ±0.20°: 7.8241, 8.0677, 11.8678, 12.0458, 14.1289, 14.6628, 16.1633, 18.4062, 19.3972, 21.1388, and 24.3347. More preferably, it also includes diffraction peaks at 2θ±0.20° of: 9.7530, 15.6548, 16.3717, 18.0425, 20.4815, 21.6118, 22.6746, 22.9815, 23.4008, 25.8514, and 28.7348.

[0226] Particularly preferred is that the solvate crystal form B has an XRPD pattern as shown in Figure 3.

[0227] In another preferred embodiment, the polymorph is solvate crystal form B. Differential thermal analysis results of crystal form B show that there are endothermic peaks at 119.6℃ (peak temperature), 148.0℃ (peak temperature), and 258.2℃ (peak temperature), and an exothermic peak at 199.8℃ (peak temperature).

[0228] In another preferred embodiment, the polymorph is a solvate crystal form B, which has a DSC pattern as shown in Figure 4.

[0229] In one specific embodiment of the present invention, a method for preparing solvate crystal form B is also provided, comprising: a) suspending and stirring the starting material in ethanol at room temperature; b) centrifuging to separate the solid, and then drying it in an open container under room temperature and humidity to obtain the target crystal form B.

[0230] In another preferred embodiment, the polymorph is solvate crystal form C, wherein the XRPD pattern of crystal form C contains at least the following diffraction peaks at 2θ±0.20°: 9.3364, 10.8253, 12.4948, 15.3668, 16.4963, 17.5285, 17.9766, 21.6255, and 24.9988.

[0231] Preferably, the (8R,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[α]phenanthrene-17-ylfuran- The XRPD pattern of 2-carboxylic acid ester crystal form C contains at least the following diffraction peaks at 2θ±0.20°: 9.3364, 10.8253, 12.4948, 13.1241, 14.4081, 15.3668, 16.4963, 17.5285, 17.9766, 19.0582, 19.5076, 21.6255, and 24.9988. More preferably, it also includes diffraction peaks at 2θ±0.20° of: 8.1113, 13.9482, 14.9936, 18.7095, 22.2902, 23.0597, 24.2476, 26.1344, 26.3568, 27.0548, 28.2364, 29.4411, 31.0022, 31.8382, and 37.5931.

[0232] Particularly preferred is that the solvate crystal form C has an XRPD pattern as shown in Figure 5.

[0233] In another preferred embodiment, the polymorph is solvate crystal form C, and the differential thermal analysis results of crystal form C show that there are endothermic peaks at 156.2℃ (peak temperature), 157.4℃ (peak temperature) and 258.1℃ (peak temperature).

[0234] In another preferred embodiment, the polymorph is a solvate crystal form C, which has a DSC pattern as shown in Figure 6.

[0235] In one specific embodiment of the present invention, a method for preparing solvate crystal form C is also provided, comprising: a) suspending and stirring the starting material in 1,4-dioxane / n-heptane (1:2, v / v) at room temperature; b) centrifuging to separate the solid, and then drying it in an open container under room temperature and humidity to obtain the target crystal form C.

[0236] In another preferred embodiment, the polymorph is a solvate crystal form E, wherein the XRPD pattern of crystal form E contains at least the following diffraction peaks at 2θ±0.20°: 10.8909, 12.4553, 13.1421, 15.5862, 17.4834, 17.9850, and 19.2262.

[0237] Preferably, the (8R,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopentano[α]phenanthrene-17 The XRPD pattern of 2-furan-2-carboxylic acid ester crystal form E contains at least the following diffraction peaks at 2θ ± 0.20°: 8.0799, 9.4158, 10.8909, 12.4553, 13.1421, 15.5862, 16.7023, 17.4834, 17.9850, 19.2262, 19.6761, and 21.6316. More preferably, it also includes diffraction peaks at 2θ±0.20° of: 13.3591, 13.9946, 14.4352, 15.0316, 18.3663, 18.7598, 18.9295, 21.8673, 22.3063, 24.5835, 25.1068, 25.3157, 25.7008, 26.4426, 27.1314, 28.1896, 28.5237, 29.9213, 35.9890, and 37.5706.

[0238] Particularly preferred is that the solvate crystal form E has an XRPD pattern as shown in Figure 7.

[0239] In another preferred embodiment, the polymorph is a solvate crystal form E, and the differential thermal analysis results of crystal form E show that there are endothermic peaks at 131.2℃ (peak temperature) and 258.3℃ (peak temperature).

[0240] In another preferred embodiment, the polymorph is a solvate crystal form E, which has a DSC pattern as shown in Figure 8.

[0241] In one specific embodiment of the present invention, a method for preparing solvate crystal form E is also provided, comprising: a) suspending and stirring the starting material in isopropanol at room temperature; b) centrifuging to separate the solid, and then drying it in an open container under room temperature and humidity to obtain the target crystal form E.

[0242] In another preferred embodiment, the polymorph is a solvate crystal form G, wherein the XRPD pattern of the crystal form G contains at least the following diffraction peaks at 2θ±0.20°: 10.7288, 12.2027, 15.3382, 16.4599, 17.0935, and 17.5680.

[0243] Preferably, the XRPD pattern of the (8R,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[α]phenanthrene-17-ylfuran-2-carboxylic acid ester crystal form G contains at least the following diffraction peaks at 2θ±0.20°: 9.3084, 10.7288, 12.2027, 14.1646, 15.3382, 16.4599, 17.0935, 17.5680, and 19.4359. More preferably, it also includes diffraction peaks at 2θ±0.20° of: 7.9625, 12.8501, 14.8697, 18.6017, 18.9050, 21.2465, 21.5707, 24.7033, and 26.9966.

[0244] Particularly preferred is that the solvate crystal form G has an XRPD pattern as shown in Figure 9.

[0245] In another preferred embodiment, the polymorph is a solvate crystal form G, and the differential thermal analysis results of crystal form G show that there are endothermic peaks at 92.8℃ (peak temperature) and 258.3℃ (peak temperature).

[0246] In another preferred embodiment, the polymorph is a solvate crystal form G, which has a DSC pattern as shown in Figure 10.

[0247] In one specific embodiment of the present invention, a method for preparing solvate crystal form G is also provided, comprising: a) suspending and stirring the starting material in 2-methyltetrahydrofuran / n-heptane (1:1, v / v) at 40–60 °C, and filtering to obtain a supernatant; b) cooling the supernatant from 40–60 °C to 2–7 °C at a rate of 1 °C / min, and maintaining the temperature at 2–7 °C for 1–3 days; c) centrifuging to separate the solid, and drying it in an open container under humid conditions to obtain the target crystal form G.

[0248] In another preferred embodiment, the polymorph is a solvate crystal form H, wherein the XRPD pattern of crystal form H contains at least the following diffraction peaks at 2θ±0.20°: 12.0361, 14.1461, 15.7442, 16.8217, 17.4163, and 24.7468.

[0249] Preferably, the (8R,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopentano[α]phenanthrene The XRPD pattern of 17-ylfuran-2-carboxylic acid ester crystal form H contains at least the following diffraction peaks at 2θ±0.20°: 10.8332, 12.0361, 12.8852, 14.1461, 15.7442, 16.8217, 17.4163, 19.7156, 21.0801, 21.7331, and 24.7468. More preferably, it also includes diffraction peaks at 2θ±0.20° of: 7.8983, 9.4784, 13.9427, 14.9085, 18.3991, 18.9884, 19.1454, 21.9545, 23.7319, 25.4235, 25.8434, 27.4457, 28.0745, 30.3708, 35.3259, and 36.5337.

[0250] Particularly preferred is that the solvate crystal form H has an XRPD pattern as shown in Figure 11.

[0251] In another preferred embodiment, the polymorph is a solvate crystal form H, and the differential thermal analysis results of crystal form H show that there is an endothermic peak at 153.9℃ (peak temperature).

[0252] In another preferred embodiment, the polymorph is a solvate crystal form H, which has a DSC spectrum as shown in Figure 12.

[0253] In one specific embodiment of the present invention, a method for preparing solvate crystal form H is also provided, comprising: a) suspending and stirring the starting material in N-methylpyrrolidone / water (1:4, v / v) at room temperature; b) centrifuging to separate the solid, and then drying it in an open container under room temperature and humidity to obtain the target crystal form H.

[0254] In another preferred embodiment, the polymorph is a isomorphous solvate crystal form D, wherein the XRPD pattern of crystal form D contains at least the following diffraction peaks at 2θ±0.20°: 11.0035, 12.4283, 13.1918, 15.8641, 17.4204, and 17.9797.

[0255] Preferably, the XRPD pattern of the (8R,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[α]phenanthrene-17-ylfuran-2-carboxylic acid ester crystal form D contains at least the following diffraction peaks at 2θ±0.20°: 8.0939, 11.0035, 12.4283, 13.1918, 14.4935, 15.8641, 17.4204, and 17.9797. More preferably, it also includes diffraction peaks at 2θ±0.20° of: 9.5504, 14.1043, 15.1282, 16.9629, 18.9617, 19.4353, 19.9097, 21.6488, 22.0686, 24.9683, 25.2690, 25.6853, 26.5393, 27.2064, 28.0602, and 31.2955.

[0256] Particularly preferred is that the isomorphous solvate crystal form D has an XRPD pattern as shown in Figure 13.

[0257] In another preferred embodiment, the polymorph is isomorphous solvate crystal form D. Differential thermal analysis results of crystal form D show that there are endothermic peaks at 163.3℃ (peak temperature) and 163.9℃ (peak temperature), and an exothermic peak at 196.2℃ (peak temperature).

[0258] In another preferred embodiment, the polymorph is a isomorphous solvate crystal form D, which has a DSC pattern as shown in Figure 14.

[0259] In one specific embodiment of the present invention, a method for preparing isomorphous solvate crystal form D is also provided, comprising: a) suspending and stirring the starting material in acetone or tetrahydrofuran / water (1:1, v / v) at room temperature; b) centrifuging to separate the solid to obtain the target crystal form D.

[0260] In another preferred embodiment, the polymorph is isomorphous solvate crystal form F, wherein the XRPD pattern of crystal form F contains at least the following diffraction peaks at 2θ±0.20°: 9.6556, 12.5755, 14.4123, 14.7320, and 21.6671.

[0261] Preferably, the XRPD pattern of the (8R,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)-11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H-cyclopenta[α]phenanthrene-17-ylfuran-2-carboxylic acid ester crystal form F contains at least the following diffraction peaks at 2θ±0.20°: 7.3652, 9.6556, 12.5755, 14.4123, 14.7320, 18.4093, 19.1579, and 21.6671. More preferably, it also includes diffraction peaks at 2θ±0.20° of: 13.5773, 15.7837, 16.8104, 20.6120, 22.1919, 24.1664, 28.6021, 31.8928, and 36.4652.

[0262] Particularly preferred is that the isomorphous solvate crystal form F has an XRPD pattern as shown in Figure 15.

[0263] In another preferred embodiment, the polymorph is isomorphous solvate crystal form F, and the differential thermal analysis results of crystal form F show that there is an endothermic peak at 258.6℃ (peak temperature).

[0264] In another preferred embodiment, the polymorph is a isomorphous solvate crystal form F, which has a DSC spectrum as shown in Figure 16.

[0265] In one specific embodiment of the present invention, a method for preparing isomorphous solvate crystal form F is also provided, comprising: a) gas-solid permeation of starting material in methanol or acetonitrile; b) standing at room temperature for 7 days to obtain isomorphous solvate crystal form F.

[0266] In this invention, a pharmaceutical composition comprising an effective amount of the crystal form is also provided, optionally, the composition further comprising a pharmaceutically acceptable carrier.

[0267] The compositions of the present invention are suitable for oral, injectable, nasal spray, oral inhalation aerosol, and topical skin application routes of administration. Nasal spray, oral inhalation aerosol, and topical skin application routes are preferred.

[0268] Dosage forms include tablets, injections, syringes, sprays, aerosols, and creams, with sprays, aerosols, and creams being preferred.

[0269] In this invention, the use of the crystal form and the pharmaceutical composition containing the crystal form in the preparation of a medicament for treating asthma, rhinitis or neurodermatitis is also provided.

[0270] The detection method used in this invention

[0271] X-ray powder diffractometer (XRPD)

[0272] XRPD: PANalytical Empyrean and X'Pert 3 Data were acquired using an X-ray powder diffractometer. Cu target, Kα wavelength, tube voltage 45 kV, tube current 40 mA; intensity ratio Kα2 / Kα1: 0.50; scanning range (°2TH): 3°~40°, scan time per step: 46.7 seconds, scan step size (°2Theta): 0.0263, scan time: 5 minutes.

[0273] Differential Scanning Calorimeter (DSC)

[0274] DSC data were acquired using a TA Discovery 2500 differential scanning calorimeter. 25°C - set the endpoint temperature; heating rate: 10°C / min.

[0275] Thermogravimetric analyzer (TGA)

[0276] TGA data were collected using a TA Q5000 / Discovery 5500 thermogravimetric analyzer. Temperature range: room temperature - 350℃; heating rate: 10℃ / min.

[0277] Dynamic water adsorption (DVS)

[0278] Dynamic moisture adsorption (DVS) curves were acquired on the DVS Intrinsic of SMS (Surface Measurement Systems). Relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg(NO3)2, and KCl. Temperature: 25°C; Protective gas and flow rate: N2, 200 mL / min; dm / dt: 0.002% / min; Minimum dm / dt equilibration time: 10 min; Maximum equilibration time: 180 min.

[0279] High-performance liquid chromatography (HPLC)

[0280] HPLC analysis was performed using an Agilent 1260 high-performance liquid chromatograph. Mobile phase: 25 mM NaOH; Detector: DAD / VWD; Column temperature: 30℃; Flow rate: 1.0 mL / min; Waters X-bridge C18, 150 × 4.6 mm column; Detection wavelength: UV at 256 nm; Injector temperature: room temperature; Injection volume: 2 μL; Mobile phase: A: 0.1% K₂HPO₄ in H₂O, B: ACN; Gradient: First, mobile phase B was slowly increased from 20% to 60% for 9 min; second, mobile phase B was slowly increased from 60% to 90% for 9 min; then, mobile phase B was maintained at 95% for 12 min; finally, mobile phase B was slowly decreased from 95% to 20% for 12 min. Total run time: 42 min.

[0281] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0282] The novel polymorphs of this invention exhibit significant efficacy, good stability, high yield, and high purity. These novel polymorphs facilitate the selection and design of drug delivery routes and the determination of pharmaceutical formulation process parameters, thereby improving the quality of drug production.

[0283] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0284] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be used in the methods of this invention.

[0285] Unless otherwise specified, all experimental materials and reagents used in the following examples are available from commercially available sources.

[0286] Example 1: Preparation of Crystal-A Type A

[0287] Weigh 108.8 mg of solvate crystal form D, add 3.0 mL of ethyl acetate, sonicate to dissolve and filter; add 3.0 mL of n-heptane solvent to the filtrate, no solid precipitates; continue to slowly add 9.0 mL of n-heptane solvent to the sample, the sample becomes turbid; transfer the sample to 50 °C and suspend and stir for 3.5 hours, centrifuge to separate the solid, transfer the solid to 50 °C and vacuum dry for 2.5 hours, collect the solid to obtain amorphous form A.

[0288] The obtained solid was subjected to X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with that in Figure 1, which proved that the obtained solid was amorphous type A. The powder diffraction data of amorphous type A are shown in Table 1 below.

[0289] Table 1: Powder diffraction data of crystal-amorphous type A

[0290] Example 2: Preparation of solvate crystal form B

[0291] Weigh 81.1 mg of the starting sample (i.e., compound of formula (I-1)) into a 5 mL vial, add 0.5 mL of ethanol, suspend and stir the sample at room temperature for 3 days, centrifuge to separate the solid, dry it in a room with a temperature of room temperature and humidity for 2 days, and collect the solid to obtain solvate crystal form B.

[0292] The obtained solid was subjected to X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with that in Figure 3, which proved that the obtained solid was solvate crystal form B. The powder diffraction data of solvate crystal form B are shown in Table 2 below.

[0293] Table 2: Powder diffraction data of solvate crystal form B

[0294] Example 3: Preparation of solvate crystal form C

[0295] Weigh 80.4 mg of the starting sample into a 5 mL vial, add 0.5 mL of 1,4-dioxane / n-heptane (1:2, v / v), suspend and stir the sample at room temperature for 3 days, centrifuge to separate the solid, dry in a room with a humid environment for 2 days, and collect the solid to obtain solvate crystal form C.

[0296] The obtained solid was subjected to X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with that in Figure 5, which proved that the obtained solid was solvate crystal form C. The powder diffraction data of solvate crystal form C are shown in Table 3 below.

[0297] Table 3: Powder diffraction data of solvate crystal form C

[0298] Example 4: Preparation of solvate crystal form E

[0299] Weigh 79.3 mg of the starting sample into a 5 mL vial, add 0.5 mL of isopropanol, suspend and stir the sample at room temperature for 3 days, centrifuge to separate the solid, dry in a room with a humid environment for 9 hours, and collect the solid to obtain solvate crystal form E.

[0300] The obtained solid was subjected to X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with that in Figure 7, which proved that the obtained solid was solvate crystal form E. The powder diffraction data of solvate crystal form E are shown in Table 4 below.

[0301] Table 4: Powder diffraction data of solvate crystal form E

[0302] Example 5: Preparation of solvate crystal form G

[0303] Weigh 80.7 mg of the starting sample into a 5 mL vial, add 3.0 mL of 2-methyltetrahydrofuran / n-heptane (1:1, v / v), stir and equilibrate at 50 °C for about 4 hours, filter the supernatant using a PTFE membrane with a pore size of 0.45 μm, place the supernatant in a biochemical incubator, cool it from 50 °C to 5 °C at a rate of 0.1 °C / min, and then maintain the temperature at 5 °C for 2 days. Centrifuge to separate the solid to obtain solvate crystal form G.

[0304] The obtained solid was subjected to X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with that in Figure 9, which proved that the obtained solid was a solvate crystal form G. The powder diffraction data of solvate crystal form G are shown in Table 5 below.

[0305] Table 5: Powder diffraction data of solvate crystal form G

[0306] Example 6: Preparation of solvate crystal form H

[0307] Weigh 80.9 mg of the starting sample into a 5 mL vial, add 0.5 mL of N-methylpyrrolidone / water (1:4, v / v), suspend and stir the sample at room temperature for 3 days, centrifuge to separate the solid, and dry it in a humid environment at room temperature for 2 days. Collect the solid to obtain the solvate crystal form H.

[0308] The obtained solid was subjected to X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with that in Figure 11, which proved that the obtained solid was solvate crystal form H. The powder diffraction data of solvate crystal form H are shown in Table 6 below.

[0309] Table 6: Powder diffraction data of solvate crystal form H

[0310] Example 7: Preparation of isomorphous solvate crystal form D

[0311] Weigh 80.8 mg of the starting sample into a 5 mL vial, add 0.5 mL of acetone, suspend and stir the sample at room temperature for 3 days, centrifuge to separate the solid, and dry it at room temperature for 2 days. Collect the solid to obtain isomorphous solvate crystal form D.

[0312] The obtained solid was subjected to X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with that in Figure 13, which proved that the obtained solid was a isomorphous solvate of crystal form D. The powder diffraction data of isomorphous solvate of crystal form D are shown in Table 7 below.

[0313] Table 7: Powder diffraction data of isomorphous solvate crystal form D

[0314] Example 8: Preparation of isomorphous solvate crystal form D

[0315] Weigh 80.9 mg of the starting sample into a 5 mL vial, add 0.5 mL of tetrahydrofuran / water (1:1, v / v), suspend and stir the sample at room temperature for 3 days, centrifuge to separate the solid, dry it at room temperature for 2 days, and collect the solid to obtain isomorphous solvate crystal form D.

[0316] The obtained solid was subjected to X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with that in Figure 13, which proved that the obtained solid was a isomorphous solvate of crystal form D. The powder diffraction data of isomorphous solvate of crystal form D are shown in Table 7 above.

[0317] Example 9: Preparation of isomorphous solvate crystal form F

[0318] Weigh approximately 20.0 mg of the starting material (compound of formula (I-1)) into a 3 mL vial. Place the vial containing the sample open into a 20 mL bottle containing 4 mL of methanol solvent, and seal the bottle opening with the cap. Allow the sample to stand at room temperature for 7 days, and collect the solid to obtain the target isomorphous solvate crystal form F.

[0319] The obtained solid was subjected to X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with that in Figure 15, which proved that the obtained solid was a isomorphous solvate crystal form F. The powder diffraction data of isomorphous solvate crystal form F are shown in Table 8 below.

[0320] Table 8: Powder diffraction data of isomorphous solvate crystal form F

[0321] Example 10: Preparation of isomorphous solvate crystal form F

[0322] Weigh approximately 20.1 mg of the starting material into a 3 mL vial. Place the vial containing the sample open into a 20 mL bottle containing 4 mL of acetonitrile solvent, and seal the bottle opening with the cap. Allow the sample to stand at room temperature for 7 days, and collect the solid to obtain the target isomorphous solvate crystal form F.

[0323] The obtained solid was subjected to X-ray powder diffraction test, and its X-ray powder diffraction pattern was consistent with that in Figure 15, which proved that the obtained solid was a isomorphous solvate crystal form F. The powder diffraction data of isomorphous solvate crystal form F are shown in Table 8 above.

[0324] Example 11: Study on the relationship between thermodynamic stability and hygroscopicity

[0325] Hygroscopicity of the non-crystalline type A was assessed using a dynamic moisture adsorption (DVS) meter. Starting at 0% relative humidity (0%RH), the percentage change in sample mass was collected under constant temperature of 25°C as humidity varied (0%RH-95%RH-0%RH).

[0326] The DVS plot of crystal-agnostic type A is shown in Figure 17, and the XRPD overlay results of crystal-agnostic type A before and after the DVS test are shown in Figure 18.

[0327] The results showed that the water adsorption of the non-crystalline type A at 25℃ / 80%RH was 0.3386%, indicating slight hygroscopicity, and no crystal form change was observed in the sample after DVS testing.

[0328] Example 12: Equilibrium Solubility

[0329] The equilibrium solubility of non-crystalline A was assessed in water and biological solvent systems at room temperature. Samples were added to each solvent at a concentration of 5 mg / mL, and the mixture was magnetically stirred for 24 hours (500 rpm) at room temperature. Samples were then centrifuged and filtered. Solid samples were tested for XRPD, and liquid samples were tested for concentration and pH using HPLC. The solubility test results are summarized in Table 9.

[0330] The XRPD overlay of the solid after the solubility test of the non-crystalline type A is shown in Figure 19.

[0331] Solubility results showed that amorphous form A had high solubility in the FeSSIF system, and no crystal form transformation occurred after solubility evaluation.

[0332] Table 9: Summary of Equilibrium Solubility Assessment Results

[0333] Example 13: Solid stability

[0334] The physical and chemical stability of amorphous type A samples was assessed by XRPD and HPLC after being placed at 80°C for 24 hours and at 25°C / 60%RH and 40°C / 75%RH for one week. The stability assessment results are summarized in Table 10.

[0335] The XRPD overlay of the non-crystalline A stability assessment sample is shown in Figure 20, and the HPLC results are summarized in Table 11.

[0336] The results showed that no significant changes in purity or crystal form transformation were observed in amorphous type A after stability assessment.

[0337] Table 10: Summary of Solid Stability Assessment

[0338] Table 11: Summary of HPLC results for stability assessment of samples without crystalline form A

[0339] Example 14: Light stability

[0340] The physical and chemical stability of amorphous type A samples was determined by XRPD and HPLC after one week of exposure to 4500 Lux light.

[0341] The results of the light stability assessment are summarized in Table 12. The XRPD overlay of the non-crystalline A light stability assessment sample is shown in Figure 21, and the HPLC results are summarized in Table 13.

[0342] The results showed that the purity of amorphous A decreased slightly after the light stability assessment, but the crystal form did not change.

[0343] Table 12: Summary of Light Stability Assessment

[0344] Table 13: Summary of HPLC results for the light stability evaluation of crystal-amorphous A-type samples

[0345] The results showed that crystal form A had good solubility and stability.

[0346] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A polymorph of Formula (I) ###0001### characterized in that, the crystalline form of the polymorph is selected from the group consisting of anhydrous Form A, solvate Form B, solvate Form C, solvate Form E, solvate Form G, solvate Form H, isomorphous solvate Form D, isomorphous solvate Form F, Where m is 1-10; n is 0-20; X is selected from the following group: water, methanol, ethanol, acetonitrile, ethyl acetate, ethyl acetate / n-heptane, 1,4-dioxane, 1,4-dioxane / n-heptane, isopropanol, 2-methyltetrahydrofuran, 2-methyltetrahydrofuran / n-heptane, N-methylpyrrolidone, N-methylpyrrolidone / water, tetrahydrofuran, tetrahydrofuran / water, acetone. In another preferred embodiment, m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In another preferred embodiment, n is 0, 0.5, 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, or 14. In another preferred embodiment, the polymorph is a crystalline form of a compound of formula (I-1) (8R,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-17-(((fluoromethyl)thio)carbonyl)- 11-hydroxy-10,13,16-trimethyl-3-oxo-8,9,10,11,12,13,14,15,16,17-decahydro-3H- cyclopenta[α]phenanthren-17-yl furan-2-carboxylate:

2. The crystal form as described in claim 1, characterized in that, The n is 0, and the crystal form is amorphous type A; the XRPD pattern of amorphous type A contains three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the following group: 7.3435±0.2°, 9.7701±0.2°, 12.8476±0.2°, 13.4629±0.2°, 14.6917±0.2°, 14.9150±0.2°, 15.8911±0.2°, 18.7354±0.2°.

3. The crystal form as described in claim 2, characterized in that, The crystal-agnostic type A also has one or more 2θ diffraction peaks selected from the group consisting of: 19.6114±0.2°, 20.4651±0.2°, 22.4373±0.2°, 22.6151±0.2°, 24.2667±0.2°, 25.4833±0.2°, 26.7725±0.2°, 27.0642±0.2°, 29.4052±0.2°, and 32.8443±0.2°.

4. The crystal form as described in claim 2, 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 1; 2) The DSC spectrum of the crystal-amorphous type A is basically as shown in Figure 2; 3) The DSC spectrum of the amorphous type A has an endothermic peak in the range of 256.5℃-260.5℃; 4) The aqueous type A is an anhydrous compound. In another preferred embodiment, the method for preparing the amorphous type A includes: a) Mix isomorphous solvate D with ethyl acetate, sonicate to dissolve, filter, and obtain filtrate; b) Stir at 20–30°C, add n-heptane dropwise to the filtrate to obtain the reaction solution; c) Transfer the reaction solution to 45–55°C and suspend it under stirring for 2–6 hours, then centrifuge to separate the solids; d) Transfer the solid to a vacuum dryer at 45-55°C for 1-3 hours, collect the solid, and obtain amorphous type A. In another preferred embodiment, the mass-to-volume ratio of the solvate crystal form D to ethyl acetate is (10-50):1 (mg / mL), preferably (20-40):1 (mg / mL). In another preferred embodiment, the mass-to-volume ratio of the solvate crystal form D to n-heptane is (5-11):1 (mg / mL), preferably (7-9):1 (mg / mL).

5. The crystal form as described in claim 1, characterized in that, X is ethanol, and the crystal form is solvate crystal form B; the XRPD pattern of solvate crystal form B contains three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the following group: 7.8241±0.2°, 8.0677±0.2°, 11.8678±0.2°, 12.0458±0.2°, 14.1289±0.2°, 14.6628±0.2°, 16.1633±0.2°, 18.4062±0.2°, 19.3972±0.2°, 21.1388±0.2°, 24.3347±0.2°.

6. The crystal form as described in claim 5, characterized in that, The solvate crystal form B also has one or more 2θ diffraction peaks selected from the group consisting of: 9.7530±0.2°, 15.6548±0.2°, 16.3717±0.2°, 18.0425±0.2°, 20.4815±0.2°, 21.6118±0.2°, 22.6746±0.2°, 22.9815±0.2°, 23.4008±0.2°, 25.8514±0.2°, and 28.7348±0.2°.

7. The crystal form as described in claim 5, characterized in that, The solvate crystal form B also has one or more features selected from the group consisting of: 1) The XRPD pattern of the solvate crystal form B is basically characterized as shown in Figure 3; 2) The DSC spectrum of the solvate crystal form B is basically characterized as shown in Figure 4; 3) The DSC spectrum of the solvate crystal form B has endothermic peaks in the ranges of 117.6℃-121.6℃, 146.0℃-150.0℃ and 256.2℃-260.2℃, and exothermic peaks in the range of 197.8℃-201.8℃; 4) The solvate crystal form B is an ethanol solvate. In another preferred embodiment, the method for preparing the solvate crystal form B includes: a) Mix the compound of formula (I-1) with ethanol; b) Stir at 20–30°C for 1–5 days; c) Centrifuge to separate the solid, dry it in a humid environment for 1-3 days, collect the solid, and obtain solvate crystal form B. In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) to ethanol is (140-180):1 (mg / mL), preferably (150-170):1 (mg / mL).

8. The crystal form as described in claim 1, characterized in that, X is 1,4-dioxane, and the crystal form is solvate crystal form C; the XRPD pattern of solvate crystal form C contains three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the following group: 9.3364±0.2°, 10.8253±0.2°, 12.4948±0.2°, 13.1241±0.2°, 14.4081±0.2°, 15.3668±0.2°, 16.4963±0.2°, 17.5285±0.2°, 17.9766±0.2°, 19.0582±0.2°, 19.5076±0.2°, 21.6255±0.2°, 24.9988±0.2°.

9. The crystal form as described in claim 8, characterized in that, The solvate crystal form C also has one or more 2θ diffraction peaks selected from the group consisting of: 8.1113±0.2°, 13.9482±0.2°, 14.9936±0.2°, 18.7095±0.2°, 22.2902±0.2°, 23.0597±0.2°, 24.2476±0.2°, 26.1344±0.2°, 26.3568±0.2°, 27.0548±0.2°, 28.2364±0.2°, 29.4411±0.2°, 31.0022±0.2°, 31.8382±0.2°, and 37.5931±0.2°.

10. The crystal form as described in claim 8, characterized in that, The solvate crystal form C also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the solvate crystal form C is basically characterized as shown in Figure 5; 2) The DSC spectrum of the solvate crystal form C is basically characterized as shown in Figure 6; 3) The DSC spectrum of the solvate crystal form C has endothermic peaks in the ranges of 154.2℃-158.2℃, 155.4℃-159.4℃, and 256.1℃-260.1℃; 4) The solvate crystal form C is a 1,4-dioxane solvate. In another preferred embodiment, the method for preparing the solvate crystal form C includes: a) Mix the compound of formula (I-1) with 1,4-dioxane / n-heptane (1:(1-3), v / v); b) Stir at 20–30°C for 1–5 days; c) After centrifugation to separate the solid, dry it in a humid environment for 1 to 3 days, collect the solid, and obtain the solvate crystal form C. In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) and 1,4-dioxane / n-heptane (1:(1-3), v / v) is (140-180):1 (mg / mL), preferably (150-170):1 (mg / mL).

11. The crystal form as described in claim 1, characterized in that, X is isopropanol, and the crystal form is solvate crystal form E; the XRPD pattern of solvate crystal form E contains three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the following group: 8.0799±0.2°, 9.4158±0.2°, 10.8909±0.2°, 12.4553±0.2°, 13.1421±0.2°, 15.5862±0.2°, 16.7023±0.2°, 17.4834±0.2°, 17.9850±0.2°, 19.2262±0.2°, 19.6761±0.2°, 21.6316±0.2°.

12. The crystal form as described in claim 11, characterized in that, The solvate crystal form E also has one or more 2θ diffraction peaks selected from the group consisting of: 13.3591±0.2°, 13.9946±0.2°, 14.4352±0.2°, 15.0316±0.2°, 18.3663±0.2°, 18.7598±0.2°, 18.9295±0.2°, 21.8673±0.2°, and 22.3063±0.2°. 24.5835±0.2°, 25.1068±0.2°, 25.3157±0.2°, 25.7008±0.2°, 26.4426±0.2°, 27.1314±0.2°, 28.1896±0.2°, 28.5237±0.2°, 29.9213±0.2°, 35.9890±0.2°, 37.5706±0.2°.

13. The crystal form as described in claim 11, characterized in that, The solvate crystal form E also has one or more features selected from the group consisting of: 1) The XRPD pattern of the solvate crystal form E is basically characterized as shown in Figure 7; 2) The DSC spectrum of the solvate crystal form E is basically characterized as shown in Figure 8; 3) The DSC spectrum of the solvate crystal form E has endothermic peaks in the ranges of 129.2℃-133.2℃ and 256.3℃-260.3℃; 4) The solvate crystal form E is an isopropanol solvate. In another preferred embodiment, the method for preparing the solvate crystal form E includes: a) Mix the compound of formula (I-1) with isopropanol; b) Stir at 20–30°C for 1–5 days; c) After centrifugation to separate the solid, dry it under humid conditions in a room for 8-10 hours, collect the solid, and obtain the solvate crystal form E. In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) to isopropanol is (140-180):1 (mg / mL), preferably (150-170):1 (mg / mL).

14. The crystal form as described in claim 1, characterized in that, X is 2-methyltetrahydrofuran, and the crystal form is solvate crystal form G; the XRPD pattern of solvate crystal form G contains three or more (e.g., 4, 5, or 6) 2θ diffraction peaks selected from the following group: 9.3084±0.2°, 10.7288±0.2°, 12.2027±0.2°, 14.1646±0.2°, 15.3382±0.2°, 16.4599±0.2°, 17.0935±0.2°, 17.5680±0.2°, 19.4359±0.2°.

15. The crystal form as described in claim 14, characterized in that, The solvate crystal form G also has one or more 2θ diffraction peaks selected from the group consisting of: 7.9625±0.2°, 12.8501±0.2°, 14.8697±0.2°, 18.6017±0.2°, 18.9050±0.2°, 21.2465±0.2°, 21.5707±0.2°, 24.7033±0.2°, and 26.9966±0.2°.

16. The crystal form as described in claim 14, characterized in that, The solvate crystal form G also has one or more features selected from the group consisting of: 1) The XRPD pattern of the solvate crystal form G is basically characterized as shown in Figure 9; 2) The DSC spectrum of the solvate crystal form G is basically characterized as shown in Figure 10; 3) The DSC spectrum of the solvate crystal form G has endothermic peaks in the ranges of 90.8℃-94.8℃ and 256.3℃-260.3℃; 4) The solvate crystal form G is a 2-methyltetrahydrofuran solvate. In another preferred embodiment, the method for preparing the solvate crystal form G includes: a) Mix the compound of formula (I-1) with 2-methyltetrahydrofuran / n-heptane (1:(0.5-3), v / v); b) Stir at 40–60°C for 3–5 hours, filter using a filter membrane with a pore size of 0.3–0.5 μm, and collect the supernatant; c) Cool the supernatant from 40-60°C to 2-7°C at a rate of 0.05-0.5°C / min, and maintain the temperature at 2-7°C for 1-3 days; d) After centrifugation to separate the solid, dry it in a humid environment for 1-2 days and collect the solid to obtain solvate crystal form G. In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) and 2-methyltetrahydrofuran / n-heptane (1:(0.5-3), v / v) is (20-40):1 (mg / mL), preferably (20-30):1 (mg / mL).

17. The crystal form as described in claim 1, characterized in that, X is N-methylpyrrolidone, and the crystal form is solvate crystal form H; the XRPD pattern of solvate crystal form H contains three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the following group: 10.8332±0.2°, 12.0361±0.2°, 12.8852±0.2°, 14.1461±0.2°, 15.7442±0.2°, 16.8217±0.2°, 17.4163±0.2°, 19.7156±0.2°, 21.0801±0.2°, 21.7331±0.2°, 24.7468±0.2°.

18. The crystal form as described in claim 17, characterized in that, The solvate crystal form H also has one or more 2θ diffraction peaks selected from the group consisting of: 7.8983±0.2°, 9.4784±0.2°, 13.9427±0.2°, 14.9085±0.2°, 18.3991±0.2°, 18.9884±0.2°, 19.1454±0.2°, 21.9545±0.2°, 23.7319±0.2°, 25.4235±0.2°, 25.8434±0.2°, 27.4457±0.2°, 28.0745±0.2°, 30.3708±0.2°, 35.3259±0.2°, and 36.5337±0.2°.

19. The crystal form as described in claim 17, characterized in that, The solvate crystal form H also has one or more features selected from the group consisting of: 1) The XRPD pattern of the solvate crystal form H is basically characterized as shown in Figure 11; 2) The DSC spectrum of the solvate crystal form H is basically characterized as shown in Figure 12; 3) The DSC spectrum of the solvate crystal form H has an endothermic peak in the range of 151.9℃-155.9℃; 4) The solvate crystal form H is an N-methylpyrrolidone solvate. In another preferred embodiment, the method for preparing the solvate crystal form H includes: a) Mix the compound of formula (I-1) with N-methylpyrrolidone / water (1:(2-6), v / v); b) Stir at 20–30°C for 1–5 days; c) Centrifuge to separate the solid, dry it in a humid environment for 1-3 days, collect the solid, and obtain the solvate crystal form H. In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) and N-methylpyrrolidone / water (1:(2-6), v / v) is (140-180):1 (mg / mL), preferably (150-170):1 (mg / mL).

20. The crystal form as described in claim 1, characterized in that, X is acetone or tetrahydrofuran, and the crystal form is isomorphous solvate crystal form D; the XRPD pattern of the isomorphous solvate crystal form D contains three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the following group: 8.0939±0.2°, 11.0035±0.2°, 12.4283±0.2°, 13.1918±0.2°, 14.4935±0.2°, 15.8641±0.2°, 17.4204±0.2°, 17.9797±0.2°.

21. The morphic form of claim 20, characterized by: The isomorphous solvate crystal form D also has one or more 2θ diffraction peaks selected from the group consisting of: 9.5504±0.2°, 14.1043±0.2°, 15.1282±0.2°, 16.9629±0.2°, 18.9617±0.2°, 19.4353±0.2°, 19.9097±0.2°, 21.6488±0.2°, 22.0686±0.2°, 24.9683±0.2°, 25.2690±0.2°, 25.6853±0.2°, 26.5393±0.2°, 27.2064±0.2°, 28.0602±0.2°, and 31.2955±0.2°.

22. The crystal form as described in claim 20, characterized in that, The isomorphous solvate crystal form D also has one or more characteristics selected from the group below: 1) The XRPD pattern of the isomorphous solvate crystal form D is basically characterized as shown in Figure 13; 2) The DSC spectrum of the isomorphous solvate crystal form D is basically characterized as shown in Figure 14; 3) The DSC spectrum of the isomorphous solvate crystal form D has endothermic peaks in the ranges of 161.3℃-165.3℃, 161.9℃-165.9℃ and 256.7℃-260.7℃, and exothermic peaks in the range of 194.2℃-198.2℃; 4) The solvate crystal form D is an isomorphous solvate. In another preferred embodiment, the method for preparing the solvate crystal form D includes: a) Mix the compound of formula (I-1) with acetone; b) Stir at 20–30°C for 1–5 days; c) Centrifuge to separate the solid, dry it in a humid environment for 1-3 days, collect the solid, and obtain the solvate crystal form D. In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) to acetone is (140-180):1 (mg / mL), preferably (150-170):1 (mg / mL). In another preferred embodiment, the method for preparing the solvate crystal form D includes: a) Mix the compound of formula (I-1) with tetrahydrofuran / water (1:(0.5-3), v / v); b) Stir at 20–30°C for 1–5 days; c) Centrifuge to separate the solid, dry it in a humid environment for 1-3 days, collect the solid, and obtain the solvate crystal form D. In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) and tetrahydrofuran / water (1:(0.5-3), v / v) is (140-180):1 (mg / mL), preferably (150-170):1 (mg / mL).

23. The crystal form as described in claim 1, characterized in that, X is methanol or acetonitrile, and the crystal form is isomorphous solvate crystal form F; the XRPD pattern of the isomorphous solvate crystal form F contains three or more (e.g., four, five, or six) 2θ diffraction peaks selected from the following group: 7.3652±0.2°, 9.6556±0.2°, 12.5755±0.2°, 14.4123±0.2°, 14.7320±0.2°, 18.4093±0.2°, 19.1579±0.2°, 21.6671±0.2°.

24. The crystal form as described in claim 23, characterized in that, The isomorphous solvate crystal form F also has one or more 2θ diffraction peaks selected from the group consisting of: 13.5773±0.2°, 15.7837±0.2°, 16.8104±0.2°, 20.6120±0.2°, 22.1919±0.2°, 24.1664±0.2°, 28.6021±0.2°, 31.8928±0.2°, and 36.4652±0.2°.

25. The crystal form as described in claim 23, characterized in that, The isomorphous solvate crystal form F also has one or more characteristics selected from the group consisting of: 1) The XRPD pattern of the isomorphous solvate crystal form F is basically characterized as shown in Figure 15; 2) The DSC spectrum of the isomorphous solvate crystal form F is basically characterized as shown in Figure 16; 3) The DSC spectrum of the isomorphous solvate crystal form F has an endothermic peak in the range of 256.6℃-260.6℃; 4) The crystal form F of the isomorphous solvate is an isomorphous solvate. In another preferred embodiment, the method for preparing the isomorphous solvate crystal form F includes: a) The compound of formula (I-1) is placed in a sealed container containing methanol, and the compound of formula (I-1) and methanol are not in direct contact; b) After standing at 20-30°C for 6-8 days, the isomorphous solvate crystal form F is obtained. In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) to methanol is (2-8):1 (mg / mL), preferably (4-6):1 (mg / mL). In another preferred embodiment, the method for preparing the isomorphous solvate crystal form F includes: a) The compound of formula (I-1) is placed in a sealed container containing acetonitrile, and the compound of formula (I-1) and acetonitrile are not in direct contact; b) After standing at 20-30°C for 6-8 days, the isomorphous solvate crystal form F is obtained. In another preferred embodiment, the mass-to-volume ratio of the compound of formula (I-1) to acetonitrile is (2-8):1 (mg / mL), preferably (4-6):1 (mg / mL).

26. A pharmaceutical composition comprising, The pharmaceutical composition comprises a polymorph of formula (I) as described in any one of claims 1-25, and optionally further comprises a pharmaceutically acceptable carrier and / or excipient.

27. The pharmaceutical composition of claim 26, wherein, The composition is suitable for oral, injection, nasal spray, oral inhalation aerosol, and topical skin application.

28. The pharmaceutical composition of claim 26, wherein The composition is suitable for administration via nasal spray, oral inhalation aerosol, and topical skin application.

29. The pharmaceutical composition of claim 26, wherein The composition can be formulated into tablets, injections, syringes, sprays, aerosols, and creams.

30. The pharmaceutical composition of claim 26, wherein The composition can be prepared as a spray, an aerosol, and a cream.

31. Use of the polymorph according to any one of claims 1 to 25, wherein the polymorph is used in the form of a pharmaceutical composition. for the manufacture of a medicament for the treatment or prevention of rhinitis, asthma or neurodermatitis.

32. The use of the pharmaceutical composition according to any one of claims 26-30, characterized in that, for the manufacture of a medicament for the treatment or prevention of rhinitis, asthma or neurodermatitis. for the manufacture of a medicament for the treatment or prevention of rhinitis, asthma or neurodermatitis.

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